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"abstract": "A 50-year-old man undergoing operations for sigmoid colon cancer, small intestine invasion, and liver metastasis was given adjuvant chemotherapy postoperatively. During the course, lung, brain and bone metastasis were found, FOLFIRI therapy was started. Fifth FOLFIRI therapy was performed, but on the night of the next day, he was transported on an emergency basis to our hospital because of a coma. Laboratory examination revealed hyperammonemia, so aminoleban was started for its treatment. After 3 days in the hospital, consciousness and serum ammonia were improved. Cases of hyperammonemia caused by 5-FU have been reported in the literature, and this case was diagnosed with the same. Hyperammonemia should be taken into account as a differential diagnosis in the disturbance of consciousness in chemotherapy.",
"affiliations": "Dept. of Surgery, Yodogawa Christian Hospital.",
"authors": "Toyokawa|Akihiro|A|;Nakajima|Takayoshi|T|;Inui|Kyoko|K|;Yamashita|Hironari|H|;Gon|Hidetoshi|H|;Kanemitsu|Kiyonori|K|;Tanaka|Kenichi|K|;Tsukamoto|Tadashi|T|;Hamabe|Yutaka|Y|;Ishida|Takeshi|T|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "36(7)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms; D003244:Consciousness Disorders; D005472:Fluorouracil; D006801:Humans; D022124:Hyperammonemia; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1167-9",
"pmc": null,
"pmid": "19620810",
"pubdate": "2009-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of hyperammonemia with encephalopathy related to FOLFIRI chemotherapy for advanced colon cancer.",
"title_normalized": "a case of hyperammonemia with encephalopathy related to folfiri chemotherapy for advanced colon cancer"
} | [
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"companynumb": "JP-PFIZER INC-2009259511",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"actiondrug": "5",
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"activesubstancename": "FLUOROURACIL"
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{
"abstract": "Awareness with recall under general anesthesia remains a rare but important issue that warrants further study.\n\n\n\nWe present a series of seven cases of awareness that were identified from provider-reported adverse event data from the electronic anesthesia records of 647,000 general anesthetics.\n\n\n\nThe low number of identified cases suggests an under-reporting bias. Themes that emerge from this small series can serve as important reminders to anesthesia providers to ensure delivery of an adequate anesthetic for each patient. Commonalities between a majority of our identified anesthetic awareness cases include: obesity, use of total intravenous anesthesia, use of neuromuscular blockade, and either a lack of processed electroencephalogram (EEG) monitoring or documented high depth of consciousness index values. An interesting phenomenon was observed in one case, where adequately-dosed anesthesia was delivered without technical issue, processed EEG monitoring was employed, and the index value suggested an adequate depth of consciousness throughout the case.\n\n\n\nProvider-reported adverse event data in the immediate post-operative period are likely insensitive for detecting cases of intraoperative awareness. Though causation cannot firmly be established from our data, themes identified in this series of cases of awareness with recall under general anesthesia provide important reminders for anesthesia providers to maintain vigilance in monitoring depth and dose of anesthesia, particularly with total intravenous anesthesia.",
"affiliations": "Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, USA.;Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, USA.;Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, UPMC Montefiore, Suite 467, Pittsburgh, PA, 15213, USA.;Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, UPMC Montefiore, Suite 467, Pittsburgh, PA, 15213, USA. vogtkm@upmc.edu.",
"authors": "Deis|Amanda S|AS|;Schnetz|Michael P|MP|;Ibinson|James W|JW|;Vogt|Keith M|KM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12871-020-00974-3",
"fulltext": "\n==== Front\nBMC Anesthesiol\nBMC Anesthesiol\nBMC Anesthesiology\n1471-2253 BioMed Central London \n\n974\n10.1186/s12871-020-00974-3\nResearch Article\nRetrospective analysis of cases of intraoperative awareness in a large multi-hospital health system reported in the early postoperative period\nDeis Amanda S. 1 Schnetz Michael P. 1 Ibinson James W. 234 Vogt Keith M. vogtkm@upmc.edu 256 1 grid.412689.00000 0001 0650 7433Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, USA \n2 grid.21925.3d0000 0004 1936 9000Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, UPMC Montefiore, Suite 467, Pittsburgh, PA 15213 USA \n3 grid.21925.3d0000 0004 1936 9000Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, USA \n4 grid.413935.90000 0004 0420 3665Department of Anesthesiology, Surgical Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, USA \n5 grid.21925.3d0000 0004 1936 9000Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, USA \n6 Center for the Neural Basis of Cognition, Pittsburgh, USA \n9 3 2020 \n9 3 2020 \n2020 \n20 6218 7 2019 28 2 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nAwareness with recall under general anesthesia remains a rare but important issue that warrants further study.\n\nMethods\nWe present a series of seven cases of awareness that were identified from provider-reported adverse event data from the electronic anesthesia records of 647,000 general anesthetics.\n\nResults\nThe low number of identified cases suggests an under-reporting bias. Themes that emerge from this small series can serve as important reminders to anesthesia providers to ensure delivery of an adequate anesthetic for each patient. Commonalities between a majority of our identified anesthetic awareness cases include: obesity, use of total intravenous anesthesia, use of neuromuscular blockade, and either a lack of processed electroencephalogram (EEG) monitoring or documented high depth of consciousness index values. An interesting phenomenon was observed in one case, where adequately-dosed anesthesia was delivered without technical issue, processed EEG monitoring was employed, and the index value suggested an adequate depth of consciousness throughout the case.\n\nConclusions\nProvider-reported adverse event data in the immediate post-operative period are likely insensitive for detecting cases of intraoperative awareness. Though causation cannot firmly be established from our data, themes identified in this series of cases of awareness with recall under general anesthesia provide important reminders for anesthesia providers to maintain vigilance in monitoring depth and dose of anesthesia, particularly with total intravenous anesthesia.\n\nKeywords\nIntraoperative awarenessGeneral anesthesiaDepth of consciousness monitoringProcessed electroencephalogramhttp://dx.doi.org/10.13039/100005831Foundation for Anesthesia Education and ResearchMRTG-CT-2-2017Vogt Keith M. National Institute of General Medical SciencesT32 GM075770K23GM132755Schnetz Michael P. Vogt Keith M. issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAccidental intraoperative awareness with recall (AWR) is the unanticipated explicit recollection of intraoperative events during anesthesia. Though important to understand and prevent, it is fortunately a rare event. In fact, the incidence estimates vary widely, likely due to methodology differences in identification of awareness events. Several randomized controlled trials with AWR as the primary endpoint have used structured interviews to detect awareness events and expert panel review to adjudicate possible cases of AWR [1–6]. Averaging across the data from these trials gives an incidence of 0.25% for definite AWR and an additional 0.32% of patients having possible AWR. This is corroborated by an incidence of 0.44% in a recent meta-analysis that included randomized trials focused on either anesthetic regimens or anesthetic depth monitors (but not necessarily specifically focused on AWR detection) [7].\n\nRetrospectively identifying cases of AWR, when no structured patient interview has been conducted, is expected to have a lower sensitivity. This is illustrated by much lower calculated incidences of AWR within retrospective studies of varying methodology: 0.023% in a single-institution retrospective chart review [8] and 0.0051% in the United Kingdom’s 5th National Audit Project [9]. Thus, retrospective anlayses have limited sensitivity, and may detect AWR events at rates 10–100 times lower than propsective trials. Surveying practicioners seems equally insensitive, with rates of 0.0043% [10] and 0.0065% [11] reported.\n\nDespite this low prevalence, AWR is a clinically important phenomenon to understand and prevent. The Psych-SOS study completed post-traumatic stress disorder (PTSD) assessments of patients from three major awareness prevention trials and found a 43% incidence of PTSD in those who experienced AWR, compared to 16% in a matched cohort without AWR [12]. Though the longevity of PTSD has not been studied in a large cohort of AWR patients, symptoms can last for many years after the event [13, 14]. Even without a PTSD diagnosis, many AWR patients experience some negative symptoms such as sleep disturbance, anxiety, fear, panic, depression, and inability to work [15–17].\n\nThe purpose of this investigation was to identify cases of AWR at our institution by a retrospective review of routinely collected adverse event data. We expected to find many AWR cases, based on the very large number of anesthetic records available for review. However, the small number of cases identified precluded a formal analysis. Our results are presented as a truncated AWR case series, focused on general anesthetics. Commonalities between these cases are discussed to highlight some important considerations to maintain vigilance in AWR prevention.\n\nMethods\nCases of AWR were collected from the Electronic Anesthesia Record (EAR) system of the University of Pittsburgh Medical Center. This is a large multi-hospital health system, with a mix of tertiary/academic centers and suburban hospitals that share a centralized EAR. The system-wide EAR was queried for all available electronic anesthesia records over the period 9/13/2010 to 1/12/2019. Patients with AWR were identified using quality improvement records attached to our EAR. In this system, providers voluntarily denote an adverse event flag (labelled “Intraoperative Recall”) any time before the EAR chart is finalized, which is typically after patient discharge from Post-Anesthesia Care Unit (PACU). Following identification of those anesthetics that had the adverse event flag for “Intraoperative Recall”, the patient charts were reviewed by the authors for data thought to be relevant to the awareness event. We limited the subsequent analysis to cases done under general anesthesia. Data abstracted included the surgery performed, anesthetics administered, patient characteristics, and the patient’s past medical and surgical histories. Written documentation was searched for descriptions of the character of the experiences reported by the patients during the awareness event. All authors reviewed the documentation available for each case and made a determination by consensus of the likelihood of an AWR event (rated as Probable, Possible or inconclusive). Additionally, cases were classified using the Michigan Awareness Classification Instrument [18]. Case durations were calculated using the induction and emergence times documented on the EAR. In the UPMC system, the BIS monitor (Medtronic/Covidien, Mansfield, MA, USA) is the processed electroencephalographic (EEG) monitoring device typically available in most anesthetizing locations. Age-adjusted minimum alveolar concentration (aaMAC) was calculated for any volatile agents used, using previously-established formulas [19]. For the purposes of describing patient body habitus, we classified body-mass index (BMI) as normal-range (BMI = 18.5–30), obese (BMI = 30–40), and morbidly obese (BMI > 40).\n\nResults\nDuring the study period, 1,273,060 total anesthetic records were available for query. Only 10 cases were identified in which the “Intraoperative Recall” event flag was marked. Thus, the calculated incidence of AWR from this dataset, using this method of identification was only 0.00079%. Three of these cases were documented as sedation with monitored anesthesia care, and these were excluded from further analysis. The number of general anesthesia cases queried was 647,009, giving a calculated incidence of 1:92,429 (0.0011%) of AWR under general anesthesia in our EAR. We briefly describe the 7 identified cases of AWR during general anesthesia in a condensed case series below. A summary of key case details is provided in Table 1. To retain patient anonymity, no patient-specific information has been included.\nTable 1 Summary of key characteristics of identified AWR cases done under general anesthesia\n\nCase #\tSurgery Type\tAge (decade)\tGender\tASA PS\tPremedication\tPatient risk factors for AWR\tMaintenance anesthetics used\tNotes\tClassification of Recall\t\n1\tSpine\t30s\tM\t2\tmidazolam & fentanyl\tnone\tSevoflurane, remifentanil\tEarly lowering of anesthetic agent and discontinuation of remifentanil infusion.\n\nBIS not used.\n\n\tPossible; Class 2\t\n2\tHead & Neck\t70s\tM\t3\tmidazolam\tmorbid obesity\tSevoflurane\tBIS not used\tPossible; Class 1\t\n3\tOrthopedic\t60s\tF\t3\tmidazolam\tobesity\tSevoflurane\tSevoflurane < 0.5 aaMAC for much of case, with BIS < 60\tProbable; Class 5D\t\n4\tGeneral\t30s\tF\t3\tnone\tmorbid obesity\tTIVA with propofol, dexmedetomidine, & ketamine\tBIS > 65 during entire case\tPossible; Class 2\t\n5\tGeneral (abdominal)\t50s\tF\t3\tmidazolam\tnone\tTIVA with propofol, dexmedetomidine, & ketamine\tBIS < 47 for entire case\tPossible; Class 2\t\n6\tGeneral\t60s\tF\t2\tmidazolam\tnone\tTIVA with dexmedetomidine and remifentanil, then propofol\tBIS > 60 for much of case\tinconclusive\t\n7\tPlastic\t20s\tF\t2\tmidazolam\tobesity\tTIVA with propofol, & dexmedetomidine & ketamine\tIV infiltration occurred.\n\nBIS not used\n\n\tinconclusive\t\nClassification of recall event is based on concordance of authors. Each case is classified as Probable, Possible, or inconclusive, for the likelihood of a true AWR event. Further, the perceptions described are described using the Michigan Awareness Classification Instrument [18], as described in the text\n\n\n\nCase 1 occurred in a male patient in his 30’s with American Society of Anesthesiologists (ASA) physical status (PS) II presenting for elective spine surgery. This patient had a normal-range BMI. The patient was premedicated with 50 mg of fentanyl and 2 mg of midazolam. General anesthesia was induced with 130 mg of propofol, and muscle paralysis initiated with 50 mg of rocuronium. Intermittent boluses of rocuronium were used to maintain paralysis. Maintenance of anesthesia was with sevoflurane, and the lowest concentration during the majority of the 3.5 h-long case was 1.77% (aaMAC = 1.11). However, the concentration decreased to 0.9 to 1.1% (aaMAC = 0.57–0.69) in the approximately 10 min prior to turning the patient supine. This volatile anesthetic was augmented with a remifentanil infusion at 0.1 to 0.2 mcg/kg/min, and this infusion was discontinued approximately 10 min prior to turning supine. A total of 200 mcg of fentanyl was given in divided doses after extubation, approximately 20 min after discontinuation of the remifentanil infusion. Mean arterial pressures (MAP) was maintained in the range 80 mmHg to 120 mmHg, but this required a phenylephrine infusion at rates up to 0.5 mcg/kg/min plus intermittent boluses of ephedrine. His heart was in sinus rhythm, rates ranging 45 to 80 beats per minute (bpm). Processed EEG monitoring was not used.\n\nCase 2 occurred in a morbidly obese male patient in his 70’s, ASA-PS III, for elective head/neck surgery. He was premedicated with 50 mcg of fentanyl and 2 mg of midazolam. General anesthesia was induced with 200 mg of propofol and 100 mcg of fentanyl. Muscle paralysis was maintained with boluses of rocuronium. Maintenance of anesthesia was achieved with intermittent boluses of fentanyl and sevoflurane; the lowest end-tidal sevoflurane concentration was 1.45% (aaMAC = 0.98). Vitals were remarkable for atrial fibrillation, with heart rates between 60 to 95 bpm and no hypotension. Processed EEG monitoring was not used. Case duration was 2.5 h.\n\nCase 3 occurred in an obese female patient in her 60’s, ASA-PS III, for orthopedic surgery following a traumatic fracture. She was premedicated with 2 mg of midazolam. General anesthesia was induced with 180 mg of propofol, and 100 mg of lidocaine was given. Muscle paralysis initiated with 190 mg of succinylcholine and 30 mg of rocuronium. Maintenance of anesthesia was achieved with sevoflurane, and end-tidal concentrations ranged from 0.3 to 1.3% (aaMAC = 0.19–0.82) during the case. The BIS™ monitor was applied, and the highest BIS index value recorded was 54.8. Case duration was 2 h. Vital signs during the case were heart rates between 55 to 75 bpm and MAP ranging from 95 mmHg to 115 mmHg, with minimal support by intermittent phenylephrine and ephedrine.\n\nCase 4 occurred in a morbidly obese female patient in her 30’s, ASA-PS III. She presented for elective abdominal surgery and received no premedication. Anesthesia was induced with 200 mg of propofol, 16 mcg of dexmedetomidine, and 20 mg of ketamine. Muscle paralysis initiated with 160 mg of succinylcholine and 90 mg of rocuronium with intermittent boluses of rocuronium throughout the case to maintain paralysis. The patient had a history of difficult airway management but was uneventfully intubated with a Glidescope. Total intravenous anesthesia (TIVA) was maintained with three infusions: propofol ranging from 100 to 150 mcg/kg/min, with additional intermittent boluses; dexmedetomidine at 0.4 mcg/kg/hr; and ketamine at 0.2 mg/kg/hr. Processed EEG monitoring was utilized during the case, but not applied until 5 min after incision, which was about 30 min after induction. The BIS index ranged 65–75 in the first 30 min after application. At this time, a relief in hands-on providers occurred, and midazolam 2 mg was given. The highest recorded BIS index was 79.2, and this occurred during the middle portion of the case approximately 45 min after induction. The BIS index was > 65 for the majority of the surgical case. Vital signs were unremarkable with no support. Case duration was just over 2 h.\n\nCase 5 occurred in a female patient in her 50’s, ASA-PS III, with normal range BMI. She presented for general surgery. She was premedicated with midazolam 2 mg. Anesthesia was induced with 150 mg of propofol followed by rocuronium 30 mg to facilitate tracheal intubation. TIVA was maintained using a propofol infusion with a basal rate of 100 mcg/kg/min, with intermittent boluses, dexmedetomidine infusion at 0.2 mcg/kg/hr and ketamine infusion at 0.2 mg/kg/hr. The highest documented BIS index was 46.6. Vitals signs were remarkable only for mild bradycardia, with heart rates in the 50’s pre-induction. She was normotensive throughout the two-hour case, with no support.\n\nCase 6 occurred in a female patient in her 60’s, with ASA-PS II and normal-range BMI, who underwent an elective plastic surgery. Prior anesthesia complications included postoperative nausea and vomiting. She was premedicated with midazolam 2 mg. General anesthesia was induced with 50 mg of propofol and 50 mcg of fentanyl. Paralysis was maintained with intermittent boluses of rocuronium. Maintenance of anesthesia employed remifentanil at 0.2 to 0.6 mcg/kg/min and dexmedetomidine between 0.2 to 0.7 mcg/kg/hr. Approximately 20 min after surgical incision (and 40 min after induction) a propofol infusion at 50 mcg/kg/min was started, and the dose was subsequently increased to 75 mcg/kg/min for the last hour of the case. Vitals were unremarkable, with minimal intermittent doses of phenylephrine and ephedrine. The highest BIS index of 75.2 occurred near the start of surgery, about 15 min after induction. The patient was administered more fentanyl and propofol at that time, and the BIS index subsequently remained between 47 and 61 for the remainder of the two-hour case. Other than selection of the “Intraoperative Awareness” flag, there is no further documentation of awareness.\n\nCase 7 occurred in an obese female patient in her 20’s, with ASA-PS III, who presented for elective plastic surgery. The patient was premedicated with 2 mg of midazolam. General anesthesia was induced with 200 mg of propofol and 100 mg of lidocaine was given. Muscle paralysis was initiated with 10 mg of vecuronium and maintained with intermittent boluses. Maintenance of anesthesia was attempted with a TIVA approach utilizing infusions of propofol at 75 mcg/kg/min, dexmedetomidine at 0.6 mcg/kg/hr and intermittent boluses of midazolam (6 mg additional given). Vitals were notable for MAP ranges between 70 mmHg to 110 mmHg, sinus rhythm with heart rates 75 bpm to 100 bpm. Processed EEG monitoring was utilized during the case and notable BIS index ranging from 68 to 75 in the 25 min following incision. Despite additional intravenous (IV) medications including another 2 mg of midazolam, 150 mg of propofol bolus, and increased infusion dose of propofol to 125 mcg/kg/hr, the BIS index remained elevated above 70. An additional 10 mg dose of vecuronium was given and did not result in loss of TOF. It was then recognized that her IV access had been lost. The patient was started immediately on sevoflurane at 3.5%. A right internal jugular line was placed for definitive access. Additional midazolam was given and prior maintenance TIVA was continued. Notably, the BIS index ranged 30 to 40 for the remainder of the two-hour case. The awareness flag was selected by the anesthesiologist with concern for possible awareness. There is no further documentation of AWR.\n\nDiscussion\nTo our knowledge, this is the largest pool of cases systematically evaluated for adverse event data related to anesthetic AWR. Additionally, our use of electronic anesthesia records allowed for a more accurate assessment of important data including BIS index, end-tidal volatile concentration, and vitals, which would be inherently limited in any review of paper records, as demonstrated previously [20]. Even using conservative estimates for the incidences of AWR (0.01%), one might anticipate ~ 65 cases from a dataset of over 647,000 general anesthesia records. However, our actual results were an order of magnitude lower, consistent with lower estimates using some other non-prospective identification methodologies [9–11]. We strongly suspect that our health system’s EAR adverse event data significantly underestimates the true incidence of AWR in our patient population. Thus, our case cohort is a potentially biased sample of early-presenting AWR cases, and we recognize that our identified cases have significant limitations in their predictive ability for AWR. Nonetheless, we are presenting the series of seven general anesthetic cases identified and have recognized some themes that are worthy of discussion.\n\nMost well-known risk factors for AWR are based on descriptive data or case reports [21, 22]. The occurrence of AWR during cardiac, obstetric, and trauma surgical cases, seems intuitive, as these are situations in which it is likely to deliver lower anesthetic doses. Some patient-related risk factors are also not surprising, as they would predispose to anesthetic-resistance, including obesity and chronic alcohol or sedative use. Notably, most of these case- or patient- related risk factors did not emerge in our cohort, except that 4/7 were obese. In fact, all but one (case 3) were elective patients admitted from home.\n\nSeveral risk factors for AWR related to medication choices have been variably reported in the literature. Relevant to our case series, the use of neuromuscular blocking drugs can mask patient movement that would likely provide an early clinical sign of light anesthesia. Correlation between pharmacologic paralysis and AWR has been suggested [23, 24], as well as increased distress of AWR patients who were unable to move during the awareness event [22]. It is notable that paralysis was used in all seven of our identified cases, substantiating this correlation. The pre-induction administration of benzodiazepines intuitively should be protective against AWR, by providing amnesia. In some studies, their administration has been anti-correlated to AWR risk [25, 26]. However, similar to larger studies [27], our series demonstrate that AWR can certainly still occur despite benzodiazepine premedication, as these were part of the anesthetic in all but case 4.\n\nThe use of TIVA has been correlated to AWR [27]. It makes intuitive sense that the use of TIVA may increase the risk, for two reasons related to specific favorable properties of volatile anesthetics. First, end-tidal gas monitoring allows breath to breath measurement of the dose of anesthetic delivered. If used in combination with processed EEG monitoring, expired anesthetic concentration provides potentially synergistic information that can be used to ensure an adequate dose and depth of anesthesia. Second, IV failure can cause an occult disruption of anesthetic delivery, and this is much more likely to go unrecognized than a breathing circuit disconnect. Only one case of IV infiltration was identified within the cohort of general anesthetics. However, it is worthy of note that one of the three sedation cases with AWR that were identified by our initial query also had IV infiltration noted as the suspected etiology. This highlights the importance of particular vigilance in assuring IV patency during TIVA cases to avoid AWR. Further, It has been previously demonstrated that lower-dose propofol TIVA with neuromuscular blockade and alfentanil, with or without midazolam premedication, resulted in a high incidence of AWR [28]. A TIVA technique with propofol ≤100 mcg/kg/min was used in cases 4, 5 and 7. Though cases 5 and 7 employed midazolam premedication, the lower propofol dosing strategy may have contributed to AWR in these three cases.\n\nImproper or no use of depth of consciousness monitoring could play a role in AWR. The utility of processed EEG monitoring in preventing awareness has been shown not superior to end-tidal anesthetic gas concentration alarms, but is better than clinical signs alone [27]. It is also worthy of note that the previously-cited study on AWR with propofol TIVA [28] relied on clinical assessment to titrate anesthetic depth. This could seem to suggest that processed EEG monitoring should be applied in TIVA cases, whenever possible. However, notably the ASA’s practice advisory only recommends that their use be considered on a case-by-case basis [21]. It does, however, stand to reason that, if a processed EEG monitor is employed, the anesthetic should be modified if index values are consistent with light anesthesia. In our series, cases 1 and 2 did not employ BIS monitoring, likely due to field avoidance concerns, but these cases did employ volatile anesthesia. Cases 4 and 6 (both TIVA) employed BIS monitoring, but index values were elevated ≥60 during most of the case. Though retrospective and anecdotal, this does raise the question as to whether additional or multimodal anesthetics would have both reduced the BIS index and/or prevented AWR. Case 3 illustrates the situation of reassuring BIS index, but a low anesthetic gas concentration. This suggests that clinicians should consider ensuring both adequate empiric anesthetic dose and reassuring depth of consciousness index values.\n\nThe timeline within the case in which AWR seemed to occur in our case series is also worthy of note. Cases 1, 4, and 5 document specific recall of events near the end of their surgical experiences. This serves as a reminder that AWR most often occurs with light anesthesia, and patients are most likely to experience light anesthesia during emergence. Providers must balance the desire for a timely wake-up against the risk of a patient becoming aware while still experiencing noxious stimulation. Though not suggested by events in our case series, this can also be an issue in cases with a prolonged time between IV induction and initiation of the maintenance anesthetic, as with difficult airway management. The administration of additional anesthetic should be considered during this initial period, as appropriate.\n\nFinally, patients with a history of AWR are at 5-fold increased propensity for experiencing AWR again - even when they are enrolled in an AWR-prevention trial [29]. This seems to suggest that a subset of the population might show anesthetic resistance, even in the setting of reassuring depth of consciousness monitoring and clinical signs. This is illustrated by case 5, where the BIS index and vital signs were consistent with the appearance of adequate general anesthesia. An interesting population-based measure of this phenomenon is illustrated by the spread of data in the first figure of Aranake’s previous study on AWR [29]. The top of the figure shows many data points with BIS indices above 60, despite being in a range of age-adjusted MAC that should be clinically adequate to ensure unconsciousness and amnesia. This unusual discordance in EEG response to anesthetics may be an area for future neuroscience investigation, to provide better, more personalized, anesthetic care for patients.\n\nLimitations\nThis case series has several limitations. The retrospective nature of the study was not able to discern clinical decision-making details that may have been involved in each case, and this limits the ability to specifically determine causative factors for each AWR event. We also do not have long-term psychiatric follow-up documented for any of the patients. The design was also limited in ability to identify cases, relying on self-reporting by providers marking an event flag in the EAR. This inherently restricted the time window for identifying and reporting AWR to the immediate post-operative period. Previous studies have suggested that up to 2/3 of cases present only after PACU discharge [9]. These factors likely contributed to our lower incidence, compared to previous studies that employed longer follow-up periods in their methodology.\n\nFuture directions\nWe are implementing system-wide provider education surrounding anesthetic awareness prevention to reduce the occurrence of these potentially devastating events, including highlighting some of the important themes suggested by these cases. We are also reviewing our event reporting system, in general, with an aim to improve the capture rate of AWR and other rare, but important adverse events. Finally, the lack of specificity in documentation surrounding this series of AWR events suggests the need for a structured form to be used when both collecting data and offering follow-up to patients after an AWR event.\n\nConclusions\nIn a systematic, retrospective analysis of electronic anesthesia records, we have demonstrated that provider-reported adverse event data recorded in the immediate post-operative period is insensitive for detecting cases of intraoperative awareness. In the series of cases of awareness under general anesthesia that were identified, there are several important points for anesthesia providers to consider, including maintaining vigilance in monitoring both depth and dose of anesthesia, particularly with total intravenous anesthesia.\n\nAbbreviations\nASAAmerican Society of Anesthesiologists\n\nAWRAwareness with recall\n\nBMIBody-mass index\n\nbpmbeats per minute\n\nEARElectronic anesthesia record\n\nEEGElectroencephalogram\n\nIVIntravenous\n\nMAPMean arterial pressure\n\nPACUPost-anesthesia care unit\n\nPSPhysical status\n\nPTSDPost-traumatic stress disorder\n\nTIVATotal intravenous anesthesia\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThe authors thank Dr. Steven L. Whitehurst for assistance in querying the electronic anesthetic record system to identify cases.\n\nAuthor’s contributions\nASD acquired, analyzed, and interpreted data and drafted the manuscript. MPS assisted with data acquisition, interpreted the data, and substantially revised the manuscript. JWI interpreted the data and substantially revised the manuscript. KMV conceived of the project, assisted with data acquisition, interpreted the data, and drafted and substantially revised the manuscript. All authors have read and approved the final manuscript.\n\nFunding\nKMV received salary support during time spent working on this project from a Foundation for Anesthesia Education and Research mentored research training grant (MRTG-CT 2–2017), and the National Institute of General Medical Sciences (K23 GM132755). Salary support for MPS was provided by an institutional training grant from the National Institute of General Medical Sciences (T32 GM075770). The funding agencies had no role in the design of the study, had no involvement in the collection, analysis, or interpretation of data, as well as no part in writing or approving the manuscript.\n\nThe statements and opinions contained herein are solely the authors’.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nEthics approval and consent to participate\nThis study was approved by the University of Pittsburgh institutional review board (STUDY 18100077) on 11/26/2018. The need for individual patient consent was waived by the institutional review board for this minimal-risk retrospective review.\n\nConsent for publication\nNo personally-identifiable patient information is included in this publication. Patient consent for anonymous publication was obtained from all patients as part of our institution’s standard consent form for anesthesia care.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Xu L Wu AS Yue Y The incidence of intra-operative awareness during general anesthesia in China: a multi-center observational study Acta Anaesthesiol Scand 2009 53 7 873 882 10.1111/j.1399-6576.2009.02016.x 19496761 \n2. Avidan MS Jacobsohn E Glick D Burnside BA Zhang L Villafranca A Karl L Kamal S Torres B O'Connor M Prevention of intraoperative awareness in a high-risk surgical population N Engl J Med 2011 365 7 591 600 10.1056/NEJMoa1100403 21848460 \n3. Avidan MS Zhang L Burnside BA Finkel KJ Searleman AC Selvidge JA Saager L Turner MS Rao S Bottros M Anesthesia awareness and the bispectral index N Engl J Med 2008 358 11 1097 1108 10.1056/NEJMoa0707361 18337600 \n4. Mashour GA Shanks A Tremper KK Kheterpal S Turner CR Ramachandran SK Picton P Schueller C Morris M Vandervest JC Prevention of intraoperative awareness with explicit recall in an unselected surgical population: a randomized comparative effectiveness trial Anesthesiology 2012 117 4 717 725 10.1097/ALN.0b013e31826904a6 22990178 \n5. Zhang C Xu L Ma YQ Sun YX Li YH Zhang L Feng CS Luo B Zhao ZL Guo JR Bispectral index monitoring prevent awareness during total intravenous anesthesia: a prospective, randomized, double-blinded, multi-center controlled trial Chin Med J 2011 124 22 3664 3669 22340221 \n6. Myles PS Leslie K McNeil J Forbes A Chan MT Bispectral index monitoring to prevent awareness during anaesthesia: the B-aware randomised controlled trial Lancet 2004 363 9423 1757 1763 10.1016/S0140-6736(04)16300-9 15172773 \n7. Messina AG Wang M Ward MJ Wilker CC Smith BB Vezina DP Pace NL Anaesthetic interventions for prevention of awareness during surgery Cochrane Database Syst Rev 2016 10 CD007272 27755648 \n8. Mashour GA Wang LY Turner CR Vandervest JC Shanks A Tremper KK A retrospective study of intraoperative awareness with methodological implications Anesth Analg 2009 108 2 521 526 10.1213/ane.0b013e3181732b0c 19151282 \n9. Pandit JJ Andrade J Bogod DG Hitchman JM Jonker WR Lucas N Mackay JH Nimmo AF O'Connor K O'Sullivan EP 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors Br J Anaesth 2014 113 4 549 559 10.1093/bja/aeu313 25204697 \n10. Jonker WR Hanumanthiah D O'Sullivan EP Cook TM Pandit JJ th National Audit Project of the Royal College of A, Association of Anaesthetists of Great B, Ireland, College of Anaesthetists of I: A national survey (NAP5-Ireland baseline) to estimate an annual incidence of accidental awareness during general anaesthesia in Ireland Anaesthesia 2014 69 9 969 976 10.1111/anae.12776 24975139 \n11. Pandit JJ Cook TM Jonker WR O’Sullivan E th National Audit Project of the Royal College of A, the Association of Anaesthetists of Great Britain I A national survey of anaesthetists (NAP5 baseline) to estimate an annual incidence of accidental awareness during general anaesthesia in the UK Br J Anaesth 2013 110 4 501 509 10.1093/bja/aet016 23482998 \n12. Whitlock EL Rodebaugh TL Hassett AL Shanks AM Kolarik E Houghtby J West HM Burnside BA Shumaker E Villafranca A Psychological sequelae of surgery in a prospective cohort of patients from three intraoperative awareness prevention trials Anesth Analg 2015 120 1 87 95 10.1213/ANE.0000000000000498 25383719 \n13. Leslie K Chan MT Myles PS Forbes A McCulloch TJ Posttraumatic stress disorder in aware patients from the B-aware trial Anesth Analg 2010 110 3 823 828 10.1213/ANE.0b013e3181b8b6ca 19861364 \n14. Osterman JE Hopper J Heran WJ Keane TM van der Kolk BA Awareness under anesthesia and the development of posttraumatic stress disorder Gen Hosp Psychiatry 2001 23 4 198 204 10.1016/S0163-8343(01)00142-6 11543846 \n15. Schwender D Kunze-Kronawitter H Dietrich P Klasing S Forst H Madler C Conscious awareness during general anaesthesia: patients’ perceptions, emotions, cognition and reactions Br J Anaesth 1998 80 2 133 139 10.1093/bja/80.2.133 9602573 \n16. Samuelsson P Brudin L Sandin RH Late psychological symptoms after awareness among consecutively included surgical patients Anesthesiology 2007 106 1 26 32 10.1097/00000542-200701000-00009 17197842 \n17. Aceto P Perilli V Lai C Sacco T Ancona P Gasperin E Sollazzi L Update on post-traumatic stress syndrome after anesthesia Eur Rev Med Pharmacol Sci 2013 17 13 1730 1737 23852895 \n18. Mashour GA Esaki RK Tremper KK Glick DB O'Connor M Avidan MS A novel classification instrument for intraoperative awareness events Anesth Analg 2010 110 3 813 815 10.1213/ANE.0b013e3181b6267d 19713251 \n19. Nickalls RW Mapleson WW Age-related iso-MAC charts for isoflurane, sevoflurane and desflurane in man Br J Anaesth 2003 91 2 170 174 10.1093/bja/aeg132 12878613 \n20. Driscoll WD Columbia MA Peterfreund RA Awareness during general anesthesia: analysis of contributing causes aided by automatic data capture J Neurosurg Anesthesiol 2007 19 4 268 272 10.1097/ANA.0b013e318139f7df 17893580 \n21. American Society of Anesthesiologists Task Force on Intraoperative A Practice advisory for intraoperative awareness and brain function monitoring: a report by the american society of anesthesiologists task force on intraoperative awareness Anesthesiology 2006 104 4 847 864 10.1097/00000542-200604000-00031 16571982 \n22. Ghoneim MM Block RI Haffarnan M Mathews MJ Awareness during anesthesia: risk factors, causes and sequelae: a review of reported cases in the literature Anesth Analg 2009 108 2 527 535 10.1213/ane.0b013e318193c634 19151283 \n23. Cook TM Andrade J Bogod DG Hitchman JM Jonker WR Lucas N Mackay JH Nimmo AF O'Connor K O'Sullivan EP 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: patient experiences, human factors, sedation, consent, and medicolegal issues Br J Anaesth 2014 113 4 560 574 10.1093/bja/aeu314 25204696 \n24. Pollard RJ Coyle JP Gilbert RL Beck JE Intraoperative awareness in a regional medical system: a review of 3 years’ data Anesthesiology 2007 106 2 269 274 10.1097/00000542-200702000-00014 17264720 \n25. Errando CL Sigl JC Robles M Calabuig E Garcia J Arocas F Higueras R Del Rosario E Lopez D Peiro CM Awareness with recall during general anaesthesia: a prospective observational evaluation of 4001 patients Br J Anaesth 2008 101 2 178 185 10.1093/bja/aen144 18515816 \n26. Wang Y Yue Y Sun YH Wu AS Wu QW Zhang YQ Feng CS Investigation and analysis of incidence of awareness in patients undergoing cardiac surgery in Beijing, China Chin Med J 2005 118 14 1190 1194 16117864 \n27. Mashour GA Avidan MS Intraoperative awareness: controversies and non-controversies Br J Anaesth 2015 115 Suppl 1 i20 i26 10.1093/bja/aev034 25735710 \n28. Miller DR Blew PG Martineau RJ Hull KA Midazolam and awareness with recall during total intravenous anaesthesia Can J Anaesthesia 1996 43 9 946 953 10.1007/BF03011809 \n29. Aranake A Gradwohl S Ben-Abdallah A Lin N Shanks A Helsten DL Glick DB Jacobsohn E Villafranca AJ Evers AS Increased risk of intraoperative awareness in patients with a history of awareness Anesthesiology 2013 119 6 1275 1283 10.1097/ALN.0000000000000023 24113645\n\n",
"fulltext_license": "CC BY",
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"issue": "20(1)",
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"keywords": "Depth of consciousness monitoring; General anesthesia; Intraoperative awareness; Processed electroencephalogram",
"medline_ta": "BMC Anesthesiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000768:Anesthesia, General; D004569:Electroencephalography; D005260:Female; D006761:Hospitals; D006801:Humans; D058926:Intraoperative Awareness; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D012189:Retrospective Studies",
"nlm_unique_id": "100968535",
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"pmid": "32151241",
"pubdate": "2020-03-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "25383719;22990178;9602573;24975139;19151282;17893580;23852895;11543846;22340221;19496761;19861364;16571982;8874913;17197842;25204697;12878613;21848460;27755648;19151283;18337600;18515816;23482998;24113645;15172773;25735710;17264720;19713251;25204696;16117864",
"title": "Retrospective analysis of cases of intraoperative awareness in a large multi-hospital health system reported in the early postoperative period.",
"title_normalized": "retrospective analysis of cases of intraoperative awareness in a large multi hospital health system reported in the early postoperative period"
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"abstract": "It has been well documented that patients may develop cytokine-release syndrome (CRS) following the administration of monoclonal antibodies, such as chimeric antigen receptor-modified T cell. Cytokine-release syndrome is a common complication in patients who have received haploidentical donor allogeneic haematopoietic cell transplantation (haplo-HCT). Although severe CRS after haplo-HCT is a potentially life-threatening toxicity, a standard treatment has not been established. Cytokine blockade with tocilizumab, an anti-IL-6 receptor antibody, has been effective for the treatment of patients with CRS after chimeric antigen receptor-modified T-cell treatment and has also improved CRS after haplo-HCT. A 46-year-old man was diagnosed with haemophagocytic syndrome associated with Epstein-Barr virus-positive diffuse large B-cell lymphoma. Salvage chemotherapy was unsuccessful; consequently, he received haplo-HCT. On day +4, he developed grade 3 CRS, subsequently high-dose corticosteroid initiated. Nevertheless, on day +6, he developed grade 4 CRS, resulting in requirement for ventilator support and multiple vasopressors. Corticosteroid could not improve severe CRS; therefore, tocilizumab was administered on day +14. Serum C-reactive protein level transiently decreased and weaned multiple vasopressors. Although CRS improved, he developed candidaemia; consequently, he died on day +34. Tocilizumab could transiently improve severe CRS after haplo-HCT. Although tocilizumab may have led to the improvement of CRS, a remaining concern is whether it inhibited the patient's ability to mount antifungal immunity, leading to their demise.",
"affiliations": "Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.",
"authors": "Ureshino|Hiroshi|H|http://orcid.org/0000-0002-5034-3699;Ando|Toshihiko|T|;Kizuka|Haruna|H|;Kusaba|Kana|K|;Sano|Haruhiko|H|;Nishioka|Atsujiro|A|;Itamura|Hidekazu|H|;Shindo|Takero|T|;Kubota|Yasushi|Y|;Kojima|Kensuke|K|;Kimura|Shinya|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2481",
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"issn_linking": "0278-0232",
"issue": "36(1)",
"journal": "Hematological oncology",
"keywords": "cytokine-release syndrome; haploidentical donor allogeneic haematopoietic cell transplantation; interleukin-6; tocilizumab",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D013577:Syndrome; D000075442:Transplantation, Haploidentical",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "324-327",
"pmc": null,
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"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Tocilizumab for severe cytokine-release syndrome after haploidentical donor transplantation in a patient with refractory Epstein-Barr virus-positive diffuse large B-cell lymphoma.",
"title_normalized": "tocilizumab for severe cytokine release syndrome after haploidentical donor transplantation in a patient with refractory epstein barr virus positive diffuse large b cell lymphoma"
} | [
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"companynumb": "JP-PFIZER INC-2018095693",
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"abstract": "PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor-positive (ER(+)) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER(+)HER2(-) breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/fulvestrant.\n\n\n\nER(+) breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens.\n\n\n\nMK-2206 induced apoptosis in parental ER(+) but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%-63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation.\n\n\n\nMK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER(+)HER2(-) breast cancer. Clin Cancer Res; 22(11); 2650-8. ©2016 AACRSee related commentary by Jansen et al., p. 2599.",
"affiliations": "Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. cma@dom.wustl.edu mjellis@bcm.edu.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.;Cancer Therapy Evaluation Program, NCI, Bethesda, MD.;Mayo Clinic, Rochester, Minnesota.;Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. cma@dom.wustl.edu mjellis@bcm.edu.",
"authors": "Ma|Cynthia X|CX|;Sanchez|Cesar|C|;Gao|Feng|F|;Crowder|Robert|R|;Naughton|Michael|M|;Pluard|Timothy|T|;Creekmore|Allison|A|;Guo|Zhanfang|Z|;Hoog|Jeremy|J|;Lockhart|A Craig|AC|;Doyle|Austin|A|;Erlichman|Charles|C|;Ellis|Matthew J|MJ|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; D007004:Hypoglycemic Agents; C548887:MK 2206; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol; D051057:Proto-Oncogene Proteins c-akt",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-15-2160",
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"issue": "22(11)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004958:Estradiol; D005260:Female; D000077267:Fulvestrant; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D006943:Hyperglycemia; D007004:Hypoglycemic Agents; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009570:Nitriles; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen; D016896:Treatment Outcome; D014230:Triazoles",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "2650-8",
"pmc": null,
"pmid": "26783290",
"pubdate": "2016-06-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "24663045;25239610;20530877;22149876;21420991;26158448;22853014;22300766;19366795;3037531;20644199;22932669;16088978;10579998;9865903;19654113;16467120;16288292;11078488;22155872;22581179;23000897;21362200;23065000;20571069;22923433;26563128;19451168;10102273;12040186;22025163;22766518",
"title": "A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer.",
"title_normalized": "a phase i study of the akt inhibitor mk 2206 in combination with hormonal therapy in postmenopausal women with estrogen receptor positive metastatic breast cancer"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US00787",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INVESTIGATIONAL PRODUCT"
},
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{
"abstract": "Mutations in the ATP1A2 gene cause familial hemiplegic migraine type 2, alternating hemiplegia of childhood, and cerebellar function deficits, epilepsy, and mental retardation. These symptoms are likely related to glutamatergic hyperexcitability. Our patient is a 12-year-old boy with a history of complex partial seizures, attention-deficit/hyperactivity disorder, and fine motor difficulty. During early childhood, he had episodes of a self-resolving right-sided hemiparesis and focal epilepsy. His seizures did not respond to several antiepileptic medications but stopped after he received valproate. His intermittent episodes of hemiplegia persisted. Additionally, he had pronounced bilateral fine motor impairment and significant executive deficits that gradually worsened. The whole exome sequencing revealed a de novo missense mutation in the ATP1A2 gene and a maternally inherited POLG gene mutation of unknown clinical significance. We hypothesized that glutamatergic excitotoxicity due to the ATP1A2 mutation contributed to the pathogenesis of our patient's condition. He was started on N-methyl-D-aspartate receptor antagonists (memantine and dextromethorphan), as well as coenzyme Q10 One year later, he showed significant improvement in sustained attention, learning efficiency, general cognitive efficiency, and fine motor dexterity. We postulate that N-methyl-D-aspartate receptor antagonists were effective for behavioral, cognitive, and cerebellar symptoms in our patient with ATP1A2 gene mutation.",
"affiliations": "Division of Neurology, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan.;Division of Neurology, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan.;Division of Neurology, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan ahuq@med.wayne.edu.",
"authors": "Ueda|Keisuke|K|;Serajee|Fatema|F|;Huq|Ahm M|AM|",
"chemical_list": "D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014451:Ubiquinone; D003915:Dextromethorphan; D000074002:DNA Polymerase gamma; C413027:POLG protein, human; C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase; C024989:coenzyme Q10; D008559:Memantine",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2017-0852",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "141(Suppl 5)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D001289:Attention Deficit Disorder with Hyperactivity; D002648:Child; D000074002:DNA Polymerase gamma; D003915:Dextromethorphan; D004828:Epilepsies, Partial; D018691:Excitatory Amino Acid Antagonists; D006429:Hemiplegia; D006801:Humans; D008297:Male; D008559:Memantine; D019957:Motor Skills Disorders; D020125:Mutation, Missense; D016194:Receptors, N-Methyl-D-Aspartate; D000254:Sodium-Potassium-Exchanging ATPase; D013577:Syndrome; D014451:Ubiquinone",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "S390-S394",
"pmc": null,
"pmid": "29610157",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical Benefit of NMDA Receptor Antagonists in a Patient With ATP1A2 Gene Mutation.",
"title_normalized": "clinical benefit of nmda receptor antagonists in a patient with atp1a2 gene mutation"
} | [
{
"companynumb": "US-ABBVIE-18P-163-2327284-00",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
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"drugadditional": "3",
... |
{
"abstract": "Transient left ventricular (LV) ballooning syndrome, or Takotsubo syndrome, is characterized by a reversible LV dysfunction. The pathophysiology has not been fully elucidated, but an excess of catecholamines seems to have an essential role. The case of a 27-year-old man who developed transient LV dysfunction resembling Takotsubo syndrome after self-injection of adrenaline is described. The present case may provide additional evidence to the hypothesis of excess sympathetic activation in LV ballooning syndrome.",
"affiliations": "Department of Internal Medicine III, University of Heidelberg, INF 410, Heidelberg 69120, Germany. christian.volz@med.uni-heidelberg.de",
"authors": "Volz|Hans Christian|HC|;Erbel|Christian|C|;Berentelg|Johannes|J|;Katus|Hugo A|HA|;Frey|Norbert|N|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D004837:Epinephrine",
"country": "England",
"delete": false,
"doi": "10.1016/s0828-282x(09)70517-3",
"fulltext": null,
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"issn_linking": "0828-282X",
"issue": "25(7)",
"journal": "The Canadian journal of cardiology",
"keywords": null,
"medline_ta": "Can J Cardiol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors; D003937:Diagnosis, Differential; D004837:Epinephrine; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D008297:Male; D012651:Self Medication; D054549:Takotsubo Cardiomyopathy; D014662:Vasoconstrictor Agents; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "8510280",
"other_id": null,
"pages": "e261-2",
"pmc": null,
"pmid": "19584984",
"pubdate": "2009-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11451258;15703419;17573507",
"title": "Reversible left ventricular dysfunction resembling Takotsubo syndrome after self-injection of adrenaline.",
"title_normalized": "reversible left ventricular dysfunction resembling takotsubo syndrome after self injection of adrenaline"
} | [
{
"companynumb": "DE-MYLANLABS-2017M1009371",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "We treated a 66-year-old Japanese male with unresectable hepatocellular carcinoma (u-HCC) for multiple (>5) liver tumors (maximum 2.6 cm in size, Child-Pugh B score 7) in September 2018. The patient had a history of psoriasis vulgaris and sorafenib (SOR) was introduced (800 mg/day) because of transcatheter arterial chemoembolization (TACE) refractoriness. However, psoriasis vulgaris exacerbation and a high fever were observed 2 weeks later, and the patient was admitted, after which improvement of psoriasis vulgaris was obtained with external medicine administration and SOR intake discontinuation. Few reports have noted exacerbation of psoriasis vulgaris caused by SOR treatment.",
"affiliations": "Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan. hirage@m.ehime-u.ac.jp.;Department of Dermatology, Ehime Prefectural Central Hospital, Matsuyama, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.;Gastroenterology Center, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan.",
"authors": "Adachi|Tomoko|T|;Hiraoka|Atsushi|A|http://orcid.org/0000-0003-1989-0480;Okazaki|Hidenori|H|;Nagamatsu|Kensuke|K|;Izumoto|Hirofumi|H|;Yoshino|Takeaki|T|;Tsuruta|Miho|M|;Aibiki|Toshihiko|T|;Okudaira|Tomonari|T|;Yamago|Hiroka|H|;Iwasaki|Ryuichiro|R|;Suga|Yoshifumi|Y|;Mori|Kenichiro|K|;Miyata|Hideki|H|;Tsubouchi|Eiji|E|;Ninomiya|Tomoyuki|T|;Michitaka|Kojiro|K|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-020-01134-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(5)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Hepatocellular carcinoma; Psoriasis vulgaris; Sorafenib",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009536:Niacinamide; D010671:Phenylurea Compounds; D011565:Psoriasis; D000077157:Sorafenib; D016896:Treatment Outcome",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "891-895",
"pmc": null,
"pmid": "32468502",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Exacerbation of psoriasis vulgaris by sorafenib treatment for hepatocellular carcinoma.",
"title_normalized": "exacerbation of psoriasis vulgaris by sorafenib treatment for hepatocellular carcinoma"
} | [
{
"companynumb": "JP-BAYER-2019-034805",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PETROLATUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThere are many contradictions about pregnancy and fetal/neonatal outcomes after topical use of timolol alone or timolol in combination with other antiglaucoma medications.\n\n\nMETHODS\nSeventy-five pregnant women exposed to antiglaucoma medications were followed prospectively by phone interviews. 27 women used timolol as monotherapy, 48 women used timolol as a part of multidrug therapy. We selected a control group of 187 healthy pregnant women.\n\n\nRESULTS\nTopical use of timolol alone or timolol in combination with other antiglaucoma medications does not influence pregnancy or fetal/neonatal outcomes.\n\n\nCONCLUSIONS\nBeta-blocker is the first choice treatment for glaucoma in pregnancy but, when necessary, multidrug therapy should not to be excluded.",
"affiliations": "Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Department of Statistics, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.;Teratology Information Service, Department of Obstetrics and Gynecology, Fetal Diagnosis and Therapy Unit, Catholic University of Sacred Heart, Policlinico A. Gemelli Hospital, Rome, Italy.",
"authors": "Pellegrino|Marcella|M|;D'Oria|Luisa|L|;De Luca|Carmen|C|;Chiaradia|Giacomina|G|;Licameli|Angelo|A|;Neri|Caterina|C|;Nucci|Marta|M|;Visconti|Daniela|D|;Caruso|Alessandro|A|;De Santis|Marco|M|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D013999:Timolol",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886312666171030125804",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "13(1)",
"journal": "Current drug safety",
"keywords": "Congenital anomalies; Teratology Information Service (TIS).; drugs; glaucoma; pregnancy; prenatal diagnosis",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists; D000328:Adult; D000959:Antihypertensive Agents; D000013:Congenital Abnormalities; D003376:Counseling; D004359:Drug Therapy, Combination; D005260:Female; D005901:Glaucoma; D006801:Humans; D007255:Information Services; D007429:Intraocular Pressure; D007558:Italy; D011247:Pregnancy; D011256:Pregnancy Outcome; D011446:Prospective Studies; D018600:Teratology; D013999:Timolol",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "3-11",
"pmc": null,
"pmid": "29086700",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Glaucoma Drug Therapy in Pregnancy: Literature Review and Teratology Information Service (TIS) Case Series.",
"title_normalized": "glaucoma drug therapy in pregnancy literature review and teratology information service tis case series"
} | [
{
"companynumb": "PHHY2018IT122445",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TIMOLOL"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "Polymyxins B and E (colistin) exert a bactericidal effect on the gram-negative bacterial cell wall, causing permeability changes in the cytoplasmic membrane, leading to cell death. Their use was substantially decreased in clinical practice from the 1970s to 2000s due to their significant nephrotoxicity and neurotoxicity compared to the newly introduced antibiotics. The increasing prevalence of multidrug-resistant gram-negative bacteria infections in this century has led to an upsurge in the use of these \"older\" drugs. Respiratory paralysis caused by neuromuscular blockage associated with the use of polymyxin B and E was reported mostly in literature published in the 1960s to 1970s with a few reports after 2000. In addition, such a reaction might be enhanced by the presence of other classes of drugs. We report a case of polymyxin B and E-induced apnea in a patient receiving \"muscle relaxants.\"",
"affiliations": "University of Kentucky Medical Center, Lexington, KY, USA.;University of Kentucky Medical Center, Lexington, KY, USA.;University of Kentucky HealthCare, Lexington, KY, USA.;University of Kentucky Medical Center, Lexington, KY, USA.",
"authors": "Myint|Thein|T|;Evans|Martin E|ME|;Burgess|Donna R|DR|;Greenberg|Richard N|RN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2324709616638362",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961663836210.1177_2324709616638362Case ReportRespiratory Muscle Paralysis Associated With Colistin, Polymyxin B, and Muscle Relaxants Drugs A Case ReportMyint Thein MBBS1Evans Martin E. MD1Burgess Donna R. RPh2Greenberg Richard N. MD11 University of Kentucky Medical Center, Lexington, KY, USA2 University of Kentucky HealthCare, Lexington, KY, USAThein Myint, MBBS, University of Kentucky Medical Center, 740 S Limestone Street, K512, Lexington, KY 40536-0293, USA. Email: thein.myint3@uky.edu14 3 2016 Jan-Mar 2016 4 1 232470961663836219 12 2015 2 2 2016 16 2 2016 © 2016 American Federation for Medical Research2016American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).Polymyxins B and E (colistin) exert a bactericidal effect on the gram-negative bacterial cell wall, causing permeability changes in the cytoplasmic membrane, leading to cell death. Their use was substantially decreased in clinical practice from the 1970s to 2000s due to their significant nephrotoxicity and neurotoxicity compared to the newly introduced antibiotics. The increasing prevalence of multidrug-resistant gram-negative bacteria infections in this century has led to an upsurge in the use of these “older” drugs. Respiratory paralysis caused by neuromuscular blockage associated with the use of polymyxin B and E was reported mostly in literature published in the 1960s to 1970s with a few reports after 2000. In addition, such a reaction might be enhanced by the presence of other classes of drugs. We report a case of polymyxin B and E–induced apnea in a patient receiving “muscle relaxants.”\n\nrespiratory muscle paralysiscolistinpolymyxin Bmuscle relaxant drugscover-dateJanuary-March 2016\n==== Body\nIntroduction\nPolymyxins B (PMB) and E (colistimethate sodium, colistin [CMS]) exert a bactericidal effect on the gram-negative bacterial cell wall, causing permeability changes in the cytoplasmic membrane, leading to cell death. They were introduced into medical practice in the 1950s but their use was substantially decreased from the 1970s to 2000s due to significant nephrotoxicity and neurotoxicity compared to the newly introduced antibiotics. The increasing prevalence of multidrug-resistant gram-negative bacteria infections in this century has led to an upsurge in the use of these “older” drugs. Reports of potentially severe and life-threatening respiratory paralysis caused by neuromuscular blockage associated with their use have been published, mostly in the 1960s to 1970s.1,2 Reports also suggested that polymyxin-related neuromuscular blockade might be enhanced by the presence of other drugs with similar toxicities such as neomycin,3 anesthetics,4 and neuromuscular blocking agents,5 including pipecuronium.6 We report a case with episodes of both CMS and subsequent PMB-induced apnea in a patient receiving “muscle relaxants.”\n\nCase Report\nA 57-year-old male with history of diabetes mellitus, atrial fibrillation, and degenerative joint disease underwent a left L4-L5 hemilaminectomy, medial facetectomy, and microdiskectomy to relieve the symptoms of spinal stenosis. The surgery was complicated by a methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. A surface culture of the open surgical site grew MSSA, Candida albicans, and multidrug resistant Pseudomonas aeruginosa (resistant to levofloxacin; minimum inhibitory concentration [MIC] >16 µg/mL), intermediate susceptibility to cefepime (MIC = 8 µg/mL) and piperacillin/tazobactam (MIC = 32 µg/mL), but sensitive to meropenem (MIC <1 µg/mL). A surveillance culture 1 month prior to this wound infection did not grow a multidrug-resistant Pseudomonas aeruginosa. He was discharged to a nursing home to receive intravenous (IV) meropenem 1 g every 8 hours and oral fluconazole 400 mg daily. He was also prescribed the muscle relaxant cyclobenzaprine (Flexeril) 10 mg 3 times a day as needed for muscle spasm. One week later, cyclobenzaprine was changed to tizanidine (Zanaflex) 1 mg at bedtime. Two weeks later, when Pseudomonas aeruginosa resistant to meropenem (MIC = 8) was recovered from an open wound with a purulent discharge, IV CMS was started at 3 mg/kg/day divided into 2 doses, and the dose of IV meropenem was increased to 2 g every 8 hours. CMS was chosen rather than an aminoglycoside as his infectious disease physician believed this offered the patient the best chance to receive a possible synergic combination to treat the multiresistant Pseudomonas.7 After completing the 3 weeks of IV CMS, and 5 weeks of meropenem and fluconazole, he was discharged from the nursing home. His tizanidine dose was increased to 4 mg every 8 hours 2 weeks later. He received 3 additional weeks of IV CMS and IV meropenem at home (Figure 1). During this time he became progressively weak with frequent falls and also became short of breath. During the third week at home, he stopped talking, could not move his arms, and had labored respirations. He was intubated when seen as an emergency and brought to a hospital. His serum electrolytes and renal function tests are shown in Table 1. His serum creatinine had risen from 0.6 mg/dL prior to CMS to 1.1 mg/dL. A creatinine clearance was 110 mL/min at this admission. Computed tomography (CT) showed no intracranial lesions. A CT angiography of the head and neck showed no significant stenosis. He was given tissue plasminogen activator for the treatment of a probable ischemic stroke. Tizanidine and CMS were discontinued and PMB started with a loading dose of 160 mg IV followed by 100 mg every 12 hours. IV meropenem and oral fluconazole were also restarted. He was extubated 1 day after the admission.\n\nFigure 1. Time Line of Antibiotics and muscle relaxants.\n\nTable 1. Laboratory Results Before, on the Day of Admission, and on the Third Day of Admission.\n\nLabs\tNormal Range\tPrior to Starting Colistin\t2 Weeks After Colistin\t5 Weeks After Colistin\t6 Weeks After Colistin (on the Date of Admission)\tThird Day of Admission\t\nPotassium\t3.7-4.8 mmol/L\t4.5\t4.5\t3.9\t3.0\t3.5\t\nMagnesium\t1.9-2.4 mg/dL\tNA\t1.5\t1.7\t0.9\t1.5\t\nCalcium\t8.9-10.2 mg/dL\t8.4\t9.2\t9.5\t9.3\t8.8\t\nCorrected calcium\t8.9-10.2 mg/dL\t10.0\t10.7\t10.7\t10.8\tNA\t\nAlbumin\t3.3-4.6 g/dL\t2.0\t2.1\t2.5\t2.1\tNA\t\nCreatinine\t0.8-1.3 mg/dL\t0.62\t1.11\t1.17\t1.09\t0.99\t\nWhite blood cell\t3.7-10.3 k/µL\t8.0\t6.1\t9.5\t8.7\t8.7\t\nC-reactive protein\t0-0.9 mg/dL\t5.4\t2.1\t5.4\tNA\t10.4\t\nAbbreviation: NA, not available.\n\nOn the fourth day after admission (and no longer receiving a muscle relaxant), he developed slurred speech, inability to move both his upper extremities, and apnea 10 minutes after completion of an infusion of PMB. He was intubated again. A CT scan of his head did not show changes, and his electroencephalogram was within normal limits. His antibiotics were discontinued (Figure 1). Three days later he was extubated as his right upper extremity weakness had improved. It was noted that his peripheral eosinophil count had increased to 7% after 4 weeks of meropenem and fluconazole and 2 weeks of CMS, and then to 11% 2 weeks later. It was 19% at the time when all antibiotics were stopped. One month later it had fallen to 10%. The patient was not restarted on any antibiotics. The wound was treated with wet to dry dressing changes and debrided 5 months later. The patient remains with a chronic nonhealing wound.\n\nDiscussion\nPolymyxins B and E are small basic peptides (molecular weight ~ 1000) and cationic detergents that exert a bactericidal effect on the gram-negative bacterial cell wall, causing permeability changes in the cytoplasmic membrane, leading to cell death.1,8 Their use was substantially decreased in clinical practice from the 1970s to 2000s due to their significant nephrotoxicity and neurotoxicity compared to the “newly” introduced antibiotics.9 The increasing prevalence of multidrug-resistant gram-negative bacteria infections in this century has led to an upsurge in the use of PMB and CMS.\n\nRespiratory muscle paralysis is a rare but potentially fatal complication of the use of PMB and CMS.2 The incidence of CMS associated neurotoxicity reported in the literature prior to 1975 ranged from 7.3% to 27%, with paresthesia constituting most of the reports.1,10 Lindesmith et al2 described 21 cases of reversible respiratory paralysis in 1968; 15 cases were associated with CMS and 6 cases with PMB therapy. The number of doses associated with episodes of respiratory arrest ranged from a single dose to 45 doses of antibiotics. Onset of paralysis occurred from 1 to 26 hours after a dose of PMB or CMS. Most of those cases were described in patients with renal disease,2 suggesting that the risk of polymyxin-associated neuromuscular blockade is increased with impaired renal function.\n\nOther neurotoxic effects include circumoral paresthesia or numbness, tingling or formication of the extremities, generalized pruritus, vertigo, dizziness, and slurring of speech.1,2,9 Untreated neurotoxicity associated with PMB or CMS is a precipitating factor for respiratory muscle paralysis and respiratory failure.\n\nThe proposed mechanism of CMS neurotoxicity is a noncompetitive myoneuronal presynaptic blockade of acetylcholine release that may be enhanced by hypocalcemia-induced prolongation of depolarization.9 Concomitant drug therapies including other neurotoxic drugs (anesthetics, aminoglycosides, and paralytics), corticosteroids, narcotics, and muscle relaxants (which were given to this patient) probably increase the risk of CMS neurotoxicity.1,9\n\nAfter the resurgence in the use of CMS and PMB for multidrug-resistant gram-negative bacteria in this century, there have been several case reports of PMB- or CMS-related respiratory apnea that required intubation.11-17 Seven of 9 cases were associated with CMS (Table 2).\n\nTable 2. Case Reports Summary of Colistin/Polymyxin-Induced Apnea That Required Intubation, Published After 2010.\n\nNo.\tStudy\tAge\tGender\tIndication\tIV Drug and Dose\tDuration of Antibiotic Administration Prior to Onset of Apnea\tDuration of Endotracheal Intubation, Outcome\tAssociated With Underlying Renal Disease\tConcomitant Neurotoxic Drugs\t\n1\tWahby et al11 (2010)\t33\tFemale\tMDR Acinetobacter baumannii\t170 mg of colistin base activity every 12 h\t5 days\t5 days, survived\tNA\tMethylprednisolone, hydromorphone\t\n2\tSpapen et al12 (2011)\t51\tMale\tNew Delhi metallo-β-lactamase-1 Escherichia coli\tColistin 3 million units every 8 h\t19 days\tNA, died\tNo\tAnesthetic agent\t\n3\tWunsch et al,13 case 1 (2012)\t48\tMale\tCarbapenem resistant Klebsiella pneumoniae\tPolymyxin 125 mg every 12 h\t1 hour\tNA\tNo\tIV amikacin\t\n4\tWunsch et al,13 case 2 (2012)\t58\tMale\tMDR Klebsiella pneumoniae\tPolymyxin B 80 mg every 12 h\t2 days\t1 day\tYes\tNA\t\n\t\t\t\t\tSecond test dose of IV polymyxin\t2 hours\t1 day, survived\t\t\t\n5\tFernandez et al14 (2013)\t75\tMale\tMDR Pseudomonas aeruginosa\tColistin 3 million international units every 8 h\t36 hours\t1 day, died\tNo\tNA\t\n6\tWadia and Tran15 (2014)\t51\tMale\tAcinetobacter baumannii, ESBL Proetus mirabilis\tColistin 275 mg q12h\t8 days\tNA, survived\tNo\tNA\t\n7\tShrestha et al16 (2014)\t31\tFemale\tPan resistant Pseudomonas\tColistin 200 mg q12h\t3 days\t1 day, survived\tYes\tNA\t\n8\tNigam et al17 (2015)\t20\tFemale\tMDR Pseudomonas\tColistin 1 million units q8h\t5 days\tNo intubation, survived\tNA\tNo\t\n9\tOur patient\t57\tMale\tMDR Pseudomonas aeruginosa\tColistin 120 mg IV q12h; polymyxin B 100 mg IV q12\t6 weeks, and again for only 3 days\t3 days twice, survived\tNo\tTizanidine\t\nAbbreviations: MDR, multidrug-resistant; NA, not available; IV, intravenous.\n\nOur patient received intravenous CMS 3 mg/kg/day divided into 2 doses for 6 weeks. He did not appear to have underlying renal insufficiency prior to admission, and his creatinine clearance was never below 95 mL/min during his hospital stay. His serum calcium was within normal limits. He did not have tetany, arrhythmia, seizure, or involuntary movements although he was slightly hypokalemic and hypomagnesemic. He developed shortness of breath after a prolonged course of IV CMS and apnea after 3 days of PMB. He developed eosinophilia but did not have a rash or organ injury. Stool parasite studies were negative as was serum antibody for Strongyloides stercoralis. Eosinophilia associated with CMS or PMB has been reported in 1.6% of patients receiving these drugs.1 Our patient’s eosinophilia could have resulted from exposure to one or more of medications that included meropenem, fluconazole, tizanidine, CMS, and PMB.\n\nNeurological diseases such as stroke and seizure were excluded in this patient. He was not receiving any steroids. His respiratory paralysis reversed after stopping PMB and CMS.\n\nThe patient received the muscle relaxants cyclobenzaprine (Flexeril) and tizanidine (Zanaflex), which could have potentially increased neuromuscular blockage leading to his first episode of respiratory muscle paralysis, though this interaction has not been reported.9 The dose of tizanidine, 4 mg every 8 hours, was also relatively high. He did not receive concurrent curariform muscle relaxants or other neurotoxic drugs (tubocurarine, succinylcholine, gallamine, decamethnium, and sodium citrate), which have been associated with respiratory depression.1 The patient’s CMS- and PMB-induced apnea might have been enhanced by the muscle relaxants. His Naranjo adverse drug reaction probability scale of 7 indicates these event were probably an adverse drug reaction.18\n\nWith an increasing use of IV CMS and PMB to treat multidrug-resistant gram-negative bacteria infections, clinicians must be aware of respiratory muscle paralysis as a rare and potentially fatal side effect of these drugs. Patients receiving these drugs should have regular reviews for drug-drug interactions, as well as renal and neurological assessments.11 If the patient develops neurotoxicity, CMS or PMB should be stopped. There is no role for reversal agents such as neostigmine, although calcium infusions and antihistamines have been suggested to have some benefit in reversing the paralysis.2 As this reaction can be reversible, continuous renal replacement therapy or hemodialysis seems a reasonable option to help in patients with acute renal failure or with high serum levels of polymyxins.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 \nKoch-Weser J Sidel VW Federman EB Kanarek P Finer DC Eaton AE. \nAdverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy . Ann Intern Med . 1970 ;72 :857 -868 .5448745 \n2 \nLindesmith LA Baines RD JrBigelow DB Petty TL. \nReversible respiratory paralysis associated with polymyxin therapy . Ann Intern Med . 1968 ;68 :318 -327 .4306125 \n3 \nLee C de Silva AJ. \nInteraction of neuromuscular blocking effects of neomycin and polymyxin B . Anesthesiology . 1979 ;50 :218 -220 .219730 \n4 \nZauder HL Barton N Bennett EJ Lore J. \nColistimethate as a cause of postoperative apnoea . Can Anaesth Soc J . 1966 ;13 :607 -610 .5957445 \n5 \nBurkett L Bikhazi GB Thomas KC JrRosenthal DA Wirta MG Foldes FF. \nMutual potentiation of the neuromuscular effects of antibiotics and relaxants . Anesth Analg . 1979 ;58 :107 -115 .571233 \n6 \nde Gouw NE Crul JF Vandermeersch E Mulier JP van Egmond J Van Aken H. \nInteraction of antibiotics on pipecuronium-induced neuromuscular blockade . J Clin Anesth . 1993 ;5 :212 -215 .8391282 \n7 \nZusman O Avni T Leibovici L \nSystematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems . Antimicrob Agents Chemother . 2013 ;57 :5104 -5111 .23917322 \n8 \nBrunton LL Chabner BA Knollmann BC , eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics . 12th ed. \nNew York, NY : McGraw-Hill ; 2011 .\n9 \nFalagas ME Kasiakou SK. \nToxicity of polymyxins: a systematic review of the evidence from old and recent studies . Crit Care . 2006 ;10 :R27 .16507149 \n10 \nFekety FR JrNorman PS Cluff LE. \nThe treatment of gram-negative bacillary infections with colistin. The toxicity and efficacy of large doses in forty-eight patients . Ann Intern Med . 1962 ;57 :214 -229 .13892094 \n11 \nWahby K Chopra T Chandrasekar P. \nIntravenous and inhalational colistin-induced respiratory failure . Clin Infect Dis . 2010 ;50 :e38 -e40 .20146630 \n12 \nSpapen HD Honore PM Gregoire N \nConvulsions and apnoea in a patient infected with New Delhi metallo-beta-lactamase-1 Escherichia coli treated with colistin . J Infect . 2011 ;63 :468 -470 .21798284 \n13 \nWunsch H Moitra VK Patel M Dzierba AL. \nPolymyxin use associated with respiratory arrest . Chest . 2012 ;141 :515 -517 .22315119 \n14 \nFernandez AB Perez M Soto L. \nSudden respiratory muscle paralysis and apnea in a patient infected with multidrug-resistant Pseudomonas aeruginosa treated with intravenous colistin . Int J Infect Dis . 2013 ;17 :e357 .23266335 \n15 \nWadia S Tran B. \nColistin-mediated neurotoxicity . BMJ Case Rep . 2014 ;2014 . doi:10.1136/bcr-2014-205332. \n16 \nShrestha A Soriano SM Song M Chihara S. \nIntravenous colistin-induced acute respiratory failure: a case report and a review of literature . Int J Crit Illness Inj Sci . 2014 ;4 :266 -270 .\n17 \nNigam A Kumari A Jain R Batra S. \nColistin neurotoxicity: revisited . BMJ Case Rep . 2015 ;2015 . doi:10.1136/bcr-2015-210787. \n18 \nNaranjo CA Shear NH Lanctot KL. \nAdvances in the diagnosis of adverse drug reactions . J Clin Pharmacol . 1992 ;32 :897 -904 .1447396\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "4(1)",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "colistin; muscle relaxant drugs; polymyxin B; respiratory muscle paralysis",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709616638362",
"pmc": null,
"pmid": "27047979",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "8391282;23917322;571233;21798284;5957445;25199193;219730;26206782;4306125;5448745;13892094;23266335;1447396;22315119;20146630;25337492;16507149",
"title": "Respiratory Muscle Paralysis Associated With Colistin, Polymyxin B, and Muscle Relaxants Drugs: A Case Report.",
"title_normalized": "respiratory muscle paralysis associated with colistin polymyxin b and muscle relaxants drugs a case report"
} | [
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"abstract": "BACKGROUND\nCorticosteroid withdrawal (CW) after pediatric kidney transplantation potentially improves growth while avoiding metabolic and other adverse events. We have recently reported the results of a 196 subject randomized controlled trial comparing early CW (tacrolimus, mycophenolate mofetil (MMF), daclizumab, and corticosteroids until day 4) with tacrolimus, MMF, and corticosteroid continuation (CC). At 6 months, CW subjects showed better growth with no adverse impact on acute rejection or graft survival (Am J Transplant 2010; 10: 828-836). This 2-year investigator-driven follow-up study aimed to determine whether improved growth persisted in the longer term.\n\n\nMETHODS\nData regarding growth, graft outcomes and adverse events were collected at 1 year (113 patients) and 2 years (106 patients) after transplantation. The primary endpoint, longitudinal growth calculated as delta height standard deviation score, was analyzed using a mixed model repeated measures model.\n\n\nRESULTS\nCorticosteroid withdrawal subjects grew better at 1 year (difference in adjusted mean change, 0.25; 95% confidence interval, 0.10, 0.40; P = 0.001). At 2 years, growth remained numerically better in CW subjects (0.20 (-0.01, 0.41); P = 0.06), and significantly better in prepubertal subjects (0.50 (0.16, 0.84); P = 0.004). Bacterial and viral infection was significantly more common in CW subjects at 1 year only. Corticosteroid withdrawal and CC subjects received similar exposure to both tacrolimus and MMF at 1 and 2 years. No significant difference in patient or graft survival, rejection, estimated glomerular filtration rate, or other adverse events was detected.\n\n\nCONCLUSIONS\nEarly CW effectively and safely improves growth up to 2 years after transplantation, particularly in prepubertal children.",
"affiliations": "1 Department of Paediatric Nephrology, Royal Manchester Children's Hospital,Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. 2 Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom. 3 Research and Innovation Department, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. 4 Centre for Biostatistics, University of Manchester, Manchester, United Kingdom. 5 Department of Nephrology, Kidney Transplantation and Hypertension, Children's Memorial Health Institute, Warsaw, Poland. 6 Department of Paediatric Nephrology, Great Ormond Street Hospital, London, United Kingdom. 7 Department of Paediatric Nephrology, Nottingham University Hospitals, Nottingham, United Kingdom. 8 Department of Paediatric Nephrology, Leeds General Infirmary, Leeds, United Kingdom. 9 Department of Paediatric Nephrology, University Hospital Motol, Prague, Czech Republic. 10 Department of Paediatric Nephrology, Royal Hospital for Sick Children, Glasgow, United Kingdom. 11 Department of Paediatric Nephrology, Semmelweis University of Medicine, Budapest, Hungary. 12 Department of Pediatric Nephrology, Universitair Ziekenhuis KU Leuven, Belgium. 13 Department of Paediatric Nephrology, Birmingham Children's Hospital, Birmingham, United Kingdom. 14 Department of Pediatrics, Cliniques Universitaires Saint-Luc, Université catholique de Louvain Medical School, Brussels, Belgium. 15 Department of Pediatric Nephrology, Hopital Femme Mere Enfant, Lyon, France. 16 Department of Paediatric Nephrology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom. 17 Department of Paediatrics, Azienda Ospedaliera di Padova, Padova, Italy. 18 Department of Pediatric Nephrology, Red Cross Children's Hospital, Cape Town, South Africa. 19 Department of Paediatrics I, University Children's ",
"authors": "Webb|Nicholas J A|NJ|;Douglas|Sarah E|SE|;Rajai|Azita|A|;Roberts|Stephen A|SA|;Grenda|Ryszard|R|;Marks|Stephen D|SD|;Watson|Alan R|AR|;Fitzpatrick|Maggie|M|;Vondrak|Karel|K|;Maxwell|Heather|H|;Jaray|Jeno|J|;Van Damme-Lombaerts|Rita|R|;Milford|David V|DV|;Godefroid|Nathalie|N|;Cochat|Pierre|P|;Ognjanovic|Milos|M|;Murer|Luisa|L|;McCulloch|Mignon|M|;Tönshoff|Burkhard|B|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D000077561:Daclizumab; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000000498",
"fulltext": null,
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"issn_linking": "0041-1337",
"issue": "99(6)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D002657:Child Development; D002675:Child, Preschool; D000077561:Daclizumab; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "1178-85",
"pmc": null,
"pmid": "25539467",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Corticosteroid-free Kidney Transplantation Improves Growth: 2-Year Follow-up of the TWIST Randomized Controlled Trial.",
"title_normalized": "corticosteroid free kidney transplantation improves growth 2 year follow up of the twist randomized controlled trial"
} | [
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"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-03875",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "Objective : Only a few cases of insufficiency fractures of the tibial plateau following bisphosphonate use have been reported. The authors report a case with bisphosphonate (BP) -related atypical insufficiency fracture of tibial plateau, which developed delayed union. Patient : A 65-year-old Japanese woman presented with left knee pain without any trauma. She had a 5-year history of risedronate use for primary osteoporosis. Initial X-rays were unremarkable, but magnetic resonance imaging (MRI) confirmed an insufficiency fracture at the left tibial plateau at 3 weeks after the initial visit. Risedronate treatment was stopped because we diagnosed her with a BP-related atypical insufficiency fracture of the tibial plateau. She was treated with rest, a lateral wedge insole and protective weight-bearing with a T-cane for 3 months. Result : At 3-month follow-up, the patient still had a pain and a delayed healing on radiographs. Six months later, X-rays showed that the fracture site had a sclerotic change, but MRI revealed delayed union. At 8-month follow-up, the fracture was healed without any symptoms. Conclusion : All clinicians need to be aware of the delayed healing of atypical insufficiency fracture related with prolonged BP use. J. Med. Invest. 68 : 186-188, February, 2021.",
"affiliations": "Department of Orthopedic Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japan.;Department of Orthopedic Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japan.;Department of Orthopedic Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japan.;Department of Orthopedic Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japan.;Department of Orthopedic Surgery, Yamaguchi University School of Medicine, Yamaguchi, Japan.;Department of Orthopedic Surgery, Ogori Daiichi General Hospital, Yamaguchi, Japan.",
"authors": "Suthar|Ashish|A|;Yukata|Kiminori|K|;Suetomi|Yutaka|Y|;Yamazaki|Kazuhiro|K|;Sakai|Takashi|T|;Fujii|Hiroshi|H|",
"chemical_list": "D004164:Diphosphonates",
"country": "Japan",
"delete": false,
"doi": "10.2152/jmi.68.186",
"fulltext": null,
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"issn_linking": "1343-1420",
"issue": "68(1.2)",
"journal": "The journal of medical investigation : JMI",
"keywords": "Atypical fracture; Bisphosphonate; Insufficiency fracture; Osteoporosis; Tibial plateau",
"medline_ta": "J Med Invest",
"mesh_terms": "D000368:Aged; D004164:Diphosphonates; D005260:Female; D005593:Fracture Fixation, Internal; D015775:Fractures, Stress; D006801:Humans; D013977:Tibia; D013978:Tibial Fractures",
"nlm_unique_id": "9716841",
"other_id": null,
"pages": "186-188",
"pmc": null,
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"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bisphosphonate-related atypical insufficiency fracture of the tibial plateau : A case report.",
"title_normalized": "bisphosphonate related atypical insufficiency fracture of the tibial plateau a case report"
} | [
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"companynumb": "JP-TEVA-2021-JP-1927275",
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"activesubstancename": "RISEDRONATE SODIUM"
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{
"abstract": "We are reporting a unique case of drosophila larva nasal myiasis (NM) in a 72-year-old male patient admitted to the ICU with diffuse muscle weakness and respiratory failure due to myasthenia gravis crisis and septic shock due to pseudomonas pneumonia. The myiasis was noticed on the third day of admission two days following traumatic insertion of a nasogastric tube. The patient underwent nasal endoscopic mechanical extraction and lidocaine nasal spray with saline nasal flushes. To our knowledge, this is the first case report of NM in a myasthenia gravis (MG) patient. Chronic muscle weakness in MG patients might play a role in having NM as these patients are less likely to be able to protect themselves from flies. Managing NM in our patient was challenging due to the potential neurologic side effects of most of treatment options mentioned in the literature.",
"affiliations": "Marshall Internal Medicine, United States.;Marshall Neurology, United States.;Marshall Internal Medicine, United States.;Marshall Pulmonary Critical Care, United States.;Marshall Neurology, United States.;Marshall Pulmonary Critical Care, United States.",
"authors": "Katabi|Abdulrahman|A|;Aguirre|Morgan|M|;Obeidat|Yasmeen|Y|;Al-Ourani|Mohammed|M|;Assad|Salman|S|;Zeid|Fuad|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101212",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30426-3\n10.1016/j.rmcr.2020.101212\n101212\nCase Report\nNasal myiasis in myasthenic crisis, a case report and literature review\nKatabi Abdulrahman katabi@marshall.edua∗ Aguirre Morgan b Obeidat Yasmeen a Al-Ourani Mohammed c Assad Salman b Zeid Fuad c a Marshall Internal Medicine, United States\nb Marshall Neurology, United States\nc Marshall Pulmonary Critical Care, United States\n∗ Corresponding author. katabi@marshall.edu\n02 9 2020 \n2020 \n02 9 2020 \n31 1012124 7 2020 21 7 2020 26 8 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We are reporting a unique case of drosophila larva nasal myiasis (NM) in a 72-year-old male patient admitted to the ICU with diffuse muscle weakness and respiratory failure due to myasthenia gravis crisis and septic shock due to pseudomonas pneumonia. The myiasis was noticed on the third day of admission two days following traumatic insertion of a nasogastric tube. The patient underwent nasal endoscopic mechanical extraction and lidocaine nasal spray with saline nasal flushes. To our knowledge, this is the first case report of NM in a myasthenia gravis (MG) patient. Chronic muscle weakness in MG patients might play a role in having NM as these patients are less likely to be able to protect themselves from flies. Managing NM in our patient was challenging due to the potential neurologic side effects of most of treatment options mentioned in the literature.\n\nKeywords\nNasal MyiasisMaggots infestationMyasthenia gravisMyasthenia crisisNosocomial myiasis\n==== Body\n1 Introduction\nNasal myiasis is a rare case of invasion of fly larvae into the nasal cavities. It usually affects immobile and debilitated patients [1]. It begins when the fly enters the nasal cavity and lays its eggs. The eggs hatch into larvae within 24 hours. The larvae reach full maturation within 2–3 days then migrate to look for dry environments to continue their life cycle [2]. Myiasis also can happen in other areas of the body including wounds and the gastrointestinal system. The consequences range from simple subcutaneous skin nodules to serious complications such as basal skull invasion or blindness due to invasion of the optic nerve [3].\n\n2 Case presentation\nThe patient is a 72-year-old male with a past medical history of myasthenia gravis, type 2 diabetes, atrial fibrillation, and pulmonary embolism. He presented to the emergency room with a 2-day history of worsening dysarthria, diffuse muscle weakness, and altered mental status. He was diagnosed with myasthenia gravis 3 months prior after having progressive weakness and dysphagia resulting in him becoming bedbound and requiring percutaneous endoscopic gastrostomy (PEG). His symptoms were managed with daily prednisone and pyridostigmine. He had recently been discharged from an acute rehab facility with normal mentation and improving strength.\n\nOn presentation, he was admitted to the ICU for septic shock, acute respiratory failure secondary to myasthenic crisis, pseudomonas pneumonia, proteus UTI, and acute renal failure. Head CT was nonacute. He was intubated immediately following arrival and started on broad-spectrum antibiotics, intravenous immunoglobulin (IVIG), and intravenous heparin in place of his home apixaban. Due to abdominal pain, a nasogastric tube was placed until proper location of PEG tube was confirmed. Following NG tube placement, patient's hemoglobin dropped, requiring multiple transfusions, so anticoagulation was held. A significant amount of blood was suctioned from his NG tube. On the third day of admission, alive maggots were seen in the contents suctioned via the NG tube and were noticed inside his nostrils (Fig. 1). The ear, nose, and throat (ENT) specialist was consulted and performed nasal endoscopy. The maggots were found to be feeding on a large blood clot that had formed following NG tube insertion.Fig. 1 Maggots extracted from the patient's nostrils.\n\nFig. 1\n\nDuring nasal endoscopy, lidocaine and oxymetazoline were applied locally, and mechanical extraction of maggots and blood clot was successful. Additional lidocaine was applied to the nasal airway. Repeat endoscopy showed resolution of nasal myiasis and complete extraction of the blood clot. There was no recurrence during his hospitalization. He was treated with plasmapheresis followed by IVIG for myasthenic crisis, and his mental status and muscle strength improved. He was not successfully extubated due to prolonged intubation and profound respiratory muscle weakness, and tracheostomy was performed. The patient was discharged to a long-term acute care facility for further recovery.\n\n3 Discussion\nPredisposing factors to developing nasal myiasis include atrophic rhinitis, malignancy, blood, or necrotic tissue on which the maggots feed after a fly lays eggs near the nasal region [4,5]. Fortunately, our patient did not have malignancy or necrotic tissue, rather, due to anticoagulation, excessive bleeding from nasogastric tube placement resulted in a large blood clot on which the maggots fed.\n\nThe time of onset on the third day of admission makes it uncertain whether the fly eggs were laid prior to or during his hospitalization, though the lifecycle of drosophilia supports this being a nosocomial infection. He was intubated and on sedation; therefore, he was unable to protect himself from flies landing on him. In previous literature, there is a trend of myiasis occurring in critically ill patients on mechanical ventilation [6,7]. To consider the possibility that it was acquired at home, the patient's muscle weakness due to myasthenic crisis would have made him unable to swat away a fly landing near his nasal mucosa.\n\nIn previous case reports, mechanical removal of larvae has been consistently described, but medical treatments have varied between cases. In addition to lidocaine nasal spray, other effective medications include, ivermectin, local chloroform [5], or pyrantel pamoate [8]. In this case, treatment options are limited to topical lidocaine, as other agents are known to worsen myasthenia gravis.\n\n4 Conclusions\nNosocomial NM is a serious infestation to several body tissues. General debility or weakness might play a role in having NM due to inability to keep the flies away from nasal orifices. Lack of evidence on consensus treatment will make managing these cases more challenging, especially in patients with neurological comorbidities due to medications side effects.\n==== Refs\nReferences\n1 Smith D.R. Clevenger R.R. Nosocomial nasal myiasis Arch. Pathol. Lab Med. 110 1986 439 440 3754428 \n2 Fernández-Moreno M.A. Farr C.L. Kaguni L.S. Drosophila melanogaster as a model system to study mitochondrial biology Methods Mol. Biol. 372 2007 33 49 10.1007/978-1-59745-365-3_3 18314716 \n3 Sunny B. Sulthana L. James A. Maggot infestation: various treatment modalities J. Am. Coll. Clin. Wound Spec. 8 2016 Jan 1 51 53 30276127 \n4 Sharma H. Dayal D. Agrawal S.P. Nasal myiasis: review of 10 years experience J. Laryngol. Otol. 103 1989 489 491 10.1017/s0022215100156695 2754318 \n5 Calvopina M. Ortiz-Prado E. Castañeda B. Human myiasis in Ecuador PLoS Neglected Trop. Dis. 2020 10.1371/journal.pntd.0007858 0007858-2020 \n6 Lee Y.T. Chen T.L. Lin Y.C. Nosocomial nasal myiasis in an intubated patient J. Chin. Med. Assoc. 74 2011 369 371 10.1016/j.jcma.2011.06.001 21872818 \n7 Nazni W.A. Jeffery J. Lee H.L. Nosocomial nasal myiasis in an intensive care unit Malays. J. Pathol. 33 2011 53 56 21874753 \n8 Aydin E. Uysal S. Akkuzu B. Nasal myiasis by fruit fly larvae: a case report Eur. Arch. Oto-Rhino-Laryngol. 263 2006 1142 1143 10.1007/s00405-006-0112-0\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "31()",
"journal": "Respiratory medicine case reports",
"keywords": "Maggots infestation; Myasthenia crisis; Myasthenia gravis; Nasal Myiasis; Nosocomial myiasis",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101212",
"pmc": null,
"pmid": "32963957",
"pubdate": "2020",
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"references": "16832625;3754428;21874753;21872818;2754318;18314716;30276127;32084134",
"title": "Nasal myiasis in myasthenic crisis, a case report and literature review.",
"title_normalized": "nasal myiasis in myasthenic crisis a case report and literature review"
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-52224",
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"abstract": "It is widely known that some patients surgically treated for subdural hematoma (SDH) experience neurologic deficits not clearly explained by the acute brain injury or known sequelae like seizures. There is increasing evidence that cortical spreading depolarization (CSD) may be the cause. A recent article demonstrated that CSD occurred at a rate of 15 % and was associated with neurological deterioration in a subset of patients following chronic subdural hematoma evacuation. Furthermore, CSD can lead to ischemia leading to worsening neurologic deficits. CSD is usually detected on electrocorticography (ECoG) and needs cortical strip electrode placement with equipment and expertise that may not be readily available.\n\n\n\nWe report three cases of patients with subdural hematoma (SDH) not undergoing ECoG in whom CSD was suspected to be the cause of their neurologic deficits post evacuation. Extensive workup including neuroimaging and electroencephalography (EEG) were inconclusive. Patients were subsequently treated with ketamine infusion and had resultant neurological recovery.\n\n\n\nKetamine infusion can help reverse neurologic deficits in patients with SDH in whom the deficits are not explained by neuroimaging or electrographic seizure. CSD is a known phenomenon that can result in neurological injury and must remain in the differential diagnosis of such patients. Though only limited cases are discussed (n = 3), this small case series provides the basis for conducting clinical trials evaluating the efficacy of ketamine in improving functional outcome in brain-injured patients demonstrating evidence of CSD.",
"affiliations": "Department of Neurosurgery, Northwell Health, Manhasset, NY 11030, USA.;Department of Neurosurgery, Northwell Health, Manhasset, NY 11030, USA.;Department of Neurology, Northwell Health, Manhasset, NY 11030, USA.;Department of Pharmacy, Northwell Health, Manhasset, NY 11030, USA.;Department of Neurosurgery, Northwell Health, Manhasset, NY 11030, USA.;Department of Neurosurgery, Northwell Health, Manhasset, NY 11030, USA.;Department of Neurosurgery, Northwell Health, Manhasset, NY 11030, USA.;Department of Neurosurgery, Northwell Health, Manhasset, NY 11030, USA. Electronic address: DLeDoux@northwell.edu.",
"authors": "Wanchoo|Sheshali|S|;Khazanehdari|Shahab|S|;Patel|Arpan|A|;Lin|Amanda|A|;Rebeiz|Tania|T|;DeMatteo|Celine|C|;Ullman|Jamie|J|;Ledoux|David|D|",
"chemical_list": "D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2020.106318",
"fulltext": null,
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"issn_linking": "0303-8467",
"issue": "200()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Cortical spreading depression; Empiric treatment; Ketamine; Subdural hematoma",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D013181:Cortical Spreading Depression; D004569:Electroencephalography; D036262:Empirical Research; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D006408:Hematoma, Subdural; D006801:Humans; D007649:Ketamine; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "7502039",
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"pmid": "33268191",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ketamine for empiric treatment of cortical spreading depolarization after subdural hematoma evacuation.",
"title_normalized": "ketamine for empiric treatment of cortical spreading depolarization after subdural hematoma evacuation"
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"activesubstancename": "KETAMINE"
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"drug... |
{
"abstract": "Coronavirus disease 2019 (COVID-19) has been declared pandemic since March 2020. In Europe, Italy was the first nation affected by this infection. We report anamnestic data, clinical features, and therapeutic management of 2 lung transplant recipients with confirmed COVID-19 pneumonia. Both patients were in good clinical condition before the infection and were receiving immunosuppression with calcineurin inhibitors (CNI), mycophenolate mofetil, and corticosteroids. Whereas mycophenolate mofetil was withdrawn in both cases, CNI were suspended only in the second patient. The first patient always maintained excellent oxygen saturation throughout hospitalization with no need for additional oxygen therapy. He was discharged with a satisfactory pulmonary function and a complete resolution of radiological and clinical findings. However, at discharge SARS-CoV-2 RNA could still be detected in the nasopharyngeal swab and in the stools. The second patient required mechanical ventilation, had a progressive deterioration of his clinical conditions, and had a fatal outcome. Further insight into SARS-CoV-2 infection is eagerly awaited to improve the outcome of transplant recipients affected by COVID-19 pneumonia.",
"affiliations": "Department of Cardio-Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy.;Thoracic Surgery and Lung Transplant Center, Department of Cardio-Thoracic, Vascular Sciences and Public Health, Padova University-Hospital, Padova, Italy.;Division of Infectious and Tropical Disease, Padova University-Hospital, Padova, Italy.;Thoracic Surgery and Lung Transplant Center, Department of Cardio-Thoracic, Vascular Sciences and Public Health, Padova University-Hospital, Padova, Italy.;Department of Women's and Children's Health, University of Padova, Padova, Italy.;Pathological Anatomy Unit, Department of Cardio-Thoracic, Vascular Sciences and Public Health, Padova University-Hospital, Padova, Italy.;Pulmonology Unit, AULSS2 Marca Trevigiana, Ospedale Cà Foncello, Treviso, Italy.;Division of Infectious and Tropical Disease, Padova University-Hospital, Padova, Italy.;Thoracic Surgery and Lung Transplant Center, Department of Cardio-Thoracic, Vascular Sciences and Public Health, Padova University-Hospital, Padova, Italy.",
"authors": "Cozzi|Emanuele|E|;Faccioli|Eleonora|E|0000-0002-2095-5678;Marinello|Serena|S|;Loy|Monica|M|;Congedi|Sabrina|S|;Calabrese|Fiorella|F|0000-0001-5351-9226;Romagnoli|Micaela|M|;Cattelan|Anna M|AM|;Rea|Federico|F|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15993",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "20(10)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; immunosuppressant; immunosuppression/immune modulation; infection and infectious agents - viral; lung disease: infectious; lung transplantation/pulmonology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000368:Aged; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D003550:Cystic Fibrosis; D006801:Humans; D007166:Immunosuppressive Agents; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D011184:Postoperative Period; D029424:Pulmonary Disease, Chronic Obstructive; D012121:Respiration, Artificial; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2933-2937",
"pmc": null,
"pmid": "32400074",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "COVID-19 pneumonia in lung transplant recipients: Report of 2 cases.",
"title_normalized": "covid 19 pneumonia in lung transplant recipients report of 2 cases"
} | [
{
"companynumb": "IT-PFIZER INC-2020412760",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": null,
... |
{
"abstract": "Late-onset myasthenia gravis (LOMG; onset after 50 years of age) has different therapeutic decisionmaking challenges than MG in younger patients.\n\n\n\nThis is a retrospective series of seven patients with acetylcholine receptor antibody-positive MG, all treated with rituximab.\n\n\n\nThe mean age of onset was 66 years. Three patients were nonresponders to previous therapy and six had developed side effects to prednisone. All patients were treated with at least one dose of rituximab. The MG Foundation of America Post-Intervention Status ranged from MM-0 to MM-3 within a mean of 18.5 weeks. All patients were able to reduce or discontinue maintenance medications. No significant adverse events occurred.\n\n\n\nThis series highlights the safety and efficacy of rituximab in LOMG. The presence of multiple comorbidities and the risks of other immunotherapy in older patients makes rituximab an attractive option. More experience is needed to clarify the use of rituximab for patients in this age group.",
"affiliations": "Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.",
"authors": "Sahai|Supreet K|SK|;Maghzi|A Hadi|AH|;Lewis|Richard A|RA|0000-0002-1140-4575",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1002/mus.26876",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-639X",
"issue": "62(3)",
"journal": "Muscle & nerve",
"keywords": "AChR antibodies; B-cell depletion; late-onset; myasthenia gravis; rituximab; treatment",
"medline_ta": "Muscle Nerve",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "7803146",
"other_id": null,
"pages": "377-380",
"pmc": null,
"pmid": "32239711",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rituximab in late-onset myasthenia gravis is safe and effective.",
"title_normalized": "rituximab in late onset myasthenia gravis is safe and effective"
} | [
{
"companynumb": "US-TEVA-2020-US-1843877",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Vascularized composite allografts (VCA), which restore severely damaged body parts that cannot be repaired with conventional surgical techniques, often undergo acute skin rejection episodes in the early postgraft period. Although the risk of human VCA to be affected by chronic rejection was initially unknown, such cases were recently observed.\n\n\n\nChronic rejection targets preferentially the skin (dermal sclerosis, adnexal atrophy, necrosis) and vessels (graft vasculopathy) and may cause graft dysfunction, often resulting in ischemic graft loss. Both immune (cell-mediated and antibody-mediated) and nonimmune mechanisms seem to be involved. The early diagnosis and management of chronic rejection are challenging. Changes of chronic rejection may be seen macroscopically on the skin and can be confirmed with skin and deep tissue biopsies. New noninvasive imaging techniques, which allow visualization of the allograft vasculature, seem promising for the noninvasive detection of graft vasculopathy.\n\n\n\nAlthough some features of chronic rejection of VCA start to be known, several important questions remain to be answered, concerning namely the proper definition of chronic rejection, precise diagnostic criteria, better understanding of triggering factors and pathogenetic mechanisms involved and, most importantly, adequate treatment. Ideally, chronic rejection should be prevented in the future by efficient tolerance-inducing protocols.",
"affiliations": "Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Université Lyon 1.;Department of Transplantation, Edouard Herriot Hospital, Lyon, France.;Department of Dermatology, Edouard Herriot Hospital, Lyon, France.",
"authors": "Morelon|Emmanuel|E|;Petruzzo|Palmina|P|;Kanitakis|Jean|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MOT.0000000000000571",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2418",
"issue": "23(5)",
"journal": "Current opinion in organ transplantation",
"keywords": null,
"medline_ta": "Curr Opin Organ Transplant",
"mesh_terms": "D006084:Graft Rejection; D006801:Humans; D063986:Vascularized Composite Allotransplantation",
"nlm_unique_id": "9717388",
"other_id": null,
"pages": "582-591",
"pmc": null,
"pmid": "30102615",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Chronic rejection in vascularized composite allotransplantation.",
"title_normalized": "chronic rejection in vascularized composite allotransplantation"
} | [
{
"companynumb": "FR-ASTELLAS-2016US030693",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nTo evaluate the risks and benefits of endoscopic submucosal dissection (ESD) in addition to chemoradiotherapy (CRT) for the treatment of superficial esophageal squamous cell carcinoma (SESCC).\n\n\nMETHODS\nWe retrospectively reviewed the treatment outcomes of 47 patients with SESCC treated between October 2000 and December 2011. Sixteen patients with invasion into the submucosal layer (T1b) or the muscularis mucosa (m3) with positive vascular invasion were treated with CRT after ESD (ESD-CRT group). The lymph node area was irradiated to a total dose of 40-44 Gy and a boost radiation was administered if PET-positive lymph nodes or positive margins were observed. The remaining 31 patients received definitive CRT only (dCRT group).\n\n\nRESULTS\nThe radiation field was significantly larger in the ESD-CRT group; the \"long T\" was used in 11 patients (35.4%) in the dCRT group and 15 (93.7%) in the ESD-CRT group (p = 0.0001). The total radiation dose was smaller in the ESD-CRT group; 40 Gy was used in 10 patients (62.5%) in the ESD-CRT group and all but one patient in the dCRT group received ≥60 Gy (p = 0.00001). The 3-year overall survival rates in the dCRT and ESD-CRT groups were 63.2% and 90.0% respectively (p = 0.118). Recurrence developed in nine patients (29.0%) in the dCRT group and one (6.3%) in the ESD-CRT group. Local recurrence was observed in six patients (19%) in the dCRT group and none in the ESD-CRT-group (p = 0.029). Pericardial effusion (≥Grade 3) occurred in three patients (9.7%) in the dCRT group and none in the ESD-CRT group.\n\n\nCONCLUSIONS\nESD followed by CRT is an effective and safe approach for SESCC at m3 or T1b. This combination of ESD and CRT improves the local control rate, and it could decrease the number of cardiac toxicities due to a radiation-dose reduction relative to CRT alone.",
"affiliations": "Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. gen-kawa@umin.ac.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. rsasa@clg.niigata-u.ac.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. eabe@med.niigata-u.ac.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. ao4854@gmail.com.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. spt34r29@space.ocn.ne.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. ktanaka510218@gmail.com.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. kmaruyam@med.niigata-u.ac.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. kaidu@med.niigata-u.ac.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. ayukawa@yahoo.co.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. n-yamana0713@ma.tlp.ne.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. junyangl@163.com.;Departments of Gastroenterology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. yasuzuka2000@yahoo.co.jp.;Departments of Gastroenterology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. masakoba@med.niigata-u.ac.jp.;Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata, Japan. h-aoyama@med.niigata-u.ac.jp.",
"authors": "Kawaguchi|Gen|G|;Sasamoto|Ryuta|R|;Abe|Eisuke|E|;Ohta|Atsushi|A|;Sato|Hiraku|H|;Tanaka|Kensuke|K|;Maruyama|Katsuya|K|;Kaizu|Motoki|M|;Ayukawa|Fumio|F|;Yamana|Nobuko|N|;Liu|Junyang|J|;Takeuchi|Manabu|M|;Kobayashi|Masaaki|M|;Aoyama|Hidefumi|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13014-015-0337-4",
"fulltext": "\n==== Front\nRadiat OncolRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central London 2563683033710.1186/s13014-015-0337-4ResearchThe effectiveness of endoscopic submucosal dissection followed by chemoradiotherapy for superficial esophageal cancer Kawaguchi Gen gen-kawa@umin.ac.jp Sasamoto Ryuta rsasa@clg.niigata-u.ac.jp Abe Eisuke eabe@med.niigata-u.ac.jp Ohta Atsushi ao4854@gmail.com Sato Hiraku spt34r29@space.ocn.ne.jp Tanaka Kensuke ktanaka510218@gmail.com Maruyama Katsuya kmaruyam@med.niigata-u.ac.jp Kaizu Motoki kaidu@med.niigata-u.ac.jp Ayukawa Fumio ayukawa@yahoo.co.jp Yamana Nobuko n-yamana0713@ma.tlp.ne.jp Liu Junyang junyangl@163.com Takeuchi Manabu yasuzuka2000@yahoo.co.jp Kobayashi Masaaki masakoba@med.niigata-u.ac.jp Aoyama Hidefumi h-aoyama@med.niigata-u.ac.jp Departments of Radiation Oncology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata Japan Departments of Gastroenterology, Niigata University Medical and Dental Hospital, Asahimachi-dori, Chuo-ku, Niigata Japan 31 1 2015 31 1 2015 2015 10 3115 9 2014 21 1 2015 © Kawaguchi et al.; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTo evaluate the risks and benefits of endoscopic submucosal dissection (ESD) in addition to chemoradiotherapy (CRT) for the treatment of superficial esophageal squamous cell carcinoma (SESCC).\n\nMethods and materials\nWe retrospectively reviewed the treatment outcomes of 47 patients with SESCC treated between October 2000 and December 2011. Sixteen patients with invasion into the submucosal layer (T1b) or the muscularis mucosa (m3) with positive vascular invasion were treated with CRT after ESD (ESD-CRT group). The lymph node area was irradiated to a total dose of 40–44 Gy and a boost radiation was administered if PET-positive lymph nodes or positive margins were observed. The remaining 31 patients received definitive CRT only (dCRT group).\n\nResults\nThe radiation field was significantly larger in the ESD-CRT group; the “long T” was used in 11 patients (35.4%) in the dCRT group and 15 (93.7%) in the ESD-CRT group (p = 0.0001). The total radiation dose was smaller in the ESD-CRT group; 40 Gy was used in 10 patients (62.5%) in the ESD-CRT group and all but one patient in the dCRT group received ≥60 Gy (p = 0.00001). The 3-year overall survival rates in the dCRT and ESD-CRT groups were 63.2% and 90.0% respectively (p = 0.118). Recurrence developed in nine patients (29.0%) in the dCRT group and one (6.3%) in the ESD-CRT group. Local recurrence was observed in six patients (19%) in the dCRT group and none in the ESD-CRT-group (p = 0.029). Pericardial effusion (≥Grade 3) occurred in three patients (9.7%) in the dCRT group and none in the ESD-CRT group.\n\nConclusions\nESD followed by CRT is an effective and safe approach for SESCC at m3 or T1b. This combination of ESD and CRT improves the local control rate, and it could decrease the number of cardiac toxicities due to a radiation-dose reduction relative to CRT alone.\n\nKeywords\nSuperficial esophageal cancerEndoscopic submucosal dissectionChemoradiotherapyCombinationPericardial effusionissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nDue to the development of endoscopic methods of diagnosis, the frequency of the detection of superficial esophageal carcinoma has increased relative to the frequency of the detection of esophageal squamous-cell carcinoma of all stages [1]. Radical surgery with extended lymph node dissection has been the main method used for treating patients with clinical stage I esophageal cancer with submucosal invasion (T1b). Although the survival rate of patients with submucosal tumors treated surgically at 3 years is over 80%, esophagectomy is highly invasive and associated with increased morbidity and mortality [2,3]. Definitive chemoradiotherapy (dCRT) has become one of the less invasive alternative modalities [4]. Although the overall survival afforded by dCRT is comparable that of surgery, its higher risk of locoregional progression compared to surgery remains a problem [5].\n\nEndoscopic submucosal dissection (ESD) is an advanced form of endoscopic mucosal resection (EMR) that enables the removal of larger epithelial neoplasms in an en bloc manner for complete resection, allowing detailed investigations of the depth of invasion [6]. ESD is widely used to treat superficial esophageal squamous cell carcinomas (SESCCs) that are confined to the lamina propria mucosae (T1a); however, the indications for ESD has expanded to tumors that have invasion to muscularis mucosa (m3) or submucosa (T1b) [7]. Despite the excellent local tumor control after ESD, a potential shortcoming of ESD-alone treatment for m3 or T1b tumors is its high accompanying frequency of lymph node metastasis.\n\nIt is well known that if the invasion of a tumor is limited to the lamina propria mucosae (m2), the risk of lymph node recurrence is extremely low. However, if the tumor invades deeper than the muscularis mucosa or pathology results show lymphovascular invasion, the rate of subsequent lymph node recurrence jumps to 10%–50% depending on the depth of invasion [8-10]. Therefore, ESD alone cannot be considered curative. In order to prevent locoregional progression after ESD for m3 or T1b tumors, adjuvant chemoradiotherapy (CRT) might be effective. Herein, we report the treatment outcomes from our initial experience with this treatment approach.\n\nSubjects and methods\nThe subjects were 47 consecutive patients with Stage I (UICC 7th) primary SESCCs who underwent CRT in our hospital between February 2000 and December 2011. Sixteen patients underwent CRT after ESD because their pathology reports indicated invasion to the muscularis mucosa (m3) or deeper (T1b) with or without lymphovascular invasion. These 16 patients constitute the ESD-CRT group.\n\nSix patients underwent dCRT only because ESD was not available in our institution before 2003, and the remaining 25 patients received dCRT only due to the suspicion of submucosal invasion (T1b) or the massive degree of extension in the circumference or longitudinal direction on their endoscopic ultrasound (EUS)-based diagnosis. These 31 patients constitute the dCRT-group. Written informed consent to the treatment was obtained from all patients. This study was approved by the Institutional Review Board of Niigata University Hospital (IRB number 1881).\n\nChemoradiotherapy (CRT)\nRadiation therapy planning was carried out with a computed tomography (CT)-simulator and radiation treatment planning system: the Eclipse ver. 8.9 (Varian Medical Systems, Palo Alto, CA, USA) or the Focus ver. 3.0.0 or XiO ver. 4.40 (Elekta, Stockholm, Sweden) or the Pinnacle ver. 7.4 (Philips, Eindhoven, The Netherlands). Inhomogeneity correction was applied in all cases.\n\nIn the initial plan, the clinical target volume (CTV) included the bilateral supraclavicular and the mediastinal lymph nodes regions to bifurcation of the trachea for cervical esophageal cancers, so called “Short T” field. And the bilateral supraclavicular, all of the mediastinal, the lesser curvature, and the celiac axis lymph nodes regions were included for thoracic cancers, so called “Long T” field. For the primary tumor sites in the boost plan, the CTV margin was 2 cm in superior and inferior directions, and 0.5 cm in the other directions beyond the borders of the gross tumor volume (GTV). For the lymph node metastasis, the CTV margin was 0.5 cm uniformly. The planning target volume (PTV) was generated by using 1.0 to 1.5 cm expansion in superior and inferior directions, and 0.5 cm expansion in the other directions beyond the borders of the CTV in the initial and boost plans. The prescription dose of the initial plan was 40 Gy in 20 fractions except for one patient who received 44 Gy in 22 fractions. The sites of positive margin in the ESD-CRT group, primary tumor sites in the dCRT group, and 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET)-positive lymph nodes were irradiated to the total dose of 60 to 66 Gy in the boost plans.\n\nThe regimen of chemotherapy was as follows: standard-dose FP (CDDP 70 mg/m2, day 1, 5-FU 700 mg/m2 days 1–4, every 4 weeks) for patients <70 years old, Low-dose-FP (CDDP 3–4 mg/m2 and 5-FU 200–250 mg/m2 for all radiation treatment days) for patients aged 70–74 years, and low-dose-5-FU (250 mg/m2 for all radiation treatment days) for patients ≥75 years old. If the patient’s creatinine clearance was less than 60 mL/min, nedaplatin was used instead of CDDP.\n\nStatistics\nWe analyzed the patients’ data regarding initial response, pattern of recurrence, toxicities, and overall survival. Toxicities were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Welch’s t-test was used for the statistical analyses of age, observation period and radiation dose. Fisher’s exact probability test was used for the analyses of gender and adverse events. Mann-Whitney’s U-test was used for the analyses of tumor location, tumor depth, radiation field and chemotherapy. The survival rates and the locoregional tumor control rate were examined using the Kaplan-Meier method, with statistical significance assessed by the log-rank test. Survival rates were calculated from the initiation of CRT. Any recurrence and any death were counted as an event in the disease free survival (DFS). Death owing to the esophageal cancer or the adverse events was counted as an event in the cause-specific survival (CSS). P-values <0.05 were considered significant.\n\nResults\nPatients and treatment\nThe background and treatments of the dCRT and ESD-CRT groups are summarized in Table 1. No significant between-group difference was seen in the location of tumor or the depth of invasion. With respect to the radiation field, the long T was used in 11 patients (35.4%) in the dCRT group and 15 (93.7%) in the ESD-CRT group (p = 0.0001). The total dose was 40 Gy in 10 patients (62.5%) in the ESD-CRT group. In contrast, all but one of the 31 patients in the dCRT group received ≥60 Gy (p = 0.00001).Table 1 \nBackground and treatments of the 47 patients\n\n\n\t\ndCRT\n\t\nESD-CRT\n\t\np\n-value\n\t\nPatients\tn = 31\tn = 16\t\t\nAge (median)\t33–80 (68)\t42–77 (65)\t0.31\t\nGender (male:female)\t25:6\t15:1\t0.229\t\nObservation period (median)\t2.5–93.1 (34.2)\t6.5–78.4 (39.0)\t0.682\t\nLocation\t\t\t0.959\t\n Cervical\t2\t0\t\t\n Upper thoracic\t1\t1\t\t\n Middle thoracic\t18\t10\t\t\nLower thoracic\t10\t5\t\t\nTumor depth\t\t\t\t\n\tM3: 3\tM3: 2\t0.297\t\n\tSM1: 15\tSM1: 4\t\t\n\tSM2: 13\tSM2: 10\t\t\nRadiation field\t\t\t\t\n Long T\t11\t15\t0.0001\t\n Short T\t3\t1\t\t\n Local\t17\t0\t\t\nRadiation dose (Gy)\t\t\t\t\n 40 (−44)\t0\t10\t0.00001\t\n 54\t1\t0\t\t\n 60\t13\t6\t\t\n 60<\t17\t0\t\t\nChemotherapy\t\t\t\t\n Standard-dose FP\t12\t10\t0.046\t\n Low-dose FP\t6\t4\t\t\n Low-dose 5-FU\t9\t2\t\t\n Others\t4\t0\t\t\n\nAbbreviations: dCRT definitive chemoradiotherapy, ESD-CRT endoscopic submucosal dissection + chemoradiotherapy.\n\n\n\nRegarding the regimen of chemotherapy, the standard-dose FP regimen was used significantly more frequently in the ESD-CRT group (10/16, 62.5%) than in the dCRT group (12/31, 38.7%) (p = 0.046). The observation period was 2.5–93.1 mos (median 34.2 mos) in the dCRT group and 6.5–78.4 mos (median 39.0 mos) in the ESD-CRT group (p = 0.68).\n\nSurvival\nFor both groups combined, the 3-year overall survival rate was 71.6% (95% confidence interval [CI] 57.2%–86.1%). In the dCRT group, the 3-year overall survival rate was 63.2% (95% CI 44.8%–81.6%), and that in the ESD-CRT group was 90% (95% CI 71.4–100%) (p = 0.118) (Figure 1). The 3-year DFS rates were 63.1% (95% CI 48.0%–78.2%) in both groups included, 54.2% (95% CI 35.6%–72.8%) in the dCRT group and 82.1% (95% CI 59.1%–100%) in the ESD-CRT group (p = 0.116). The 3-year CSS rates were 79.2% (95% CI 66.0%–92.3%) in both groups included, 79.8% (95% CI 63.6%–96.1%) in the dCRT group and 90% (95% CI 71.4%–100%) in the ESD-CRT group (p = 0.578). The causes of death in the dCRT group were attributed to primary cancer in three patients, treatment-related adverse events in three, and other causes in six. No patients in the ESD-CRT group died of cancer, and two patients died of myocardial infarction.Figure 1 \nThe overall survival rates of the ESD-CRT (n = 16) and dCRT (n = 31) patients. ESD-CRT: endoscopic submucosal dissection + chemoradiotherapy; dCRT: definitive chemoradiotherapy. The 3-year overall survival rate of the dCRT group (63.2%) was lower but not significantly different (p = 0.118) from that of the ESD-CRT group (90.0%).\n\n\n\nTumor control and pattern of recurrences\nIn the dCRT group, the initial tumor response was a complete response (CR) in all but one patient, who showed a partial response (PR). Tumor recurrence developed in nine patients (29.0%) in the dCRT group and one patient (6.2%) in the ESD-CRT group. The pattern of recurrence is summarized in Table 2. Local recurrence was predominant in the dCRT group (6/9, 66.7%), whereas there were no case of local recurrence in the ESD-CRT group (p = 0.029). Lymph node metastases outside of the radiation field developed in one patient in each group. Distant metastases developed in 2 patients who belonged to the dCRT group but none in the ESD-CRT group. The 3-year locoregional tumor control rates of 80.1% (95% CI 67.5%–92.4%) for the combined groups, 73.3% (95% CI 56.2%–90.3%) in the dCRT group and 92.3% (95% CI: 77.8%–100%) in the ESD-CRT group (p = 0.152) (Figure 2).Table 2 \nRecurrence patterns and salvage therapies\n\n\n\nGroup\n\t\nRadiation field Chemotherapy\n\t\nRecurrence time\n\t\nRecurrence area\n\t\nSalvage therapy\n\t\nOutcome Observation period\n\t\ndCRT\tLocal\t6 mos\tThoracic vertebrae\tNo therapy\tDeath from cancer\t\nLow-dose FP\t8.3 mos\t\ndCRT\tLocal\t15.2 mos\tLocal\tArgon plasma\tDeath from cancer\t\nLow-dose 5-FU\tCoagulation\t34.2 mos\t\ndCRT\tLocal\t8.7 mos\tLocal\tSurgery\tDeath from other cause\t\nSt-dose FP\t18.1 mos\t\ndCRT\tLong T\t11.2 mos\tLocal\tESD\tNo evidence of recurrence\t\nLow-dose FP\t85.9 mos\t\ndCRT\tLocal\t11.2 mos\tLN\tRadiation\tDeath from other cause\t\nSt-dose FP\t(Out of field)\t19.3 mos\t\ndCRT\tLong T\t0 month\tLocal\tESD\tTreatment-related death\t\nSt-dose FP\t28.2 mos\t\ndCRT\tShort T\t9.2 mos\tLocal\tSurgery\tDeath from other cause\t\nSt-dose FP\t29.4 mos\t\ndCRT\tLocal\t16.5 mos\tLocal\tESD\tAlive with cancer\t\nLow-dose 5-FU\t21.7 mos\t\ndCRT\tLong T\tUnknown\tCarcinomatous\tNo therapy\tDeath from cancer\t\nLow-dose 5-FU\tpericarditis\t46.5 mos\t\nESD-CRT\tLong T\t14.4 mos\tLN\tSurgery\tNo evidence of recurrence\t\nSt-dose FP\t(Out of field)\t68.9 mos\t\n\nAbbreviations: ESD endoscopic submucosal dissection, FP 5-FU + CDDP, St-dose standard-dose, LN lymph node.\n\nFigure 2 \nLocoregional tumor control rates of the ESD-CRT and dCRT groups. The 3-year locoregional tumor control rates of the dCRT group (73.3%) was lower but not significantly different from that of the ESD-CRT group (92.3%; p = 0.152).\n\n\n\nToxicities\nThe adverse events are summarized in Table 3. Radiation pneumonitis (≥Grade 3) developed in two patients in the dCRT group and none in the ESD-CRT group (p = 0.43). Pericardial effusion (≥Grade 3) occurred in three patients in the dCRT group and none in the ESD-CRT group (p = 0.277). Esophageal stricture (≥Grade 3) appeared in one patient (3%) and four patients (25%) in the dCRT and ESD-CRT groups, respectively (p = 0.040).Table 3 \nAdverse events* in the dCRT group and the ESD + CRT group\n\n\n\nAdverse event ≥ G3\n\t\ndCRT\n\t\nESD-CRT\n\t\np\n-value\n\t\nLeukopenia\t13 (41.9%)\t4 (25%)\t0.206\t\nAnemia\t2 (6.5%)\t–\t0.43\t\nThrombocytopenia\t1 (3.2%)\t–\t0.66\t\nEsophagitis\t3 (9.7%)\t2 (12.5%)\t0.264\t\nNausea\t1 (3.2%)\t3 (18.8%)\t0.108\t\nPneumonia\t2 (6.5%)\t–\t0.43\t\n\tGrade 5: 1\t\t\t\nGastric ulcer\t1 (3.2%)\t–\t0.66\t\n\tGrade 5: 1\t\t\t\nEsophageal stenosis\t1 (3.2%)\t4 (25%)\t0.04\t\nPericardial effusion\t3 (9.7%)\t–\t0.277\t\n\tGrade 5: 1\t\t\t\nMyocardial infarction\t–\tGrade5: 2\t0.111\t\nTotal of grade 5\t3\t2\t0.42\t\n*Adverse events ≥ G3 in NCI-CTCAE ver.4.0.\n\n\n\nDiscussion\nDefinitive CRT has become one of the less invasive treatment options compared to surgery for SESCC. In a Japanese Phase II trial (JCOG9708), it was found that the survival after dCRT was comparable to survival following surgery in stage I disease, with a 4-year survival rate of 80.5% [4]. However, 21 of 72 patients showed local relapses that needed salvage treatment. Yamamoto et al. retrospectively compared treatment outcomes between dCRT and esophagectomy in patients with clinical stage I esophageal squamous cell carcinoma. Although the overall survival of the dCRT group was comparable with the hazard ratio of 0.95, the incidence of local recurrence in the dCRT group was significantly higher than that in the esophagectomy group (p < 0.0001) [11]. Therefore the local tumor control remains the biggest problem of the dCRT.\n\nA potential solution could be the use of EMR or ESD before CRT [12,13]. The local control rates of ESD are reported to be over 95% [7], although the frequency of lymph node metastases is not negligible for m3 and T1b cases. Therefore, the combination therapy of ESD and CRT might offset their shortcomings and be less invasive than a surgical approach. Shimizu et al. reported that after EMR combined with CRT to a total dose of 40 to 46 Gy for 16 patients with SESCCs invading the muscularis mucosa or upper submucosa, no local or distant metastasis was observed [13].\n\nIn the present study, no local tumor recurrence or in-field lymph node recurrence occurred among the patients who underwent CRT of 40 Gy in 20 fractions after ESD for m3 or T1b SESCCs. The tumor recurrence was significantly less frequent in the ESD-CRT group (6.2%, 1/16) than in the dCRT group (29.0%, 9/31). Especially, no local recurrence was observed in the ESD-CRT group compared to 19.3% (6/31) in the dCRT group.\n\nIn regard to the toxicities, it is noteworthy that symptomatic radiation-induced pericardial effusion (PCE) developed only in patients in the dCRT group (9.7%). PCE is not unusual and is potentially life-threatening, hence this is one of the most important toxicities. Wei et al. reported that when V30 of the pericardium was greater than 46% versus less than or equal to 46%, the rate of PCE at 18 mos post-therapy was 73% versus 13%, respectively (p = 0.001) [14]. Martel et al. demonstrated that both an average dose > 27.1 Gy (p = 0.014) and a maximum dose > 47.0 Gy (p = 0.014) have a significant relationship with the incidence of PCE [15]. Fukada et al. reported that the incidence of symptomatic PCE was significantly higher in the patients who received a mean pericardial dose exceeding 36.5 Gy (p < 0.0001) [16]. In the present study, a significant dose reduction could be achieved in the ESD-CRT group compared to the dCRT group, although the treatment field was significantly larger. The decrease of the rate of PCE in our ESD-CRT group compared to the dCRT group would thus be explained by the dose reduction achieved in the ESD-CRT group. Regarding the esophageal stricture, it appeared in four patients (25%) in the ESD-CRT groups. However, three of four patients had a stricture under the influence of ESD before CRT and did not worsen after CRT.\n\nThe present study has several limitations. The study design was not a randomized assignment, the sample size was small, and the treatment indications for the dCRT group were different from those of the ESD-CRT group. The difference in indications between the two treatments might have affected the local control rate in that the outcome of the dCRT group was worse than that of the ESD-CRT group, but in-field lymph node recurrences were prevented well in both groups.\n\nConclusions\nOur results suggest that CRT after ESD is an effective and safe approach for patients with SESCC invading the m3 or T1b. If the patient’s case meets the indications for ESD, this combination treatment should be actively considered because performing ESD before CRT improves the local control rate, and doing so can decrease the number of cardiac toxicities due to a radiation-dose reduction relative to CRT alone.\n\nGen Kawaguchi and Hidefumi Aoyama contributed equally to this work.\n\nCompeting interests\n\nThe authors declare that they have no competing interests. This study was partially supported by Niigata University Hospital Clinical Research Support Project (H.A.).\n\nAuthors’ contributions\n\nAll authors were involved in the treatment of the included patients. All authors reviewed and approved the final manuscript.\n\nAcknowledgement\nPart of this study was reported at the 55th Annual Meeting of the American Society of Radiation Oncology (ASTRO), Atlanta, GA, USA on September 22nd, 2013.\n==== Refs\nReferences\n1. Tachimori Y Ozawa S Fujishiro M Matsubara H Numasaki H Oyama T Comprehensive registry of esophageal cancer in Japan, 2006 Esophagus 2014 11 21 47 10.1007/s10388-013-0393-5 \n2. Griffin SM Shaw IH Dresner SM Early complications after Ivor Lewis subtotal esophagectomy with two-field lymphadenectomy: Risk factors and management J Am Coll Surg 2002 194 285 97 10.1016/S1072-7515(01)01177-2 11893132 \n3. Tachibana M Kinugasa S Yoshimura H Shibakita M Tonomoto Y Dhar DK Clinical outcomes of extended esophagectomy with three-field lymph node dissection for esophageal squamous cell carcinoma Am J Surg 2005 189 98 109 10.1016/j.amjsurg.2004.10.001 15701501 \n4. Kato H Sato A Fukuda H Kagami Y Udagawa H Togo A A phase II trial of chemoradiotherapy for stage I esophageal squamous cell carcinoma: Japan Clinical Oncology Group Study (JCOG9708) Jpn J Clin Oncol 2009 39 638 43 10.1093/jjco/hyp069 19549720 \n5. Motoori M Yano M Ishihara R Yamamoto S Kawaguchi Y Tanaka K Comparison between radical esophagectomy and definitive chemoradiotherapy in patients with clinical T1bN0M0 esophageal cancer Ann Surg Oncol 2012 19 2135 41 10.1245/s10434-012-2231-8 22302264 \n6. Oyama T Tomori A Hotta K Morita S Kominato K Tanaka M Endoscopic submucosal dissection of early esophageal cancer Clin Gastroenterol Hepatol 2005 3 S67 70 10.1016/S1542-3565(05)00291-0 16013002 \n7. Honda K Akiho H Endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms World J Gastrointest Pathophysiol 2012 3 44 50 10.4291/wjgp.v3.i2.44 22532931 \n8. Akutsu Y Uesato M Shuto K Kono T Hoshino I Horibe D The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: A retrospective analysis of 295 patients Ann Surg 2013 257 1032 8 10.1097/SLA.0b013e31827017fc 23108117 \n9. Takubo K Aida J Sawabe M Kurosumi M Arima M Fujishiro M Early squamous cell carcinoma of the oesophagus: The Japanese viewpoint Histopathology 2007 51 733 42 10.1111/j.1365-2559.2007.02766.x 17617215 \n10. Ancona E Rampado S Cassaro M Battaglia G Ruol A Castoro C Prediction of lymph node status in superficial esophageal carcinoma Ann Surg Oncol 2008 15 3278 88 10.1245/s10434-008-0065-1 18726651 \n11. Yamamoto S Ishihara R Motoori M Kawaguchi Y Uedo N Takeuchi Y Comparison between definitive chemoradiotherapy and esophagectomy in patients with clinical stage I esophageal squamous cell carcinoma Am J Gastroenterol 2011 106 1048 54 10.1038/ajg.2011.42 21343920 \n12. Kurokawa Y Muto M Minashi K Boku N Fukuda H Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group A phase II trial of combined treatment of endoscopic mucosal resection and chemoradiotherapy for clinical stage I esophageal carcinoma: Japan Clinical Oncology Group Study JCOG0508 Jpn J Clin Oncol 2009 39 686 9 10.1093/jjco/hyp078 19703839 \n13. Shimizu Y Kato M Yamamoto J Nakagawa S Tsukagoshi H Fujita M Emr combined with chemoradiotherapy: a novel treatment for superficial esophageal squamous-cell carcinoma Gastrointestinal Endosc 2004 59 199 204 10.1016/S0016-5107(03)02688-9 \n14. Wei X Liu HH Tucker SL Wang S Mohan R Cox JD Risk factors for pericardial effusion in inoperable esophageal cancer patients treated with definitive chemoradiation therapy Int J Radiat Oncol Biol Phys 2008 70 707 14 10.1016/j.ijrobp.2007.10.056 18191334 \n15. Martel MK Sahijdak WM Ten Haken RK Kessler ML Turrisi AT Fraction size and dose parameters related to the incidence of pericardial effusions Int J Radiat Oncol Biol Phys 1998 40 155 61 10.1016/S0360-3016(97)00584-1 9422572 \n16. Fukada J Shigematsu N Takeuchi H Ohashi T Saikawa Y Takaishi H Symptomatic pericardial effusion after chemoradiation therapy in esophageal cancer patients Int J Radiat Oncol Biol Phys 2013 87 487 93 10.1016/j.ijrobp.2013.07.008 23968770\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1748-717X",
"issue": "10()",
"journal": "Radiation oncology (London, England)",
"keywords": null,
"medline_ta": "Radiat Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D003131:Combined Modality Therapy; D004210:Dissection; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D004945:Esophagoscopy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D011879:Radiotherapy Dosage; D050397:Radiotherapy, Intensity-Modulated; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101265111",
"other_id": null,
"pages": "31",
"pmc": null,
"pmid": "25636830",
"pubdate": "2015-01-31",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16013002;14745392;21343920;22532931;17617215;15701501;19703839;23108117;18191334;11893132;9422572;23968770;19549720;22302264;18726651",
"title": "The effectiveness of endoscopic submucosal dissection followed by chemoradiotherapy for superficial esophageal cancer.",
"title_normalized": "the effectiveness of endoscopic submucosal dissection followed by chemoradiotherapy for superficial esophageal cancer"
} | [
{
"companynumb": "JP-BAUSCH-BL-2015-010497",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "A cost-effective alternative approach capable of determining the prevalence of substance use in communities can complement the existing efforts of combating drug abuse and addiction. In this study, the prevalence of 10 illicit and 19 prescribed psychoactive drugs of potential abuse was determined utilizing wastewater-based epidemiology, and compared in two adjoined urban communities and a rural community. This is the first application of the Monte Carlo simulation method to account multiple uncertainties and propagation of errors associated with the individual parameter of wastewater based epidemiological estimations in the U.S. A significantly higher prevalence of cocaine [3830 (mean difference, MD: 2960) mg/d/1000 people] was found in the central business district while the per-capita consumption rates of amphetamine [738 (MD: 338) mg/d/1000 people] and methamphetamine [1660 (MD: 629) mg/d/1000 people] were higher in a rural community. Among narcotics, the per-capita consumption rate of fentanyl and morphine was significantly higher in urban communities while codeine, hydrocodone, hydromorphone, and buprenorphine were dominant in a rural community. The significantly higher prevalence of buprenorphine (˜20-30 folds), oxycodone (˜2-3 folds), and alprazolam (˜2-3 folds) determined in these communities compared to the conventional estimates based on the electronically reported prescriptions and drug-related inpatient hospitalizations suggest the abuse of these drugs.",
"affiliations": "Department of Chemistry, Murray State University, Murray, KY, United States.;Department of Chemistry, Murray State University, Murray, KY, United States.;Department of Mathematics and Statistics, Murray State University, Murray, KY, United States.;Department of Chemistry, Murray State University, Murray, KY, United States. Electronic address: bsubedi@murraystate.edu.",
"authors": "Croft|Tara L|TL|;Huffines|Rhiannon A|RA|;Pathak|Manoj|M|;Subedi|Bikram|B|",
"chemical_list": "D013287:Illicit Drugs; D011619:Psychotropic Drugs; D062065:Waste Water; D014874:Water Pollutants, Chemical",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jhazmat.2019.121306",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0304-3894",
"issue": "384()",
"journal": "Journal of hazardous materials",
"keywords": "Ammoniacal-nitrogen-based-population; Drug consumption; Illicit drugs; Monte Carlo simulation; Wastewater-based epidemiology",
"medline_ta": "J Hazard Mater",
"mesh_terms": "D006801:Humans; D013287:Illicit Drugs; D007629:Kentucky; D009010:Monte Carlo Method; D011619:Psychotropic Drugs; D012424:Rural Population; D019966:Substance-Related Disorders; D014505:Urban Population; D062065:Waste Water; D000079686:Wastewater-Based Epidemiological Monitoring; D014874:Water Pollutants, Chemical",
"nlm_unique_id": "9422688",
"other_id": null,
"pages": "121306",
"pmc": null,
"pmid": "31622847",
"pubdate": "2020-02-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28240866;29574368;30059885;31211480;22804833;26896168;26210032;28783904;24950813;24865581;24283359;21683444;21968350;28259433;30550910;29727969;30554870;30189576;24636801;22572562;23259772;21745676;22100367;22836098;27318754;29798668;29108696;28554112;21257204;28929740;27267725",
"title": "Prevalence of illicit and prescribed neuropsychiatric drugs in three communities in Kentucky using wastewater-based epidemiology and Monte Carlo simulation for the estimation of associated uncertainties.",
"title_normalized": "prevalence of illicit and prescribed neuropsychiatric drugs in three communities in kentucky using wastewater based epidemiology and monte carlo simulation for the estimation of associated uncertainties"
} | [
{
"companynumb": "US-OTSUKA-2019_036084",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "The number of new psychoactive substances (NPS) available is constantly increasing, making it difficult for toxicology laboratories to keep screening methods up to date. Full scan high-resolution mass spectrometry (HRMS) is a versatile technique which allows for progressive updating of spectral databases to increase the scope of screening. It also allows for retrospective screening of data-specifically, reprocessing of data files using an updated spectral database without the need for re-extraction or reanalysis.The coronial case reported here illustrates the application of retrospective processing of HRMS data in the detection of emerging NPS. A 28-year-old male with a history of illicit drug use was found deceased at home. Initial routine screening of the post-mortem peripheral blood identified only methylamphetamine, amphetamine and trace amounts of lorazepam. A compound with an accurate mass and isotope ratio consistent with the opioid AH-7921 was also detected in the liquid chromatography (LC)-HRMS screen; however; the retention time and mass spectrum did not match the library. Further investigation confirmed the compound to be U-47700, another opioid and structural isomer of AH-7921. Several months later, after additional NPS had been added to the in-house HRMS database, retrospective screening of the HRMS data was performed, revealing the presence of designer benzodiazepines, diclazepam and flubromazepam as well as the psychedelic drug 2,5-dimethoxy-4-chloroamphetamine (DOC). Quantitative analysis gave the following results in peripheral post-mortem blood: U-47700 (330 μg/L), diclazepam (70 μg/L), flubromazepam (10 μg/L), methylamphetamine (290 μg/L) and amphetamine (150 μg/L) (DOC not quantitated). These substances, along with lorazepam and etizolam, were also confirmed in the post-mortem urine and an investigation into blood and urinary metabolites was carried out. All analyses were performed using the same LC-quadrupole-time of flight method. The cause of death was aspiration (of gastric content into airways and lungs) due to mixed drug toxicity.",
"affiliations": "Forensic Science SA (Toxicology), Adelaide, South Australia, Australia.;Forensic Science SA (Toxicology), Adelaide, South Australia, Australia.;Forensic Science SA (Toxicology), Adelaide, South Australia, Australia.;Forensic Science SA (Toxicology), Adelaide, South Australia, Australia.;Forensic Science SA (Toxicology), Adelaide, South Australia, Australia.",
"authors": "Partridge|Emma|E|;Trobbiani|Stephen|S|;Stockham|Peter|P|;Charlwood|Cheryl|C|;Kostakis|Chris|C|",
"chemical_list": "D001549:Benzamides; D015198:Designer Drugs; D011619:Psychotropic Drugs; C000614521:U-47700; C020967:2-chlorodiazepam; D001569:Benzodiazepines; C000628386:flubromazolam; D003975:Diazepam",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bky039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "42(9)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D001549:Benzamides; D001569:Benzodiazepines; D015198:Designer Drugs; D003975:Diazepam; D053593:Forensic Toxicology; D006801:Humans; D013058:Mass Spectrometry; D011041:Poisoning; D011619:Psychotropic Drugs; D012015:Reference Standards; D015203:Reproducibility of Results; D012189:Retrospective Studies",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "655-660",
"pmc": null,
"pmid": "29945197",
"pubdate": "2018-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Case Study Involving U-47700, Diclazepam and Flubromazepam-Application of Retrospective Analysis of HRMS Data.",
"title_normalized": "a case study involving u 47700 diclazepam and flubromazepam application of retrospective analysis of hrms data"
} | [
{
"companynumb": "AU-BAUSCH-BL-2018-032756",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHAMPHETAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Inflammation of the appendix is one of the most common conditions requiring emergent surgical intervention. Computed tomography commonly demonstrates a dilated appendix with adjacent inflammation. Traditionally, luminal obstruction of the appendix has been thought to be the primary etiology of appendicitis. However, current evidence suggests that etiology of appendicitis is multifactorial and can involve a number of different pathogenic pathways. Here we present a case of acute eosinophilic appendicitis with radiologic-pathologic correlation from a hypersensitivity reaction pathway. Acute eosinophilic appendicitis may represent an early precursor to conventional acute suppurative (phlegmonous) appendicitis, or a variant form of acute appendicitis.",
"affiliations": "Department of Radiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.;Department of Radiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.;Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.;Department of Radiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. Electronic address: whangg@med.usc.edu.",
"authors": "Yaeger|Andrew A|AA|;Cheng|Phillip M|PM|;Tatishchev|Sergei|S|;Whang|Gilbert|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinimag.2018.06.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-7071",
"issue": "51()",
"journal": "Clinical imaging",
"keywords": "Abdominal pain; Allergy; Appendicitis; Computed tomography; Eosinophilia",
"medline_ta": "Clin Imaging",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D001064:Appendicitis; D001065:Appendix; D004802:Eosinophilia; D006801:Humans; D007249:Inflammation; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "337-340",
"pmc": null,
"pmid": "29960267",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute eosinophilic appendicitis: a radiologic-pathologic correlation.",
"title_normalized": "acute eosinophilic appendicitis a radiologic pathologic correlation"
} | [
{
"companynumb": "US-APOTEX-2018AP017706",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "Liver transplantation (LT) for patients with propionic acidemia (PA) is an emerging therapeutic option. We present a retrospective review of patients with PA who underwent LT at a tertiary liver center between 1995 and 2015. A total of 14 children were identified (8 males) with median age at initial presentation of 3 days (range, 0-77 days). Pretransplant median protein restriction was 1 g/kg/day (range, 0.63-1.75 g/kg/day), 71% required supportive feeding, and 86% had developmental delay. Frequent metabolic decompensations (MDs) were the main indication for LT with a median age at transplantation of 2.4 years (range, 0.8-7.1 years). Only 1 graft was from a living donor, and 13 were from deceased donors (4 auxiliary). The 2-year patient survival was 86%, and overall study and graft survival was 79% and 69%, respectively. Three patients died after LT: at 43 days (biliary peritonitis), 225 days (acute-on-chronic rejection with multiorgan failure), and 13.5 years (posttransplant lymphoproliferative disease). Plasma glycine and propionylcarnitine remained elevated but reduced after transplant. Of 11 survivors, 5 had at least 1 episode of acute cellular rejection, 2 sustained a metabolic stroke (with full recovery), and 3 developed mild cardiomyopathy after LT. All have liberalized protein intake, and 9 had no further MDs: median episodes before transplant, 4 (range, 1-30); and median episodes after transplant, 0 (range, 0-5). All survivors made some developmental progress after LT, and none worsened at a median follow-up of 5.8 years (range, 2-23 years). LT in PA significantly reduces the frequency of MDs, can liberalize protein intake and improve quality of life, and should continue to be considered in selected cases.",
"affiliations": "Paediatric Inherited Metabolic Diseases, Evelina Children's Hospital, London, United Kingdom.;Liver Transplantation Surgery, Institute for Liver Studies, King's College Hospital, London, United Kingdom.;Liver Transplantation Surgery, Institute for Liver Studies, King's College Hospital, London, United Kingdom.;Paediatric Liver, Gastroenterology and Nutrition Centre, King's College Hospital, London, United Kingdom.;Paediatric Liver, Gastroenterology and Nutrition Centre, King's College Hospital, London, United Kingdom.;Paediatric Inherited Metabolic Diseases, Evelina Children's Hospital, London, United Kingdom.",
"authors": "Curnock|Richard|R|;Heaton|Nigel D|ND|;Vilca-Melendez|Hector|H|;Dhawan|Anil|A|;Hadzic|Nedim|N|;Vara|Roshni|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/lt.25679",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "26(3)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D056693:Propionic Acidemia; D011788:Quality of Life; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "419-430",
"pmc": null,
"pmid": "31715057",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Liver Transplantation in Children With Propionic Acidemia: Medium-Term Outcomes.",
"title_normalized": "liver transplantation in children with propionic acidemia medium term outcomes"
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"abstract": "In the large Zika virus (ZIKV) epidemic that occurred in Brazil in 2015, the intrauterine fetal exposure to ZIKV was associated with a significant risk of developing microcephaly and neurological disorders in the infected infants. ZIKV-associated disease has since been reported in 24 countries in the Americas. At present, definitive evidence is lacking regarding the intrauterine co-exposure to ZIKV and other viral infections and whether the coinfection impacts the risk of acquiring either infection or disease severity. Here, we provide evidence of intrauterine exposure to both ZIKV and human immunodeficiency virus (HIV) infections, causing congenital Zika syndrome in an HIV-exposed uninfected infant. Clinical, imaging and laboratory examinations of the pregnant woman and the newborn were performed. Histopathology, ZIKV/HIV-specific immunoassays, and ultrastructural evaluation of the placenta were performed. The Zika-asymptomatic, HIV-positive pregnant woman underwent ultrasounds revealing fetal cerebral ventriculomegaly, microcephaly, and brain atrophy. Her baby girl was born small for gestational age and with the neurological sequelae of congenital Zika syndrome. The evaluation of the abnormally large term placenta revealed severe damage to the maternal decidua and chorionic villi, cells positive for ZIKV-specific antigens but not for HIV antigens, and intracellular membranous clusters of virus-like particles approximately 25 nm in diameter. The rapid progression and severity of the congenital Zika syndrome may be related to the uncontrolled HIV disease in the mother. The poor inflammatory response observed in the placenta may have reduced the inherent risk of mother-to-child transmission of HIV.",
"affiliations": "Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.;Faculdade de Medicina de Campos, Campos dos Goytacazes, Brazil.;Faculdade de Medicina de Campos, Campos dos Goytacazes, Brazil.;Faculdade de Medicina de Campos, Campos dos Goytacazes, Brazil.;Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.;Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.;Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.;Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.;Laboratório de Tecnologia Virológica, Biomanguinhos, Rio de Janeiro, Brazil.;Anatomia Patológica, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.;Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.;Laboratório de Biotecnologia, Universidade Estadual do Norte Fluminense, Campos dos Goytacazes, Brazil.;Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.",
"authors": "Rabelo|Kíssila|K|;de Souza Campos Fernandes|Regina Célia|RC|;de Souza|Luiz José|LJ|;Louvain de Souza|Thais|T|;Dos Santos|Flávia Barreto|FB|;Guerra Nunes|Priscila Conrado|PC|;de Azeredo|Elzinandes Leal|EL|;Salomão|Natália Gedeão|NG|;Trindade|Gisela Freitas|GF|;Basílio-de-Oliveira|Carlos A|CA|;de Carvalho|Jorge José|JJ|;Medina-Acosta|Enrique|E|;Paes|Marciano Viana|MV|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2017.01704",
"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2017.01704ImmunologyCase ReportPlacental Histopathology and Clinical Presentation of Severe Congenital Zika Syndrome in a Human Immunodeficiency Virus-Exposed Uninfected Infant Rabelo Kíssila 1de Souza Campos Fernandes Regina Célia 23de Souza Luiz José 2Louvain de Souza Thais 23dos Santos Flávia Barreto 4Guerra Nunes Priscila Conrado 4de Azeredo Elzinandes Leal 4Salomão Natália Gedeão 5Trindade Gisela Freitas 6Basílio-de-Oliveira Carlos A. 7de Carvalho Jorge José 1Medina-Acosta Enrique 3*Paes Marciano Viana 5*1Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil2Faculdade de Medicina de Campos, Campos dos Goytacazes, Brazil3Laboratório de Biotecnologia, Universidade Estadual do Norte Fluminense, Campos dos Goytacazes, Brazil4Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil5Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil6Laboratório de Tecnologia Virológica, Biomanguinhos, Rio de Janeiro, Brazil7Anatomia Patológica, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, BrazilEdited by: Juarez Antonio Simões Quaresma, Universidade Federal do Pará, Brazil\n\nReviewed by: Sunil Joshi, Old Dominion University, United States; Yan Li, Experimental Therapeutics Centre (A*STAR), Singapore; Rajanish Giri, Indian Institute of Technology Mandi, India\n\n*Correspondence: Enrique Medina-Acosta, quique@uenf.br; Marciano Viana Paes, marciano@ioc.fiocruz.brSpecialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology\n\n07 12 2017 2017 8 170402 10 2017 20 11 2017 Copyright © 2017 Rabelo, de Souza Campos Fernandes, Souza, Louvain de Souza, Santos, Guerra Nunes, Azeredo, Salomão, Trindade, Basílio-de-Oliveira, Carvalho, Medina-Acosta and Paes.2017Rabelo, de Souza Campos Fernandes, Souza, Louvain de Souza, Santos, Guerra Nunes, Azeredo, Salomão, Trindade, Basílio-de-Oliveira, Carvalho, Medina-Acosta and PaesThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.In the large Zika virus (ZIKV) epidemic that occurred in Brazil in 2015, the intrauterine fetal exposure to ZIKV was associated with a significant risk of developing microcephaly and neurological disorders in the infected infants. ZIKV-associated disease has since been reported in 24 countries in the Americas. At present, definitive evidence is lacking regarding the intrauterine co-exposure to ZIKV and other viral infections and whether the coinfection impacts the risk of acquiring either infection or disease severity. Here, we provide evidence of intrauterine exposure to both ZIKV and human immunodeficiency virus (HIV) infections, causing congenital Zika syndrome in an HIV-exposed uninfected infant. Clinical, imaging and laboratory examinations of the pregnant woman and the newborn were performed. Histopathology, ZIKV/HIV-specific immunoassays, and ultrastructural evaluation of the placenta were performed. The Zika-asymptomatic, HIV-positive pregnant woman underwent ultrasounds revealing fetal cerebral ventriculomegaly, microcephaly, and brain atrophy. Her baby girl was born small for gestational age and with the neurological sequelae of congenital Zika syndrome. The evaluation of the abnormally large term placenta revealed severe damage to the maternal decidua and chorionic villi, cells positive for ZIKV-specific antigens but not for HIV antigens, and intracellular membranous clusters of virus-like particles approximately 25 nm in diameter. The rapid progression and severity of the congenital Zika syndrome may be related to the uncontrolled HIV disease in the mother. The poor inflammatory response observed in the placenta may have reduced the inherent risk of mother-to-child transmission of HIV.\n\nZika virusplacentacongenital Zika syndromehistopathologymicrocephalyhuman immunodeficiency virusFundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro10.13039/501100004586E-26/010.001.498/2016, E-26/110.511/2014\n==== Body\nIntroduction\nThe enveloped, positive-strand RNA Zika flavivirus (ZIKV) can be transmitted to humans through Aedes mosquito bites, from mother to child, by unprotected sexual intercourse and by blood transfusion (1). The transplacental transmission of ZIKV is highly neurotropic and teratogenic, resulting in severe congenital microcephaly and a broad spectrum of gross and microscopic neuropathologic abnormalities (2, 3). The estimated absolute risk of a notified microcephaly case varies from 0.03 to 17.1% depending on geographical area, the definition of microcephaly used and the ZIKV infection rate (4).\n\nThe ZIKV particle is approximately 25–30 nm and shares many structural similarities with other flaviviruses such as Dengue, West Nile, Japanese encephalitis, and Yellow Fever (5). Its viral genome encodes a polyprotein precursor that is processed into the structural proteins [capsid (C), pre-membrane (prM), and envelope (E)] and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (6). The human immunodeficiency virus (HIV), which belongs to the Retroviridae family, features two distinct genotypes, HIV-1 and HIV-2. HIV particles are approximately 120 nm in size and contain two single-stranded RNA copies of 9.2 kb (7).\n\nWithin less than 2 years from the emergence of an epidemic of ZIKV in Brazil in 2015, 24 countries in the Americas and the Caribbean have reported cases of microcephaly associated with the mother-to-child intrauterine transmission of ZIKV (8). The cellular and molecular pathways that ZIKV uses to breach the human placental barrier to reach the embryo have not been fully elucidated. ZIKV RNA has been detected in various samples from infected individuals: the amniotic fluid, intervillar space, decidua, and chorionic villi (CV) of the placenta, in addition to fetal tissues (9–12). Other placental cells [syncytiotrophoblasts (STB), cytotrophoblasts (CTB), decidual and endothelial cells, macrophages, and dendritic cells] are also permissive to ZIKV (13, 14). At present, there is no decisive proof of intrauterine co-exposure to ZIKV and other viral or parasitic infections and no data on whether such co-exposure impacts the risk of infection or disease severity. One recent report described a case of ZIKV infection acquired during the first trimester in an HIV-infected pregnant woman from Brazil, which was associated with congenital defects and fetal demise. Unfortunately, evaluation of the placenta was not performed (15).\n\nHere, we provide evidence of the intrauterine exposure to both ZIKV and HIV, infection of the placenta with ZIKV, and the outcome of severe congenital Zika syndrome in an HIV-exposed uninfected infant.\n\nCase and Methods\nClinical Presentation\nA 32-year-old, HIV-positive, primiparous woman from the Northwestern region of the State of Rio de Janeiro, Brazil, had an ultrasound exam at 17 weeks of gestation that was unremarkable about her female fetus. Three weeks later, a second ultrasound revealed fetal cerebral ventriculomegaly. At 24 weeks of gestation, a third ultrasound demonstrated microcephaly and brain atrophy with non-visualization of the cavum septi pellucidi. Prenatal serology was negative for IgM against TORCH antigens (Table S1 in Supplementary Material). The ZIKV infection in the pregnant woman was asymptomatic, but she cited having been bitten by mosquitoes during pregnancy. Two weeks before delivery, the mother had an HIV viral load of 9,323 copies/mL and a CD4+ T-lymphocyte count of 373 cells/μL. Since her HIV diagnosis in the year 2012, the woman had occasionally used antiretroviral treatment consisting of Tenofovir, Lamivudine, and Lopinavir/Ritonavir, but she did not have any AIDS-defining illness. Before delivery, she received Zidovudine for the prevention of mother-to-child transmission of HIV. At 38 weeks of gestation (June 1st, 2016), her baby girl was born by cesarean delivery. She was small for gestational age (below the third percentile: weight 1.375 g, height 35 cm, and cephalic circumference 24.5 cm) and the placenta weighed 325 g (placental coefficient: 0.236; reference value: 0.182 ± 0.023). The newborn physical examination showed a flat midface, low nasal bridge and short nose, overlapping sutures and redundant occipital skin folds, asymmetrical microphthalmia, upper and lower limb contractures, and valgus deformities of the knees. A cranial computed tomography scan revealed cerebral atrophy with the partial collapse of the skull (Figure 1A), ventriculomegaly, supratentorial hydrocephalus, ocular globe asymmetry and multiple intracranial periventricular calcifications (Figure 1B), along with intraocular calcifications (Figure 1C). Indirect ophthalmoscopy revealed atrophy at all quadrants, including the optic nerve in the right eye, and atrophy and peripheral pigmentation in the upper and posterior poles of the retina in the left eye. The echocardiographic evaluation showed a patent foramen ovale. A qPCR test for ZIKV in a liquor sample taken at birth yielded inconclusive results (data not shown). At ages of 2 and 4 months, the infant had an undetectable HIV viral load. When the child was 6 months of age, the mother’s serum tested IgG-positive and IgM-negative for ZIKV and negative for anti-Dengue and anti-Chikungunya viral antibodies (Table S1 in Supplementary Material). The timeline of events and findings is presented in Figure S1 in Supplementary Material.\n\nFigure 1 Cranial computed tomography (CT) images of the baby born after Zika virus infection in pregnancy. (A) Sagittal localizer CT image of the markedly abnormal skull shape, (B) axial CT images showing microcephaly, cerebral atrophy, and multiple dense intracranial periventricular calcifications located in the subcortical white matter at the gray matter–white matter interface, and (C) ocular calcification.\n\nEthical Procedures\nAll procedures performed during this work were approved by the Ethics Committee of the Oswaldo Cruz Foundation/FIOCRUZ (CAEE: 65924217.4.0000.5248). The mother of the index patient gave written consent and permission for the publication of data and images.\n\nSample Collection\nAt delivery, samples from the index case placenta were collected and fixed following various histopathological techniques. Blood samples from the pregnant woman were collected postpartum. A spinal liquor sample was collected from the infant. Samples were collected at the Hospital Plantadores de Cana, Campos dos Goytacazes, RJ, Brazil. As a reference control, a sample of term placenta from a healthy donor was included.\n\nHistopathological Analysis\nSamples from the placentas were fixed in formalin (10%), dehydrated in ethanol, clarified in xylene and blocked in paraffin resin. Tissue sections were cut (4 µm thick), deparaffinized in three baths of xylene and rehydrated with decreasing concentrations of ethanol (100 to 70%). Sections were stained with hematoxylin and eosin for histological examination and with periodic acid–Schiff to examine extracellular matrix (EM) morphometry. Stained specimens were visualized by light microscopy (Olympus, Tokyo, Japan), and digital images were obtained using Image-Pro Plus software version 4.5. The case and control samples were coded and handled in a blind test.\n\nMorphometry and Statistical Analysis\nThe slides were visualized under a light microscope (Olympus), and the EM area was analyzed using Image-Pro Plus software version 4.5. Fifty fields were randomly acquired at 400× magnification from both placentas (Zika-infected and control). The regions stained with PAS were measured, and the percentage of EM was calculated (histological feature/total area of the image). Data were analyzed with GraphPad Prism software v 6.0 (GraphPad Software, CA, USA) using non-parametric statistical tests. Significant differences between the analyzed groups were determined using the Mann–Whitney test with a threshold of P < 0.05.\n\nImmunohistochemistry Procedures\nThe paraffin-embedded tissues were cut (4 µm), deparaffinized in xylene and rehydrated with alcohol. Antigen retrieval was performed by heating the tissue in the presence of citrate buffer. Next, tissues were blocked for endogenous peroxidase with 3% hydrogen peroxidase in methanol and rinsed in Tris–HCl (pH 7.4). Sections were incubated in Protein Blocker solution (Spring Bioscience, CA, USA) for 5 min at room temperature to reduce non-specific binding. They were then incubated overnight at 4°C with a 1:200 dilution of the mouse monoclonal antibody 4G2 (16), which is specific for the fusion loop at the extremity of domain II of the Flavivirus group antigen envelope (E) protein (16), or the mouse monoclonal IgG antibody against Zika virus non-structural protein NS1 (Arigo Biolaboratories, Taiwan, Republic of China), or with a 1:40 dilution of the mouse monoclonal antibody specific for the p24 protein of HIV (Agilent—Dako, CA, USA). The next day, sections were incubated with a rabbit anti-mouse IgG conjugated to horseradish peroxidase (Spring Bioscience Corporation, CA, USA) for 40 min at room temperature. Reactions were revealed with diaminobenzidine (Agilent) as a chromogen, and the sections were counterstained with Meyer’s hematoxylin (Agilent).\n\nImmunofluorescence Assay\nThe paraffin-embedded tissues were processed as above, except for incubation with 1% bovine serum albumin for 30 min, and permeabilized with 0.5% Triton X-100 at room temperature. Slides were co-stained overnight at 4°C with a 1:200 dilution of a mouse monoclonal antihuman proliferating cell nuclear antigen (PCNA) IgG (ThermoFisher, OK, USA) or a mouse monoclonal anti-Zika NS1 IgG, and a rabbit monoclonal antihuman CD11b IgG (Abcam, Cambridge, UK); or with a 1:40 dilution of the mouse monoclonal antibody specific for the p24 protein of HIV (Agilent—Dako, USA). Sections were incubated with Alexa 488-conjugated rabbit anti-mouse IgG, Alexa 555-conjugated goat anti-rabbit IgG, or Alexa 555-conjugated goat anti-mouse IgG (ThermoFisher). Slides were analyzed using a Zeiss LSM 510 Meta confocal microscope (Carl Zeiss, Oberkochen, Germany).\n\nElectron Microscopy Procedures\nTissue samples were fixed with 2.5% glutaraldehyde in sodium cacodylate buffer (0.1 M, pH 7.2), post-fixed with 1% buffered osmium tetroxide, dehydrated in an acetone series (30, 50, 70, 90, and 100%), and embedded in EPON polymerized at 60°C for 3 days. Ultrathin sections (60–90 nm) were contrasted with uranyl acetate and lead citrate and were visualized using a JEOL 1001 transmission electron microscope (Jeol Ltd., Tokyo, Japan).\n\nResults\nHistopathological analysis of the ZIKV-infected placenta revealed severe damage to the maternal decidua and CV. In the control placenta, we observed a regular structure of decidual parenchyma with typical decidual cells (DC) and capillaries exhibiting regular endothelial cells. Likewise, CV showed normal STB, CTB, and endothelial cells (Figures 2A–C). The most prominent lesion in the placenta from the Zika-infected patient was the presence of large and diffuse areas of fibrinoid necrosis (FN) in the maternal decidua (Figures 2D,E,G,H). The maternal portions of the placenta also presented diffuse edema, fibrosis, vascular endothelial thickening, degeneration, vascular congestion (VC) and focal areas of mononuclear or perivascular inflammatory infiltrates (Figures 2D,E,G–J). The decidua showed dense and heterogeneous calcification, which can be consistent with third-trimester gestation (Figures 2G,I). Since the histopathological analysis indicated degeneration of the decidua, the EM was assessed using PAS staining. Morphological analysis revealed a significant reduction in the total area of EM in the placenta from the Zika-infected patient (12.02% ± 1.33) compared with the control placenta (17.52% ± 1.45) (Figures 2K–M). An investigation of the CV revealed an area of extensive hemorrhage and prominent STB (Figures 2F,N). A higher density of PCNA was observed in the STB of the index placenta compared with the control placenta (Figures 2O,P). PCNA acts as a scaffold to recruit proteins involved in DNA replication or repair.\n\nFigure 2 Histopathological analysis of the placenta. (A–C) Placenta of a non-ZIKV patient stained with H&E and presenting normal features: maternal decidua (Dec), decidual cells (DC), chorionic villi (CV), syncytiotrophoblasts (STB), cytotrophoblasts (CTB), extracellular matrix (EM), and blood vessels (BV). (D–J,N) Sections of ZIKV-infected placental tissue stained with H&E, showing abnormalities in the decidua, including edema (E), fibrosis (F), fibrinoid necrosis (FN), mononuclear inflammatory infiltrate (Inf), macrophages (Mø), endothelial thickening (Th), cellular degeneration [arrowhead in panel (D)], calcification (Ca), and other pathological features in CV, such as perivascular inflammatory infiltrate (PInf), vascular congestion (VC), hemorrhage (He), and inordinate proliferative STB [arrowheads in panel (N)]. (K) Placental sections from a non-ZIKV and (L) a ZIKV-infected patient stained with PAS, evidencing highlighting the EM. (M) The percent EM area was quantified in both cases; asterisks indicate statistically significant differences between samples: *P < 0.05. (O) Immunofluorescence analysis of proliferating cell nuclear antigen expression in the STB of a ZIKV-infected and (P) a non-ZIKV patient.\n\nPlacentas were tested for the presence of ZIKV antigens using an immunohistochemistry assay. Virus antigens were observed only in samples from the ZIKV-infected patient. No immunostaining was observed in samples from the control placenta (Figures 3A,D,E). ZIKV envelope proteins were identified mainly in DC (Figures 3B,C), whereas the NS1 protein was detected in the cytoplasm of several placental cells, such as decidual and endothelial cells in the maternal decidua. In the CV, the NS1 protein was detected in CTB, STB, and Hofbauer cells, which strongly suggests that viral replication occurred in these cells (Figures 3F–H). Further evidence for ZIKV replication in these cells was provided by the positive immunofluorescence signal for NS1 protein (green fluorescence) in several placental cells and its co-localization with CD11b (red fluorescence), used to identify infected mononuclear cells (Figure 3J). As expected, no positive reactions against NS1 were observed in control tissue (Figure 3I). The term placenta was negative for HIV-specific p24 protein as assessed by immunohistochemistry and fluorescence (Figure S2 in Supplementary Material).\n\nFigure 3 Detection of ZIKV in the placenta. (A,D,E) The E and NS1 antigens of ZIKV were not detected by immunohistochemistry in the control placenta. (B,C) Detection of ZIKV E protein in decidual cells (DC) by immunohistochemistry in the infected placenta. (F–H) The NS1 protein of ZIKV was also detected by immunochemistry in the endothelium (En), DC, syncytiotrophoblasts (STB), cytotrophoblasts (CTB), and Hofbauer cells (Hf). (I,J) Co-localization by immunofluorescence of the NS1 protein (fluorescent green) and CD11b for identification of leukocytes (fluorescent red). Nuclei were stained using DAPI (fluorescent blue). (I) ZIKV NS1 antigen was not detected in the control placenta. (J) Cells presenting dual staining (green and red) were observed in the ZIKV-infected placenta.\n\nNo evidence of ultrastructural changes was noted in the control patient (Figures 4A–C). In contrast, the infected placenta showed various alterations such as thickening of the endothelial basement membrane (Figure 4D), the nuclei of the STB with dispersed chromatin aggregated in the vicinity of the nuclear membrane, and rarefied cytoplasm with absent organelles (Figure 4E). Moreover, smaller mitochondria and fewer cristae were observed, and the endoplasmic reticulum (ER) exhibited dilated cisterns in CTB (Figure 4F). Ultrathin sections of placental tissue allowed the identification of clusters with dense virus-like particles, located in damaged cytoplasmic vesicles of CTB (Figure 4G). We also observed these virus-like particles near disrupted areas of the ER. The remains of membranes could be seen at the periphery of these clusters (Figure 4H). These particles were approximately 25 nm in diameter, which is consistent with the physical dimensions of ZIKV (Figure 4I). We did not observe virus-like particles with diameters consistent with mature or immature HIV (range 110–146 nm).\n\nFigure 4 Electron microscopy analysis of ultrathin placental sections showed virus-like particles. (A–C) Electron microscopy of ultrathin sections of one non-ZIKV case exhibited regular endothelial cells (En), syncytiotrophoblasts (STB), and CTB organelles, such as mitochondria (M) and endoplasmic reticulum (ER). (D–F) Electron micrographs of ZIKV-infected placenta showing thickening of the basement membrane (Th) of the endothelium (En), dispersed chromatin in syncytiotrophoblast nuclei (N) gathered in the vicinity of the nuclear membrane, and rarefied cytoplasm with absent organelles (arrowhead); mitochondria (M) in cytotrophoblasts were smaller, with fewer cristae, and the ER exhibited dilated cisterns. (G) Cytotrophoblast of a ZIKV-infected patient with a cluster of virions in the cytoplasm. (H) In the same area, at a higher magnitude, we observed these virus-like particles located near disrupted ER. (I) Measurement using the scale bar showed that the particles have a diameter of approximately 25 nm, consistent with ZIKV.\n\nDiscussion\nOverall, the clinical and placental evaluations support a diagnosis of intrauterine infection with ZIKV and exposure to HIV infection, with an outcome of severe congenital Zika syndrome in an HIV-exposed uninfected infant. Similar structural abnormalities of the skull and brain have been documented in presumed and confirmed ZIKV infection in pediatric HIV-unexposed cohorts (17, 18). We note that the progression of the fetal disease to microcephaly occurred within a period of 7 weeks in the second trimester, a timeframe that is consistent with the maternal perfusion of the placenta occurring in the late first to the second trimester. We speculate that the ZIKV infection of the fetus occurred early in the second trimester because the extent of the sequelae did not include abnormalities otherwise related to first-trimester development (i.e., holoprosencephaly and craniosynostosis) (18). ZIKV RNA and ZIKV antigens have been detected in several types of placental cells from pregnancies with histopathologic alterations by ZIKV infection and localized ZIKV antigens or RNA in placental all cells (12, 19). Furthermore, published data indicate that infection with another flavivirus, such as Dengue, is associated with a transient decrease in HIV viral load, and no severe Dengue or HIV progression is observed during coinfection (20). This is consistent with our observations of the current HIV-positive pregnant patient infected by ZIKV. Notwithstanding the histopathological damage associated with the ZIKV infection of the placenta and the detectable viral load of HIV in the pregnant woman, the HIV did not infect the placenta. Importantly, a recent study correlating the placental characteristics from pregnancies in HIV-infected-positive and HIV-negative women described no specific lesions in infected placentas (21). Moreover, the birth head circumference of the newborns was similar in the two groups. In addition, vertical transmission was avoided by the use of antiretroviral drugs (21).\n\nNotwithstanding the extent and severity of the gross damage caused to both the placenta and the fetal brain by the ZIKV infection, the severe intrauterine growth deficiency was compatible with life. In cases of maternal coinfection (i.e., Cytomegalovirus and HIV coinfection), in which there is a considerable inflammatory response in the placenta, often one viral infection predisposes the patient to a higher risk of acquiring the other (22). In a recent prospective cohort study in 134 ZIKV-positive/HIV-negative pregnant women with new-onset rash manifestations, neither the severity of maternal ZIKV disease, the virus RNA load nor the prior existence of Dengue antibodies was significantly associated with abnormal birth outcomes (23). We cannot rule out a collateral damage effect from the HIV co-exposure on the placental histopathological abnormalities caused by ZIKV infection.\n\nThe findings in the abnormally large term placenta suggest that ZIKV spread from the maternal decidua to the CV and reached the fetus by replication and transmission from cell to cell. This hypothesis is based on the detection of NS1 protein in the cytoplasm of several placental cells, such as decidual and endothelial cells in the maternal decidua, and CTB, STB, and Hofbauer cells, which supports the hypothesis of active viral replication. The occurrence of membranous clusters of viral particles in the cytoplasm of CTB is therefore reminiscent of replication factories. Moreover, the observed enrichment with the PCNA expression signal (a protein involved in DNA replication and repair) (24) in the STB indicates an attempt by the cells to repair the injured DNA. Some studies showed that the binding of PCNA to repair proteins is direct, and that the inhibition of its expression impairs the mechanism of DNA repair (25, 26). Tissue alterations such as FN, edema, calcification, and mononuclear inflammatory infiltrates are commonly seen in ZIKV-infected premature placentas (9, 12, 18). Significantly, diffuse fibrosis, vascular endothelial thickening, cellular degeneration, hemorrhage, and VC had not been previously reported in ZIKV-infected term placentas. Furthermore, we observed infected mononuclear cells that are capable of supporting replicating virus, including dendritic cells and macrophages (Hofbauer cells), which are known to be primary targets of another flavivirus, Dengue (27). However, an in vitro study with cells isolated from mature placenta showed that placental macrophages and CTB are permissive to ZIKV infection (14). In addition, Tabata et al. (13) observed that all placental cells, as well as immune cells, in the tissue present receptors capable of binding to the virus and mediating cell entry by endocytosis.\n\nConcluding Remarks\nIt is important to note that the viral antigens persisted in the placental tissue months after the infection occurred. Ultimately, the presence of dense, virus-like particles consistent with the size of ZIKV, seen near the ER of CTB, was the most definitive indication of a persistent viral infection in placenta, from the second trimester until delivery. Our results confirm that maternal ZIKV infection during pregnancy can result in placental and fetal injury. Furthermore, in countries where the prevalence of HIV-positive pregnant women is high, such as in Sub-Saharan African nations (5.3% average prevalence), more cases of severe Zika disease in HIV-exposed fetuses are expected to occur if the epidemic potential of ZIKV increases there (28). The present index case serves as evidence for the importance of preparedness.\n\nEthics Statement\nThis study was carried out in accordance with the recommendations of “Ethics Committee of the Oswaldo Cruz Foundation/FIOCRUZ (CAEE: 65924217.4.0000.5248)” with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the “Ethics Committee of the Oswaldo Cruz Foundation/FIOCRUZ.”\n\nAuthor Contributions\nKR, MP, RF, and EM-A designed the study. LS, CB-d-O, TS, and RF collected samples and performed clinical and tomography exams. KR performed all research experiments for placental evaluation. FS, PN, EA, NS, and GT optimized or supported immunohistochemical experiments. KR and EM-A wrote the manuscript. KR, MP, CB-d-O, and JC analyzed the experimental results. MP, JC, RF, and TS edited the manuscript. All the authors gave final approval.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe authors thank the Hospital Plantadores de Cana for the care of the patient and the assistance with sample collection, and the Platform of Confocal and Electron Microscopy at the State University of Rio de Janeiro and the Platform of Electron Microscopy in Fiocruz. This work was supported by the CNPq (308780/2015-9) and the FAPERJ (E-26/110.511/2014, E- 26/010.001.498/2016 and E26/202.003/2016).\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at http://www.frontiersin.org/article/10.3389/fimmu.2017.01704/full#supplementary-material.\n\nFigure S1 Timeline of relevant events, studies and findings in the presented case of intrauterine co-exposure to ZIKV and human immunodeficiency virus (HIV).\n\nClick here for additional data file.\n\n Figure S2 Immunohistochemistry and fluorescence for p24 human immunodeficiency virus (HIV) protein. Tissue sections were deparaffinized and rehydrated, and antigen retrieval was performed by heating the tissue in the presence of citrate buffer. Sections were blocked and then incubated overnight at 4°C with a 1:40 dilution of the mouse monoclonal antibody specific for the p24 protein of HIV. The next day, sections were incubated with a rabbit anti-mouse IgG-HRP conjugate for immunohistochemistry or Alexa 555-conjugated goat anti-mouse IgG for immunofluorescence. Reactions were revealed with diaminobenzidine as the chromogen and the sections were counterstained with Meyer’s hematoxylin for immunohistochemistry. (A,C) The p24 antigen of HIV was not detected by immunohistochemistry or by immunofluorescence in the control placenta. (B,D) The p24 antigen of HIV was not detected by immunohistochemistry or by immunofluorescence in the ZIKV index case placenta.\n\nClick here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n1 Song BH Yun SI Woolley M Lee YM . Zika virus: history, epidemiology, transmission, and clinical presentation . J Neuroimmunol (2017 ) 308 :50 –64 .10.1016/j.jneuroim.2017.03.001 28285789 \n2 Adibi JJ Marques ETA Cartus A Beigi RH . Teratogenic effects of the Zika virus and the role of the placenta . Lancet (2016 ) 387 :1587 –90 .10.1016/S0140-6736(16)00650-4 26952548 \n3 Schwartz DA . Autopsy and postmortem studies are concordant: pathology of Zika virus infection is neurotropic in fetuses and infants with microcephaly following transplacental transmission . Arch Pathol Lab Med (2017 ) 141 :68 –72 .10.5858/arpa.2016-0343-OA 27557413 \n4 Jaenisch T Rosenberger KD Brito C Brady O Brasil P Marques ET . Risk of microcephaly after Zika virus infection in Brazil, 2015 to 2016 . Bull World Health Organ (2017 ) 95 :191 –8 .10.2471/BLT.16.178608 28250532 \n5 Faye O Freire CCM Iamarino A Faye O De Oliveira JVC Diallo M \nMolecular evolution of Zika virus during its emergence in the 20th century . PLoS Negl Trop Dis (2014 ) 8 :e2636 10.1371/journal.pntd.0002636 24421913 \n6 Chambers TJ Hahn CS Galler R Rice CM \nFlavivirus genome organization, expression and replication . Annu Rev Microbiol (1990 ) 44 :649 –88 .10.1146/annurev.mi.44.100190.003245 2174669 \n7 Goff S \nRetroviridae: the retroviruses and their replication . 4th ed In: Knipe DM Howley PM , editors. Fields Virology . (Vol. 2 ), Philadelphia, PA : Lippincott, Williams & Wilkins (2001 ). p. 1871 –940 .\n8 Faria NR Quick J Morales I Theze J de Jesus JG Giovanetti M \nEpidemic establishment and cryptic transmission of Zika virus in Brazil and the Americas . Nature (2017 ) 546 :406 –24 .10.1038/nature22401 28538727 \n9 De Noronha L Zanluca C Luize M Azevedo V Luz KG Nunes C . Zika virus damages the human placental barrier and presents marked fetal neurotropism . Mem Inst Oswaldo Cruz (2016 ) 111 :287 –93 .10.1590/0074-02760160085 27143490 \n10 Calvet G Aguiar RS Melo ASO Sampaio SA De Filippis I Fabri A \nDetection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil : a case study . Lancet (2016 ) 16 :653 –60 .10.1016/S1473-3099(16)00095-5 26897108 \n11 Driggers RW Ho CY Korhonen EM Kuivanen S Jaaskelainen AJ Smura A \nZika virus infection with prolonged maternal viremia and fetal brain abnormalities . N Engl J Med (2016 ) 374 :2142 –51 .10.1056/NEJMoa1601824 27028667 \n12 Bhatnagar J Rabeneck DB Martines RB Reagan-Steiner S Ermias Y Estetter LBC \nZika virus RNA replication and persistence in brain and placental tissue . Emerg Infect Dis (2017 ) 23 :405 –14 .10.3201/eid2303.161499 27959260 \n13 Tabata T Petitt M Puerta-guardo H Fang-hoover J Harris E Tabata T \nZika virus targets different primary human placental cells, suggesting two routes for vertical transmission . Cell Host Microbe (2016 ) 20 :155 –66 .10.1016/j.chom.2016.07.002 27443522 \n14 Quicke KM Bowen JR Johnson EL Schinazi RF Chakraborty R Suthar MS \nZika virus infects human placental macrophages . Cell Host Microbe (2016 ) 20 :83 –90 .10.1016/j.chom.2016.05.015 27247001 \n15 João EC da Silveira Gouvea MIF de Lourdes Benamor Teixeira M Mendes-Silva W Esteves JS Santos EM \nZika virus infection associated with congenital birth defects in a HIV-infected pregnant woman . Pediatr Infect Dis J (2016 ) 36 :1 10.1097/INF.0000000000001482 \n16 Henchal E Gentry M McCown J Brandt W . Dengue virus-specific and flavivirus group determinants identified with monoclonal antibodies by indirect immunofluorescence . Am J Trop Med Hyg (1982 ) 31 :830 –6 .10.4269/ajtmh.1982.31.830 6285749 \n17 Soares de Oliveira-Szejnfeld P Levine D Melo AS Amorim MMR Batista AG Chimeli L \nCongenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally . Radiology (2016 ) 281 :203 –18 .10.1148/radiol.2016161584 27552432 \n18 Martines RB Bhatnagar J Keating MK Silva-flannery L Gary J Goldsmith C \nEvidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses—Brazil 2015 . MMWR Morb Mortal Wkly Rep (2016 ) 65 :2015 –6 .10.15585/mmwr.mm6506e1 \n19 Schwartz DA \nViral infection, proliferation, and hyperplasia of Hofbauer cells and absence of inflammation characterize the placental pathology of fetuses with congenital Zika virus infection . Arch Gynecol Obstet (2017 ) 295 :1361 –8 .10.1007/s00404-017-4361-5 28396992 \n20 Torrentes-Carvalho A Hottz ED Marinho CF da Silva JB-C de Oliveira Pinto LM Fialho LG \nCharacterization of clinical and immunological features in patients coinfected with dengue virus and HIV . Clin Immunol (2016 ) 164 :95 –105 .10.1016/j.clim.2016.01.005 26826597 \n21 Kalk E Schubert P Bettinger JA Cotton MF Esser M Slogrove A \nPlacental pathology in HIV infection at term: a comparison with HIV-uninfected women . Trop Med Int Health (2017 ) 22 :604 –13 .10.1111/tmi.12858 28214384 \n22 Eaton JW Rehle TM Jooste S Nkambule R Kim AA Mahy M \nRecent HIV prevalence trends among pregnant women and all women in sub-Saharan Africa . AIDS (2014 ) 28 :S507 –14 .10.1097/QAD.0000000000000412 25406753 \n23 Halai U Nielsen-Saines K Moreira M Sequeira P Pereira Junior J Zin A \nMaternal Zika virus disease severity, virus load, prior dengue antibodies and their relationship to birth outcomes . Clin Infect Dis (2017 ) 65 :877 –83 .10.1093/cid/cix472 28535184 \n24 Schönenberger F Deutzmann A Ferrando-May E Merhof D . Discrimination of cell cycle phases in PCNA-immunolabeled cells . BMC Bioinformatics (2015 ) 16 :180 .10.1186/s12859-015-0618-9 26022740 \n25 Inoue A Kikuchi S Hishiki A Shao Y Heath R Evison BJ \nA small molecule inhibitor of monoubiquitinated proliferating cell nuclear antigen (PCNA) inhibits repair of interstrand DNA cross-link, enhances DNA double strand break, and sensitizes cancer cells to cisplatin . J Biol Chem (2014 ) 289 :7109 –20 .10.1074/jbc.M113.520429 24474685 \n26 Fu D Samson LD Hübscher U van Loon B . The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, mediated by the hydrophobic pocket of PCNA and perturbed in naturally-occurring ALKBH2 variants . DNA Repair (Amst) (2015 ) 35 :13 –8 .10.1016/j.dnarep.2015.09.008 26408825 \n27 Miagostovich MP Ramos RG Nicol AF Nogueira RM Cuzzi-Maya T Oliveira AV \nRetrospective study on dengue fatal cases . Clin Neuropathol (1997 ) 16 :204 –8 .9266146 \n28 Johnson EL Chakraborty R \nHIV-1 at the placenta . Curr Opin Infect Dis (2016 ) 29 :248 –55 .10.1097/QCO.0000000000000267 27027245\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "8()",
"journal": "Frontiers in immunology",
"keywords": "Zika virus; congenital Zika syndrome; histopathology; human immunodeficiency virus; microcephaly; placenta",
"medline_ta": "Front Immunol",
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"nlm_unique_id": "101560960",
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"pages": "1704",
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"pmid": "29270171",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "2174669;24421913;24474685;25406753;26022740;26408825;26826597;26890059;26897108;26952548;27027245;27028667;27143490;27247001;27443522;27552432;27557413;27959260;28214384;28250532;28285789;28396992;28403053;28535184;28538727;6285749;9266146",
"title": "Placental Histopathology and Clinical Presentation of Severe Congenital Zika Syndrome in a Human Immunodeficiency Virus-Exposed Uninfected Infant.",
"title_normalized": "placental histopathology and clinical presentation of severe congenital zika syndrome in a human immunodeficiency virus exposed uninfected infant"
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"abstract": "A 35-year-old male was diagnosed with chronic myeloid leukemia in the chronic phase and was prescribed 100 mg daily dasatinib. However, dasatinib was discontinued due to thrombocytopenia, and within six months, the disease progressed to the lymphoid blastic phase. Hyper-cyclophosphamide, vincristine, adriamycin and dexamethasone chemotherapy combined with 140 mg dasatinib or 600 mg imatinib was prescribed. The two inhibitors were soon discontinued due to severe thrombocytopenia and jaundice, respectively. Myelosuppression persisted subsequent to the nadir. Bone marrow (BM) aspiration and biopsy revealed hypercellular marrow filled with blasts. Sequencing of the leukemia cells revealed overlapping peaks for the wild-type sequence and the T315I mutant sequence. The patient was treated with 500 mg bosutinib (which was later reduced to 300 mg) for pretransplant cytoreduction. After 5 months, the patient's spleen exhibited a reduction in volume and the percentage of blasts in the BM decreased from 96.1 to 17.5%. The patient successfully underwent cord blood transplantation. The patient has been disease-free for 5 months subsequent to transplantation. This case suggests that bosutinib may be effective for cytoreduction prior to stem cell transplantation, unless the leukemia cells consistently harbor the T315I mutation.",
"affiliations": "Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.;Department of Hematology, Toranomon Hospital, Toranomon, Minato, Tokyo 105-8470, Japan.;Department of Clinical Laboratory, The University of Tokyo Hospital, Hongo, Bunkyo, Tokyo 113-8655, Japan.;Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.;Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.;Department of Clinical Laboratory, The University of Tokyo Hospital, Hongo, Bunkyo, Tokyo 113-8655, Japan.;Department of Pathology, JCHO Tokyo Yamate Medical Center, Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.;Department of Clinical Laboratory, The University of Tokyo Hospital, Hongo, Bunkyo, Tokyo 113-8655, Japan.;Department of Hematology, Toranomon Hospital, Toranomon, Minato, Tokyo 105-8470, Japan.;Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.",
"authors": "Komeno|Yukiko|Y|;Uchida|Naoyuki|N|;Satoh|Yumiko|Y|;Uryu|Hideki|H|;Iwata|Yuko|Y|;Masuda|Akiko|A|;Iihara|Kuniko|K|;Yatomi|Yutaka|Y|;Taniguchi|Shuichi|S|;Ryu|Tomiko|T|",
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"doi": "10.3892/ol.2017.5989",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2017.5989OL-0-0-5989ArticlesBosutinib as a fourth-line therapy for a patient with T315I-positive lymphoid blastic phase chronic myeloid leukemia: A case report Komeno Yukiko 1Uchida Naoyuki 2Satoh Yumiko 3Uryu Hideki 1Iwata Yuko 1Masuda Akiko 3Iihara Kuniko 4Yatomi Yutaka 3Taniguchi Shuichi 2Ryu Tomiko 11 Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan2 Department of Hematology, Toranomon Hospital, Toranomon, Minato, Tokyo 105-8470, Japan3 Department of Clinical Laboratory, The University of Tokyo Hospital, Hongo, Bunkyo, Tokyo 113-8655, Japan4 Department of Pathology, JCHO Tokyo Yamate Medical Center, Hyakunin-cho, Shinjuku, Tokyo 169-0073, JapanCorrespondence to: Dr Yukiko Komeno, Department of Hematology, Japan Community Healthcare Organization (JCHO) Tokyo Yamate Medical Center, 3-22-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan, E-mail: ykomeno-tky@umin.ac.jp6 2017 05 4 2017 05 4 2017 13 6 4285 4289 14 10 2015 17 2 2017 Copyright: © Komeno et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.A 35-year-old male was diagnosed with chronic myeloid leukemia in the chronic phase and was prescribed 100 mg daily dasatinib. However, dasatinib was discontinued due to thrombocytopenia, and within six months, the disease progressed to the lymphoid blastic phase. Hyper-cyclophosphamide, vincristine, adriamycin and dexamethasone chemotherapy combined with 140 mg dasatinib or 600 mg imatinib was prescribed. The two inhibitors were soon discontinued due to severe thrombocytopenia and jaundice, respectively. Myelosuppression persisted subsequent to the nadir. Bone marrow (BM) aspiration and biopsy revealed hypercellular marrow filled with blasts. Sequencing of the leukemia cells revealed overlapping peaks for the wild-type sequence and the T315I mutant sequence. The patient was treated with 500 mg bosutinib (which was later reduced to 300 mg) for pretransplant cytoreduction. After 5 months, the patient's spleen exhibited a reduction in volume and the percentage of blasts in the BM decreased from 96.1 to 17.5%. The patient successfully underwent cord blood transplantation. The patient has been disease-free for 5 months subsequent to transplantation. This case suggests that bosutinib may be effective for cytoreduction prior to stem cell transplantation, unless the leukemia cells consistently harbor the T315I mutation.\n\nchronic myeloid leukemiablastic phasetyrosine kinase inhibitorbosutinibT315I mutation\n==== Body\nIntroduction\nChronic myeloid leukemia (CML) is a myeloproliferative disorder that arises in hematopoietic stem cells (1). It is characterized by a reciprocal t(9;22) translocation that leads to the formation of the Philadelphia chromosome, which in turn produces the BCR-ABL1 fusion protein. BCR-ABL1 is a constitutively active tyrosine kinase, which transmits proliferation and survival signals through the Src family kinases, Lyn and Hck, to the downstream targets, STAT5 and Ras/ERK (2,3).\n\nCML has a triphasic clinical course (1). In the chronic phase (CP), excessive proliferation of mature myeloid cells occurs (1). In the accelerated phase (AP), CML cells accumulate chromosomal and genetic abnormalities, and blasts in the peripheral blood (PB) or bone marrow (BM) increase to 10–20% (1). Eventually, the disease progresses to the blastic phase (BP), where blasts account for >20% of the cells in the PB or BM (1). In ~70% of BP cases the blast lineage is myeloid, whereas in the remaining 20–30% of BP cases the lineage is lymphoid (1).\n\nTyrosine kinase inhibitors (TKIs) have markedly improved the prognosis of patients with CML. Currently, five different TKIs are available for the treatment of CML: Imatinib, nilotinib, dasatinib, bosutinib and ponatinib (4). Imatinib, nilotinib and dasatinib are approved for first-line treatment of CML, and bosutinib and ponatinib are available for resistant and intolerant CML patients. As of July 2015, ponatinib is not yet available in Japan. Secondary resistance to TKIs occurs in 20–30% of patients with CML, and is mainly due to mutations in the ABL1 kinase domain (5,6). The most intractable mutation is the T315I gatekeeper mutation, which potently interferes with the binding of TKIs to BCR-ABL1 (7). Of the five TKIs, only ponatinib is active against the T315I mutant (4,8–11). Stem cell transplantation is currently reserved for patients with CML-AP/BP and selected cases of CML-CP (4,12,13).\n\nBosutinib is a dual Src and ABL1 tyrosine kinase inhibitor (14–21). It is active against various BCR-ABL1 mutations, including those associated with imatinib, dasatinib and nilotinib resistance. However, bosutinib is not active against the T315I and V299L BCR-ABL1 mutations (4,10,11). Bosutinib inhibits Src family kinases, including Src, Lyn, Fgr and Hck (14). However, unlike other TKIs, bosutinib has exhibited minimal inhibitory activity against platelet-derived growth factor receptor and c-KIT (14). Therefore, bosutinib has a distinct toxicity profile compared to other TKIs (15–21). The present case study provides a report of a patient with T315I-positive CML-BP who was successfully treated with bosutinib as a fourth-line therapy prior to cord blood transplantation.\n\nMaterials and methods\n\nSequencing of the ABL1 kinase domain of BCR-ABL1\nTotal RNA was extracted from total BM cells using ISOGEN (Nippon Gene, Tokyo, Japan) and 1 µg from each sample was reverse transcribed using a Transcriptor 1st Strand cDNA Synthesis kit (Roche Diagnostics, Tokyo, Japan). The ABL1 tyrosine kinase domain of BCR-ABL1 was amplified with nested RT-PCR with the following primers: 1st forward, (designed on BCR gene), 5′-TTCAGAAGCTTCTCCCTGCAT-3′ and reverse (located in ABL gene), 5′-CTTCGTCTGAGATACTGGATTCCT-3′; 2nd forward (located in ABL gene), 5′-AAGCGCAACAAGCCCACTGTCTAT-3′ and reverse (located in ABL gene), 5′-CTTCGTCTGAGATACTGGATTCCT-3′. Amplified fragments were directly sequenced using an ABI PRISM 310 Genetic Analyzer (Applied Biosystems; Thermo Fisher Scientific, Inc., Waltham, MA, USA). Written informed consent was obtained from the patient in the present study, according to the Declaration of Helsinki.\n\nStaining\nBM aspirate smears were stained with May-Grünwald's and Giemsa's staining solution. Images were acquired at room temperature using a BX50 light microscope (Olympus Corporation, Tokyo, Japan) equipped with a DS-Fi2 camera, Digital Sight DS-U3 controller and NIS-Elements D software version 3.20 (all Nikon Corporation, Tokyo, Japan). BM biopsy samples were fixed in 10% neutral buffered formalin solution, decalcified in Osteosoft (Merck KGaA, Darmstadt, Germany), sectioned (3-µm thick), and stained with hematoxylin and eosin. Images were acquired at room temperature using a BX53 light microscope equipped with DP21 camera/controller (both Olympus Corporation).\n\nCase report\nA previously healthy 35-year-old Japanese male visited the Department of Surgery for a left inguinal hernia in March 2014. The patient had mild hepatomegaly and marked splenomegaly. His blood cell counts were: White blood cells (WBC) 345,820/µl (blasts 4.0%, promyelocytes 0.0%, myelocytes 24.5%, metamyelocytes 3.5%, band 16.5%, segmented 44.5%, monocytes 1.0%, lymphocytes 1.0%, eosinophils 2.0%, basophils 3.0%), hemoglobin 7.3 g/dl and platelets 113×103/µl. The following day, the patient was referred to the Department of Hematology. BM aspiration and biopsy revealed hypercellular marrow with 9.4% blasts (Fig. 1A) and the karyotype was 46,XY, t(9;22)(q34;q11.2)[20/20]. The patient was diagnosed with CML-CP. However, the disease rapidly progressed to AP (platelets 65×103/µl). The patient was hospitalized in April 2014, and 100 mg dasatinib was prescribed. WBC and platelet counts normalized, while hemoglobin levels increased. The splenomegaly was also reduced from 8 to 3.5 cm below the umbilicus. On the 9th day of hospitalization, the patient was discharged. The patient continued to take dasatinib until his platelet count lowered to 49×103/µl, when dasatinib was discontinued one month subsequent to the initial prescription. One month later, administration of dasatinib was resumed. Subsequent to this visit, no contact could be made with the patient.\n\nIn September 2014, the patient was hospitalized due to active nasal bleeding. Blood test results revealed levels of: WBC 3,790/µl, hemoglobin 7.6 g/dl and platelets 8×103/µl. BM aspiration and biopsy revealed hypercellular marrow with peroxidase-negative blasts (85.5%, Fig. 1B) characterized as CD10+/CD19+/CD20−/CD34+/CD7dim. Cytogenetic analysis revealed a Philadelphia chromosome with additional aberrations: 46, XY, t(9;22)(q34;q11.2), del(15)(q?)[6/20], 47,idem, +der(22)t(9;22)[2/20], 50,idem,+X,del(13)(q?),+14,+21, +der(22)t(9;22)[3/20],46,XY[8/20]. A diagnosis of CML B-lymphoid BP was made. Hyper-CVAD (cyclophosphamide, vincristine sulfate, adriamycin, dexamethasone) chemotherapy was started in combination with 140 mg dasatinib (22). The patient's platelet counts remained as low as 10×103/µl, despite frequent transfusions. When dasatinib induced thrombocytopenia in the patient by day 7, it was discontinued and the patient was switched to 600 mg imatinib. Active nasal bleeding persisted even following cauterization. Therefore, dexamethasone was reduced from 8 doses to 5 doses to reduce mucosal toxicity. When the bilirubin and alkaline phosphatase levels reached 3.7 mg/dl and 1,012 IU/l, respectively, by day 16, imatinib was discontinued. However, pancytopenia persisted, and when BM aspiration and biopsy was performed on day 37, the blast level was 81.4%. Considering the high leukemia burden of the patient, allogeneic stem cell transplantation was considered to be a high risk treatment (4,12,13). Therefore, the patient underwent follow-up care in an outpatient setting, with transfusions performed 2–3 times per week.\n\nIn December 2014, the patient was re-admitted for leukemia debulking with bosutinib. BM aspiration and biopsy revealed hypercellular BM filled with blasts (96.1%). Cytogenetic analysis revealed 46,XY,t(9;22)(q34;q11.2),del(15)(q?)[18/19] and 50,idem,+X,add(1)(p11), add(13)(q12),+14,+21,+der(22)t(9;22)[1/19]. Quantitative PCR detected major BCR-ABL1 at 3.1×105 copy/µg RNA. The T315I mutation was detected in the major BCR-ABL1 sequencing. In the sequencing chromatogram, peaks of the wild type allele were revealed to overlap with the T315I mutant allele (Fig. 2), suggesting that almost half of the leukemia cells lacked the T315I mutation. Administration of bosutinib at 500 mg per day was prescribed (Fig. 3). Notably, blasts in the PB, as well as hepatosplenomegaly, disappeared within 2 and 3 weeks, respectively. Adverse effects experienced by the patient included diarrhea [CTCAE v4.0 Grade (G) 2], anorexia (G3), jaundice (G3, bilirubin 4.6 mg/dl), systemic erythema (G2) and papilloedema (G1). Bosutinib was discontinued on day 8 due to jaundice, yet was resumed at a dose of 300 mg on day 14. This lower dose was better tolerated, however the levels of alanine transaminase (ALT) became elevated (G3, 187 IU/l), which required temporary interruption. The patient was referred to a collaborating hospital for transplantation in February 2015. After two months of bosutinib prescription, the blast level was decreased to 19.4%, and major BCR-ABL1 level was 3.5×104 copy/µg RNA. The patient continued to take bosutinib while waiting for the transplantation. After four months of bosutinib prescription, the patient's BM became more hypocellular (Fig. 4A) and his spleen did not show regrowth (Fig. 4B). Blasts in the BM were reduced to 17.5%, and a cytogenetic analysis revealed a normal karyotype (46, XY [20/20]). Sequencing of ABL1 of the BM sample only detected the T315I mutant allele (Fig. 2B). Stem cell transplantation was still considered necessary due to persistent pancytopenia and transfusion dependence, despite the absence of disease progression (based on the percentage of blasts in the PB or splenomegaly status). Subsequent to taking bosutinib for five months, the patient underwent cord blood transplantation at the end of April 2015 that was accompanied by high-dose cytarabine (2 g × 2/day for two days) followed by a conditioning regimen of fludarabine (180 mg/m2), an intravenous injection of busulfan (12.8 mg/kg) and melphalan (80 mg/m2). Engraftment was confirmed on day 25. BM aspiration was performed on day 36. The blast count was 0%, the karyotype was 46,XX [20/20] (as a result of a female donor), and BCR-ABL1 was not detected by quantitative PCR. Subsequent to becoming transfusion-independent, the patient was discharged from the hospital on day 64. Acute graft-vs.-host disease (GVHD) was observed in skin (stage I), but not in the liver (stage 0) or gut (stage 0) (Grade I). Major BCR-ABL1 level in PB was <0.0018% by International Scale at one month and two months subsequent to transplantation. Tacrolimus for GVHD treatment was discontinued at four months. At five months, the patient has no sign of relapse, and follow up was begun in an outpatient setting.\n\nDiscussion\nPoint mutations in the ABL1 kinase domain have been associated with resistance to TKIs in patients with CML (4–6,10,11). In the present case report, a patient with T315I mutation-positive CML-BC demonstrated a response to bosutinib over five months, and successfully underwent cord blood transplantation. Initially, when exhibiting CML-CP, the patient was intolerant to treatment with dasatinib [due to thrombocytopenia and low compliance (23). In addition, the patients CML-BP disease was resistant to chemotherapy combined with the TKIs, dasatinib or imatinib (22). Correspondingly, the patient was revealed to carry the T315I mutation. It has been reported that bosutinib is ineffective against T315I-mutated BCR-ABL1 in vitro (4,10,11). In addition, in phase 1 and 2 clinical trials, CML-CP patients with the T315I mutation exhibited poor responses compared to those without the mutation (15–17). In Japan, bosutinib became available in December 2014 (21), whereas ponatinib (8,9) and the non-TKI, omacetaxine (24), which have been shown to be active against T315I-positive cases, were not available at this time. In the present case, the sequencing chromatogram of ABL1 implied that at least half of the leukemia cells carried wild-type BCR-ABL1 (Fig. 2A). Indeed, bosutinib was effective in debulking the leukemia cells in the patient. Furthermore, ABL1 sequencing subsequent to the administration of bosutinib detected only the T315I peak (Fig. 2B). Thus, the present results demonstrate that when a patient carries cells with the T315I mutation, sequencing chromatograms of ABL1 can potentially provide an estimate of the T315I-positive leukemia cell burden. Additionally, in cases where resistance/intolerance to multiple TKIs is a factor, bosutinib may potentially provide an effective pre-transplant therapy while promising new drugs including ponatinib (8,24), omacetaxine (24) and axitinib (25) that target the T315I mutation are becoming widely available. Furthermore, for individual situations, certain drugs may or may not be suitable due to preexisting comorbidities and/or pretreatments.\n\nIt has been reported that Src family kinases, including Lyn, Hck, and Fgr, perform critical roles in BCR-ABL1-independent TKI resistance (5,6) and disease progression in CML, particularly during the progression to B lymphoid BP (26–29). In leukemia cells from patients with CML who exhibited disease progression during imatinib therapy, Hck and Lyn were revealed to be strongly expressed and/or activated (26). Correspondingly, downregulation of Lyn by siRNA induced apoptosis in BCR-ABL1 positive blasts, particularly lymphoid blasts (27). In addition, mouse models have demonstrated that Lyn, Hck and Fgr are required for the transition from CML-CP to lymphoid BP (28,29). In the present case, the percentage of blasts in the BM decreased from 96.1 to 17.5% following treatment with Bosutinib. In addition, the spleen demonstrated sustained shrinkage over five months of the bosutinib treatment regimen. The reduction in leukemia load was more than would be expected just from the killing of T315I-negative blasts. Thus, it is possible that the dual Src/ABL1 kinase inhibitor, bosutinib, was able to effectively suppress Src, Lyn and Hck in the T315I-positive lymphoid BP cells, thereby additionally inducing anti-leukemia effects. It will be important for future studies to compare the sensitivity of CML cells from lymphoid BP vs. myeloid BP to bosutinib. To date, no such data are available (18,21).\n\nThe clinical course in this report suggested that the interruption of dasatinib for any reasons during CML treatment, particularly in late-CP or AP/BC, may induce a resistant clone against TKIs, even if the resistant mutated clone existed in BM prior to treatment with dasatinib. Indeed, poor adherence may be the predominant reason for failure to achieve adequate molecular responses in patients treated with imatinib for >2 years (23). A management of adverse effects and a continuation of TKI are essential for CML treatment. The selection of an appropriate TKI for each patient with CML with individual situations during TKI treatment as well as at a diagnosis of CML is the key to the best possible outcome (30).\n\nIn conclusion, the present case represents a patient with T315I-positive CML-BP. The patient responded to bosutinib as a fourth-line treatment. Bosutinib was also useful as a pre-transplant therapy for reducing leukemia cell load. Thus, patients who are resistant or intolerant to multiple TKIs, unless the leukemia cells are uniformly T315I-positive, may benefit from a bosutinib treatment regimen.\n\nAcknowledgments\nThe authors would like to thank Dr. Shinya Kimura (Department of Hematology and Oncology, Saga University) and Dr. Chiaki Nakaseko (Department of Hematology, Chiba University Hospital) for their help.\n\nFigure 1. May-Grünwald Giemsa staining of BM aspirate smears. (A) BM at the initial diagnosis of CML-CP. Black arrows illustrate the blasts. (B) BM at the diagnosis of CML-BP. Original magnification, ×400. BM, bone marrow; CML, chronic myeloid leukemia; CP, chronic phase; BP, blastic phase.\n\nFigure 2. Sequencing chromatograms of the BCR-ABL1 fusion gene, particularly the regions flanking amino acid T315 of ABL1. (A) Sequencing chromatogram that was obtained prior to bosutinib administration. The central codon, ACT, corresponds to wild-type T315. The overlapping peaks of wild-type and C >T (T315I) mutation ABL1 are indicated with an arrow. (B) Sequencing chromatogram that was obtained four months subsequent to bosutinib administration. Only the T315I peak (ATT, indicated with an arrow) was detected.\n\nFigure 3. Summary of the clinical symptoms, blood analyses, and course of treatment for the present case report. Hepatosplenomegaly is indicated according to the size below the costal arches. mPSL, methylprednisolone; ALT, alanine transaminase; WBC, white blood cells; DRPM, doripenem; Neu, neutrophils; Hb, hemoglobin; Plt, platelets; G-CSF, granulocyte-colony stimulating factor (filgrastim); RCC 2U, 2 units of red cell concentrates; PC 10U, 10 units of platelet concentrates.\n\nFigure 4. The patient's leukemia load was reduced with administration of bosutinib. (A) Hematoxylin and eosin staining of bone marrow biopsy samples that were collected prior to and 1 and 4 months subsequent to the administration of bosutinib. A reduction in cellularity was observed with time. Original magnification, ×40. (B) Plain abdominal computed tomography scans were obtained prior to and 1 and 4 months subsequent to administration of bosutinib. Spleen volume was reduced following one month of bosutinib treatment. For the next three months, this reduced spleen volume was maintained.\n==== Refs\nReferences\n1 Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H Thiele J Vardiman JW WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th Edition International Agency for Research on Cancer Lyon 130 139 2008 \n2 Wilson MB Schreiner SJ Choi HJ Kamens J Smithgall TE Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr-Abl signal transduction and oncogenesis Oncogene 21 8075 8088 2002 10.1038/sj.onc.1206008 12444544 \n3 Lionberger JM Wilson MB Smithgall TE Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck J Biol Chem 275 18581 18585 2000 10.1074/jbc.C000126200 10849448 \n4 Baccarani M Deininger MW Rosti G Hochhaus A Soverini S Apperley JF Cervantes F Clark RE Cortes JE Guilhot F European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013 Blood 122 872 884 2013 10.1182/blood-2013-05-501569 23803709 \n5 O'Hare T Zabriskie MS Eiring AM Deininger MW Pushing the limits of targeted therapy in chronic myeloid leukaemia Nat Rev Cancer 12 513 526 2012 10.1038/nrc3317 22825216 \n6 Eide CA O'Hare T Chronic myeloid leukemia: Advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors Curr Hematol Malig Rep 10 158 166 2015 10.1007/s11899-015-0248-3 25700679 \n7 Azam M Seeliger MA Gray NS Kuriyan J Daley GQ Activation of tyrosine kinases by mutation of the gatekeeper threonine Nat Struct Mol Biol 15 1109 1118 2008 10.1038/nsmb.1486 18794843 \n8 Cortes JE Kantarjian H Shah NP Bixby D Mauro MJ Flinn I O'Hare T Hu S Narasimhan NI Rivera VM Ponatinib in refractory Philadelphia chromosome-positive leukemias N Engl J Med 367 2075 2088 2012 10.1056/NEJMoa1205127 23190221 \n9 Cortes JE Kim DW Pinilla-Ibarz J le Coutre P Paquette R Chuah C Nicolini FE Apperley JF Khoury HJ Talpaz M A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias N Engl J Med 369 1783 1796 2013 10.1056/NEJMoa1306494 24180494 \n10 Redaelli S Piazza R Rostagno R Magistroni V Perini P Marega M Gambacorti-Passerini C Boschelli F Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants J Clin Oncol 27 469 471 2009 10.1200/JCO.2008.19.8853 19075254 \n11 Redaelli S Mologni L Rostagno R Piazza R Magistroni V Ceccon M Viltadi M Flynn D Gambacorti-Passerini C Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors Am J Hematol 87 E125 E128 2012 10.1002/ajh.23338 23044928 \n12 Barrett AJ Ito S The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century Blood 125 3230 3235 2015 10.1182/blood-2014-10-567784 25852053 \n13 Saussele S Silver RT Management of chronic myeloid leukemia in blast crisis Ann Hematol 94 Suppl 2 S159 S165 2015 10.1007/s00277-015-2324-0 25814082 \n14 Rix LL Remsing Rix U Colinge J Hantschel O Bennett KL Stranzl T Müller A Baumgartner C Valent P Augustin M Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells Leukemia 23 477 485 2009 10.1038/leu.2008.334 19039322 \n15 Cortes JE Kantarjian HM Brummendorf TH Kim DW Turkina AG Shen ZX Pasquini R Khoury HJ Arkin S Volkert A Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib Blood 118 4567 4576 2011 10.1182/blood-2011-05-355594 21865346 \n16 Gambacorti-Passerini C Brümmendorf TH Kim DW Turkina AG Masszi T Assouline S Durrant S Kantarjian HM Khoury HJ Zaritskey A Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up Am J Hematol 89 732 742 2014 10.1002/ajh.23728 24711212 \n17 Khoury HJ Cortes JE Kantarjian HM Gambacorti-Passerini C Baccarani M Kim DW Zaritskey A Countouriotis A Besson N Leip E Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure Blood 119 3403 3412 2012 10.1182/blood-2011-11-390120 22371878 \n18 Kantarjian HM Cortes JE Kim DW Khoury HJ Brümmendorf TH Porkka K Martinelli G Durrant S Leip E Kelly V Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors Blood 123 1309 1318 2014 10.1182/blood-2013-07-513937 24345751 \n19 Cortes JE Kim DW Kantarjian HM Brümmendorf TH Dyagil I Griskevicius L Malhotra H Powell C Gogat K Countouriotis AM Gambacorti-Passerini C Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: Results from the BELA trial J Clin Oncol 30 3486 3492 2012 10.1200/JCO.2011.38.7522 22949154 \n20 Brümmendorf TH Cortes JE de Souza CA Guilhot F Duvillié L Pavlov D Gogat K Countouriotis AM Gambacorti-Passerini C 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imatinib J Clin Oncol 28 2381 2388 2010 10.1200/JCO.2009.26.3087 20385986 \n24 Cortes J Lipton JH Rea D Digumarti R Chuah C Nanda N Benichou AC Craig AR Michallet M Nicolini FE Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation Blood 120 2573 2580 2012 10.1182/blood-2012-03-415307 22896000 \n25 Pemovska T Johnson E Kontro M Repasky GA Chen J Wells P Cronin CN McTigue M Kallioniemi O Porkka K Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation Nature 519 102 105 2015 10.1038/nature14119 25686603 \n26 Donato NJ Wu JY Stapley J Gallick G Lin H Arlinghaus R Talpaz M BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571 Blood 101 690 698 2003 10.1182/blood.V101.2.690 12509383 \n27 Ptasznik A Nakata Y Kalota A Emerson SG Gewirtz AM Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells Nat Med 10 1187 1189 2004 10.1038/nm1127 15502840 \n28 Hu Y Liu Y Pelletier S Buchdunger E Warmuth M Fabbro D Hallek M Van Etten RA Li S Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia Nat Genet 36 453 461 2004 10.1038/ng1343 15098032 \n29 Hu Y Swerdlow S Duffy TM Weinmann R Lee FY Li S Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice Proc Natl Acad Sci USA 103 16870 16875 2006 10.1073/pnas.0606509103 17077147 \n30 Larson RA Is there a best TKI for chronic phase CML? Blood 126 2370 2375 2015 10.1182/blood-2015-06-641043 26585806\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-1074",
"issue": "13(6)",
"journal": "Oncology letters",
"keywords": "T315I mutation; blastic phase; bosutinib; chronic myeloid leukemia; tyrosine kinase inhibitor",
"medline_ta": "Oncol Lett",
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"nlm_unique_id": "101531236",
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"pages": "4285-4289",
"pmc": null,
"pmid": "28599428",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "22371878;24345751;12509383;22949154;12444544;25700679;25686603;24151050;23044928;24180494;15502840;17077147;15098032;25540064;10849448;26585806;19075254;24711212;22896000;23803709;18794843;21865346;25196702;19039322;25814082;25852053;20385986;22825216;23190221",
"title": "Bosutinib as a fourth-line therapy for a patient with T315I-positive lymphoid blastic phase chronic myeloid leukemia: A case report.",
"title_normalized": "bosutinib as a fourth line therapy for a patient with t315i positive lymphoid blastic phase chronic myeloid leukemia a case report"
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"abstract": "BACKGROUND\nThere is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines.\n\n\nOBJECTIVE\nTo investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries.\n\n\nMETHODS\nWe identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.\n\n\nRESULTS\nAntihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible.\n\n\nCONCLUSIONS\nSome second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.",
"affiliations": "Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.;Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.;Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden; Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow, United Kingdom.;Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.;Clinical Pharmacology Unit, University of Verona, Verona, Italy.;Republic Fund for Health Insurance, Belgrade, Serbia.;Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden; Centre for Pharmacoepidemiology, Karolinska University Hospital, Solna, Stockholm, Sweden; Stockholm, County Council, Stockholm, Sweden.;Erasmus University Medical Centre, Rotterdam, Netherlands.;Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.",
"authors": "Poluzzi|Elisabetta|E|;Raschi|Emanuel|E|;Godman|Brian|B|;Koci|Ariola|A|;Moretti|Ugo|U|;Kalaba|Marija|M|;Wettermark|Bjorn|B|;Sturkenboom|Miriam|M|;De Ponti|Fabrizio|F|",
"chemical_list": "D006634:Histamine H1 Antagonists",
"country": "United States",
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"doi": "10.1371/journal.pone.0119551",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2578593410.1371/journal.pone.0119551PONE-D-14-41515Research ArticlePro-Arrhythmic Potential of Oral Antihistamines (H1): Combining Adverse Event Reports with Drug Utilization Data across Europe Use of Antihistamines in Europe and Potential Proarrhythmic RiskPoluzzi Elisabetta \n1\nRaschi Emanuel \n1\nGodman Brian \n2\n\n3\nKoci Ariola \n1\nMoretti Ugo \n4\nKalaba Marija \n5\nWettermark Bjorn \n2\n\n6\n\n7\nSturkenboom Miriam \n8\nDe Ponti Fabrizio \n1\n*\n1 \nDepartment of Medical and Surgical Sciences, Alma Mater Studiorum—University of Bologna, Bologna, Italy\n\n2 \nDivision of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden\n\n3 \nStrathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow, United Kingdom\n\n4 \nClinical Pharmacology Unit, University of Verona, Verona, Italy\n\n5 \nRepublic Fund for Health Insurance, Belgrade, Serbia\n\n6 \nCentre for Pharmacoepidemiology, Karolinska University Hospital, Solna, Stockholm, Sweden\n\n7 \nStockholm, County Council, Stockholm, Sweden\n\n8 \nErasmus University Medical Centre, Rotterdam, Netherlands\nTalkachova Alena Academic Editor\nUniversity of Minnesota, UNITED STATES\nCompeting Interests: All authors have completed the Unified Competing Interest form available on request from the corresponding author. E.P., E.R., A.K., U.M., M.K., B.W., F.D.P. declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. B.W. is involved in the regional Drug and Therapeutics Committee and national groups developing guidance for the rational introduction of new medicines in Sweden. The institution of B.G. (Karolinska Institutet) received part of the grant for the ARITMO project to collect European drug utilization data. M.S. is heading a research group that has received grants and also conducts studies for companies, but none related to the present work. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: EP ER UM FDP MS. Performed the experiments: AK BG MK BW. Analyzed the data: BG AK MK BW. Contributed reagents/materials/analysis tools: AK. Wrote the paper: EP ER AK UM BG MK BW MS FDP.\n\n* E-mail: fabrizio.deponti@unibo.it18 3 2015 2015 10 3 e011955115 9 2014 14 1 2015 © 2015 Poluzzi et al2015Poluzzi et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background\nThere is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in ’90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines.\n\nAim\nTo investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries.\n\nMethods\nWe identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.\n\nResults\nAntihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible.\n\nConclusions\nSome second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.\n\nThe research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 241679 – the ARITMO project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nThere is appreciable utilisation of antihistamines in European countries principally for the treatment of allergies. Their main therapeutic effects are mediated by their activity on H1 receptors in immunoregulating cells, CNS, and smooth muscle. [1].\n\nTheir pharmacological profile can be grouped into either first-generation antihistamines, e.g., diphenhydramine, and second-generation, e.g., cetirizine and loratadine. First-generation agents readily reach the CNS, have high affinity for central H1 receptors and are mainly used in the treatment of disorders related to the vomiting centre (motion sickness, post-operative or drug-induced nausea and vomiting, vertigo, etc.) and for sedation (insomnia and anaesthesia). Second-generation antihistamines only partially cross the blood brain barrier and are preferred in allergic disorders (urticaria, conjunctivitis, rhinitis and hay fever) because of the lack of central side effects [2]. Many administration routes are available for prescribing or self purchasing. Pharmacological properties, indications, route of administration and formulations strongly influence the safety of use of antihistamines.\n\nDrowsiness is the most frequent consequence of the oldest agents, whereas second-generation antihistamines were developed to minimise this effect [1]: only high doses or predisposing factors can impair patients’alertness. Antagonism of muscarinic, serotoninergic and alpha-adrenergic transmission are responsible for other central and peripheral effects including, for instance, blurred vision, urinary retention, constipation, weight gain, and orthostatic hypotension. These side-effects are also more frequent for the first- rather than for the second-generation agents.\n\nCardiac toxicity is less frequent than the side-effects described above. However, it is potentially more severe for patients, with no well defined differences between first and second-generation antihistamines.\n\nBecause of the relatively low incidence, the arrhythmogenic risk has principally been evaluated in preclinical models rather than in patients. In fact, astemizole and terfenadine represented probably the first examples of widely used drugs withdrawn or strongly restricted in the label due to risk of QT prolongation. This regulatory measure was also based on the contemporary marketing approval of many second-generation agents perceived as safer for cardiac risk (e.g., fexofenadine, represents the active metabolite of terfenadine, and was especially developed to avoid the interaction with cardiac potassium channels and relevant ventricular arrhythmia). The accurate clinical evaluation on the arrhythmogenic potential has become mandatory before marketing authorisation (i.e., Thorough QT study—TQT) since 2005. So far, though, these studies have only been conducted for three agents, namely bilastine, levocetirizine and rupatadine, and in all cases provided negative results [3–6].\n\nAlmost all other antihistamines have not been included among drugs with this risk (absence from Arizona CERT list, crediblemeds.org). The only exception is diphenhydramine, which is included in the third list (i.e., conditional risk of TdP: substantial evidence supports the conclusion that these drugs prolong QT and have a risk of developing TdP, but only under certain known conditions).\n\nSummary of Product Characteristics of medicinal products containing antihistamines do not highlight this possible risk, apart from the inclusion of “tachycardia” among rare adverse events in the side effect paragraph. No mention of proarrhythmic risk in cautions was found.\n\nAim\nTo primarily investigate the pro-arrhythmic potential of antihistamines in practice, by combining the analysis of safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries.\n\nThe analysis of spontaneous reporting data will identify antihistamines with alert signals for arrhythmia. Drug utilization data among European Countries will estimate population exposure to these drugs in order to map the level of pro-arrhythmic potential due to antihistamine utilization. The secondary aim is to update physicians and regulators about possible differences in the proarrhythmic potential of antihistamines.\n\nMethods\nEthics Statement\nAll data analyses performed in this retrospective study are based on anonymized data, which did not allow the identification of individual patients. The study dealt with two independent data sources, namely (a) spontaneous reports, which are publicly available from the FAERS database and (b) drug utilization data, which can be accessed by other researchers only upon request to relevant personnel. Therefore, submission to and approval by the Institutional Review Board was waived.\n\nPharmacovigilance Data\nThe FDA Adverse Event Reporting System (FAERS) database contains over 4 million reports of Adverse Drug Reactions (ADRs) of worldwide human drugs and biological products and offers public access to raw data starting from 2004. By virtue of its large population coverage (including all US reports and serious/unexpected reports from European Countries) and free availability, FAERS is an attracting source to explore rare adverse drug reactions (such as arrhythmias) and highly informative of the global pattern of arrhythmogenic events. [7–10].\n\nIn a recent study [9], we described the consensus process to define the arrhythmogenic potential of drugs within the FP7 funded ARITMO project (www.aritmo-project.org). In line with this approach, we decided to investigate the arrhythmogenic potential of antihistamines by collecting all cases reported in the 2004–2011 period on: torsades de pointes (TdP), QT abnormalities (both symptomatic and asymptomatic), ventricular arrhythmia and sudden cardiac death/cardiac arrest (respectively VA and SCD/CA). In particular, we first analyzed cases of TdP or QT abnormalities (TdP/QTabn) as they are strongly intertwined with a high degree of drug-attributable risk, whereas we considered separately ventricular arrhythmia and cardiac arrest/sudden cardiac death (as they are not necessarily correlated with each other, have a lower degree of drug-attributable risk, but represent possible symptomatic consequences of severe QT prolongation and can increase the sensitivity of the analysis).\n\nThe Reporting Odds Ratio (ROR) with 95% CI was calculated for each group of events; disproportion was considered in case of 95% Confidence Interval (95CI) (one-tailed) lower limit >1. In addition, concomitant drugs were taken into account in order to better characterize each single case. We checked for co-reporting of cardiovascular classes (digitalis: C01A; Class I/III antiarrhythmics: C01B; diuretics: C03; beta blockers: C07; calcium channel blockers: C08 and ACE inhibitors/ARBs: C09) and lists I and II of the AZCERT program (crediblemeds.org). AZCERT program currently represents the most authoritative source of evidence on the torsadogenic risk of drugs and it was, therefore, used as a reference to establish the notoriety of the arrhythmogenic risk, in order to discuss the novelty of the signals.\n\nIn order to allow conjunction analyses with drug utilization data and provide a public health perspective, antihistamines were classified based on pharmacovigilance data as follows.\n\nStronger signals: at least 3 cases without concomitant proarrhythmic drugs and ROR lower limit >1for TdP/QTabn.\n\nWeaker signals: at least 3 cases without concomitant proarrhythmic drugs (see above) and ROR lower limit >1for VA or CA/SCD.\n\nDrug Utilization Data\nAfter identification of pharmacovigilance signals from FAERS, drug utilization data allowed us to map the risk derived from exposure to antihistamines in European Countries [10]. In this study, data were collected from administrative databases through health authorities and health insurance personnel across Europe. Consistent and reliable data were obtained from 13 European Countries, which allowed adequate estimation of European population exposure since the 13 Countries have differences in geography and financing of healthcare: i.e. comprised Western (Austria, France, Italy, Norway, Spain [Catalonia], Sweden, and the UK [England and Scotland]), as well as Central and Eastern (Croatia, Serbia, Slovenia, Estonia, Lithuania) European Countries and regions. With only a few exceptions, administrative databases contained data on reimbursed prescriptions in ambulatory care and covered the entire population (see also Raschi et al. [10] for details of data characteristics in each specific Country).\n\nTotal dispensed data (ATC code: R06) were expressed as defined daily doses (DDD) per 1,000 inhabitants per day (now referred to as DID) for the 2005–2009/2010 period. In the analyses, we considered a detectable use of at least 0.01 DID. The mean annual DID value was used to estimate the actual population exposure over the period of interest and to distinguish antihistamine use on the basis of pharmacovigilance signals. A time-trend analysis was also carried out, where appropriate.\n\nResults\nPharmacovigilance Data\nOverall, 27 antihistamines were reported in at least one case of the outcomes of interest. They were found in 109 cases of TdP/QT abnormalities (the most specific case definition); loratadine, cetirizine and diphenhydramine accounted for the highest number of cases (26) and in particular loratadine and cetirizine were reported in 17 and 13 cases of TdP, respectively (Table 1). Eight drugs resulted in a ROR significantly >1 for these outcomes, but only 5 were reported in at least 3 cases without concomitant confounding factors/drugs: cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine (Table 1). On the basis of our signal definition, these five drugs present stronger alert signals.\n\n10.1371/journal.pone.0119551.t001Table 1 Disproportionality analysis for antihistamines with cases of QT prolongation/TdP.\n\tCases of TdP; QTs; QTa\t\nROR\n\t\nCI lower\n\t\nCI upper\n\t\nCases without concomitant AZCERT drugs or CV drugs\n\t\nalimemazine\t0; 2; 3\t9.14\t3.75\t22.28\t2\t\nazelastine\t0; 1, 0\t\nna\n\t\nna\n\t\nna\n\t1\t\ncetirizine\t13; 4; 9\t3.36\t2.28\t4.96\t18\t\ndesloratadine\t0; 2, 5\t3.20\t1.52\t6.74\t5\t\ndexchlorpheniramine\t5; 5; 2\t7.00\t3.94\t12.41\t2\t\ndiphenhydramine\t6; 4; 16\t1.99\t1.35\t2.92\t12\t\ndoxylamine\t0; 0; 1\tna\tna\tna\t1\t\nebastine\t0; 1, 0\tna\tna\tna\t1\t\nepinastine\t1; 0; 0\tna\tna\tna\t0\t\nfexofenadine\t2; 2; 8\t4.03\t2.28\t7.13\t5\t\nketotifen\t0; 0; 4\t2.87\t1.07\t7.69\t2\t\nlevocetirizine\t0; 0; 3\t\n2.63\n\t\n0.84\n\t\n8.19\n\t3\t\nloratadine\t17; 4; 5\t4.79\t3.25\t7.07\t8\t\nmeclozine\t1; 0; 0\t\nna\n\t\nna\n\t\nna\n\t0\t\nmepyramine\t0; 0; 1\t\nna\n\t\nna\n\t\nna\n\t1\t\npromethazine\t2; 2; 5\t\t\n0.91\n\t\n3.39\n\t1\t\nrupatadine\t1; 0; 4\t347.30\t93.24\t1293.68\t0\t\nNOTES: in italic, not statistically significant ROR; na = number of cases <3; TdP = Torsades de Pointes, QTs = symptomatic QT prolongation, QTa = asymptomatic QT prolongation.\n\nBy considering also more sensitive outcomes, antihistamines were reported in 278 cases of VA (Table 2) with the 60% represented by non-fatal ventricular tachycardia (non-fatVT), whereas cases of CA/SCD were 610, covered for the 90% by CA reports (Table 3). Diphenhydramine was largely the most reported agent in both outcomes, followed by cetirizine and loratadine in VA series and loratadine, doxylamine, dexchlorfeniramine and fexofenadine in CA/SCD list.\n\n10.1371/journal.pone.0119551.t002Table 2 Disproportionality analysis for antihistamines with cases of ventricular arrhythmia.\n\tcases of VF; fatVT; non-fatVT\t\nROR\n\t\nCI lower\n\t\nCI upper\n\t\ncases without concomitant AZCERT or CV drugs\n\t\nalimemazine\t0;4;0\t\n1.83\n\t\n0.68\n\t\n4.95\n\t1\t\nazelastine\t1;0;2\t\n1.48\n\t\n0.47\n\t\n4.65\n\t2\t\nbrompheniramine\t0;1;1\t\n0.82\n\t\n0.20\n\t\n3.30\n\t1\t\nbuclizine\t0;0;1\t\nna\n\t\nna\n\t\nna\n\t0\t\ncarbinoxamine\t0;1;2\t\n2.47\n\t\n0.78\n\t\n7.83\n\t3\t\ncetirizine\t7;3;24\t\n1.11\n\t\n0.79\n\t\n1.56\n\t20\t\nchlorphenamine\t0;0;5\t\n1.00\n\t\n0.41\n\t\n2.41\n\t5\t\ncyclizine\t1;0;8\t\n22.54\n\t\n10.63\n\t\n47.77\n\t4\t\ndesloratadine\t1;1;26\t\n3.35\n\t\n2.29\n\t\n4.89\n\t24\t\ndexbrompheniramine\t0;1;1\t\n14.02\n\t\n3.07\n\t\n63.99\n\t2\t\ndexchlorpheniramine\t0;13;13\t\n3.94\n\t\n2.65\n\t\n5.85\n\t19\t\ndiphenhydramine\t6;33;53\t\n1.81\n\t\n1.47\n\t\n2.22\n\t50\t\ndoxylamine\t0;3;1\t\n1.04\n\t\n0.39\n\t\n2.80\n\t2\t\nebastine\t0;0;1\t\nna\n\t\nna\n\t\nna\n\t1\t\nepinastine\t1;0;1\t\n1.77\n\t\n0.44\n\t\n7.22\n\t2\t\nfexofenadine\t1;3;19\t\n1.97\n\t\n1.30\n\t\n2.99\n\t15\t\nketotifen\t0;0;1\t\nna\n\t\nna\n\t\nna\n\t1\t\nlevocetirizine\t0;1;4\t\n1.11\n\t\n0.46\n\t\n2.69\n\t4\t\nloratadine\t5;3;24\t1.49\t1.05\t2.12\t26\t\nmeclozine\t0;0;1\t\nna\n\t\nna\n\t\nna\n\t0\t\npheniramine\t1;0;0\t\nna\n\t\nna\n\t\nna\n\t0\t\nthiethylperazine\t0;1;1\t\n1.89\n\t\n0.26\n\t\n13.81\n\t2\t\ntriprolidine\t0;0;1\t\nna\n\t\nna\n\t\nna\n\t1\t\nNOTES: in italic, not statistically significant ROR; na = number of cases <3;VF = ventricular fibrillation; fatVT = fatal or life-threatening ventricular fibrillation; non-fatVT = other VT cases.\n\n10.1371/journal.pone.0119551.t003Table 3 Disproportionality analysis for antihistamines with cases of cardiac arrest (CA) or sudden cardiac death (SCD).\n\tcases of CA; SCD\t\nROR\n\t\nCI lower\n\t\nCI upper\n\t\ncases without concomitant AZCERT or CV drugs\n\t\nalimemazine\t7;1\t2.77\t1.36\t5.63\t4\t\nazelastine\t4;1\t\n1.84\n\t\n0.75\n\t\n4.49\n\t4\t\nbrompheniramine\t3;3\t\n1.85\n\t\n0.82\n\t\n4.18\n\t6\t\ncarbinoxamine\t8;4\t8.13\t4.42\t14.95\t12\t\ncetirizine\t14;6\t\n0.48\n\t\n0.31\n\t\n0.74\n\t15\t\nchlorcyclizine\t0;1\tna\tna\tna\t0\t\nchlorphenamine\t3;4\t\n1.03\n\t\n0.49\n\t\n2.18\n\t6\t\ncyproheptadine\t15;0\t8.49\t4.92\t14.66\t1\t\ndesloratadine\t10;3\t\n1.11\n\t\n0.64\n\t\n1.93\n\t11\t\ndexchlorpheniramine\t27;8\t3.97\t2.82\t5.60\t21\t\ndimetindene\t0;1\t\nna\n\t\nna\n\t\nna\n\t0\t\ndiphenhydramine\t366;21\t6.13\t5.52\t6.82\t215\t\ndoxylamine\t34;2\t7.83\t5.51\t11.12\t18\t\nebastine\t2;0\t\n2.78\n\t\n0.67\n\t\n11.55\n\t2\t\nfexofenadine\t24;10\t2.17\t1.54\t3.06\t9\t\nlevocetirizine\t5;1\t\n0.98\n\t\n0.44\n\t\n2.21\n\t6\t\nloratadine\t39;4\t1.48\t1.09\t2.01\t17\t\nmeclozine\t3;0\t\n1.13\n\t\n0.36\n\t\n3.54\n\t2\t\nthiethylperazine\t0;1\t\nna\n\t\nna\n\t\nna\n\t1\t\nNOTES: in italic, not statistically significant ROR; na = number of cases <3\n\nAlmost all signals emerging from analysis of TdP/QT abnormalities were confirmed by both groups of more sensitive outcomes (i.e., VA and SCD). The following additional drugs showed signal for at least one outcome group: cyclizine and dexchlorpheniramine appeared as a signal by considering the cases of VA, whereas alimemazine, carbinoxamine, cyproeptadine and doxylamine appeared with the outcomes of CA or SCD (Table 4). These latter 6 drugs could be included in a list of weaker signals.\n\n10.1371/journal.pone.0119551.t004Table 4 Integration of results from different outcomes for signal identification.\n\tAt least 3 Cases of TdP; QTs; QTa\t\nSignificant ROR of TdP-QT\n\t\nAt least 3 Cases of VA\t\nSignificant ROR of VA\n\t\nAt least 3 Cases of CA or SCD\t\nSignificant ROR of CA or SCD\t\nLabeled AZCERT\n\t\nSignal\n\t\nalimemazine\tY\n1\n\n\tY\tY\tN\tY\tY\t\tWeaker\t\nazelastine\tN\tN\tY\tN\tY\tN\t\t\t\nbrompheniramine\tN\tna\tN\tna\tY\tN\t\t\t\nbuclizine\tna\tna\tN\tna\tNa\tna\t\t\t\ncarbinoxamine\tna\tna\tY\tN\tY\tY\t\tWeaker\t\ncetirizine\tY\tY\tY\tN\tY\tN\t\tStronger\t\nchlorphenamine\tNa\tna\tY\tN\tY\tN\t\t\t\ncyclizine\tNa\tna\tY\tY\tNa\tna\t\tWeaker\t\ncyproheptadine\tNa\tna\tna\tna\tY\tY\t\tWeaker\t\ndesloratadine\tY\tY\tY\tY\tY\tN\t\tStronger\t\ndexbrompheniramine\tNa\tna\tN\tna\tNa\tna\t\t\t\ndexchlorpheniramine\tY\n1\n\n\tY\tY\tY\tY\tY\t\tWeaker\n2\n\n\t\ndiphenhydramine\tY\tY\tY\tY\tY\tY\tIII\tStronger\t\ndoxylamine\tN\tna\tY\tN\tY\tY\t\tWeaker\t\nebastine\tN\tna\tN\tna\tN\tna\t\t\t\nepinastine\tN\tna\tN\tna\tNa\tna\t\t\t\nfexofenadine\tY\tY\tY\tY\tY\tY\t\tStronger\t\nketotifen\tY\n1\n\n\tY\tN\tna\tNa\tna\t\t\nborderline\n\n2\n\n\t\nlevocetirizine\tY\tN\tY\tN\tY\tN\t\t\t\nloratadine\tY\tY\tY\tY\tY\tY\t\tStronger\t\nmeclozine\tN\tna\tN\tna\tY\tN\t\t\t\nmepyramine\tN\tna\tna\tna\tNa\tna\t\t\t\npheniramine\tNa\tna\tN\tna\tNa\tna\t\t\t\npromethazine\tY\n1\n\n\tN\tna\tna\tNa\tna\t\t\t\nrupatadine\tY\n1\n\n\tY\tna\tna\tNa\tna\t\t\nborderline\n\n2\n\n\t\nthiethylperazine\tna\tna\tN\tna\tN\tna\t\t\t\ntriprolidine\tna\tna\tN\tna\tNa\tna\t\t\t\n\n1\nless than 3 cases without AZCERT drugs or CV drugs; QTs = symptomatic QT prolongation, QTa = asymptomatic QT prolongation.\n\n\n2 stronger signal was not reached only due to lack of 3 cases without AZCERT drugs or CV drugs\n\n\nDrug Utilization Data\nConsiderable heterogeneity was observed in antihistamine utilization across Europe: e.g., in 2009, this ranged from 0.9 DID in Lithuania to 8.7 in Estonia, 18.8 in Slovenia, 22.4 in Scotland, 37.4 in France and 59.9 in Norway (Fig. 1). However, there was an appreciable increase in antihistamine utilisation throughout the study period. This ranged from a 7% increase in Norway to 21% in Austria (2010 vs 2005). Serbia is an exception, with a peak in 2007 but a negligible variation throughout the study period. Concerning the contribution of different supplying regimens to the collected data, Serbia and Sweden showed very different situations. In Serbia, total utilization including dispensed prescriptions of drugs not covered by the Health Insurance Fund was appreciably higher than reimbursed utilisation (8.8 to 12.3 total vs. 2.0 to 3.2 reimbursed utilisation), whereas in Sweden, there was lower over the counter (OTC) use than reimbursed utilisation (10.1 to 11.6 OTC and 23.3 to 24.6 reimbursed).\n\n10.1371/journal.pone.0119551.g001Fig 1 Cross-National Comparison: time trend.\nAUT: Austria; CRO: Croatia; EST: Estonia; FRA: France; IT: Italy; LIT: Lithuania; NOR: Norway; SPA: Spain (Catalonia); SCO: Scotland; SER: Serbia; SLO: Slovenia; SWE: Sweden. ENG: 2008–2010; EST: 2006–2010; FRA: 2005–2008; ITA: 2006–2010; SPA: 2006–2010; SWE: 2007–2010. Data from Norway and Sweden include also hospital data. Data from Sweden also includes OTC data.\n\nAntihistamines with stronger signals represented a very different percentage of the total antihistamine utilization in each Country, e.g. ranging from 43% in Spain (Catalonia) to 97% in Croatia (Fig. 2). Among these, cetirizine was >29 DID in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia (Fig. 3). Drugs with weak signals accounted for no more than 10% (in Sweden) and in most Countries their use was negligible.\n\n10.1371/journal.pone.0119551.g002Fig 2 Antihistamine utilisation on the basis of pharmacovigilance signals.\n10.1371/journal.pone.0119551.g003Fig 3 Utilisation of different antihistamines with stronger signals.\nDiscussion\nThis study attempts, for the first time, to combine analysis of drug utilisation and pharmacovigilance data to interpret signals of arrhythmogenicity related to antihistamines. Our findings showed signals of arrhythmogenicity especially for second-generation agents for which no previous pharmacovigilance data were published: cetirizine, desloratadine, fexofenadine, loratadine. Among old agents, only diphenhydramine fulfilled criteria for signal generation. These five drugs covered more than 40% of total consumption of antihistamines in each European Country, ranging from 43% in Spain to 97% in Croatia. On the other hand, utilisation of drugs with weaker signal (cyclizine, dexchlorpheniramine, alimemazine, carbinoxamine, cyproeptadine and doxylamine) was negligible, except for Sweden, Norway and France where it ranged from 6 to 10% of total antihistamine utilisation.\n\nConcerning pharmacovigilance results, it should be reminded that generated signals represent input to systematically review all available case-reports in the literature [11] and to perform formal analytical studies (i.e., case-control studies) to confirm or refuse actual causal-effect relationship in order to better substantiate possible regulatory and clinical decisions; on the other hand, signals can per se stimulate attention of regulators and in some cases justify regulatory interventions before confirmation of safety concerns, especially when therapeutic alternatives with solid evidence of safety are available on the market. In this context, Countries with overall high use of antihistamines with unexpected signals (i.e., Croatia, Norway, England and Sweden) should probably take measures to limit population exposure to these drugs. Also the contribution to total exposure from OTC use should be taken into account by regulators, because of difficult patient monitoring by physicians. As a matter of fact, differences seen between Serbia and Sweden may be due to differences in patient co-payments (high vs. low OTC consumption).\n\nWhen findings on antihistamines are compared with those in other therapeutic areas, some general issues should be first considered: the absolute number of cases of arrhythmia is low (especially against antipsychotics and antibiotics [10;12]); patients exposed to antihistamines have probably less risk factors for arrhythmia (most prevalent indications for antihistamine use are mild and not related to cardiovascular comorbidities); on the other hand, strict monitoring of patients treated with antihistamines is rare and this may contribute to the lack of identification of non-severe events (e.g., asymptomatic QT abnormalities). Therefore, reports of arrhythmia by antihistamines are more likely to have a higher drug-attributable component: antihistamines induced arrhythmia less frequently than other drugs, probably because exposed patients had no additional risk factors rather because intrinsically lower risk.\n\nReasons listed above can potentially explain the lack of antihistamines in the AZCERT list. In fact, only diphenhydramine is included in the III list (i.e., weak evidence of risk, which may be clinically relevant only in susceptible patients). All other antihistamines, therefore, generated unknown signals and each of them should be specifically discussed. With regard to desloratadine, a recent prescription event monitoring (PEM) [13] showed no evidence for arrhythmia when used in general practice in England. On fexofenadine, the case of TdP reported in 1999 by Pinto et al. [14] remained the only one in the literature attributed to this agent and all articles published later excluded a drug-attributable risk of arrhythmia [15–17]. On the other hand, it should be acknowledged that fexofenadine monotherapy (i.e. without any concomitant drug) was reported in a not negligible percentage of cases of arrhythmia recorded in FDA Adverse Event Reporting System: 5 out of 12 cases of TdP/QTabn, 15 out of 24 VA cases and 7 out of 34 of CA/SCD cases. As for loratadine and cetirizine, some published papers reported cases of arrhythmia in patients taking poly-pharmacy or overdose [18–22], but the specific contribution of antihistamines in the adverse events was not finally identified. The debate is still ongoing, but so far large observational analyses [23] and preclinical studies [24–26] failed to demonstrate a role of these two agents in cardiac repolarisation impairments.\n\nIn the risk—benefit assessment of each medicine, also indication and setting of use should be taken into account. In particular, some antihistamines are used especially as antinausea/antiemesis drugs, e.g., promethazine and cyclizine. For these drugs, the peculiar clinical setting, i.e., palliative care in patients with cancer or critically-ill patients, may facilitate the occurrence of TdP and a comparison with alternative drugs used in the same conditions, e.g., ondansetron, could better clarify their possible proarrhythmic risk.\n\nSome antihistamines, although not showing clear signals in current analysis, ask for continuing surveillance. Agents largely used only in a few countries also need further investigation on their proarrhythmic risk in the national database. In particular, the very high use of levocetirizine in France (53% of the total defined daily doses of antihistamines) and the fact that most FAERS cases of arrhythmia reporting levocetirizine are from France (8/14) suggests the need to specifically analyse the French spontaneous report databases-. Differences in safety profile, and in signal generation, between enantiomer and racemic mixture (i.e., levocetirizine and cetirizine) should not surprise because of possible differences in doses, metabolism and stereoselective targets [27].\n\nSurveillance is also recommended for antihistamines, which met some of the considered criteria, but did not reach the full definition of signal. This is especially the case of rupatadine, which was marketed in 2008 and shows steadily increasing use: e.g. Spain and Italy showed a consumption of 0.71 and 0.38 defined daily doses in the observed time-window. On the basis of our data, rupatadine was reported in 1 case of TdP and 4 of asymptomatic QT prolongation, reporting odds ratio resulted statistically significant, but in most cases known proarrhythmic drugs were co-prescribed. Information of its proarrhythmic profile includes also a Thorough QT study [6], which provided negative results, and, by contrast, a recent warning from the Italian Medicine Agency on some spontaneous reports of cardiac rhythm impairment [http://www.agenziafarmaco.gov.it/sites/default/files/Rupatadina_29.5.2013.pdf].\n\nHigh consumption of antihistamines in Norway and Sweden found in our study is in line with a previous drug utilisation survey [28], which proposed a higher data quality as potential reason for this finding. In this regard, each Country should check for data quality before definitively deciding regulatory strategies (e.g., Lithuania should verify its very low consumption of antihistamines, which may be due to issues of reimbursement restrictions similar to the situation for proton pump inhibitors and statins versus Western European countries [29]).\n\nStrengths and Limitations\nIntrinsic limitations of pharmacovigilance analyses are well known and should be briefly acknowledged here: [11] while modern adverse event reporting into FAERS suggests that so-called Weber effect and stimulated reporting do not significantly and systematically affect spontaneous reporting analyses [30;31], the issue of under-reporting together with the lack of data on population exposure actually do not allow calculation of incidence rate of ADRs from spontaneous reporting systems, even when they are as large as FDA Adverse Event Reporting System. Therefore, signal detection asks per se for confirmation through additional analytical studies or systematic review of clinical data with relevant meta-analyses, especially for rare events. Our specific methodology attempted to characterize statistically significant signals (i.e., disproportionality formally obtained) considering additional qualitative information (i.e., number of cases without confounders) and the clinical relevance of the event of interest (i.e., TdP, which carries stronger drug-related component as compared to ventricular arrhythmia) in order to prioritize signals for potential regulatory consideration (e.g., according to the extent of local drug use).\n\nAlso drug utilisation data suffer from well-known limitations: discrepancy between supplied and actually administered drugs is common to all drug utilisation data collections. Moreover, in some countries, only reimbursed prescriptions can be collected, and reimbursement systems are heterogeneous across Europe. Also when Countries are able to collect sales data, hospital data could be missing, although for some drug classes (e.g., antihistamines) they represent only a low percentage of the total consumption. Despite limitations, the DDD system is a recognized tool for standardizing doses in drug utilization research and is currently recommended by the WHO for international drug utilization studies [32].\n\nAlthough also serious and rare European reports are submitted to the FDA, our data may be affected by specific drug marketing penetration (e.g., drugs only marketed in Europe). In addition, the characterization of signals is dynamic so that a given antihistamine may change strength of signal (i.e., strong vs weak) depending on the availability of new pharmacovigilance data over time. This is particularly important for drugs classified as weak or borderline signals, which therefore require monitoring in the next years to fully appreciate their actual post-marketing safety profile.\n\nThis study attempted to overcome the lack of information on exposed population in spontaneous reporting sources, by linking FAERS findings with drug consumption. It should be kept in mind that results derived from a combination of both data sources must be interpreted very cautiously, because information are obtained from separate databases, which are affected by different bias (see above). In addition, the link between drug utilization data and spontaneous reports is not straightforward. In most of the cases, adverse events track the magnitude of utilization, meaning that the volume of spontaneous reports largely mirror the prescribing trend. As a matter of fact, it should be acknowledged that antihistamines with strong signal are also largely and consistently used across Europe.\n\nHowever, the aim of our study was to approach pharmacovigilance data (derived by the clinical pharmacology perspective of single patients) in a population risk perspective and to provide risk weighting at the population level. Although pharmacovigilance and drug utilization data sources did not cover the same geographical area (only Europe for drug utilization and theoretically all Countries for pharmacovigilance), we used these two dataset for different purposes: (a) FAERS, the largest public pharmacovigilance database, to accurately classify and characterize torsadogenic signals by antihistamines, and (b) European drug utilization data to map the overall antihistamine use (i.e., estimate the European population exposure).\n\nConclusions\nCombined analysis of pharmacovigilance and drug utilisation data can provide useful elements for clinicians and regulators in terms of population perspectives of safety concerns of drugs.\n\nSome antihistamines resulted in signals of torsadogenic risk and most of them are largely used especially in some European Countries.\n\nNational Agencies should focus their attention on own peculiar uses of antihistamines and define strategies to minimise proarrhythmic potential, also in the light of their multiple place in therapy and the difficulty in monitoring their use by physicians because of the high frequency of self-medication. Educational initiatives focussed on recognition of patient susceptibility and possible differences in the potential risk among single agents should be addressed.\n\nThe authors are indebted to the following data owners for assistance in data collection: Christian Berg (Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway), Marion Bennie (Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow, UK), Iain Bishop (Information Services Division, National Services Scotland, Edinburgh, United Kingdom), Ott Laius (State Agency of Medicines, Tartu, Estonia), Manuela Schmitzer (HVB, Vienna, Austria), Catherine Sermet (IRDES, Paris, France), Kristina Garuoliene (National Reimbursement Unit, Vilnius, Lithuania), Jurij Furst (National Health Insurance Institute, Ljubljana, Slovenia), Ljiljana Sović Brkičic (Croatian Institute for Health Insurance, Zagreb, Croatia), Corrine Zara (Barcelona Health Region, Catalan Health Services, Barcelona, Spain).\n==== Refs\nReferences\n1 \nGrant JA . Molecular pharmacology of second-generation antihistamines . Allergy Asthma Proc \n2000 ; 21 :135 –140 .\n10892514 \n2 \nSimons FE , Simons KJ . Histamine and H1-antihistamines: celebrating a century of progress . J Allergy Clin Immunol \n2011 ; 128 :1139 –1150 . 10.1016/j.jaci.2011.09.005 \n22035879 \n3 \nGraff C , Struijk JJ , Kanters JK , Andersen MP , Toft E , Tyl B . Effects of bilastine on T-wave morphology and the QTc interval: a randomized, double-blind, placebo-controlled, thorough QTc study . Clin Drug Investig \n2012 ; 32 :339 –351 . 10.2165/11599270-000000000-00000 \n22393898 \n4 \nTyl B , Kabbaj M , Azzam S , Sologuren A , Valiente R , Reinbolt E \net al\nLack of significant effect of bilastine administered at therapeutic and supratherapeutic doses and concomitantly with ketoconazole on ventricular repolarization: results of a thorough QT study (TQTS) with QT-concentration analysis . J Clin Pharmacol \n2012 ; 52 :893 –903 . 10.1177/0091270011407191 \n21642470 \n5 \nHulhoven R , Rosillon D , Letiexhe M , Meeus MA , Daoust A , Stockis A . Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study . Eur J Clin Pharmacol \n2007 ; 63 :1011 –1017 .\n17891537 \n6 \nDonado E , Izquierdo I , Perez I , Garcia O , Antonijoan RM , Gich I \net al\nNo cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a 'thorough QT/QTc study' performed according to ICH guidelines . Br J Clin Pharmacol \n2010 ; 69 :401 –410 . 10.1111/j.1365-2125.2009.03599.x \n20406224 \n7 \nPoluzzi E , Raschi E , Motola D , Moretti U , De Ponti F . Antimicrobials and the risk of torsades de pointes: the contribution from data mining of the US FDA Adverse Event Reporting System . Drug Saf \n2010 ; 33 :303 –314 . 10.2165/11531850-000000000-00000 \n20297862 \n8 \nPoluzzi E , Raschi E , Piccinni C , De Ponti F . Data Mining Techniques in Pharmacovigilance: analysis of the publicly accessible FDA Adverse Event Reporting System (AERS)In: Data Mining Applications in Engineering and Medicine ed Karahoca Adem , InTech , 2012 : 265 –302 .\n9 \nPoluzzi E , Raschi E , Koci A , Moretti U , Spina E , Behr ER \net al\nAntipsychotics and torsadogenic risk: signals emerging from the US FDA Adverse Event Reporting System database . Drug Saf \n2013 ; 36 :467 –479 . 10.1007/s40264-013-0032-z \n23553446 \n10 \nRaschi E , Poluzzi E , Godman B , Koci A , Moretti U , Kalaba M \net al\nTorsadogenic risk of antipsychotics: combining adverse event reports with drug utilization data across Europe . PLoS One \n2013 ; 8 :e81208 \n10.1371/journal.pone.0081208 \n24278396 \n11 \nBate A , Evans SJ . Quantitative signal detection using spontaneous ADR reporting . Pharmacoepidemiol Drug Saf \n2009 ; 18 :427 –436 . 10.1002/pds.1742 \n19358225 \n12 \nPoluzzi E , Raschi E , Motola D , Moretti U , De Ponti F . Antimicrobials and the risk of torsades de pointes: the contribution from data mining of the US FDA Adverse Event Reporting System . Drug Saf \n2010 ; 33 :303 –314 . 10.2165/11531850-000000000-00000 \n20297862 \n13 \nLayton D , Wilton L , Shakir SA . Examining the tolerability of the non-sedating antihistamine desloratadine: a prescription-event monitoring study in England . Drug Saf \n2009 ; 32 :169 –179 . 10.2165/00002018-200932020-00009 \n19236123 \n14 \nPinto YM , van G, I , Heeringa M , Crijns HJ . QT lengthening and life-threatening arrhythmias associated with fexofenadine . Lancet \n1999 ; 353 :980 \n10459910 \n15 \nScherer CR , Lerche C , Decher N , Dennis AT , Maier P , Ficker E \net al\nThe antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia . Br J Pharmacol \n2002 ; 137 :892 –900 .\n12411421 \n16 \nDhar S , Hazra PK , Malakar S , Mistri G . Fexofenadine-induced QT prolongation: a myth or fact? \nBr J Dermatol \n2000 ; 142 :1260 –1261 .\n10848773 \n17 \nCraig-McFeely PM , Freemantle SL , Pearce GL , Shakir SA . QT lengthening and life-threatening arrhythmias associated with fexofenadine . Br J Gen Pract \n2000 ; 50 :148 \n10750217 \n18 \nAntonelli D , Atar S , Freedberg NA , Rosenfeld T . Torsade de pointes in patients on chronic amiodarone treatment: contributing factors and drug interactions . Isr Med Assoc J \n2005 ; 7 :163 –165 .\n15792261 \n19 \nAtar S , Freedberg NA , Antonelli D , Rosenfeld T . Torsades de pointes and QT prolongation due to a combination of loratadine and amiodarone . Pacing Clin Electrophysiol \n2003 ; 26 :785 –786 .\n12698686 \n20 \nTsuruoka S , Ioka T , Wakaumi M , Sakamoto K , Ookami H , Fujimura A . Severe arrhythmia as a result of the interaction of cetirizine and pilsicainide in a patient with renal insufficiency: first case presentation showing competition for excretion via renal multidrug resistance protein 1 and organic cation transporter 2 . Clin Pharmacol Ther \n2006 ; 79 :389 –396 .\n16580907 \n21 \nKosoglou T , Salfi M , Lim JM , Batra VK , Cayen MN , Affrime MB . Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine . Br J Clin Pharmacol \n2000 ; 50 :581 –589 .\n11136297 \n22 \nRenard S , Ostorero M , Yvorra S , Zerrouk Z , Bargas E , Bertocchio P \net al [Torsades de pointes caused by cetirizine overdose ]. Arch Mal Coeur Vaiss \n2005 ; 98 :157 –161 .\n15787309 \n23 \nde Abajo FJ , Rodriguez LA . Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs . Br J Clin Pharmacol \n1999 ; 47 :307 –313 .\n10215756 \n24 \nKatchman AN , Koerner J , Tosaka T , Woosley RL , Ebert SN . Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs . J Pharmacol Exp Ther \n2006 ; 316 :1098 –1106 .\n16278312 \n25 \nTaglialatela M , Pannaccione A , Castaldo P , Giorgio G , Zhou Z , January CT \net al\nMolecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines . Mol Pharmacol \n1998 ; 54 :113 –121 .\n9658196 \n26 \nLacerda AE , Roy ML , Lewis EW , Rampe D . Interactions of the nonsedating antihistamine loratadine with a Kv1.5-type potassium channel cloned from human heart . Mol Pharmacol \n1997 ; 52 :314 –322 .\n9271355 \n27 \nCaillet C , Chauvelot-Moachon L , Montastruc JL , Bagheri H . Safety profile of enantiomers vs. racemic mixtures: it's the same? \nBr J Clin Pharmacol \n2012 ; 74 :886 –889 . 10.1111/j.1365-2125.2012.04262.x \n22404187 \n28 \nRavera S , Hummel SA , Stolk P , Heerdink RE , de Jong-van den Berg LT , de Gier JJ . The use of driving impairing medicines: a European survey . Eur J Clin Pharmacol \n2009 ; 65 :1139 –1147 . 10.1007/s00228-009-0695-7 \n19621220 \n29 \nGaruoliene K , Godman B , Gulbinovic J , Wettermark B , Haycox A . European countries with small populations can obtain low prices for drugs: Lithuania as a case history . Expert Rev Pharmacoecon Outcomes Res \n2011 ; 11 :343 –349 . 10.1586/erp.11.24 \n21671703 \n30 \nHoffman KB , Demakas AR , Dimbil M , Tatonetti NP , Erdman CB . Stimulated Reporting: The Impact of US Food and Drug Administration-Issued Alerts on the Adverse Event Reporting System (FAERS) . Drug Saf \n2014 ; 37 :971 –980 . 10.1007/s40264-014-0225-0 \n25255848 \n31 \nHoffman KB , Dimbil M , Erdman CB , Tatonetti NP , Overstreet BM . The Weber effect and the United States Food and Drug Administration's Adverse Event Reporting System (FAERS): analysis of sixty-two drugs approved from 2006 to 2010 . Drug Saf \n2014 ; 37 :283 –294 . 10.1007/s40264-014-0150-2 \n24643967 \n32 \nWorld Health Organization . Introduction to Drug Utilization Research . Oslo : WHO Library Cataloguing-in-Publication Data , 2003 .\n\n",
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"issn_linking": "1932-6203",
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"journal": "PloS one",
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"medline_ta": "PLoS One",
"mesh_terms": "D000284:Administration, Oral; D016907:Adverse Drug Reaction Reporting Systems; D001145:Arrhythmias, Cardiac; D016208:Databases, Factual; D004363:Drug Utilization; D005060:Europe; D006634:Histamine H1 Antagonists; D006801:Humans; D060735:Pharmacovigilance",
"nlm_unique_id": "101285081",
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"pages": "e0119551",
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"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15787309;20406224;10848773;19621220;24278396;9658196;21642470;17891537;15792261;23553446;19236123;10459910;11136297;10892514;25255848;16278312;9271355;10750216;22393898;10215756;12411421;22404187;19358225;24643967;16580907;20297862;21671703;22035879;12698686",
"title": "Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe.",
"title_normalized": "pro arrhythmic potential of oral antihistamines h1 combining adverse event reports with drug utilization data across europe"
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"abstract": "BACKGROUND\nGanglioglioma (GG) and pilocytic astrocytoma (PA) represent the most frequent low-grade gliomas (LGG) occurring in paediatric age. LGGs not amenable of complete resection (CR) represent a challenging subgroup where traditional treatments often fail. Activation of the MAP Kinase (MAPK) pathway caused by the BRAFV600E mutation or the KIAA1549-BRAF fusion has been reported in pediatric GG and PA, respectively.\n\n\nMETHODS\nWe report on a case of BRAFV600E mutated cervicomedullary GG treated with standard chemotherapy and surgery. After multiple relapse, BRAF status was analyzed by immunohistochemistry and sequencing showing a BRAFV600E mutation. Treatment with Vemurafenib as single agent was started. For the first time, a radiological and clinical response was obtained after 3 months of treatment and sustained after 6 months.\n\n\nCONCLUSIONS\nOur experience underline the importance of understanding the driver molecular alterations of LGG and suggests a role for Vemurafenib in the treatment of pediatric GG not amenable of complete surgical resection.",
"affiliations": "Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165, Rome, Italy. fradelbufalo@yahoo.it.;Department of Neuroscience and Neurorehabilitation, Neurosurgery Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant' Onofrio 4, 00165, Rome, Italy. andrea.carai@opbg.net.;Department of Radiology, Unit of Neuroradiology, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant' Onofrio 4, 00165, Rome, Italy. lorenzo.figatalamanca@opbg.net.;Paediatric Neurosurgery Department, Alder Hey Children's NHS Foundation Trust, Liverpool, UK. Benedetta.Pettorini@alderhey.nhs.uk.;Paediatric Neurosurgery Department, Alder Hey Children's NHS Foundation Trust, Liverpool, UK. Conor.Mallucci@alderhey.nhs.uk.;Department of Radiological, Oncological and Pathological Science, Sapienza University, Viale Regina Elena 291, 00161, Rome, Italy. felice.giangaspero@uniroma1.it.;Department of Radiological, Oncological and Pathological Science, Sapienza University, Viale Regina Elena 291, 00161, Rome, Italy. manila_antonelli@yahoo.it.;Bone Marrow Transplantation Unit, Microcitemico Children's Hospital, Via Jenner s/n 09121, Cagliari, Italy. manuelabadiali@asl8cagliari.it.;Public Health, Clinic and Molecular Medicine Department, Microcitemico Children's Hospital, Via Jenner s/n 09121, Cagliari, Italy. lorymoi@hotmail.it.;Pharmacy Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165, Rome, Italy. giuseppe2.bianco@opbg.net.;Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165, Rome, Italy. antonella.cacchione@opbg.net.;Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165, Rome, Italy. franco.locatelli@opbg.net.;Department of Experimental Medicine, Sapienza University, Viale Regina Elena 291, 00161, Rome, Italy. elisabetta.ferretti@uniroma1.it.;Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165, Rome, Italy. angela.mastronuzzi@opbg.net.",
"authors": "del Bufalo|Francesca|F|;Carai|Andrea|A|;Figà-Talamanca|Lorenzo|L|;Pettorini|Benedetta|B|;Mallucci|Conor|C|;Giangaspero|Felice|F|;Antonelli|Manila|M|;Badiali|Manuela|M|;Moi|Loredana|L|;Bianco|Giuseppe|G|;Cacchione|Antonella|A|;Locatelli|Franco|F|;Ferretti|Elisabetta|E|;Mastronuzzi|Angela|A|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf",
"country": "England",
"delete": false,
"doi": "10.1186/s12967-014-0356-1",
"fulltext": "\n==== Front\nJ Transl MedJ Transl MedJournal of Translational Medicine1479-5876BioMed Central London 2552446435610.1186/s12967-014-0356-1ResearchResponse of recurrent BRAFV600E mutated ganglioglioma to Vemurafenib as single agent del Bufalo Francesca fradelbufalo@yahoo.it Carai Andrea andrea.carai@opbg.net Figà-Talamanca Lorenzo lorenzo.figatalamanca@opbg.net Pettorini Benedetta Benedetta.Pettorini@alderhey.nhs.uk Mallucci Conor Conor.Mallucci@alderhey.nhs.uk Giangaspero Felice felice.giangaspero@uniroma1.it Antonelli Manila manila_antonelli@yahoo.it Badiali Manuela manuelabadiali@asl8cagliari.it Moi Loredana lorymoi@hotmail.it Bianco Giuseppe giuseppe2.bianco@opbg.net Cacchione Antonella antonella.cacchione@opbg.net Locatelli Franco franco.locatelli@opbg.net Ferretti Elisabetta elisabetta.ferretti@uniroma1.it Mastronuzzi Angela angela.mastronuzzi@opbg.net Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy Department of Neuroscience and Neurorehabilitation, Neurosurgery Unit, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’ Onofrio 4, 00165 Rome, Italy Department of Radiology, Unit of Neuroradiology, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’ Onofrio 4, 00165 Rome, Italy Paediatric Neurosurgery Department, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK Department of Radiological, Oncological and Pathological Science, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy Neuromed Institute, IRCCS, Via Atinense 18, 86077 Isernia, Pozzilli, IS Italy Bone Marrow Transplantation Unit, Microcitemico Children’s Hospital, Via Jenner s/n 09121, Cagliari, Italy Public Health, Clinic and Molecular Medicine Department, Microcitemico Children’s Hospital, Via Jenner s/n 09121, Cagliari, Italy Pharmacy Unit, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy University of Pavia, Strada Nuova, 27100 Pavia, Italy Department of Experimental Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy 19 12 2014 19 12 2014 2014 12 35627 8 2014 4 12 2014 © del Bufalo et al.; licensee BioMed Central. 2014This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nGanglioglioma (GG) and pilocytic astrocytoma (PA) represent the most frequent low-grade gliomas (LGG) occurring in paediatric age. LGGs not amenable of complete resection (CR) represent a challenging subgroup where traditional treatments often fail. Activation of the MAP Kinase (MAPK) pathway caused by the BRAFV600E mutation or the KIAA1549-BRAF fusion has been reported in pediatric GG and PA, respectively.\n\nCase presentation\nWe report on a case of BRAFV600E mutated cervicomedullary GG treated with standard chemotherapy and surgery. After multiple relapse, BRAF status was analyzed by immunohistochemistry and sequencing showing a BRAFV600E mutation. Treatment with Vemurafenib as single agent was started. For the first time, a radiological and clinical response was obtained after 3 months of treatment and sustained after 6 months.\n\nConclusion\nOur experience underline the importance of understanding the driver molecular alterations of LGG and suggests a role for Vemurafenib in the treatment of pediatric GG not amenable of complete surgical resection.\n\nKeywords\nLow Grade GliomaGangliogliomaMAP Kinase pathwayBRAF V600EVemurafenibissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nGanglioglioma (GG) and pilocytic astrocytoma (PA) represent the most frequent low-grade gliomas (LGG) occurring in paediatric age. When complete resection (CR) is obtained, the prognosis of these tumours is excellent. If CR is not safely achievable, the management can be extremely challenging and often ineffective despite chemo and/or radiotherapy, leading to a worse prognosis.\n\nActivation of the MAP Kinase (MAPK) pathway has been shown to be the main molecular alteration present in LGG and can be caused by duplication or mutation of the BRAF gene [1]. In PA the most frequent genetic alteration consists in a duplication of the 7q34 region leading to a KIAA1549-BRAF fusion protein that is constitutively active whereas in GG the BRAFV600E mutation is more frequent. Inhibitors of MAPK pathway have been considered as a potential target therapy for these tumours [2,3]. Among such inhibitors Vemurafenib, a competitive small molecule that selectively recognizes the ATP binding domain of the BRAFV600E mutant, has proved effective in the treatment of metastatic melanoma, a neoplasm frequently mutated for BRAF. More recently, an activity of this drug was proved also in pediatric BRAFV600E mutated malignant astrocytomas [4-6].\n\nHerein, we report on a case of BRAFV600E mutated cervicomedullary LGG successfully treated with Vemurafenib as single agent after failure of conventional treatment.\n\nCase report\nA 28-month-old boy was transferred to our emergency department from a local hospital in assisted ventilation for a respiratory insufficiency in June 2009. MRI performed during diagnostic work up revealed a bulky mass with cystic component extending from medulla into cervical spinal cord to C5 and dislocating the pons, the floor of the IV ventricle, the cerebellar vermis and tonsils (Figure 1A). As gross total resection (GTR) was not considered feasible, surgical decompression and a biopsy of the exophitic portion of the lesion were performed revealing a LGG with features compatible with PA. Polysomnographic exam revealed a relevant number of episodes of oxygen desaturation >4% of central origin. Tracheotomy was performed and chemotherapy according to the SIOP LGG 2004 protocol started. Unfortunately, the tumour did not respond to treatment showing a gradual clinical and radiological progression with worsening of the nocturnal episodes of desaturation and progressive increase of size of both a cystic portion of the lesion and the solid component (Figure 1B). A second surgery was performed in 2012 in order to reduce the cystic component of the lesion. The histological examination of the residual lesion showed the presence, in addition to the glial component, of mature ganglion cells, leading to a diagnosis of ganglioglioma (GG) (Figure 2) with classical morphology, i.e. neoplastic astrocytes and ganglion cells with dysplastic, binucleated neuron, embedded in tissue with eosinhophilic granular body and lymphocytic intratumoral infiltrate. MRI 3 months after surgery revealed a new disease progression with evidence of multicystic component in the brainstem and cervical spine, which appeared to be related to syringobulbia and syringomyelia secondary to cerebrospinal fluid outflow impairment (Figure 1C). In order to improve local control of the cystic component, a new attempt of debulking was performed; intraoperative brainstem monitoring showed functional responses in the context of the solid component of the tumour and further resection was then abandoned. Two syringe-subarachnoid stents were then inserted to achieve decompression of the cysts. Unfortunately, after an initial stabilization, slow clinical and radiological progression were documented (Figure 1D) and the child began to experience swallowing difficulties and worsening of nocturnal oxygen desaturations. Radiotherapy was not advised due to patient’s age and proton beam therapy was not deemed feasible due to extension of disease in a critical location.Figure 1 \nSerial MRI features of the lesion. Sagittal T2 weighted images show, at onset, a bulky mass extending from medulla into cervical spinal cord, dislocating the pons, the floor of the IV ventricle, the cerebellar vermis and tonsils (A); increased size of both cystic and solid component of the lesion after surgical decompression and chemotherapy (B); a new disease progression three months after second surgery (C); further increase of cystic components (D); a relevant reduction in size of both the solid and the cystic components of the lesion six months after the start of treatment (E).\n\nFigure 2 \nTumor histology at second biopsy. (A) At the second biopsy, the neoplasm showed the presence of clusters of mature ganglion cells (arrow) in the mist of bland astrocytic cells. (B) The ganglion cells showed strong immunoreactivity for synaptophysin (C). Electropherogram illustrate BRAF V600E (GTG/GAG) mutation detection (arrow) in tumor DNA derived from formalin-fixed paraffin-embedded specimens.\n\n\n\nConsidering the progressive clinical deterioration of the patient and the absence of other effective options, molecular testing for evaluation of a target therapy was performed on the tumour tissue from the first biopsy: according to data from the literature, the KIAA-BRAF fusion gene detection and BRAFV600E testing were performed on fresh frozen (FF) tumor tissue by RT-PCR, PCR amplification and subsequent sequencing.\n\nDNA was extracted from FF tissue specimen using the QIAamp DNA Mini Kit, as described by the manufacturer (Qiagen S.A., Courtaboeuf France). Total RNA was extracted from FF tissue using Eurogold Trifast (by Euroclone). DNA and RNA concentrations were quantified using the Nanodrop ND-1000 UV–vis spectrophotometer (Labtech France, Palaiseau, France) and the integrity of nucleic acid was determinated using Quanti-it RNA Assay kit and quanti-dsDNA BR assay kit with Quibit fluorometer (by Invitrogen- Life Technologies). Final products were stored at −20°C until use.\n\nMoreover standard diagnostic procedure were performed. Sections were stained with ematoxilin and eosin, and immunohistochemical stain for synaptophysin (Mouse Monoclonal Antibody Synaptophysin diluition 1:200, Novocastra Clone 27G12), was performed on paraffin section using labelled strepavidin-biotin peroxidise technique. Antigen retrieval was effected by pressure cooking in citrate buffer pH6. The sections was counterstained with hematoxilin.\n\nKIAA1549:BRAF fusion-gene by sequencing\nReverse-transcription polymerase chain reaction (RT-PCR) was performed on 1 μg of total RNA using High Capacity cDNA Reverse Transcriptionkit (Life Technologies) according to the manufacturer’s protocol. The integrity of the resulting cDNA was checked by amplifying the wild-type locus of the BRAF gene (in exon 6 / 7) and then submitted to PCR with specific pairs of primers flanking the fusion point between the KIAA1549 (in exon 15 or 16) and BRAF (in exon 9 or 11) genes as described by Jones et al. [7]. The purified PCR products were then sequenced using the BigDye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems, Courtaboeuf, France) with the forward and reverse primer used to perform the PCR. Sequencing was performed using the ABI 3130 XL DNA analyser (Applied Biosystem). The sequences of primers used were as follows: KIAA1549 exon 15: 5′-CGG AAA CAC CAG GTC AAC GG-3′; KIAA1549 exon 16: 5′-AAA CAG CAC CCC TTC CCA GG-3′; BRAF exon 9: 5′-CTC CAT CAC CAC GAA ATC CTT G-3′; BRAF exon 11: 5′-GTT CCA AAT GAT CCA GAT CCA TTC-3′. RT-PCR from RNA didn’t show the presence of the KIAA1549-BRAF fusion gene (data not shown).\n\nBRAFV600E mutation analysis\nMutational analysis was performed amplifying DNA with the primers as follows: BRAF exon 15, 5′- TCA TAA TGC TTG CTC TGA TAG GA-3′ (sense) and 5′-GGC CAA AAA TTT AAT CAG TGG A-3′ (antisense). The PCR products were purified using the automated system Biomek NXp by Beckman Coulter and Agentcourt AMPure XP reagents. Purified products were submitted to PCR cycle sequencing conditions as follow: denaturation at 95°C for 30 s, annealing at 50°C for 15 s, and extention at 60°C for 240 s. The cycle sequencing products were purified using the same automated system and Agentcourt Clean SEQ reagents. Sequencing analysis was performed using the ABI 3130 XL DNA analyser (Applied Biosystem). DNA analysis sequencing revealed BRAFV600E mutation (Figure 2C).\n\nBased on these results, a treatment with Vemurafenib was started on compassionate use in November 2013 (240 mg, 370 mg/m2, twice a day (BID), equivalent to the minimal dose that proved active in the adult cohort). The therapy was overall well tolerated: accurate dermatological and ECG monitoring were performed and no ECG changes nor skin lesions were observed. The only side effect reported was a transient grade 3 Common Toxicity Criteria (version 4) skin rash that resolved spontaneously. MRI performed 3 months after the start of treatment revealed, for the first time, a reduction in size of both the solid and the cystic components of the disease, a trend confirmed after 6 months of treatment (Figure 1E). Accordingly, clinical symptoms improved with complete restoration of the swallowing function and reduction of the nocturnal episodes of desaturation.\n\nDiscussion\nGangliogliomas are rare, well-differentiated, neuroepithelial tumors that most commonly affect children and young adults. They occur more commonly in the supratentorial region, mostly in the temporal lobe (up to 85%), but can occasionally develop also in the brainstem, cerebellopontine angle, thalamus, optic nerve and spinal cord. Included in the broad category of LGG, they are considered indolent tumors with excellent long-term survival [8].\n\nSurgery is generally recognized as the treatment of choice for GGs, aimed at achieving a safe complete tumour resection [9]. Accordingly, the location of the tumour has also an impact on the PFS, influencing the management of the disease and the possibility of achieving a radical surgery [10]. On these bases, LGGs occurring along the midline (chiasma/hypothalamus, basal ganglia and brainstem) display a poorer outcome as compared to tumours in other locations, with a higher risk of disease progression and an indolent course, resulting in a high OS [11]. The role of chemotherapy in the treatment of LGG is still debated: several approaches have been evaluated showing variable response rates with substantially low 5-years PSF [12]. Despite these results, to date it represents the only available approach to delay RT in younger children with unresectable LGG.\n\nRadiotherapy (RT) is considered the treatment of choice for LGG not amenable of surgical resection, therefore representing the best option for centrally located tumours [13,14]. Unfortunately, adverse effects preclude its use in younger children (until at least 5, possibly 8 years of age), leading to a substantial increase in the risk of progression for this category of patients. Moreover, even when used in older children, long term vasculopathy, hearing loss and neurocognitive and endocrinological sequelae remain a relevant concern [15]. Therefore, taking into consideration the natural history of tumour stabilization, its indolent course and the high likelihood of long-term survival, the use of RT must be carefully weighed.\n\nOur child presented with a rare cervicomedullary GG. Although the histology resulted favorable, the location and the age of the child represented relevant negative prognostic factors, preventing complete surgical removal of the lesion and the use of RT. In order to obtain a stabilization of the disease, standard chemotherapy based on SIOP LGG 2004 protocol was administered. Unfortunately, but not surprisingly, the child clinically and radiologically progressed at the end of the treatment, confirming the indolent but progressive course of this disease.\n\nThe recent finding of driver genomic alterations in BRAF gene in LGG and the development of new molecules that interfere with this deregulated signaling are highly attractive, especially in patients with midline, unresectable tumours, and when RT is not recommended, in order to overcome treatment limitations and improve cure rate.\n\nIn 2008, different groups identified gains at 7q34 of approximately 2 megabases in size in most LGG, representing segmental duplications of the region [1,2,16-18]. This duplication leads to the formation of a fusion between the KIAA1549 locus and BRAF and the resulting protein displays a constitutively activated kinase activity causing an aberrant activation of the downstream MAPK/ERK pathway. Subsequent studies revealed other, less common, molecular alterations in BRAF gene driving activation of the same pathway [3,19,20]: the most frequent is the point mutation that occurs at codon 600 (BRAFV600E), firstly associated with several non-CNS human tumors, that results in substitution of valine by glutamic acid [21,22].\n\nBRAFV600E mutation appears to be particularly associated with paediatric GG where its status changes based on the anatomical location. Although Schindler et al. could not identify it, the mutation seems to be present in a relatively high percentage of cases with brainstem location [3,23-25].\n\nThe prognostic relevance of BRAF duplication/mutation is not clear yet: some reports suggest an association with a better outcome in children displaying BRAF fusion and a trend toward a lower PFS in LGG expressing BRAFV600E mutation while other groups could not confirm these findings [26-30]. Dahiya et al. revealed a significantly worse recurrence-free survival of BRAFV600E-mutated GG compared to negative tumors, suggesting a negative prognostic role for this mutation in GG [8].\n\nNovel therapies targeting the altered BRAF pathway have been developed, including the oral drug Vemurafenib. After showing impressive, although transient, results on recurrent melanoma, it has been approved by the FDA for the treatment of unresectable or metastatic melanoma. The drug proved well tolerated so far in adults, with arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin lesions reported as main toxicities [31]. Overall, a variety of skin toxicities has been reported and therefore a careful examination is recommended during treatment [32].\n\nThe use of an oral target therapy to control the disease in children with unresectable LGG is highly suitable. In vitro and in vivo studies of paediatric astrocytoma cell lines expressing BRAFV600E mutation have been performed and show that target inhibition of mutated BRAF exerts an antiproliferative activity and slows tumour growth, improving survival [4]. With this strong supportive rationale, a safety and pilot efficacy clinical trial of Vemurafenib against BRAFV600E mutant recurrent or refractory LGG in children has recently started (ClinicalTrials.gov Identifier: NCT01748149). To the best of our knowledge, only one report on the use of this drug in pediatric low grade GG has been published and showed encouraging results, in association with vinorelbine [33].\n\nTaking into consideration all these evidences and the persistent progression of our patient, we decided to evaluate the presence of BRAFV600E mutation in order to initiate treatment with Vemurafenib. Since no pharmacokinetic data nor toxicity analysis are available in the pediatric population to date, we decided to start the treatment with the minimal dose that proved active in the adult cohort, and maintained it in consideration of the results shown [34]. The excellent, rapid and sustained response documented in our child after 6 months of treatment shows a relevant efficacy of this small-molecule inhibitor in a challenging subcategory of LGG, although a longer follow-up is required to define the long-term response to this drug. Notably, our patient did not receive any other concurrent chemotherapy, proving that the observed response can be attributed exclusively to the BRAF inhibitor.\n\nThe lesson provided by the use of Vemurafenib in melanoma patients, however, warns treatment [35]. Moreover, in the context of malignant GG, few reports have proved a not uniform activity of Vemurafenib [6]. Although not clear yet, these diverse responses are likely related to the complex genetic aberrations present in malignant gliomas which might induce the overactivation of MAP kinase through alternative pathways, regardless of the BRAF status, and thus impair the efficacy of the treatment. Similarly, the mechanisms underlying the acquired resistance are multiple and not fully understood yet. Most of them rely upon the alternative reactivation of the MAP kinase signaling pathway through the mutational activation of other key molecule of the pathway, such as NRAS, MEK1 or MEK2, or the occurrence of BRAF-V600E splice variants [36-38]. Moreover, MAPK pathway-independent mechanisms of resistance have been also suggested, involving alterations that lead to the upregulation of the PI3K-AKT signaling pathway [39]. Therefore, the combination with either MEK, ERK or PI3K inhibitors might be considered to overcome both intrinsic and acquired resistance.\n\nThe optimal tolerance to the treatment and the advantage of the oral administration represent relevant aspects in the context of LGG as they reduce the burden of the frequent hospitalization that these children and their families face, sometimes for several years. It is important to point out, however, that the induction of secondary cutaneous lesions and the promotion of proliferation of pre-malignant cells harboring RAS mutation in non-cutaneous tissues, reported in some adult patients, raise considerable concern, especially in the pediatric population. Therefore, a careful case-specific consideration of the risk/benefit ratio is mandatory until more detailed documentation will be provided by clinical trials.\n\nConclusions\nTo our knowledge, this is the first case describing the use of Vemurafenib as single agent in paediatric GG. Our experience, although limited to a case report, and the review of the literature underline the importance of understanding the driver molecular alterations of LGG to improve treatment strategies, through target therapies, and ultimately outcome of these patients. As specific BRAF inhibitors are now available, the evaluation of BRAF status in children with tumors not amenable of GTR should be considered in order to offer a valuable therapeutic alternative. A wider molecular signature, moreover, might be required in case of low response or relapse, in order to further improve the activity by multiple targeting. Large clinical trials are needed to further evaluate the pharmacokinetic profile, safety and efficacy of BRAF inhibitor in the treatment of LGG with this signature and the time of suspension of this therapy, considering the possibility of relapse/progression of disease at the end of treatment.\n\nConsent\nWritten informed consent was obtained from the patient’s parent for the publication of this report and any accompanying images.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nFdB contributed to treat the patient and wrote the article; AC performed surgery and wrote the article; BP and CM, performed surgery and followed the patient; LFT performed MRI studies; FG supervised histological and molecular studies and interpreted data; MA, MB and LM performed histological and molecular analysis; GB and AC provided the treatment and contributed to the writing; FL and EF have critically reviewed the manuscript; AM treated the patient, interpreted data and wrote the article. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank patient’s family for collaboration.\n\nSource of fundings\nNo funding was secured for this study.\n==== Refs\nReferences\n1. Pfister S Janzarik WG Remke M Ernst A Werft W Becker N Toedt G Wittmann A Kratz C Olbrich H Ahmadi R Thieme B Joos S Radlwimmer B Kulozik A Pietsch T Herold-Mende C Gnekow A Reifenberger G Korshunov A Scheurlen W Omran H Lichter P BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas J Clin Invest 2008 118 1739 1749 10.1172/JCI33656 18398503 \n2. Jacob K Albrecht S Sollier C Faury D Sader E Montpetit A Serre D Hauser P Garami M Bognar L Hanzely Z Montes JL Atkinson J Farmer JP Bouffet E Hawkins C Tabori U Jabado N Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours Br J Cancer 2009 101 722 733 10.1038/sj.bjc.6605179 19603027 \n3. 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Poulikakos PI Persaud Y Janakiraman M Kong X Ng C Moriceau G Shi H Atefi M Titz B Gabay MT Salton M Dahlman KB Tadi M Wargo JA Flaherty KT Kelley MC Misteli T Chapman PB Sosman JA Graeber TG Ribas A Lo RS Rosen N Solit DB RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E) Nature 2011 480 387 390 10.1038/nature10662 22113612 \n39. Villanueva J Vultur A Lee JT Somasundaram R Fukunaga-Kalabis M Cipolla AK Wubbenhorst B Xu X Gimotty PA Kee D Santiago-Walker AE Letrero R D’Andrea K Pushparajan A Hayden JE Brown KD Laquerre S McArthur GA Sosman JA Nathanson KL Herlyn M Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF‑1R/PI3K Cancer Cell 2010 18 683 695 10.1016/j.ccr.2010.11.023 21156289\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1479-5876",
"issue": "12()",
"journal": "Journal of translational medicine",
"keywords": null,
"medline_ta": "J Transl Med",
"mesh_terms": "D000970:Antineoplastic Agents; D001932:Brain Neoplasms; D002675:Child, Preschool; D018303:Ganglioglioma; D006801:Humans; D007211:Indoles; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; D000077484:Vemurafenib",
"nlm_unique_id": "101190741",
"other_id": null,
"pages": "356",
"pmc": null,
"pmid": "25524464",
"pubdate": "2014-12-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21424530;19016743;22113612;22038996;22157620;22356324;22492957;22665535;23090984;23502427;23358987;23435618;23609006;23583981;23625612;23442159;24265153;24375920;24725538;24238153;24602192;12068308;21274720;19581535;19581536;19603027;19915144;20425220;20818844;20976706;20861086;21156289;17712732;18398503;18408760;18716556;18974108;21610142",
"title": "Response of recurrent BRAFV600E mutated ganglioglioma to Vemurafenib as single agent.",
"title_normalized": "response of recurrent brafv600e mutated ganglioglioma to vemurafenib as single agent"
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"companynumb": "US-ROCHE-2312068",
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"abstract": "Subcutaneous fat necrosis (SCFN) is a rare condition that may occur in the neonatal period. SCFN is an inflammatory disorder of the adipose tissue, usually found in full-term healthy infants who have a history of intrauterine or perinatal distress. It is usually a self-limited condition; however, in some cases, it can get complicated, leading to severe hypercalcemia that may be life-threatening.\n\n\n\nWe report and describe a classic presentation of SCFN that led to severe hypercalcemia refractory to standard treatment. The diagnosis of SCFN was made based on the finding of subcutaneous nodules and of hypercalcemia. The serum calcium level reached 16.6 mg/dL. Hypercalcemia was treated first with intravenous infusions of fluids and furosemide and then of methylprednisolone. This standard treatment was not effective; therefore, we administered a single low dose of zoledronic acid, which, in turn, was efficacious in ultimately managing the hypercalcemia.\n\n\n\nOur case shows how a single low dose of zoledronic acid was safe and effective in managing severe hypercalcemia unresponsive to conventional treatment while minimizing the risk of hypocalcemic rebounds.",
"affiliations": "Division of Pediatrics, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale degli Infermi, Biella, Italy.;U.O.C. Neonatologia - TIN - Nido, ARNAS Civico, Palermo, Italy.;Dipartimento di Scienze per la Promozione della Salute e Materno Infantile G. D'Alessandro, University of Palermo, School of Medicine, Palermo, Italy.;U.O.C. Neonatologia - TIN - Nido, ARNAS Civico, Palermo, Italy.;Division of Pediatrics, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale degli Infermi, Biella, Italy.;U.O.C. Neonatologia - TIN - Nido, ARNAS Civico, Palermo, Italy.",
"authors": "Militello|Maria Angela|MA|;Re|Maria Paola|MP|;Vitaliti|Giuliana|G|;Finazzo|Francesca|F|;Manzoni|Paolo|P|;Vitaliti|Salvino Marcello|SM|",
"chemical_list": "D050071:Bone Density Conservation Agents; D005938:Glucocorticoids; D049994:Sodium Potassium Chloride Symporter Inhibitors; D000077211:Zoledronic Acid; D005665:Furosemide; D002118:Calcium; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0039-1691777",
"fulltext": null,
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"issn_linking": "0735-1631",
"issue": "36(S 02)",
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D050071:Bone Density Conservation Agents; D002118:Calcium; D004351:Drug Resistance; D005218:Fat Necrosis; D005260:Female; D005665:Furosemide; D005938:Glucocorticoids; D006801:Humans; D006934:Hypercalcemia; D007231:Infant, Newborn; D008775:Methylprednisolone; D049994:Sodium Potassium Chloride Symporter Inhibitors; D050151:Subcutaneous Fat; D047929:Term Birth; D000077211:Zoledronic Acid",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "S134-S138",
"pmc": null,
"pmid": "31238374",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of Zoledronic Acid in a Neonate with Subcutaneous Fat Necrosis Complicated with Severe, Refractory Hypercalcemia.",
"title_normalized": "use of zoledronic acid in a neonate with subcutaneous fat necrosis complicated with severe refractory hypercalcemia"
} | [
{
"companynumb": "IT-VALIDUS PHARMACEUTICALS LLC-IT-2021VAL000743",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "BACKGROUND\nThe drip-and-ship approach allows intravenous tissue plasminogen activator therapy and adjuvant endovascular treatment in acute ischemic stroke, even in rural areas. Here, we examined the safety and time course of the drip-and-ship approach.\n\n\nMETHODS\nFifty consecutive cases treated with the drip-and-ship approach (drip-and-ship group) in June 2009 to March 2016 were retrospectively examined. Changes in mean blood pressure, systemic complications, and neurological complications were compared according to method of transportation. Time courses were compared between drip-and-ship and direct admission groups during the same period.\n\n\nRESULTS\nIn the drip-and-ship group, 33 and 17 patients were transferred to hospital by ambulance and helicopter, respectively. One patient suffered hemorrhagic infarction during transportation by ambulance. Mean blood pressure change was lower in patients transferred by helicopter than ambulance (<5 mmHg versus 12.2 mmHg, respectively). The mean onset-to-door times in the drip-and-ship and direct admission groups were 71 and 64 minutes, respectively, and mean door-to-needle times were 70 and 47 minutes, respectively (P =.002). Although mean transportation time from the primary stroke hospital to our hospital was 32 minutes, the entry-to-exit time from the primary stroke hospital was 113 minutes. Thereafter, there was an average delay of 100 minutes until reperfusion compared with the direct admission group.\n\n\nCONCLUSIONS\nDrip-and-ship was relatively safe in this small series. Transportation by helicopter was less stressful for acute ischemic stroke patients. It is important to reduce door-to-needle time and needle-to-departure time in the primary stroke hospital to minimize the time until treatment in cases of acute ischemic stroke.",
"affiliations": "Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan. Electronic address: hishi@yamaguchi-u.ac.jp.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.",
"authors": "Ishihara|Hideyuki|H|;Oka|Fumiaki|F|;Oku|Takayuki|T|;Shinoyama|Mizuya|M|;Suehiro|Eiichi|E|;Sugimoto|Kazutaka|K|;Suzuki|Michiyasu|M|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2017.03.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "26(11)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Acute ischemic stroke; endovascular treatment; reperfusion; t-PA; transportation",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure; D002545:Brain Ischemia; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D010360:Patient Transfer; D012189:Retrospective Studies; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "2477-2481",
"pmc": null,
"pmid": "28935501",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Safety and Time Course of Drip-and-Ship in Treatment of Acute Ischemic Stroke.",
"title_normalized": "safety and time course of drip and ship in treatment of acute ischemic stroke"
} | [
{
"companynumb": "JP-ROCHE-2002780",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Choroid plexus carcinomas (CPCs) are rare, aggressive pediatric brain tumors with no established curative therapy for relapsed disease, and poor survival rates. TP53 Mutation or dysfunction correlates with poor or no survival outcome in CPCs. Here, we report the case of a 4 month-old female who presented with disseminated CPC. After initial response to tumor resection and adjuvant-chemotherapy, the tumor recurred and metastasized with no response to aggressive relapse therapy suggesting genetic predisposition. This patient was then enrolled to a Molecular Guided Therapy Clinical Trial. Genomic profiling of patient tumor and normal sample identified a TP53 germline mutation with loss of heterozygosity, somatic mutations including IDH2, and aberrant activation of biological pathways. The mutations were not targetable for therapy. However, targeting the altered biological pathways (mTOR, PDGFRB, FGF2, HDAC) guided identification of possibly beneficial treatment with a combination of sirolimus, thalidomide, sunitinib, and vorinostat. This therapy led to 92% reduction in tumor size with no serious adverse events, excellent quality of life and long term survival.",
"affiliations": "Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.;Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.",
"authors": "Cornelius|Albert|A|;Foley|Jessica|J|;Bond|Jeffrey|J|;Nagulapally|Abhinav B|AB|;Steinbrecher|Julie|J|;Hendricks|William P D|WPD|;Rich|Maria|M|;Yendrembam|Sangeeta|S|;Bergendahl|Genevieve|G|;Trent|Jeffrey M|JM|;Sholler|Giselle S|GS|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2017.00652",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2017.00652PharmacologyCase ReportMolecular Guided Therapy Provides Sustained Clinical Response in Refractory Choroid Plexus Carcinoma Cornelius Albert *Foley Jessica Bond Jeffrey Nagulapally Abhinav B. Steinbrecher Julie Hendricks William P. D. Rich Maria Yendrembam Sangeeta Bergendahl Genevieve Trent Jeffrey M. Sholler Giselle S. *Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum Health\nGrand Rapids, MI, United StatesEdited by: Nicolas Andre, AP HM, France\n\nReviewed by: Min Hee Kang, Texas Tech University Health Sciences Center, United States; Dhiraj Kumar, University of Texas MD Anderson Cancer Center, United States\n\n*Correspondence: Albert Cornelius Albert.Cornelius@helendevoschildrens.org;Giselle S. Sholler Giselle.SaulnierSholler@helendevoschildrens.orgThis article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Pharmacology\n\n25 9 2017 2017 8 65216 6 2017 01 9 2017 Copyright © 2017 Cornelius, Foley, Bond, Nagulapally, Steinbrecher, Hendricks, Rich, Yendrembam, Bergendahl, Trent and Sholler.2017Cornelius, Foley, Bond, Nagulapally, Steinbrecher, Hendricks, Rich, Yendrembam, Bergendahl, Trent and ShollerThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Choroid plexus carcinomas (CPCs) are rare, aggressive pediatric brain tumors with no established curative therapy for relapsed disease, and poor survival rates. TP53 Mutation or dysfunction correlates with poor or no survival outcome in CPCs. Here, we report the case of a 4 month-old female who presented with disseminated CPC. After initial response to tumor resection and adjuvant-chemotherapy, the tumor recurred and metastasized with no response to aggressive relapse therapy suggesting genetic predisposition. This patient was then enrolled to a Molecular Guided Therapy Clinical Trial. Genomic profiling of patient tumor and normal sample identified a TP53 germline mutation with loss of heterozygosity, somatic mutations including IDH2, and aberrant activation of biological pathways. The mutations were not targetable for therapy. However, targeting the altered biological pathways (mTOR, PDGFRB, FGF2, HDAC) guided identification of possibly beneficial treatment with a combination of sirolimus, thalidomide, sunitinib, and vorinostat. This therapy led to 92% reduction in tumor size with no serious adverse events, excellent quality of life and long term survival.\n\nchoroid plexus carcinomamolecular guided therapymTORTP53IDH2\n==== Body\nIntroduction\nIn January 2011, a 4 month old female presented with increased emesis and a bulging fontanelle and was diagnosed with Choroid Plexus Carcinoma (CPC) in the right ventricle with metastatic tumor cells present in the cerebral spinal fluid (CSF) and leptomeningeal carcinomatosis. After a complete tumor resection, the patient received the following adjuvant-chemotherapy for 12 cycles (cyclophosphamide, carboplatin, etoposide) according to published CPC therapy and was in remission (Berrak et al., 2011).\n\nWithin 1 year of completing chemotherapy the tumor recurred in August 2012 at 23 months of age. MRI revealed new lesions in the right and left ventricles; the spine and CSF were negative for disease. She began treatment with relapse chemotherapy which included bevacizumab, irinotecan, and temozolomide during which time the tumor progressed. This was followed by high dose methotrexate and vincristine which resulted in stable disease but significant vomiting. The patient then received high dose carboplatin and vincristine alternating with ifosfamide and etoposide with stable disease but significant hematologic and infectious toxicity. The patient again received high dose methotrexate and vincristine but at this time had progression of disease and metastases to the spine (Table 1). Notably, the patient had no definitive response to any standard relapse chemotherapy options.\n\nTable 1 Relapse chemotherapy treatment strategy, molecular guided therapy strategy, and associated costs.\n\nDates\tStandard treatment\tResponse\tAdverse events (>Grade 2)\tStandard drugs\tDrug cost $\tDays\tAdditional costs\tSubtotal $ per month\tTotal $ per month\t\nSept–Nov 2012 (3 cycles)\tBevacizumab 10 mg/kg Irinotecan 125 mg/m2 Temodar 140 mg/m2 × 5 days\tP D\tLow blood counts\tTemozolamide Irinotecan Bevacizumab Supportive Meds\t1,500\n 75\n 700\n 1,500\t5 1 1 5\tClinic Facility: $500/day Clinic Exam: $200/day Transfusion: $1,000 each Admission:$4,000/day\tDrug $4,823 Medical $5,900\t$10,723\t\nDec–Jan 2013 (2 cycles)\tMethotrexate 8 gm/m2 Viscristine 1.5 mg/m2\tS D\tLow blood counts Nausea and Vomiting\tMethotrexate Vincristine Supportive Meds\t1,300\n 20\n 1,500\t3 1 4\t\tDrug $6,920 Medical $17,600 AE: $8,000\t$32,520\t\nMar–Jul 2013 (2 cycles of each)\tIfosfamide 1,800 mg/m2 × 5 days Etoposide 100 mg/m2 × 5 days Alternating with: Viscristine 1.5 mg/m2 Carboplatin 560 mg/m2\tS D\tLow blood counts Nausea and Vomiting Infections (Abscess) Anorexia\tIfosfamide Etoposide Supportive Meds Viscristine Carboplatin Supportive Meds\t100\n 20\n 1,500\n 20\n 80\n 1,500\t5 5 5 1 1 3\t\tDrug $4,100 Medical $23,700 AE: $20,000 Drug $4,823 Medical $14,000 AE:$20,000\t$47,800 $38,823\t\nAug–Sept 2013 (1 cycles)\tMethotrexate 8 gm/m2 Viscristine 1.5 mg/m2\tP D\tLow blood counts Nausea/ Vomit Anorexia\tMethotrexate Vincristine Supportive Meds\t1300 20 1,500\t\t\tDrug $6,920 Medical $17,600 AE: $8,000\t$32,520\t\n\tMGT Treatment\t\t\tMGT Drugs\t\t\t\t\t\t\nSept 2013–Sept 2016\tThalidomide 4 mg/kg/day Sunitinib 15 mg/m2/dose Sirolimus 1 mg/m2/day Vorinostat 200 mg/m2/dose Supportive Meds\tP R\tLow blood counts\tThalidomide Sunitinib Sirolimus Vorinostat Supportive Meds\t12,566 2,123 1,252 969 0\t28 21 28 14\t1 Clinic Exam: $220 Sequencing Cost: $2000\t$18,910\t$19,130\t\nPD (Progressive Disease), SD (Stable Disease).\n\nBackground\nChoroid plexus carcinomas (CPCs) are rare, aggressive brain tumors arising from the cerebral ventricular epithelium and comprising 10–20% of intracranial tumors in children less than 1 year of age. The annual incidence is 0.3 cases per million (Sun et al., 2014). CPCs are associated with a poor prognosis with the 5-year event-free survival rate at 10–50% dependent on extent of surgical resection (Wrede et al., 2007; Sun et al., 2014). Adjuvant chemotherapy may be beneficial in CPC (Wrede et al., 2007), but it remains to be determined which agents are the most beneficial. The genetic basis of CPC is poorly understood. CPC is known to have a strong association with Li-Fraumeni Syndrome and TP53 mutations, but understanding of the underlying biology and molecular alterations in these cancers is incomplete. While genome-wide sequence variation, copy number alteration, or methylation have been reported (Rickert et al., 2002; Ruland et al., 2014; Merino et al., 2015; Tong et al., 2015) we do not yet have a comprehensive description of the genomic landscape of CPC. Approximately 50% of patients have—TP53 mutations, while CPCs in patients without a mutation in TP53, harbored other alterations in the p53 pathway, suggesting that p53 signaling dysfunction is involved in CPC formation (Tabori et al., 2010). Patients with TP53 mutations had a worse prognosis, with 100% survival in patients with TP53 wild type tumors and negative TP53 immunostaining, and 0% survival in patients with TP53 immunopositivity, a marker for TP53 dysfunction (Tabori et al., 2010).\n\nCPCs are aggressive tumors and have a high incidence of recurring and spreading to multiple regions of the body (Ogiwara et al., 2012). Lack of epidemiological data, few reported cases, and controversies surrounding treatment regimens makes it difficult to establish a standardized therapeutic approach in managing CPC. Currently, total tumor resection is the primary goal for treatment. A study by Bettegowda et al. found that 80% of patients who underwent gross total resection remained disease free (Bettegowda et al., 2012). In spite of total resection and adjuvant therapy, the tumor relapsed in our patient suggesting underlying genetic predisposition.\n\nA need exists for improved targeted therapy options for patients with CPC, especially with mutations in the TP53 pathway, or other rare cancers. In order to understand the underlying genetic mechanisms of a malignancy genomic sequencing and analysis may lead to identification of novel therapies or repurposing of older medications. One such approach is described here with targeting the tumor biology directed therapy rather than the conventional chemotherapy. It is important to report upon these methods and those who have responded when targeted therapy has been used. Here we report one such exceptional responder.\n\nDiscussion\nResection of one of the progressing tumors was performed and this patient was enrolled on Molecular Guided Therapy NMTRC008 study “Feasibility Trial Using Molecular Guided Therapy for the Treatment of Patients with Relapsed and Refractory Childhood Cancer” after obtaining written informed consent for study and written informed consent was obtained from the patient for the publication of this case report (Clinical Trial Indentifier: NCT01802567, Study ID: NMTRC008). This study was conducted under FDA approval for IDE G100111. Patient safety was evaluated by monitoring of adverse events and response was determined by radiological examination with serial MRI of the brain. The tumor was sent for DNA and RNA sequencing and the genomic analysis was discussed in a Molecular Tumor Board where a precision medicine therapy was designed for this patient.\n\nDNA mutation analysis\nTumor samples from the patient were analyzed for DNA mutation using Ion AmpliSeq™ Cancer Hotspot Panel v2 (Thermo Fisher Scientific, Waltham, MA) on Ion Torrent (Thermo Fisher Scientific) at the Spectrum Health Laboratory. Whole-exome sequencing (WES) was performed at The Translational Genomics Research Institute (TGen) through hybridization using SureSelect Human All Exon 50 Mb kit (Agilent Technologies, Santa Clara, CA) and sequenced on the Illumina HiSeq2000 using paired-end read chemistry and read lengths of at least 105 bp.\n\nThe overall somatic exome mutation burden was low (Table 1, Figure 1A, and Table S1). We found only eight somatic missense substitutions, three frameshift and four somatic insertions/deletions predicted to alter protein sequence at >20% variant allele frequency (VAF) (Table 1). Somatic alterations between 10–20% VAF (Table S1), Loss of Heterozygosity (Table S2), and Germline (Table S3) are reported as Supplementary. Both sequencing technologies identified amino acid substitution IDH2W164C at 23% VAF in the tumor tissue (Table 1, Figure 1B). IDH2 was recognized as cancer genes in a study involving 21 tumor types (Lawrence et al., 2014).\n\nFigure 1 Genomic Analysis of the CPC patient. (A) Circos plot of WES results. (B) Mutation Diagrams of IDH2 and TP53 (Tetramerization) in context of protein domains. (C) Differential gene expression in the CPC patient. Gene expression levels were compared to a normal whole body reference composed of 45 normal tissues and assigned as Z-scores. (D) Schematic presentation of signaling pathways affected in the CPC patient's tumor and drug targets. These pathways include mTOR, PDGFRB, FGF2, HDAC3, and HDAC8. The treatments chosen for this patient include Sunitinib, Thalidomide, Sirolimus, and Vorinostat.\n\nExome sequencing of normal tissue found TP53 amino acid substitution F338C at 51% VAF, demonstrating heterozygosity in the germline. Ion Torrent as well as exome sequencing found this substitution at 81% VAF in the tumor (Table 2, Figure 1B). Exome sequencing of the tumor/normal pair established loss of heterozygosity based on Fisher's exact test (p < 0.01), consistent with the results of Ion Torrent sequencing at much higher coverage. This variant has not been observed in large scale population sequencing studies and is predicted to have functional consequences based on PolyPhen2 and SIFT. It seems reasonable to conclude that the combination of (1) a damaging and rare variant in germline with (2) somatic alteration of the wild type allele (loss of heterozygosity) in the tumor played a role in the development of this tumor. Overall, no known targetable mutations were found for both somatic and germline variation associated with cell proliferative disorders.\n\nTable 2 Description of Somatic acquired point mutations and rare polymorphism detected in CPC patient by whole-exome sequencing.\n\nGene chr:start\tdbSNP\tRef\tAlt\tClassification\tAA change\tTumor (normal) read depth\tTumor VAF (%)\tPolyphen2\tSIFT\tMutation taster\t\nTREH 11:1185290 44\trs11448549\tC\tCG\tFrameshift\tG569fs\t55 (74)\t94\t–\t–\t–\t\nRIC8A 11:209894\trs3832797\tACCC\tA\tProteinDel\tP209del\t43 (44)\t82\t–\t–\t–\t\nKIAA1751 1:1900106\trs61233860\tT\tTCTC\tProteinIns\tK404dup\t38 (27)\t62\t–\t–\t–\t\nOR2T35 1:2488019 44\trs143010547\tTCAGC ACG\tT\tFrameshift\tC203fs\t43 (41)\t51\t–\t–\t–\t\nGGTLC2 22:229892 70\trs2330126\tG\tA\tMissense\tD75N\t21 (28)\t50\tB\tT\tD\t\nFAM205A 9:3472405 9\trs117821239\tG\tA\tMissense\tH1060Y\t43 (98)\t38\tP\tT\tP\t\nCARKD 13:1112908 34\t–\tG\tT\tMissense\tR380L\t35 (28)\t35\t–\t–\t–\t\nSSPO 7:1495185 32\trs11353848\tTC\tT\tFrameshift\tQ4202fs\t49 (43)\t33\t–\t–\t–\t\nPLEKHG5 1:6529182\trs113541584\tTTCC\tT\tProteinDel\tE802del\t37 (28)\t28\t–\t–\t–\t\nNCKIPSD 3:4871634 0\t–\tC\tT\tMissense\tE588K\t47 (67)\t27\tD\tD\tD\t\nOR4N5 14:2061199 4\t–\tT\tG\tMissense\tF34V\t46 (68)\t27\tD\tT\tN\t\nZNF683 1:2669128 6\trs372936882\tCCCAC CGAGC GCTGG GGTGC CCCAG\tC\tProteinDel\tL243_ W250d el\t52(22)\t24\t–\t–\t–\t\nIDH2 15:906318 61\t–\tC\tA\tMissense\tW164C\t30 (22)\t23\tD\tD\tD\t\nFAM198A 3:4307387 3\t–\tG\tA\tMissense\tA40T\t85 (108)\t22\tB\tT\tN\t\nPRB2 12:1154600 6\t–\tG\tA\tMissense\tP336S\t33 (22)\t20\tB\t–\tN\t\nRARE POLYMORPHISM DETECTED AS LOSS OF HETEROZYGOSITY\t\nGene chr:start\tdbSN P\tRef\tAlt\tClassification\tAA change\tTumor (normal) read depth\tNormal VAF (%)\tTumor VAF (%)\tPolyphen2\tSIFT\tMutation taster\t\nTP53 17:7574014\t–\tA\tC\tMissense\tF338C\t35 (52)\t51\t81\tD\tD\tD\t\nRef, Reference Allele; Alt, Alternative (Tumor) Allele; AA, Amino Acid; VAF, Variant Allele Frequency; ProteinDel, in-frame deletion; ProteinIns, in-frame insertion; Polyphen2- B, Benign; P, Possibly damaging; D, Probably damaging; SIFT- D, Deleterious; T, Tolerated; MutationTaster- D, Disease_causing; N, Polymorphism; P, Polymorphism_automatic. Alterations with VAF > 20% and decreasing order included.\n\nCopy number variation\nSeveral segmental changes consistent with chromosomal instability were identified using WES. This includes large-scale gains in chromosomes 4 (p11-q35.2) and 8 (p11.1-q22.2) as well as focal losses at 9p, 11q, 15q, 16q, 17q, and 22q (Figure 1A, Figure S1). Among the genes localized within large-scale gains are well-established oncogenes: FGFR1, FGFR3, KIT, PDGFRA.\n\nPathway analysis and drug targets\nThe resected relapsed tumor sample was sent to the CLIA-certified Clinical Reference Laboratory (CRL) for mRNA expression analysis using U133 2.0 Plus GeneChip (RIN = 9.8). A portion of the same RNA preparation was used for RNA-Seq obtained using Illumina HiSeq2000 at Translational Genomics Research Institute (TGen). The RNA expression levels were compared to a normal whole body reference composed of 45 normal tissues. Differential expression data was interpreted in the context of systems biology annotation for the purpose of identifying activated cellular processes targetable by drugs. Differentially expressed genes are presented as a waterfall graph (Figure 1C). To investigate relationships, mechanisms and functions encoded by differentially expressed genes, z-scores from RNA expression were further analyzed by QIAGEN's Ingenuity Pathway Analysis (IPA, http://www.qiagen.com/ingenuity). IPA identified activation of mTOR signaling pathway (z-score = 2.7). IPA Causal analytics tools predicted activation of TP53 (z-score = 3.7) as an Upstream Regulator, raising the possibility that the consequences of the TP53 mutation are complex. IPA also predicted activation of EIF4E (z-score = 3.2) and “inhibition” of sirolimus drug (z-score = –4.3) by Causal Network Analysis. Our patient also had overexpression of targetable genes namely PDGFRB (z-score = 4.6), FGF2 (z-score = 9.8), histone deacetylase HDAC3 (z-score = 5.2), and HDAC8 (z-score = 2.1).\n\nDrug treatments were identified based on gene expression profile of the patient's tumor (Figure 1D). These genome-wide Z-scores are used as input to OncInsights drug identification service (Intervention Insight LLC, Waltham, MA). The OncInsight's algorithms are based on biomarker rules, drug target expression, network-based methods, drug response, and drug sensitivity signatures (Saulnier Sholler et al., 2015).\n\nMolecular tumor board decision\nBased on the genomic analysis of the subject's tumor, the molecular tumor board consisting of oncologists, pharmacists, bioinformaticians, and researchers, discussed the patient's previous therapy and current condition. Given the incurable nature of the disease and extensive inpatient therapy the patient previously received which caused significant toxicity, the family requested only oral medications to be prescribed to allow time at home. A treatment regimen was chosen with regards to safety, low toxicity, and targeted mechanism. The chosen pharmacologic agents included sirolimus (targeting mTOR), thalidomide (targeting FGF2), sunitinib (targeting PDGFRB), and vorinostat (targeting HDAC) per the overexpression of pathways and genes shown in Figure 1D.\n\nTreatment course and adverse events\nThe therapy was given as described in Table 1 as continuous 28 day cycles. This oral treatment combination was well-tolerated with no serious adverse events or admissions and excellent quality of life. The adverse events noted include expected Grade 3 neutropenia and thrombocytopenia in cycle 3, 10, 15, and 19. In cycle 3, vorinostat was adjusted to 5 days/week and then in cycle 11 the vorinostat was adjusted to 4 days/week to prevent thrombocytopenia. A decision was made in cycle 19 to discontinue vorinostat and at the end of cycle 24 to discontinue sunitinib (due to long term risk of secondary cancers). The patient continues on thalidomide and sirolimus for another 15 cycles without adverse events.\n\nRadiological response—MRI\nAfter 36 months of the MGT treatment, the patient's MRI showed a 92% tumor reduction from 7.1 × 5.3 × 8.9 mm (335 mm3) to 3 × 3 × 3 mm (27 mm3) (Figure 2). The spinal tumor and disease noted in the CSF cleared. It is unclear whether the residual mass is active tumor, matured tumor or fibrosis but it is noted that this has not increased in size while off therapy for 1 year without additional treatment.\n\nFigure 2 Serial MRI imaging of the CPC patient. MRI at the start of molecular guided therapy regimen (left, Sept 2013), at 7 months (March 2014), at 20 months (June 2015), and at 36 months (September 2016). The arrows indicate the location of the tumor and size reduction over the course of treatment.\n\nCost of treatment\nTo assess the overall cost of this repurposed drug therapy we added the drug cost, the cost of inpatient or outpatient care during drug administration, supportive medications and the cost of caring for complications of therapy such as fever and neutropenia, transfusion or continued hospitalization for control of nausea and vomiting. We did not include additional costs such as loss of income to the family from missed days of work, or other incidental costs. We averaged the cost of each therapy per month of treatment and show the results in Table 1. While the MGT required medications of thalidomide, sunitinib, sirolimus, and vorinostat, which were in general more expensive than most chemotherapy medications (except Carboplatin and Avastin), the overall cost of therapy was less each month. One month of MGT cost $19,130 while the high-dose Methotrexate/Vincristine cost $32,520/month, Ifosfamide/Etoposide cost $47,800/month, and Vincristine/Carboplatin cost $38,823/month. Only Temodar/Irinotecan/Avastin was less expensive at $10,723/month.\n\nGenomic analysis\nGenetic basis of CPC is not fully understood, however, it is suggested that germline alterations of TP53 predispose to CPC in humans (Sevenet et al., 1999; Olivier et al., 2003; Tinat et al., 2009; Custodio et al., 2011). This was further shown in animal models that ablation of TP53 function causes CPCs in mice (Brinster et al., 1984; Saenz Robles et al., 1994). Copy number alterations that we identified, large scale gains in chromosomes 4 and 8 as well as a focal loss in chromosome 22q, have been described previously in CPC (Rickert et al., 2002; Ruland et al., 2014; Merino et al., 2015; Tong et al., 2015). In evaluating expression data, Koos et al. (2009) demonstrated activation of PDGFRB in CPC by comparison with choroid plexus papilloma, and quantified response to imatinib in cell culture. Indeed, we found a rare germline missense mutation of TP53F338C in our patient. This variant has not been reported in large scale population sequencing studies. PolyPhen2 and SIFT analysis predicted this missense variant as a damaging mutation that may have pathological consequences. One report suggested this mutant may retain partial transactivity (Kawaguchi et al., 2005). Our analysis further predicted that the patient's tumor expressed only mutant TP53 with loss of heterozygosity of the other wild-type TP53 allele. TP53 mutations with loss of heterozygosity often have high metastatic and chemotherapy resistant properties due to accumulation of mutant TP53 with oncogenic gain-of-function (Gonzalez et al., 1995; Alexandrova et al., 2017). A study reported that whereas prognosis was excellent for CPC patients with wild type TP53, 5-year overall survival of patients with TP53 immunopositivity (TP53 dysfuntion) dropped to 0% (Bettegowda et al., 2012). These findings were consistent with our patient whose tumor relapsed in <2 years and it was refractory to standard aggressive relapse treatments.\n\nWe also identified a novel somatic missense mutation on IDH2W164C. IDH mutations have been found in other cancers particularly gliomas and acute myeloid leukemia (Dang et al., 2010; Yang et al., 2012). The association of IDH mutations and TP53 in tumorigenesis has been explored in gliomas. The majority of the literature examined IDH1, which occurs more frequently. However, Yan et al. did find that 80% of anaplastic astrocytomas and glioblastomas with a mutation in IDH1 or IDH2 also had a mutation in TP53 (Yan et al., 2009). Though the association of IDH1 and TP53 has been examined in the literature, the role of IDH2 remains more difficult to characterize given the relatively few tumors that are IDH2 mutated. The role of IDH2 missense mutation at tryptophan 164 identified in our patient is not known. However, this mutation remains an interesting target to study the tumorigenic mutants of IDH2.\n\nAlthough several compounds have been developed as TP53 mutant inhibitors (Parrales and Iwakuma, 2015), no specific inhibitor has been identified for the particular TP53 mutation found in our patient. Similarly, there was no inhibitor for the IDH2 mutation seen here. This led us to focus our effort toward differentially expressed genes. Pathway analyses identified biological processes and signaling pathways that were significantly enriched for genes of which expressions were altered in the patient's tumor including mTOR pathway, PDGFRB, FGF2, HDAC3, and HDAC8. Interestingly, there appears to be a correlation between mutations identified and pathways/ genes altered in the subject's tumor. For example, activation of wild type TP53 was shown to inhibit mTOR activity and its downstream targets (Feng et al., 2005). Constitutive activation of mTOR pathway in our subject's tumor may presumably be attributed to loss of normal TP53 function. A study found that missense mutations in the TP53 gene caused induction of PDGFRB and metastasis (Weissmueller et al., 2014), similar to what we observed in our patient. These findings emphasized that targeting aberrant pathways is a viable option for the treatment of patients.\n\nAnti-cancer activity of Sirolimus and other mTOR inhibitors have been explored in many cancers (Polivka and Janku, 2014) but very little is known in CPC. Our patient's tumor demonstrated overexpression of EIF4E, an oncogene and downstream molecule of mTOR (Dowling et al., 2010). Targeting mTOR with sirolimus was shown to inhibit EIF4E (Martin et al., 2014). We assumed this will potentially block cell proliferation. FGF2, a known angiogenic factor, was highly upregulated (z-score = 9.86) in our patient's tumor, making it an important target. Thalidomide is a potent inhibitor of angiogenesis and FGF2. Thalidomide was withdrawn from the market due to teratogenicity but, in recent years, there has been a renewed interest in the use of thalidomide as an antitumor agent. The main use of thalidomide is in the treatment of multiple myeloma (Rajkumar et al., 2006). In pediatric brain tumors, thalidomide given as a metronomic therapy in combination with other agents has shown some response (Peyrl et al., 2012; Porkholm et al., 2014). A recent study demonstrated successful treatment of refractory metastatic gastroesophageal adenocarcinoma with thalidomide in combination with rapamycin (sirolimus). The decision to include sunitinib and vorinostat was based on our findings that PDGFRB and HDAC3/8 were overexpressed in our patient's tumor. Sunitinib is an oral small molecule tyrosine kinase inhibitor that has activity against PDGFRB, a proto-oncogene that can be activated in cancer cells (Chow and Eckhardt, 2007). Vorinostat is a known pan HDAC inhibitor (Conti et al., 2010). It has been used in several brain tumor clinical trials both as single agent therapy and in combination with other drugs (Bezecny, 2014). Interestingly, HDAC inhibition through vorinostat was shown to induce degradation of mutant p53 in cancer cells (Marks, 2007; Li et al., 2011). These results further emphasized that there are overlapping pathways between mutations observed in our patient's tumor and biological pathways altered. Treatment with this combination resulted in a sustained response in our patient with excellent quality of life. These findings suggest that this drug combination is a reasonable adjuvant treatment option for relapsed CPC.\n\nConcluding remarks\nMolecularly targeted therapies tailored to the patient's genetic profile offer a novel approach to obtain improved survival outcomes. In this case study, we report a child with recurrent and metastatic CPC. Due to the refractory and incurable nature of the disease, the patient was enrolled on a clinical trial studying molecular guided therapy. Under this protocol, we molecularly profiled the subject's tumor. Genetic variations as well as a number of genes highly over and under expressed relative to normal tissues were identified, which led to a therapeutic plan. After 36 months of the molecular guided therapy treatment, the patient's MRI showed 92% tumor reduction and the metastatic tumor was cleared. The residual 3 mm nodule remaining is not resectable and may no longer be active tumor as this has not increased in size off therapy. The patient, now 6 years old, continues to thrive 1 year after completion of molecular guided therapy treatment (4 years from enrollment on study).\n\nUsing genomic analysis of patient tumors may be one way to identify medications which can be repurposed for new indications. One of the most common criticisms of molecularly guided therapy is the cost of many of the medications, this may not be the case when considering older medications. While some medications may be costlier, our analysis of this patient demonstrated that the overall cost of therapy was less using molecular guided therapy than conventional chemotherapy. When considering the cost of therapy, physicians and payers should consider not only the cost of medications requested, but also the overall cost of therapy including inpatient time and treatment of toxicities.\n\nThis case study demonstrates successful treatment of a patient who presented with a refractory and incurable metastatic CPC and highlights the importance of incorporating molecular guided therapy in treatment options for such cases. To the best of our knowledge, this is the first report of adjuvant therapy in this combination with CSF clearing and a sustained response. This clinical report may guide future clinical trials and therapies that are molecularly-guided for each patient.\n\nAuthor contributions\nExperimental Design of Clinical Trial: GS, JT, JF, AC, and GB. Patient Care of Case: AC, JS, JF, and MR. Bioinformatic Analysis: JB, AN, and WH. Data Analysis: GS, AC, WH, AN, JT, and MR. Writing of Manuscript: AC, GS, JF, MR, and JS. Editing of Manuscript: SY, GS, and GB.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. The funding sources include Dell, Beat NB Foundation, Meryl and Charles Witmer Foundation. The funding organizations did not have a role in the research or writing of the manuscript. The research was approved by the Western Institutional Review Board as well as by local Institutional Review Boards at 21 enrolling hospitals.\n\nSupplementary material\nThe Supplementary Material for this article can be found online at: http://journal.frontiersin.org/article/10.3389/fphar.2017.00652/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\nAlexandrova E. M. Mirza S. A. Xu S. Schulz-Heddergott R. Marchenko N. D. Moll U. M. (2017 ). p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo . Cell Death Dis. \n8 :e2661 \n10.1038/cddis.2017.80 28277540 \nBerrak S. G. Liu D. D. Wrede B. Wolff J. E. (2011 ). Which therapy works better in choroid plexus carcinomas? \nJ. 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Manchado E. Saborowski M. Morris J. P. Wagenblast E. Davis C. A. . (2014 ). Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling . Cell \n157 , 382 –394 . 10.1016/j.cell.2014.01.066 24725405 \nWrede B. Liu P. Wolff J. E. (2007 ). Chemotherapy improves the survival of patients with choroid plexus carcinoma: a meta-analysis of individual cases with choroid plexus tumors . J. Neurooncol. \n85 , 345 –351 . 10.1007/s11060-007-9428-x 17576522 \nYan H. Parsons D. W. Jin G. McLendon R. Rasheed B. A. Yuan W. . (2009 ). IDH1 and IDH2 mutations in gliomas . N. Engl. J. Med. \n360 , 765 –773 . 10.1056/NEJMoa0808710 19228619 \nYang H. Ye D. Guan K. L. Xiong Y. (2012 ). IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives . Clin. Cancer Res. \n18 , 5562 –5571 . 10.1158/1078-0432.CCR-12-1773 23071358\n\n",
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"journal": "Frontiers in pharmacology",
"keywords": "IDH2; TP53; choroid plexus carcinoma; mTOR; molecular guided therapy",
"medline_ta": "Front Pharmacol",
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"pmid": "28993730",
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"references": "20692206;14583457;24838514;19717644;17576522;9816078;24068529;16365178;21445348;23708663;22147459;17322921;10521299;24390350;25336695;15928081;20308654;21637290;25720842;24725405;19652052;21970783;17327610;20005306;22938081;24478045;11891207;8139568;24333502;23071358;24692119;26732534;19228619;25965574;6327063;28277540;16007150;20976614;20460513",
"title": "Molecular Guided Therapy Provides Sustained Clinical Response in Refractory Choroid Plexus Carcinoma.",
"title_normalized": "molecular guided therapy provides sustained clinical response in refractory choroid plexus carcinoma"
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"abstract": "The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1).\n\n\n\nNon-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin's lymphoma. Drug concentrations were measured by HPLC.\n\n\n\nIn the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration-time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin's lymphoma.\n\n\n\nBased on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin's lymphoma.",
"affiliations": "Department of Family and Child Nursing, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.;Department of Pharmacy, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.;Center for Cancer Research, National Cancer Institute, 8560 Progress Drive, Fredrick, MD, 21702, USA.;Department of Pharmacy, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.;Swedish Cancer Institute, Swedish Medical Center, 1221 Madison St #500, Seattle, WA, 98104, USA.;Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, 200 First St SW, Rochester, MN, 55905, USA.;Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, 200 First St SW, Rochester, MN, 55905, USA.;Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, 200 First St SW, Rochester, MN, 55905, USA.;Department of Pharmacy, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.;Department of Pharmacy, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. mhebert@u.washington.edu.",
"authors": "Kantrowitz-Gordon|Ira|I|;Hays|Karen|K|;Kayode|Olumide|O|;Kumar|Aditya R|AR|;Kaplan|Henry G|HG|;Reid|Joel M|JM|;Safgren|Stephanie L|SL|;Ames|Matthew M|MM|;Easterling|Thomas R|TR|;Hebert|Mary F|MF|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D001761:Bleomycin; D014747:Vinblastine; C027169:5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide; D003606:Dacarbazine; D004317:Doxorubicin; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide",
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"issue": "81(3)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Dacarbazine; Metabolites; Pharmacokinetics; Pregnancy",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D016903:Drug Monitoring; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D007231:Infant, Newborn; D009367:Neoplasm Staging; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D016896:Treatment Outcome; D014747:Vinblastine",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "455-460",
"pmc": null,
"pmid": "29305638",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "7172404;17666365;24531558;20666963;22845052;1260772;22570290;5728154;6616025;179708;7362796;23749243;21328291;7459286;15480663;10473105;11318431;4026274;16326099;14902970;1424418;1587764;17710513;15601802;15696014",
"title": "Pharmacokinetics of dacarbazine (DTIC) in pregnancy.",
"title_normalized": "pharmacokinetics of dacarbazine dtic in pregnancy"
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{
"abstract": "Acute vascular injury during total knee arthroplasty (TKA) is an extremely rare complication, but one which can have devastating consequences threatening the limb and/or life of the patient if not diagnosed and managed at the earliest. The clinical presentation can vary from acute haemorrhage or ischemia in the peri operative period; to a delayed presentation of recurrent swelling and pain secondary to a geniculate or popliteal artery pseudoaneurysm. This is the first reported case of an acute inferolateral genicular artery haemorrhage following TKA and the associated medical complications. It was successfully managed with emergency percutaneous endovascular coiling and appropriate medical management. This case highlights that clinical suspicion, prompt diagnosis and urgent intervention with a multidisciplinary approach can help successfully manage a vascular insult.",
"affiliations": "P D Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim (West), Mumbai, 400016, Maharashtra, India.;P D Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim (West), Mumbai, 400016, Maharashtra, India.;P D Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim (West), Mumbai, 400016, Maharashtra, India.;P D Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim (West), Mumbai, 400016, Maharashtra, India.;P D Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim (West), Mumbai, 400016, Maharashtra, India.;P D Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim (West), Mumbai, 400016, Maharashtra, India.;P D Hinduja Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim (West), Mumbai, 400016, Maharashtra, India.",
"authors": "Agarwala|Sanjay|S|;Menon|Aditya|A|;Gupta|Manas|M|;Kulkarni|Aniruddha|A|;Kapadia|Farhad|F|;Padate|Balakrishna|B|;Dubey|Abha|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.jcot.2018.04.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0976-5662",
"issue": "10(5)",
"journal": "Journal of clinical orthopaedics and trauma",
"keywords": "Arterial haemorrhage; Disseminated intravascular coagulation; Endovascular coiling; Haemarthrosis; Lateral genicular artery injury; Total knee arthroplasty; Vascular injury",
"medline_ta": "J Clin Orthop Trauma",
"mesh_terms": null,
"nlm_unique_id": "101559469",
"other_id": null,
"pages": "991-994",
"pmc": null,
"pmid": "31528082",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "12508712;12540673;12915840;14681604;15788322;18162694;18676115;20452472;20580198;23433418;23747133;24482614;25467223;28445317",
"title": "Multidimensional management of a vascular injury following total knee arthroplasty: A rare case report.",
"title_normalized": "multidimensional management of a vascular injury following total knee arthroplasty a rare case report"
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"abstract": "BACKGROUND\nLittle is known about the internet search activity of people with suicidal thoughts and behaviors (STBs). This data source has the potential to inform both clinical and public health efforts, such as suicide risk assessment and prevention.\n\n\nOBJECTIVE\nWe aimed to evaluate the internet search activity of suicidal young people to find evidence of suicidal ideation and behavioral health-related content.\n\n\nMETHODS\nIndividuals aged between 15 and 30 years (N=43) with mood disorders who were hospitalized for STBs provided access to their internet search history. Searches that were conducted in the 3-month period prior to hospitalization were extracted and manually evaluated for search themes related to suicide and behavioral health.\n\n\nRESULTS\nA majority (27/43, 63%) of participants conducted suicide-related searches. Participants searched for information that exactly matched their planned or chosen method of attempting suicide in 21% (9/43) of cases. Suicide-related search queries also included unusual suicide methods and references to suicide in popular culture. A majority of participants (33/43, 77%) had queries related to help-seeking themes, including how to find inpatient and outpatient behavioral health care. Queries related to mood and anxiety symptoms were found among 44% (19/43) of participants and included references to panic disorder, the inability to focus, feelings of loneliness, and despair. Queries related to substance use were found among 44% (19/43) of participants. Queries related to traumatic experiences were present among 33% (14/43) of participants. Few participants conducted searches for crisis hotlines (n=3).\n\n\nCONCLUSIONS\nIndividuals search the internet for information related to suicide prior to hospitalization for STBs. The improved understanding of the search activity of suicidal people could inform outreach, assessment, and intervention strategies for people at risk. Access to search data may also benefit the ongoing care of suicidal patients.",
"affiliations": "Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, United States.;Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, United States.;Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, United States.;Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, United States.;Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, United States.;Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, United States.",
"authors": "Moon|Khatiya C|KC|https://orcid.org/0000-0002-1496-4447;Van Meter|Anna R|AR|https://orcid.org/0000-0003-0012-206X;Kirschenbaum|Michael A|MA|https://orcid.org/0000-0002-5365-1822;Ali|Asra|A|https://orcid.org/0000-0001-8552-330X;Kane|John M|JM|https://orcid.org/0000-0002-2628-9442;Birnbaum|Michael L|ML|https://orcid.org/0000-0002-4285-7868",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.2196/28262",
"fulltext": "\n==== Front\nJMIR Ment Health\nJMIR Ment Health\nJMH\nJMIR Mental Health\n2368-7959\nJMIR Publications Toronto, Canada\n\nv8i10e28262\n34677139\n10.2196/28262\nOriginal Paper\nOriginal Paper\nInternet Search Activity of Young People With Mood Disorders Who Are Hospitalized for Suicidal Thoughts and Behaviors: Qualitative Study of Google Search Activity\nTorous John\nBin Morshed Mehrab\nDi Matteo Daniel\nMoon Khatiya C MD https://orcid.org/0000-0002-1496-4447\n12Department of Psychiatry Zucker Hillside Hospital 75-59 263rd Street Kaufmann Building, Suite k204 Glen Oaks, NY, 11004 United States 1 7184704367 kmoon2@northwell.edu\n\nVan Meter Anna R PhD 123https://orcid.org/0000-0003-0012-206X\n\nKirschenbaum Michael A MD 12https://orcid.org/0000-0002-5365-1822\n\nAli Asra MA 13https://orcid.org/0000-0001-8552-330X\n\nKane John M MD 123https://orcid.org/0000-0002-2628-9442\n\nBirnbaum Michael L MD 123https://orcid.org/0000-0002-4285-7868\n\n1 Department of Psychiatry Zucker Hillside Hospital Glen Oaks, NY United States\n2 Department of Psychiatry The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, NY United States\n3 Feinstein Institute of Medical Research Manhasset, NY United States\nCorresponding Author: Khatiya C Moon kmoon2@northwell.edu\n10 2021\n22 10 2021\n8 10 e282625 3 2021\n16 5 2021\n1 6 2021\n22 6 2021\n©Khatiya C Moon, Anna R Van Meter, Michael A Kirschenbaum, Asra Ali, John M Kane, Michael L Birnbaum. Originally published in JMIR Mental Health (https://mental.jmir.org), 22.10.2021.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Mental Health, is properly cited. The complete bibliographic information, a link to the original publication on https://mental.jmir.org/, as well as this copyright and license information must be included.\n\nBackground\n\nLittle is known about the internet search activity of people with suicidal thoughts and behaviors (STBs). This data source has the potential to inform both clinical and public health efforts, such as suicide risk assessment and prevention.\n\nObjective\n\nWe aimed to evaluate the internet search activity of suicidal young people to find evidence of suicidal ideation and behavioral health–related content.\n\nMethods\n\nIndividuals aged between 15 and 30 years (N=43) with mood disorders who were hospitalized for STBs provided access to their internet search history. Searches that were conducted in the 3-month period prior to hospitalization were extracted and manually evaluated for search themes related to suicide and behavioral health.\n\nResults\n\nA majority (27/43, 63%) of participants conducted suicide-related searches. Participants searched for information that exactly matched their planned or chosen method of attempting suicide in 21% (9/43) of cases. Suicide-related search queries also included unusual suicide methods and references to suicide in popular culture. A majority of participants (33/43, 77%) had queries related to help-seeking themes, including how to find inpatient and outpatient behavioral health care. Queries related to mood and anxiety symptoms were found among 44% (19/43) of participants and included references to panic disorder, the inability to focus, feelings of loneliness, and despair. Queries related to substance use were found among 44% (19/43) of participants. Queries related to traumatic experiences were present among 33% (14/43) of participants. Few participants conducted searches for crisis hotlines (n=3).\n\nConclusions\n\nIndividuals search the internet for information related to suicide prior to hospitalization for STBs. The improved understanding of the search activity of suicidal people could inform outreach, assessment, and intervention strategies for people at risk. Access to search data may also benefit the ongoing care of suicidal patients.\n\nsuicide\nmood disorders\ndepression\ninternet\nsearch engine\nGoogle search\ndigital health\nmobile health\nadolescent\nyoung adult\n==== Body\npmcIntroduction\n\nThe high prevalence of suicidal behaviors is a public health crisis. Suicide is a leading cause of death among young people in the United States and accounts for nearly 1 million deaths annually worldwide [1]. Suicidality is a major target of both preventative public health efforts and clinical behavioral medicine. Nonetheless, after decades of research, little progress has been made in the prediction and reduction of suicide incidence [2]. Innovative approaches are needed to identify individuals at high risk for suicide and to engage them in care.\n\nTechnology has the great potential to aid these efforts by improving the current methods for assessing suicidal thoughts and behaviors (STBs) both in and outside of clinical settings. STBs are traditionally evaluated with intermittent semistructured patient interviews or with patient self-report measures. Unfortunately, both purposeful concealment and the underreporting of STBs are common [3,4]. Additionally, traditional clinical assessment does not occur often enough to reveal the day-to-day fluctuations of STBs that patients experience [5-7]. Prior studies have demonstrated that data gathered from various digital platforms, including smartphone apps, wearable devices, social media, and internet search engines, can enhance the traditional evaluation of STBs and other psychiatric symptoms [5,6,8-10]. The use of these information sources is acceptable to patients [9,11,12], and data gathered from digital platforms can be collected passively in real time and in the same settings in which patients are likely to experience symptoms. Thus, digital data have greater potential to provide a more complete assessment of STBs compared to data collected via traditional methods. There is also emerging evidence that aggregates of digital data can be used to create digital phenotypes—clusters of symptoms and behaviors that correlate with outcomes—of patients with STBs [13]. The improved characterization of these phenotypes could enhance suicide risk prediction models for both individuals and populations.\n\nLittle is known about the internet search activity of people with STBs, but this digital data source has the potential to improve both clinical and public health efforts, such as suicide risk assessment and prevention. Google is the most highly trafficked website in the world [14]. In a survey, a majority (59%) of young people reported learning about suicide from web-based sources [15]. Young people who report that they engage in STBs also report that they have been exposed to web-based, suicide-related content [16,17]. Incorporating search data into the assessment of STBs confers a number of advantages over traditional clinical assessment methods. For example, search data do not rely on self-reports, making these data less susceptible to purposeful concealment, accidental omission, or recall bias. Additionally, search data leave a longitudinal record that can provide a more accurate characterization of the temporal evolution of STBs. Finally, search data can facilitate the delivery of search engine–driven, just-in-time interventions that aim to prevent suicide attempts—a feat that is incredibly challenging to accomplish with the current interval clinical assessment model [10].\n\nMost previous literature on examining suicide-related internet search activity has relied on either population-level data from search trends or self-reports of search activity from samples of participants in the community whose suicide risk levels and psychiatric histories are unknown. These methods have some important limitations, including the fact that population-level data do not necessarily correlate with individual-level behavior patterns, thus limiting their clinical utility [18]. Additionally, studies that rely on self-reports are limited by recall bias as well as a lack of objective corroboration of symptoms and behaviors.\n\nTo determine if search data are capable of providing information on the clinically meaningful contexts surrounding suicidality, we performed a qualitative analysis of search data collected from adolescents and young adults who were diagnosed with mood disorders and hospitalized for STBs. To our knowledge, this is the first study in which search archives were extracted directly from participants with confirmed clinical diagnoses and established STBs. We hypothesized that participants’ search activity would include references to behavioral health and suicide-related information in the months before a psychiatric hospitalization for STBs.\n\nMethods\n\nRecruitment\n\nParticipants aged between 15 and 30 years who had previously been diagnosed with a primary mood disorder were screened for eligibility by Northwell Health’s Zucker Hillside Hospital inpatient and outpatient psychiatric departments. We focused on individuals with mood disorders because STBs are a more common reason for hospitalization in this population. Only individuals who had been hospitalized due to STBs were included in this study. Recruitment occurred between March 2016 and December 2018. This study was approved by the Institutional Review Board of Northwell Health. Written informed consent was obtained from adult participants and legal guardians of participants aged under 18 years. Assent was obtained from participating minors. All participants were receiving treatment as usual.\n\nData Collection\n\nParticipants were asked to extract their search activity by logging on to their Google account and requesting their data archive. Participation involved 1 to 2 visits after consent, during which all historical search data were requested, downloaded, and collected. These data archives included user-generated search terms that were time-stamped. Historical clinical data, including dates of psychiatric hospitalizations, presenting symptoms, and diagnoses, were obtained from medical records.\n\nFor this study, we focused just on search data from the 3-month period prior to each psychiatric hospitalization for STBs. We selected 3 months because we thought that this amount of time represented a period that was long enough to adequately capture suicide-related searches (SRSs) that were conducted as symptoms escalated to the point of necessitating hospitalization. If a participant experienced multiple hospitalizations, each hospitalization was evaluated as a distinct entity with its own corresponding search history. Thus, there were more search histories than there were participants. If a participant had multiple hospitalizations in a 3-month period, overlapping search queries were only analyzed once.\n\nData Analysis\n\nFive reviewers (authors AA, MLB, MAK, ARVM, and KCM) simultaneously manually reviewed each search query and extracted those that included terms related to suicide and behavioral health. Relevant searches were highlighted. The findings were then discussed as a team to reach a consensus and identify relevant search categories. Extracted search terms were then coded into 5 thematic categories. These included STBs, help seeking, symptoms of mental health disorders, trauma and negative life events, and drugs of abuse. A similar method of categorization was previously used successfully by our group in a study of the search queries of patients with psychosis [8]. These thematic categories coincided with factors that are recognized as modulators of suicide risk [19] and were chosen because they were thought to be sufficiently broad enough to capture a wide array of behavioral health–related symptoms and behaviors that are searched for by individuals.\n\nThe reviewers excluded ambiguous searches unless additional clinical context was available. For example, searches involving the name of prescription medications that could also be used as drugs of abuse (ie, Adderall [dextroamphetamine-amphetamine] and Xanax [alprazolam]) were counted in the analysis only if they included additional content that could guide categorization (eg, “how to overdose on klonopin” or “side effects of adderall”) but not if they were limited to the name of the medication alone. We also excluded searches that were not germane to suicide or behavioral health.\n\nThe reviewers familiarized themselves with the available clinical documentation prior to the assessment of search histories. The available clinical documentation included patient demographics, the primary diagnosis, the reason for hospitalization, and the attempted or planned method of suicide. Knowledge of the clinical documentation was used to contextualize search content and assess if flagged search queries were in fact related to the participants’ clinically documented symptoms and behaviors. Reviewers met as a team to resolve discrepancies in the appropriate categorization of individual search queries.\n\nResults\n\nParticipants’ Characteristics and Search Themes\n\nA total of 43 participants provided access to their Google search data. These 43 participants had 63 hospitalizations for STBs (number of hospitalizations per person: mean 1.5). Search histories from the 3-month period prior to each hospitalization were extracted and analyzed. A total of 37,738 search queries were reviewed. Participant demographics are summarized in Table 1. The prevalence of different search themes among participants is presented in Table 2.\n\nTable 1 Participant demographics.\n\nCharacteristic\tValue\t\nAge (years), mean (SD)\t20.6 (3.1)\t\nGender, n (%)\t\n\n\tMale\t18 (42)\t\n\n\tFemale\t25 (58)\t\nRace, n (%)\t\n\n\tBlack or African American\t8 (19)\t\n\n\tAsian American or Pacific Islander\t6 (14)\t\n\n\tWhite\t21 (48)\t\n\n\tMixed or other\t8 (19)\t\nEthnicity, n (%)\t\n\n\tHispanic or Latino\t10 (23)\t\n\n\tNot Hispanic or Latino\t32 (74)\t\n\n\tUnknown\t1 (2)\t\nPrimary diagnosis, n (%)\t\n\t\n\n\tMajor depressive disorder\t37 (86)\t\n\n\tBipolar disorder\t5 (12)\t\n\n\tUnspecified mood disorder or other\t1 (2)\t\n\nTable 2 Prevalence of search themes.\n\nSearch theme\tNumber of participants (%)\tNumber of search historiesa (%)\t\nSuicide\t27 (63)\t36 (57)\t\nHelp seeking\t33 (77)\t43 (68)\t\nSubstance use\t19 (44)\t25 (40)\t\nMood and anxiety symptoms\t19 (44)\t24 (38)\t\nTrauma and negative life events\t14 (33)\t17 (27)\t\naEach search history contains searches that were conducted during the 3-month period prior to a unique hospitalization.\n\nSRS Queries\n\nQueries related to suicide were found in 36 search histories representing 27 out of the 43 (63%) unique participants. Participants’ SRSs varied in terms of their temporal proximity to hospitalization. Further, 4 participants conducted all of their SRSs in the week preceding hospitalization, 6 participants conducted all of their SRSs within 3 weeks before hospitalization, and 14 participants conducted all of their SRSs ≥4 weeks before hospitalization.\n\nExemplars of search queries are presented in Table 3. SRSs included queries related to the television show 13 Reasons Why—a popular show about a teenage girl who dies by suicide that was airing during the recruitment period—as well as other suicide-related topics in news media. Some participants searched for highly specific and unusual suicide methods. For example, one participant conducted numerous searches related to giving themselves cancer and was investigating the possibility of purchasing live cancer cells on web-based platforms. This participant also searched for a specific species of poisonous frog and investigated the cyanide content of apple seeds. Another participant performed numerous searches related to methods, such as how to overdose on various medications, “how to take apart a shaving razor,” and “how to get the blade out of a pencil sharpener.” Another participant searched “easy ways to get pneumonia,” and another searched “how long can a human go without food.” Other participants conducted SRSs that were less specific but nonetheless indicated thoughts about death. For example, one simply searched “I want to die,” another queried “would you say suicide is a cry for help,” and a third asked “why wont I just kill myself already?” Search queries about suicide-related tattoos, famous suicide-related quotes, and literature about suicide were made by 6 participants. Searches for suicide chat rooms were conducted by 2 participants.\n\nOf the 43 participants, 9 (21%) searched for information that was directly related to their planned or chosen method of suicide. These 9 participants were represented by 10 search histories. In all of these cases, the planned or used method of suicide was drug overdose, as noted in the clinical record. For example, one such participant who was hospitalized after attempting suicide by overdosing on NyQuil (doxylamine and acetaminophen) conducted 8 searches in the week before hospitalization regarding overdosing on NyQuil, including “how many Nyquil [sic] pills does it take to kill me?”\n\nTable 3 Notable search queries.\n\nThemes and participants\tQueries\t\nSuicide\t\n\n\tParticipant A\t“pro suicide chat rooms”\n\n\t\n\n\tParticipant B\t“giving your self cancer”\n\n“live cancer cells for sale”\n\n“poison dart frog for sale”\n\n“apple seeds cyanide”\n\n\t\n\n\tParticipant C\t“how to take apart a shaving razor”\n\n“how to get the blade out of a pencil sharpener”\n\n“how painful is slitting your wrists”\n\n“if you bang your head against the wall can you die”\n\n“least painful way to commit suicide”\n\n\t\n\n\tParticipant D\t“best pills to overdose on”\n\n\t\n\n\tParticipant E\t“would you say suicide is a cry for help”\n\n\t\nHelp-seeking behavior\t\n\n\tParticipant A\t“mobile crisis hotline”\n\n“psychiatrist works with aetna”\n\n“top psychiatrist near me”\n\n\t\n\n\tParticipant B\t“how does a therapist help with anxiety”\n\n\t\n\n\tParticipant C\t“how does a psychologist decide if you need medication”\n\n“what does a psychologist do”\n\n\t\n\n\tParticipant D\t“can I turn myself into a mental hospital”\n\n\t\nDrugs and other substances\t\n\n\tParticipant A\t“funniest things to do after eating an edible”\n\n“does heating up weed make it smell”\n\n\t\n\n\tParticipant B\t“cbd for newbies”\n\n\t\nMood and anxiety symptoms\t\n\n\tParticipant A\t“do you have to cut yourself to be depressed”\n\n“what make me doubt myself all the time”\n\n“what does dreading everything mean”\n\n“why are there days where I be confused and don’t know what to do and I have a feeling in my chest”\n\n“what if I don’t know what I want to do for my future because I don’t see a future for myself”\n\n“waking up with a panic feeling in my chest”\n\n\t\n \tParticipant B\t“everything seems too overwhelming and pointless”\n\n\t\n \n \tParticipant C\t“screaming in sleep”\n\n“different person after depression”\n\n\t\n \n \tParticipant D\t“how to be happy”\n\n“I am so lonely”\n\n\t\n \tParticipant E\t“I am so done”\n\n\t\nTrauma and negative life events\t\n\n\tParticipant A\t“how do you get over a heartbreak?”\n\n\t\n\n\tParticipant B\t“how to deal with losing a best friend”\n\n\t\n\nHelp-Seeking Searches\n\nQueries related to behavioral health care were found in 43 search histories representing 33 of the 43 participants (77%). Searches regarding suicide hotlines or crisis lines were only conducted by 3 participants. Most commonly (n=13), search histories contained queries regarding outpatient resources, including searches for specific behavioral health clinics and general information about outpatient behavioral health care. The names of specific behavioral health providers were queried 11 times. Information about the etiology of, differences among, and clinical course of different psychiatric disorders were queried in 12 search histories. Queries regarding inpatient psychiatric care were found in 10 search histories, including questions about the conditions and rules of a psychiatric unit. For example, one participant searched whether they would be able to use their phone while hospitalized. Search histories also contained queries about substance abuse resources (n=4), crisis resources (n=4), public assistance programs (n=2), and social support (n=3). In 5 search histories, participants searched for alternative interventions, such as pet therapy, meditation apps, and complementary medicine. In 19 search histories, 15 of the 43 participants (35%) searched for information about psychiatric medications, including side effects, desired effects, dosages, and general psychoeducation.\n\nDrugs and Other Substances\n\nQueries related to drugs of abuse were found in 25 search histories representing 19 of the 43 (44%) participants. Alcohol was the most commonly queried substance; it was represented in 13 search histories. Cannabis-related searches were present in 10 search histories. Two participants searched for unusual ways to attain intoxication; one asked “can ibuprofen get you high,” and the other queried “how to properly get high off computer duster.” One participant conducted a search about purchasing a drug testing kit. Other participants conducted searches for salvia, ketamine, tobacco and nicotine, amphetamines, and crack cocaine.\n\nMood and Anxiety Symptoms\n\nQueries related to mood and anxiety symptoms were found in 24 search histories representing 19 of the 43 individuals (44%). Such searches included those for music, movies, tattoos, internet memes, and quotes related to depression. For example, one participant searched “depression movies,” another searched “mental illness quotes” and “tattoos about depression,” and another searched “15 saddest country songs.” Other participants searched for information related to despair. For example, one participant queried “I am so lonely,” another queried “can no longer focus on anything or learn,” and a third queried “everything seems too overwhelming and pointless.”\n\nTrauma and Negative Life Events\n\nQueries related to traumatic or otherwise negative life events were found in 17 search histories representing 14 of the 43 participants (33%). In this category, 4 participants conducted searches related to sex crimes, including searches about how to report rape, how to escape domestic violence, and general information regarding sexual assault and harassment and searches related to support groups for sexual assault survivors. Further, 3 participants conducted searches related to unwanted pregnancies, including those about seeking abortion and emergency contraception. Additionally, 7 participants conducted searches related to difficulties in interpersonal relationships, including the dissolution of friendships and romantic relationships. Finally, 1 participant searched for information on dealing with bullies, and 2 participants conducted searches related to notorious gun violence events, including the Newtown, Connecticut, school shooting.\n\nDiscussion\n\nPrincipal Findings\n\nIn this study we explored the internet search queries of young people with mood disorders that were made in the months leading up to a hospitalization for STBs. This study yielded a number of important findings. Our study confirms that patients with STBs conduct SRSs and other clinically meaningful searches prior to hospitalization.\n\nA majority (27/43, 63%) of the participants in our sample conducted SRSs. This finding is consistent with those of previous research showing that people with self-reported STBs search for suicide-related content on web-based platforms [20,21]. However, to our knowledge, ours is the first study to extract search data from individuals with clinically confirmed STBs. Additionally, in a sizable minority of cases (9/43, 21%), suicide methods that were searched exactly matched participants’ planned or selected method of attempting suicide in real life. Although more research is needed to understand how the presence or content of SRSs relates to suicidal behavior, our data suggest that SRSs may indicate a heightened suicide risk because, at least for some individuals, the internet likely aids suicide planning.\n\nSearch queries that were not explicitly related to suicide nonetheless revealed highly sensitive and clinically meaningful experiences that can otherwise go unreported in a traditional clinical interview. For example, searches about experiences with sexual abuse, the dissolution of relationships, bullying, loneliness, panic, and substance use could put clinical symptoms into context if they are known to a clinician. In addition, many searches related to the self-expression of mood symptoms were found in our sample, such as searches regarding movies, books, memes, and tattoos about depression. This finding suggests that suicidal young people are interested in consuming and sharing content related to their experiences with behavioral health, though the influence that this type of content has on symptoms and behaviors is unclear.\n\nWe also found that a majority (33/43, 77%) of our participants searched for help seeking–related information, including information about behavioral health services and psychoeducational resources. Unfortunately, there is a substantial body of prosuicide content on the internet and evidence that exposure to prosuicide content can increase the incidence of suicidal ideation and worsen mood symptoms in young people [22,23]. Our data reinforce the need for point-of-search interventions that counteract prosuicide information. The fact that young people are searching for help-seeking and suicide-related information on web-based platforms represents a potential opportunity to intervene. For example, if help-seeking searches were known to a clinician, they could serve as a jumping-off point for talking about treatment options. In addition, although search engines currently return information for suicide prevention hotlines when people search for the term suicide, we have shown that many suicide-related, mood-related, and help-seeking searches do not include this term. Only 3 individuals in our sample specifically searched for suicide hotlines, suggesting that this may not be an appealing intervention for many individuals. Optimizing algorithms to identify likely suicide-related, symptom-related, and help-seeking terms may result in the development of more impactful point-of-search interventions and improve pathways to care.\n\nPrevious research supports the idea that the incidence of suicidal ideation does not increase in a linear fashion in the days immediately preceding a suicide attempt and has a high level of moment-to-moment variability over a given period of time [6,7,24]. Such research also suggests that individuals with STBs can be grouped into different phenotypes—those whose suicidal ideation varies considerably in frequency and intensity and those whose suicidal ideation is more stable over time. These different groups may require different types of assessment and intervention. In our sample, 4 participants completed all of their SRSs in the week before hospitalization, possibly suggesting that their STBs were escalating prior to hospitalization. In contrast, 14 individuals stopped conducting SRSs 3 weeks before their hospitalization, possibly suggesting that the STBs that resulted in hospitalization may have been more impulsive. Although additional research is required to understand the motivation behind and impact of each search, our findings support the notion that different patterns in the temporal evolution of SRSs exist and suggest that internet search data, along with other digital and clinical data, can be used to identify STB phenotypes and tailor interventions accordingly in the future [13].\n\nLimitations\n\nOur study has several important limitations. First, the study was conducted at a single site with a small, albeit diverse, population of young people aged 15 to 30 years. The generalizability of our results is therefore limited. In addition, we are unable to comment on the prevalence or content of SRSs among older adults or younger children. This study was limited to participants with mood disorders; comorbidities and other primary diagnoses were not considered.\n\nSecond, our study lacked a formal comparison group, so we cannot state conclusively that the results are unique to individuals with STBs. However, notably, a similar previous study of individuals with psychosis did not yield significant numbers of SRSs, suggesting that these types of searches do not occur at similar rates across patient populations [8].\n\nThird, search queries alone do not provide enough context for confidently stating the motivations and intentions behind each search. For example, searches about suicide chat rooms or memes could represent suicidal intent, help-seeking behavior, curiosity, or other intentions. It is also possible that people with access to participants’ devices conducted searches while on participants’ accounts, further limiting our understanding of participants’ intentions. We sought to mitigate uncertainty by cross-referencing search queries with clinical data when such data were available in the medical records, which provided context for categorization, and conferring with one another to resolve ambiguity in the meanings of or intentions behind queries. However, even these actions introduce bias into the assessment and thematic categorization of search queries. Future studies should consider accessing browser histories, which could provide additional information that is related to motivation and is based on what websites participants visited after making their queries.\n\nFourth, it is possible that some clinically relevant search queries were not captured in our data set. Participants who were motivated to conceal their searches may have done so. For example, search queries that were conducted while participants used Google’s incognito mode were unavailable to us, as were searches that participants deleted prior to the download of this study’s data. In addition, searches that were conducted through alternative search engines were not assessed in this study.\n\nFinally, we only analyzed searches that were conducted 3 months before a hospitalization. It is possible that individuals conduct SRSs well before this time or that only searches that are conducted in close temporal proximity to hospitalization have predictive value. Future research should consider not only the temporal association between an individual’s searches and STBs but also whether the time of day, search frequency, or other non–content-related information about searches relates to suicide risk.\n\nFuture Directions\n\nThe understanding that people at high risk for suicide are indeed searching for suicide-related content represents an opportunity to use these data for treatment planning and risk assessment. For example, in the future, internet search data could potentially be used as clinical collateral, particularly during initial psychiatric assessments where patients may be hesitant to share their experiences with STBs. Additionally, the search data of established patients could augment infrequent psychiatric assessments by allowing for the closer monitoring of STBs in between clinical appointments. Access to this information can help both clinicians and patients understand STBs in the context of surrounding life events and mood symptoms with more granularity than is currently typical.\n\nAlthough it is currently not possible to systematically use search data in clinical evaluation and management, patients can download and share their own web-based activity with their treatment providers. However, for this to occur, statistical tools that can process search data and return relevant information in a format that is clinically usable and scalable need to be developed. Additionally, our work suggests that search histories can be used to establish novel risk factors for suicide. Ultimately, the further clarification of such risk factors may be better suited to more robust statistical approaches (such as machine learning approaches) for analyzing larger numbers of participants. Furthermore, questions about legal considerations, effectiveness, integration into clinical workflows, and reimbursement also need to be addressed before these methods can reasonably be implemented.\n\nFinally, the clinical use of internet search data must be undertaken with the utmost concern for patient privacy. Search data often contain highly sensitive information that people may be uncomfortable sharing. If search data are to be integrated into clinical workflows or search engine–led interventions, it is important that users consent to the review of search data and that they be continuously informed about how these data might be used in a transparent and collaborative manner.\n\nWe thank the patients of Zucker Hillside Hospital who consented to participating in this study. We additionally thank Whitney Muscat for her work on data collection for this study.\n\nAbbreviations\n\nSRS suicide-related search\n\nSTB suicidal thought and behavior\n\nConflicts of Interest: MLB owns stock in Northshore Therapeutics. JMK is a consultant to or receives honoraria from Alkermes, Allergan Inc, Dainippon Sumitomo Pharma, H. Lundbeck A/S, Intra-Cellular Therapies, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals Inc, Merck, Minerva, Neurocrine Biosciences, Otsuka Pharmaceutical, Reviva Pharmaceuticals, Roche, Saladex Biomedical Inc, Sunovion, Takeda, and Teva Pharmaceuticals. JMK receives grant support from Otsuka Pharmaceutical, H. Lundbeck A/S, Sunovion, and Janssen Pharmaceuticals. He is a shareholder in Vanguard Research Group and LB Pharmaceuticals Inc.\n==== Refs\n1 Suicide National Institute of Mental Health 2020-05-05 https://www.nimh.nih.gov/health/statistics/suicide\n2 Franklin JC Ribeiro JD Fox KR Bentley KH Kleiman EM Huang X Musacchio KM Jaroszewski AC Chang BP Nock MK Risk factors for suicidal thoughts and behaviors: A meta-analysis of 50 years of research Psychol Bull 2017 02 143 2 187 232 10.1037/bul0000084 27841450 2016-54856-001 27841450\n3 Christl B Wittchen HU Pfister H Lieb R Bronisch T The accuracy of prevalence estimations for suicide attempts. how reliably do adolescents and young adults report their suicide attempts? Arch Suicide Res 2006 10 3 253 263 10.1080/13811110600582539 16717042 N41J201R01GH5377 16717042\n4 Nock MK Banaji MR Assessment of self-injurious thoughts using a behavioral test Am J Psychiatry 2007 05 164 5 820 823 10.1176/ajp.2007.164.5.820 17475742 164/5/820 17475742\n5 Torous J Staples P Shanahan M Lin C Peck P Keshavan M Onnela JP Utilizing a personal smartphone custom app to assess the Patient Health Questionnaire-9 (PHQ-9) depressive symptoms in patients with major depressive disorder JMIR Ment Health 2015 03 24 2 1 e8 10.2196/mental.3889 26543914 v2i1e8 26543914\n6 Kleiman EM Turner BJ Fedor S Beale EE Huffman JC Nock MK Examination of real-time fluctuations in suicidal ideation and its risk factors: Results from two ecological momentary assessment studies J Abnorm Psychol 2017 08 126 6 726 738 10.1037/abn0000273 28481571 2017-20211-001 28481571\n7 Gratch I Choo TH Galfalvy H Keilp JG Itzhaky L Mann JJ Oquendo MA Stanley B Detecting suicidal thoughts: The power of ecological momentary assessment Depress Anxiety 2021 01 38 1 8 16 10.1002/da.23043 32442349 32442349\n8 Kirschenbaum MA Birnbaum ML Rizvi A Muscat W Patel L Kane JM Google search activity in early psychosis: A qualitative analysis of internet search query content in first episode psychosis Early Interv Psychiatry 2020 10 14 5 606 612 10.1111/eip.12886 31637869 31637869\n9 Birnbaum ML Rizvi AF Confino J Correll CU Kane JM Role of social media and the internet in pathways to care for adolescents and young adults with psychotic disorders and non-psychotic mood disorders Early Interv Psychiatry 2017 08 11 4 290 295 10.1111/eip.12237 25808317 25808317\n10 Birnbaum ML Garrett C Baumel A Scovel M Rizvi AF Muscat W Kane JM Using digital media advertising in early psychosis intervention Psychiatr Serv 2017 11 01 68 11 1144 1149 10.1176/appi.ps.201600571 28712355 28712355\n11 Bucci S Barrowclough C Ainsworth J Machin M Morris R Berry K Emsley R Lewis S Edge D Buchan I Haddock G Actissist: Proof-of-Concept trial of a theory-driven digital intervention for psychosis Schizophr Bull 2018 08 20 44 5 1070 1080 10.1093/schbul/sby032 29566206 4939353 29566206\n12 Hoffman L Benedetto E Huang H Grossman E Kaluma D Mann Z Torous J Augmenting mental health in primary care: A 1-year study of deploying smartphone apps in a multi-site primary care/behavioral health integration program Front Psychiatry 2019 02 28 10 94 10.3389/fpsyt.2019.00094 10.3389/fpsyt.2019.00094 30873053 30873053\n13 Kleiman EM Turner BJ Fedor S Beale EE Picard RW Huffman JC Nock MK Digital phenotyping of suicidal thoughts Depress Anxiety 2018 07 35 7 601 608 10.1002/da.22730 29637663 29637663\n14 Alexa - Top sites Alexa 2021-10-01 https://www.alexa.com/topsites\n15 Dunlop SM More E Romer D Where do youth learn about suicides on the internet, and what influence does this have on suicidal ideation? J Child Psychol Psychiatry 2011 10 52 10 1073 1080 10.1111/j.1469-7610.2011.02416.x 21658185 21658185\n16 Katsumata Y Matsumoto T Kitani M Takeshima T Electronic media use and suicidal ideation in Japanese adolescents Psychiatry Clin Neurosci 2008 12 62 6 744 746 10.1111/j.1440-1819.2008.01880.x 10.1111/j.1440-1819.2008.01880.x 19068014 PCN1880 19068014\n17 Zahl DL Hawton K Media influences on suicidal behaviour: an interview study of young people Behav Cogn Psychother 2004 04 16 32 2 189 198 10.1017/s1352465804001195\n18 Tran US Andel R Niederkrotenthaler T Till B Ajdacic-Gross V Voracek M Low validity of Google Trends for behavioral forecasting of national suicide rates PLoS One 2017 08 16 12 8 e0183149 10.1371/journal.pone.0183149 28813490 PONE-D-16-50373 28813490\n19 Risk and protective factors Centers for Disease Control and Prevention 2020-05-12 https://www.cdc.gov/suicide/factors/index.html\n20 Mok K Jorm AF Pirkis J Suicide-related internet use: A review Aust N Z J Psychiatry 2015 08 49 8 697 705 10.1177/0004867415569797 25698810 0004867415569797 25698810\n21 Daine K Hawton K Singaravelu V Stewart A Simkin S Montgomery P The power of the web: a systematic review of studies of the influence of the internet on self-harm and suicide in young people PLoS One 2013 10 30 8 10 e77555 10.1371/journal.pone.0077555 24204868 PONE-D-13-14108 24204868\n22 Marchant A Hawton K Stewart A Montgomery P Singaravelu V Lloyd K Purdy N Daine K John A A systematic review of the relationship between internet use, self-harm and suicidal behaviour in young people: The good, the bad and the unknown PLoS One 2017 08 16 12 8 e0181722 10.1371/journal.pone.0181722 28813437 PONE-D-17-07909 28813437\n23 Westerlund M Hadlaczky G Wasserman D The representation of suicide on the internet: implications for clinicians J Med Internet Res 2012 09 26 14 5 e122 10.2196/jmir.1979 23010086 v14i5e122 23010086\n24 Rizk MM Choo TH Galfalvy H Biggs E Brodsky BS Oquendo MA Mann JJ Stanley B Variability in suicidal ideation is associated with affective instability in suicide attempters with borderline personality disorder Psychiatry 2019 82 2 173 178 10.1080/00332747.2019.1600219 31013205 31013205\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2368-7959",
"issue": "8(10)",
"journal": "JMIR mental health",
"keywords": "Google search; adolescent; depression; digital health; internet; mobile health; mood disorders; search engine; suicide; young adult",
"medline_ta": "JMIR Ment Health",
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"pubdate": "2021-10-22",
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"title": "Internet Search Activity of Young People With Mood Disorders Who Are Hospitalized for Suicidal Thoughts and Behaviors: Qualitative Study of Google Search Activity.",
"title_normalized": "internet search activity of young people with mood disorders who are hospitalized for suicidal thoughts and behaviors qualitative study of google search activity"
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"abstract": "Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.",
"affiliations": "Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.;Medical College of Wisconsin, Milwaukee, WI 53226, United States of America.;Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, United States of America.;Medical College of Wisconsin, Milwaukee, WI 53226, United States of America.;Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.;Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.;Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America; Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, United States of America.;Division of Pediatric Pharmacology, Medical Toxicology and Therapeutic Innovation, The Children's Mercy Hospital, Kansas City, MO 64108, United States of America.;Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, United States of America.",
"authors": "James|Laura|L|;Yan|Ke|K|;Pence|Lisa|L|;Simpson|Pippa|P|;Bhattacharyya|Sudeepa|S|;Gill|Pritmohinder|P|;Letzig|Lynda|L|;Kearns|Gregory|G|;Beger|Richard|R|",
"chemical_list": "D001647:Bile Acids and Salts; D015415:Biomarkers; D006002:Glycodeoxycholic Acid; D000082:Acetaminophen; D013657:Taurodeoxycholic Acid; D005999:Glycochenodeoxycholic Acid; D000410:Alanine Transaminase",
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"doi": "10.1371/journal.pone.0131010",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2620810410.1371/journal.pone.0131010PONE-D-15-06655Research ArticleComparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity Bile Acid and Acetaminophen Protein Adducts in ChildrenJames Laura \n1\n\n2\n*Yan Ke \n3\nPence Lisa \n4\nSimpson Pippa \n3\nBhattacharyya Sudeepa \n1\n\n2\nGill Pritmohinder \n1\n\n2\nLetzig Lynda \n1\n\n2\nKearns Gregory \n5\nBeger Richard \n4\n\n1 \nDepartment of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States of America\n\n2 \nArkansas Children’s Hospital Research Institute, Little Rock, AR 72202, United States of America\n\n3 \nMedical College of Wisconsin, Milwaukee, WI 53226, United States of America\n\n4 \nDivision of Systems Biology, National Center for Toxicological Research, Jefferson, AR 72079, United States of America\n\n5 \nDivision of Pediatric Pharmacology, Medical Toxicology and Therapeutic Innovation, The Children’s Mercy Hospital, Kansas City, MO 64108, United States of America\nMenezes Gustavo Batista Editor\nUFMG, BRAZIL\nCompeting Interests: The authors have the following interests: Dr. Laura James is part owner of Acetaminophen Toxicity Diagnostics, (ATD) LLC, which has developed a rapid assay for the measurement of acetaminophen protein adducts. ATD, LLC did not participate in the study design or analysis of the data. Laura James received partial salary support from a grant awarded to ATD, LLC from the National Institutes of Diabetes, Digestive and Kidney Disease (DK79387). ATD, LLC has a patent pending [Anti-Acetaminophen Antibodies and Acetaminophen Protein Adducts, PTO Ref No. 62/086,923]. Data management for the study was provided by KAI Research, Inc, an Altarum Company. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: LJ RB. Performed the experiments: LP LL. Analyzed the data: PS KY SB. Contributed reagents/materials/analysis tools: SB PG. Wrote the paper: LJ SB GK PG RB.\n\n* E-mail: jameslaurap@uams.edu24 7 2015 2015 10 7 e013101019 2 2015 26 5 2015 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.\n\nThis work was funded in part by a grant (DK75936 to LJ) from the National Institutes of Diabetes, Digestive and Kidney Diseases of the United States Department of Health and Human Services and the Arkansas Biosciences Institute which is funded by Arkansas Tobacco Settlement Funds. Data AvailabilityAll relevant data are available via Figshare (http://dx.doi.org/10.6084/m9.figshare.1412829).Data Availability\nAll relevant data are available via Figshare (http://dx.doi.org/10.6084/m9.figshare.1412829).\n==== Body\nIntroduction\nAcetaminophen (APAP) overdose is a major cause of acute liver failure and acute liver injury in the western world [1]. Hepatic metabolism of APAP is known to be a critical factor in the development of hepatotoxicity. Following low dose exposure, APAP is primarily metabolized through conjugation reactions, and oxidation reactions play a relatively minor role. However, following exposure to large doses of APAP, conjugation pathways are saturated and a relatively greater proportion of the drug undergoes oxidative metabolism. Oxidation, which occurs through the cytochrome P450 enzymes located in the centrilobular regions of the liver, generates the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which, along with the depletion of hepatic glutathione, is recognized to be a critical initiating step in the development of hepatotoxicity [2]. NAPQI binds to cysteine groups on proteins to form APAP protein adducts, which are released from the centrilobular hepatocytes, in addition to alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and enter the peripheral circulation during hepatocyte lysis [3]. Previous experimental and clinical studies suggest that serum levels of APAP protein adducts can serve as biomarkers of APAP-related hepatotoxicity, reflecting the oxidative metabolism of the drug [4–6]. Other mechanisms are known to contribute to the toxicity and include oxygen and nitrogen stress [7], mitochondrial permeability transition [8,9], and intracellular signaling mechanisms involving c-Jun N-terminal protein kinase activation [10].\n\nOver the last decade, “omics”-based approaches have been increasingly used to investigate mechanisms of drug induced liver injury, including APAP toxicity. Metabolomics-based approaches have been used to examine the relationship of intermediates of fatty acid oxidation, energy production, and redox balance to the overall toxicity response [11–14]. For example, Clayton et al. showed that variability in the diet could influence conjugation reactions and modulate the overall toxicity response in the rat model of APAP toxicity [11]. In addition, metabolomic approaches have further demonstrated the role of mitochondrial dysfunction in APAP toxicity by showing the elevation of circulating long chain acylcarnitines, substrates of β-oxidation, in experimental and clinical studies [13,15–17].\n\nAlteration of bile acid transport is a known mechanism of drug induced liver injury [18,19]. Elevations of bile acids have been reported for a number of hepatotoxins regardless of the specific pattern of liver injury (necrosis, steatosis, cholestatic, and idiosyncratic). In experimental models of drug induced liver injury, the most significant alterations in bile acid homeostasis were shown for toxins that cause either necrosis or cholestasis [20]. In addition, in mice treated with toxic doses of APAP, it was shown that dietary modulations that alter the existing bile acid pool changed the sensitivity of mice to APAP toxicity [21].\n\nIn the following study, targeted bile acid analysis was performed in serum samples from children and adolescents with APAP overdose, healthy children with no recent APAP exposure and hospitalized children receiving APAP per standard of care. Bile acids were compared to APAP protein adducts, an indicator of the oxidative metabolism of APAP [6,22] and ALT, the most widely used clinical indicator of liver injury.\n\nPatients and Methods\nThe study was a multicenter study of APAP toxicity in children ages 2–18 years and was approved by the institutional review boards of all participating institutions, in accordance with the guidelines of the 1975 Declaration of Helsinki. Written, parental consent was obtained for all participating subjects and written assent was obtained in subjects over 7 years of age. Informed consent (and assent) documents were approved by the UAMS Institutional Review Board as well as the institutional review boards of all participating sites: Akron Children's Hospital Institutional Review Board, Baylor College of Medicine Institutional Review Board, Children's Mercy Hospital Institutional Review Board, Children's National Medical Center Institutional Review Board, Cook Children's Hospital Institutional Review Board, ProMedica Health Systems Institutional Review Board, and The University of Louisville Institutional Review Board. Following informed consent and assent when age appropriate, blood samples were collected from study subjects classified into three subject groups defined as Group A (Therapeutic APAP dose, consisting of hospitalized children with various medical conditions receiving APAP per standard of care); Group B (Controls, healthy children with no use of APAP in the preceding 14 days); and Group C (APAP Overdose, consisting of children requiring hospitalization for treatment of APAP overdose, based on an assessment of history of ingestion and quantitation of APAP in peripheral blood [23]). For subjects in Group A, timed blood samples were collected prior to receipt of the first APAP dose “on study” and thereafter at 8 and 24 h after the first dose of APAP, followed by convenience sampling throughout the period of hospitalization. A single blood sample was collected in Group B subjects and admission and daily morning blood samples were collected in subjects in Group C. Blood samples were centrifuged within 30 minutes of collection and the serum was stored at -80°C.\n\nClinical data collection\nClinical and demographic data were collected prospectively using a study-specific electronic data base that included subject age, gender, weight, height, body mass index, past medical history, and relevant history concerning recent APAP dosing and concomitant medications. Data on dose (mg/kg), frequency, route of administration (oral, rectal, intravenous) were collected for APAP (Group A) and for N-acetylcysteine (NAC), the clinical antidote for APAP overdose (Group C). Clinical laboratory data recorded in the data base included determinations of APAP and ALT performed by participating hospital clinical laboratories. APAP and NAC dosing, route, and frequency were at the discretion of the treating physician.\n\nAPAP protein adduct assay\nAPAP protein adducts in serum were analyzed using a previously published and validated assay [6,22,24]. Serum was gel filtered using 96 well desalting plates (Pierce, Rockford, IL) and hydrolyzed with protease (Sigma, St Louis, MO) to release APAP-cysteine from APAP protein adducts [6,22]. After precipitation and extraction, samples were injected onto a high performance with liquid chromatography system (ESA Corp, Chelmsford, MA) and resolved on a 150 mm C18 column (Symmetry, Waters, Milford, MA). APAP cysteine was detected using a coulometric electrochemical detector and quantified relative to a standard curve of authentic APAP cysteine using Coularray Software (Thermo Scientific, Chelmsford, MA). Final APAP cysteine adduct values were reported as nmol APAP protein adduct/ml serum.\n\nMetabolomic analysis of bile acids\nTargeted metabolomic analysis of nine bile acids was performed using ultra performance liquid chromatography with triple quadrupole mass spectrometry as previously described [25]. Bile acids measured included Cholic acid (CA); Chenodeoxycholic acid (CDCA); Deoxycholic acid (DCA); Taurocholic acid (TCA); Taurodeoxycholic acid (TDCA); Tauchenodeoxycholic acid (TCDCA); Glycocholic acid (GCA); Glycodeoxycholic acid (GDCA); Glycochenodeoxycholic acid (GCDCA). Serum samples (50 μl) were thawed and spiked with isotope labeled individual bile acid standards. The samples were then de-proteinized, dried, reconstituted in methanol:water (50:50, v/v) and subjected to UPLC separation using an Acquity UPLC system (Waters, Milford, MA) equipped with an Acquity UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm particle size). A Waters Xevo Triple quadrupole mass spectrometer operated in ESI-negative mode was used for absolute quantitation of bile acids in serum using stable isotope standards. Multiple Reaction Monitoring transitions for bile acids were optimized by direct infusion of standards.\n\nStatistical analysis\nNon-parametric statistical tests (Kruskal-Wallis) were used to compare clinical and laboratory data among the three groups of subjects (p<0.05) and the Mann-Whitney test was used for pairwise comparisons between two groups (p<0.05). Pearson’s correlation coefficients were calculated for comparison of peak measurements of bile acids to peak APAP protein adducts. Receiver operator curve (ROC) analysis was conducted to identify “cut points” of bile acid measurements that best discriminated subject samples with peak APAP protein adduct values of ≥ 1.0 vs. peak adduct < 1.0 nmol/mL, a previously determined “toxicity threshold” for APAP protein adducts in patients with APAP liver injury [6,24].\n\nResults\nClinical and demographic data\nA total of 88 children (Group A, 15; Group B, 19; Group C, 64) completed the study. Demographic and clinical data characteristics by group are summarized in Table 1. Children in Groups A and C were older than those of Group B and had higher body weights. More females (68.37%) than males participated in the study as a whole, but there were more males (73.33%) than females in Group A. No significant differences in race were detected among the groups (data not shown), but there were more Hispanics in Group B (5 of 15; p = 0.033), compared to Group A (0 of 19) and Group C (5 of 63).\n\n10.1371/journal.pone.0131010.t001Table 1 Demographic characteristics of study subjects by groups.\nGroup (N)\tAPAP Therapeutic Exposure Group A (15)\tHealthy Control Group B (19)\tAPAP Overdose Group C (64)\tGlobal p-value*\n\tA vs. B**\n\tA vs. C**\n\tB vs. C**\n\t\nAge (years)*\n\t14.08 (2.00, 18.08)\t9.33 (2.67, 16.17)\t15.54 (1.50, 18.25)\t<0.001\t0.042\t0.189\t<0.001\t\nWeight (kg)*\n\t60.90 (11.60, 98.70)\t40.80 (11.40, 99.80)\t63.55 (10.00, 117.20)\t0.001\t0.218\t0.187\t<0.001\t\nGender (% Male)\t73.33\t31.58\t21.88\t<0.001\t0.016\t<0.001\t0.385\t\nData are presented as median and range.\n\n*p value for three way comparison and **p value for pairwise comparisons.\n\nThe median (range) daily dose of APAP for subjects in Group A was determined for the initial 24 and 48 h of the study. The daily dose of APAP was higher (p = 0.014) in the initial 24 h (31.0 [6.2–100.6] mg/kg APAP) compared to the initial 48 h (20.5 [3.1–57.5] mg/kg APAP), indicating a decline in the median daily dose between study day 1 and day 2. Daily doses were within the recommended dose range for APAP use in children [26].\n\nAPAP overdose patients may be relatively asymptomatic during the initial 24 hours following APAP overdose, as the development of overt toxicity may not be apparent until 24 to 48 hours after the time of ingestion. Thus, patients are evaluated for the potential risk of hepatotoxicity through the use of a nomogram (ie, Rumack nomogram [27]) based on quantified levels of APAP plotted as a function of the time elapsed since the occurrence of the APAP ingestion. Among the 64 Group C patients, 40 were judged to be “at risk” for liver injury on the basis of the Rumack nomogram [27]. Additional clinical factors which prompted hospitalization and NAC treatment were the elevation of ALT values at the time of presentation to the hospital (n = 5 subjects), and the co-ingestion of antihistamines (n = 2 subjects), which may alter gastric motility and thus limit utility of the nomogram [28]. The time of the ingestion could not be determined for one subject. Thus, overall, 73% of Group C patients were viewed to be “at risk” for the development of liver injury. There were no deaths or liver transplants in the study cohort.\n\nGroup C Treatment Data\nAll children in Group C received treatment with NAC. Since the efficacy of NAC in preventing hepatic injury is a function of the time it is administered relative to the time of the drug overdose [29], the data analysis was stratified by time to the first dose of NAC relative to the reported time of the APAP ingestion. Time data was known for 60 of 64 subjects in Group C. Distribution of time to first dose of NAC was <10 h for 34 (56.7%) subjects, 10–24 h for 12 (20%) subjects, and ≥24 h for 14 (23.3%) subjects, and was consistent with published studies in APAP toxicity in children [30]. Eleven of the 64 (17.2%) subjects in Group C had ALT values > 1000 IU/L.\n\nToxicity and metabolism data\n\nTable 2 provides summary data of descriptive statistics for serum ALT (IU/L) and serum APAP protein adducts (nmol/mL). Since multiple measures were obtained for the study subjects in Groups A and C, the data were analyzed by peak measured value for ALT and APAP protein adducts. Peak ALT differed among the three groups (p = 0.003) and was higher in Groups A (p = 0.003) and C (p = 0.001) than in Group B. However, peak ALT for Group C was not higher than Group A, likely as a function of the large subset of patients within Group C that received early treatment with NAC and thus did not develop toxicity. In contrast, APAP protein adducts differed among the three groups and were statistically different between each group.\n\n10.1371/journal.pone.0131010.t002Table 2 Summary data for peak alanine aminotransferase values (ALT), acetaminophen (APAP) protein adducts, and bile acids by group.\n\tTherapeutic Exposure Group A\tHealthy Control Group B\tOverdose Group C\tp-value*\n\tA vs. B**\n\tA vs. C**\n\tB vs. C**\n\t\nALT (IU/L)\t40.00 (7.00, 191.00)\t16.00 (10.00, 37.00)\t29.00 (8.00, 9909.00)\t\n0.003\n\t\n0.003\n\t0.965\t\n0.001\n\t\nAdduct (nmol/mL)\t0.16 (0.01, 2.11)\t0.006 (0.00, 0.01)\t0.30 (0.03, 7.92)\t\n<0.001\n\t\n<0.001\n\t\n0.005\n\t\n<0.001\n\t\nTCA (uM)\t0.23 (0.02, 5.22)\t0.35 (0.004, 1.46)\t0.06 (0.005, 8.70)\t\n<0.001\n\t0.238\t\n0.027\n\t\n<0.001\n\t\nGCA (uM)\t0.45 (0.14, 9.55)\t0.15 (0.03, 1.19)\t0.21 (0.01, 15.59)\t\n0.018\n\t\n0.007\n\t\n0.021\n\t0.248\t\nGDCA (uM)\t1.18 (0.36, 4.60)\t0.19 (0.008, 1.85)\t1.04 (0.08, 16.52)\t\n<0.001\n\t\n<0.001\n\t0.866\t\n<0.001\n\t\nTDCA (uM)\t0.31 (0.05, 4.07)\t0.05 (0.005, 0.93)\t0.24 (0.02, 12.04)\t\n<0.001\n\t\n<0.001\n\t0.263\t\n<0.001\n\t\nCA (uM)\t1.34 (0.18, 18.26)\t6.41 (0.34, 49.64)\t0.61 (0.03, 10.42)\t\n<0.001\n\t\n<0.001\n\t0.100\t\n<0.001\n\t\nCDCA (uM)\t0.07 (0.009, 1.03)\t0.20 (0.00, 0.54)\t0.17 (0.03, 3.46)\t0.066\t0.252\t\n0.017\n\t0.540\t\nDCA (uM)\t0.19 (0.06, 2.47)\t0.09 (0.005, 2.52)\t0.29 (0.02, 3.90)\t0.058\t0.056\t0.750\t\n0.024\n\t\nGCDCA (uM)\t0.10 (0.00, 3.21)\t0.04 (0.003, 0.26)\t0.19 (0.02, 3.69)\t\n<0.001\n\t0.238\t0.132\t\n<0.001\n\t\nTCDCA (uM)\t0.16 (0.00, 2.29)\t0.12 (0.004, 0.74)\t0.15 (0.008, 4.02)\t0.596\t0.425\t0.528\t0.451\t\nData presented as median (range).\n\n*p value for three way comparison.\n\n**p value for pairwise comparison.\n\nBold p values indicate significance p<0.01; bold, italicized p values represent p = 0.01–0.05.\n\nBile acid metabolites\nSummary data, presented as peak values, for bile acids by subject group are presented in Table 2. Significant differences were detected among the three groups for serum levels of 6 of the 9 bile acids (excluding TCDCA, CDCA, and DCA, **three way comparison). As shown in Table 2, pair-wise comparisons between groups showed that the greatest differences in bile acids were observed for subjects in Group C (overdose) compared to Group B (healthy controls). TDCA, GDCA, and GCDCA were elevated in Group C compared to values in healthy controls. In contrast, TCA and CA were decreased in Group C compared to Group B (healthy controls). However, comparison of bile acids in Group C (overdose) to Group A (therapeutic exposure) revealed fewer differences among the bile acids. Only CDCA was higher in Group C than in Group A subjects (p<0.05), while TCA and GCA were lower in Group C than in Group A. Comparison between Groups A and B showed greater variability among bile acids in Group A than Group B, possibly as a function of the heterogeneous nature of disease among the subjects in Group A.\n\nComparison of bile acids to toxicity parameters\nDue to the limited subject sampling scheme of this pediatric study, relative comparison of temporal changes in bile acids, APAP protein adducts and ALT in the early hours after the APAP overdose was not possible. As an alternative, the time to reach peak measurement for individual bile acids was examined and compared as a function of APAP protein adduct concentrations. APAP protein adduct values ≥ 1.0 nmol/mL have been shown to have high sensitivity and specificity (97 and 95%, respectively) in patients with APAP liver injury (defined as an ALT value of > 1000 IU/L) [6,24]. As shown in Fig 1, time to reach peak measure for each bile acid was shorter in subjects with APAP protein adducts < 1.0 nmol/mL, compared to subjects with APAP protein adducts ≥ 1.0 nmol/mL. Correlation analysis was also performed for peak APAP protein adducts versus peak bile acid levels. The highest correlations were noted for TDCA (R = 0.604; p<0.001), GDCA (R = 0.581; p<0.001), and GCDCA (R = 0.571; p<0.001).\n\n10.1371/journal.pone.0131010.g001Fig 1 Comparison of time to reach peak bile acid, presented as a function of peak APAP protein adduct < or ≥ 1.0 nmol/mL APAP protein adduct.\n*denotes > 2.0 times the 25–75th percentile; Odenotes > 1.5 times the 25–75th percentile. GCA, Glycocholic acid; GDCA, Glycodeoxycholic acid; TDCA, Taurodeoxycholic acid.\n\nIn subsequent analysis, ROC analysis was conducted to identify bile acid cut points that maximized the sum of sensitivity and specificity for discriminating patients with peak adducts < 1.0 nmol/mL or ≥ 1.0 nmol/mL. TDCA values > 0.56 uM had the highest area under the curve value for discriminating subjects at the adduct toxicity cut point of 1.0 nmol/mL (Fig 2), followed by GDCA.\n\n10.1371/journal.pone.0131010.g002Fig 2 Receiver operator curve (ROC) analysis of bile acids (BA) that best distinguished subjects with acetaminophen protein adducts < 1 versus ≥ 1.0 nmol/mL.\nTDCA, Taurodeoxycholic acid; GCDA, Glycodeoxycholic acid.\n\nIn previous work, APAP protein adducts and ALT were shown to be higher in patients with greater delays in receiving treatment with NAC [31]. Thus, the relationship of bile acids to initiation of treatment with NAC was examined and compared to that of APAP protein adducts and ALT. Table 3 provides correlations between individual parameters in relationship to time to NAC treatment. None of the bile acids were highly correlated with time to NAC treatment; ALT and APAP protein adducts were modestly correlated with time to NAC treatment.\n\n10.1371/journal.pone.0131010.t003Table 3 Correlation analysis of peak biomarker versus time to treatment with N-acetylcysteine (NAC)*.\nParameter vs. Time to NAC*\n\tR value\tP Value\t\nALT\t0.569\tp<0.001\t\nAPAP Protein Adduct\t0.489\tp<0.001\t\nGDCA\t0.421\tp<0.001\t\nTDCA\t0.397\tp = 0.002\t\nGCA\t0.372\tp = 0.004\t\nGCDCA\t0.332\tp = 0.010\t\nDCA\t0.319\tp = 0.013\t\nTCDCA\t0.287\tp = 0.026\t\nTCA\t0.202\tp = 0.121\t\nCA\t0.201\tp = 0.123\t\nCDCA\t0.181\tp = 0.166\t\n*Log transformation of peak measurement of parameter.\n\nThus, overall, the data suggest that several of the conjugated bile acids associate with toxicity severity in APAP overdose, as defined by both ALT values and APAP protein adduct concentrations.\n\nDiscussion\nBile acids are formed during the biotransformation of cholesterol through two metabolic pathways known as the “classical” or neutral pathway and the “alternative” or acidic pathway. The classical pathway produces primary bile acids and involves microsomal cholesterol 7α-hydroxylase (CYP7A1), while the alternative pathway involves biotransformation of cholesterol through mitochondrial sterol 27-hydroxylase (CYP27A1) followed by oxysterol 7α-hydroxylase (CYP7B1) [32]. More than 90% of bile acids in humans are derived from the classical pathway, represented by cholic acid (CA) and chenodeoxycholic acid (CDCA), which are conjugated by either taurine or glycine for secretion into bile. Deoxycholic acid is a secondary bile acid that is formed through dehydroxylation by intestinal bacteria and is reabsorbed through enterohepatic recirculation to maintain a constant pool of bile acids [33].\n\nThe increased availability of metabolomics technology has enabled investigations of the relationship between small molecules of endogenous metabolism and the development of liver injury in experimental models of APAP toxicity [11,13,25,34]. A 1975 publication found that a composite measure of bile acids was more sensitive than serum AST for detecting APAP liver injury verified by liver biopsy [35]. Using a multicenter, prospective sample collection design, serum bile acids were compared among hospitalized children and adolescents with APAP overdose, low dose APAP exposure, and healthy children with no recent APAP exposure. Multiple differences in individual bile acids were observed among the three groups (Table 2). Elevations of conjugated bile acids (e.g., GDCA, TDCA and GCDCA) were observed in the APAP overdose group compared to the healthy control group. However, differences in the conjugated bile acids were less pronounced between the two APAP exposure groups (Groups A and C), possibly as a function of the disease heterogeneity of the subjects in Group A, or the relatively low morbidity of the pediatric cohort of the study [32]. Conjugated bile acid elevation was associated with the severity of toxicity (Fig 1), which we defined on the basis of APAP protein adduct levels based on our previous data [6,24]. Comparison of bile acids (Fig 2) in patients with an APAP protein adduct level > 1.0 nmol/mL, a previously identified “cut-point” value with high sensitivity and specificity for APAP toxicity in patients with an ALT values above 1000 IU/L, showed modest, but statistically significant correlations between peak measurements of adducts and peak measurements of TDCA (R = 0.604; p<0.001), GDCA (R = 0.581; p<0.001), and GCDCA (R = 0.571; p<0.001). Similar to our study, a recent report examined specific bile acids in adults (median [range] of age, 34 [18–61 years]) with APAP-related acute liver failure and found that GCDCA, TCDCA, GCA, TCA, GDCA, and TDCA were elevated in patients above the values found in controls and that GDCA was significantly higher in APAP non-survivors, compared to survivors [36]. Of note, the authors found that GDCA values were higher in the APAP liver failure group than in patients with cholestatic liver injury. Our study differed from this earlier study in that our study population was younger and had lower morbidity and no mortality and thus comparison of individual bile acids to survival was not possible.\n\nExamination of the primary bile acids showed that CA was lower in the APAP overdose group (compared to Group B), while CDCA was only reduced in Group A when compared to Group B. The lower levels of CA in the APAP overdose subjects could be consistent with a protective mechanism of the liver and a shift from the classical to the alternative pathway of metabolism, as has been shown for non-alcoholic fatty liver disease [32].\n\nThe mechanistic significance of elevated bile acids in children with APAP overdose and liver injury is unclear. Previous studies in rodent models of APAP toxicity [25,37] found elevations of taurocholic and deoxycholic acid in blood samples of rats treated with APAP and noted correlations among bile acids and serum ALT and among bile acids and necrosis scores [25]. In addition, genes regulating bile acid synthesis (Cyp7A1 and Cyp8B1) and cholesterol transport (Abcd1) were down-regulated, while genes that increased bile acid transport (Mrp2, Mrp3, Mrp4) were up-regulated [37]. Thus, data in the experimental model of APAP toxicity (ie., bile acid perturbations and changes in gene regulation) indicated the occurrence of transient intrahepatic cholestasis [25]. During bile acid metabolism, bile acids are conjugated by taurine or glycine at the carboxyl position to form metabolites that are more hydrophilic and thus less toxic to hepatocytes [33]. Treatment with taurine (2-aminoethanesulfonic acid), a conditionally essential organic acid formed as an end-product of methionine and cysteine metabolism [38], was protective in a number of organ injury models, including experimental studies of APAP toxicity [39]. Taurine also has anti-oxidant effects in vitro [40]. The taurine conjugates of bile salts (e.g., ursodeoxycholic acid) are hepatoprotective and stimulate bile acid excretion by evoking signaling mechanisms involving intracellular calcium [41]. Thus, the pattern of increased levels of conjugated bile acids in subjects with APAP overdose could be consistent with a regulatory, protective response of the liver. In a metabolomic profiling study conducted in rodents, the upregulation of primary bile acids and their conjugates was observed for toxins that had primarily either a necrotic pattern of liver injury (APAP, bendazac, methapyrilene, and ticlopidine) or a cholestatic liver injury pattern (eg., DL-ethionine) [20]. Bile acids were not increased in response to nephrotoxins or muscular toxins. Thus, it was postulated that bile acids may represent very sensitive markers of drug induced liver injury and be tested as potential candidate biomarkers for future application in liver screening panels.\n\nAPAP protein adducts reflect the contribution of oxidative metabolism to APAP toxicity [42] and are specific to APAP exposure [5]. In addition, the sensitivity of the analytical assay for quantitation of APAP protein adducts is such that very low levels of adducts can be quantified in subjects receiving APAP in the clinical setting [43]. As shown in Table 2, differences in adduct levels between “therapeutic” exposure (Group A) and “toxic” (Group C) were apparent in this study. The elevation of bile acids is not specific to APAP toxicity and it is likely that bile acids are elevated in other forms of drug-induced liver injury in man [22], as well as other disease conditions, including NAFLD and cholestatic liver disease. Further study of bile acids as potential predictors of survival, as suggested by others [36], appears warranted. Our data demonstrate that understanding bile acid profiles in the context of other medical conditions and exposure to “low dose” APAP is also an important component of biomarker examination (Table 3). In previous work, we found observed a relationship of peak adduct levels to treatment delay with NAC. [31] The relationship of biomarker profiles to the initiation of treatment with NAC is also an important consideration in studies of biomarkers in APAP toxicity (Table 3).\n\nIt has also possible that perturbations of bile acid profiles may be useful in the future to examine the homeostatic integrity of the liver in the recovery and regeneration stages of liver injury. This concept has been tested in a previous clinical study in which bile acid profiles in biliary fluid were examined pre- and post- liver transplant as a functional indicator of metabolic capacity [44]. The limited sampling nature of the present study did not allow full comparison of the predictive toxicity potential of APAP protein adducts versus bile acids. An important question to address in future studies would be whether or not elevation of bile acids proceeded or followed APAP protein adduct elevations and the relative temporal relationships of these biomarkers to ALT elevations in patients with APAP overdose and resulting toxicity.\n\nSeveral additional limitations of the present study merit consideration. The three subject groups differed somewhat by age and by distribution of gender (Table 2). In addition, the doses of APAP administered in Group A were not controlled by the study and were administered on an as needed basis due to the age group of the study. Group A subjects were heterogeneous with respect to the medical conditions requiring hospitalization which may have contributed to the variability of bile acid profiles in this group. In addition, bile acids may be influenced by diet and other environmental effects. The subjects in Group C represent a previously healthy cohort of patients with minimal pre-existing morbidity and no mortality. A particular advantage of the pediatric population is the relative lack of pre-existing liver disease as would be anticipated to be more common in older populations. In addition, co-ingestions with other drugs, such as opioids, are relatively rare in pediatric APAP toxicity [30], as opposed to adults with APAP overdoses resulting in severe liver injury and liver failure [1].\n\nThe data provided herein have application to other studies of drug induced liver injury and suggests a potential role for bile acid profiles as sensitive determinants of liver injury in drug development. Additional research to further understand the mechanistic significance of bile acid elevations in APAP exposure and toxicity is of interest, especially in light of recent studies that have illustrated the role of bile acids as signaling molecules that are important in lipid and glucose metabolism. Finally, this study illustrates how metabolomic approaches can be used as a tool for biomarker discovery and hypothesis generation in the clinical setting of drug toxicity and liver injury.\n\nWe are indebted to our medical and nursing colleagues and the children and their parents who agreed to take part in this study. The following site coordinators participated in this study: Lee Howard, RN, CCRC, Arkansas Children’s Hospital Research Institute, Section of Clinical Pharmacology and Toxicology, Arkansas Children’s Hospital; Missi Thomas, RN, CCRC, Kosair Charities Pediatric Clinical Research Unit/University of Louisville/Kosair Children’s Hospital; Michael Venneman, RN, MSN, MBA, CCRC Children’s Mercy Hospital and Clinics; Elaine Williams, RN, MSN Children’s National Medical Center; Amanda Hodge, RD, LD and Tonia Polanski, RN, BSN, CPN Akron Children’s Hospital; Juli Kidd, RN, CCRC Cook Children’s Health Care System; Evan R. Hempel, Project Manager KAI Research, Inc, an Altarum Company.\n==== Refs\nReferences\n1 \nLarson AM , Polson J , Fontana RJ , Davern TJ , Lalani E , Hynan LS , et al\nAcetaminophen-induced acute liver failure: results of a United States multicenter, prospective study . 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Drug Metab Dispos \n2009 ; 37 : 1779 –1784 . 10.1124/dmd.108.026195 \n19439490 \n25 \nSun J , Ando Y , Ahlory-Dieker D , Schnackenberg LK , Yang X , Greenhaw J , Pence L , Qian F , Salminen W , Mendrick DL , Beger RD \nSystems biology investigation to discover metabolic biomarkers of acetaminophen-induced hepatic injury using integrated transcriptomics and metabolomics . J Molecular Biomarkers & Diagnosis \n2013 ; S1 .\n26 \nSullivan J , Farrar HC , and the Section on Clinical Pharmacology and Therapeutics and Committee on Drugs Clinical Report : Fever and Antipyretic Use in Children . Pediatrics \n2011 ; doi: 10.1542?peds.2010-3852 \n\n27 \nRumack BH , Matthew H \nAcetaminophen poisoning and toxicity . Pediatrics \n1975 ; 55 : 871 –876 .\n1134886 \n28 \nSchwartz EA , Hayes BD , Sarmiento KF \nDevelopment of hepatic failure despite use of intravenous acetylcysteine after a massive ingestion of acetaminophen and diphenhydramine . Ann Emerg Med \n2009 ; 54 : 421 –423 . 10.1016/j.annemergmed.2008.10.001 \n18986731 \n29 \nSmilkstein MJ , Knapp GL , Kulig KW , Rumack BH \nEfficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) . N Engl J Med \n1988 ; 319 : 1557 –1562 .\n3059186 \n30 \nAlander SW , Dowd MD , Bratton SL , Kearns GL \nPediatric acetaminophen overdose: risk factors associated with hepatocellular injury . Arch Pediatr Adolesc Med \n2000 ; 154 : 346 –350 .\n10768670 \n31 \nJames LP , Capparelli EV , Simpson PM , Letzig L , Roberts D , Hinson JA , et al\nAcetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose . Clin Pharmacol Ther \n2008 ; 84 : 684 –690 . 10.1038/clpt.2008.190 \n18923390 \n32 \nLake AD , Novak P , Shipkova P , Aranibar N , Robertson D , Reily MD , et al\nDecreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease . Toxicol Appl Pharmacol \n2013 ; 268 : 132 –140 . 10.1016/j.taap.2013.01.022 \n23391614 \n33 \nChiang JY \nBile acid metabolism and signaling . Compr Physiol \n2013 ; 3 : 1191 –1212 . 10.1002/cphy.c120023 \n23897684 \n34 \nSun J , Schnackenberg LK , Holland RD , Schmitt TC , Cantor GH , Dragan YP , et al\nMetabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS . J Chromatogr B Analyt Technol Biomed Life Sci \n2008 .\n35 \nJames O , Lesna M , Roberts SH , Pulman L , Douglas AP , Smith PA , et al\nLiver damage after paracetamol overdose. Comparison of liver-function tests, fasting serum bile acids, and liver histology . Lancet \n1975 ; 2 : 579 –581 .\n51407 \n36 \nWoolbright BL , McGill MR , Staggs VS , Winefield RD , Gholami P , Olyaee M , et al\nGlycodeoxycholic acid levels as prognostic biomarker in acetaminophen-induced acute liver failure patients . Toxicol Sci \n2014 ; 142 : 436 –444 . 10.1093/toxsci/kfu195 \n25239633 \n37 \nAleksunes LM , Slitt AL , Maher JM , Augustine LM , Goedken MJ , Chan JY , et al\nInduction of Mrp3 and Mrp4 transporters during acetaminophen hepatotoxicity is dependent on Nrf2 . Toxicol Appl Pharmacol \n2008 ; 226 : 74 –83 .\n17935745 \n38 \nWaters E , Wang JH , Redmond HP , Wu QD , Kay E , Bouchier-Hayes D \nRole of taurine in preventing acetaminophen-induced hepatic injury in the rat . Am J Physiol Gastrointest Liver Physiol \n2001 ; 280 : G1274 –1279 .\n11352821 \n39 \nDas J , Ghosh J , Manna P , Sil PC \nTaurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation . Toxicology \n2010 ; 269 : 24 –34 . 10.1016/j.tox.2010.01.003 \n20067817 \n40 \nRedmond HP , Wang JH , Bouchier-Hayes D Taurine attenuates nitric oxide- and reactive oxygen intermediate-dependent hepatocyte injury . Arch Surg \n1996 ; 131 : 1280 –1287 ; discussion 1287–1288.\n8956769 \n41 \nMilkiewicz P , Roma MG , Elias E , Coleman R \nHepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways . Gut \n2002 ; 51 : 113 –119 .\n12077103 \n42 \nJames LP , Mayeux PR , Hinson JA \nAcetaminophen-induced hepatotoxicity . Drug Metab Dispos \n2003 ; 31 : 1499 –1506 .\n14625346 \n43 \nJames LP , Chiew A , Abdel-Rahman SM , Letzig L , Graudins A , Day P , et al\nAcetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations . Eur J Clin Pharmacol \n2012 .\n44 \nLegido-Quigley C , McDermott L , Vilca-Melendez H , Murphy GM , Heaton N , Lindon JC , et al\nBile UPLC-MS fingerprinting and bile acid fluxes during human liver transplantation . Electrophoresis \n2011 ; 32 : 2063 –2070 . 10.1002/elps.201000512 \n21732555\n\n",
"fulltext_license": "CC0",
"issn_linking": "1932-6203",
"issue": "10(7)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000410:Alanine Transaminase; D001647:Bile Acids and Salts; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D062787:Drug Overdose; D005260:Female; D005999:Glycochenodeoxycholic Acid; D006002:Glycodeoxycholic Acid; D006706:Homeostasis; D006801:Humans; D008297:Male; D055432:Metabolomics; D011485:Protein Binding; D012680:Sensitivity and Specificity; D013657:Taurodeoxycholic Acid",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0131010",
"pmc": null,
"pmid": "26208104",
"pubdate": "2015",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "23431354;18472313;18923390;21316383;3059186;12944587;15486922;24007882;23897684;17054417;18986731;11352821;18337250;1134886;2200409;19439490;25239633;17935745;11901099;16317692;16625200;12077103;20067817;24085190;19256530;23360887;10768670;8956769;14625346;19667173;1992763;24958141;16530510;4746326;21274877;21732555;3714342;9500703;24521011;23391614;51407;23052410",
"title": "Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity.",
"title_normalized": "comparison of bile acids and acetaminophen protein adducts in children and adolescents with acetaminophen toxicity"
} | [
{
"companynumb": "US-JNJFOC-20150811146",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe incidence of hip periprosthetic fractures (PPF) has been increasing in recent years. In Vancouver type B1 there are several osteosynthesis options. The aim of this paper is to assess both the treatment and results of Vancouver type B1 PPF in patients operated at our centre.\n\n\nMETHODS\nAn observational retrospective study of patients operated at Hospital Universitario Miguel Servet for type B1 PPF via osteosynthesis with plate between January 2014 and March 2017. Such details were documented and analysed as type of implant used for fixation, patient demographics, complications, time to union and function score using the Harris Hip Score. The minimum follow up was 2 years.\n\n\nRESULTS\nOverall, 37 patients (21 women) were available for review with a mean age of 80.7 years (range 54-99). 8 of these patients died, with an average age of 85.6 (83-95). Out of these 8 dead patients, 4 died in the first year, with an average age of 87 (83-95). 19 fractures had cemented stems whereas 18 were uncemented. According to prosthesis type, 8 had a cemented partial arthroplasty, 11 a cemented total hip arthroplasty (THA), 18 a non-cemented THA; with an average period until PPF of 2.5 years (0.2-5.6), 7 years (0.09-18.1) and 8.1 years (2.6-12.7) respectively. Devises used for stabilisation of the fracture included 27 Cable-Ready® plates (Zimmer-Biomet), 5 Dall-Miles® plates (Stryker) and 5 femur NCB® plates (Zimmer-Biomet). Complications included 5 acute superficial infections of surgical wound, 1 chronic infection, 5 pressure ulcers (4 sacral, 1 heel), 7 patients required intra-operational blood transfusion. The mean time to union was 10.35 weeks (range 6-13). The mean Harris Hip Score postoperatively was 65 (44-95).\n\n\nCONCLUSIONS\nTreatment via open reduction and internal fixation with locked lateral plate covering most of the femur in elderly patients or those with poor bone quality, or a plate with proximal cerclages and distal screws in patients with better bone quality are appropriate treatment methods. To achieve good results using these techniques, we consider minimisation of soft tissue dissection highly important likewise using a meticulous osteosynthesis technique with special attention to biology and biomechanics.",
"affiliations": "Department of Orthopaedic Surgery and Traumatology, Miguel Servet University Hospital, Zaragoza, Spain; Department of Surgery, Medicine School, University of Zaragoza, Spain; Institute for Health Research Aragón, Zaragoza, Spain. Electronic address: adrianroche@hotmail.com.;Department of Orthopaedic Surgery and Traumatology, Miguel Servet University Hospital, Zaragoza, Spain; Department of Surgery, Medicine School, University of Zaragoza, Spain; Institute for Health Research Aragón, Zaragoza, Spain. Electronic address: jjmateo@comz.org.;Department of Orthopaedic Surgery and Traumatology, Miguel Servet University Hospital, Zaragoza, Spain; Department of Surgery, Medicine School, University of Zaragoza, Spain; Institute for Health Research Aragón, Zaragoza, Spain. Electronic address: cmartinh@me.com.;Department of Orthopaedic Surgery and Traumatology, Miguel Servet University Hospital, Zaragoza, Spain. Electronic address: maria.arnaudas@gmail.com.;Department of Orthopaedic Surgery and Traumatology, Miguel Servet University Hospital, Zaragoza, Spain; Department of Surgery, Medicine School, University of Zaragoza, Spain; Institute for Health Research Aragón, Zaragoza, Spain. Electronic address: jgilalba@unizar.es.",
"authors": "Roche-Albero|Adrián|A|;Mateo-Agudo|Jesús|J|;Martín-Hernández|Carlos|C|;Arnaudas-Casanueva|María|M|;Gil-Albarova|Jorge|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.injury.2021.03.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-1383",
"issue": "52(8)",
"journal": "Injury",
"keywords": "Bridge plate; Locking compression plate; Osteosynthesis; Periprosthetic hip fracture",
"medline_ta": "Injury",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D019644:Arthroplasty, Replacement, Hip; D001860:Bone Plates; D005260:Female; D005264:Femoral Fractures; D005593:Fracture Fixation, Internal; D017102:Fracture Healing; D006801:Humans; D008875:Middle Aged; D057068:Periprosthetic Fractures; D012189:Retrospective Studies",
"nlm_unique_id": "0226040",
"other_id": null,
"pages": "2451-2458",
"pmc": null,
"pmid": "33773803",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Osteosynthesis in Vancouver type B1 periprosthetic fractures.",
"title_normalized": "osteosynthesis in vancouver type b1 periprosthetic fractures"
} | [
{
"companynumb": "ES-AMGEN-ESPSP2021199181",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "4",
... |
{
"abstract": "Squamous cell carcinoma of the extrahepatic bile duct is quite rare. A 77-year-old woman with jaundice and general fatigue was referred to our hospital. Multiphase contrast-enhanced computed tomography visualized a 17-mm solid mass in the junction of the cystic and common bile ducts. The patient underwent pylorus-preserving pancreaticoduodenectomy. The pathological findings demonstrated keratin-positive poorly differentiated squamous cell carcinoma of the extrahepatic bile duct (T3N0M0, stage IIIA). Although adjuvant chemotherapy with gemcitabine was administered, the patient exhibited local recurrence at the site of anastomosis of biliojejunostomy 20 months after resection and died 32 months after resection.",
"affiliations": "Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.",
"authors": "Goto|Takuma|T|;Sasajima|Junpei|J|;Koizumi|Kazuya|K|;Sugiyama|Yoshiaki|Y|;Kawamoto|Toru|T|;Fujibayashi|Shugo|S|;Moriichi|Kentaro|K|;Yamada|Masataka|M|;Fujiya|Mikihiro|M|;Kohgo|Yutaka|Y|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.6226",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(12)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms; D017734:Bile Ducts, Extrahepatic; D002294:Carcinoma, Squamous Cell; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1581-4",
"pmc": null,
"pmid": "27301509",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary Poorly Differentiated Squamous Cell Carcinoma of the Extrahepatic Bile Duct.",
"title_normalized": "primary poorly differentiated squamous cell carcinoma of the extrahepatic bile duct"
} | [
{
"companynumb": "JP-ACCORD-041950",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nExisting therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients).\n\n\nMETHODS\nPatients treated with clofarabine for LCH, JXG, or RDD by Texas Children's Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity.\n\n\nRESULTS\nPatients were treated with a median of three chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m(2) /day for 5 days. Cycles were administered every 28 days for a median of six cycles (range: 2-8 cycles). Seventeen of 18 patients are alive. All surviving patients showed demonstrable improvement after two to four cycles of therapy, with 11 (61%) complete responses, 4 (22%) partial responses, and 2 patients still receiving therapy. Five patients experienced disease recurrence, but three of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections.\n\n\nCONCLUSIONS\nClofarabine has activity against LCH, JXG, and RDD in heavily pretreated patients, but prospective multi-center trials are warranted to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population.",
"affiliations": "Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas.",
"authors": "Simko|Stephen J|SJ|;Tran|Huy D|HD|;Jones|Jeremy|J|;Bilgi|Mrinalini|M|;Beaupin|Lynda Kwon|LK|;Coulter|Don|D|;Garrington|Timothy|T|;McCavit|Timothy L|TL|;Moore|Colin|C|;Rivera-Ortegón|Francisco|F|;Shaffer|Linda|L|;Stork|Linda|L|;Turcotte|Lucie|L|;Welsh|Esperanza C|EC|;Hicks|M John|MJ|;McClain|Kenneth L|KL|;Allen|Carl E|CE|",
"chemical_list": "D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D000077866:Clofarabine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.24772",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(3)",
"journal": "Pediatric blood & cancer",
"keywords": "Langerhans cell histiocytosis; Rosai-Dorfman disease; clofarabine; histiocytosis; juvenile xanthogranuloma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000227:Adenine Nucleotides; D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D005260:Female; D006646:Histiocytosis, Langerhans-Cell; D015618:Histiocytosis, Sinus; D006801:Humans; D007223:Infant; D008297:Male; D012008:Recurrence; D016879:Salvage Therapy; D014972:Xanthogranuloma, Juvenile",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "479-87",
"pmc": null,
"pmid": "24106153",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "20220088;16291085;22354543;20434166;17288522;18623218;17194658;8469221;16302214;15049016;20361277;15486072;16804933;19731321;8699998;18338395;20589639;16115942;17940639;1707752;23255383;22284564;19767778;23589673;19125089",
"title": "Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease.",
"title_normalized": "clofarabine salvage therapy in refractory multifocal histiocytic disorders including langerhans cell histiocytosis juvenile xanthogranuloma and rosai dorfman disease"
} | [
{
"companynumb": "US-MYLANLABS-2015M1012092",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe clinical efficacy and safety of a three-drug combination of melphalan, prednisone, and thalidomide were assessed in patients with multiple myeloma who were not candidates for high-dose therapy as a first-line treatment. Because the side effects of thalidomide at a dose of ≥ 100 mg daily can be a barrier to effective treatment for these patients, we evaluated the efficacy and safety of a reduced dose of thalidomide, 50 mg, for non-transplant candidates.\n\n\nMETHODS\nTwenty-one patients were treated in 4-week cycles, receiving 4 mg/m(2) melphalan and 40 mg/m(2) prednisone on days 1-7 and 50 mg thalidomide daily. The primary efficacy outcome was the overall response rate. Aspirin (100 mg daily) was also provided as prophylactic treatment for thromboembolism.\n\n\nRESULTS\nThe overall response rate was 57.1%; a complete response was seen in 23.8% of patients, a partial response in 33.3%, and stable disease in 9.5%. After a median follow-up time of 16.1 months, the median time to progression was 11.4 months (95% confidence interval, 2.1 to 20.6); the median overall survival was not reached. Grades 3 and 4 adverse events included infection (10%), peripheral neuropathy (5%), diarrhea (5%), thrombosis (10%), and loss of consciousness (10%). Two patients discontinued treatment due to loss of consciousness and neuropathy.\n\n\nCONCLUSIONS\nLow-dose thalidomide (50 mg) plus melphalan and prednisone is an effective combination drug therapy option for newly diagnosed myeloma patients who are ineligible for high-dose chemotherapy.",
"affiliations": "Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.",
"authors": "Chang|Hye Jung|HJ|;Lee|Jae Hoon|JH|;Do|Young Rok|YR|;Bae|Sung-Hwa|SH|;Lee|Jung-Lim|JL|;Nam|Seung Hyun|SH|;Yoon|Sung-Soo|SS|;Bang|Soo-Mee|SM|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D018931:Antineoplastic Agents, Hormonal; D013792:Thalidomide; D008558:Melphalan; D011241:Prednisone",
"country": "Korea (South)",
"delete": false,
"doi": "10.3904/kjim.2011.26.4.403",
"fulltext": "\n==== Front\nKorean J Intern MedKJIMThe Korean Journal of Internal Medicine1226-33032005-6648The Korean Association of Internal Medicine 10.3904/kjim.2011.26.4.403Original ArticleA Combination of Melphalan, Prednisone, and 50 mg Thalidomide Treatment in Non-Transplant-Candidate Patients with Newly Diagnosed Multiple Myeloma Chang Hye Jung 1Lee Jae Hoon 2Do Young Rok 3Bae Sung-Hwa 4Lee Jung-Lim 5Nam Seung Hyun 6Yoon Sung-Soo 7Bang Soo-Mee 11 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.2 Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea.3 Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea.4 Department of Internal Medicine, Catholic University of Daegu, Daegu, Korea.5 Department of Internal Medicine, Daegu Fatima Hospital, Daegu, Korea.6 Department of Internal Medicine, Seoul Veterans Hospital, Seoul, Korea.7 Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.Correspondence to Soo-Mee Bang, M.D. Department of Internal Medicine, Seoul National University Bundang Hospital, Gumi-dong, Bundang-gu, Seongnam 463-707, Korea. Tel: 82-31-787-7039, Fax: 82-31-787-4052, smbang7@snu.ac.kr12 2011 28 11 2011 26 4 403 409 22 12 2010 05 4 2011 13 5 2011 Copyright © 2011 The Korean Association of Internal Medicine2011This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background/Aims\nThe clinical efficacy and safety of a three-drug combination of melphalan, prednisone, and thalidomide were assessed in patients with multiple myeloma who were not candidates for high-dose therapy as a first-line treatment. Because the side effects of thalidomide at a dose of ≥ 100 mg daily can be a barrier to effective treatment for these patients, we evaluated the efficacy and safety of a reduced dose of thalidomide, 50 mg, for non-transplant candidates.\n\nMethods\nTwenty-one patients were treated in 4-week cycles, receiving 4 mg/m2 melphalan and 40 mg/m2 prednisone on days 1-7 and 50 mg thalidomide daily. The primary efficacy outcome was the overall response rate. Aspirin (100 mg daily) was also provided as prophylactic treatment for thromboembolism.\n\nResults\nThe overall response rate was 57.1%; a complete response was seen in 23.8% of patients, a partial response in 33.3%, and stable disease in 9.5%. After a median follow-up time of 16.1 months, the median time to progression was 11.4 months (95% confidence interval, 2.1 to 20.6); the median overall survival was not reached. Grades 3 and 4 adverse events included infection (10%), peripheral neuropathy (5%), diarrhea (5%), thrombosis (10%), and loss of consciousness (10%). Two patients discontinued treatment due to loss of consciousness and neuropathy.\n\nConclusions\nLow-dose thalidomide (50 mg) plus melphalan and prednisone is an effective combination drug therapy option for newly diagnosed myeloma patients who are ineligible for high-dose chemotherapy.\n\nMultiple myelomaThalidomideMelphalanPrednisone\n==== Body\nINTRODUCTION\nMultiple myeloma accounts for approximately 10% of hematological malignancies and has increased in frequency due to aging of the general population [1]. Half of all multiple myeloma patients are older than 70 years of age, and 20% are older than 80 years of age [2]. In Korea, the incidence of multiple myeloma has increase steadily over the last 25 years [3], and the current incidence rate exceeds 1.0/100,000. Aging is an important factor that has contributed to the increase in the incidence of multiple myeloma in Korea [4].\n\nThalidomide has been successfully combined with corticosteroids and alkylating agents in the treatment of multiple myeloma. Palumbo et al. [5] showed that a combination of melphalan, prednisone, and thalidomide (MPT) showed a significant difference in progression-free survival compared with melphalan and prednisone alone (MP), but had no benefit for overall survival. Studies by the Intergroupe Francophone du Myelome (IFM), 01/01 trial [6] and Wijermans et al. [7] showed similar results. The IFM 99-06 trial reported a significant overall survival advantage for MPT compared with MP treatment [8]. These results indicated that the MPT combination can be considered an effective first-line treatment for elderly patients with multiple myeloma.\n\nThe optimal dose of thalidomide in an MPT regimen has yet to be determined. In two previous studies, the dose of thalidomide was 100 mg daily [5,6], and another study used a dose of 200 mg daily [7]. In the IFM 99-06 study, patients received a median dose of 200 mg/day [8]. However, these doses resulted in numerous adverse effects. Although toxic effects of MPT such as thromboembolism are manageable (e.g., low-dose aspirin for the prophylaxis of deep venous thromboembolism), a reduction in the dose of thalidomide as soon as symptoms appear is recommended. Thalidomide toxicity increases with the dose [9]. The side effects of thalidomide at a dose of ≥ 100 mg daily are barriers to effective treatment for patients who are not candidates for high-dose therapy as a first-line treatment. Therefore, we evaluated the efficacy and safety of a reduced dose of thalidomide, 50 mg daily, in an MPT regimen for non-transplant candidates.\n\nMETHODS\nPatients\nThe study enrolled patients from seven clinical centers in Korea. Patients were previously untreated myeloma patients who were between the ages of 18 and 85 years, had measurable disease, a monoclonal (M) protein concentration of ≥ 1 g/dL or a urine M protein concentration of ≥ 400 mg/day, an expected survival time of ≥ 3 months, and a creatinine clearance rate of ≥ 20 mL/min. Exclusion criteria were presence of another cancer, psychiatric disease, or any grade 2 peripheral neuropathy. Abnormal cardiac function, preexisting pulmonary embolism, and abnormal liver function were not criteria for exclusion.\n\nThe study protocol was approved by the institutional review boards of each participating center. All patients gave written informed consent before entering the study, which was performed in accordance with the Declaration of Helsinki and the Korean Multiple Myeloma Working Party (KMMWP-KMM62).\n\nStudy design\nThis study was an open-label, non-randomized, clinical trial conducted at seven hospitals in Korea. The primary efficacy outcome was the overall response rate (ORR), classified as a complete response (CR), very good partial response (VGPR), or a partial response (PR). Secondary outcomes included time to disease progression (TTP), overall survival (OS), and toxicity. TTP was defined as the time from initiation of treatment to disease progression; deaths resulting from causes other than disease progression were censored. OS was defined as the time interval from initiation of treatment to death from any cause. Duration of response was defined as the period from the first observation of a PR to the date of disease progression; deaths resulting from causes other than progression were censored.\n\nTreatment and dose modification\nTreatment consisted of 4-week cycles of melphalan (4 mg/m2) and prednisone (40 mg/m2) on days 1-7, with 50 mg thalidomide given daily. Patients were also given 100 mg aspirin daily to prevent deep vein thromboembolism. Dose reduction of MPT was allowed after the first 4-week cycle. Treatment continued for six cycles or more, at the investigator's discretion, until disease progression, withdrawal of consent, or unacceptable treatment-related toxicity occurred. Melphalan and thalidomide could be withheld during cycle 1 for reasons of neutropenia or thrombocytopenia higher than grade 3. Patients with delayed recovery of hematologic toxicity (i.e., grade > 1 for more than 2 weeks) had a 25% dose reduction of melphalan.\n\nAssessment of response and toxicity\nPatient response was assessed using serum and urine M protein concentrations measured after cycle 2 and after every other cycle thereafter. Response to treatment, determined at the time of maximal response, was defined according to the European Group for Blood and Marrow Transplantation criteria [9]. Additional categories of near-complete response (nCR), defined by the absence of M protein after electrophoresis with positive immunofixation, and VGPR, defined by a > 90% reduction in M protein, were included. CR required confirmed disappearance of M protein in the serum and urine by immunofixation studies and < 5% plasma cells upon bone marrow examination. A PR was defined as a ≥ 50% reduction in serum M protein and a reduction in 24-hour urine M protein of ≥ 90% or to < 200 mg, plus no increase in the number or size of lytic bone lesions or any other evidence of disease progression. Progressive disease (PD) was defined as recurrence of disease after a CR or a > 25% increase in M protein from its lowest point. Patients who did not meet the criteria for CR, PR, or PD were classified as having stable disease. Adverse events were assessed during each cycle and graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0 (NCI-CTC v3.0).\n\nStatistical analysis\nThis study was initially planned using a grouped sequential design [10] with an expected risk reduction (RR) of 70% in the MPT arm compared with a 50% RR in the MP arm (refer to Appendix 1). However, after the first stage, investigators decided to terminate the study early for two reasons: lack of insurance coverage for thalidomide and delayed enrollment. All statistical analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). OS and TTP were estimated using the Kaplan-Meier method.\n\nRESULTS\nPatient characteristics\nTwenty-one patients with newly diagnosed multiple myeloma, who were non-transplant candidates, were enrolled in our study between June 2006 and December 2008. Clinical characteristics of the cohort are summarized in Table 1. In brief, the median patient age was 70 years (range, 59 to 79), with three patients (14.3%) older than 75 years, and 47.6% of the patients were men. Six (28.6%) and 15 (71.4%) patients were classified as Durie-Salmon stages II and III, respectively.\n\nResponse\nA total of 21 patients received 92 cycles of MPT (median, 4 cycles; range, 1 to 12) (Table 2). Responses of three patients could not be evaluated because of death or loss to follow-up within two cycles of MPT therapy. Among 18 patients available for evaluation, five patients (23.8%) achieved a CR after two cycles of therapy, including two patients with an nCR, and six patients (33.3%) had a PR, including one patient with a VGPR, resulting in an ORR of 57.1%. The median duration of response was 5.5 months (range, 0.7 to 17.5).\n\nSurvival\nThe median duration of follow-up was 16.1 months (range, 2.1 to 42.5). The median TTP was 11.4 months (95% confidence interval, 2.1 to 20.6); the median OS was not reached (Fig. 1).\n\nToxicities\nTwenty patients were assessed for toxicity from MPT. Hematologic and non-hematologic toxicities are shown in Table 3. Grades 3 and 4 hematologic toxicities included neutropenia (5%), thrombocytopenia (5%), and anemia (5%). Grades 3 and 4 non-hematologic toxicities were thromboembolism (10%), infection (10%), loss of consciousness (10%), and diarrhea (5%). Peripheral neuropathy was noted in 50% of patients, including 5% with grade 3 neuropathy. Fatigue, nausea, and hepatotoxicity of grades 1 and 2 were also reported during MPT therapy.\n\nOne patient (4.8%) died of an unknown cause after she had received one cycle of MPT. No autopsy was performed. One patient experienced loss of consciousness after he had received one cycle of chemotherapy. No specific abnormalities were found in this patient upon brain imaging, but it was decided that he would discontinue the MPT regimen. Another patient had grade 3 sensory neuropathy after he had been treated with four cycles of MPT. He achieved CR, and it was decided that he would discontinue MPT, as he did not want maintenance therapy.\n\nDISCUSSION\nHigh-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) has improved the survival of both young [10] and elderly patients with multiple myeloma [11]. However, about half of patients with newly diagnosed multiple myeloma are over 70 years of age or have inadequate end-organ function, which are potential limitations for treatment with HDT and ASCT. The combination of melphalan and prednisone has been the standard treatment for such patients, but patient outcomes are less than satisfactory [12].\n\nRecently, thalidomide used in combination with MP has become a first-line treatment regimen in non-transplant candidates and has resulted in superior outcomes in elderly patients compared with MP treatment alone [5-8]. Although MPT has shown promising results, the optimal dose of thalidomide has yet to be established. The Nordic group suggested that increasing the dose of thalidomide to 400 mg/day in very elderly patients could be associated with greater toxicity and more adverse outcomes [13]. Therefore, to reduce the adverse effects associated with thalidomide, the dose of thalidomide was decreased from 800 mg in the first trial to 100 mg, and more recently, to 50 mg/day [14-16]. The goal of clinicians is to use as low a dose of thalidomide as possible.\n\nThis study used 50 mg thalidomide plus MP and demonstrated a 57.1% ORR. In comparison, the IFM 01/01 trial, which included patients older than 75 years, showed a 62% ORR after MPT treatment [6]. Complete and partial response rates were 23.8% and 33.3% in this study and 7% and 41% in the IFM 01/01 trial, respectively. The median progression-free survival (PFS) time was 24.1 months in the IFM 01/01 trial, and the median time to progression was 11.4 months in this study. Our study showed similar response rates but shorter response durations than did the IFM 01/01 trial. The use of novel agents (thalidomide, bortezomib, lenalidomide) is also associated with high response rates, and recent trials showed that patients achieving CR had significantly longer PFS than patients achieving PR [17]. Although our study demonstrated a higher CR rate than the IFM 01/01 trial reported, the duration of response and survival were less satisfactory for our cohort. However, our definition of CR was different from that of the IFM 01/01 trial, as we included nCR patients, whereas the IFM 01/01 trial did not. Additionally, patients in the IFM 01/01 trial were treated for 12 cycles, whereas our patients were typically treated for six cycles. These differences might explain the apparent discrepancy between the studies in CR rate and survival.\n\nWith respect to the withdrawal rate from the IFM 01/01 trial, 48 patients (42.4%) discontinued treatment due to toxicities, whereas two patients (10%) discontinued treatment in our study. Additionally, the IFM 01/01 trial reported that 20% of patients required a dose reduction of thalidomide to 50 mg/day due to grades 1 and 2 peripheral neuropathy. Waage et al. [13] had similar results for a patient who was not eligible for HDT with ASCT. They demonstrated a 57% ORR and a median of 15 months PFS with MP and 200 or 400 mg of thalidomide. Fifty-nine patients (32.4%) discontinued thalidomide treatment due to toxicity. These data suggest that patients with multiple myeloma treated with 50 mg thalidomide had good compliance.\n\nVenous thromboembolism (VTE) is a critical clinical condition manifesting as deep vein thrombosis and/or pulmonary embolism. Thalidomide treatment is associated with an increased risk of VTE, especially when used in combination with dexamethasone and/or chemotherapy. The risk is generally greatest in patients treated with thalidomide as a first-line therapy, as opposed to patients treated after relapse [18]. The percentage of thromboembolic events with thalidomide therapy in our study (10%) was higher than previously reported in Korean patients in general (3.9%) [19]. However, this incidence was lower than data from Western cohorts, which showed 6-17% incidences of VTE [5,6,8] after MPT treatment. Our study cohort included just 21 patients, which may have affected our interpretation of side effects.\n\nThe small number of patients enrolled in our study is a major limitation of this study. Despite the original study design, we decided to terminate this trial early for two reasons: absence of adequate insurance coverage of thalidomide and delayed enrollment of patients. Thalidomide is not covered by insurance for use as a first-line chemotherapy drug in Korea, but only as a secondary treatment after progression with first-line chemotherapy. Furthermore, patients with newly diagnosed multiple myeloma who were first treated with MP plus 50 mg thalidomide (MPT50) in our study, at high personal cost, could not use thalidomide combination therapy as a second-line chemotherapy option due to lack of insurance coverage. These challenges also resulted in delayed patient enrollment. Additionally, the availability of other new, active drugs (i.e., bortezomib and lenalidomide), which elicited good responses from patients not eligible for transplant [20,21], delayed enrollment of a sufficient number of patients. We evaluated the responses of 20 patients, 12 of whom responded to MPT50. According to the algorithm for enrollment (Appendix 1), our ideal cohort should have been 40 patients. Due to the various factors that prevented enrollment of a sufficient number of patients in a timely fashion, we decided to end this trial early.\n\nIn conclusion, our results suggest that MPT50 is an effective first-line treatment option for non-transplant-eligible patients with multiple myeloma, including elderly patients. To better identify the most appropriate patients for MPT50 therapy, however, additional large-scale prospective studies are needed.\n\nNo potential conflict of interest relevant to this article was reported.\n\nAppendix 1\nAlgorithm for patient enrollment, according to expected response\n\n\nCR, complete response; PR, partial response.\n\nFigure 1 (A) Time to progression and (B) overall survival.\n\nTable 1 Patient characteristics (n = 21)\n\nECOG, Eastern Cooperative Oncology Group score.\n\nTable 2 Response rates of patients after a combination of melphalan, prednisone, and thalidomide therapy (n = 21)\n\nTable 3 Adverse toxicity events after a combination of melphalan, prednisone, and thalidomide treatment\n\nValues are presented as number (%).\n==== Refs\n1 Kyle RA Rajkumar SV Multiple myeloma N Engl J Med 2004 351 1860 1873 15509819 \n2 Phekoo KJ Schey SA Richards MA A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK Br J Haematol 2004 127 299 304 15491289 \n3 Kim HJ Heo DS Bang YJ Multiple myeloma in Korea: clinical analysis and treatment results in 61 cases Korean J Intern Med 1987 2 120 124 3154811 \n4 Lee JH Bang SM Epidemiological change of multiple myeloma in Korea Korean J Hematol 2006 41 225 234 \n5 Palumbo A Bringhen S Caravita T Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial Lancet 2006 367 825 831 16530576 \n6 Hulin C Facon T Rodon P Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial J Clin Oncol 2009 27 3664 3670 19451428 \n7 Wijermans P Schaafsma M Termorshuizen F Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study J Clin Oncol 2010 28 3160 3166 20516439 \n8 Facon T Mary JY Hulin C Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial Lancet 2007 370 1209 1218 17920916 \n9 Yakoub-Agha I Attal M Dumontet C Thalidomide in patients with advanced multiple myeloma: a study of 83 patients--report of the Intergroupe Francophone du Myelome (IFM) Hematol J 2002 3 185 192 12189564 \n10 Attal M Harousseau JL Stoppa AM A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: intergroupe Francais du Myelome N Engl J Med 1996 335 91 97 8649495 \n11 Qazilbash MH Saliba RM Hosing C Autologous stem cell transplantation is safe and feasible in elderly patients with multiple myeloma Bone Marrow Transplant 2007 39 279 283 17262062 \n12 Myeloma Trialists' Collaborative Group Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials J Clin Oncol 1998 16 3832 3842 9850028 \n13 Waage A Gimsing P Fayers P Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma Blood 2010 116 1405 1412 20448107 \n14 Singhal S Mehta J Desikan R Antitumor activity of thalidomide in refractory multiple myeloma N Engl J Med 1999 341 1565 1571 10564685 \n15 Hus I Dmoszynska A Manko J An evaluation of factors predicting long-term response to thalidomide in 234 patients with relapsed or resistant multiple myeloma Br J Cancer 2004 91 1873 1879 15520820 \n16 Steurer M Spizzo G Mitterer M Gastl G Low-dose thalidomide for multiple myeloma: interim analysis of a compassionate use program Onkologie 2004 27 150 154 15138347 \n17 Harousseau JL Attal M Avet-Loiseau H The role of complete response in multiple myeloma Blood 2009 114 3139 3146 19638622 \n18 El Accaoui RN Shamseddeen WA Taher AT Thalidomide and thrombosis: a meta-analysis Thromb Haemost 2007 97 1031 1036 17549307 \n19 Koh Y Bang SM Lee JH Low incidence of clinically apparent thromboembolism in Korean patients with multiple myeloma treated with thalidomide Ann Hematol 2010 89 201 206 19705118 \n20 San Miguel JF Schlag R Khuageva NK Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma N Engl J Med 2008 359 906 917 18753647 \n21 Zonder JA Crowley J Hussein MA Superiority of lenalidomide (Len) plus high-dose dexamethasone (HD) compared to HD alone as treatment of newly-diagnosed multiple myeloma (NDMM): results of the randomized, double-blinded, placebo-controlled SWOG trial S0232 Blood 2007 110 77\n\n",
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"issue": "26(4)",
"journal": "The Korean journal of internal medicine",
"keywords": "Melphalan; Multiple myeloma; Prednisone; Thalidomide",
"medline_ta": "Korean J Intern Med",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D018931:Antineoplastic Agents, Hormonal; D016001:Confidence Intervals; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007723:Korea; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D011241:Prednisone; D012306:Risk; D013792:Thalidomide; D013997:Time Factors; D016896:Treatment Outcome",
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"pubdate": "2011-12",
"publication_types": "D016428:Journal Article",
"references": "18753647;17262062;15509819;20448107;16530576;9850028;17549307;19451428;8649495;15138347;15491289;17920916;10564685;20516439;19638622;19705118;3154811;12189564;15520820",
"title": "A combination of melphalan, prednisone, and 50 mg thalidomide treatment in non-transplant-candidate patients with newly diagnosed multiple myeloma.",
"title_normalized": "a combination of melphalan prednisone and 50 mg thalidomide treatment in non transplant candidate patients with newly diagnosed multiple myeloma"
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"abstract": "OBJECTIVE\nWith increased opioid use, drug-drug interactions (DDIs) and associated adverse events are growing among geriatric patients. However, the clinical significance of potential metabolic DDIs associated with opioid use has not been fully evaluated among geriatric patients. Particularly, cytochrome (CYP) P450 enzymes are important in drug metabolism of oxycodone and a black box warning for oxycodone reveals serious risks associated with drug-oxycodone interactions. This study focused on the use of oxycodone in geriatric patients to evaluate its adverse drug reactions (ADRs) and DDIs associated with CYP P450 enzymes.\n\n\nMETHODS\nA retrospective cohort study using patients treated at Korea Veterans Hospital was performed. Data from male patients aged 65 years and older who received oxycodone were analysed. Binomial variables describing patient-related characteristics, drug-related characteristics and CYP-mediating drugs were constructed. Associations between these variables and the frequency of ADRs were determined. The odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariable and multivariable analyses, respectively.\n\n\nCONCLUSIONS\nAmong 111 patients, 32.4% experienced at least one ADR. The most common ADR was gastrointestinal-related (n = 21), followed by dizziness and drowsiness (n = 8). Use of either CYP2D6 inhibitors or CYP3A4 inhibitors increased the rate of ADRs by 20.4 and 25.4 times, respectively. In the case of patients taking both inhibitors, the adjusted OR was 48.6, and the attributable risk was 97.9%.\n\n\nCONCLUSIONS\nThis study suggests that inappropriate combinations of oxycodone with CYP2D6 inhibitors and/or CYP3A4 inhibitors may warrant treatment modification to avoid ADRs in geriatric patients. Clinicians should monitor any signs of ADRs that may reflect DDIs while a geriatric patient is taking oxycodone.",
"affiliations": "College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.;Graduate School of Converging Clinical & Public Health, Ewha Womans University, Seoul, Korea.;College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.;College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.;College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.",
"authors": "Kim|Joo Hee|JH|;Kim|Ji Young|JY|;Lee|Nari|N|;Yee|Jeong|J|;Gwak|Hye Sun|HS|https://orcid.org/0000-0003-0278-2563",
"chemical_list": "D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D010098:Oxycodone",
"country": "England",
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"doi": "10.1111/jcpt.13113",
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"issue": "45(5)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "CYP2D6; CYP3A4; drug-drug interactions; geriatric patients; oxycodone",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000701:Analgesics, Opioid; D015331:Cohort Studies; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D006801:Humans; D008297:Male; D010098:Oxycodone; D056910:Republic of Korea; D012189:Retrospective Studies",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "976-982",
"pmc": null,
"pmid": "32068910",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The impact of drug interactions on adverse effects of oral oxycodone in male geriatric patients.",
"title_normalized": "the impact of drug interactions on adverse effects of oral oxycodone in male geriatric patients"
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"companynumb": "KR-ROCHE-2700604",
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"abstract": "OBJECTIVE\nLenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease.\n\n\nMETHODS\nEligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1-21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15), each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily). The maximum tolerated dose (MTD) of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25%) subjects experiences a dose-limiting toxicity (DLT). Patients should also be able to receive daily low molecular weight heparin (LMWH) (e.g. dalteparin 5000 IU s.c. daily) as a prophylactic anticoagulant for venous thromboembolic events (VTEs). Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively) were enrolled in this study.\n\n\nRESULTS\nMedian duration of treatment was 11 weeks (range 1-66), and median number of treatment cycles were three (range 1-14). The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs) (all grades) included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia); thrombocytopenia (75%); dermatological toxicity (75%); diarrhea and nausea (42% each); and neuropathy (42%).\n\n\nCONCLUSIONS\nThis phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1-21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial.\n\n\nBACKGROUND\nClinicalTrials.gov NCT01547260.",
"affiliations": "Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, Uppsala, Sweden; Department of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden.;Department of Oncology and Pathology (Radiumhemmet), Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.;Department of Oncology and Pathology (Radiumhemmet), Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.",
"authors": "Ullenhag|Gustav J|GJ|;Rossmann|Eva|E|;Liljefors|Maria|M|",
"chemical_list": "D000925:Anticoagulants; D003841:Deoxycytidine; D013792:Thalidomide; C056507:gemcitabine; D000077269:Lenalidomide; D017985:Dalteparin",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0121197",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2583749910.1371/journal.pone.0121197PONE-D-14-19777Research ArticleA Phase I Dose-Escalation Study of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer Lenalidomide Combined with Gemcitabine in Advanced Pancreatic CancerUllenhag Gustav J. \n1\n\n2\nRossmann Eva \n3\nLiljefors Maria \n3\n*\n1 \nDepartment of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, Uppsala, Sweden\n\n2 \nDepartment of Oncology, Uppsala University Hospital, Entrance 78, 751 85 Uppsala, Sweden\n\n3 \nDepartment of Oncology and Pathology (Radiumhemmet), Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden\nKorc Murray Academic Editor\nIndiana University School of Medicine, UNITED STATES\nCompeting Interests: The authors have read the journal's policy and one author of this manuscript has the following competing interest. Maria Liljefors has declared one compensated advisory role with Celgene Corporation. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The other authors have declared that no competing interests exist.\n\nConceived and designed the experiments: ML GU. Performed the experiments: ER. Analyzed the data: ML. Contributed reagents/materials/analysis tools: ML GU. Wrote the paper: ML GU. Study-design: ML ER GU. Responsibility for the patients during the study-period (screening, inclusion, on-study period, follow-up period): ML GU.\n\n* E-mail: maria.gustafsson-liljefors@karolinska.se2 4 2015 2015 10 4 e012119730 7 2014 19 1 2015 © 2015 Ullenhag et al2015Ullenhag et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Purpose\nLenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease.\n\nPatients and Methods\nEligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1–21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15), each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily). The maximum tolerated dose (MTD) of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25%) subjects experiences a dose-limiting toxicity (DLT). Patients should also be able to receive daily low molecular weight heparin (LMWH) (e.g. dalteparin 5000 IU s.c. daily) as a prophylactic anticoagulant for venous thromboembolic events (VTEs). Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively) were enrolled in this study.\n\nResults\nMedian duration of treatment was 11 weeks (range 1–66), and median number of treatment cycles were three (range 1–14). The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs) (all grades) included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia); thrombocytopenia (75%); dermatological toxicity (75%); diarrhea and nausea (42% each); and neuropathy (42%).\n\nDiscussion\nThis phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1–21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial.\n\nTrial Registration\nClinicalTrials.gov NCT01547260\n\n\nThis study was supported by the Swedish Cancer Society, The Karolinska Institute Foundation and the Stockholm County Council, the Research Foundation Stiftelsen Onkologiska Klinikens i Uppsala Forskningsfond, Lion´s Cancer Fund and in part by a grant from Celgene Corporation, Summit, NJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityData are available upon request due to ethical restrictions for researchers who meet the criteria for access to confidential data. Data are from the database PheedIt (SAS Institute) at KPE Karolinska. Requests for data may be submitted to Dr. Liljefors at the Department of Oncology, Karolinska Hospital, 171 76 Stockholm, Tel +46-8 5177 6136, maria.gustafsson-liljefors@karolinska.se.Data Availability\nData are available upon request due to ethical restrictions for researchers who meet the criteria for access to confidential data. Data are from the database PheedIt (SAS Institute) at KPE Karolinska. Requests for data may be submitted to Dr. Liljefors at the Department of Oncology, Karolinska Hospital, 171 76 Stockholm, Tel +46-8 5177 6136, maria.gustafsson-liljefors@karolinska.se.\n==== Body\nIntroduction\nPancreatic cancer is characterised by aggressive growth, treatment resistance and poor prognosis [1]. The majority of patients presents with advanced, inoperable disease. The five-year survival rate is less than 5% [2]. Even those patients who are candidates for surgical resection experience a poor prognosis with a five-year survival rate of only 8–20% [3, 4].\n\nFor patients with advanced disease, gemcitabine is standard treatment which may be combined with 5-FU. The median survival is 5.6 months [5]. Several studies of gemcitabine combined with other cytotoxic chemotherapy agents have failed to improve survival compared with gemcitabine alone [6]. Targeting the vascular endothelial growth factor (VEGF) receptor in pancreatic carcinomas using bevacizumab [7] or axitinib [8] in combination with gemcitabine did not improve survival. However, FOLFIRINOX has been shown to improve overall survival in patients with metastatic disease when compared to gemcitabine, but with added toxicity [9]. In addition, targeting the epidermal growth factor receptor (EGFR) (erlotinib) has shown to improve survival in combination with gemcitabine. The modest improvement in survival was statistically significant in patients with metastatic, but not in locally advanced disease [10]. Furthermore, overall survival was extended with two months in median with the addition of nab-paclitaxel to gemcitabine in pancreatic cancer patients with metastatic disease (MPACT trial) [11]. Thus, irrespective of treatment regimens, survival of pancreatic cancer patients remains poor and new therapeutic strategies are urgently needed.\n\nLenalidomide (Celgene Corporation, Summit, NJ) is a thalidomide analogue that was approved by the U.S. Food and Drug Administration (FDA) and by the European Medicine Agency (EMA) for relapsed or refractory multiple myeloma (MM) [12, 13]. Although the antitumour mechanism of action of lenalidomide is not fully understood, a number of mechanisms have been postulated, involving both immunomodulatory and anti-angiogenetic properties [14]. Lenalidomide has been demonstrated to possess anti-angiogenic activity through inhibition of bFGF, VEGF and by TNF-alpha induced endothelial cell migration [15]. Lenalidomide also has immunomodulatory and anti-inflammatory effects by augmenting natural killer (NK)—cell cytotoxicity [16], by regulating T-cell co-stimulation [16–18] and by altering cytokine production [19], which could confer antitumor activity [20].\n\nIn solid tumors, safety and potential clinical efficacy of lenalidomide has been observed in patients with advanced disease who have previously received multi-modality treatment receiving lenalidomide administered as single [21–24] or as combination therapy [25]. The combination of pomalidomide, the 3rd generation of Immunomodulatory drugs (IMiDs), with gemcitabine, was safe in most patients as first-line treatment for metastatic pancreatic cancer [26]. In addition, treatment with lenalidomide combined with gemcitabine has been explored in metastatic pancreatic cancer patients [26, 27].\n\nBeside the cytotoxic activity of gemcitabine, accumulating evidence has indicated that the product promote specific anticancer immune responses that contribute to the therapeutic effects. Gemcitabine may augment immune responses in several ways; By activating T cells [28] increasing the amount of DC:s [29] increasing the amounts of antigens loaded onto antigen-presenting cells (APC) [30], down-regulating T-regulatory cells [31, 32], and IL-6 [33]. Administration of gemcitabine can make the tumor cells more susceptible to T-cell mediated destruction by inducing up-regulation of death receptors [34] and has shown to enhance immune responses against cancer vaccines [28]. Those data supports that lenalidomide and gemcitabine should be of major interest to explore for combination therapy. The primary objective of this study was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with gemcitabine as first line treatment for patients with advanced pancreatic cancer. There is no previous dose escalation study with this combination in pancreatic cancer patients.\n\nPatients and Methods\nThe protocol for this trial and supporting TREND checklist are available as supporting information; see S1 Checklist and S1 Protocol.\n\nTo our knowledge, all ongoing and related trials for this drug/intervention are registered.\n\nPatient population\nEligible patients had histologically or cytologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the pancreas. No prior chemotherapy for metastatic disease or locally advanced disease was allowed. Participants may have been previously treated with gemcitabine, fluorouracil, or capecitabine in the adjuvant setting. Patients should also be able to receive daily low molecular weight heparin (LMWH) (e.g. dalteparin 5000 IU subcutaneously daily) as prophylactic anticoagulant. Female subjects of childbearing potential should agree to use effective contraception without interruption, 4 weeks before starting study drug, throughout the study and for 4 weeks after end of study drug therapy. A negative urine pregnancy test in women of child-bearing potential before the start of treatment was required.\n\nMale subjects must agree to use condoms throughout study drug therapy and for one week after cessation of study therapy. Other eligibility criteria included: age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, life expectancy > 12 weeks, adequate bone marrow function (defined as absolute neutrophil count (ANC) >1.5 x 109/L, platelet count >100 x 109/L), adequate renal and hepatic function (defined as serum creatinine <2,0 mg/dL (< 177 μmol/L) and total bilirubin < 3 x the institutional upper limit of normal (ULN), AST/SGOT and ALT/SGPT <3 x ULN or < 5 x ULN for patients with liver metastases.\n\nExclusion criteria included prior systemic therapy for adenocarcinoma of the pancreas\n\n(except in the adjuvant setting, see above), use of any other experimental therapies within 28 days prior to Cycle 1 Day 1, a history of or active deep vein thrombosis (DVT) or pulmonary embolism (PE) that were not managed on a stable dose of appropriate anticoagulant, known brain metastases, prior history of malignancy within 5 years (except basal or squamous cell carcinoma or carcinoma in situ of the cervix or breast, localized prostate cancer with PSA < 1.0 mg/dL) or pregnant or lactating females. An independent data and safety monitoring board (DSMB) monitored data throughout the study with respect to the occurrence of secondary primary malignancies (SPMs).\n\nPatients were treated according to the Declaration of Helsinki’s ethical principles for medical research involving human subjects. The trial was performed according to GCP guidelines and was approved by the Regional Ethical Review Board for each Institution on the 6th of October 2009 (Regionala etikprövningsnämnden i Uppsala and Regionala etikprövningsnämnden i Stockholm) and by the Medical Products Agency in Uppsala, Sweden. The study was registered at ClinicalTrials.gov only after inclusion began since registration was not a routine procedure in Sweden in 2009. All patients provided an informed written consent prior to study entry.\n\nStudy design and treatment assessment\nThis was a dual-agent, two-centre, open-label phase I study conducted at the Karolinska University Hospital Solna, Sweden and Uppsala University Hospital, Uppsala, Sweden. The opportunity to participate included referred patients. The primary objective of this dose-escalation part of the study (phase I) was to determine the maximum tolerated dose (MTD) and safety of lenalidomide in combination with gemcitabine in patients with untreated advanced pancreatic cancer.\n\nLenalidomide was administered orally once daily for 21 days of a 28 day cycle. The prescribed dose of lenalidomide was given as a single dose each morning. Gemcitabine was administered by a nurse at a fix dose of 1000 mg/m2 intravenously over 30 minutes, on days 1, 8 and 15 every 28 day. All patients received prophylactic low molecular weight heparin (LMWH) (dalteparin, Pfizer Inc. New York, USA) (5000 IU s.c. once daily) during lenalidomide treatment. If platelet count was < 50 x 109/L, anticoagulant therapy was withheld until recovery to platelet count to > 50 x 109/L. All patients were on treatment until disease progression, unacceptable toxicity or consent withdrawal.\n\nThe dose-escalation scheme of lenalidomide was as follows; cohort I: capsule lenalidomide 15 mg once daily (dose-level 1), cohort II: capsule lenalidomide 20 mg once daily (dose-level 2) and cohort III: capsule lenalidomide 25 mg once daily (dose-level 3) (Table 1). The lenalidomide dose in cohort III was the highest planned dose per protocol. This dose was chosen based on results from previous phase I clinical trials data in patients with MM [35] and solid malignancies, including pancreatic carcinoma, using lenalidomide as a single-agent [22–24], or combined with other cytotoxic drugs, but with the addition of G-CSF treatment [25].\n\n10.1371/journal.pone.0121197.t001Table 1 Dose escalation and reduction schedule.\n\nDose level\n\t\nCohort\n\t\nLenalidomide dose\n\t\nGemcitabine dose\n\t\n\n(mg/day)\n\t\n(mg/m\n2\n)\n\t\n\nDays 1–21 of each\n\t\nDays 1, 8 and 15 of each\n\t\n\n28-day cycle\n\t\n28-day cycle\n\t\n\n-2\n\t\t5\t500\t\n\n-1\n\t\t10\t750\t\n\n1\n\tI\t15\t1000\t\n\n2\n\tII\t20\t1000\t\n\n3\n\tIII\t25\t1000\t\nThe dose of lenalidomide was escalated in sequential cohorts of three patients each. Dose-escalation continued if none of three patients experienced a dose-limiting toxicity (DLT). A cohort was expanded to four patients if one of the first three patients had a DLT during the first treatment cycle. There are several strategies for dose escalation when combining two drugs in phase I trials [36, 37]. Since gemcitabine is an established treatment for these patients, only lenalidomide was dose escalated and we used a modified 3:3 design in order to rapidly establish MTD. Enrollment to dose-cohorts level 2 and level 3 was withheld until the last enrolled patient in the previous dose-cohort had reached the end of cycle 1, i.e. at least 28 days of cycle 1. The maximum tolerated dose (MTD) of lenalidomide was defined as the highest dose level at which no more than one out of four (25%) patients experiences a DLT. If two or more out of four patients within the same cohort encounter DLT, MTD was exceeded and the lower dose level was considered to be MTD. Adverse events (AEs) were defined by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. DLTs were evaluated during the first treatment cycle (28 days) and defined as follows: a) inability to deliver all scheduled doses during cycle 1 due to an unexpected drug-related toxicity (if gemcitabine-related toxicity was an expected toxicity, it was not considered a DLT), and/or b) inability to deliver the intended doses of lenalidomide in cycle 1 due to drug-related toxicity as outlined below: any grade 3 or 4 non-hematological toxicity lasting for ≥ 14 days, febrile neutropenia, any grade 4 neutropenia lasting for ≥ 7 days, grade 4 thrombocytopenia or grade 4 liver enzyme toxicity. Grade 3 or 4 venous thromboembolic events were not considered to DLT as long as anticoagulant therapy could be administered. Criteria for safety evaluation were completion of the first treatment cycle or early discontinuation owing to DLT.\n\nPatients who did not finish the first cycle due to AEs other than DLTs were replaced.\n\nEvents were classified as Not suspected (the relationship of the AE to study drug made a causal relationship unlikely or remote, or other medications, therapeutic interventions, or underlying conditions provided sufficient explanation for the observed event) or Suspected (the relationship of the AE to study drug made a causal relationship possible, and other medications, therapeutic interventions, or underlying conditions did not provide sufficient explanation for the observed event). All AEs were recorded by the Investigator(s) during the period between start of the first cycle (Day 1) until 30 days following the last dose of study drug administration.\n\nDose modification and interruption\nDose-modifications were not permitted for lenalidomide during cycle 1 in any dose cohort, unless DLT occured. If the patient experienced drug-related toxicity assessed as related to gemcitabine during cycle 1, the gemcitabine dose was modified to dose level -1 at day 8, see Table 1. If AE not restored to grade ≤ 2 within 7 days, dose reduction to dose level -2 of gemcitabine was advised at day 15. In subsequent cycles, dose-modifications and/or interruptions for both lenalidomide and gemcitabine were prescribed (Table 1) in patients who developed hematologic or non-hematologic toxicities related to the treatment.\n\nThe dose of lenalidomide and gemcitabine in the subsequent cycle was based on toxicity and dose-reduction noted in the previous cycle. Additionally, before initiating a new treatment cycle, the following conditions had to be met; neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 75 x 109/L, lenalidomide-related allergic reaction/hypersensitivity or sinus bradycardia/ other cardiac arrhythmia that may have noted had to be resolved to ≤ grade 1 severity. Other lenalidomide/gemcitabine related adverse events that may had been noted had to be resolved to ≤ grade 2 severity.\n\nAssessments\nPrior to treatment (baseline-visit), patients were evaluated by a complete medical history and physical examination including assessment of ECOG performance status, complete blood count (including differential and platelet counts), serum chemistry (including electrolytes and liver function tests), coagulation tests (international normalized ratio (INR), and activated partial thromboplastin time (APT), thyroid stimulating hormone (TSH) levels and serum tumour marker (CA 19–9), urine pregnancy test (in women of child-bearing potential) and electrocardiogram (ECG) as well as an computer tomography (CT) scan of the chest and abdomen.\n\nDuring treatment, patients were examined every 28th day. On day 1 of each cycle, patients underwent interval medical history and physical examination, assessment of ECOG performance status, evaluation of adverse events and concomitant medications. Complete blood counts were repeated days 1, 4–5, 8, 11–12, 15, 21–23 during cycle 1, days 1, 8, 15, 21–23 during cycle 2 and days 1, 8 and 15 of the subsequent cycles. Serum chemistry including CA19-9 was repeated on day 1 of each cycle. TSH levels were analysed every second month. At the completion of every other cycle, disease assessments were performed by CT scans. All patients were monitored for secondary primary malignancies. At treatment discontinuation, patients underwent evaluations as at the baseline-visit. Safety assessments were also done approximately 28 days post last dose of study drug.\n\nTreatment compliance\nAt all times, when the study drug was dispensed, research center personnel reviewed the instructions, printed on the packaged together with the patients. The patients were asked to keep a diary. Research personnel counted and recorded the number of used and unused study drug capsules at each visit and reconciled with the patient diary.\n\nConcomitant therapy\nPatients received supportive care, including transfusions of blood and blood products, antibiotics, and antiemetics when appropriate. The use of granulocyte colony-stimulating factor (G-CSF) was permitted after cycle 1. Concomitant use of chemotherapy, radiation, or other investigational agents was not allowed while the patients received study drug.\n\nStatistical analysis\nData from all patients who received one or more doses of drug were included in the analyses. Descriptive statistics were used to analyse and present the data.\n\nResults\nAn electronic case report form (eCRF), PheedIt (SAS Institute) was used to record the results.\n\nClinical characteristics\nThirteen patients from two clinical sites were enrolled from the 14th January 2010 to the 20th May 2011. One patient did not receive lenalidomide during cycle one, due to drug exchange mistake (protocol violation). The patient was taken out of the study immediately. As the patient did not receive the allocated intervention, he is not included in the analysis. An additional patient was screened for the study and signed the informed consent in December 2009 but she never started treatment since her condition deteriorated rapidly. The first follow up was on the 12th October 2010 and the last follow up was on the 10th April 2014. Baseline demographic and clinical characteristics of the patients are shown in Table 2. Median time from initial diagnosis of advanced disease to start of treatment with lenalidomide and gemcitabine was 9.5 weeks (range 4–208 weeks).\n\n10.1371/journal.pone.0121197.t002Table 2 Patients baseline characteristics and number of patients per cohort.\n\nPatient no.\n\t\nSex/age (years)\n\t\nECOG Performance status\n\t\nSite of metastasis at inclusion\n\t\nPrevious treatment\n*\n\t\nTime from diagnosis of advanced disease to start of study (weeks)\n\t\nCohort\n\t\nDose lenalidomide (mg/day)\n\t\n\n111\n\tM/64\t0\tLiver\tNone\t53\tI\t15\t\n\n112\n\tF/63\t0\tLiver\tSurgery\t10\tI\t15\t\n\n113\n\tM/64\t1\tLiver\tNone\t4\tI\t15\t\n\n114\n\tM/79\t0\tLiver\tSurgery\t208\tI\t15\t\n\n121\n\tF/69\t1\tLiver\tNone\t9\tII\t20\t\n\n122\n\tF/68\t1\tLungs\tNone\t6\tII\t20\t\n\n123\n\tM/69\t0\tPeritoneum\tNone\t7\tII\t20\t\n\n131\n\tM/44\t1\tPeritoneum\tSurgery\t9\tIII\t25\t\n\n133\n\tM/65\t0\tNodes\tNone\t4\tIII\t25\t\n\n134\n\tM/68\t0\tNodes\tNone\t10\tIII\t25\t\n\n135\n\tM/62\t0\tLiver\tNone\t10\tIII\t25\t\n\n136\n\tF/55\t0\tLiver\tSurgery and chemotherapy#\n\t51\tIII\t25\t\n*Surgery = Pancreaticoduodenectomy.\n\n#Adjuvant chemotherapy with gemcitabine and capecitabine for 6 months\n\nDLT and MTD\nNo DLTs were observed in cohorts I (lenalidomide dose 15mg/day) or II (lenalidomide dose 20mg/day). One patient in cohort I (patient no. 113) developed urticaria grade 3 and erythema grade 2 at day 6 in cycle 1. The lenalidomide administration was temporarily held. It was not considered a DLT but the patient was replaced to have an adequate number of patients to determine MTD. One other patient in cohort III (patient no. 131) developed abdominal pain grade 3, vomiting grade 2 and grade 3 rash at day 7 in cycle 1. The nausea/vomiting and rash persisted for 7 days while the grade 3 abdominal pain continued after the hold of both study drugs. The symptoms were considered to be related to the underlying disease and therapy was permanently withheld. The patient was non-evaluable for DLT and an additional patient was enrolled in the cohort.\n\nThe only DLT was a cardiac failure grade 3 in cohort III (patient no 135). The patient had no sign of preexisting cardiac disease at the baseline visit. The patient complained of moderate fatigue and dyspnea on exertion but not at rest, at day 26 of cycle 1. Chest-X-ray showed enlargement of the heart compared to baseline and apical vascular redistribution, compatible with left-sided heart failure. Echocardiography showed a marginal dilatation of the left atrium but the ejection fraction was within normal limits. There were no changes in the ECG including QTs interval. Routinely performed blood tests indicating heart disease were normal. By lowering the dose of lenalidomide in the subsequent cycles, the patient was on therapy for further nine cycles without any clinical symptoms or signs of cardiac failure.\n\nAfter the DLT of a transient cardiac failure at the 25-mg dose level, a second additional patient was enrolled in cohort III. Dose-escalation was stopped at the dose of 25 mg of lenalidomide in combination with gemcitabine 1000 mg/m2, the highest planned dose level.\n\nTreatment exposures, delays and dose reductions\nA total of 64 cycles of lenalidomide in combination with gemcitabine were administered. The numbers of cycles and treatment duration are shown in Table 3. The median number of treatment cycles per patient was three (range 1–14). Median treatment duration was 9 weeks (range 7–23 weeks), 9 weeks (range 8–11 weeks), and 44 weeks (range 1–66 weeks) for patients in cohort I, cohort II and cohort III, respectively. For all patients, median treatment duration was 11 weeks (range 1–66 weeks).\n\n10.1371/journal.pone.0121197.t003Table 3 Treatment exposures, number of treatment cycles and median delivered dose of the study drugs.\n\nPat no.\n\t\nCohort\n\t\nDose lenalidomide (mg/day) Days 1–21 of each 28-day cycle\n\t\nNo. of treatment cycles\n\t\nDose (%)\n**\nCycle 1\n\t\nMedian Dose (%)\n***\nCycle 2 and beyond\n\t\nTreatment duration (weeks)\n\t\n\t\t\t\tLenalidomide\tGemcitabine\tLenalidomide\tGemcitabine\t\t\n\n111\n\tI\t15\t2\t100\t85\t100\t75\t7\t\n\n112\n\tI\t15\t6\t100\t100\t85\t80\t23\t\n\n113\n\tI\t15\t2\t30\t100\t67\t75\t7\t\n\n114\n\tI\t15\t3\t100\t85\t79\t84\t11\t\n\n121\n\tII\t20\t3\t100\t100\t50\t67\t8\t\n\n122\n\tII\t20\t3\t100\t100\t100\t100\t11\t\n\n123\n\tII\t20\t3\t100\t85\t67\t50\t9\t\n\n131\n\tIII\t25\t1\t30\t70\tNA*\n\tNA\t1\t\n\n133\n\tIII\t25\t14\t100\t100\t80\t78\t66\t\n\n134\n\tIII\t25\t13\t100\t100\t40\t51\t56\t\n\n135\n\tIII\t25\t10\t100\t100\t55\t90\t44\t\n\n136\n\tIII\t25\t4\t100\t100\t100\t100\t16\t\n*NA = not applicable\n\n** Administered dose / planned dose according to the protocol per cohort (%)\n\n*** Median administered dose / planned dose according to the protocol per patient per cohort (%)\n\nIn treatment cycle no. 1, the median delivered dose of the intended dose was 100% for both lenalidomide (range 30–100%) and gemcitabine (range 70–100%) (Table 3). From treatment cycle no. 2, the corresponding values were 79% (range 40–100%) for lenalidomide and 78% (range 50–100) for gemcitabine. Fig 1 shows the median delivered doses (in % of full doses) for lenalidomide and gemcitabine, respectively, in treatment cycles 1–14 for all patients.\n\n10.1371/journal.pone.0121197.g001Fig 1 Median delivered doses (% of full doses) for lenalidomide (black bars) and gemcitabine (grey bars), respectively, in treatment cycles 1–14 for all patients on study.\nFor an individual patient, the dose of lenalidomide per cycle was calculated by the following formula: the actual administered dose (mg) multiplied by the number of actual treatment days (n) divided by the planned administered dose (mg) multiplied by the planned treatment days (n) according to the protocol per cohort.\n\nFor an individual patient, the dose of gemcitabine per cycle was calculated by the following formula: the actual administered dose (1000 mg/m2 x any dose reduction in % if appropriate) multiplied by the number of actual treatment occasions (n) divided by the planned administered dose (1000 mg/m2) multiplied by the planned treatment occasions (n) according to the protocol.\n\nDose delays were uncommon. In four patients, nine cycles were delayed mainly due to haematologic toxicities. Dose-reductions were frequently seen both for lenalidomide and gemcitabine (Table 4). In cohort I, 8 out of 13 (62%) treatment cycles were dose-reduced. The corresponding values for cohort II was 44% and for cohort III 71%. Forty-two cycles out of 64 (65.6%) were administered at reduced doses of lenalidomide, gemcitabine or both. Sixteen cycles were administered at a reduced level due to haematologic toxicities (two cycles due to leucopenia grade 2 and one cycle due to leucopenia grade 3; one cycle due to neutropenia grade 1, six cycles due to neutropenia grade 3, five cycles due to neutropenia grade 4 and one cycle due to thrombocytopenia grade 3). Seven cycles were administered at a reduced dose level due to non-haematologic toxicities (one cycle due to urticaria/rash grade 1, three cycles due to urticaria/rash grade 3, one cycle due to neuropathy grade 3, one cycle due to hyperbilirubinemia grade 4 and one cycle due to vomiting grade 2). One cycle was reduced as a consequence of a DLT (see above).\n\n10.1371/journal.pone.0121197.t004Table 4 Dose-reductions by cycle and cohort. Number of cycles with dose-reductions.\n\nCohort no.\n\t\nPatients(n)\n\t\nTreatment cycles (n)\n\t\nNo. of treatment cycles with dose-reductions (% of total no. of cycles)\n\t\nNo. of treatment cycles with dose-reductions of resp. study drug (% of total no. of dose-reduced cycles)\n\t\n\t\t\t\t\nLenalidomide\n\t\nGemcitabine\n\t\nBoth\n\t\nI\t4\t13\t8 (62)\t1 (13)\t3 (38)\t4 (50)\t\nII\t3\t9\t4 (44)\t0 (0)\t2 (50)\t2 (50)\t\nIII\t5\t42\t30 (71)\t6 (20)\t0 (0)\t24 (80)\t\n\nTotal\n\t\n12\n\t\n64\n\t\n42 (65)\n\t\n7 (17)\n\t\n5/42 (12)\n\t\n30 (71)\n\t\nSafety and toxicity\nThe most common AEs (all grades) attributed to therapy during the first treatment cycle (Table 5) were hematological and dermatologic toxicities, gastrointestinal (GI) intolerance, and fatigue. Leucopenia and neutropenia were reported in 75% (all grades) of the patients with 78% grade 1–2 and 22% grade 3–4 for leucopenia, and 56% grade 1–2 and 44% grade 3–4 for neutropenia. There was no febrile neutropenia. Thrombocytopenia and anemia was noted in 58% and 25% (all grades), respectively, but only grade 1 or 2. Among non-hematological toxicities, dermatologic toxicities (75% all grades, 50% grade 1 or 2) and GI intolerance were common (67% all grades, but only grade 1 or 2). Nausea was the most common gastrointestinal toxicity (25%), but only grade 1 or 2. Fatigue was common (58%), but all except one episode were grade 1.\n\n10.1371/journal.pone.0121197.t005Table 5 Summary of maximum grade for study related toxicity during treatment cycle number 1.\n\nToxicity\n\t\nNumber of patients\n*\n\t\nTotal grade 1–4 (% of patients)\n\t\n\nGrade of AEs\n**\n\t0\t1\t2\t3\t4\t\t\n\nBlood/bone marrow\n\t\t\t\t\t\t\t\nAnemia\t9\t1\t2\t0\t0\t3 (25)\t\nLeukopenia\t3\t3\t4\t2\t0\t9 (75)\t\nNeutropenia\t3\t1\t4\t3\t1\t9 (75)\t\nThrombocytopenia\t5\t7\t0\t0\t0\t7 (58)\t\nFebrile neutropenia\t12\t0\t0\t0\t0\t0 (0)\t\n\nCardiac arrhythmia\n\t\t\t\t\t\t\t\nSupraventricular extrasystoles\t11\t1\t0\t0\t0\t1 (8)\t\n\nCardiac general\n\t\t\t\t\t\t\t\nLeft ventricular systolic dysfunction\t11\t0\t0\t1\t0\t1 (8)\t\nHypotension\t11\t1\t0\t0\t0\t1 (8)\t\n\nConstitutional symptoms\n\t\t\t\t\t\t\t\nFatigue\t5\t6\t0\t1\t0\t7 (58)\t\nFever, in the absence of neutropenia (ANC <1.0 x 109/L)\t11\t0\t1\t0\t0\t1 (8)\t\nWeight loss\t10\t2\t0\t0\t0\t2 (17)\t\n\nDermatology/skin\n\t\t\t\t\t\t\t\nUrticaria/Rash\t9\t1\t0\t2\t0\t3 (25)\t\nDry skin\t10\t2\t0\t0\t0\t2 (17)\t\nPruritus/itching\t9\t1\t1\t1\t0\t3 (25)\t\nErythema\t11\t0\t1\t0\t0\t1 (8)\t\n\nEndocrine\n\t\t\t\t\t\t\t\nThyroid function\t12\t0\t0\t0\t0\t0 (0)\t\n\nGastrointestinal\n\t\t\t\t\t\t\t\nConstipation\t11\t1\t0\t0\t0\t1 (8)\t\nDiarrhea\t10\t1\t1\t0\t0\t2 (17)\t\nDry mouth\t10\t2\t0\t0\t0\t2 (17)\t\nNausea\t9\t1\t2\t0\t0\t3 (25)\t\nVomiting\t11\t0\t1\t0\t0\t1 (8)\t\nAnorexia\t11\t1\t0\t0\t0\t1 (8)\t\n\nHemorrhage\n\t\t\t\t\t\t\t\nMelena\t11\t0\t1\t0\t0\t1 (8)\t\n\nInfection\n\t\t\t\t\t\t\t\nFebrile neutropenia (ANC <1.0 x 109/L, fever ≥38.5°C)\t12\t0\t0\t0\t0\t0 (0)\t\nViral infection\t10\t1\t1\t0\t0\t2 (17)\t\n\nLymphatics\n\t\t\t\t\t\t\t\nEdema; limb\t11\t1\t0\t0\t0\t1 (8)\t\n\nMetabolic\n\t\t\t\t\t\t\t\nALAT elevated\t10\t2\t0\t0\t0\t2 (17)\t\nASAT elevated\t9\t30\t0\t0\t0\t3 (25)\t\nBilirubin elevated\t12\t0\t0\t0\t0\t0 (0)\t\nCreatinine elevated\t12\t0\t0\t0\t0\t0 (0)\t\n\nNeurology\n\t\t\t\t\t\t\t\nDizziness\t8\t4\t0\t0\t0\t4 (33)\t\nNeuropathy—sensory/motor\t12\t0\t0\t0\t0\t0 (0)\t\n\nPain\n\t\t\t\t\t\t\t\nMuscle\t10\t1\t1\t0\t0\t2 (17)\t\nAbdominal\t11\t0\t0\t1\t0\t1 (8)\t\n\nPulmonary/Upper respiratory\n\t\t\t\t\t\t\t\nDyspnea\t10\t2\t0\t0\t0\t2 (17)\t\nCough\t11\t0\t1\t0\t0\t1 (8)\t\nHoarseness\t11\t1\t0\t0\t0\t1 (8)\t\n\nRenal\n\t\t\t\t\t\t\t\nRenal failure\t12\t0\t0\t0\t0\t0 (0)\t\n\nVascular\n\t\t\t\t\t\t\t\nThrombosis/thrombus/embolism\t12\t0\t0\t0\t0\t0 (0)\t\n*Represents the number of subjects (of total n = 12) experiencing adverse event during cycle number 1 with lenalidomide and gemcitabine.\n\n**Graded using NCI CTCAE V 3.0\n\nALAT = Alanine aminotransferase; ASAT = Aspartate aminotransferase\n\nGrade 3 to 4 adverse events that were possibly related to study treatment for all cycles are listed in Table 6. As noted during and after the first treatment cycle, myelosuppression was common with neutropenia or leucopenia in 83% (all grades) of the patients. 58% and 25% were grade 3–4 neutropenia and leucopenia. In cohort III, all patients that experienced neutropenia (80%) were of grade 3–4 as compared 50% and 33% in cohorts I and II, respectively. Leucopenia grade 3–4 was noted in 40% of the patients in cohort III, but 25% and 0% in cohort I and II, respectively. During the cumulative of treatment cycles, thrombocytopenia was noticed in 75% (all grades, 8% grade 3–4) and anemia was reported 42% (all grades, 8% grade 3–4), without any major difference in frequency and severity between the cohorts. Treatment did not affect lymphocytes, monocytes, eosinophils or basophils counts (data not shown).\n\n10.1371/journal.pone.0121197.t006Table 6 Summary of maximum grade for toxicity (aggregate for all treatment cycles) (NCI CTCAE.V3.0.).\n\nToxicity\n\t\nCohort I (n = 4)\n\t\nCohort II (n = 3)\n\t\nCohort III (n = 5)\n\t\nTotal (n = 12)\n\t\n\tG* 1–4 No** (%)\tG 3–4 No (%)\tG 1–4 No (%)\tG 3–4 No (%)\tG 1–4 No (%)\tG 3–4 No (%)\tG 1–4 No (%)\tG 3–4 No (%)\t\n\nBlood/bone marrow\n\t\t\t\t\t\t\t\t\t\nAnemia\t2 (50)\t1 (25)\t2 (67)\t0 (0)\t1(20)\t0 (0)\t5 (42)\t1(8)\t\nLeukopenia\t3(75)\t1 (25)\t3 (100)\t0 (0)\t4(80)\t2(40)\t10 (83)\t3 (25)\t\nNeutropenia\t3(75)\t2(50)\t3(100)\t1 (33)\t4(80)\t4(80)\t10(83)\t7(58)\t\nThrombocytopenia\t4(100)\t1(25)\t2(67)\t0(0)\t3(60)\t0(0)\t9(75)\t1 (8)\t\nFebrile neutropenia\t0 (0)\t0 (0)\t0 (0)\t0(0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\n\nCardiac arrhythmia\n\t\t\t\t\t\t\t\t\t\nSupraventricular extrasystoles\t0 (0)\t0(0)\t1 (33)\t0(0)\t0(0)\t0(0)\t1(8)\t0(0)\t\n\nCardiac general\n\t\t\t\t\t\t\t\t\t\nLeft ventricular systolic dysfunction\t0(0)\t0(0)\t0(0)\t0(0)\t1(20)\t1(20)\t1(8)\t1(8)\t\nHypotension\t1(25)\t0(0)\t0(0)\t0(0)\t0(0)\t0(0)\t1(8)\t0(0)\t\n\nConstitutional symptoms\n\t\t\t\t\t\t\t\t\t\nFatigue\t4(100)\t0(0)\t3(100)\t0(0)\t3(60)\t0(0)\t10(83)\t0(0)\t\nFever, in the absence of neutropenia (ANC <1.0 x 109/L)\t0(0)\t0(0)\t2(67)\t0(0)\t0(0)\t0(0)\t2(17)\t0(0)\t\nWeight loss\t1(25)\t0(0)\t0(0)\t0(0)\t2(40)\t0(0)\t3(25)\t0(0)\t\n\nDermatology/skin\n\t\t\t\t\t\t\t\t\t\nUrticaria/Rash\t2(50)\t1(25)\t0(0)\t0(0)\t1(20)\t1(20)\t3(25)\t2(17)\t\nDry skin\t1(25)\t0(0)\t0(0)\t0(0)\t2(40)\t0(0)\t3(25)\t0(0)\t\nPruritus/itching\t1(25)\t1(25)\t0(0)\t0(0)\t2(40)\t0(0)\t3(25)\t1(8)\t\nErythema\t1(25)\t0(0)\t0(0)\t0(0)\t0(0)\t0(0)\t1(8)\t0(0)\t\n\nGastrointestinal\n\t\t\t\t\t\t\t\t\t\nConstipation\t0(0)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t1(8)\t0(0)\t\nDiarrhea\t3(75)\t0(0)\t0(0)\t0(0)\t2(40)\t1(20)\t5(42)\t1(8)\t\nDry mouth\t1(25)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t2(17)\t0(0)\t\nNausea\t0(0)\t0(0)\t2(67)\t0(0)\t3(60)\t0(0)\t5(42)\t0(0)\t\nVomiting\t1(25)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t2(17)\t0(0)\t\nAnorexia\t2(50)\t0(0)\t1(33)\t0(0)\t1(20)\t0(0)\t4(33)\t0(0)\t\nStomatitis\t1(25)\t0(0)\t0(0)\t0(0)\t0(0)\t0(0)\t1(8)\t0(0)\t\nPerforation\t0 (0)\t0 (0)\t1(33)\t1 (33)***\n\t0 (0)\t0 (0)\t1 (8)\t1 (8)\t\n\nHemorrhage\n\t\t\t\t\t\t\t\t\t\nMelena\t0(0)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t1(8)\t0(0)\t\n\nInfection\n\t\t\t\t\t\t\t\t\t\nFebrile neutropenia (ANC <1.0 x 109/L, fever ≥38.5°C)\t0(0)\t0(0)\t0(0)\t0(0)\t0(0)\t0(0)\t0(0)\t0(0)\t\nViral infection\t1(25)\t0(0)\t0(0)\t0(0)\t2(40)\t0(0)\t3(25)\t0(0)\t\n\nLymphatics\n\t\t\t\t\t\t\t\t\t\nEdema; limb\t1(25)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t2(17)\t0(0)\t\n\nMetabolic\n\t\t\t\t\t\t\t\t\t\nALAT elevated\t1(25)\t0(0)\t1(33)\t1(33)\t3(60)\t0(0)\t5(42)\t1(8)\t\nASAT elevated\t1(25)\t0(0)\t2(67)\t1(33)\t3(60)\t0(0)\t6(50)\t1(8)\t\nBilirubin elevated\t1(25)\t0(0)\t1(33)\t1(33)\t0(0)\t0(0)\t2(17)\t1(8)\t\nCreatinine elevated\t1(25)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t2(17)\t0(0)\t\n\nNeurology\n\t\t\t\t\t\t\t\t\t\nDizziness\t3(75)\t0(0)\t1(33)\t0(0)\t1(20)\t0(0)\t5(42)\t0(0)\t\nNeuropathy—sensory/motor\t2(50)\t1(25)\t1(33)\t0(0)\t2(40)\t0(0)\t5(42)\t1(8)\t\nMood alteration\t0(0)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t1(8)\t0(0)\t\n\nPain\n\t\t\t\t\t\t\t\t\t\nMuscle\t1(25)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t2(17)\t0(0)\t\nAbdominal\t0(0)\t0(0)\t1(33)\t0(0)\t3(60)\t1(20)\t4(33)\t1(8)\t\n\nPulmonary/Upper respiratory\n\t\t\t\t\t\t\t\t\t\nDyspnea\t1(25)\t0(0)\t0(0)\t0(0)\t1(20)\t0(0)\t2(17)\t0(0)\t\nCough\t1(25)\t0(0)\t0(0)\t0(0)\t2(40)\t0(0)\t3(25)\t0(0)\t\nHoarseness\t0(0)\t0(0)\t0(0)\t0(0)\t2(40)\t0(0)\t2(17)\t0(0)\t\n\nVascular\n\t\t\t\t\t\t\t\t\t\nThrombosis/thrombus/embolism\t0(0)\t0(0)\t1(33)\t1(33)\t1(20)\t1(20)\t2(17)\t2(17)\t\n*G = Grade\n\n**Represents the number of subjects experiencing adverse event with lenalidomide and gemcitabine.\n\n*** One patient with grade 4 gastrointestinal perforation underwent acute surgery, died postoperatively day 6 in acute respiratory insufficiency.\n\nThe incidence of dermatological toxicity (urticaria/dry skin/pruritus/erythema) during cumulative of treatment cycles was as noted after the first treatment cycle, that is approximately 75% for all skin-toxicities together. Among other non-hematological toxicities, fatigue was the most prominent AE during the whole study period, presented in 83% of the patients, but all episodes were grade 1–2, equally distributed between the cohorts. GI toxicities were common (diarrhea and nausea, both 42%, and anorexia, 33%), but only one episode of diarrhea was grade 3. Among metabolic AEs, elevations of ALAT and ASAT were reported in 42% and 50% (all grades), respectively, but only 8% were grade 3–4 and these occurred after cycle 1 and were not considered DLTs. There was no evidence for any other biochemical toxicities, including thyroid or renal function tests.\n\nFive patients (42%, all of grade 1–2) had neurological side-effects, such as dizziness including light headedness and vertigo. Neuropathy was reported in 42%, mainly as neurosensory toxicity (33%, all grade 1–2) with paraesthesia and sensory alteration. The fourth patient enrolled at dose level 1 (15 mg/day), developed grade 3 neuromotor toxicity with cramps and objective weakness in both hands, interfering with activities of daily living. There was no somnolence reported.\n\nDuring the entire trial, there were two grade 3 VTEs which occurred after cycle 1. Both patients had unilateral deep vein thrombosis at the end of cycle 2 and 3, respectively, but did not result in treatment discontinuation, but an increment in the prophylactic dose of LMWH. One patient experienced grade 4 gastric perforation 4 days after the last lenalidomide dose in cycle 3. The patient underwent acute surgery but died at day six postoperatively in acute respiratory insufficiency, see section SAEs below.\n\nSerious adverse events (SAEs)\nFour SAEs were reported during the study period out of which one was classified as a DLT (see above) and suspected as a causal relationship to lenalidomide treatment (pat no 135). One patient (pat no 122) experienced a grade 4 gastric perforation 4 days after the last lenalidomide dose in cycle 3. The patient underwent acute surgery but died 6 days postoperatively in acute respiratory insufficiency. At the time of start of treatment, the patient had disease-related pleural effusion that was managed by therapeutic thoracentes. Although a causal relationship with the trial drugs was classified as not suspected it could not be completely ruled out that gastrointestinal perforation was related to study treatment. One patient (pat no 131) required hospital admission for the treatment of grade 3 abdominal pain, and grade 2 vomiting. A relationship with the trial drugs were classified as not suspected, but due to the underlying disease (see section DLT).\n\nDuring the first week in treatment cycle no 3, 1 patient (pat no 121) developed grade 4 hyperbilirubinemia and grade 2 fever. A causal relationship was classified as not suspected as the patient had an acute pancreatitis due to dysfunction of a biliary stent.\n\nProphylactic anti-thrombotic treatment\nThe prophylactic dose of LMWH was reduced in patient no 111 during treatment cycle no. 1 due to thrombocytopenia grade 1. In patient no. 133, the prophylactic LMWH therapy was interrupted for thirteen days between cycle no. 12 and 13, due to thrombocytopenia grade 2. In one other patient (no. 134), LMWH therapy was withheld for three days during cycle no. 1 due to melena grade 1 that was not considered to be related to therapy but to underlying disease.\n\nSecondary primary malignancies (SPMs)\nThere were no SPMs.\n\nDiscussion\nThis is the first phase I dose escalation trial report combining lenalidomide and standard chemotherapy with gemcitabine in patients with advanced adenocarcinoma of the pancreas. Detailed toxicity data is crucial to recommend a safe and tolerable dose of lenalidomide in combination with gemcitabine. Based on the results from this study, the MTD of lenalidomide administered daily on days 1–21 of a 28 day cycle was defined as 25 mg per day in combination with gemcitabine 1000 mg/m2 on days 1, 8 and 15 as first line treatment in patients with advanced pancreatic cancer. This dose level is recommended for further studies in the phase II setting.\n\nDLT consisted of one episode with symptomatic, but transient, grade 3 heart failure, at the highest dose level of lenalidomide (25 mg/day) in combination with standard dosing of gemcitabine. According to the Summary of Product Characteristics (SPC) of lenalidomide, congestive heart failure was listed as a common grade 3/4 AE (in 1–10% of patients with MM) [13]. In phase I trials in solid tumors, when using lenalidomide as monotherapy [23, 24] or in combination with chemotherapy [25, 27], no events of cardiac failure has been reported, but episodes of palpitations, arrhythmias and increments in QTs interval have been noted.\n\nThe most common lenalidomide-related adverse events are myelosuppression with neutropenia/leucopenia and thrombocytopenia, VTEs, fatigue and skin-toxicity [14, 38]. All those side-effects were also frequently seen in the present study. Although neutropenia was the most common grade 3–4 toxicity (58%) in the present study, there was no febrile neutropenia. This is in line with one study [26, 27] but in contrast to results achieved in other phase I/II trials combining lenalidomide and lenalidomide-like compounds with gemcitabine [26, 39], or other cytotoxic drugs [25], where episodes of neutropenia frequently have been associated with fever and usually been classified as DLT. An explanation for this discrepancy might be the limited number of patients in our study and differences in the dose escalation schedules. Compared to treatment with lenalidomide as single agent in solid tumors [23, 24], the rate of neutropenia, leucopenia and thrombocytopenia was increased in all cohorts with the addition of gemcitabine. Furthermore, as in the previous studies [23, 24], neutropenia and leucopenia seemed to be dose dependent and reversible. Thrombocytopenia was mild with only one grade 3 and no grade 4 events as compared to 20% (grade 3 + grade 4) observed in an earlier study with the same combination [26, 27]. The rate of thrombocytopenia was however increased compared to lenalidomide as a single agent [5, 40], or with gemcitabine combined with other immunomodulating agents [26, 39].\n\nCompared with other malignancies, patients with advanced pancreatic cancer have an increased risk for venous thromboembolism (VTE) [41, 42]. Chemotherapy per see also increases the risk of VTE in pancreatic cancer patients [43]. Furthermore, VTE is a known complication of lenalidomide with concurrent administration of high-dose dexamethasone or chemotherapy in MM [44], but also in patients with advanced pancreatic cancer [45]. The risk of VTE toxicity was of special concern also in our study, why all patients were treated with LMWH. The rate of observed grade 3 VTEs in this trial of 17% is within the same range as reported for other studies using lenalidomide or pomalidomide in combination with gemcitabine for advanced pancreatic cancer, using aspirin as prophylactic anticoagulant [26, 27, 45]. As in concert with other trials, no significant added toxicity was observed from the addition of a prophylactic LMWH schedule to chemotherapy [46]. No patients discontinued protocol therapy due to VTEs. There were only a few episodes of LMWH interruptions or dose-reductions (all due to thrombocytopenia), indicating that the addition of LMWH is safe.\n\nUrticaria/rash, dry skin and mouth and pruritus are the most common dermatological toxicities reported for lenalidomide [38]. The episodes of those AEs in the present study were noted in 9 out of 12 (75%) patients with 25% of grade 3 but no grade 4. One patient (no. 113) developed concomitant grade 3 urticaria and grade 2 erythema during the first treatment cycle and the lenalidomide administration was temporarily held. Interestingly, all dermatological toxicities except for one were noted during treatment cycle number 1. However, the high frequency of dermatological toxicity observed in the current trial in combination with gemcitabine, compared to lenalidomide as single-agent in solid tumors [23, 24], or in combination with dexamethasone in MM [14], might be attributed to overlapping toxicity.\n\nOne patient in cohort II experienced grade 4 gastrointestinal perforation after the third treatment cycle and underwent acute surgery. Gastrointestinal perforation is not described in the formal European product information for MM [13], but described in the attached report on GI Safety citing the US product information that includes data from patients with myelodysplastic syndromes [47]. A risk of gastrointestinal perforation with antiangiogenesis inhibitors, such as bevacizumab [48], including pomalidomide combined with gemcitabine [26], mandates close attention to this issue in future studies.\n\nThe risk of SPM must be considered in lenalidomide-treated patients. The increased risk of SPMs has mainly been related to the use of lenalidomide maintenance therapy in MM [49], with reported median time to the diagnosis of SPMs of 28–30 months [50]. In the current study with relatively few patients and a short survival we did not detect any SPM.\n\nThe MTD dose of lenalidomide in this study is basically the same as recommendations in other phase I studies [22–25, 35], with respect to some specific differences in days “off” and “on”-administration of lenalidomide. If this schedule is proven to be effective in future studies we believe that there will be no strong barriers to implementation. However, the patients were in a good performance status at baseline limiting the generalizability of our findings. Of note is that the recent study by Infante et al previously referred to in this article suggests that lenalidomide + gemcitabine is not an effective treatment due to toxicity and lack of antitumoral effects. This study started in parallel with our study, it is american and it used a different design compared to ours [27].\n\nIn conclusion, we show that the combination of lenalidomide and gemcitabine is tolerable and safe as first line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests that the optimal dosing of lenalidomide is 25 mg daily on days 1–21 and of gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28 day cycle. This dose level of lenalidomide was further evaluated in a phase II trial with the aim to analyse the immunological response and clinical efficacy of lenalidomide on combination with gemcitabine as first line therapy in patients with advanced pancreatic cancer.\n\nSupporting Information\nS1 Flow Diagram (PDF)\n\nClick here for additional data file.\n\n S1 Protocol (PDF)\n\nClick here for additional data file.\n\n S1 TREND Checklist Trend Checklist.\n(PDF)\n\nClick here for additional data file.\n\n We thank Ms. Leila Relander for excellent secretarial help. We are grateful to Lena Bernrup, Maria Olsson, Annelie Billgren and Mats Hellström.\n==== Refs\nReferences\n1 \nAlexakis N , Halloran C , Raraty M , Ghaneh P , Sutton R , Neoptolemos JP . Current standards of surgery for pancreatic cancer . Br J Surg . 2004 ;91 (11 ):1410 –27 . 10.1002/bjs.4794 PubMed .15499648 \n2 \nFreelove R , Walling AD . Pancreatic cancer: diagnosis and management . Am Fam Physician . 2006 ;73 (3 ):485 –92 . PubMed .16477897 \n3 \nHowe HL , Wu X , Ries LA , Cokkinides V , Ahmed F , Jemal A , et al\nAnnual report to the nation on the status of cancer, 1975–2003, featuring cancer among U.S. Hispanic/Latino populations . Cancer . 2006 ;107 (8 ):1711 –42 . 10.1002/cncr.22193 PubMed .16958083 \n4 \nSohn TA , Yeo CJ , Cameron JL , Koniaris L , Kaushal S , Abrams RA , et al\nResected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators . J Gastrointest Surg . 2000 ;4 (6 ):567 –79 . PubMed .11307091 \n5 \nBurris HA 3rd, Moore MJ , Andersen J , Green MR , Rothenberg ML , Modiano MR , et al\nImprovements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 1997 ;15 (6 ):2403 –13 . PubMed .9196156 \n6 \nTabernero J , Macarulla T . Changing the paradigm in conducting randomized clinical studies in advanced pancreatic cancer: an opportunity for better clinical development . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2009 ;27 (33 ):5487 –91 . 10.1200/JCO.2009.23.3098 PubMed .19858387 \n7 \nKindler HL , Niedzwiecki D , Hollis D , Sutherland S , Schrag D , Hurwitz H , et al\nGemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303) . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2010 ;28 (22 ):3617 –22 . 10.1200/JCO.2010.28.1386 PubMed 20606091 \n8 \nKindler HL , Ioka T , Richel DJ , Bennouna J , Letourneau R , Okusaka T , et al\nAxitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study . Lancet Oncol . 2011 ;12 (3 ):256 –62 . 10.1016/S1470-2045(11)70004-3 PubMed .21306953 \n9 \nConroy T , Desseigne F , Ychou M , Bouche O , Guimbaud R , Becouarn Y , et al\nFOLFIRINOX versus gemcitabine for metastatic pancreatic cancer . The New England journal of medicine . 2011 ;364 (19 ):1817 –25 . 10.1056/NEJMoa1011923 PubMed .21561347 \n10 \nMoore MJ , Goldstein D , Hamm J , Figer A , Hecht JR , Gallinger S , et al\nErlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2007 ;25 (15 ):1960 –6 . 10.1200/JCO.2006.07.9525 PubMed .17452677 \n11 \nVon Hoff DD , Ervin T , Arena FP , Chiorean EG , Infante J , Moore M , et al\nIncreased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine . The New England journal of medicine . 2013 ;369 (18 ):1691 –703 . Epub 2013/10/18. 10.1056/NEJMoa1304369 PubMed .24131140 \n12 FDA US Food and Drug Administration (FDA) 2013. Available: www.fda.gov.\n13 European Medicine Agency (EMA) Science Medicine Health. SPC_Lenalidomide_PDF.REVLIMID—revised Feb 2013 2013. Available: http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000717/WC500056018.pdf.\n14 \nAndhavarapu S , Roy V . Immunomodulatory drugs in multiple myeloma . Expert Rev Hematol . 2013 ;6 (1 ):69 –82 . 10.1586/ehm.12.62 PubMed .23373782 \n15 \nDredge K , Horsfall R , Robinson SP , Zhang LH , Lu L , Tang Y , et al\nOrally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro . Microvasc Res . 2005 ;69 (1–2 ):56 –63 . 10.1016/j.mvr.2005.01.002 PubMed .15797261 \n16 \nWu L , Parton A , Lu L , Adams M , Schafer P , Bartlett JB . Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers . Cancer immunology, immunotherapy: CII . 2011 ;60 (1 ):61 –73 . 10.1007/s00262-010-0919-9 PubMed .20848094 \n17 \nLeBlanc R , Hideshima T , Catley LP , Shringarpure R , Burger R , Mitsiades N , et al\nImmunomodulatory drug costimulates T cells via the B7-CD28 pathway . Blood . 2004 ;103 (5 ):1787 –90 . 10.1182/blood-2003-02-0361 PubMed .14512311 \n18 \nTeo SK . Properties of thalidomide and its analogues: implications for anticancer therapy . AAPS J . 2005 ;7 (1 ):E14 –9 . 10.1208/aapsj070103 PubMed 16146335 \n19 \nCorral LG , Haslett PA , Muller GW , Chen R , Wong LM , Ocampo CJ , et al\nDifferential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha . Journal of immunology . 1999 ;163 (1 ):380 –6 PubMed .10384139 \n20 \nCrane E , List A . Immunomodulatory drugs . Cancer Invest . 2005 ;23 (7 ):625 –34 . 10.1080/07357900500283101 PubMed .16305990 \n21 \nAmato RJ , Hernandez-McClain J , Saxena S , Khan M . Lenalidomide therapy for metastatic renal cell carcinoma . Am J Clin Oncol . 2008 ;31 (3 ):244 –9 . 10.1097/COC.0b013e31815e451f PubMed .18525302 \n22 \nBartlett JB , Michael A , Clarke IA , Dredge K , Nicholson S , Kristeleit H , et al\nPhase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers . British journal of cancer . 2004 ;90 (5 ):955 –61 . 10.1038/sj.bjc.6601579 PubMed 14997189 \n23 \nMiller AA , Case D , Harmon M , Savage P , Lesser G , Hurd D , et al\nPhase I study of lenalidomide in solid tumors . J Thorac Oncol . 2007 ;2 (5 ):445 –9 . 10.1097/01.JTO.0000268679.33238.67 PubMed .17473661 \n24 \nSharma RA , Steward WP , Daines CA , Knight RD , O'Byrne KJ , Dalgleish AG . Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide: phase I clinical trial of three dosing schedules in patients with solid malignancies . Eur J Cancer . 2006 ;42 (14 ):2318 –25 . 10.1016/j.ejca.2006.05.018 PubMed .16899362 \n25 \nSanborn SL , Gibbons J , Krishnamurthi S , Brell JM , Dowlati A , Bokar JA , et al\nPhase I trial of docetaxel given every 3 weeks and daily lenalidomide in patients with advanced solid tumors . Invest New Drugs . 2009 ;27 (5 ):453 –60 . 10.1007/s10637-008-9200-x PubMed .19011760 \n26 \nInfante JR , Jones SF , Bendell JC , Spigel DR , Yardley DA , Weekes CD , et al\nA phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer . Eur J Cancer . 2011 ;47 (2 ):199 –205 . 10.1016/j.ejca.2010.09.002 PubMed .21051221 \n27 \nInfante JR , Arkenau HT , Bendell JC , Rubin MS , Waterhouse D , Jones GT , et al\nLenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas: a Sarah Cannon Research Institute phase II trial . Cancer biology & therapy . 2013 ;14 (4 ):340 –6 . Epub 2013/01/30. 10.4161/cbt.23625 PubMed 23358470 \n28 \nPlate JM , Plate AE , Shott S , Bograd S , Harris JE . Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer immunology, immunotherapy : CII . 2005 ;54 (9 ):915 –25 . Epub 2005/03/23. 10.1007/s00262-004-0638-1 PubMed .15782312 \n29 \nSoeda A , Morita-Hoshi Y , Makiyama H , Morizane C , Ueno H , Ikeda M , et al\nRegular dose of gemcitabine induces an increase in CD14+ monocytes and CD11c+ dendritic cells in patients with advanced pancreatic cancer . Japanese journal of clinical oncology . 2009 ;39 (12 ):797 –806 . Epub 2009/10/03. 10.1093/jjco/hyp112 PubMed .19797418 \n30 \nNowak AK , Lake RA , Marzo AL , Scott B , Heath WR , Collins EJ , et al\nInduction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells . Journal of immunology . 2003 ;170 (10 ):4905 –13 . Epub 2003/05/08. PubMed .12734333 \n31 \nCorreale P , Cusi MG , Tsang KY , Del Vecchio MT , Marsili S , Placa ML , et al\nChemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2005 ;23 (35 ):8950 –8 . Epub 2005/08/03. 10.1200/JCO.2005.12.147 PubMed .16061910 \n32 \nShevchenko I , Karakhanova S , Soltek S , Link J , Bayry J , Werner J , et al\nLow-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer . International journal of cancer Journal international du cancer . 2013 ;133 (1 ):98 –107 . Epub 2012/12/13. 10.1002/ijc.27990 PubMed .23233419 \n33 \nVizio B , Novarino A , Giacobino A , Cristiano C , Prati A , Ciuffreda L , et al\nPotential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome . Experimental and therapeutic medicine . 2012 ;4 (1 ):70 –8 . Epub 2012/10/13. 10.3892/etm.2012.553 PubMed 23060925 \n34 \nBergmann-Leitner ES , Abrams SI . Treatment of human colon carcinoma cell lines with anti-neoplastic agents enhances their lytic sensitivity to antigen-specific CD8+ cytotoxic T lymphocytes . Cancer immunology, immunotherapy: CII . 2001 ;50 (9 ):445 –55 . Epub 2002/01/05. PubMed .11761438 \n35 \nRichardson PG , Schlossman RL , Weller E , Hideshima T , Mitsiades C , Davies F , et al\nImmunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma . Blood . 2002 ;100 (9 ):3063 –7 . 10.1182/blood-2002-03-0996 PubMed .12384400 \n36 \nLe Tourneau C , Michiels S , Gan HK , Siu LL . Reporting of time-to-event end points and tracking of failures in randomized trials of radiotherapy with or without any concomitant anticancer agent for locally advanced head and neck cancer . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2009 ;27 (35 ):5965 –71 . 10.1200/JCO.2009.22.3685 PubMed .19805677 \n37 \nStorer BE . An evaluation of phase I clinical trial designs in the continuous dose-response setting . Statistics in medicine . 2001 ;20 (16 ):2399 –408 . PubMed .11512130 \n38 \nBringhen S , Gay F , Pautasso C , Cerrato C , Boccadoro M , Palumbo A . Evaluation of the pharmacokinetics, preclinical, and clinical efficacy of lenalidomide for the treatment of multiple myeloma . Expert Opin Drug Metab Toxicol . 2012 ;8 (9 ):1209 –22 . 10.1517/17425255.2012.712685 PubMed .22862790 \n39 \nMaples WJ , Stevenson J , Sumrall SV , Naughton M , Kauh J , Schwartz J . Advanced pancreatic cancer: a multi-institutional trial with gemcitabine and thalidomide . Journal of Clinical Oncology ASCO Annual Meeting Proceedings (Post-meeting Edition) . 2004 ;22 (14 s):4082 .\n40 \nCunningham D , Chau I , Stocken DD , Valle JW , Smith D , Steward W , et al\nPhase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2009 ;27 (33 ):5513 –8 . 10.1200/JCO.2009.24.2446 PubMed .19858379 \n41 \nKhorana AA , Fine RL . Pancreatic cancer and thromboembolic disease . Lancet Oncol . 2004 ;5 (11 ):655 –63 . 10.1016/S1470-2045(04)01606-7 PubMed .15522652 \n42 \nMandala M , Tondini C . The impact of thromboprophylaxis on cancer survival: focus on pancreatic cancer . Expert Rev Anticancer Ther . 2011 ;11 (4 ):579 –88 . 10.1586/era.10.184 PubMed .21504325 \n43 \nBlom JW , Osanto S , Rosendaal FR . High risk of venous thrombosis in patients with pancreatic cancer: a cohort study of 202 patients . Eur J Cancer . 2006 ;42 (3 ):410 –4 . 10.1016/j.ejca.2005.09.013 PubMed .16321518 \n44 \nPalumbo A , Rajkumar SV , Dimopoulos MA , Richardson PG , San Miguel J , Barlogie B , et al\nPrevention of thalidomide- and lenalidomide-associated thrombosis in myeloma . Leukemia . 2008 ;22 (2 ):414 –23 . 10.1038/sj.leu.2405062 PubMed .18094721 \n45 \nArkenau H , Infante JR , Bendell JC , Burris HA , Rubin MS , Waterhouse DM , et al\nLenalidomide in combination with gemcitabine in patients with untreated metastatic carcinoma of the pancreas: A Sarah Cannon Research Institute phase II trial. Abstract no 14640 . Journal of Clinical Oncology ASCO Annual Meeting Proceedings (Post-meeting Edition) . 2011 ;29 (15 Suppl (May 20 Supplement)):e14640 .\n46 \nMaraveyas A , Waters J , Roy R , Fyfe D , Propper D , Lofts F , et al\nGemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer . Eur J Cancer . 2012 ;48 (9 ):1283 –92 . 10.1016/j.ejca.2011.10.017 PubMed .22100906 \n47 Revlimid, highlights of prescribing information 2013. Available: http://www.revlimid.com/docs/Revlimid-Full-PI.pdf.\n48 \nAbu-Hejleh T , Mezhir JJ , Goodheart MJ , Halfdanarson TR . Incidence and management of gastrointestinal perforation from bevacizumab in advanced cancers . Curr Oncol Rep . 2012 ;14 (4 ):277 –84 . 10.1007/s11912-012-0238-8 PubMed .22532266 \n49 \nDimopoulos MA , Richardson PG , Brandenburg N , Yu Z , Weber DM , Niesvizky R , et al\nA review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide . Blood . 2012 ;119 (12 ):2764 –7 . 10.1182/blood-2011-08-373514 PubMed .22323483 \n50 \nMcCarthy PL , Owzar K , Hofmeister CC , Hurd DD , Hassoun H , Richardson PG , et al\nLenalidomide after stem-cell transplantation for multiple myeloma . The New England journal of medicine . 2012 ;366 (19 ):1770 –81 . 10.1056/NEJMoa1114083 PubMed .22571201\n\n",
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"mesh_terms": "D000230:Adenocarcinoma; D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D000971:Antineoplastic Combined Chemotherapy Protocols; D017985:Dalteparin; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D005221:Fatigue; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D000077269:Lenalidomide; D007970:Leukopenia; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia; D010179:Pancreas; D010190:Pancreatic Neoplasms; D013792:Thalidomide",
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"title": "A phase I dose-escalation study of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer.",
"title_normalized": "a phase i dose escalation study of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer"
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"abstract": "Metformin has been used for many years as oral anti-hyperglycaemic agent in the treatment of type 2 diabetes mellitus either in Poland or in the world. Metformin is the most commonly prescribed agent, but acute poisonings of this agent are rare. A review of our experience indicates, that poisoning with this agent may lead to life-threatening or fatal metformin toxicity. The authors of this publication postulate, that each patient with metformin exposure should be hospitalized. Physician must be vigilant to recognize anti-hyperglycaemic agent poisonings like biguanides when hypoglycaemia and acidosis are present in laboratory results. We present patients with metformin toxicity, some of them with fatal course.",
"affiliations": "Oddział Anestezjologii i Intensywnej Terapii, W.S.S. im. M. Pirogowa w Łodzi.;Oddział Toksykologii, Klinika Chorób Zawodowych i Toksykologii, Instytutu Medycyny Pracy w Łodzi.;Oddział Toksykologii, Klinika Chorób Zawodowych i Toksykologii, Instytutu Medycyny Pracy w Łodzi.;Pracownia Diagnostyki Toksykologicznej, Instytutu Medycyny Pracy w Łodzi.;Oddział Toksykologii, Klinika Chorób Zawodowych i Toksykologii, Instytutu Medycyny Pracy w Łodzi.;Oddział Toksykologii, Klinika Chorób Zawodowych i Toksykologii, Instytutu Medycyny Pracy w Łodzi.",
"authors": "Krawczyk|Katarzyna|K|;Bak|Marek|M|;Kuropatwa|Julia|J|;Winnicka|Renata|R|;Kołacinski|Zbigniew|Z|;Krakowiak|Anna|A|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "Poland",
"delete": false,
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"issn_linking": "0033-2240",
"issue": "70(8)",
"journal": "Przeglad lekarski",
"keywords": null,
"medline_ta": "Przegl Lek",
"mesh_terms": "D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D013405:Suicide",
"nlm_unique_id": "19840720R",
"other_id": null,
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"pmid": "24466714",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Metformin poisoning--clinical features, diagnostics and treatment--case presentations.",
"title_normalized": "metformin poisoning clinical features diagnostics and treatment case presentations"
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"companynumb": "PL-MYLANLABS-2014M1004724",
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
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"abstract": "Type II endoleaks are a common complication after endovascular abdominal aortic aneurysm repair, with transarterial embolization using synthetic surgical glue being an established treatment option. We report a case of paraplegia due to spinal cord ischemia after lumbar arteries embolization by Glubran-lipiodol glue for a type II endoleak. Special attention must be given by interventional specialists when applying surgical diluted glues for the treatment of type II endoleaks to avoid distal embolization and subsequent spinal cord ischemia.",
"affiliations": "Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy. Electronic address: efrem.civilini@gmail.com.",
"authors": "Sanz-Sánchez|Jorge|J|;Poretti|Dario|D|;Poletto|Giorgio|G|;Civilini|Efrem|E|",
"chemical_list": "D003487:Cyanoacrylates; C421460:glubran",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2019.05.054",
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"issn_linking": "0890-5096",
"issue": "61()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D000369:Aged, 80 and over; D017544:Aortic Aneurysm, Abdominal; D019917:Blood Vessel Prosthesis Implantation; D003487:Cyanoacrylates; D004621:Embolization, Therapeutic; D057867:Endoleak; D057510:Endovascular Procedures; D005548:Foreign-Body Migration; D006801:Humans; D008297:Male; D010264:Paraplegia; D020760:Spinal Cord Ischemia; D016896:Treatment Outcome",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "472.e1-472.e3",
"pmc": null,
"pmid": "31394248",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Paraplegia Due to Spinal Cord Ischemia after Endovascular Treatment of a Type II Endoleak.",
"title_normalized": "paraplegia due to spinal cord ischemia after endovascular treatment of a type ii endoleak"
} | [
{
"companynumb": "IT-GUERBET-IT-20190147",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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"actiondrug": "6",
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"activesubstancename": "ETHIODIZED OIL"
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... |
{
"abstract": "A 44-year-old woman presented with a 3-month history of back pain, gait disturbance, and insomnia. She had moon face and central obesity but no goiter. Cushing's syndrome due to left adrenal adenoma was diagnosed. She also had low triiodothyronine syndrome and central hypothyroidism. Treatment involved adrenalectomy followed by 30 mg/day of hydrocortisone. Inappropriate secretion of thyroid-stimulating hormone occurred postoperatively. She developed Graves' disease nine months postoperatively and was treated with methimazole. Excess glucocorticoids followed by their withdrawal may influence the hypothalamic-pituitary-thyroid axis and immune system. Therefore, a careful evaluation of the thyroid function and antibodies is important after surgery for Cushing's syndrome.",
"affiliations": "Thyroid Center, Shin Koga Hospital, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University Medical Center, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University Medical Center, Japan.;Department of General and Family Medicine, Kurume University Medical Center, Japan.",
"authors": "Hiromatsu|Yuji|Y|;Eguchi|Hiroyuki|H|;Nakamura|Yui|Y|;Mukohara|Kei|K|",
"chemical_list": "D013972:Thyrotropin; D006854:Hydrocortisone",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.4469-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32893226\n10.2169/internalmedicine.4469-20\nCase Report\nGraves' Disease after Adrenalectomy for Cushing's Syndrome\nHiromatsu Yuji 12 Eguchi Hiroyuki 2 Nakamura Yui 2 Mukohara Kei 3 \n1 Thyroid Center, Shin Koga Hospital, Japan\n\n2 Division of Endocrinology and Metabolism, Department of Medicine, Kurume University Medical Center, Japan\n\n3 Department of General and Family Medicine, Kurume University Medical Center, Japan\nCorrespondence to Dr. Yuji Hiromatsu, yuji@med.kurume-u.ac.jp\n\n\n5 9 2020 \n1 1 2021 \n60 1 99 103\n14 1 2020 21 6 2020 Copyright © 2021 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 44-year-old woman presented with a 3-month history of back pain, gait disturbance, and insomnia. She had moon face and central obesity but no goiter. Cushing's syndrome due to left adrenal adenoma was diagnosed. She also had low triiodothyronine syndrome and central hypothyroidism. Treatment involved adrenalectomy followed by 30 mg/day of hydrocortisone. Inappropriate secretion of thyroid-stimulating hormone occurred postoperatively. She developed Graves' disease nine months postoperatively and was treated with methimazole. Excess glucocorticoids followed by their withdrawal may influence the hypothalamic-pituitary-thyroid axis and immune system. Therefore, a careful evaluation of the thyroid function and antibodies is important after surgery for Cushing's syndrome.\n\nCushing's syndromeGraves' diseasecentral hypothyroidismsyndrome of inappropriate secretion of thyroid-stimulating hormone\n==== Body\nIntroduction\nCushing's syndrome is a disorder caused by chronic glucocorticoid excess, resulting in various symptoms, such as moon face, central obesity, a “buffalo hump,” red striae, and fatigue (1). The excess glucocorticoid affects the hypothalamic-pituitary-thyroid axis and results in central hypothyroidism and low triiodothyronine (T3) syndrome (2,3). The excess glucocorticoid also suppresses the immune system (4). Rapid withdrawal of glucocorticoid sometimes causes steroid withdrawal syndrome (SWS) and syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH) despite treatment with physiological doses of hydrocortisone (5,6). The resolution of hypercortisolism may also trigger the development of autoimmune disorders, including autoimmune thyroid diseases (1,7-14).\n\nWe herein report a case of Graves' disease after unilateral adrenalectomy for Cushing's syndrome.\n\nCase Report\nA 44-year-old woman presented to our hospital with a 3-month history of back pain, gait disturbance, insomnia, and depression. She had moon face, central obesity, hypertrichosis, and pitting edema on her legs and feet. She also had a 2-year history of hypertension. The patient had no family history of thyroid disease or other autoimmune diseases.\n\nHer height was 172.7 cm, and her body weight was 71.5 kg. Her blood pressure was 132/107 mmHg. No goiter, exophthalmos, Graefe's sign, or Dalrymple's sign was present. Laboratory tests showed leukocytosis [white blood cell count, 10,900 cells/mL (neutrophils, 82.5%; eosinophils, 0.5%)] and hypokalemia (potassium, 3.4 mmol/L). Her serum free thyroxine (FT4) level was normal (0.82 ng/dL; reference range, 0.76-1.65 ng/dL), but her thyroid-stimulating hormone (TSH) level (0.377 IU/mL; reference range, 0.541-4.261 IU/mL) and free T3 (FT3) level (1.65 pg/mL; reference range, 2.39-4.06 pg/mL) were low. Her plasma adrenocorticotropic hormone (ACTH) level (<2.0 pg/mL; reference range, 7.2-63.3 pg/mL) was suppressed, and her plasma cortisol level (17.2 μg/dL; reference range, 6.24-18.0 μg/dL) and 24-h urinary free cortisol level (967 μg/day) were elevated. Loss of diurnal variation of plasma ACTH and cortisol was observed. The oral administration of 1 mg of dexamethasone at 11:00 PM did not suppress the plasma cortisol level at 8:00 AM the following morning (17.9 μg/dL).\n\nComputed tomography revealed a 30-mm tumor in the left adrenal gland (Fig. 1A). Magnetic resonance imaging did not show a pituitary tumor. 99mTc-methylene diphosphonate (MDP) scintigraphy indicated multiple fractures in the seventh to ninth right ribs, fourth and fifth lumbar vertebrae, bilateral sacroiliac joints, and left ilium (Fig. 1B). The patient was diagnosed with Cushing's syndrome due to a left adrenal adenoma. She also had low T3 syndrome and central hypothyroidism.\n\nFigure 1. Computed tomography (CT) and whole-body 99mTc-methylene diphosphonate bone scintigraphy. (A) CT revealed a 30-mm left adrenal tumor (arrow). (B) A bone scan showed a significant abnormal isotope uptake in multiple ribs and vertebrae, the sacroiliac joints, and the right ileum.\n\nUnilateral adrenalectomy was performed 5 months after the first visit to our hospital, and oral hydrocortisone was administered at 30 mg/day after surgery. She had general malaise and hypotension for 3 months despite medication with 30 mg/day hydrocortisone. Five months after surgery, the dose of hydrocortisone was reduced to 20 mg/day. Inappropriate secretion of TSH had been observed from 1 month after surgery (FT3, 4.16 pg/mL; TSH, 0.575 IU/mL) to 7 months after surgery (FT3, 4.12 pg/mL; TSH, 1.361 IU/mL).\n\nThe patient developed tachycardia and diffuse goiter 9 months after the adrenalectomy and was diagnosed with Graves' disease [FT3, 10.27 pg/mL; FT4, 3.16 ng/dL; TSH, <0.003 IU/mL; anti-thyroglobulin antibody, 1,063.2 IU/mL (reference range, <40.6 IU/mL); anti-thyroid peroxidase antibody, 225.5 IU/mL (reference range, <9.4 IU/mL); anti-TSH receptor antibody (third-generation TRAb electrochemiluminescence immunoassay), 7.4 IU/L (reference range, <2.0 IU/L); and thyroid-stimulating antibody (TSAb Bioassay Enzyme Immunoassay; Yamasa, Choshi, Japan), 1,196% (reference range, <120%)]. Ultrasonography showed the diffuse enlargement of her thyroid glands with increased blood flow.\n\nShe was started on oral methimazole at 15 mg/day. She remained euthyroid on oral methimazole at 5 mg/day for 15 months after adrenalectomy. The serum thyroid-stimulating antibody level gradually decreased to 216% 17 months after adrenalectomy and 149% 23 months after surgery (Fig. 2).\n\nFigure 2. Clinical course. FT3: free triiodothyronine, FT4: free thyroxine, TSH: thyroid-stimulating hormone, TRAb: anti-TSH receptor antibody, TSAb: thyroid-stimulating antibody\n\nDiscussion\nExcess glucocorticoid followed by its withdrawal may influence the hypothalamic-pituitary-thyroid axis and immune system (1-14). In our case, low T3 syndrome and TSH suppression were present before adrenalectomy. The patient developed SITSH one month after surgery and Graves' disease nine months after adrenalectomy.\n\nThe serum TSH level is suppressed in patients with Cushing's syndrome. Hypercortisolemia decreases the TSH pulse amplitude and nocturnal surge (15,16) and suppresses TSH secretion through the suppression of the thyrotropin-releasing hormone gene expression (17) or through the direct suppression of TSH secretion via leptin, dopamine, annexin 1, and somatostatin (18-21). Increased activity of type II deiodinase by glucocorticoids also causes increased local T3 levels, eventually leading to suppression of thyrotropin-releasing hormone and TSH secretion (6,22).\n\nAlthough the FT4 level was within the reference range in our case, central hypothyroidism with a reduced T4 level is sometimes present in patients with Cushing's syndrome. The prevalence of central hypothyroidism ranges from 18% to 26% (2,23).\n\nIn our patient, SWS was observed after adrenalectomy despite supplementation with oral hydrocortisone at 30 mg/day. She also complained of anorexia and fatigue. Her serum TSH and FT3 levels were higher than the upper limit of normal, which indicated SITSH. A recent report described SITSH as a clinical condition with the presence of normal or elevated TSH secretion despite inappropriately high levels of thyroid hormones in patients who receive insufficient hydrocortisone replacement following surgery for Cushing's syndrome (6). Because the symptoms of hyperthyroidism due to SITSH overlap with those of SWS, SITSH is considered the main cause of SWS (23). Tamada et al. (6) reported that SITSH was detected in the first month of follow-up when the daily hydrocortisone replacement doses were <20 mg. SITSH was present in 75% of patients with Cushing's syndrome up to 6 months after surgery and disappeared by 12 months after surgery (6). In contrast, Dogansen et al. (2) failed to detect SITSH in the early postoperative period with their prednisolone replacement doses.\n\nSeveral reports have described the exacerbation or development of autoimmune disorders, including thyroid diseases, after surgery for Cushing's syndrome (7-14). Although the pathogenesis underlying the exacerbation of autoimmune thyroid disease is not well known, rebound immunity and activation of latent autoimmune thyroid disease have been postulated. In previous studies, the prevalence of autoimmune dysfunction after surgery for Cushing's syndrome was 16.7% in adults (24) and 7.8% in children (25). The prevalence of autoimmune thyroid disease after surgery for Cushing's syndrome reportedly ranges from 10% to 35% (9,13,26). Colao et al. (14) reported an increased prevalence of positive thyroglobulin and thyroid peroxidase antibody titers in patients after Cushing's syndrome remission than during active Cushing's syndrome (60% vs. 20%). Niepomniszcze et al. (27) reported that thyroid autoimmunity was detected in 21.7% of patients at the time of diagnosis of Cushing's syndrome and in 65.2% of patients after remission of hypercortisolism. Several case reports have described Graves' disease after surgery for Cushing's syndrome (24,25,27-29), reporting prevalence rates of 0.8% to 8.5% (Table). Most patients developed autoimmune thyroid disorders 7 to 10 months after surgery. Graves' disease developed 3 to 100 months after surgery for Cushing's syndrome. Therefore, physicians need to be aware of this possible outcome.\n\nTable. Previous Reports on Exacerbation or Development of Graves’ Disease after Adrenalectomy for Cushing’s Syndrome.\n\nReference\tSex\tAge\tTime of presentation of Graves’ disease after surgery\tTSH receptor antibody and iodine uptake\tPrevalence of Graves’ disease\tTreatment used\t\n27\t-\t-\t3 M, 14 M, 18 M, \n100 M, -20 Y\t-\t8.5% \n(5/59)\t\t\n28\tMale\t49\t80 D\tTRAb-, TSAb- positive\t-\tRemission without treatment\t\n29\tFemale\t50\t9 M\tTRAb 30 IU/L, I uptake 31% at 2 hr\t-\tPTU\t\n24\tFemale\t58\t27 M\tTRAb 9.8 IU/L, I uptake 37.8% at 24 hr\t1.5% \n(1/66)\tMMI\t\n25\tFemale\t15\t12 M\t-\t0.8% \n(1/127)\t\t\npresent study\tFemale\t44\t9 M\tTRAb 7.4 IU/L, \nTSAb 1196%\t-\tMMI\t\nTSH: thyroid-stimulating hormone, D: days, M: months, Y: years, TRAb: anti-TSH receptor antibody, TSAb: thyroid-stimulating antibody, PTU: propylthiouracil, MMI: methimazole\n\nIt is reasonable to hypothesize that predisposed patients are protected from autoimmune attack by immunologic tolerance related to steroid excess and overt thyroid dysfunction that develops after the decline in glucocorticoid concentration (9). However, the possibility of other mechanisms precipitating the occurrence of the disease, such as iodine excess, cannot be ruled out. The present case had SITSH for a six-month period until two months before the diagnosis of Graves' disease, although the role of SITSH in the development of Graves' disease is unclear.\n\nIn conclusion, this study suggests that the thyroid function and antibody tests should be carefully evaluated before and after surgery for Cushing's syndrome.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe thank Angela Morben, DVM, ELS for editing a draft of this manuscript.\n==== Refs\n1. Pivonello R , Isidori AM , De Martino MC , Newell-Price J , Biller BM , Colao A \nComplications of Cushing's syndrome: state of the art\n. Lancet Diabetes Endocrinol \n4 : 611 -629\n, 2016 .27177728 \n2. Dogansen SC , Yalin GY , Canbaz B , Tanrikulu S , Yarman S \nDynamic changes of central thyroid functions in the management of Cushing's syndrome\n. Arch Endocrinol Metab \n62 : 164 -171\n, 2018 .29641732 \n3. Tamada D , Kitamura T , Onodera T , Hamasaki T , Otsuki M , Shimomura I \nClinical significance of fluctuations in thyroid hormones aftersurgery for Cushing's syndrome\n. Endocr J \n62 : 805 -810\n, 2015 .26156592 \n4. Oppong E , Cato AC \nEffects of glucocorticoids in the immune system\n. Adv Exp Med Biol \n872 : 217 -233\n, 2015 .26215996 \n5. Bhattacharyya A , Kaushal K , Tymms DJ , Davis JR \nSteroid withdrawal syndrome after successful treatment of Cushing's syndrome: a reminder\n. Eur J Endocrinol \n153 : 207 -210\n, 2005 .16061825 \n6. Tamada D , Onodera T , Kitamura T , et al \nHyperthyroidism due to thyroid-stimulating hormone secretion after surgery for Cushing's syndrome: a novel cause of the syndrome of inappropriate secretion of thyroid-stimulating hormone\n. J Clin Endocrinol Metab \n98 : 2656 -2662\n, 2013 .23671315 \n7. Uthman I , Senecal JL \nOnset of rheumatoid arthritis after surgical treatment of Cushing's disease\n. J Rheumatol \n22 : 1964 -1966\n, 1955 .\n8. Noguchi Y , Tamai H , Fujisawa K , et al \nSystemic lupus erythematosus after pituitary adenomectomy in a patient with Cushing's disease\n. Clin Endocrinol \n48 : 670 -672\n, 1998 .\n9. Haraguchi K , Hiramatsu K , Onaya T \nTransient thyrotoxicosis after unilateral adrenalectomy in two patients with Cushing's syndrome\n. Endocrinol Jpn \n31 : 577 -582\n, 1984 .6519031 \n10. Takasu N , Komiya I , Nagasawa Y , Asawa T , Yamada T \nExacerbation of autoimmune thyroid dysfunction after unilateral adrenalectomy in patients with Cushing's syndrome due to an adrenocortical adenoma\n. N Engl J Med \n322 : 1708 -1712\n, 1990 .2342537 \n11. Colombo P , Passini E , Ambrosi B \nAutoimmune thyroid disease after successful treatment of Cushing's syndrome\n. J Endocrinol Invest \n17 : 289 -290\n, 1994 .7930383 \n12. Cioni K , Pantaleoni M , Toschi E , Frank G , Marrama P , Velardo A \nExacerbation of autoimmune hypothyroidism after hemi-hypophysectomy in a patient with Cushing's disease\n. Minerva Endocrinol \n18 : 139 -141\n, 1993 .8183181 \n13. Yamakita N , Sakata S , Hayashi H , Maekawa H , Miura K \nCase report: silent thyroiditis after adrenalectomy in a patient with Cushing's syndrome\n. Am J Med Sci \n305 : 304 -306\n, 1993 .8484389 \n14. Colao A , Pivonello R , Faggiano A , et al \nIncreased prevalence of thyroid autoimmunity in patients successfully treated for Cushing's disease\n. Clin Endocrinol \n53 : 13 -19\n, 2000 .\n15. Adriaanse R , Brabant G , Endert E , Wiersinga WM \nPulsatile thyrotropin secretion in patients with Cushing's syndrome\n. Metabolism \n43 : 782 -786\n, 1994 .8201971 \n16. Bartalena L , Martino E , Petrini L , et al \nThe nocturnal serum thyrotropin surge is abolished in patients with adrenocorticotropin (ACTH)-dependent or ACTH-independent Cushing's syndrome\n. J Clin Endocrinol Metab \n72 : 1195 -1199\n, 1991 .1851180 \n17. Alkemade A , Unmehopa UA , Wiersinga WM , Swaab DF , Fliers E \nGlucocorticoids decrease thyrotropin-releasing hormone messenger ribonucleic acid expression in the paraventricular nucleus of the human hypothalamus\n. J Clin Endocrinol Metab \n90 : 323 -327\n, 2005 .15509645 \n18. Saane LM , Carro E , Tovar S , Casanueva FF , Dieguez C \nRegulation of in vivo TSH secretion by leptin\n. Regul Pept \n92 : 25 -29\n, 2000 .11024561 \n19. Lewis BM , Dieguez C , Lewis MD , Scanlon MF \nDopamine stimulates release of thyrotropin-releasing hormone from perfused intact rat hypothalamus via hypothalamic D2-receptors\n. J Endocrinol \n115 : 419 -424\n, 1987 .2965205 \n20. Taylor AD , Flower RJ , Buckingham JC \nDexamethasone inhibits the release of TSH from the rat anterior pituitary gland in vitro mechanisms dependent on de novo protein synthesis and lipocortin 1\n. J Endocrinol \n147 : 533 -544\n, 1995 .8543924 \n21. Estupina C , Belmar J , Tapia-Arancibia L , Astier H , Arancidia S \nRapid and opposite effects of dexamethasone on in vivo and in vitro hypothalamic somatostatin release\n. Exp Brain Res \n113 : 337 -342\n, 1997 .9063719 \n22. St Germain DL , Galton VA , Hernandez A \nMinireview: defining the roles of the iodothyronine deiodinase: current concepts and challenges\n. Endocrinol \n150 : 1097 -1107\n, 2009 .\n23. Mathioudakis N , Thapa S , Wand GS , Salvatori R \nCTH-secreting pituitary microadenomas are associated with a higher prevalence of central hypothyroidism compared to other microadenoma types\n. Clin Endocrinol (Oxf) \n77 : 871 -876\n, 2012 .22587880 \n24. da Mota F , Murray C , Ezzat S \nOvert immune dysfunction after Cushing's syndrome remission: a consecutive case series and review of the literature\n. J Clin Endocrinol Metab \n96 : E1670 -E1674\n, 2011 .21816785 \n25. Tatsi C , Keil M , Lyssikatos C , Belyavskaya E , Stratakis CA , Lodish MB \nIncidence of autoimmune and related disorders after resolution of endogenous Cushing syndrome in children\n. Horm Metab Res \n50 : 290 -295\n, 2018 .29458220 \n26. Takasu N , Ohara N , Yamada T , Komiya I \nDevelopment of autoimmune thyroid dysfunction after bilateral adrenalectomy in a patient with Carney's complex and after removal of ACTH-producing pituitary adenoma in a patient with Cushing's disease\n. J Endocrinol Invest \n16 : 697 -702\n, 1993 .8282966 \n27. Niepomniszcze H , Pitoia F , Katz SB , Chervin R , Bruno OD \nPrimary thyroid disorders in endogenous Cushing's syndrome\n. Eur J Endocrinol \n147 : 305 -311\n, 2002 .12213667 \n28. Morita H , Isaji M , Mune T , et al \nTransient Graves disease developing after surgery for Cushing disease\n. Am J Med Sci \n323 : 162 -165\n, 2002 .11908863 \n29. Arikan E , Guldiken S , Altun BU , Kara M , Tugrul A \nExacerbations of Graves' disease after unilateral adrenalectomy for Cushing's syndrome\n. J Endocrinol Invest \n27 : 574 -576\n, 2004 .15717657\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Cushing's syndrome; Graves' disease; central hypothyroidism; syndrome of inappropriate secretion of thyroid-stimulating hormone",
"medline_ta": "Intern Med",
"mesh_terms": "D000315:Adrenalectomy; D000328:Adult; D003480:Cushing Syndrome; D005260:Female; D006111:Graves Disease; D006801:Humans; D006854:Hydrocortisone; D007037:Hypothyroidism; D013972:Thyrotropin",
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"title": "Graves' Disease after Adrenalectomy for Cushing's Syndrome.",
"title_normalized": "graves disease after adrenalectomy for cushing s syndrome"
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"abstract": "Alert intensivists about the diagnostic pitfalls arising from hyperammonemia due to Ureaplasma infections in post-transplant patients.\n\n\n\nClinical observation of one patient.\n\n\n\nA 65-year-old female with a medical history of semi-recent kidney transplant was admitted to the Intensive Care Unit for refractory status epilepticus. There were no lesions on brain imaging. Bacterial cultures and viral PCR of cerebrospinal fluid were negative. The first blood ammonia level measured on day 2 was 13 times the normal level, but biological liver tests were normal. The persistence of elevated ammonia levels led to the initiation of symptomatic ammonia lowering-treatments and continuous renal replacement therapy, which led to its decrease without normalization. An Ureaplasma spp infection was then diagnosed. Levofloxacin and doxycyline were administered resulting in normalization of ammonia levels within 48 h. However repeat MRI showed diffuse cortical cytotoxic edema and the patient remained in a minimally conscious state. She eventually died 4 months later from a recurrent infection.\n\n\n\nUreaplasma infection must be suspected in cases of neurological symptoms associated with hyperammonemia without liver failure, following an organ transplant. Only urgent treatment could improve the prognosis and prevent severe neurological damage or death.",
"affiliations": "Sainte Anne Hospital, Department of Neurointensive Care, Paris, France.;Fondation Ophtalmologique Adolphe de Rothschild, Department of Neurointensive Care, Paris, France.;Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France.;Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurointensive Care, Paris, France.;Fondation Ophtalmologique Adolphe de Rothschild, Department of Neuroradiology, Paris, France.;French National Reference Center for bacterial STI, Pellegrin Hospital, Bordeaux, France.;Fondation Ophtalmologique Adolphe de Rothschild, Department of Neurointensive Care, Paris, France.;Fondation Ophtalmologique Adolphe de Rothschild, Department of Neurointensive Care, Paris, France. Electronic address: nengrand@fo-rothschild.fr.",
"authors": "Legouy|Camille|C|;Hu|Alice|A|;Mochel|Fanny|F|;Weiss|Nicolas|N|;Collin|Adrien|A|;Pereyre|Sabine|S|;Perrin|Mathilde|M|;Engrand|Nicolas|N|",
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"journal": "Journal of critical care",
"keywords": "Electroencephalography; Hyperammonemia; ICU; Immunosuppressed patient; Kidney transplantation; Refractory status epilepticus; Ureaplasma spp",
"medline_ta": "J Crit Care",
"mesh_terms": "D000368:Aged; D003422:Critical Care; D004569:Electroencephalography; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007362:Intensive Care Units; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D016133:Polymerase Chain Reaction; D011183:Postoperative Complications; D011379:Prognosis; D013226:Status Epilepticus; D014509:Ureaplasma; D016869:Ureaplasma Infections",
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"pmid": "32062289",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ureaplasma parvum causes hyperammonemia presenting as refractory status epilepticus after kidney transplant.",
"title_normalized": "ureaplasma parvum causes hyperammonemia presenting as refractory status epilepticus after kidney transplant"
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"abstract": "The pediatric sedative combination of meperidine, promethazine, and chlorpromazine (MPC) has been widely used for more than 40 years. Despite its relatively poor efficacy and questionable safety profile, many emergency departments (EDs) continue to stock specially formulated mixtures of these three agents. We report a case of iatrogenic cardiac arrest in a 2-month-old infant in whom a consulting resident administered too much MPC (10 times the expected dose) by the wrong route (intravenous instead of intramuscular). The child was successfully resuscitated with no apparent neurologic deficit. Subsequently, we have removed MPC entirely from our ED and instituted a policy restricting ED procedural sedation privileges to emergency physicians. We urge other EDs to do likewise.",
"affiliations": "Department of Emergency Medicine, Adventist Medical Center, Portland, Oregon, USA.",
"authors": "Brown|E T|ET|;Corbett|S W|SW|;Green|S M|SM|",
"chemical_list": "D004338:Drug Combinations; D008614:Meperidine; D011398:Promethazine; D002746:Chlorpromazine",
"country": "United States",
"delete": false,
"doi": "10.1097/00006565-200110000-00008",
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"issn_linking": "0749-5161",
"issue": "17(5)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D002746:Chlorpromazine; D016292:Conscious Sedation; D004338:Drug Combinations; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D006323:Heart Arrest; D006801:Humans; D007049:Iatrogenic Disease; D007223:Infant; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D008508:Medication Errors; D008614:Meperidine; D011398:Promethazine",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "351-3",
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"pmid": "11673713",
"pubdate": "2001-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Iatrogenic cardiopulmonary arrest during pediatric sedation with meperidine, promethazine, and chlorpromazine.",
"title_normalized": "iatrogenic cardiopulmonary arrest during pediatric sedation with meperidine promethazine and chlorpromazine"
} | [
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"companynumb": "US-VALIDUS PHARMACEUTICALS LLC-US-2021VAL000094",
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"activesubstancename": "CHLORPROMAZINE"
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"abstract": "BACKGROUND\nNeuroendocrine carcinoma of the breast (NECB) is a rare type of malignant tumor. Due to the rarity of NECB, the relevant literature mostly comprises case reports. Available data on treatment options for NECB are very limited.\n\n\nMETHODS\nA 62-year-old woman presented to our hospital in October 2016 for intermittent vomiting and diarrhea and masses in the liver found on abdominal computed tomography (CT) imaging. She was diagnosed in July 2012 with neuroendocrine carcinoma of the right breast in local hospital. The patient initially presented with a painful lesion of the right breast. She then undergone surgical resection and adjuvant chemotherapy with pirarubicin and paclitaxel for four cycles as well as endocrine therapy. She was regularly followed every 3 mo after surgery. Enhanced abdominal CT imaging at our hospital revealed multiple suspicious masses in the liver with the largest lesion measuring 8.4 cm × 6.3 cm. Chest CT revealed masses in the anterior chest wall and lung. Core needle biopsy of the lesion revealed liver metastases of NECB. A bone scan showed right second anterior rib metastases. Upper endoscopy and colonoscopy did not provide any evidence of another possible primary tumor. She stopped receiving endocrine therapy and then received etoposide and cisplatin (EP) chemotherapy as a first-line treatment regimen for six cycles at our hospital after liver, bone, and lung metastases. On October 2017, the chemotherapy regimen was changed to S-1 (40 mg twice daily, days 1-14) combined with temozolomide (200 mg once daily, days 10-14) (STEM) every 21 d as a second-line treatment regimen due to disease progression. Progression-free survival (PFS) and adverse effects after treatment were analyzed, and the efficacy of the STEM regimen was assessed using RECIST version 1.1. This patient achieved a partial response after using the STEM regimen, with a PFS of 23 mo. Adverse effects included only grade 1 digestive tract reactions with no need for a reduction in chemotherapy.\n\n\nCONCLUSIONS\nThis case report suggests that the STEM regimen may be effective and well tolerated as the second-line treatment for advanced NECB. STEM is still highly effective in patients who show disease progression with the EP regimen. More evidence is needed to prove the validity of STEM.",
"affiliations": "Beijing University of Chinese Medicine; Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China.;Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China.;Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China.;Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China.;Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China. tanhuangying@263.net.",
"authors": "Wang|Xin|X|;Shi|Yan-Fen|YF|;Duan|Jiang-Hui|JH|;Wang|Chao|C|;Tan|Huang-Ying|HY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i24.7146",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i24.pg7146\n10.12998/wjcc.v9.i24.7146\nCase Report\nS-1 plus temozolomide as second-line treatment for neuroendocrine carcinoma of the breast: A case report\nWang X et al. STEM chemotherapy for NECB\nWang Xin Beijing University of Chinese Medicine; Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China\n\nShi Yan-Fen Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China\n\nDuan Jiang-Hui Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China\n\nWang Chao Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China\n\nTan Huang-Ying Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China. tanhuangying@263.net\n\nAuthor contributions: Wang X reviewed the literature and contributed to manuscript drafting; Shi YF provided pathological information; Duan JH analyzed and interpreted the imaging findings; Wang C contributed to data collection; Tan HY was responsible for the revision of the manuscript; all authors have read and approved the final version of the manuscript.\n\nCorresponding author: Huang-Ying Tan, MD, PhD, Chief Physician, Department of Integrative Oncology, China-Japan Friendship Hospital, No. 2 Yinghuadong Street, Beijing 100029, China. tanhuangying@263.net\n\n26 8 2021\n26 8 2021\n9 24 71467153\n4 1 2021\n27 4 2021\n6 7 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nNeuroendocrine carcinoma of the breast (NECB) is a rare type of malignant tumor. Due to the rarity of NECB, the relevant literature mostly comprises case reports. Available data on treatment options for NECB are very limited.\n\nCASE SUMMARY\n\nA 62-year-old woman presented to our hospital in October 2016 for intermittent vomiting and diarrhea and masses in the liver found on abdominal computed tomography (CT) imaging. She was diagnosed in July 2012 with neuroendocrine carcinoma of the right breast in local hospital. The patient initially presented with a painful lesion of the right breast. She then undergone surgical resection and adjuvant chemotherapy with pirarubicin and paclitaxel for four cycles as well as endocrine therapy. She was regularly followed every 3 mo after surgery. Enhanced abdominal CT imaging at our hospital revealed multiple suspicious masses in the liver with the largest lesion measuring 8.4 cm × 6.3 cm. Chest CT revealed masses in the anterior chest wall and lung. Core needle biopsy of the lesion revealed liver metastases of NECB. A bone scan showed right second anterior rib metastases. Upper endoscopy and colonoscopy did not provide any evidence of another possible primary tumor. She stopped receiving endocrine therapy and then received etoposide and cisplatin (EP) chemotherapy as a first-line treatment regimen for six cycles at our hospital after liver, bone, and lung metastases. On October 2017, the chemotherapy regimen was changed to S-1 (40 mg twice daily, days 1-14) combined with temozolomide (200 mg once daily, days 10-14) (STEM) every 21 d as a second-line treatment regimen due to disease progression. Progression-free survival (PFS) and adverse effects after treatment were analyzed, and the efficacy of the STEM regimen was assessed using RECIST version 1.1. This patient achieved a partial response after using the STEM regimen, with a PFS of 23 mo. Adverse effects included only grade 1 digestive tract reactions with no need for a reduction in chemotherapy.\n\nCONCLUSION\n\nThis case report suggests that the STEM regimen may be effective and well tolerated as the second-line treatment for advanced NECB. STEM is still highly effective in patients who show disease progression with the EP regimen. More evidence is needed to prove the validity of STEM.\n\nNeuroendocrine carcinoma\nBreast\nS-1\nTemozolomide\nCase report\n==== Body\npmcCore Tip: Neuroendocrine carcinoma of the breast (NECB) is a highly malignant tumor. There is no standard treatment protocol for NECB due to its rarity. We treated an NECB patient with the S-1 combined with temozolomide (STEM) regimen as a second-line treatment due to disease progression. The effect of the STEM regimen on the patient was good, and she achieved a progression-free survival of 23 mo. During the chemotherapy period, the patient achieved a partial response and suffered only grade 1 adverse reactions. This report can serve as a reference for clinical practice.\n\nINTRODUCTION\n\nNeuroendocrine carcinoma (NEC) constitutes a group of rare neuroendocrine neoplasms (NENs) that can be distributed throughout the body, but they are commonly found in the gastroenteropancreatic and respiratory systems[1]. NEC of the breast (NECB) is very rare, accounting for approximately 0.1% of all breast cancers and 1% of neuroendocrine tumours (NETs)[2]. Because of the high malignancy of NEC, it is prone to metastasis. Currently, there is no standard treatment for patients with advanced NECB. Capecitabine combined with temozolomide (CAPTEM) is the regimen used for poorly differentiated NEC[3-6]. Since S-1 is also a 5-fluorouracil (5-FU) prodrug that can increase anticancer activity and reduce drug toxicity, we administered S-1 combined with temozolomide (STEM) as a second-line treatment regimen to an advanced NECB patient after the failure of the first-line treatment with etoposide and cisplatin (EP). This patient achieved a good objective response with acceptable toxicities.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 62-year-old woman presented to our hospital in November 2016 complaining of intermittent nausea, vomiting, and diarrhea and multiple masses in the liver found on routine abdominal computed tomography (CT) imaging.\n\nHistory of present illness\n\nThe patient underwent right-sided modified radical mastectomy including lymphadenectomy with nipple and areola preservation 4 years ago at a local hospital. No lymph node metastases were detected. Postoperative pathology revealed poorly-differentiated NEC of the right breast with a size of 1.5 cm × 1.5 cm × 1 cm. Immunohistochemical staining revealed expression of chromogranin A (CgA), synaptophysin (Syn), and hormone receptors [estrogen receptor (ER) and progesterone receptor (PR)]. Staining for human epidermal growth factor receptor 2 (HER-2) was negative. The Ki-67 index was 50%-75%. Curative resection was followed by four cycles of adjuvant chemotherapy with the pirarubicin and paclitaxel regimen. The patient had been receiving endocrine therapy after operation and regular follow-up every 3 mo.\n\nHistory of past illness\n\nThe patient had a free previous medical history.\n\nPersonal and family history\n\nThe patient dined any personal and family history.\n\nPhysical examination\n\nThe physical examination revealed no obvious abnormalities.\n\nLaboratory examinations\n\nLaboratory examination revealed no obvious abnormalities.\n\nImaging examinations\n\nAn initial imaging evaluation by enhanced abdominal CT revealed multiple masses in the liver, with the largest one measuring about 8.4 cm × 6.3 cm. Chest CT showed a mass on the right front chest wall and a small nodule in the upper lobe of the right lung.\n\nThe liver lesions were further evaluated by abdominal magnetic resonance imaging (MRI), which revealed multiple masses in the liver with the largest one measuring about 8.8 cm × 6.7 cm. A whole body bone scan revealed increased bone metabolism in the second anterior rib on the right, which was considered local bone invasion caused by chest wall masses combined with previous chest CT findings.\n\nFurther diagnostic work-up\n\nFurther clinical work-up including upper endoscopy and colonoscopy did not reveal further pathological findings, not providing any evidence of another possible primary tumor.\n\nThe pathological consultation performed at our hospital of the primary breast lesion showed an NEC in the right breast with no metastases in the axillary lymph nodes. Immunohistochemical staining revealed expression of Syn, CgA, and hormone receptors (ER > 50%, slightly weaker expression of PR). Staining for HER-2 was negative. The Ki-67 index was approximately 50%.\n\nThis patient underwent a liver and chest wall biopsy at our hospital. Liver and bone metastases of the NECB were detected. Immunohistochemical analysis of a biopsy taken from the lesion in the liver and chest wall showed an NEC with positive expression of CgA and Syn as well as strong expression for ER (> 95%). The expression of O6-methylguanine DNA methyltransferase (MGMT) and somatostatin receptor SSTR2 was negative. The Ki67 index was approximately 70% (Figure 1).\n\nFigure 1 Pathological analysis and immunohistochemical staining. A: Hematoxylin and eosin (100 ×) staining of right breast tissue; B: Hematoxylin and eosin (100 ×) staining of liver core biopsy specimen; C: Ki-67 index of 70%; D: Immunohistochemical staining (100 ×) reveals positivity for synaptophysin.\n\nFINAL DIAGNOSIS\n\nThe final diagnosis of the presented case was stage IV NECB with liver, lung, and bone metastases.\n\nTREATMENT\n\nApparently, this patient presented with liver, lung, and bone metastases at 4 years after right modified radical mastectomy. Systemic chemotherapy was initiated using chemotherapeutic regimen based on etoposide (120 mg, days 1-3, intravenously) and cisplatin (40 mg, days 1-3, intravenously) every 21 d as a first-line treatment in November 2016. After administration of six cycles of chemotherapy in March 2017, the patient was referred to our hospital. CT imaging revealed a partial response.\n\nAt 6 mo after the cessation of EP chemotherapy, the disease progressed. Then, she began receiving S-1 (40 mg twice daily, days 1-14) combined with temozolomide (200 mg once daily, days 10-14) orally every 21 d beginning in October 2017. The last time that the patient received STEM chemotherapy was July 2019.\n\nOUTCOME AND FOLLOW-UP\n\nThe patient underwent blood cell counts and creatinine and liver function tests at every cycle. Radiological assessment was performed every three cycles to evaluate the efficacy using RECIST version 1.1. The side effects were categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.\n\nAbdominal MRI analysis after one year of the STEM regimen showed a significant reduction in hepatic lesions until September 2019, when MRI analysis showed an increase in liver lesions, indicating disease progression (Figure 2). After receiving the STEM regimen, this patient achieved a partial response, with a progression-free survival (PFS) time of 23 mo. STEM treatment was well tolerated by the patient. Grade 1 digestive tract adverse reactions occurred, but a dose reduction was not needed (Table 1).\n\nFigure 2 Follow-up abdominal magnetic resonance imaging at the beginning, 1 year, and 2 years post administration of STEM chemotherapy. A: Abdominal magnetic resonance imaging (MRI) of the patient with hepatic metastasis performed in October 2017; B: MRI in November 2018; C: MRI in September 2019. D: Whole-body bone scans performed in November 2016. In October 2017, the enhanced image revealed a large mass of the right lobe of the liver, with marked enhancement of the edge, which was reduced in November 2018 and had progressed by September 2019. The whole-body bone scans showed right second anterior rib metastases.\n\nTable 1 Timeline\n\nApril 2012\tJuly 2012\t2012-2016\tOctober 2016\tOctober 2016\tNovember 2016-March 2017\tOctober 2017-July 2019\t\nFeel pain of the right breast\tRight-sided modified radical mastectomy. Diagnosis of neuroendocrine carcinoma of the breast\tEndocrine therapy + regular follow-up\tIntermittent nausea, vomiting and diarrhea; multiple masses in the liver found on routine abdominal CT imaging\tDiagnosis of neuroendocrine carcinoma of the breast stage IV with liver, lung, and bone metastases\tEtoposide and cisplatin chemotherapyfor 6 cycles\tS-1 combined with temozolomide chemotherapy\t\n\tLocal hospital\tLocal hospital\t\tOur hospital\tOur hospital\tOur hospital\t\nCT: Computed tomography.\n\nThe patient experienced twice hepatic artery embolization afterwards. She then orally received a small molecule inhibitor of multiple receptor tyrosine kinases, with inhibitory effects on tumor angiogenesis and growth. The therapy is still being continued and the patient is still alive.\n\nDISCUSSION\n\nNENs are a rare and heterogeneous group of tumors that can be divided into well-differentiated NETs and poorly-differentiated NEC. NEC is associated with a poor prognosis and rapid progression with a high Ki-67 proliferation index of > 20%. According to the 2012 World Health Organization, breast tumors with neuroendocrine features are divided into three categories: Well-differentiated NETs, poorly differentiated NEC, and invasive carcinoma with neuroendocrine differentiation. Interestingly, poorly differentiated NECs are morphologically identical to small-cell lung cancer (SCLC)[7]. NECB is rare in both breast cancer and extrapulmonary NEC. Based on the data collected from the Surveillance, Epidemiology And End Results (SEER) database, Wang et al[8] reported that from 2003 to 2009, there were only 142 cases of primary NECB among 381786 cases of invasive breast carcinoma.\n\nNECB usually expresses neuroendocrine markers such as CgA, Syn, and CD56, tends to express hormone receptors such as ER and PR, and is usually negative for HER-2[9]. Imaging examinations such as mammography or MRI are necessary, but a definitive diagnosis depends on the pathology examination of the tissue after surgery or biopsy. In this case, immunohistochemical staining of the lesions in the breast, liver, and chest revealed expression of CgA, Syn, and hormone receptors. Staining for HER-2 was negative.\n\nNECB is not different from other types of breast cancer in terms of its clinical characteristics. Most patients initially present with a hard breast lump. It is reported to be more common in older women[8]. In our case, the patient’s age was 62 years, which is consistent with the findings of previous reports. The most common distant metastatic sites are the liver and bone[10]. Long-term follow-up is necessary because NECB can metastasize to many sites, even after many years of treatment[11]. In this patient, liver and right-rib metastases occurred approximately 4 years after surgery.\n\nThere is no standard treatment protocol for NECB due to its rarity. Radical mastectomy and axillary clearance are the only curative methods for early NECB. However, NECB is highly malignant and prone to metastasis. Chemotherapy is needed for patients with a high risk of recurrence or advanced unresectable tumors. Chemotherapy for NECB generally conforms to the principles of chemotherapy for other types of breast cancer or SCLC[12,13], which include anthracyclines and taxanes or platinum-based regimen. Etoposide combined with cisplatin or carboplatin (EP/EC) is recommended as the first-line treatment option for patients with unresectable advanced NEC. However, NEC is heterogeneous, and NEC tumors at different sites respond differently to platinum-based chemotherapy[14]. A retrospective study[14] of 252 patients with advanced gastrointestinal NEC showed that patients who were treated with EP or EC as the first-line regimen had a response rate of approximately 30% in terms of achieving stable disease. The median PFS was 4 mo. We administered EP as the first-line treatment for our NECB patient, and she achieved a partial response with a PFS of 11 mo.\n\nSecond-line treatments for NEC have been reported, such as 5-FU combined with oxaliplatin or irinotecan (FOLFOX/FOLFIRI) and a temozolomide-based regimen[15-18]. However, there are no related reports on NECB. S-1 is a novel oral 5-FU prodrug comprising three components. Considering that S-1 is also a fluoropyrimidine antimetabolite agent that can increase anticancer activity and significantly reduce drug toxicity[19], we treated this patient with the STEM regimen as second-line treatment. The effect of the STEM regimen on the patient was good, and she achieved a PFS of 23 mo. During the chemotherapy period, the patient achieved a partial response and suffered only grade 1 adverse reactions. It is important to note that this patient, for whom the previous chemotherapy regimen had failed, still responded to the STEM regimen. This patient was amenable to the oral chemotherapy regimen due to its convenience and relatively few side effects.\n\nPatients positive for somatostatin receptors can benefit from treatment with somatostatin analogues (SSAs) and peptide receptor radionuclide therapy[20,21]. In addition, novel targeted therapies may provide additional treatment options for NECB[22].\n\nTumor size and stage, hormone receptor status, and the Ki67 proliferation index are independent prognostic factors[8,23]. Oral treatment with the STEM regimen was highly effective in this case, which may be related to the relatively low Ki67 index and negative MGMT expression[22].\n\nCONCLUSION\n\nOur understanding of treatment efficacy for NECB is limited due to its rarity. As shown in this case, the STEM regimen is a promising alternative therapy that elicits few side effects and has a high curative effect. This report can serve as a reference for clinical practice. However, the efficacy of this regimen as a second-line solution for NECB requires further exploration.\n\nInformed consent statement: This patient provided informed written consent prior to study enrollment.\n\nConflict-of-interest statement: The authors have no conflicts of interest to report.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: January 4, 2021\n\nFirst decision: April 25, 2021\n\nArticle in press: July 6, 2021\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Mitra S S-Editor: Gao CC L-Editor: Wang TQ P-Editor: Li JH\n==== Refs\n1 Modlin IM Oberg K Chung DC Jensen RT de Herder WW Thakker RV Caplin M Delle Fave G Kaltsas GA Krenning EP Moss SF Nilsson O Rindi G Salazar R Ruszniewski P Sundin A Gastroenteropancreatic neuroendocrine tumours Lancet Oncol 2008 9 61 72 18177818\n2 Ogawa H Nishio A Satake H Naganawa S Imai T Sawaki M Yamamoto E Miyata T Neuroendocrine tumor in the breast Radiat Med 2008 26 28 32 18236131\n3 Rogowski W Wachuła E Gorzelak A Lebiedzińska A Sulżyc-Bielicka V Iżycka-Świeszewska E Żołnierek J Kos-Kudła B Capecitabine and temozolomide combination for treatment of high-grade, well-differentiated neuroendocrine tumour and poorly-differentiated neuroendocrine carcinoma - retrospective analysis Endokrynol Pol 2019 70 313 317 30843182\n4 Chatzellis E Angelousi A Daskalakis K Tsoli M Alexandraki KI Wachuła E Meirovitz A Maimon O Grozinsky-Glasberg S Gross D Kos-Kudła B Koumarianou A Kaltsas G Activity and Safety of Standard and Prolonged Capecitabine/Temozolomide Administration in Patients with Advanced Neuroendocrine Neoplasms Neuroendocrinology 2019 109 333 345 31167197\n5 Fine RL Gulati AP Krantz BA Moss RA Schreibman S Tsushima DA Mowatt KB Dinnen RD Mao Y Stevens PD Schrope B Allendorf J Lee JA Sherman WH Chabot JA Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience Cancer Chemother Pharmacol 2013 71 663 670 23370660\n6 Ramirez RA Beyer DT Chauhan A Boudreaux JP Wang YZ Woltering EA The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors Oncologist 2016 21 671 675 27226359\n7 Tan PH Schnitt SJ van de Vijver MJ Ellis IO Lakhani SR Papillary and neuroendocrine breast lesions: the WHO stance Histopathology 2015 66 761 770 24845113\n8 Wang J Wei B Albarracin CT Hu J Abraham SC Wu Y Invasive neuroendocrine carcinoma of the breast: a population-based study from the surveillance, epidemiology and end results (SEER) database BMC Cancer 2014 14 147 24589259\n9 López-Bonet E Alonso-Ruano M Barraza G Vazquez-Martin A Bernadó L Menendez JA Solid neuroendocrine breast carcinomas: incidence, clinico-pathological features and immunohistochemical profiling Oncol Rep 2008 20 1369 1374 19020716\n10 Wei B Ding T Xing Y Wei W Tian Z Tang F Abraham S Nayeemuddin K Hunt K Wu Y Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma Cancer 2010 116 4463 4473 20572042\n11 Valente I Tringali G Martella EM Pallavera L D'Aloia C Primary neuroendocrine carcinoma of the breast: A case report of liver and lymph node metastases after eight years from diagnosis Breast J 2020 26 505 507 31513314\n12 Garcia-Carbonero R Sorbye H Baudin E Raymond E Wiedenmann B Niederle B Sedlackova E Toumpanakis C Anlauf M Cwikla JB Caplin M O'Toole D Perren A Vienna Consensus Conference participants ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas Neuroendocrinology 2016 103 186 194 26731334\n13 Inno A Bogina G Turazza M Bortesi L Duranti S Massocco A Zamboni G Carbognin G Alongi F Salgarello M Gori S Neuroendocrine Carcinoma of the Breast: Current Evidence and Future Perspectives Oncologist 2016 21 28 32 26659223\n14 Sorbye H Welin S Langer SW Vestermark LW Holt N Osterlund P Dueland S Hofsli E Guren MG Ohrling K Birkemeyer E Thiis-Evensen E Biagini M Gronbaek H Soveri LM Olsen IH Federspiel B Assmus J Janson ET Knigge U Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study Ann Oncol 2013 24 152 160 22967994\n15 Welin S Sorbye H Sebjornsen S Knappskog S Busch C Oberg K Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy Cancer 2011 117 4617 4622 21456005\n16 Hentic O Hammel P Couvelard A Rebours V Zappa M Palazzo M Maire F Goujon G Gillet A Lévy P Ruszniewski P FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3 Endocr Relat Cancer 2012 19 751 757 22940375\n17 Hadoux J Malka D Planchard D Scoazec JY Caramella C Guigay J Boige V Leboulleux S Burtin P Berdelou A Loriot Y Duvillard P Chougnet CN Déandréis D Schlumberger M Borget I Ducreux M Baudin E Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma Endocr Relat Cancer 2015 22 289 298 25770151\n18 Lamarca A Frizziero M Barriuso J McNamara MG Hubner RA Valle JW Urgent need for consensus: international survey of clinical practice exploring use of platinum-etoposide chemotherapy for advanced extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC) Clin Transl Oncol 2019 21 950 953 30506132\n19 Wang D Yu X Wang X High/positive expression of 5-fluorouracil metabolic enzymes predicts better response to S-1 in patients with gastric cancer: a meta-analysis Int J Biol Markers 2016 31 e101 e109 27012156\n20 Terlević R Perić Balja M Tomas D Skenderi F Krušlin B Vranic S Demirović A Somatostatin receptor SSTR2A and SSTR5 expression in neuroendocrine breast cancer Ann Diagn Pathol 2019 38 62 66 30476894\n21 Savelli G Zaniboni A Bertagna F Bosio G Nisa L Rodella C Biasiotto G Bettinsoli G Migliorati E Peli A Falchi R Giuffrida F Giubbini R Peptide Receptor Radionuclide Therapy (PRRT) in a Patient Affected by Metastatic Breast Cancer with Neuroendocrine Differentiation Breast Care (Basel) 2012 7 408 410 24647781\n22 Vranic S Palazzo J Sanati S Florento E Contreras E Xiu J Swensen J Gatalica Z Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast Clin Breast Cancer 2019 19 131 136 30268765\n23 Cloyd JM Yang RL Allison KH Norton JA Hernandez-Boussard T Wapnir IL Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast Breast Cancer Res Treat 2014 148 637 644 25399232\n\n",
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"title": "S-1 plus temozolomide as second-line treatment for neuroendocrine carcinoma of the breast: A case report.",
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"abstract": "We report a case of HIV-negative Burkitt lymphoma (BL) that relapsed 9 years after complete remission. We performed a polymerase chain reaction analysis of three regions of the VDJ junction of the immunoglobulin heavy chain (IGH) gene and compared the clonality of the first and second BL lesions, which were found to be clonally distinct. The patient received the R-Hyper CVAD/R-MA regimen; however, leukoencephalopathy subsequently developed due to the effect of cytarabine, and the regimen was changed to R-IVAM. The patient achieved complete remission and received high-dose chemotherapy following autologous stem cell transplantation. He maintained the complete remission for 72 months after transplantation. Given this outcome, we suggest that clonally distinct relapse of HIV-negative BL may exhibit a good prognosis.",
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"pmid": "25555480",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17132719;4303830;18398744;6546890;7833470;8695860;5030826;8616769;15370204;24224624;23689288;23446093;21300984;8823324;11237070",
"title": "A case of clonally distinct relapse of Burkitt lymphoma 9 years after complete remission.",
"title_normalized": "a case of clonally distinct relapse of burkitt lymphoma 9 years after complete remission"
} | [
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"companynumb": "JP-MYLANLABS-2016M1010237",
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"abstract": "Recombinant tissue plasminogen activator (rt-PA) is the most promising agent use for salvaging ischemic myocardium in acute infarction. To assess the safety and efficacy of rt-PA thrombolytic therapy, an open label clinical trial was conducted. Patients of acute myocardial infarction with angina, occurring within the five previous hours, was treated with rt-PA 100 mg infusion within three hours; followed with coronary arteriography to assess the patency rate of infarct vessels. Twenty-five cases of acute myocardial infarction were studied over a 10-month period. The patients, 24 male and one female, were aged 58.1 +/- 7.7 years. Rt-PA was given at 3.17 +/- 1.0 hour. Infarct-related vessels had opened in 21/24 cases when examined with coronary arteriogram three hours after infusion. Good antegrade flow of grade 2 to 3 was gained in 20/24 cases, representing an 83% success rate. One patient expired from cardiogenic shock during the infusion; another was expired from noncardiac accident after coronary bypass graft. The total inhospital mortality rate was about 8%. There was no major bleeding complication except in one case with gastrointestinal bleeding requiring transfusion.\n\n\nCONCLUSIONS\nrt-PA is safe and effective in the treatment of acute myocardial infarction in the early stage. Coronary arteriography can be safely delayed until three hours postinfusion, and the achieved reperfusion rate is up to 83%.",
"affiliations": null,
"authors": "Wang|S P|SP|;Liu|C P|CP|;Charng|M J|MJ|;Chou|C Y|CY|;Tsai|J H|JH|;Pan|J P|JP|;Shyong|W C|WC|;Chan|W L|WL|;Kong|C W|CW|;Chang|M S|MS|",
"chemical_list": "D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0578-1337",
"issue": "43(4)",
"journal": "Zhonghua yi xue za zhi = Chinese medical journal; Free China ed",
"keywords": null,
"medline_ta": "Zhonghua Yi Xue Za Zhi (Taipei)",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "0005327",
"other_id": null,
"pages": "223-8",
"pmc": null,
"pmid": "2509051",
"pubdate": "1989-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The efficacy and safety of recombinant tissue plasminogen activator infusion in acute myocardial infarction.",
"title_normalized": "the efficacy and safety of recombinant tissue plasminogen activator infusion in acute myocardial infarction"
} | [
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"abstract": "To determine the significance of acute disulfiram poisoning in pediatric population.\nDisulfiram poisoning in children is uncommon, can occur in children who have ingested large amount of drug because of careless and unsafe storage. Only few cases have been reported in literature. Although well tolerated by most patients, severe toxic side effects have been also reported including hepatitis, encephalopathy, psychosis, optic, and peripheral neuropathy.\nThis is a case report of disulfiram toxicity in a 4.5-year girl who ingested 4-5 tablets of disulfiram (approximately 1-1.25 g) accidentally and presented with hypoglycemia and encephalopathy. After initial stabilization in emergency room, the child was shifted to intensive care unit (ICU) where the child was managed conservatively. Blood sugars normalized after 8 hours of admission. Magnetic resonance imaging (MRI) brain showed bilateral globus pallidus hyperintensity in T2-weighted (T2W) and diffusion-weighted (DW) images and hypointensity in T1-weighted (T1W) images including diffusion restriction.\nAcute disulfiram poisoning can occur in children who have ingested large amount of drug because of unsafe storage. It can lead to hepatitis, encephalopathy, psychosis, optic, and peripheral neuropathy. Mainstay of treatment is supportive care, airway protection, oxygen, and dextrose-containing intravenous fluid should be given.\nAcute disulfiram poisoning should be an important differential in diagnosis of any child presenting with idiopathic encephalopathy along with extrapyramidal symptoms with basal ganglia signal changes in MRI of brain in a previously healthy child.\nBhalla K, Mittal K, Gupta A, Nehra D. Acute Disulfiram Poisoning in a Child: A Case Report and Review of Literature. Indian J Crit Care Med 2020;24(3):203-205.",
"affiliations": "Department of Pediatrics, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India.;Department of Pediatrics, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India.;Department of Cardiology, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India.;Department of Pharmacology, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India.",
"authors": "Bhalla|Kapil|K|;Mittal|Kundan|K|;Gupta|Ashish|A|;Nehra|Deepak|D|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.5005/jp-journals-10071-23371",
"fulltext": "\n==== Front\nIndian J Crit Care Med\nIndian J Crit Care Med\nIJCCM\nIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine\n0972-5229 1998-359X Jaypee Brothers Medical Publishers \n\n10.5005/jp-journals-10071-23371\nCase Report\nAcute Disulfiram Poisoning in a Child: A Case Report and Review of Literature\nBhalla Kapil 1 Mittal Kundan 2 Gupta Ashish 3 Nehra Deepak 4 1,2 Department of Pediatrics, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India\n3 Department of Cardiology, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India\n4 Department of Pharmacology, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India\nAshish Gupta, Department of Cardiology, Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India, Phone: +91-0124-4010624, e-mail: ashishg19995@gmail.com\n3 2020 \n24 3 203 205\nCopyright © 2020; Jaypee Brothers Medical Publishers (P) Ltd.2020© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.ABSTRACT\nAim\nTo determine the significance of acute disulfiram poisoning in pediatric population.\n\nBackground\nDisulfiram poisoning in children is uncommon, can occur in children who have ingested large amount of drug because of careless and unsafe storage. Only few cases have been reported in literature. Although well tolerated by most patients, severe toxic side effects have been also reported including hepatitis, encephalopathy, psychosis, optic, and peripheral neuropathy.\n\nCase description\nThis is a case report of disulfiram toxicity in a 4.5-year girl who ingested 4–5 tablets of disulfiram (approximately 1–1.25 g) accidentally and presented with hypoglycemia and encephalopathy. After initial stabilization in emergency room, the child was shifted to intensive care unit (ICU) where the child was managed conservatively. Blood sugars normalized after 8 hours of admission. Magnetic resonance imaging (MRI) brain showed bilateral globus pallidus hyperintensity in T2-weighted (T2W) and diffusion-weighted (DW) images and hypointensity in T1-weighted (T1W) images including diffusion restriction.\n\nConclusion\nAcute disulfiram poisoning can occur in children who have ingested large amount of drug because of unsafe storage. It can lead to hepatitis, encephalopathy, psychosis, optic, and peripheral neuropathy. Mainstay of treatment is supportive care, airway protection, oxygen, and dextrose-containing intravenous fluid should be given.\n\nClinical significance\nAcute disulfiram poisoning should be an important differential in diagnosis of any child presenting with idiopathic encephalopathy along with extrapyramidal symptoms with basal ganglia signal changes in MRI of brain in a previously healthy child.\n\nHow to cite this article\nBhalla K, Mittal K, Gupta A, Nehra D. Acute Disulfiram Poisoning in a Child: A Case Report and Review of Literature. Indian J Crit Care Med 2020;24(3):203–205.\n\nKeywords\nChildDisulfiramLiteraturePoisoningReview\n==== Body\nINTRODUCTION\nDisulfiram is an irreversible inhibitor of enzyme aldehyde dehydrogenase and has been used to treat alcohol dependence for a long time in past. Aldehyde dehydrogenase converts acetaldehyde to acetate. Drinking alcohol while taking disulfiram leads to elevated levels of acetaldehyde (product of alcohol metabolism) and precipitation of unpleasant aversive disulfiram–alcohol reaction. Symptoms of this reaction include diaphoresis, flushing, tachycardia, nausea, vomiting, palpitations, hypotension, etc. For these unpleasant symptoms, it is used in treatment of alcohol dependency. Disulfiram is commonly used in dosages of 250–500 mg/day.1 Although well tolerated by most patients, severe toxic side effects have also been reported including hepatitis, encephalopathy, psychosis, optic, and peripheral neuropathy.2 We are reporting a case of disulfiram toxicity in a 4.5-year girl who ingested 4–5 tablets of disulfiram (approximately 1–1.25 g) accidentally and presented with hypoglycemia and encephalopathy.\n\nCASE DESCRIPTION\nA 4.5-year-old female child was brought to pediatric emergency department with complain of recurrent vomiting, dizziness followed by loss of consciousness and tightness of body for last 12 hours. As told by parent, child had ingested 4–5 tablets of disulfiram accidentally 48 hours back. Her father was a chronic alcoholic and was prescribed this medication by a local doctor. On examination, the child was lethargic, pulse rate of 124 beats/minute with low volume and regular, respiratory rate 36/minute with respiratory distress in the form of use of accessory muscle of respiration. Chest auscultatory findings were normal. Per abdomen examination was normal without any organomegaly. The child was responsive to painful stimuli in the form of grimacing with eye opening. Pupil size was normal with pupillary and corneal reflexes preserved. Cranial nerve examination does not show any deficit although we could not perform all because the child was on minimal conscious state. Glasgow Coma Score was 7/15 (E2V2M3). Deep tendon reflexes were brisk and plantar extensor. Blood sugar was 12 mg/dL and was low despite dextrose infusion. Hemoglobin was 11.5 g/dL, total leukocyte count 13,000 with 66% polymorphs and 30% lymphocytes. Platelet count and peripheral smear was normal. Blood urea, creatinine, sodium, potassium, and calcium were normal. Coagulation profile was normal, and hepatic enzymes were elevated (AST 127 U/L and ALT 95 U/L). After initial stabilization in emergency room, the child was shifted to pediatric intensive care unit (ICU) where the child was managed initially with intravenous fluids, routine bed care for ICU, and subsequently intragastric (IG) feeds were started along with medications for prevention of gastroesophageal reflux disease. Blood sugars normalized after 8 hours of admission. Magnetic resonance imaging (MRI) brain showed bilateral globus pallidus hyperintensity in T2-weighted (T2W) and diffusion-weighted (DW) images and hypointensity in T1-weighted (T1W) images including diffusion restriction (Fig. 1). After 7 days, she was shifted in patient ward where she remained for 3 days and was discharged on request of the attendants on IG feed. Initially, the child came every third day for follow-up for removal of IG feeds for first 2 weeks. Subsequently, when the child did not come for follow-up, a telephonic call to attendants was made, and they informed that the child had died 7 days back at home during sleep at night.\n\nDISCUSSION\nDisulfiram poisoning in children is uncommon, can occur in children who have ingested large amount of drug because of careless and unsafe storage. Only few cases have been reported in literature. Safety and efficacy for children has not been determined.2 Acute toxicity can occur with dose higher than 500 mg/dL, and death can be possible at dose of 10–30 g/day.3 Symptoms of overdose include nausea, vomiting, pruritus, skin rash, headache, aggressive or psychotic behavior, drowsiness, coma, and ascending flaccid paralysis that can also involve cranial nerves.2,4 Vykuntaraju and Ramalingaiah reported basal ganglia infarct, encephalopathy and extrapyramidal features with globus pallidus and substantia nigra involvement in 2-year-old child.5 The exact mechanism of disulfiram-mediated encephalopathy is not known. Besides the inhibition of the acetaldehyde dehydrogenase, disulfiram also inhibits the brain dopamine β-hydroxylase to a similar degree and thereby augments dopamine and depletes norepinephrine concentrations. Dopamine-mediated cellular injury may be related to its ability to induce excitatoxic effects of glutamate, calcium-mediated cell death, and impairs the cellular ability to eliminate free oxygen radicals.3 Disulfiram and its metabolite diethyldithiocarbamate also inhibit cytochrome P450 2E1 enzyme.6\n\nA similar case was also reported by Mahajan et al., where a 5-year-old child accidentally ingested disulfiram and presented with neurologic manifestations of dystonia, complete loss of developmental milestones, and spastic tetraparesis.7 Our patient presented with hypoglycemia and encephalopathy 2 days after ingestion with raised hepatic enzymes. Hypoglycemia may be secondary to hepatic damage. No specific antidote is available for disulfiram toxicity. In acute disulfiram overdose, activated charcoal can be used, if available, and if the patient is alert and able to drink it safely. Mainstay of treatment is supportive care, airway protection, oxygen, and dextrose-containing intravenous fluid should be given.\n\nFig. 1 Magnetic resonance imaging brain showing bilateral globus pallidus hyperintensity in T2-weighted and diffusion-weighted images and hypointensity in T1-weighted images including diffusion restriction\n\nCONCLUSION\nAcute disulfiram poisoning should be an important differential in diagnosis of any child presenting with idiopathic encephalopathy along with extrapyramidal symptoms with basal ganglia signal changes in MRI of brain in a previously healthy child. Mainstay of treatment is supportive care, airway protection, oxygen, and dextrose-containing intravenous fluid should be given.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nREFERENCES\n1. Mohapatra S Rath NR. Disulfiram induced psychosis. Clin Psychopharmacol Neurosci 2017 15 1 68 69 DOI: 10.9758/cpn.2017.15.1.68 28138114 \n2. Treatment C for SA. Chapter 3-Disulfiram [Internet]. Substance Abuse and Mental Health Services Administration (US); 2009 [cited 2017 Nov 22]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK64036/ \n3. Petersen EN. The pharmacology and toxicology of disulfiram and its metabolites. Acta Psychiatr Scand Suppl 1992 369 7 13 DOI: 10.1111/j.1600-0447.1992.tb03309.x 1471556 \n4. Singh H Rahul Rao M Radha A Thyloth M. Disulfiram induced psychosis. J Addict Depend 2017 3 2 1 3 DOI: 10.15436/2471-061X-17-042 \n5. Vykuntaraju KN Ramalingaiah AH. Disulfiram poisoning causing acute encephalopathy. Indian Pediatr 2013 50 9 887 888 DOI: 10.1007/s13312-013-0222-x \n6. Kharasch ED Thummel KE Mhyre J Lillibridge JH. Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1. Clin Pharmacol Ther 1993 53 6 643 650 DOI: 10.1038/clpt.1993.85 8513656 \n7. Mahajan P Lieh-Lai MW Sarnaik A Kottamasu SR. Basal ganglia infarction in a child with disulfiram poisoning. Pediatrics 1997 99 4 605 608 DOI: 10.1542/peds.99.4.605 9093309\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0972-5229",
"issue": "24(3)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Child; Disulfiram; Literature; Poisoning; Review",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "203-205",
"pmc": null,
"pmid": "32435101",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "9093309;8513656;1471556;24096851;28138114",
"title": "Acute Disulfiram Poisoning in a Child: A Case Report and Review of Literature.",
"title_normalized": "acute disulfiram poisoning in a child a case report and review of literature"
} | [
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"companynumb": "IN-ALVOGEN-2020-ALVOGEN-108527",
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"activesubstancename": "DISULFIRAM"
},
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... |
{
"abstract": "Catheter ablation is an established treatment for atrial fibrillation (AF). The incidence of major complications related to the procedure is reported to be 4.5%, and delayed cardiac tamponade (DCT) is a rare, although recently recognized, complication. However, the mechanisms underlying the development of DCT remain unclear. We herein report the cases of two men, both 49 years of age, who developed cardiac tamponade requiring pericardiocentesis a few weeks after undergoing pulmonary vein isolation for persistent AF. Physicians should explain to the patient the potential for DCT as a complication prior to performing catheter ablation and provide careful follow-up for at least a few weeks after the session.",
"affiliations": "Department of Cardiology, Kyoto Min-iren Chuo Hospital, Japan.",
"authors": "Torihashi|Sadayoshi|S|;Shiraishi|Hirokazu|H|;Hamaoka|Tetsuro|T|;Imai|Mikimasa|M|;Kuroyanagi|Akira|A|;Nakanishi|Naohiko|N|;Nakamura|Takeshi|T|;Yamano|Tetsuhiro|T|;Matsumuro|Akiyoshi|A|;Shirayama|Takeshi|T|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.2537",
"fulltext": null,
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"issn_linking": "0918-2918",
"issue": "54(7)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000925:Anticoagulants; D001281:Atrial Fibrillation; D002305:Cardiac Tamponade; D017115:Catheter Ablation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010359:Patient Readmission; D020519:Pericardiocentesis; D010493:Pericarditis; D011667:Pulmonary Veins; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "791-6",
"pmc": null,
"pmid": "25832943",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of delayed cardiac tamponade due to pericarditis after pulmonary vein (PV) isolation for atrial fibrillation.",
"title_normalized": "two cases of delayed cardiac tamponade due to pericarditis after pulmonary vein pv isolation for atrial fibrillation"
} | [
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"companynumb": "JP-FRESENIUS KABI-FK201504440",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": nul... |
{
"abstract": "Sudden withdrawal of baclofen has been shown to provoke hallucinations. There has been no documented case showing hallucinations persisting during treatment over several years and responsive to subsequent reductions in dosage. Such a case is now reported. The chronicity of the symptoms originally suggested a psychotic illness, but this proved to be incorrect. The literature on baclofen toxicity is reviewed.",
"affiliations": null,
"authors": "Roy|C W|CW|;Wakefield|I R|IR|",
"chemical_list": "D001418:Baclofen",
"country": "England",
"delete": false,
"doi": "10.1038/sc.1986.45",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-1758",
"issue": "24(5)",
"journal": "Paraplegia",
"keywords": null,
"medline_ta": "Paraplegia",
"mesh_terms": "D000328:Adult; D001418:Baclofen; D003937:Diagnosis, Differential; D006212:Hallucinations; D006801:Humans; D008297:Male; D009128:Muscle Spasticity; D011618:Psychotic Disorders; D011782:Quadriplegia",
"nlm_unique_id": "2985038R",
"other_id": null,
"pages": "318-21",
"pmc": null,
"pmid": "3774369",
"pubdate": "1986-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Baclofen pseudopsychosis: case report.",
"title_normalized": "baclofen pseudopsychosis case report"
} | [
{
"companynumb": "GB-PFIZER INC-2018337931",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstancename": "PHENYTOIN"
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... |
{
"abstract": "Hypercalcaemia is a very common endocrine condition, yet severe hypercalcaemia as a result of fungal infection is rarely described. There are have only been two reported cases in the literature of hypercalcaemia associated with Cryptococcus infection. Although the mechanism of hypercalcaemia in these infections is not clear, it has been suggested that it could be driven by the extra-renal production of 1-alpha-hydroxylase by macrophages in granulomas. We describe the case of a 55-year-old woman with a 1,25-OH D-mediated refractory hypercalcaemia in the context of a Cryptococcus neoformans infection. She required treatment with antifungals, pamidronate, calcitonin, denosumab and high-dose glucocorticoids. A disseminated fungal infection should be suspected in immunosuppressed individuals presenting with hypercalcaemia.\nIn immunocompromised patients with unexplained hypercalcaemia, fungal infections should be considered as the differential diagnoses; Glucocorticoids may be considered to treat 1,25-OH D-driven hypercalcaemia; however, the benefits of lowering the calcium need to be balanced against the risk of exacerbating an underlying infection; Fluconazole might be an effective therapy for both treatment of the hypercalcaemia by lowering 1,25-OH D levels as well as of the fungal infection.",
"affiliations": "Department of Endocrinology, Austin Health, Victoria, Australia.;Department of Infectious Diseases, Austin Health, Victoria, Australia.;Liver Transplant Unit, Austin Health, Victoria, Australia.;Liver Transplant Unit, Austin Health, Victoria, Australia.;Department of Endocrinology, Austin Health, Victoria, Australia.",
"authors": "Zhu|Jasmine Jiang|JJ|;Naughton|William J|WJ|;Hay Be|Kim|K|;Ensor|Nicholas|N|;Cheung|Ada S|AS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573\nBioscientifica Ltd Bristol\n\n34110303\n10.1530/EDM-20-0186\nEDM200186\nAdult\nFemale\nAsian - Other\nAustralia\nBone\nMineral\nInsight into Disease Pathogenesis or Mechanism of Therapy\nInsight into Disease Pathogenesis or Mechanism of Therapy\nRefractory hypercalcaemia associated with disseminated Cryptococcus neoformans infection\nJ J Zhu and others\nHypercalcaemia in disseminated Cryptococcus\nZhu Jasmine Jiang 1\nNaughton William J 2\nHay Be Kim 3\nEnsor Nicholas 3\nCheung Ada S 14\n1 Department of Endocrinology, Austin Health, Victoria, Australia\n2 Department of Infectious Diseases, Austin Health, Victoria, Australia\n3 Liver Transplant Unit, Austin Health, Victoria, Australia\n4 Department of Medicine (Austin Health), The University of Melbourne, Victoria, Australia\nCorrespondence should be addressed to J J Zhu; Email: jasminejzhu@gmail.com\n10 5 2021\n2021\n2021 20-018610 11 2020\n10 5 2021\n© The authors\n2021\nThe authors\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..\nSummary\n\nHypercalcaemia is a very common endocrine condition, yet severe hypercalcaemia as a result of fungal infection is rarely described. There are have only been two reported cases in the literature of hypercalcaemia associated with Cryptococcus infection. Although the mechanism of hypercalcaemia in these infections is not clear, it has been suggested that it could be driven by the extra-renal production of 1-alpha-hydroxylase by macrophages in granulomas. We describe the case of a 55-year-old woman with a 1,25-OH D-mediated refractory hypercalcaemia in the context of a Cryptococcus neoformans infection. She required treatment with antifungals, pamidronate, calcitonin, denosumab and high-dose glucocorticoids. A disseminated fungal infection should be suspected in immunosuppressed individuals presenting with hypercalcaemia.\n\nLearning point\n\nIn immunocompromised patients with unexplained hypercalcaemia, fungal infections should be considered as the differential diagnoses;\n\nGlucocorticoids may be considered to treat 1,25-OH D-driven hypercalcaemia; however, the benefits of lowering the calcium need to be balanced against the risk of exacerbating an underlying infection;\n\nFluconazole might be an effective therapy for both treatment of the hypercalcaemia by lowering 1,25-OH D levels as well as of the fungal infection.\n\nPatient Demographics\n\nAdult\nFemale\nAsian - other\nAustralia\nClinical Overview\n\nBone\nMineral\nPublication Details\n\nInsight into disease pathogenesis or mechanism of therapy\nJune\n2021\n==== Body\nBackground\n\nHypercalcaemia is a very common endocrine condition, yet severe hypercalcaemia as a result of fungal infection is rarely described (1,2,3,4).\n\nCase presentation\n\nA 55-year-old woman of Polynesian descent was presented 6 weeks after her second liver transplant with tachycardia and rising inflammatory markers. She had a history of end-stage liver disease due to non-alcoholic steatohepatitis cirrhosis, type 2 diabetes mellitus, obesity, hypertension and recurrent perianal abscesses. Her first liver transplant 4 months prior had failed as a result of acute rejection, hepatic bilomas, recurrent Enterococcus faecium and Pseudomonas aeruginosa bacteraemia and cytomegalovirus viraemia. She was immunosuppressed with cyclosporine 275 mg and mycophenolate 1000 mg twice daily. Her other medications included aspirin 100 mg daily, cholecalciferol 25 mcg daily, sulfamethoxazole/trimethoprim 800/160 mg daily, enoxaparin 40 mg daily, entecavir 0.5 mg daily, valganciclovir 900 mg daily, pregabalin 25 mg twice daily and approximately 40 units of basal-bolus insulin daily. She was not taking any thiazide diuretics.\n\nA computed-tomography pulmonary angiogram revealed bilateral air space opacities (Fig. 1). Her Cryptococcus antigen titre was greater than 1 in 2560. Culture of bronchial washings demonstrated the growth of Cryptococcus neoformans. Figure 1 Bilateral scattered air space opacities demonstrated on a computer-tomography pulmonary angiogram.\n\nThe patient was commenced on induction therapy with i.v. liposomal amphotericin 300 mg daily and oral flucytosine 1 g twice daily. While on antifungal treatment, she developed invasive fungal skin lesions over her abdomen and thighs (Fig. 2) with biopsies demonstrating the growth of Cryptococcus neoformans. After 4 weeks, she transitioned to consolidation therapy with oral fluconazole 800 mg daily. Ten days later, the patient developed further skin lesions, raising concerns about disease progression and she recommenced i.v. liposomal amphotericin and oral flucytosine at the former doses. A fluorodeoxyglucose PET (FDG-PET) scan demonstrated findings in keeping with disseminated cryptococcosis, with FDG-avid lesions in the lungs as well as substantial s.c. and muscle tissue avidity (Fig. 3). Figure 2 Cutaneous cryptococcosis with ulcerated pustular lesions.\n\nFigure 3 FDG-PET demonstrating FDG-avid lesions in s.c. and muscle tissues of forearms, lower torso and lower limbs, and FDG-avid pulmonary nodules and right hilar lymphadenopathy.\n\nThree weeks after her presentation, she was noted to have elevated corrected calcium of 2.79 mmol/L (2.10–2.60). Her calcium concentrations were observed and continued to rise steadily. The patient was surprisingly asymptomatic from the hypercalcaemia. She remained alert and oriented and did not experience polyuria or polydipsia. Throughout her hospitalisation she remained ambulant, mobile and had consumed a regular diet without any nutritional or calcium supplementation.\n\nInvestigation\n\nFurther investigations when corrected calcium was 3.17 mmol/L demonstrated that the ionised calcium was 1.69 mmol/L (1.12–1.30), the parathyroid hormone 1.1 pmol/L (0.7–4.1), the thyroid stimulating hormone 4.96 mU/L (0.38–5.30), 25-hydroxy-vitamin D (25-OH D) 59 nmol/L and 1,25-dihydroxy-vitamin D (1,25-OH D) 219 pmol/L (50–190). The parathyroid hormone was measured on the Diasorin Liaison (1-84) assay which was subsequently found to report falsely high values at the lower end of the reference range. Her albumin was 35 g/L (35–52) and the estimated glomerular filtration rate was 61 mL/min/1.73 m2 (>90).\n\nTreatment\n\nAs the cause of her hypercalcaemia was not immediately apparent, she was observed for several days before treatment with 30 mg of i.v. pamidronate. Despite this, the corrected calcium continued to rise, peaking at 3.82 mmol/L. The patient received a 48 h course of i.v. calcitonin 100 mg 6 h followed by 60 mg of s.c. denosumab.\n\nOutcome and follow-up\n\nThe calcium slowly decreased but remained above 3 mmol/L. Two weeks later, the patient had a liver biopsy demonstrating acute liver rejection and was treated with i.v. pulse methylprednisolone. The calcium levels sharply declined and normalised within several days (Fig. 4). There were no granulomas on the skin or liver biopsies. Figure 4 Trajectory of hypercalcaemia. The patient received initial treatment with i.v. liposomal amphotericin (LAmB) and oral flucytosine (5-FC). The calcium levels continued to rise following a pamidronate infusion, and then subsequently lowered after commencing a course of calcitonin followed by denosumab while on fluconazole. The hypercalcaemia resolved after methylprednisolone was administered for acute rejection of the liver graft.\n\nShe was discharged to the rehabilitation unit 4 weeks later and then was discharged home following a further 4 weeks. She remains normocalcaemic and continues on oral antifungals for an ongoing lower limb cutaneous Cryptococcus infection.\n\nDiscussion\n\nHypercalcaemia mediated by 1,25-OH D has been described as a rare complication of fungal infections. There are only two case reports in the literature of hypercalcaemia associated with Cryptococcus neoformans infection (1,2). In both of these cases, the patients were infected with HIV and had a low CD4 lymphocyte count. Whilst the case described by Spindel had disseminated multiorgan Cryptococcus infection (1), Ali et al describe isolated pulmonary Cryptococcus neoformans and Coccidioides immitis infection (2). Both cases had an elevated 1,25-OH D and a peak corrected calcium in the range of 3.30–3.60 mmol/L. Hypercalcaemia was managed with i.v. fluids, antifungal treatment and one of the cases required i.v. pamidronate and hydrocortisone. Resolution of the hypercalcaemia coincided with the resolution of the Cryptococcus infection. Tuberculosis and lymphoma were excluded as alternative causes of hypercalcaemia.\n\nAlthough the mechanism of hypercalcaemia in these infections is not clear, the fact that 1,25-OH D levels were elevated in all three cases suggest that the hypercalcaemia could be at least partly driven by the extra-renal production of 1-alpha-hydroxylase by macrophages in granulomas (1,3). Indeed, Cryptococcus is known to induce a granulomatous response (5), and granulomas were found in the skin and liver biopsies of the case reported by Spindel (1). A review has suggested that 1,25-OH D may play a role in regulating immune function (4) so this pathway may become activated through adaptive mechanisms. However, there is no data to definitively support this theory.\n\nManagement of 1,25-OH D-driven hypercalcaemia includes the restriction of dietary calcium and sunlight exposure (4). Glucocorticoids inhibit 1-alpha-hydroxylase activity in macrophages as well as 1,25-OH D-mediated absorption of calcium from the gastrointestinal tract, and may also be given. However, the risks of exacerbating an underlying infection need to be carefully considered against the benefit of controlling hypercalcaemia. In our case, methylprednisolone was administered as it was essential for the survival of the liver graft and fortuitously resolved the hypercalcaemia.\n\nIn addition to its antifungal effects, fluconazole inhibits 25-hydroxylase and 1-alpha-hydroxylase, and its use in reducing 1,25-OH D levels in a patient with a CYP24A1 mutation has been described (6). In our case, the calcium levels dropped during fluconazole therapy, but this may have been confounded by concurrent calcitonin and denosumab therapy.\n\nIn summary, Cryptococcus neoformans is a rare cause of 1,25-OH D-mediated refractory hypercalcaemia which in our case required antifungal treatment, pamidronate, calcitonin, denosumab and high dose glucocorticoid treatment. Hypercalcaemia is a rare complication of disseminated fungal infection, which should be suspected in immunosuppressed individuals.\n\nDeclaration of interest\n\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\n\nASC is supported by a National Health and Medical Research Council of Australia Early Career Fellowship #1143333.\n\nPatient consent\n\nWritten consent has been obtained from the patient and is available upon request.\n\nAuthor contribution statement\n\nAll authors were involved in the clinical care of the patient and contributed to the writing of the manuscript.\n==== Refs\nReferences\n\n1 Spindel SJ Hamill RJ Georghiou PR Lacke CE Green LK Mallette LE 1995 Case report: vitamin D-mediated hypercalcemia in fungal infections. American Journal of the Medical Sciences 310 71–7 6. (10.1097/00000441-199508000-00007)\n2 Ali MY Gopal KV Llerena LA Taylor HC 1999 Hypercalcemia associated with infection by Cryptococcus neoformans and Coccidioides immitis. American Journal of the Medical Sciences 318 419–4 23. (10.1097/00000441-199912000-00010)\n3 Lionakis MS Samonis G Kontoyiannis DP 2008 Endocrine and metabolic manifestations of invasive fungal infections and systemic antifungal treatment. Mayo Clinic Proceedings 83 1046–10 60. (10.4065/83.9.1046)18775205\n4 Sharma OP 2000 Hypercalcemia in granulomatous disorders: a clinical review. Current Opinion in Pulmonary Medicine 6 442–44 7. (10.1097/00063198-200009000-00010)10958237\n5 Shibuya K Hirata A Omuta J Sugamata M Katori S Saito N Murata N Morita A Takahashi K Hasegawa C et al. 2005 Granuloma and cryptococcosis. Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy 11 115–1 22. (10.1007/s10156-005-0387-x)15990974\n6 Sayers J Hynes AM Srivastava S Dowen F Quinton R Datta HK Sayer JA 2015 Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole. Clinical Kidney Journal 8 453–45 5. (10.1093/ckj/sfv028)26251716\n\n",
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"title": "Refractory hypercalcaemia associated with disseminated Cryptococcus neoformans infection.",
"title_normalized": "refractory hypercalcaemia associated with disseminated cryptococcus neoformans infection"
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"abstract": "Use of nitrofurantoin for uncomplicated cystitis and recurrent urinary tract infections is common practice. While the majority of patients tolerate this medication without issue, it is important to be cognizant of adverse reactions, as these can impact patient's quality of life. Nitrofurantoin-induced pulmonary toxicity is a rare side effect that can present with various clinical manifestations, imaging abnormalities, and pathologic findings. We describe a case of chronic pneumonitis in a patient on suppressive nitrofurantoin therapy presenting with dyspnea and hypoxemia.",
"affiliations": "Internal Medicine, Brooke Army Medical Center, Fort Sam Houston, USA.;Department of Pulmonary and Critical Care Medicine, San Antonio Uniformed Services Health Education Consortium, Joint Base San Antonio-Fort Sam Houston, USA.",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9807\nInternal Medicine\nInfectious Disease\nPulmonology\nNitrofurantoin-Induced Pulmonary Toxicity: Always Review the Medication List\nMuacevic Alexander Adler John R Batzlaff Caitlin 1 Koroscil Matt 2 \n1 \nInternal Medicine, Brooke Army Medical Center, Fort Sam Houston, USA \n\n2 \nDepartment of Pulmonary and Critical Care Medicine, San Antonio Uniformed Services Health Education Consortium, Joint Base San Antonio-Fort Sam Houston, USA \n\nCaitlin Batzlaff caitlin.g.batzlaff.mil@mail.mil\n17 8 2020 \n8 2020 \n12 8 e980715 7 2020 14 8 2020 Copyright © 2020, Batzlaff et al.2020Batzlaff et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/35680-nitrofurantoin-induced-pulmonary-toxicity-always-review-the-medication-listUse of nitrofurantoin for uncomplicated cystitis and recurrent urinary tract infections is common practice. While the majority of patients tolerate this medication without issue, it is important to be cognizant of adverse reactions, as these can impact patient’s quality of life. Nitrofurantoin-induced pulmonary toxicity is a rare side effect that can present with various clinical manifestations, imaging abnormalities, and pathologic findings. We describe a case of chronic pneumonitis in a patient on suppressive nitrofurantoin therapy presenting with dyspnea and hypoxemia.\n\nnitrofurantointoxicitypulmonarydiffuse lung diseasedrug-induced lung diseasechronic dyspnea on exertionThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nNitrofurantoin is an oral antibiotic that functions to disrupt normal bacterial cellular function. It does this by altering ribosomes and subsequently changing protein synthesis, metabolism, and synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and the cell wall. Nitrofurantoin is also bactericidal in urine providing additional clearance of bacteria [1]. This leads to a limited resistance profile and overall mild “collateral damage” profile according to the Infectious Diseases Society of America [2]. For these reasons, it is recommended as first-line, empiric coverage for a patient presenting with acute uncomplicated cystitis. Its use is also commonly extrapolated for the prevention of recurrent urinary tract infections [3,4]. Recurrent urinary tract infections are defined as two or more infections in a six month period or three or more infections in a twelve-month period [3]. However, with prolonged use of nitrofurantoin, there have been reports of both pulmonary and hepatotoxicities [5].\n\nWhile nitrofurantoin-induced pulmonary toxicity is well known in the literature, it is not commonly included in the initial differential for chronic exertional dyspnea with hypoxemia. Here we describe a case of worsening chronic dyspnea in a patient on preventative nitrofurantoin therapy for recurrent urinary tract infections.\n\nCase presentation\nA 70-year-old female presented to the pulmonary clinic for repeat evaluation of chronic dyspnea on exertion. Her pertinent past medical history included obesity, obstructive sleep apnea, and non-obstructive coronary artery disease. Social history is notable for remote tobacco use with cessation at age 18. She had been seen for similar complaints approximately five years ago with a normal work up to include spirometry, six-minute oxygen desaturation test, chest X-ray, echocardiogram, left and right heart catheterization, and high-resolution CT chest (HRCT). At that time, she had a borderline positive methacholine-challenge test (noted to have a 28% reduction in forced expiratory volume in one second (FEV1) with the 16 mg dose of methacholine). She was trialed on inhaled corticosteroid therapy without improvement, as well as a short-acting β-agonist with subjective relief.\n\nIn February 2018, she presented to the emergency department with pre-syncopal symptoms, acute on chronic worsening of her dyspnea, and falls. The patient was afebrile and normotensive, but hypoxemic requiring supplemental oxygen via nasal cannula. Physical examination revealed bilateral fine crackles. CT pulmonary angiogram during admission revealed new diffuse peribronchovascular ground-glass opacities with sub pleural involvement, multiple perifissural nodules, and right hilar lymphadenopathy (Figure 1). \n\nFigure 1 CT imaging on presentation\nA) Coronal CT of the chest noting subpleural ground glass opacities (black arrow) and slight upper lobe predominance of ground glass opacities (red arrow). B) Coronal CT of chest noting peribronchovascular ground glass opacities (yellow arrow). C) Axial CT of chest demonstrating diffuse nodular ground glass opacities in a subpleural (blue arrows) distribution.\n\nThe pulmonology service was consulted during her admission and she underwent bronchoscopy with bronchoalveolar lavage (BAL) as well as transbronchial biopsies. BAL showed 43% lymphocytes, 16% polymorphonuclear neutrophils, 2% eosinophils. The cluster of differentiation (CD)4/CD8 ratio was ~1 (normal). She had negative bacterial and acid fast bacilli cultures on BAL. The patient had a respiratory polymerase chain reaction (PCR) panel which was negative for influenza A/B and other common respiratory pathogens including Mycoplasma pneumoniae and Chlamydia pneumoniae. Autoimmune serologic testing was negative. Her transbronchial biopsy showed normal alveolar tissue, thought to be a sampling error. The patient was not initiated on corticosteroid therapy. Prior to discharge, the patient failed an oxygen desaturation test (Table 1). She was discharged home in stable condition, with supplemental oxygen therapy, and outpatient pulmonary follow up.\n\nTable 1 Oxygen desaturation studies\nTime Frame\tSpO2 at rest on room air\tAmbulatory SpO2\tRequired O2 flow to maintain SpO2\t\n4 years prior to presentation\t96%\tNadir of 92%\tNo supplemental oxygen required \t\nOn discharge from hospital\t90%\tDropped to 88% after 3 minutes walked (total ambulation of 100 feet)\t2 liters/minute to achieve SpO2 92% in 2 minutes\t\nOn follow up, she provided interval history of recurrent urinary tract infections and chronic nitrofurantoin use. She had been on nitrofurantoin for approximately 15 months. She was given a working diagnosis of organizing pneumonia, a subset of interstitial lung disease. Nitrofurantoin was discontinued. Subsequent pulmonary function tests (PFTs) showed a greater than 10% improvement in DLCO that paralleled both symptomatic and radiographic improvement (Table 2).\n\nTable 2 Pulmonary function test results\nFVC: forced vital capacity; FEV1: forced expiratory volume in one second; TLC: total lung capacity; DLCO: carbon monoxide diffusing capacity.\n\nTime Frame\tFVC/%\tFEV1/%\tRatio\tTLC\tDLCO/% predicted\t\n3 months after presentation\t2.76/98\t2.23/105\t81\t4.36\t8.6/38\t\n9 months after presentation\t2.93/107\t2.23/108\t76\t3.60\t10.0/50\t\n14 months after presentation\t3.01/111\t2.40/117\t80\t4.61\t11.1/51\t\nSpecifically, follow up HRCT at three months and nine months demonstrated improvement in ground-glass opacities and a decrease in the size of perifissural nodules (Figures 2-3). She was instructed to avoid nitrofurantoin indefinitely to prevent further parenchymal damage.\n\nFigure 2 CT imaging three months after presentation\nCoronal CT chest imaging (A) and axial CT chest imaging (B) showing improvement of the upper lobe predominant peribronchovascular (red arrows) and subpleural nodular areas of consolidation and groundglass opacities (black arrows).\n\nFigure 3 CT imaging nine months after presentation\nCoronal CT chest imaging (A) and axial CT chest imaging (B) showing continued improvement of parenchymal disease with only subtle residual reticulations and very minimal groundglass (black arrow).\n\nDiscussion\nMost patients who present with pulmonary reactions to nitrofurantoin are women [6-8]. This inherently makes sense, as women are more likely to be diagnosed with urinary tract infections and be repeatedly exposed to the drug. Pulmonary adverse reactions are further classified based on acute versus chronic exposure. Acute adverse reactions are more common when compared to chronic [9]. Additionally women in their sixth and seventh decades of life more prone to developing each, respectively [7].\n\nAcute hypersensitivity pneumonitis presents on average 8.7 days after initiation of therapy according to a small case series [8]. Fever, dyspnea, and cough are common presenting symptoms. Objective findings include crackles on pulmonary auscultation, peripheral eosinophilia, leukocytosis, elevated erythrocyte sedimentation rate (ESR), and consolidation with pleural effusion(s) on chest X-ray [8,10]. Diagnosis is based on history, exclusion of infectious and other common cardiopulmonary diseases (heart failure, asthma, chronic obstructive pulmonary disease), and temporal relationship to nitrofurantoin. Treatment involves immediate cessation of nitrofurantoin, supportive care, appropriate documentation as an allergy, and instruction to avoid nitrofurantoin indefinitely as repeated exposure can elicit a faster and more robust reaction [8,11]. Additionally, while some literature suggest the use of glucocorticoids as an adjunct, their benefit has not been proven [6].\n\nChronic pneumonitis is most commonly observed in women in their seventh decade who are on long-term therapy [6]. Symptoms associated include dyspnea, dry cough, and fatigue. As previously discussed, fever is not commonly associated with chronic pneumonitis and its presence should prompt providers to search for alternate etiologies on presentation. The insidious onset of symptoms often leads to a lag in diagnosis, as demonstrated in this case, with the majority of patients being on long-term antibiotic therapy for over a year prior to the cessation of the offending agent [6,12].\n\nDiagnosis of chronic pneumonitis is based on history, consideration of other more common etiologies (hypersensitivity pneumonitis, sarcoidosis, rheumatologic disease, and other causes of interstitial lung disease), and clinical response after discontinuation of the offending agent. Physical exam findings are non-specific and can include inspiratory crackles, clubbing, +/- hypoxemia [6]. Imaging findings in chronic pneumonitis include most commonly a non-dominant pattern of bilateral ground-glass opacities versus less common bilateral asymmetric areas of consolidation with patchy ground-glass opacities versus rare honeycombing [6,10,13,14]. Of note, pleural effusions are uncommon in chronic pneumonitis as compared to acute hypersensitivity.\n\nChronic nitrofurantoin use is associated with a higher risk of parenchymal injury. In one retrospective, matched-cohort study of 13,421 participants. chronic nitrofurantoin therapy had an adjusted risk ratio of 1.53 (CI = 1.04-2.24) [15]. Unfortunately biopsy is not often performed prior to diagnosis and there is no pathognomonic finding for nitrofurantoin-induced lung injury [12,16]. Fortunately, severe toxicities are rather rare, occurring in one of 511 patients (0.2%; 95% CI <0.01% to 1.2%) when reviewing seventeen randomized controlled trials [9]. Clinical improvement typically is seen in weeks to months; however, a majority of patients will have some residual lung disease [6,14].\n\nConclusions\nNitrofurantoin is a bactericidal antibiotic that acts on multiple biochemical pathways of the bacterial cell. It is used as first-line, empiric therapy for uncomplicated cystitis as well as daily for prevention for recurrent urinary tract infections. Because of this, the majority of patients that will have an adverse event related to nitrofurantoin are women. Acute hypersensitivity typically presents around day eight or nine of exposure to the drug. It presents with fever, dyspnea, and cough. Labs and imaging display a peripheral eosinophilia, leukocytosis, elevated ESR, and consolidation with pleural effusion on chest X-ray. The backbone of treatment is the cessation of nitrofurantoin therapy. While acute reactions are more common, it is important to remain vigilant for chronic manifestations. When evaluating interstitial lung disease, a thorough medical history is paramount, as many pulmonary toxicities due to medications are reversible if identified early. Our patient’s history of progressively worsening dyspnea on exertion with concurrent, daily nitrofurantoin use fit with a diagnosis of chronic pneumonitis. Our patient demonstrated a peribronchovascular distribution likely consistent with organizing pneumonia, which has rarely been described in the literature. After undergoing extensive work up to rule out infectious, rheumatologic, and other cardiopulmonary disorders, she was diagnosed with nitrofurantoin-induced lung injury. Her nitrofurantoin was stopped and she had subjective improvement, as well as near-resolution of HRCT abnormalities.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Nitrofurantoin: drug information - Lexicomp 7 2020 2019 https://www.uptodate.com/contents/nitrofurantoin-drug-information \n2 International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases Clin Infect Dis Gupta K Hooton TM Naber KG 0 52 2011 \n3 Antibiotics for preventing recurrent urinary tract infection in non-pregnant women Cochrane Database Syst Rev Albert X Huertas I Pereiro I Sanfélix J Gosalbes V Perrotta C 2004 \n4 Management of urinary tract infections in adults N Engl J Med Stamm WE Hooton TM 1328 1334 328 1993 \n5 How common are pulmonary and hepatic adverse effects in older adults prescribed nitrofurantoin? J Am Geriatr Soc Claussen K Stocks E Bhat D Fish J Rubin CD 1316 1320 65 2017 28306135 \n6 Chronic nitrofurantoin-induced lung disease Mayo Clin Proc Mendez JL Nadrous HF Hartman TE Ryu JH 1298 1302 80 2005 16212142 \n7 Pulmonary reactions to nitrofurantoin. 447 cases reported to the Swedish Adverse Drug Reaction Committee 1966-1976 Eur J Respir Dis Holmberg L Boman G 180 189 62 1981 https://pubmed.ncbi.nlm.nih.gov/7308333/?from_single_result=Pulmonary+Reactions+to+Nitrofurantoin.+447+Cases+Reported+to+the+Swedish+Adverse+Drug+Reaction+Committee+1966-1976. 7308333 \n8 Nitrofurantoin-induced acute, subacute and chronic pulmonary reactions Scand J Respir Dis Sovijärvi AR Lemola M Stenius B Idänpään-Heikkilä J 41 50 58 1977 https://pubmed.ncbi.nlm.nih.gov/841294/ 841294 \n9 Nitrofurantoin's efficacy and safety as prophylaxis for urinary tract infections: a systematic review of the literature and meta-analysis of controlled trials Clin Microbiol Infect Muller AE Verhaegh EM Harbarth S Mouton JW Huttner A 355 362 23 2017 27542332 \n10 Pleural effusion: an uncommon manifestation of nitrofurantoin-induced pulmonary injury Respir Med Case Rep Davis JW Jones LS 65 67 19 2016 27625984 \n11 Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature J Infect Public Heal Kabbara WK Kordahi MC 309 313 8 2015 \n12 Nitrofurantoin-induced granulomatous interstitial pneumonia Int J Surg Pathol Sakata KK Larsen BT Boland JM Palen B Muhm JR Helmers RA Tazelaar HD 352 357 22 2014 23812013 \n13 Drug-associated organizing pneumonia: high-resolution CT findings in 9 patients J Thorac Imaging Dodd J Lee KS Johkoh T Müller M 22 26 21 2006 16538151 \n14 Unrecognized interstitial lung disease as a result of chronic nitrofurantoin use Drug Saf - Case Rep Rambaran KA Seifert CF 13 3 2016 27778245 \n15 Evaluation of the risk of nitrofurantoin lung injury and its efficacy in diminished kidney function in older adults in a large integrated healthcare system: a matched cohort study J Am Geriatr Soc Santos JM Batech M Pelter MA Deamer RL 798 805 64 2016 27100576 \n16 Nitrofurantoin pulmonary toxicity J Fam Pract Hainer BL White AA 817 823 13 1981 https://europepmc.org/article/med/7031172 7031172\n\n",
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"issue": "12(8)",
"journal": "Cureus",
"keywords": "chronic dyspnea on exertion; diffuse lung disease; drug-induced lung disease; nitrofurantoin; pulmonary; toxicity",
"medline_ta": "Cureus",
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"pubdate": "2020-08-17",
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"title": "Nitrofurantoin-Induced Pulmonary Toxicity: Always Review the Medication List.",
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"abstract": "Patients with advanced lung neuroendocrine neoplasms (NENs) have few treatment options. Capecitabine and temozolomide have recently showed significant activity in patients with pancreatic neuroendocrine tumors (NETs), but data in lung NETs are limited.\n\n\n\nWe retrospectively reviewed the records of patients treated at a large referral center to identify patients seen between January 2008 and September 2018 with metastatic lung NENs who received treatment with capecitabine and temozolomide (CAPTEM). Patients with small cell lung cancer were excluded. The primary endpoint was overall response rate per RECIST 1.1. Secondary endpoints included progression-free survival, overall survival, and toxicity.\n\n\n\nTwenty patients were identified who received treatment with capecitabine and temozolomide. Fourteen (70%) had typical lung NETs, five had (25%) atypical carcinoids, and one (5%) had disease defined as a large-cell neuroendocrine carcinoma. Nineteen patients were evaluable for response. Six (30%) patients exhibited a best response of partial response per RECIST 1.1 criteria, 11 (55%) stable disease, and 2 (10%) progressive disease; objective response rate was 30%, and disease control rate was 85%. Eleven patients eventually progressed, only six of whom exhibited progression per RECIST 1.1 criteria. Median progression-free survival was 13 months (95% confidence interval [CI], 4.4-21.6 months). Median overall survival was 68 months (95% CI, 35.3-100.7 months). Toxicity profile was mild with mainly grade 1, expected toxicities. Six patients required dose reduction because of toxicity.\n\n\n\nThe CAPTEM regimen is associated with a high response rate and a relatively tolerable toxicity profile in lung NENs. This regimen warrants further exploration in a prospective clinical trial.\n\n\n\nPatients with advanced lung neuroendocrine neoplasms have very few systemic treatment options. The capecitabine and temozolomide regimen has previously shown significant activity in patients with pancreatic neuroendocrine tumors (NETs) but has not been explored in metastatic lung NETs. This study showed that this regimen is associated with a high response rate (30%) and a relatively tolerable toxicity profile in this population.",
"affiliations": "Department of GI Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.;Department of Diagnostic Imaging, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.;Department of GI Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.",
"authors": "Al-Toubah|Taymeyah|T|0000-0003-1488-2414;Morse|Brian|B|;Strosberg|Jonathan|J|0000-0001-8405-218X",
"chemical_list": "D000069287:Capecitabine; D000077204:Temozolomide",
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"keywords": "Atypical carcinoid; Bronchial; Capecitabine; Lung; Neuroendocrine neoplasm; Neuroendocrine tumor; Temozolomide; Typical carcinoid",
"medline_ta": "Oncologist",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D012189:Retrospective Studies; D000077204:Temozolomide; D016896:Treatment Outcome",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "e48-e52",
"pmc": null,
"pmid": "31455747",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": "15084386;18473355;29891520;27552969;26291008;25218177;29055056;26703889;20824724;23969949",
"title": "Capecitabine and Temozolomide in Advanced Lung Neuroendocrine Neoplasms.",
"title_normalized": "capecitabine and temozolomide in advanced lung neuroendocrine neoplasms"
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"companynumb": "US-ZYDUS-048159",
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"abstract": "OBJECTIVE\nTo report on a patient with a symptomatic, polymicrobial Escherichia coli and multidrug-resistant (MDR), extended-spectrum β-lactamase (ESBL)-positive Klebsiella pneumoniae urinary tract infection (UTI) who was successfully treated with oral doxycycline hyclate.\n\n\nMETHODS\nA 70-year-old white male inpatient with a history of recurrent UTI, type 2 diabetes, hypertension, obesity, and diverticular disease was diagnosed with UTI and empirically treated with oral ciprofloxacin. Symptoms persisted 2 days later, and the patient was transitioned to amoxicillin/clavulanate by a different provider. The next day, upon receipt of the urine culture and susceptibility panel revealing E coli and MDR, ESBL-positive K pneumoniae infection, treatment was switched to doxycycline hyclate, which resulted in clinical improvement.\n\n\nCONCLUSIONS\nComplicated UTI involving multiple pathogens requires careful clinical judgment to select the appropriate antimicrobial agent, improve clinical outcomes, and prevent resistance. Treatment with doxycycline was based on the susceptibility panel and local resistance patterns. Advantages of doxycycline for UTI include its oral formulation, wide spectrum of activity, ability to achieve high concentration in the urine, and low toxicity.\n\n\nCONCLUSIONS\nDoxycycline hyclate may be an effective treatment option for patients with susceptible MDR UTI.",
"affiliations": "1 Husson University School of Pharmacy, Bangor, ME, USA.;2 VA Maine Healthcare System, Augusta, ME, USA.;1 Husson University School of Pharmacy, Bangor, ME, USA.;1 Husson University School of Pharmacy, Bangor, ME, USA.",
"authors": "White|Cassandra R|CR|;Jodlowski|Tomasz Z|TZ|;Atkins|Dylan T|DT|;Holland|Nicole G|NG|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190016642362",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "30(4)",
"journal": "Journal of pharmacy practice",
"keywords": "bacterial resistance; doxycycline; infectious disease; urology",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D004318:Doxycycline; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli; D006801:Humans; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D014552:Urinary Tract Infections",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "464-467",
"pmc": null,
"pmid": "27071978",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Doxycycline Therapy in a Patient With Escherichia coli and Multidrug-Resistant Klebsiella pneumoniae Urinary Tract Infection.",
"title_normalized": "successful doxycycline therapy in a patient with escherichia coli and multidrug resistant klebsiella pneumoniae urinary tract infection"
} | [
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"companynumb": "PHHY2017US121361",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM"
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"drugadditional... |
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"abstract": "Japanese spotted fever (JSF) is an uncommon but potentially fatal infection transmitted by tick bites. We herein report a fulminant case of JSF infection that occurred in an immunocompetent adult that was complicated by disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis (HLH). We discuss the difficulty in making the diagnosis and identifying the complication of HLH in our patient. HLH is a rare complication of rickettsiosis, and this is the first reported case in English of JSF complicated by HLH in an immunocompetent adult. Secondary HLH caused by rickettsiosis requires a different treatment from primary HLH. Rickettsiosis must therefore be considered in patients with HLH.",
"affiliations": "Department of General Internal Medicine, Akashi Medical Center, Japan.;Department of General Internal Medicine, Akashi Medical Center, Japan.;Department of General Internal Medicine, Akashi Medical Center, Japan.;Department of General Internal Medicine, Akashi Medical Center, Japan.;Department of General Internal Medicine, Akashi Medical Center, Japan.;Department of General Internal Medicine, Akashi Medical Center, Japan.",
"authors": "Kaneko|Masahiro|M|;Ishimaru|Naoto|N|;Nakajima|Takahiro|T|;Kanzawa|Yohei|Y|;Seto|Hiroyuki|H|;Kinami|Saori|S|",
"chemical_list": "D000977:Antiparasitic Agents",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.3631-19",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3164553210.2169/internalmedicine.3631-19Case ReportJapanese Spotted Fever with Hemophagocytic Lymphohistiocytosis Kaneko Masahiro 1Ishimaru Naoto 1Nakajima Takahiro 1Kanzawa Yohei 1Seto Hiroyuki 1Kinami Saori 1\n1 Department of General Internal Medicine, Akashi Medical Center, JapanCorrespondence to Dr. Masahiro Kaneko, qhnqj628@gmail.com\n\n24 10 2019 1 2 2020 59 3 445 451 7 7 2019 9 9 2019 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Japanese spotted fever (JSF) is an uncommon but potentially fatal infection transmitted by tick bites. We herein report a fulminant case of JSF infection that occurred in an immunocompetent adult that was complicated by disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis (HLH). We discuss the difficulty in making the diagnosis and identifying the complication of HLH in our patient. HLH is a rare complication of rickettsiosis, and this is the first reported case in English of JSF complicated by HLH in an immunocompetent adult. Secondary HLH caused by rickettsiosis requires a different treatment from primary HLH. Rickettsiosis must therefore be considered in patients with HLH. \n\nJapanese spotted feverrickettsiosishemophagocytic lymphohistiocytosis\n==== Body\nIntroduction\nJapanese spotted fever (JSF) is a rickettsial disease transmitted by tick bites in East Asia (1,2). Treatment of JSF and other forms of rickettsiosis is challenging because the diagnosis is difficult. The clinical diagnosis of JSF is similar to that of other types of rickettsiosis. A fever and rash with eschar are the most typical presentation, but eschar is not always present (3). In an endemic area, the differentiation of rashes from those of true rickettsiosis and those from a reactive symptom of common viral infections or those caused by drugs is very difficult. Serologic and genetic diagnostic methods have been developed for the definite diagnosis, but these can be time-consuming to perform or may not be routinely available (4). Clinicians must therefore often begin treatment without a definite diagnosis. Accordingly, at the initial presentation, 90% cases of rickettsiosis are misdiagnosed according to one retrospective study (5).\n\nThe statistics of the National Institute of Infectious Disease in Japan indicate that approximately 1% of cases of JSF are fatal (6). While the prognosis of JSF is generally not severe, fatal cases with severe complications, such as disseminated intravascular coagulation (DIC), acute respiratory distress syndrome, and multi-organ failure, have been reported (7,8). Avoiding these severe complications is therefore thought to be important during treatment of JSF.\n\nHemophagocytic lymphohistiocytosis (HLH) is a rare yet important complication of rickettsiosis (9). Primary and secondary HLH (sHLH) have been reported. Severe infection with extreme activation of cytokines is thought to be the cause of sHLH that develops in the course of rickettsiosis (10).\n\nCases of HLH as a complication in tsutsugamushi disease and Mediterranean spotted fever (MSF) have been reported (10,11). JSF with HLH as a complication, however, is rare (12). We herein report the first case of JSF to be complicated by HLH in an immunocompetent adult.\n\nCase Report\nA 71-year-old woman presented with a two-day history of a fever. Her body temperature was 38℃, and she had a rash. She had visited another clinic the day before admission to our hospital. She developed maculopapular rash in her trunk and extremities during intravenous fluid infusion (lactate Ringer's solution with 10 mg of metoclopramide) and was prescribed cefcapene, domperidone, rebamipide, esomeprazole, bifidobacterium, acetaminophen, and loxoprofen. No pustular formation was found, and the patient's palms and soles were intact.\n\nHer vital signs were body temperature 36.5℃, blood pressure 116/56 mmHg, pulse rate 79/min and respiratory rate 12/min. She had visited the Rokko Mountains, a known endemic area of JSF and tsutsugamushi disease, several times within the previous two weeks. Her general appearance was unremarkable, and no eschar was found. Drug-associated rash and viral infection were suspected, so only acetaminophen was continued for symptomatic relief. Later on the same day, she visited the emergency department again and requested a blood test (Table 1). Her vital signs were body temperature 38.8℃, blood pressure 122/58 mmHg, pulse rate 86/min, and respiratory rate 27/min. Only mild elevation of the values of aspartate aminotransferase (AST: 59 U/L) and C-reactive protein (CRP: 8.1 mg/dL) were found, and a follow-up visit was scheduled three days later.\n\nTable 1. Laboratory Data after Admission.\n\nDay\t\t1\t\t3\t\t4\t\t7\t\t8\t\t9\t\t10\t\nBlood count\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nHb [g/dL]\t\t11.1\t\t11.2\t\t11.4\t\t14.1\t\t12.9\t\t8.1\t\t10.5\t\nWBC [/μL]\t\t5,350\t\t4,850\t\t3,780\t\t19,790\t\t30,460\t\t27,460\t\t24,800\t\nSEG [%]\t\t\t\t\t\t\t\t51\t\t73\t\t54\t\t81\t\nSTAB [%]\t\t\t\t\t\t\t\t36\t\t20\t\t27\t\t11\t\nPlt [×104/μL]\t\t12\t\t7.5\t\t6.7\t\t2.7\t\t2.7\t\t2.6\t\t3.9\t\nBiochemistry\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nAlb [g/dL]\t\t3.4\t\t3.2\t\t2.8\t\t2.5\t\t1.8\t\t1.5\t\t1.9\t\nTbil [mg/dL]\t\t0.3\t\t0.5\t\t0.5\t\t3.8\t\t2.7\t\t2.8\t\t4.5\t\nCre [mg/dL]\t\t0.84\t\t0.87\t\t0.98\t\t3.01\t\t1.62\t\t1.68\t\t1.70\t\nALT [U/L]\t\t36\t\t43\t\t41\t\t131\t\t125\t\t3,830\t\t3,610\t\nAST [U/L]\t\t59\t\t64\t\t65\t\t350\t\t440\t\t25,220\t\t22,610\t\nγ-GTP [U/L]\t\t\t\t63\t\t60\t\t147\t\t82\t\t71\t\t115\t\nALP [U/L]\t\t217\t\t316\t\t298\t\t847\t\t689\t\t1,678\t\t3,140\t\nLDH [U/L]\t\t256\t\t373\t\t361\t\t1,082\t\t1,224\t\t18,660\t\t19,920\t\nCRP [mg/dL]\t\t8.1\t\t\t\t\t\t18.7\t\t11.8\t\t5.1\t\t7.2\t\nLactate [mmol/L]\t\t\t\t1.7\t\t\t\t8.6\t\t8.4\t\t18\t\t\t\nsIL-2R [U/mL]\t\t\t\t\t\t\t\t\t\t7,120\t\t\t\t\t\nFerritin [ng/mL]\t\t\t\t\t\t855\t\t\t\t\t\t\t\t\t\nCoagulation\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nPT [sec]\t\t12.8\t\t12.4\t\t\t\t19.7\t\t24.0\t\t180\t\t27.6\t\nPT-INR\t\t1.12\t\t1.08\t\t\t\t1.75\t\t2.15\t\t\t\t2.49\t\nAPTT [sec]\t\t32.9\t\t37.6\t\t\t\t62.7\t\t180\t\t101.7\t\t118\t\nFIB [mg/dL]\t\t\t\t\t\t\t\t172\t\t112\t\t30\t\t57\t\nFDP [μg/mL]\t\t\t\t\t\t\t\t149.9\t\t28.3\t\t13.1\t\t12.7\t\nAT3 [mg/dL]\t\t\t\t\t\t\t\t34.1\t\t34.9\t\t39.3\t\t\t\nHb: hemoglobin, WBC: white blood cell, SEG: segmented form neutrophil, STAB: band form neutrophil, Plt: platelet count, Alb: albumin, Tbil: total bilirubin, Cre: creatinine, ALT: alanine aminotransferase, AST: aspartate aminotransferase, γ-GTP: gamma-glutamyl transpeptidase, ALP: alkaline phosphatase, LDH: lactate dehydrogenase, CRP: C-reactive protein, sIL-2R: soluble interleukin-2 receptor, PT: prothrombin time, INR: international normalized ratio, APTT: activated partial thromboplastin time, FIB: fibrinogen, FDP: fibrin/fibrinogen degradation products, AT3: antithrombin III\n\nThe next day, the patient visited another hospital, as she had begun vomiting. Non-contrast chest and abdominal computed tomography was conducted to investigate the cause of the fever and vomiting, but there were no specific findings. She returned to our hospital due to severe appetite loss on day 3, one day before the scheduled appointment. She was able to eat small fruits and soft meals and could drink 500 to 1,000 mL of water every day. Her vital signs were a body temperature of 39℃, blood pressure 107/54 mmHg, pulse rate 70/min, and respiratory rate 20/min. Her rash was milder than two days before, and no petechiae or exanthema were found.\n\nLaboratory data showed hyponatremia, thrombocytopenia, and elevated values of AST (Table 1). She was hospitalized for a further evaluation. On day 4, her fever persisted, and her thrombocytopenia had worsened, with a platelet count of 6.7×104/μL with pseudo Pelger-Huët anomaly. To evaluate the possibility of myeloid leukemia, a bone marrow biopsy was performed, but there were no apparent blasts. On days 5 and 6, she remained febrile, but other vital signs were unchanged. On day 7, whole-body petechiae appeared, and thrombocytopenia progressed (Fig. 1, Table 1). Laboratory data showed a serum creatinine level of 3.01 mg/dL, total bilirubin 3.8 mg/dL, alanine aminotransferase (ALT) 131 U/L, platelet count 2.7×104/μL, prothrombin time 19.7 seconds, activated partial thromboplastin time 62.7 seconds, fibrinogen 171 mg/dL, and fibrin/fibrinogen degradation products 149.9 μg/mL. Acute kidney and liver failure and DIC were diagnosed.\n\nFigure 1. General petechiae and purpura. On day 7, petechiae and purpura developed on the whole-body surface. A and B show the feet, while C shows the trunk.\n\nHer blood pressure decreased to 80/50 mmHg with atrial fibrillation. It was early September, which is a highly endemic season of JSF in our area, so severe JSF was suspected. Minocycline and levofloxacin were started in accordance with a previous report of severe JSF (13). Bolus acetated Ringer's solution infusion was also started immediately for sepsis. Samples were sent to the Mahara Institute of Medical Acarology and Hyogo Prefectural Institute of Public Health Science for a serological analysis and polymerase chain reaction (PCR) analysis for Orientia tsutsugamushi (Ot), Rickettsia japonica (Rj), and severe fever with thrombocytopenia syndrome virus (SFTSV).\n\nHer respiratory status deteriorated during the first six hours after treatment started, and she was transferred to the intensive-care unit (ICU). Intubation was performed for progressive respiratory failure and shock. Noradrenalin up to 0.4/μg/kg/min was started for hypotension, followed by vasopressin (0.03 U/min) and glucocorticoid (hydrocortisone 200 mg/day) for septic shock unresponsive to catecholamine. Continuous hemodiafiltration was also started for anuria, and blood and platelet transfusion and anti-DIC agents (human anti-thrombin III agent and recombinant human soluble thrombomodulin alpha) were added for acutely progressive anemia, thrombocytopenia, and DIC. Despite the appropriate dosage of antibiotics and the maintenance of hydration, blood transfusion, ventilation, and hemodiafiltration, the patient's condition progressively deteriorated. She ultimately died five days (day 11) after admission to the ICU.\n\nThe results of outsourced samples were returned just before and after her death. Bone marrow aspirate showed hypocellularity and hemophagocytes (Fig. 2), and all other data (fever >38.5℃, minimum platelet count 2.6×104/μL, minimum hemoglobin concentration 8.1 g/dL, serum ferritin 855 ng/mL, and soluble interleukin (IL)-2 receptor 7,120 U/mL) were consistent with the diagnostic criteria of HLH (14). The PCR analysis for Rj was positive, and serologic testing for Rj, SFTSV, and Ot strains were all negative using the immunoperoxidase method, while only Rj was positive on an immunofluorescence assay (IgG and IgM titers on the day of ICU admission =1:80 and 1:80; IgG and IgM titers on the third day of care in the ICU =1:160 and 1:320, respectively). The final diagnosis was JSF complicated by DIC and HLH.\n\nFigure 2. Bone marrow aspiration smear of hemophagocytosis. A: Platelets and polynuclear neutrophils are phagocytosed by macrophages. B: Erythrocytes are phagocytosed by macrophages. C: Polynuclear neutrophils are phagocytosed by macrophages [May-Grünwald-Giemsa (MGG) stain; original magnification 1,000].\n\nDiscussion\nOur fatal case of JSF was difficult to diagnose at the initial presentation and was complicated by HLH. JSF is an uncommon disease but largely treatable with simple antibiotic therapy. It is a ‘must-not-miss’ differential diagnosis for clinicians working in an endemic area (2). Serologic or genomic diagnoses are often not rapidly available, and the definite diagnosis is commonly made four to five days after blood samples are collected. Theoretically, treatment should therefore be started when rickettsiosis is first suspected (15). According to a Japanese cohort study of Ot and Rj infection, being in an endemic area and the presence of a fever, rash, and eschar are the most common signs among patients with tsutsugamushi disease or JSF (3). Although eschar is thought to be the most specific sign for rickettsiosis, clinicians should be aware that about 10% of patients have no eschar (3). In our case, the lack of evidence of any tick bites delayed the initiation of treatment. To our knowledge, no studies have examined the factors underlying treatment delay of JSF or other rickettsiosis entities. The lack of eschar, however, has been proposed as an important factor influencing the delay in the initial diagnosis of rickettsiosis in some studies and has also been reported to be related to a poor prognosis (16-18). Our patient did not have severe physical or laboratory abnormalities at presentation, but the absence of eschar alone indicated a poor prognosis. Physicians should carefully follow patients, even without signs of eschar, and continue to search for such signs when rickettsiosis is suspected.\n\nIn the presently reported case, we began JSF-specific treatment seven days after the patient's first admission (eight days after the onset of symptoms). Treatment delay is thought to be one of the worst prognostic factors for rickettsiosis in general, and we believe that it contributed to the fatality in the present case (15). Several cohort studies that investigated prognostic factors of rickettsiosis, however, showed inconsistent data. For example, one cohort of patients with JSF showed a significant correlation between treatment delay and the disease severity (7), but another claimed that there was no such correlation (19). Two cohort studies targeting tsutsugamushi disease also showed no significant relationship between the severity and days from the symptom onset to the initiation of appropriate antibiotics (16,18), while another study concluded that the number of days from hospital admission to the initiation of treatment affected the disease prognosis (20). In a cohort of Rocky Mountain spotted fever (RMSF), the number of days from the symptom onset to doxycycline initiation was a significant factor influencing a fatal prognosis (21). Of note, these studies varied in sample size (n= 28 to 297), in their definitions of treatment delay (days from symptom onset to treatment or days from admission to treatment), and in outcomes (severity, development of complication, or death). Therefore, whether or not treatment delay is truly related to the prognosis of rickettsiosis remains controversial, and a further study is needed. In or near an endemic area, if patients present with a rash and fever without eschar, clinicians should consider beginning empiric therapy.\n\nWe initially treated this case as one of septic shock with DIC but eventually discovered it was complicated by HLH. HLH is classified as either primary or secondary according to the underlying etiology. Although we did not perform genetic testing for this patient, we made a clinical diagnosis of sHLH based on the patient's older age and obvious infectious trigger. The diagnosis of sHLH is still being debated, however, because the diagnostic criteria of HLH were compiled for primary pediatric HLH (22). Several modified criteria have been proposed, but this case met the HLH-2004 criteria, the most accepted criteria (14,23). Rickettsiosis was complicated by HLH in several reported cases, but in a patient with JSF, complication by HLH is rare. To our knowledge, only one case in a three-month-old infant has been reported in English (12). sHLH is not age-dependent but mainly occurs in older children and adults depending on the immunological background. The currently reported case is the first case of JSF complicated by HLH in an immunocompetent adult.\n\nThere is no standard therapy for sHLH because of the heterogenicity of the underlying diseases (14,22,23). HLH with rickettsiosis is a rare presentation, but several cases have been reported. A PubMed search of HLH cases with rickettsiosis showed 25 reports of rickettsiosis with sHLH (9-12,24-44). Twenty-seven cases were extracted from 15 of the reports (Table 2), and the other 10 (24-26,29,31,34,40,41,43,44) and several cases (9) were not used due to not matching the diagnostic criteria of HLH or a lack of detailed English information. The pathogens were mainly Ot, but other types of rickettsia were also reported (21 Ot, 4 R. conorii, 1 Rj, 1 Coxiella burnetii). The treatment strategies were mainly antibiotics. Twelve cases were treated with rickettsia-specific antibiotic therapy only (e.g. doxycycline, clarithromycin, or chloramphenicol), two cases were administered antibiotics with intravenous immunoglobulin (IVIG), eight were given antibiotics with systemic steroids with or without IVIG, two were given antibiotics with systemic steroid therapy and chemotherapy (etoposide, and/or cyclosporine), and the treatment was unknown in three cases. Twenty-three cases survived, and four died.\n\nTable 2. Clinical Characteristics, Therapy and Prognosis of 27 Cases of Rickettsiosis with HLH.\n\nreference\t\tage [years]\t\trickettsia\t\tS to T [days]\t\ttreatment\t\tprognosis\t\n(12)\t\t0\t\tRj\t\tunknown\t\tMINO, IVIG\t\tL\t\n(9)\t\t11\t\tCb\t\tunknown\t\tunknown\t\tL\t\n(9)\t\t3, 38\t\tRc\t\tunknown\t\tunknown\t\t2L\t\n(10)\t\t5\t\tRc\t\t5\t\tCPL, CLM\t\tL\t\n(27)\t\t5\t\tOt\t\t8\t\tDOXY\t\tL\t\n(28)\t\t58\t\tOt\t\t24\t\tDOXY\t\tL\t\n(28)\t\t37\t\tRc\t\t19\t\tDOXY\t\tL\t\n(30)\t\t0\t\tOt\t\t18\t\tDOXY, Blood, DEX\t\tD\t\n(32)\t\t16, 24, 33\t\tOt\t\tunknown\t\tCPL\t\t3L\t\n(33)\t\t0\t\tOt\t\t10\t\tIVIG, DOXY\t\tL\t\n(35)\t\t7, 7, 9\t\tOt\t\tunknown\t\tDOXY, AZM\t\t2L1D\t\n(36)\t\t34\t\tOt\t\t8\t\tMINO, DEX\t\tD\t\n(37)\t\t0\t\tOt\t\t8\t\tCLM, DEX, ETP\t\tL\t\n(38)\t\t9\t\tOt\t\tunknown\t\tROX, ETP, CyA, DEX, MTX, CPL\t\tL\t\n(39)\t\t22\t\tOt\t\t13\t\tDOXY\t\tL\t\n(42)\t\t0 to 11\t\tOt\t\tunknown\t\tDOXY, AZM, IVIG, Blood+/- mPSL\t\t5L1D\t\n(11)\t\t53\t\tOt\t\tunknown\t\tMINO\t\tL\t\nHLH: hemophagocytic lymphohistiocytosis, S to T: days from symptom onset to appropriate treatment initiation, Rc: Rickettsia conorii, Rj: Rickettsia japonica, Cb: Coxiella burnetii, Ot: Orientia tsutsugamushi, MINO: minocycline, IVIG: intravenous immunoglobulin, CPL: chloramphenicol, PSL: prednisolone, blood: blood product, DOXY: doxycycline, AZM: azithromycin, DEX: dexamethasone, ETP: etoposide, FOY: gabexate mesylate, ROX: roxithromycin, CLM: clarithromycin, CyA: cyclosporine, MTX: methotrexate, mPSL: methylprednisolone, D: death, L: alive\n\nIn our case, we used double antibiotics specific to Rj with systemic steroids. Chemotherapy was an option, but because the vital status of our patient was severely unstable, cytotoxic agents were withheld. Although our patient ultimately died, complication with sHLH per se is not an untreatable sign of rickettsiosis (25/29 survived). Most cases are cured by rickettsia-specific treatment only, and the clinical importance of sHLH in treatment of rickettsiosis is still unknown. In the present case, bicytopenia was controlled by blood transfusion, and we believe that the fatal course was mainly caused by sepsis and DIC induced by JSF. When clinicians detect HLH, it is important that they consider rickettsiosis and plan the treatment accordingly. There is no standard treatment for infection-induced sHLH, and only specific antimicrobial treatment is strongly recommended by the current expert consensus (23). Clinicians should therefore be aware that rickettsiosis is a ‘must-not-miss’ cause of sHLH.\n\nConclusion\nJSF is a rare but possible cause of sHLH. Clinicians should consider the possibility of rickettsiosis in patients with exposure to an endemic area and who have rashes but not eschar. Rickettsia-specific antibiotics are important for the treatment of rickettsiosis with sHLH.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe thank Doctor Hiromi Fujita at Mahara Institute of Medical Acarology, Akashi Health Center, and Hyogo Prefectural Institute of Public Health Science for performing the serologic and genomic analyses of rickettsiosis and SFTSV. We also thank Benjamin Phillis of the Akashi Medical Center for proofreading and editing the manuscript.\n==== Refs\n1. \nChung M-H , Lee S-H , Kim M-J , et al \nJapanese spotted fever, South Korea . Emerg Infect Dis \n12 : 1122 -1124 , 2006 .16836831 \n2. \nMahara F \nJapanese spotted fever: report of 31 cases and review of the literature . Emerg Infect Dis \n3 : 105 -111 , 1997 .9204291 \n3. \nSando E , Suzuki M , Katoh S , et al \nDistinguishing Japanese spotted fever and scrub typhus, central Japan, 2004-2015 . Emerg Infect Dis \n24 : 1633 -1641 , 2018 .30124190 \n4. \nKurokawa I , Kondo M , Akachi S \nEarly diagnosis of Japan spotted fever by PCR using skin samples . J Infect Chemother \n19 : 628 -632 , 2013 .23233083 \n5. \nLee N , Ip M , Wong B , et al \nRisk factors associated with life-threatening rickettsial infections . Am J Trop Med Hyg \n78 : 973 -978 , 2008 .18541779 \n6. National Institute of Infectious Diseases. INFECTIOUS AGENTS SURVEILLANCE REPORT: scrub typhus and Japanese spotted fever in Japan 2007-2016 [Internet]. [cited 2019 May 15]. Available from: https://www.niid.go.jp/niid/en/basic-science/865-iasr/7342-448te.html.\n7. \nKodama K , Senba T , Yamauchi H , Nomura T , Chikahira Y \nClinical study of Japanese spotted fever and its aggravating factors . J Infect Chemother \n9 : 83 -87 , 2003 .12673413 \n8. \nMiyashima Y , Iwamuro M , Shibata M , et al \nPrediction of disseminated intravascular coagulation by liver function tests in patients with Japanese spotted fever . Intern Med \n57 : 197 -202 , 2018 .29021432 \n9. \nLecronier M , Prendki V , Gerin M , et al \nQ fever and Mediterranean spotted fever associated with hemophagocytic syndrome: case study and literature review . Int J Infect Dis \n17 : e629 -e633 , 2013 .23402798 \n10. \nCascio A , Giordano S , Dones P , Venezia S , Iaria C , Ziino O \nHaemophagocytic syndrome and rickettsial diseases . J Med Microbiol \n60 (Pt 4 ): 537 -542 , 2011 .21163825 \n11. \nIwasaki H , Hashimoto K , Takada N , Nakayama T , Ueda T , Nakamura T \nFulminant Rickettsia tsutsugamushi infection associated with haemophagocytic syndrome . Lancet \n343 : 1236 , 1994 .7909908 \n12. \nOtsuki S , Iwamoto S , Azuma E , et al \nHemophagocytic lymphohistiocytosis due to Rickettsia japonica in a 3-month-old infant . J Pediatr Hematol Oncol \n37 : 627 -628 , 2015 .\n13. \nMahara F , Miyamoto K , Fujita H , Matsuda T \nClinical usefulness of combination therapy with minocycline and ciprofloxacin as a treatment for fulminant cases of Japanese spotted fever . Clinical Microbiology: Open Access \n3 : 1 -2 , 2014 .\n14. \nHenter J-I , Horne A , Aricó M , et al \nHLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis . Pediatr Blood Cancer \n48 : 124 -131 , 2007 .16937360 \n15. \nBennett JE , Dolin R , Blaser MJ \nMandell, Douglas, and Bennett's principles and practice of infectious diseases . 8th ed. \nElsevier/Saunders , Philadelphia, PA , 2015 : 2198 .\n16. \nLee CS , Hwang JH , Lee HB , Kwon KS \nRisk factors leading to fatal outcome in scrub typhus patients . Am J Trop Med Hyg \n81 : 484 -488 , 2009 .19706919 \n17. \nSousa R , Franca A , Doria Nobrega S , et al \nHost- and microbe-related risk factors for and pathophysiology of fatal Rickettsia conorii infection in Portuguese patients . J Infect Dis \n198 : 576 -585 , 2008 .18582199 \n18. \nKim DM , Kim SW , Choi SH , Yun NR \nClinical and laboratory findings associated with severe scrub typhus . BMC Infect Dis \n10 : 108 , 2010 .20433689 \n19. \nNakamura T , Takagaki K , Matsubara Y , Kikuchi K \nPredictive values of clinical parameters for severe Japanese spotted fever . J Infect Chemother \n17 : 246 -253 , 2011 .20827564 \n20. \nYasunaga H , Horiguchi H , Kuwabara K , Hashimoto H , Matsuda S \nDelay in tetracycline treatment increases the risk of complications in Tsutsugamushi disease: data from the Japanese Diagnosis Procedure Combination database . Intern Med \n50 : 37 -42 , 2011 .21212571 \n21. \nRegan JJ , Traeger MS , Humpherys D , et al \nRisk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011 . Clin Infect Dis \n60 : 1659 -1666 , 2015 .25697742 \n22. \nKleynberg RL , Schiller GJ \nSecondary hemophagocytic lymphohistiocytosis in adults: an update on diagnosis and therapy . Clin Adv Hematol Oncol \n10 : 726 -732 , 2012 .23271259 \n23. \nLa Rosée P , Horne A , Hines M , et al \nRecommendations for the management of hemophagocytic lymphohistiocytosis in adults . Blood \n133 : 2465 -2477 , 2019 .30992265 \n24. \nBertrand A-S , Fondain M , Rullier P , Fontaine C , Guillot B \nHaemophagocytic syndrome secondary to Mediterranean spotted fever . Ann Dermatol Venereol \n145 : 516 -520 , 2018 (in French, Abstract in English).30006110 \n25. \nIaria C , Colomba C , Di Carlo P , Scarlata F , Cascio A \nMurine typhus and hemophagocytic syndrome . J Pediatr Hematol Oncol \n40 : 493 -494 , 2018 .29683952 \n26. \nAnoun S , Traoue Y , Lahcen AO , Gamraoui K , Faez S , Oukkache B \nReactive hemophagocytic syndrome caused by Rickettsial infection: report of a case . Lab Hematol \n18 : 14 -16 , 2012 .22709789 \n27. \nJayakrishnan MP , Veny J , Feroze M \nRickettsial infection with hemophagocytosis . Trop Doct \n41 : 111 -112 , 2011 .21149571 \n28. \nPremaratna R , Williams HSA , Chandrasena TGAN , Rajapakse RPVJ , Kularatna SAM , de Silva HJ \nUnusual pancytopenia secondary to haemophagocytosis syndrome in rickettsioses . Trans R Soc Trop Med Hyg \n103 : 961 -963 , 2009 .19446860 \n29. \nPérez-de Pedro I , Macías-Vega N , Miranda-Candón I , Camps-García MT \nSevere Rickettsia conorii infection associated with hemophagocytic syndrome . Enferm Infecc Microbiol Clin \n26 : 597 -598 , 2008 .19100183 \n30. \nAgrwal S , Dabas A , Mantan M , Yadav S \nHemophagocytic lymphohistiocytosis with neurological manifestations in an infant with scrub typhus: a rare fatal occurrence . Trop Doct \n49 : 52 -53 , 2019 .30360694 \n31. \nNaoi T , Shimazaki H , Sawada M \nThe rapid effectiveness of minocycline against scrub typhus meningoencephalitis . Intern Med \n55 : 805 -809 , 2016 .27041169 \n32. \nZhou Y-H , Xia F-Q , Van Poucke S , Zheng M-H \nSuccessful treatment of scrub typhus-associated hemophagocytic lymphohistiocytosis with chloramphenicol . Medicine (Baltimore) \n95 : e2928 , 2016 .26937940 \n33. \nPazhaniyandi S , Lenin R , Sivathanu S \nHemophagocytic lymphohistiocytosis with a leukemoid reaction in an infant with scrub typhus . J Infect Public Health \n8 : 626 -629 , 2015 .26123173 \n34. \nHe S , Ge L , Jin Y , Huang A \nClinical analysis of scrub typhus-associated hemophagocytic syndrome . Zhonghua Er Ke Za Zhi \n52 : 683 -687 , 2014 (in Chinese, Abstract in English).25476431 \n35. \nSankhyan N , Saptharishi LG , Sasidaran K , Kanga A , Singhi SC \nClinical profile of scrub typhus in children and its association with hemophagocytic lymphohistiocytosis . Indian Pediatr \n51 : 651 -653 , 2014 .25129000 \n36. \nLin Y-H , Lin Y-H , Shi Z-Y \nA case report of scrub typhus-associated hemophagocytic syndrome and a review of literature . Jpn J Infect Dis \n67 : 115 -117 , 2014 .24647254 \n37. \nKwon HJ , Yoo IH , Lee J-W , et al \nLife-threatening scrub typhus with hemophagocytosis and acute respiratory distress syndrome in an infant . J Trop Pediatr \n59 : 67 -69 , 2013 .22735791 \n38. \nHan DK , Baek HJ , Shin M-G , Kim JW , Kook H , Hwang TJ \nScrub typhus-associated severe hemophagocytic lymphohistiocytosis with encephalomyelitis leading to permanent sequelae: a case report and review of the literature . J Pediatr Hematol Oncol \n34 : 531 -533 , 2012 .22627574 \n39. \nValsalan R , Kosaraju K , Sohanlal T , Prem Kumar P \nHemophagocytosis in scrub typhus . J Postgrad Med \n56 : 301 , 2010 .20935405 \n40. \nMiyakawa K , Ohsugi K , Sugahara S , Kuriyama C , Kikuchi A , Ohta M \n[Tsutsugamushi disease with hemophagocytosis complicated by Parvovirus B19 infection] . Nihon Naika Gakkai Zasshi \n95 : 2544 -2546 , 2006 (in Japanese).17240885 \n41. \nKobayashi T , Takizawa H , Hiroshima K , Uruma T , Enokihara H , Okuyama A \nA case of new type scrub typhus (tsutsugamushi disease) presenting with acute respiratory failure and hemophagocytic syndrome . Nihon Kyobu Shikkan Gakkai Zasshi \n30 : 447 -452 , 1992 (in Japanese, Abstract in English).1569724 \n42. \nJin Y , Huang L , Fan H , Lu G , Xu Y , Wu Z \nScrub typhus associated with hemophagocytic lymphohistiocytosis: a report of six pediatric patients . Exp Ther Med \n12 : 2729 -2734 , 2016 .27698778 \n43. \nChen YC , Chao TY , Chin JC \nScrub typhus-associated hemophagocytic syndrome . Infection \n28 : 178 -179 , 2000 .10879646 \n44. \nTakami A , Yamauchi H , Asakura H , Ishiyama K , Nakao S \nTsutsugamushi disease (scrub typhus)-associated hemophagocytic syndrome . Int J Hematol \n75 : 337 -338 , 2002 .11999368\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(3)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Japanese spotted fever; hemophagocytic lymphohistiocytosis; rickettsiosis",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000977:Antiparasitic Agents; D004211:Disseminated Intravascular Coagulation; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D051359:Lymphohistiocytosis, Hemophagocytic; D000073605:Spotted Fever Group Rickettsiosis; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "445-451",
"pmc": null,
"pmid": "31645532",
"pubdate": "2020-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29021432;30124190;19446860;16836831;21212571;17240885;26123173;23271259;22709789;23402798;11999368;23233083;20827564;27698778;24647254;9204291;25476431;26937940;7909908;12673413;30360694;18541779;27041169;25129000;16937360;20935405;26241724;18582199;30006110;10879646;21163825;29683952;1569724;30992265;19100183;22627574;20433689;22735791;21149571;25697742;19706919",
"title": "Japanese Spotted Fever with Hemophagocytic Lymphohistiocytosis.",
"title_normalized": "japanese spotted fever with hemophagocytic lymphohistiocytosis"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1227916",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
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... |
{
"abstract": "BACKGROUND\nLeft atrial ablation for atrial fibrillation (AF) is associated with a transiently increased risk of thromboembolic and hemorrhagic events. We tested the hypothesis that the low dose dabigatran [110mg twice a day (bid)] can be safely used as an alternative to uninterrupted acenocoumarol for periprocedural anticoagulation in left atrial ablation procedures.\n\n\nRESULTS\nA total of 149 consecutive patients undergoing pulmonary vein antral isolation for AF were included; 64 patients were on low dose dabigatran (110mg bid) and 85 patients were on acenocoumarol with therapeutic international normalized ratios. Two doses of dabigatran were withheld before the procedure and the drug was restarted 4hours after vascular hemostasis. Overall, the two groups were well-matched. Hemorrhagic and thromboembolic complications were similar in both groups within 90days from the procedure (4.7% for the dabigatran group versus 9.4% for the acenocoumarol group; P=0.275). Major hemorrhage occurred in 1.6% in the dabigatran group versus 3.5% in the acenocoumarol group (P=0.462). A single thromboembolic event occurred in the dabigatran group (1.6%) versus 2 (2.4%) in the acenocoumarol group (P=0.734). Despite higher doses of intraprocedural heparin (P<0.01), the mean activated clotting time was significantly lower in patients who were on dabigatran than those on acenocoumarol (P<0.01).\n\n\nCONCLUSIONS\nThe low dose dabigatran regimen provides safe and effective peri-procedural anticoagulation in patients undergoing left atrial ablation for AF compared with uninterrupted acenocoumarol therapy.",
"affiliations": "Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, \"Evangelismos\" General Hospital of Athens, Athens, Greece.;Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, \"Evangelismos\" General Hospital of Athens, Athens, Greece.;Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, \"Evangelismos\" General Hospital of Athens, Athens, Greece. Electronic address: k.letsas@mail.gr.;Department of Cardiology, Athens General Hospital \"G. Gennimatas,\", Athens, Greece.;Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, \"Evangelismos\" General Hospital of Athens, Athens, Greece.;Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, \"Evangelismos\" General Hospital of Athens, Athens, Greece.;Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, \"Evangelismos\" General Hospital of Athens, Athens, Greece.;Department of Cardiology, Athens General Hospital \"G. Gennimatas,\", Athens, Greece.;Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, \"Evangelismos\" General Hospital of Athens, Athens, Greece.",
"authors": "Efremidis|Michael|M|;Vlachos|Konstantinos|K|;Letsas|Konstantinos P|KP|;Giannopoulos|Georgios|G|;Lioni|Louiza|L|;Georgopoulos|Stamatis|S|;Vadiaka|Maria|M|;Deftereos|Spyridon|S|;Sideris|Antonios|A|",
"chemical_list": "D000925:Anticoagulants; D000069604:Dabigatran; D000074:Acenocoumarol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-0736",
"issue": "48(5)",
"journal": "Journal of electrocardiology",
"keywords": "Acenocoumarol; Atrial fibrillation; Catheter ablation; Dabigatran",
"medline_ta": "J Electrocardiol",
"mesh_terms": "D000074:Acenocoumarol; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019106:Postoperative Hemorrhage; D011292:Premedication; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "0153605",
"other_id": null,
"pages": "840-4",
"pmc": null,
"pmid": "26152604",
"pubdate": "2015",
"publication_types": "D018848:Controlled Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Low dose dabigatran versus uninterrupted acenocoumarol for peri-procedural anticoagulation in atrial fibrillation catheter ablation.",
"title_normalized": "low dose dabigatran versus uninterrupted acenocoumarol for peri procedural anticoagulation in atrial fibrillation catheter ablation"
} | [
{
"companynumb": "GR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-39134BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "We report a case of acute dystonia of the face, jaw and tongue caused by metoclopramide and mimicking angioedema. The patient had attacks for several years before the correct diagnosis was made and we present the first ever published video footage of an attack. This adverse drug reaction is known, but might be underdiagnosed since it can mimic a wide range of other diseases.",
"affiliations": "Department of Otorhinolaryngology Head and Neck Surgery, Koege Hospital, Koege, Denmark. eva.rye.rasmussen@dadlnet.dk",
"authors": "Rasmussen|Eva Rye|ER|;Pallesen|Kristine A U|KA|;Bygum|Anette|A|",
"chemical_list": "D018492:Dopamine Antagonists; D008787:Metoclopramide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000799:Angioedema; D018492:Dopamine Antagonists; D004421:Dystonia; D005260:Female; D006801:Humans; D008787:Metoclopramide; D008875:Middle Aged; D008881:Migraine Disorders; D014060:Tongue Diseases; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23836783",
"pubdate": "2013-07-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7059869;6382574;23060988;15888517;17054182",
"title": "Acute dystonia mimicking angioedema of the tongue: a video-illustrated case.",
"title_normalized": "acute dystonia mimicking angioedema of the tongue a video illustrated case"
} | [
{
"companynumb": "DK-WATSON-2014-23920",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nInhibitors of vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling, such as bevacizumab (Bmab), are used for the treatment of various advanced cancers. However, these inhibitors induce renal thrombotic microangiopathy (TMA). Recently, two European cohort studies showed a distinctive histopathological pseudothrombotic pattern different from TMA in Bmab-treated patients.\n\n\nMETHODS\nWe analyzed 9 renal biopsies from proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors in our Japanese cohort. Clinical and laboratory features were also assessed in these patients.\n\n\nRESULTS\nAll 9 patients had moderate to heavy proteinuria with normal or slightly elevated serum creatinine levels. On light microscopy, a patchy pattern of hemispherical/spherical lesions along glomerular capillary walls was a characteristic finding. On immunofluorescence microscopy, staining for immunoglobulins (IgM dominant) at varying intensities was observed mainly along glomerular capillary walls. Especially, hemispherical/spherical positive staining for immunoglobulins was a characteristic pattern. Immunohistochemical studies showed positive staining for immunoglobulins and negative staining for CD61-positive platelets in capillary hemispherical/spherical lesions and positive VEGF staining in podocytes. On electron microscopy, variably electron-dense material in dilated glomerular capillaries and partial effacement of podocyte foot processes were observed. After the withdrawal of VEGF-VEGFR2 inhibitors, proteinuria improved without any specific treatment in 8 patients.\n\n\nCONCLUSIONS\nHistopathological findings in our patients treated with VEGF-VEGFR2 inhibitors were consistent with those observed in the recently described new form of Bmab-associated hyaline occlusive glomerular microangiopathy. This form should be considered in proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors. Discontinuing VEGF-VEGFR2 inhibitors may lead to improvement of glomerular microangiopathy induced by these drugs.",
"affiliations": "Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Nephrology, Akita Kousei Medical Center, Akita, Japan.;Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Life Science, Graduate School of Engineering Science, Akita University, 1-1 Tegatagakuen-machi, Akita, 010-8502, Japan. wakui517@gipc.akita-u.ac.jp.;Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.",
"authors": "Ozawa|Masatoyo|M|;Ohtani|Hiroshi|H|;Komatsuda|Atsushi|A|;Wakui|Hideki|H|;Takahashi|Naoto|N|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-021-02090-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1342-1751",
"issue": "25(11)",
"journal": "Clinical and experimental nephrology",
"keywords": "Bevacizumab; Hyaline occlusive glomerular microangiopathy; Nephrotic syndrome; Onconephrology; Ramucirumab; Vascular endothelial growth factor",
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": null,
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "1193-1202",
"pmc": null,
"pmid": "34115234",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "25130034",
"title": "VEGF-VEGFR2 inhibitor-associated hyaline occlusive glomerular microangiopathy: a Japanese single-center experience.",
"title_normalized": "vegf vegfr2 inhibitor associated hyaline occlusive glomerular microangiopathy a japanese single center experience"
} | [
{
"companynumb": "JP-CHUGAI-2021025236",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "Pauci-immune necrotizing and crescentic glomerulonephritis (GN) is the most common etiology of rapidly progressive GN. Clinical presentation in those afflicted is usually related to rapid loss of kidney function. We report the case of a 70-year-old woman who came to medical attention for signs and symptoms related to lower-extremity deep vein thrombosis (DVT). At presentation, the patient had biochemical abnormalities consistent with active GN, which quickly progressed to rapid loss in kidney function requiring renal replacement therapy. Kidney biopsy revealed small-vessel vasculitis with glomerular crescents. Serologic studies were negative for antineutrophil cytoplasmic antibody antibodies and other causes of acute GN. Plasmapheresis, immunosuppressive, and anticoagulant therapies were prescribed. Absence of other apparent end-organ involvement with vasculitis pointed toward renal-limited small-vessel vasculitis, yet presence of unprovoked DVT argues for systemic vascular inflammation. This case illustrates that venous thrombosis can be the presenting manifestation in patients with vasculitis and silent, severe end-organ involvement. The epidemiology and pathophysiology of venous thromboembolism in small-vessel vasculitis are discussed in this report.",
"affiliations": "Wake Forest School of Medicine, Winston Salem, North Carolina, USA.;Department of Internal Medicine, Section of Nephrology, Baylor College of Medicine, Houston, Texas, USA.;Department of Pathology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.;Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.;Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.",
"authors": "Claudel|Sophie E|SE|;Tucker|Bryan M|BM|;Kleven|Daniel T|DT|;Pirkle|James L|JL|;Murea|Mariana|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ekir.2019.12.018",
"fulltext": "\n==== Front\nKidney Int Rep\nKidney Int Rep\nKidney International Reports\n2468-0249 Elsevier \n\nS2468-0249(20)30005-X\n10.1016/j.ekir.2019.12.018\nReview\nNarrative Review of Hypercoagulability in Small-Vessel Vasculitis\nClaudel Sophie E. sclaudel@wakehealth.edu1∗ Tucker Bryan M. 2 Kleven Daniel T. 3 Pirkle James L. Jr.4 Murea Mariana 4 1 Wake Forest School of Medicine, Winston Salem, North Carolina, USA\n2 Department of Internal Medicine, Section of Nephrology, Baylor College of Medicine, Houston, Texas, USA\n3 Department of Pathology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA\n4 Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA\n∗ Correspondence: Sophie E. Claudel, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1053. sclaudel@wakehealth.edu\n13 1 2020 \n5 2020 \n13 1 2020 \n5 5 586 599\n8 10 2019 3 12 2019 31 12 2019 © 2020 International Society of Nephrology. Published by Elsevier Inc.2020International Society of NephrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Pauci-immune necrotizing and crescentic glomerulonephritis (GN) is the most common etiology of rapidly progressive GN. Clinical presentation in those afflicted is usually related to rapid loss of kidney function. We report the case of a 70-year-old woman who came to medical attention for signs and symptoms related to lower-extremity deep vein thrombosis (DVT). At presentation, the patient had biochemical abnormalities consistent with active GN, which quickly progressed to rapid loss in kidney function requiring renal replacement therapy. Kidney biopsy revealed small-vessel vasculitis with glomerular crescents. Serologic studies were negative for antineutrophil cytoplasmic antibody antibodies and other causes of acute GN. Plasmapheresis, immunosuppressive, and anticoagulant therapies were prescribed. Absence of other apparent end-organ involvement with vasculitis pointed toward renal-limited small-vessel vasculitis, yet presence of unprovoked DVT argues for systemic vascular inflammation. This case illustrates that venous thrombosis can be the presenting manifestation in patients with vasculitis and silent, severe end-organ involvement. The epidemiology and pathophysiology of venous thromboembolism in small-vessel vasculitis are discussed in this report.\n\nKeywords\ncrescenticglomerulonephritishypercoagulationthrombosisvasculitis\n==== Body\nPauci-immune necrotizing and crescentic GN accounts for 60% to 80% of all cases of rapidly progressive GN.1 The histopathology is characterized by small-vessel fibrinoid necrosis, crescent formation affecting variable proportions of glomerular capillaries, little or no glomerular hypercellularity, and little or no deposition of immune complexes in the glomerular capillaries or interstitial arteriolar vessel walls.1,2 This pathology is most often attributed to a systemic, small-vessel, antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), as defined by the presence of circulating antineutrophil cytoplasmic antibodies (i.e., antimyeloperoxidase [anti-MPO] or anti-proteinase 3 [anti-PR3] antibodies).2 Although subcategorizations predominate (i.e., microscopic polyangiits, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis), patients often present with mixed features. Pauci-immune, ANCA-negative crescentic GN is a related entity, and the literature concerning clinical manifestations, prognosis, and comparative effectiveness of various treatment options is limited in this disorder.1\n\nSmall-vessel vasculitides commonly present with nonspecific symptoms of fatigue, weight loss, arthralgias, skin rash, changes in urine appearance or urine output, or—less commonly— hemoptysis suggestive of pulmonary-renal syndrome.3,4 Despite the well-documented link between AAV and increased incident venous thromboembolism (VTE), VTE is not a common presenting symptom in small-vessel vasculitis.5, 6, 7 Factors associated with incident VTE in AAV include the presence of PR3-positive ANCA, urinary red blood cell casts, pulmonary hemorrhage, and cardiac involvement.8 Across all cases of VTE, the overall percentage of unprovoked VTE attributable to vasculitis has not been well described. Epidemiologic studies have not discussed renal-limited vasculitis as an independent etiology of VTE,9 even in studies of autoimmune disorders.10,11 Moreover, the association between vasculitis and VTE has not been described in ANCA-negative vasculitis, likely because pauci-immune, ANCA-negative GN is poorly understood and generally understudied. In addition, a major limitation in the current literature regarding VTE in renal vasculitis is the lack of a clear pathophysiologic mechanism to explain the association. In this report we discuss a case of rapidly progressive, pauci-immune, ANCA-negative crescentic GN following presentation for an unprovoked DVT. We further discuss hypercoagulability in vasculitis, including the prevalence, possible mechanisms underlying its pathophysiology, and treatment challenges.\n\nCase Presentation\nA previously healthy 70-year-old woman presented to an outside hospital emergency department with complaints of left lower-extremity edema and pain. Initial Doppler ultrasound of the lower extremities was negative for DVT. Urinalysis showed hematuria and bacteriuria; therefore, the patient was discharged with cephalexin. Six days later, she presented again to the emergency department with worsening left lower extremity edema and was admitted to the hospital. A repeat venous Doppler ultrasound revealed extensive DVT involving the left common femoral vein, profunda femoris vein, superficial femoral vein (proximal and mid), with additional impaired compression but laminar flow seen in the left popliteal vein, posterior tibial vein, and peroneal vein. At the time of admission, a complete blood count showed a hemoglobin count of 12.1 g/dl; metabolic panel demonstrated serum creatinine (SCr) 4.5 mg/dl (baseline of 0.9 to 1.0 mg/dl), and blood urea nitrogen (BUN) 104 mg/dl (Table 1). Blood work obtained 1 month before the initial presentation showed SCr 1.19 mg/dl and BUN 18 mg/dl.Table 1 Laboratory data\n\nVariable\t38 d before admission (baseline)\t6 d before admission\tDay of admission, other hospital\tReference range, other hospital\tDay of admission, this hospitala\tReference range, this hospital\t\nSerum\t\t\t\t\t\t\t\nHemoglobin (g/dl)\t14.0\t13.4\t12.1\t12.0–15.0\t8.8\t12.0–16.0\t\nHematocrit (%)\t41.4\t40.2\t35.8\t36.0–46.0\t26.8\t37.0–47.0\t\nWhite cell count (per mm3)\t7800\t15,500\t16,700\t4500–10,500\t20,200\t4800–10,800\t\nDifferential (%)\t\t\t\t\t\t\t\n Neutrophils\t41\t69\t76\t\t84\t\t\n Lymphocytes\t25\t15\t6\t\t8\t\t\n Monocytes\t21\t13\t15\t\t8\t\t\n Eosinophils\t13\t2\t3\t\t0\t\t\n Basophils\t1\t1\t1\t\t0\t\t\nPlatelet count (per mm3)\t241,000\t218,000\t343,000\t150,000–400,000\t394,000\t160,000–360,000\t\nSodium (mmol/l)\t141\t134\t129\t135–146\t131\t135–146\t\nPotassium (mmol/l)\t4.7\t4.2\t4.5\t3.5–5.3\t3.6\t3.5–5.3\t\nUrea nitrogen (mg/dl)\t18\t16\t104\t8–24\t83\t8–24\t\nCreatinine (mg/dl)\t1.19\t1.06\t4.50\t0.50–1.10\t5.60\t0.50–1.50\t\nEstimated glomerular filtration rate (ml/min per 1.73 m2)\t46\t53\t9\t≥60\t7\t≥60\t\nAlanine aminotransferase (U/l)\t22\t15\t24\t5–50\t22\t5–50\t\nAspartate aminotransferase (U/l)\t30\t17\t34\t5–40\t24\t5–40\t\nAlkaline phosphatase (IU/l)\t67\t73\t130\t25–125\t\t\t\nProtein (g/dl)\t\t\t\t\t\t\t\n Total\t7.0\t7.0\t7.5\t6.0–8.3\t5.8\t6.0–8.3\t\n Albumin\t4.1\t4.0\t3.4\t3.5–5.0\t2.5\t3.5–5.0\t\nProthrombin time (sec)\t\t\t13.7\t11.6–15.2\t\t8.9–12.1\t\nInternational normalized ratio\t\t\t1.04\t0.00–1.49\t\t<5.00\t\nPartial thromboplastin time (sec)\t\t\t32.5\t24.0–37.0\t\t≤30\t\nUrine\t\t\t\t\t\t\t\nColor\t\tAmber\tAmber\tYellow\t\t\t\nClarity\t\tCloudy\tCloudy\tClear\t\t\t\nSpecific gravity\t\t1.016\t1.015\t1.005–1.030\t\t\t\npH\t\t5.0\t5.0\t5.0–8.0\t\t\t\nProtein (mg/dl)\t\t30\t30\tNegative\t\t\t\nWhite cells per high-power field\t\t12\t32\t0–3\t\t\t\nRed cells per high-power field\t\t>182\t>182\t0–3\t\t\t\nProtein-to-creatinine ratio (random, mg/g)\t\t\t2920.63\t0–200\t\t\t\nTo convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551.\n\nReference values are affected by many variables, including the patient population and the laboratory methods used.\n\na Twenty-one days after admission to other hospital.\n\n\n\nSystemic anticoagulation with heparin infusion for management of acute DVT was initiated. Renal function initially improved with administration of i.v. fluids and discontinuation of benazepril (Figure 1). Spot urine studies demonstrated sodium 56 mmol/liter, osmolality 448 mOsms/kg, protein/creatinine ratio of 2920 mg/g creatinine, and >182 red blood cells. Gross hematuria, present after placement of a urinary catheter, resolved early in the hospitalization and the patient had normal urine output. Within 48 hours of transitioning to rivaroxaban for long-term anticoagulation, SCr increased to 3.21 mg/dl, and international normalized ratio (INR) peaked at 4.51; therefore, rivaroxaban was discontinued, and i.v. heparin was restarted (Figure 1). Laboratory studies demonstrated persistent leukocytosis, although the patient remained afebrile, and the clinical examination, with additional workup, was negative for an infectious etiology. Computed tomography (CT) of the chest, abdomen, and pelvis with i.v. contrast was performed, redemonstrating evidence of DVT, bilateral pleural effusions, and no evidence of occult malignancy. Renal biopsy was performed on the 17th day of hospitalization, and the patient was transferred to a tertiary academic medical center on the 22nd hospital day for further management of acute renal failure.Figure 1 Serum creatinine (mg/dL) and blood urea nitrogen (mg/dL) by hospital day. Abbreviations: SCr, serum creatinine; BUN, blood urea nitrogen; PLEX, plasma exchange; HD, hemodialysis; WFBMC, Wake Forest Baptist Medical Center.\n\n\n\nRenal Biopsy Findings\nAn ultrasound-guided kidney biopsy was performed at the outside hospital on Day 17 of hospitalization (23 days after the initial presentation, 5 days before transfer to the tertiary medical center). Evaluation by light microscopy revealed that 27 of 52 glomeruli were involved with focal necrosis and/or crescent formation (Figure 2a and b); the unaffected portions of the glomeruli appeared normal, with no endocapillary or mesangial hypercellularity. Numerous tubular cross sections showed red cell casts (Figure 2c and d). There was mild edema with a mild lymphoplasmacytic interstitial infiltrate (Figure 2b and c). There was only mild interstitial fibrosis supporting the clinical findings of acute rather than chronic renal failure. The arteries showed mild arterial intimal expansion, and arterioles displayed mild hyalinosis; no arteritis was identified. Immunofluorescence staining on frozen tissue was negative for IgG, IgA, and complement C1q deposition in the glomerular, tubular, or interstitial compartment and showed mild-to-moderate IgM and complement C3 deposition within the glomerular mesangium (Figure 2f). Electron microscopy was not performed. Altogether, these findings showed evidence of a pauci-immune necrotizing and crescentic GN.Figure 2 (a) Periodic acid-Schiff staining at demonstrates glomerulus with a cellular crescent (upper left) adjacent to a normal appearing glomerulus. (b) and (c) Hematoxylin and eosin staining show cellular crescents, red blood cell casts, and mild tubulointerstitial edema and lymphoplasmacytic infiltrate. (d) Methenamine periodic acid-Schiff staining demonstrates cellular crescents and pooling of red blood cells in the Bowman’s space and renal tubules. Panel (e) Methenamine periodic acid-Schiff staining shows focal necrosis with destruction of the glomerular basement membrane. Panel (f) Direct immunofluorescence microscopy shows mild C3 deposition (1+) in the glomerular mesangium.\n\n\n\nOn the patient’s arrival at the tertiary care center, the patient’s chief complaint was worsening edema in the left lower extremity. Review of systems was negative for fever, cough, hemoptysis, fatigue, weight loss, night sweats, arthralgias, diarrhea, emesis, oral ulcerations, and rash. Past medical history included hypothyroidism; essential hypertension; pure hypercholesterolemia; and mild, intermittent asthma. She had never been treated with hormone-replacement therapy, and there was no history of pregnancy miscarriage. There was no family history of autoimmune disease, coagulation disorders, DVT, or malignancy. She did not smoke tobacco, drink alcohol, or use illicit drugs.\n\nOn physical examination, the patient appeared tired. Her temperature was 97.6 °F, pulse 88 beats per minute, blood pressure 147/81, respiratory rate 18, and oxygen saturation 94% while she was breathing ambient air. Weight was 87.8 kg, approximately 13 kg above baseline. The lungs had bibasilar coarse crackles. The left lower extremity demonstrated 3+ pitting edema to the thigh, whereas the right lower extremity demonstrated 2+ pitting edema to the mid-shin. There were no dermatologic findings, and the remainder of the examination was normal.\n\nLaboratory tests obtained for workup of acute renal failure are summarized in Table 2. SCr level peaked at 6.13 mg/dl on the 24th day of admission (30 days from initial presentation). Renal and urinary ultrasound with Doppler studies was negative for renal vein thrombosis, obstruction, and anatomic abnormalities.Table 2 Laboratory data for workup of renal failure\n\nSerum\tValue\tReference range\t\nAntinuclear antibody\t1:320, speckled\t<1:80\t\nAntiglomerular basement membrane antibody (U)\t<0.20\t<1.0\t\nAnti-MPO antibody (U)\t<0.20\t<0.40\t\nAnti-PR3 antibody (U)\t<0.20\t<0.40\t\nAntidouble stranded DNA antibody (Crithidia)\t13.5\t<30\t\nAnti-DNase B antibody (U/ml)\t<76\t0–300\t\nAntistreptolysin O antibody (IU/ml)\t<20\t0–530\t\nLupus anticoagulant\tNot detected\tNot detected\t\nCryoglobulin (% ppt)\tNegative\tNegative\t\nCreatinine kinase (IU/l)\t49\t30–223\t\nFree κ/λ ratio\t1.30\t0.26–1.65\t\nComplement C3 (mg/dl)\t177\t87–200\t\nComplement C4 (mg/dl)\t40\t19–52\t\nC-reactive protein (mg/l)\t322.8\t<3.0\t\nErythrocyte sedimentation rate (mm/h)\t89\t0–30\t\nSerum protein electrophoresis\tNo M-spike seen\t\t\nHepatitis panel\t\t\t\n Hepatitis B surface antibody\tNonreactive\tNonreactive\t\n Hepatitis B core antibody\tNonreactive\tNonreactive\t\n Hepatitis C antibody\tNonreactive\tNonreactive\t\n Hepatitis A IgG and IgM antibodies\tNonreactive\tNonreactive\t\n Hepatitis B surface antigen\tNonreactive\tNonreactive\t\nDisseminated intravascular coagulation panel\t\t\t\n International normalized ratio\t2.25\t<5.00\t\n Partial-thromboplastin time (sec)\t108.9\t≤30.0\t\n D-dimer (ng/ml FEU)\t1670\t190–500\t\n Fibrinogen (mg/dl)\t80\t180–363\t\nHypercoagulability workup\t\t\t\n Factor V Leiden mutation\tNot present\tNot present\t\n Factor II mutation\tNot present\tNot present\t\n Anticardiolipin IgA antibody\t<9.4\t<15.0\t\n Anticardiolipin IgG antibody\t<9.4\t<15.0\t\n Anticardiolipin IgM antibody\t<9.4\t<15.0\t\n Beta-2-glycoprotein IgG antibody (U/ml)\t<9.4\t<15.0\t\n Beta-2-glycoprotein IgM antibody (U/ml)\t<9.4\t<15.0\t\nReference values are affected by many variables, including the patient population and the laboratory methods used.\n\n\n\nTreatment and Outcome\nConsidering the diagnosis of small-vessel vasculitis with severe renal involvement, immunosuppressive therapy and plasma exchange were initiated. The patient was treated with pulse-dose i.v. methylprednisolone 500 mg/d for 3 consecutive days, followed by oral prednisone 60 mg daily, along with oral cyclophosphamide 1 mg/kg per day (75 mg daily). In light of severe renal dysfunction, 7 plasma-exchange treatments were prescribed over 14 days. Midway through the plasma-exchange treatment course, the patient underwent 1 session of hemodialysis. After 4 plasma-exchange treatments with albumin, the patient received alternating albumin and fresh frozen plasma replacement because of bleeding from her vascular access and labile heparin partial thromboplastin times (PTTs). In this case, the decision to initiate cyclophosphamide therapy was based on guidelines for pauci-immune crescentic GN12 and previous case reports of ANCA-negative patients,2,13 as most clinical trials include patients with detectable ANCA serology at diagnosis.14, 15, 16\n\nThe patient was discharged on hospital day 39, with SCr level of 1.86 mg/dl. Medications on discharge consisted of a tapering scale of prednisone to discontinuation over 24 weeks, oral cyclophosphamide for 4 to 6 months, with plans to continue maintenance immunosuppression with azathioprine 1.5 mg/kg per day for 24 months. Warfarin was selected for long-term anticoagulation. Three months after discharge, the patient had persistent lymphedema secondary to her DVT. Laboratory analysis showed SCr 1.40 mg/dl and BUN 22 mg/dl; urinalysis demonstrated hematuria (16 to 22 red blood cells), proteinuria (≥300 mg/dl), 31 to 40 white blood cells, and spot urine protein/creatinine ratio of 1151 mg/g creatinine (decreased from a peak of 2920 mg/g).\n\nDiscussion\nThis patient’s initial contact with medical care was motivated by lower extremity discomfort secondary to DVT. Subsequent workup led to the diagnosis of small-vessel vasculitis with negative ANCA serology and severe renal involvement. Clinical management of this patient raised key issues and gaps in the current understanding of ANCA-negative small-vessel vasculitis, which are discussed in the following section.\n\nAntineutrophil Cytoplasmic Antibody Negativity\nSome have advocated for the inclusion of ANCA-negative, pauci-immune crescentic GN in the spectrum of AAV,17 as it is possible that ANCA-negative vasculitis may simply represent a failure of current assay detection techniques.18,19 However, there is emerging evidence of a distinct pathophysiology. Several mechanisms for ANCA-negative, crescentic GN have been proposed linking non-ANCA antibodies to increased neutrophil activation in the glomerulus.1,20 Although the exact identity of these activating factors is unclear, several known inducers of neutrophil induction (e.g., autoantibodies to human lysosomal-associated membrane protein-2 and antiendothelial cell antibodies) have been implicated.21, 22, 23 Higher levels of neutrophil degranulation are seen in ANCA-negative, pauci-immune patients with GN compared with ANCA-positive patients,21 and an increased neutrophil presence in Bowman’s capsule results in more severe glomerular lesions.22 A competing hypothesis pointing to a defect in the alternative pathway of complement—leading to destructive accumulation of activated complement molecules in the glomerulus—has recently been proposed, although with less clinical correlation.24 Finally, macrophage cells that disrupt Bowman’s space in ANCA-associated GN may also play a role in ANCA-negative disease.25 In summary, the extent to which the pathology in ANCA-negative disease differs from ANCA-positive, crescentic GN remains under investigation, and molecular studies point toward mechanisms with overlapping neutrophil, complement, and macrophage dysregulation.\n\nSuperimposed Anticoagulant-Related Nephropathy\nGiven the temporal relationship between this patient’s worsening renal function, increasing INR, the predominance of red blood cells and red blood cell casts in the renal tubules on renal biopsy, and the administration of rivaroxaban, anticoagulant-related nephropathy was considered as a possible etiologic component of her deteriorating kidney function. Anticoagulant-related nephropathy was first described by Brodksy et al. (2009) in relation to administration of warfarin and has subsequently been redemonstrated with novel oral anticoagulants.26, 27, 28 It is more common in patients with underlying chronic kidney disease, and renal function can recover after discontinuation of the offending agent.29,30 In our case, the patient had no history of chronic kidney disease but had recently developed crescentic GN. Her renal function continued to decline after discontinuation of rivaroxaban, likely due to the ongoing small-vessel vasculitis. Although we attribute the findings of red cell casts to anticoagulation, it is unfortunately not possible to pinpoint the underlying etiology on histolopathology and therefore introduces the question of whether they may have been due to the vasculitis. The existing literature on red cell casts in AAV is focused primarily on urine sediment rather than renal histology,8,31 which limits our ability to address this question.\n\nHypercoagulability and the Prevalence of Venous Thromboembolism in Small-Vessel Vasculitis\nGiven the lack of available literature on pauci-immune, ANCA-negative crescentic GN, we focus our discussion primarily on evidence in AAV. Complications of hypercoagulability, such as DVT or pulmonary embolus, have been noted as extrarenal complications of AAV32 and are common in active disease.5,33,34 For example, Stassen et al. (2008) describe VTE incidence of 6.7 per 100 patient-years among patients with active AAV and 1.8 per 100 patient-years in patients with AAV in remission, which was significantly higher than the incidence of VTE in the general population of 0.3 per 100 patient-years.33 Importantly, there was no statistical difference in the distribution of classic VTE risk factors between patients with AAV who did and did not develop VTE in the follow-up period, and most patients had at least 1 traditional risk factor.33 Reports of incidence and prevalence of VTE in AAV offer large variations. In a 20-year population-based cohort, the hazard ratio for DVT in AAV was 6.25 (95% confidence interval, 1.16–33.60).7 Among AAV patients with no underlying coagulopathy or risk factors, VTE incidence was found to be 4.3 per 100 person-years by Weidner et al. (2006),32 versus 1.47 per 100 person-years described by Kang et al. (2018).35 Unfortunately, however, the concomitant presence of traditional VTE risk factors or hypercoagulable conditions is not always specified.8 For example, 1 patient in the Eisenberger et al. (2005) cohort had a pulmonary embolism approximately 3 weeks before development of microscopic polyangiitis, although it is not clear if there was a provoking factor.36 One of the earliest analyses of VTE in AAV by Merkel and colleagues (2005) described an incidence rate of 7 per 100 patient-years, although classic VTE risk factors were not specifically noted.37 Nonetheless, the majority of available evidence suggests increased risk of VTE in AAV, regardless of the subcategorization of disease (granulomatosis with polyangiitis, microscopic polyangiitis, etc.) or severity of disease.\n\nMost commonly, the reported embolic events in AAV are not the presenting feature of the disease but rather occur in the months after diagnosis.35,37 Similar to our case, exceptions to typical presentations have been previously reported. One report describes a patient presenting with intermittent fevers, night sweats, and abdominal pain who was found to have bilateral renal vein thrombosis and bilateral pulmonary emboli on admission.38 Serologic workup was positive for anti-myeloperoxidase antibodies (MPO), lupus anticoagulant, and anticardiolipin antibodies.38 Given the positive hypercoagulability workup, the unique contribution of AAV to the embolic events cannot be quantified in this case. This is consistent with the reported 8% prevalence of anticardiolipin antibody and lupus anticoagulant in primary systemic vasculitis.39\n\nIn contrast to classic AAV, hypercoagulability has not been described as a common feature of ANCA-negative, pauci-immune GN, nor has it been described as the presenting complaint in occult disease. Our patient had no known prothrombotic risk factors such as smoking, recent surgery, hormone-replacement therapy, trauma, malignancy, or immobilization, and she was up to date on her age-appropriate cancer screening. Serologic testing did not reveal an underlying hypercoagulable state, apart from nephrotic range proteinuria and associated hypoalbuminemia. Decreased serum albumin is positively associated with risk of VTE in nephrotic syndrome.40,41 The mechanism is presumed multifactorial, including compensatory hepatic hyperproduction of procoagulants (fibrinogen, factors V and VIII),42 decreased synthesis of natural anticoagulants (free protein S, antithrombin III),42 and impaired fibrinolysis, as albumin is a required cofactor for binding plasminogen to fibrin.43 The triad of hypoalbuminemia, hypercholesterolemia, and elevated fibrinogen in nephrotic syndrome further contribute to increased platelet aggregation42,43 and abnormal clot architecture.44 Although there was likely an element of concomitant anticoagulant-related nephropathy in this case, the improvement in kidney function in response to plasmapheresis therapy strongly suggested an underlying inflammatory process driven by circulating immune factors. Therefore, we conclude that the event of VTE in this case was likely related to the underlying systemic inflammatory process that led to renal decline, as otherwise hypothesized in ANCA-positive small-vessel vasculitis. Despite absence of other clinically apparent end-organ involvement with small-vessel vasculitis, the presence of DVT without other known prothrombotic factors argues for a systemic inflammatory and autoimmune condition rather than renal-limited small-vessel vasculitis.\n\nPathophysiology of Hypercoagulability in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis\nThromboembolic disease has also been increasingly recognized as a common complication in other vasculitides. The hierarchy of VTE risk among various autoimmune and vasculitis disorders has been described by several investigators.5,45, 46, 47 With the exception of Behçet disease, in which venous thrombosis is the most common vascular manifestations,34,46 the incidence of VTE in AAV appears to be higher than in other autoimmune, inflammatory conditions such as systemic lupus erythematosus, rheumatoid arthritis, or polyarteritis nodosa, suggesting a novel pathway.5,37,48 Several mechanisms have been proposed to underlie the pathophysiology of VTE in systemic inflammatory conditions of vasculitis and autoimmune disease. Figure 3 summarizes putative pathways linking inflammation and disordered immune system with development of VTE and the clinical data are summarized in Table 3.40,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 The proposed mechanisms, not mutually exclusive, perturb the elements of Virchow’s triad classically used to explain the pathophysiology of VTE: blood flow, endogenous constituents of anti- and prothrombosis, and the vessel wall.63,64 Central to the model for the development of VTE in vasculitis and autoimmune diseases is endothelial cell injury, which triggers a cascade of molecular factors that interconnect the immune and coagulation systems as summarized here.• Neutrophils are primed by proinflammatory factors, activated, and interact with endothelial cells. Proposed priming factors include granulocyte-mediated colony stimulating factor (GM-CSF),53 complement 5a (C5a),53,65 and tissue factor (TF).53 Tissue necrosis factor alpha (TNFα) was initially favored to be a key mediator;56 however, ex vivo experiments using TNFα inhibitors did not result in decreased neutrophil priming.53,55 In comparison, inhibiting C5a did prevent neutrophil priming and the downstream effects.53 In AAV, primed neutrophils are thought to be primarily activated by serum ANCAs,56,66 although additional neutrophil activators may also be involved.21,57,67 The activated neutrophils interact with the endothelial cells with consequent oxidative stress, increased expression of adhesion molecules, and further recruitment of leukocytes and platelets.55,68 Disruption of the vascular endothelium creates a microenvironment that promotes thrombosis and increases vascular wall permeability. Thrombogenic TF is released from the activated endothelial cells and exposed subendothelial matrix.69\n\n• Primed, activated TF-positive54\nneutrophils degranulate and release reactive oxygen species, TF-positive microparticles (MPs),52,53,55\nand TF-positive neutrophil extracellular trap (NET) molecules,66\nwhich activate the coagulation cascade.53,60 A detailed review of NET formation can be found in Laridan et al. (2019).70 Briefly, upon activation, the neutrophils release chromatin and other nuclear, cytoplasmic, and granular proteins in the extracellular space that encompass the NET molecular network. Both MPs and NETs precipitate the development of clots via expression of TF55 and are capable of promoting thrombin formation.53 The exposed nucleosomes that compose NETs70,71 allow for platelet, red blood cell, and plasma protein adherence, as well as clot stabilization through thrombin-dependent fibrin formation.62,71 NETs additionally cause direct endothelial damage, which is independently prothrombotic.65,68 Patients with AAV demonstrate increased coagulation cascade activity via elevated fibrin turnover,60 thrombin,60 D-dimer,58,60 thrombin antithrombin complexes,53 and fibrin degradation products.58 NETs also stimulate increased ANCA production via dendritic cell activation of autoreactive T helper and B cells, which feeds back into neutrophil activation.61,72\n\n• Inhibition of fibrinolysis. Plasminogen has been described as an autoantigen in PR3-positive small-vessel vasculitis, and its interaction with autoantibodies directed toward complementary PR3, a protein encoded by the antisense RNA of the PR3 gene, is able to block conversion to plasmin.73 Antiplasminogen antibodies have been detected in up to 26% of patients with MPO-positive and PR3-positive vasculitis, whereas only present in 2% of the control population. Antitissue plasminogen activator (tPA) antibodies were also detected in nearly 20% of patients with AAV and more commonly in patients with coexisting antiplasminogen antibodies. Functional in vitro studies showed that antiplasminogen and anti-tPA antibodies retarded fibrinolysis.49 In some studies, circulating antiplasminogen antibodies were associated with systemic and renal disease activity of AAV.49,50 Although antiplasminogen antibodies are not alone sufficient to cause a thrombotic event, they may contribute to the prothrombotic environment critical to clot formation and propagation.73\n\nFigure 3 Schematic representation of select potential mechanisms that promote thrombosis in vasculitis and autoimmune disease. Primed, activated neutrophils interact with endothelial cells, with consequent endothelial damage, production of reactive oxygen species, and release of proinflammatory cytokines and chemokines. Dysfunctional endothelial cells, activated from the oxidative stress, express adhesion receptors with further recruitment of leukocytes and platelets; and expose subendothelial tissue factor, which initiates the extrinsic coagulation pathway. Interactions between activated endothelial cells and platelets with neutrophils result in the formation of intact and fragmented neutrophil extracellular trap (NET) networks in vascular beds. The externalized histones within NETs promote the propagation of intravascular blood coagulation, von Willebrand factor binding, and platelet adhesion and activation, which amplifies thrombosis. Antiplasminogen and antitissue plasminogen activator antibodies inhibit the process of fibrinolysis, thereby supporting the propagation of blood coagulation, rather than triggering its initiation. Overall, the neutrophils, endothelial cells, NETs and circulating antibodies likely operate in concert to initiate, enhance and propagate blood clot formation.\n\nTable 3 Summary of existing literature pertaining to the pathophysiology of AAV and VTE\n\nReference\tStudy description\tEx vivo or serologic findings\tConclusions\t\nBerden et al. (2010)49\tAssessment of prevalence and function of anti-plasminogen antibodies in two populations of patients with AAV (UK n = 74; Dutch n = 38)\tAntiplasminogen antibodies present in 25% of both AAV cohorts (vs. 2% in controls). In the UK cohort, 24% of the antiplasminogen antibodies delayed fibrinolysis (vs. none of the controls), with a mean delay of 5.2 minutes (SD 2.8).\tAntiplasminogen antibodies and anti-tPA antibodies are more prevalent in AAV and can delay fibrinolysis. These antibodies were also associated with higher percentages of fibrinoid necrosis and cellular crescents, as well as worse renal function.\t\nHao et al. (2013)50\tDetection of antiplasminogen antibodies during active disease and remission in patients with AAV (n = 104)\tAntiplasminogen antibodies were detected in 18.3% of patients with AAV (vs. none of controls). Presence of antiplasminogen antibodies correlated with higher levels of ESR, creatinine, and CRP. Antibody positive patients had higher BVAS.\tPresence of circulating anti-plasminogen antibodies is associated with both active systemic and renal disease in patients with AAV.\t\nHilhorst et al. (2013)51\tAssessment of the risk of hypercoagulability in patients with AAV in remission and no recent VTE (n = 31)\tEndogenous thrombin potential was elevated in patients compared with matched controls (137% vs. 90%). Factor VIII was also elevated (159% vs. 137%), as was tissue factor pathway inhibitor (122% vs. 101%).\tPatients with AAV in remission demonstrate elevated coagulability, which may be due to persistent endothelial dysfunction and may partially explain the elevated risk of VTE.\t\nHong et al. (2012)52\tInvestigation of the role of ANCAs and neutrophil microparticles in children with AAV (n = 9)\tANCAs stimulate the release of neutrophil microparticles from primed neutrophils. The microparticles increase production and release of ROS, IL-6, IL-8, and thrombin. Patients with AAV had higher levels of circulating microparticles than inactive disease (642 x 103/ml vs. 237 x 103/ml) or controls.\tThe interaction of ANCAs with primed neutrophils generates a proinflammatory and prothrombotic environment through the release of neutrophil microparticles and their downstream effects.\t\nHuang et al. (2015)53\tInvestigation of the role of C5a priming in the pathway between ANCA stimulation and the generation of microparticles and NETs in patients with AAV (n = 11)\tNeutrophils primed with C5a released more TF-positive microparticles and NETs after ANCA activation than those primed with a positive control. The TF-positive NETs can generate thrombin and TAT complexes.\tC5a mediates the activation of the coagulation system in AAV via neutrophil activation.\t\nKambas et al. (2012)54\tInvestigation of the inclusion of TF in NETosis and its role in hypercoagulability in patients with sepsis (n = 8)\tNeutrophils release TF to NETs via autophagy. This TF stimulates generation of thrombin and subsequent PAR-1 signaling to activate the coagulation cascade.\tNeutrophil derived TF co-localized in NETs may explain the prothrombotic state in sepsis.\t\nKambas et al. (2014)55\tInvestigation of TF expression and neutrophil dynamics in patients with AAV (n =17)\tRenal biopsies demonstrate TF-positive NETs. Elevated circulating DNA and TF expressing neutrophil microparticles are correlated with disease activity.\tHypercoagulability in AAV may be due to the thrombotic potential of circulating neutrophil microparticles expressing TF and/or the downstream activation of the coagulation cascade.\t\nKessenbrock et al. (2009)56\tAssessment of the role of NETs in small-vessel vasculitis (n =12)\tANCAs activate neutrophil nuclei to induce NETosis. Both PR3 and MPO colocalize within the NET. Renal biopsies of small-vessel vasculitis also demonstrate proximity of NET components and IFNα to neutrophil infiltrates in pathologic glomeruli. Serum IFNα and circulating MPO-DNA are elevated in patients with active disease and absent in controls.\tNETosis is present in small-vessel vasculitis and is stimulated by ANCAs. NET formation was not observed in healthy controls or controls with multiple sclerosis, suggesting the specific auto-antigenicity of ANCAs in small-vessel vasculitis.\t\nKraaij et al. (2018)57\tInvestigation of NET formation in patients with MPO- and PR3-positive AAV (n = 99)\tIncreased NET formation is present in both MPO- and PR3-positive patients compared with controls. However, it does not correlate to serum ANCA levels. NETosis is higher in active disease/relapse than remission, infection, or healthy controls.\tNETosis is independent of ANCA (either MPO or PR3) but related to disease activity in patients with AAV.\t\nMa et al. (2014)58\tAnalysis of coagulation profiles in a prospective cohort of patients with AAV (n = 399)\t4% of patients with active disease developed VTE (vs. none in remission). Compared with those in remission, patients with active AAV had higher levels of serum D-dimer (0.8 mg/L [0.4, 1.5] vs. 0.28 mg/L [0.2, 0.55]), fibrin-degradation products (5.6 mg/L [5.0, 10.0] vs. 1.9 mg/L [1.2, 2.8]), and platelets (269 ± 127 x 109 /L vs. 227 ± 80 x 109 /L)\tHypercoagulability in active disease states of AAV may be due to abnormal fibrinolysis.\t\nMendoza et al. (2019)40\tProspective cohort analysis of incident VTE, microparticle tissue factor activity (MPTFa), and anti-plasminogen antibodies in patients with AAV in remission (n = 41)\t29.3% of patients developed VTE during the study period. Patients who developed VTE have higher mean peak MPTFa than controls (14.0 [4.3-36.6] vs. 0 [0-3.5]). MPTFa is associated with VTE during active disease and remission. Antiplasminogen antibody is associated with VTE during remission (HR 1.17 [1.03-1.33]). VTE risk is increased 4-times for each 1 g/dl decrease in serum albumin (HR 4.4 [1.5-12.0]).\tPatients with AAV in remission are at higher risk of VTE, possibly due to elevated MPTFa and increased antiplasminogen antibodies. Additionally, serum albumin may be a useful biomarker for assessing VTE risk.\t\nNakazawa et al. (2012)59\tCase report of fatal, concomitant DVT and pulmonary hemorrhage in a patient with MPA (n = 1)\tNETs are present within the thrombus and the glomerular crescents. The NETs within the thrombus are characterized by increased histone-citrullination compared with thrombi from control patients.\tNETosis may be contributing to both hypercoagulability and glomerular damage in patients with MPO and other forms of small-vessel vasculitis.\t\nSalmela et al. (2015)60\tProspective cohort analysis of coagulation factors in patients with AAV (n = 21)\t9.5% of patients developed VTE during the study period. Incidence rate was 9.0 per 100 person years. Both active disease and remission are associated with higher levels of Factor VIII, von Willebrand factor antigen, and von Willebrand factor ristocetin cofactor activity. Anti-thrombin activity is normal during active disease but elevated during periods of remission. In patients with active disease, D-dimer and prothrombin fragments are 5.0 and 2.6 times higher, respectively, than controls and are associated with lower eGFR.\tHypercoagulability in AAV is associated with elevated Factor VIII activity, thrombin formation, and fibrin turnover both in active disease and remission.\t\nShida et al. (2018)61\tCase report of drug-induced MPO-ANCA with subsequent analysis of the pathogenesis of NETs during spontaneous reactivation of disease (n = 1)\tAnti-NET antibody was present in the patient’s serum at time of relapse, with simultaneous increase in NET induction activity, not seen during remission.\tAnti-NET antibodies may induce NETosis to reactivate AAV, which may amplify the ANCA-NET cycle of disease activity.\t\nVan Montfoort et al. (2013)62\tCase-control analysis of circulating nucelosomes and systemic neutrophil activation in patients with DVT (n = 195)\tElevated levels of circulating nucleosomes and activated neutrophils are present in patients with DVT (vs. controls). Higher level of nucleosomes is associated with higher odds of DVT (aOR 3.0 [1.7, 5.0]).\tThe dose-dependent relationship between circulating nucleosomes, activated neutrophils, and DVT may partially explain the prothrombotic state in systemic inflammatory conditions. Circulating nucleosomes may be a useful biomarker for NETosis and risk of VTE.\t\nAAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; aOR, adjusted odds ratio; BVAS, Birmingham vasculitis activity score; CRP, C-reactive protein; CSS, Churg-Strauss syndrome; DNA, deoxyribonucleic acid; DVT, deep vein thrombosis; eGRF, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; HR, hazard ratio; IFNa, interferon alpha; IL, interleukin; IgAN, IgA nephropathy; IVC, inferior vena cava; MPA, microscopic polyangiitis; MPTFa, microparticle tissue factor activity; NET, neutrophil extracellular trap; PAN, polyarteritis nodosa; PE, pulmonary embolism; Ref, manuscript reference; ROS, reactive oxygen species; TAT, thrombin-antithrombin; TF, tissue factor; tPA, tissue plasminogen activator; UK, United Kingdom; VTE, venous thromboembolism; WG, Wegner’s granulomatosis.\n\n\n\nThe clinical significance of NETs was evaluated by Nakazawa and colleagues (2012), who described a case of MPO-positive vasculitis with diffuse alveolar hemorrhage in which thrombosis of the left common iliac vein was incidentally discovered on imaging.59 Autopsy allowed for identification of NETs within the thrombus itself 59 and within the glomerular crescents.56,59 Furthermore, there was an increased burden of histone-citrullination in the thrombus compared with thrombi from patients with non-AAV VTE,59 which is consistent with the description of NETs as a scaffold and stimulus from thrombus formation.71\nEx vivo studies indicate that NET scaffolding can be dismantled with heparin therapy.71 These findings are supported by studies demonstrating decreased serum NETs and attenuated NET activity following remission of disease.55,57,68 Active regulation of NETs could be a promising strategy to treat small-vessel vasculitis as well as thrombosis complicating the disease process.\n\nChallenges in the Treatment of Hypercoagulability in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis\nA major challenge in the treatment of small-vessel vasculitis is the potential for exacerbation of hemorrhagic complications (i.e., diffuse alveolar hemorrhage) with treatment of acute VTE secondary to hypercoagulability. This must be considered in the decision to initiate plasma exchange, as it removes essential clotting factors that regulate the coagulation cascade. Plasma exchange is recommended as an adjunct therapy for patients with severe renal disease or pulmonary hemorrhage, although there is no consensus on the definition of severe renal disease.74, 75, 76 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest 7 treatments of plasma exchange over a period of 14 days, with 60 ml/kg replaced with 5% albumin.12,17 If pulmonary hemorrhage is present, then plasma is preferred for replacement fluid.76 In clinical practice, the choice of replacement fluid in plasma exchange is variable and often depends on the clinical context.77 The theoretical risk of treating small-vessel vasculitis with plasma replacement fluid in a patient with both high risk bleeding and VTE rests on the possibility of extending the existing clot or precipitating a new thrombus following infusion of prothrombotic factors.78,79 The French Vasculitis Study Group noted 10 instances of venous thrombosis following plasma exchange (using unspecified replacement fluid); clinical implications of DVT in the context of plasmapheresis therapy were not discussed.80\n\nThe hypothesized benefit of plasma exchange in AAV relies on the removal of pathogenic ANCAs, as ANCAs are typically IgG antibodies readily eliminated during the exchange.81 In ANCA-negative small-vessel vasculitis, the beneficial effects of plasma exchange have been postulated to be derived from removal of cytokines, complement, and other proinflammatory molecules, as well as human lysosomal-associated membrane protein-2 antibody or other antibodies that are hypothesized to contribute to the disease process.23,75 It has also been suggested that some cases of ANCA-negative GN are misclassified because of poor detection of MPO in standard clinical assays and would therefore benefit from plasma exchange for removal of ANCAs.82 Although plasma exchange may benefit patients with less severe renal disease at presentation, it is an invasive and expensive therapy, with insufficient evidence to be more broadly employed.77 Furthermore, although patients receiving plasma exchange demonstrate initial improvement in renal function, studies have not shown consistent long-term effects on outcomes of dialysis-dependent renal failure or mortality.75,77,81,83,84 The highly anticipated Plasma Exchange and Glucocorticoids for Treatment of ANCA-Associated Vasculitis (PEXIVAS) trial publication may help clarify the use of plasma exchange in treating AAV, yet its utility in ANCA-negative small-vessel vasculitis will continue to remain poorly defined.85\n\nRenal biopsy is often needed to diagnose the underlying etiology of acute renal failure and is common for patients with AAV. However, biopsy carries significant risks for those who are coagulopathic owing to the chance of retroperitoneal bleeding, as exemplified by this case.86 Standard practice is to hold anticoagulation before biopsy to minimize bleeding; thus, for patients needing ongoing anticoagulation, transition to heparin infusion is preferred in the peribiopsy period to minimize time off anticoagulation.86,87 In patients taking warfarin or a factor Xa inhibitor, it is recommended to withhold these agents for at least 72 hours before biopsy, whereas a heparin infusion may be continued until several hours before biopsy.88 Anticoagulation may be resumed as soon as 12 hours postbiopsy, although a period of 48 to 72 hours is preferred, depending on the risk of thrombosis.88 An alternative to percutaneous renal biopsy is transjugular renal biopsy, which was first developed for simultaneous hepatic and renal biopsies in patients with multiorgan dysfunction.89 Although this approach can be considered, transjugular renal biopsies carry the additional risk of contrast-induced nephropathy and higher rates of capsular perforation.86 The high complication rates with a transjugular approach in patients with underlying coagulopathy is similar overall to percutaneous renal biopsy in this patient population.89\n\nAnother challenge in this case was the superimposed anticoagulant-related nephropathy. Continuation of anticoagulation was, nevertheless, mandatory in this patient. It is interesting to note that continuation of systemic anticoagulation was eventually possible, without further deterioration of renal function. We suspect that the initiation of treatment for vasculitis mitigated the glomerular pathologic changes, which, in turn, reduced the risk of further progression of anticoagulant-related nephropathy. Even though treatment with vitamin K antagonist warfarin was ultimately elected over direct oral anticoagulant therapy for treatment of acute DVT, there is insufficient literature to suggest differential risk profile for glomerular hematuria between the various pharmacologic options of systemic anticoagulation.30,90 The existing observational data comparing non-vitamin K oral anticoagulants (such as rivaroxaban, dabigatran, and apixaban) and warfarin have substantial methodologic limitations.91,92 Avoiding anticoagulation entirely is possible; using alternatives, such as vena cava filters, may be considered. However, these devices are not routinely used in the absence of an acute proximal DVT with a major contraindication to anticoagulation (i.e., massive bleeding, impending surgery), given the substantial costs, risks (i.e., infection, migration, filter thrombosis), need for a second retrieval procedure, and lack of strong evidence suggesting benefit in either VTE rate or mortality.93, 94, 95 Further prospective evidence is needed to guide treatment of hypercoagulability in patients with known anticoagulant-related nephropathy.\n\nImportantly, the state of hypercoagulability may persist even after clinical remission of AAV and ANCA-negative small-vessel vasculitis.33,35,40 The pathophysiology of sustained hypercoagulability is thought to be due to ongoing endothelial dysfunction secondary to persistently elevated endogenous thrombin potential and factor VIII,51,60 as well as antiplasminogen antibodies and microparticle tissue factor activity.40 This may suggest a benefit of ongoing anticoagulation following disease quiescence.33,40 However, just as there is no consensus on the overall immunosuppressive therapy duration for AAV,17,96 there is insufficient evidence to dictate the duration of anticoagulation therapy for thromboembolic events in patients with small-vessel vasculitis.5\n\nConclusions\nThis case describes an unusual presentation of biopsy proven pauci-immune, ANCA-negative crescentic GN. Further delay in the diagnosis of small-vessel vasculitis would have taken place if not for her VTE, which suggests occult small-vessel vasculitis may exist despite profound histopathologic activity. To our knowledge, there are no other examples of VTE as the presenting complaint of pauci-immune, ANCA-negative crescentic GN in the literature. In this case, the hematologic manifestation of vasculitis translated into development of lower extremity DVT, which rendered the disease non-renal limited and of questionable small-vessel designation. The patient’s clinical course highlights the tension in treating concomitant high-risk bleeding and hypercoagulability in renal vasculitis as well as the need for further research to clarify the subtleties in the pathophysiology and treatment of ANCA-negative small-vessel vasculitis.\n\nDisclosure\nAll the authors declared no competing interests.\n==== Refs\nReferences\n1 Chen M. Kallenberg C.G.M. Zhao M.H. 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Anti-neutrophil extracellular trap antibody in a patient with relapse of anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report BMC Nephrol 19 2018 1 6 29304774 \n62 Van Montfoort M.L. Stephan F. Lauw M.N. Circulating nucleosomes and neutrophil activation as risk factors for deep vein thrombosis Arterioscler Thromb Vasc Biol 33 2013 147 151 23104849 \n63 Reese J.M. Joseph R.P. Cherrington A. Development of participant-informed text messages to promote physical activity among African American women attending college: a qualitative mixed-methods inquiry J Transcult Nurs 28 2017 236 242 27093904 \n64 Rosendaal F.R. Causes of venous thrombosis Deep Vein Thromb Pulm Embolism 14 suppl 1 2009 1 26 \n65 Schreiber A. Rousselle A. Becker J.U. von Mässenhausen A. Linkermann A. Kettritz R. Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis Proc Natl Acad Sci 114 2017 E9618 E9625 29078325 \n66 Cartin-Ceba R. Peikert T. Specks U. Pathogenesis of ANCA-associated vasculitis Curr Rheumatol Rep 14 2012 481 493 22927039 \n67 Heeringa P. Rutgers A. Kallenberg C.G.M. The net effect of ANCA on neutrophil extracellular trap formation Kidney Int 94 2018 14 16 29933842 \n68 Söderberg D. Segelmark M. Neutrophil extracellular traps in ANCA-associated vasculitis Front Immunol 7 2016 1 9 26834743 \n69 Yau J.W. Teoh H. Verma S. Endothelial cell control of thrombosis BMC Cardiovasc Disord 15 2015 1 11 25592444 \n70 Laridan E. Martinod K. De Meyer S.F. Neutrophil extracellular traps in arterial and venous thrombosis Semin Thromb Hemost 45 2019 86 93 30634198 \n71 Fuchs T.A. Brill A. Duerschmied D. Extracellular DNA traps promote thrombosis Proc Natl Acad Sci 107 2010 15880 15885 20798043 \n72 Sangaletti S. Tripodo C. Chiodoni C. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity Blood 120 2012 3007 3018 22932797 \n73 Bautz D.J. Preston G.A. Lionaki S. Antibodies with dual reactivity to plasminogen and complementary PR3 in PR3-ANCA vasculitis J Am Soc Nephrol 19 2008 2421 2429 18701607 \n74 Balogun R.A. Abdel-rahman E.M. Therapeutic plasma exchange and renal related vasculitis: Therapeutic Apheresis Academy 2010 J Clin Apher 26 2011 291 296 21834080 \n75 Szpirt W.M. Plasma exchange in antineutrophil cytoplasmic antibody-associated vasculitis-A 25-year perspective Nephrol Dial Transplant 30 2015 i146 i149 25770166 \n76 Nguyen T.C. Kiss J.E. Goldman J.R. Carcillo J.A. The role of plasmapharesis in critical illness Crit Care Clin 28 2012 453 468 22713617 \n77 Walsh M. Catapano F. Szpirt W. Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis Am J Kidney Dis 57 2011 566 574 21194817 \n78 De Sousa E. Smith R. Chaudhry A. Willcocks L. Jayne D. Venous thromboembolism with concurrent pulmonary haemorrhage in systemic vasculitis Nephrol Dial Transplant 27 2012 4357 4361 22553370 \n79 Henderson S.R. Salama A.D. Haemorrhage and thrombosis: tackling two sides of a single vasculitic disease Nephrol Dial Transplant 27 2012 4243 4244 22899871 \n80 De Luna G. Chauveau D. Aniort J. Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: data from the French Vasculitis Study Group J Autoimmun 65 2015 49 55 26330347 \n81 Clark W.F. Huang S.H.S. Walsh M.W. Farah M. Hildebrand A.M. Sontrop J.M. Plasmapheresis for the treatment of kidney diseases Kidney Int 90 2016 974 984 27498206 \n82 Roth A.J. Ooi J.D. Hess J.J. Epitope specificity determines pathogenicity and detectability in anca-associated vasculitis J Clin Invest 123 2013 1773 1783 23549081 \n83 Solar-Cafaggi D. Atisha-Fregoso Y. Hinojosa-Azaola A. Plasmapheresis therapy in ANCA-associated vasculidites: a single-center retrospective analysis of renal outcome and mortality J Clin Apher 31 2016 411 418 26194633 \n84 Walsh M. Casian A. Flossmann O. Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear Kidney Int 84 2013 397 402 23615499 \n85 Walsh M. Merkel P.A. Peh C.A. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): Protocol for a randomized controlled trial Trials 14 2013 1 7 23286245 \n86 Hogan J.J. Mocanu M. Berns J.S. The native kidney biopsy: Update and evidence for best practice Clin J Am Soc Nephrol 11 2016 354 356 26339068 \n87 Douketis J.D. Spyropoulos A.C. Spencer F.A. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines Chest 141 2 suppl 2012 e326S e350 22315266 \n88 Luciano R.L. Moeckel G.W. Update on the native kidney biopsy: core curriculum 2019 Am J Kidney Dis 73 2019 404 415 30661724 \n89 See T.C. Thompson B.C. Howie A.J. Transjugular renal biopsy: our experience and technical considerations Cardiovasc Intervent Radiol 31 2008 906 918 18266029 \n90 de Aquino Moura K.B. Behrens P.M.P. Pirolli R. Anticoagulant-related nephropathy: systematic review and meta-analysis Clin Kidney J 12 2019 400 407 31198540 \n91 Shin J.I. Luo S. Alexander G.C. Direct oral anticoagulants and risk of acute kidney injury in patients with atrial fibrillation J Am Coll Cardiol 71 2018 251 252 29325644 \n92 Chan Y. Yeh Y. Hsieh M. The risk of acute kidney injury in Asians treated with apixaban, rivaroxaban, dabigatran, or warfarin for non-valvular atrial fibrillation: a nationwide cohort study in Taiwan Int J Cardiol 265 2018 83 89 29885705 \n93 Wassef A. Lim W. Wu C. Indications, complications and outcomes of inferior vena cava filters: A retrospective study Thromb Res 153 2017 123 128 28242032 \n94 Duffett L. Carrier M. Inferior vena cava filters J Thromb Haemost 15 2016 3 12 28019712 \n95 Bikdelki B. Chatterjee S. Desai N.R. Inferior vena cava filters to prevent pulmonary embolism J Am Coll Cardiol 70 2017 1587 1597 28935036 \n96 Salvadori M. Tsalouchos A. Antineutrophil cytoplasmic antibody associated vasculitides with renal involvement: open challenges in the remission induction therapy World J Nephrol 7 2018 71 83 29736379\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-0249",
"issue": "5(5)",
"journal": "Kidney international reports",
"keywords": "crescentic; glomerulonephritis; hypercoagulation; thrombosis; vasculitis",
"medline_ta": "Kidney Int Rep",
"mesh_terms": null,
"nlm_unique_id": "101684752",
"other_id": null,
"pages": "586-599",
"pmc": null,
"pmid": "32405580",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "19577348;30385704;23162551;19662604;28391334;21918501;28019712;22927039;27093904;26097236;21194817;30665569;16344494;23104849;19077717;29325644;27498206;16463427;7967339;20331949;25523447;19015208;20070316;27446086;28242032;22899871;26194633;21834080;30661724;27572522;21389969;29588079;15855209;9669443;22315266;24203998;26339068;26269223;23143223;23507057;29078325;29606398;22932797;18701607;25750012;24128780;21119331;26069771;24464552;30420420;20847144;23497590;20647198;31891003;22553370;24162033;31198540;22119579;26670286;24842719;23615499;29885705;10595642;15838068;29736379;31113769;31216123;24657897;29371340;2256477;23873874;26330347;25770166;23029002;19399019;23549081;29933842;19448636;28935036;20798043;18356178;18266029;25739829;28666565;17478493;22052057;22713617;29929470;30634198;20647199",
"title": "Narrative Review of Hypercoagulability in Small-Vessel Vasculitis.",
"title_normalized": "narrative review of hypercoagulability in small vessel vasculitis"
} | [
{
"companynumb": "US-JNJFOC-20200528429",
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"activesubstancename": "RIVAROXABAN"
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{
"abstract": "In the 1960s and 1970s, intestinal bypass surgery was performed to treat patients with extreme obesity. However, this is now done with great restriction due to the risk of complications, for instance, polyarthritis. An association between severe achalasia and arthritis has also been described, but very few articles on this topic are cited in PubMed, and most of the published case reports are old. In this article, we present a retrospective case series of three patients with severe achalasia and arthritis from the departments of rheumatology and surgery at a university hospital. The complaints from the esophagus as well as arthritis were resolved after esophagectomy and esophageal reconstruction. We conclude that severe achalasia can be associated with arthritis, and both can be cured by esophageal reconstruction. Thus, we want to remind of this rare, but probably largely unrecognized, association between achalasia and joint disease.",
"affiliations": "Department of Rheumatology, University Hospital, and Department of Clinical Experimental Medicine, Linköping University Department of Surgery, University Hospital, Linköping, Sweden. per.eriksson@lio.se",
"authors": "Eriksson|P|P|;Jacobs|C|C|;Johansson|K-E|KE|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D001623:Betamethasone; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1442-2050.2012.01355.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-8694",
"issue": "26(3)",
"journal": "Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus",
"keywords": null,
"medline_ta": "Dis Esophagus",
"mesh_terms": "D000328:Adult; D000714:Anastomosis, Surgical; D000893:Anti-Inflammatory Agents; D001168:Arthritis; D001623:Betamethasone; D003680:Deglutition Disorders; D004750:Enteral Nutrition; D004931:Esophageal Achalasia; D004935:Esophageal Diseases; D016629:Esophagectomy; D005260:Female; D005500:Follow-Up Studies; D005774:Gastrostomy; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D010438:Peptic Ulcer Hemorrhage; D011183:Postoperative Complications; D011239:Prednisolone; D019651:Reconstructive Surgical Procedures; D012189:Retrospective Studies; D013270:Stomach",
"nlm_unique_id": "8809160",
"other_id": null,
"pages": "226-30",
"pmc": null,
"pmid": "22591142",
"pubdate": "2013-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Remission of arthritis after esophagectomy in three patients with severe achalasia.",
"title_normalized": "remission of arthritis after esophagectomy in three patients with severe achalasia"
} | [
{
"companynumb": "PHHY2015SE004213",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "OBJECTIVE\nTo analyze the clinical characteristics of patients with hematological tumor or disease before and after reversible posterior leukoen-cephalopathy syndrome (RPLS).\n\n\nMETHODS\nFive patients were both from Peking University First Hospital Pediatric Hematology-oncology Department in the period from March 2012 to March 2017. The gender, age, BMI, underlying diseases, with or without renal damage, hypertension family history, clinical manifestations of convulsions, hemoglobin, and blood pressure, serum sodium levels before and after convulsion, and other data of the children with RPLS were retrospectively analyzed. In the meantime, we followed up the five patients for 6 months to 66 months, kept a watchful eye on their original condition and the recovery of symptoms and signs of the nervous system. The relevant literature was reviewed.\n\n\nRESULTS\nAll of the subjects were females in school-age or pre-school age. The underlying diseases were malignant tumor associated with renal involvement or on one side of nephrectomy in 4 of these subjects, while the other one was refractory autoimmune hemolytic anemia. All of the subjects suffered from mild or moderate anemia. The day before RPLS occurred they received chemotherapy made up with cyclophosphamide, vincristine, and actinomycin-D, or the therapy with cyclosporin A and glucocorticoid. The clinical manifestations were afebrile convulsion after getting up in the mooring or in the afternoon. We observed elevation of blood pressure and cutting down of serum sodium compared with themselves. All of the cases recovered soon after management with diazepam, furosemide and amlodipine besylate. Four of them had a good outcomes and did not remain any sequela, while only one girl became childish in emotion and behavior, and then returned gradually to normal two years later. However, by long-term follow-up, the elevation of blood pressure was mainly reviewed in literature.\n\n\nCONCLUSIONS\nThe patients attacked by RPLS, with hematology or oncology cases, could have the underlying disease of renal damage and anemia. Blood pressure elevation and serum sodium falling down at the same time may play an important role during the occurrence of RPLS. Remaining stable of blood pressure and electrolyte level together will possibly reduce or mitigate RPLS.",
"affiliations": "Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.;Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.;Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.;Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.;Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.;Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.;Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.;Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.",
"authors": "Wu|P H|PH|;Xie|Y|Y|;Zhao|W H|WH|;Hua|Y|Y|;Sun|Q|Q|;Li|S|S|;Wu|Y|Y|;Lu|X T|XT|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1671-167X",
"issue": "50(4)",
"journal": "Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences",
"keywords": null,
"medline_ta": "Beijing Da Xue Xue Bao Yi Xue Ban",
"mesh_terms": "D001794:Blood Pressure; D002648:Child; D002675:Child, Preschool; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D006973:Hypertension; D054038:Posterior Leukoencephalopathy Syndrome; D012189:Retrospective Studies; D012640:Seizures",
"nlm_unique_id": "101125284",
"other_id": null,
"pages": "662-665",
"pmc": null,
"pmid": "30122768",
"pubdate": "2018-08-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical characteristics analysis of children with reversible posterior leukoen-cephalopathy syndrome during the treatment of hematological tumor.",
"title_normalized": "clinical characteristics analysis of children with reversible posterior leukoen cephalopathy syndrome during the treatment of hematological tumor"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201904264",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,... |
{
"abstract": "Hypersensitivity to orthopedic implant materials has been well documented with potential catastrophic consequences if not addressed pre-operatively. The spectrum of reactions is wide, from mild non-specific pain with localized erythema to severe periprosthetic inflammatory destruction and pseudotumor formation. It is therefore essential to identify patients who have or are at risk for implant-associated hypersensitivity. Although metal sensitivity is commonly cited as the cause of these reactions, methyl methacrylate (MMA) has rarely been implicated. To the best of our knowledge, methyl methacrylate-associated pseudotumor formation has not yet been described. The following is a case report of a 68-year-old female who, after undergoing a routine cemented right total knee arthroplasty, developed a painless, enlarging mass during a 13-year period. This mass was found to be a pseudotumor in association with methyl methacrylate hypersensitivity. A review of pseudotumor pathogenesis, methyl methacrylate hypersensitivity, and preoperative preventative care is discussed.",
"affiliations": "Department of Orthopaedics, Long Island Jewish Medical Center, Hofstra Northwell Health, New Hyde Park, 11040, NY, USA. shachar.kenan@gmail.com.;Musculoskeletal Pathology, Department of Pathology, Long Island Jewish Medical Center, Hofstra Northwell Health, New Hyde Park, 11040, NY, USA.;Department of Musculoskeletal Radiology, Albert Einstein College of Medicine, New York, 10461, NY, USA.;Department of Orthopaedics, Long Island Jewish Medical Center, Hofstra Northwell Health, New Hyde Park, 11040, NY, USA.",
"authors": "Kenan|Shachar|S|http://orcid.org/0000-0002-7292-0629;Kahn|Leonard|L|;Haramati|Noga|N|;Kenan|Samuel|S|",
"chemical_list": "D008670:Metals; D020366:Methylmethacrylate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00256-016-2372-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0364-2348",
"issue": "45(8)",
"journal": "Skeletal radiology",
"keywords": "Allergy; Hypersensitivity; Methyl methacrylate; Pseudotumor; Total knee arthroplasty",
"medline_ta": "Skeletal Radiol",
"mesh_terms": "D000368:Aged; D019645:Arthroplasty, Replacement, Knee; D005260:Female; D006104:Granuloma, Plasma Cell; D006801:Humans; D006967:Hypersensitivity; D008670:Metals; D020366:Methylmethacrylate",
"nlm_unique_id": "7701953",
"other_id": null,
"pages": "1115-22",
"pmc": null,
"pmid": "27022733",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3417709;12216037;12873108;1447242;7890794;21957996;24847849;4678095;7204005;19292373;18227996;11263649;735782;20458645;23672921;9855207;421463;24994850;8682817;21543700;21498036;7615597;3554529;23590796;22159853;3995944;22218386;21818922;22018875;21955792;22336970;124737;18534517;7706360;26324830;22085108;24347449;18976382;9029473",
"title": "A rare case of pseudotumor formation associated with methyl methacrylate hypersensitivity in a patient following cemented total knee arthroplasty.",
"title_normalized": "a rare case of pseudotumor formation associated with methyl methacrylate hypersensitivity in a patient following cemented total knee arthroplasty"
} | [
{
"companynumb": "US-BAYER-2016-143956",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NAPROXEN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Renal transplant patients on immunosuppression are at risk for malignancy. One form of malignancy that commonly affects this population is Kaposi-sarcoma. Kaposi-sarcoma is a human herpesvirus-8 (HHV-8)-driven process classically associated with skin lesions in immunocompromised patients. The pulmonary system may be involved in disseminated disease. In this case, a renal transplant patient was re-admitted with acute hypoxic respiratory failure and hemoptysis of an unclear etiology. Following a broad workup, HHV-8 PCR and a lymph node biopsy confirmed pulmonary Kaposi-sarcoma. Workup for multicentric Castleman disease was negative. The patient was treated with liposomal doxorubicin, ganciclovir, and prednisone. Her immunosuppression was changed to sirolimus and she is scheduled to complete six cycles of liposomal doxorubicin.",
"affiliations": "Internal Medicine, The Ohio State University College of Medicine, Columbus, USA.;Internal Medicine, Saint Vincent Hospital, Worcester, USA.;Nephrology and Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, USA.;Nephrology and Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, USA.",
"authors": "Scheetz|Seth|S|;Pandey|Deepali|D|;Pesavento|Todd E|TE|;Singh|Priyamvada|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.6719",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.6719OncologyPulmonologyTransplantationPulmonary Presentation of Kaposi-Sarcoma in a Renal Transplant Recipient Muacevic Alexander Adler John R Scheetz Seth 1Pandey Deepali 2Pesavento Todd E 3Singh Priyamvada 3\n1 \nInternal Medicine, The Ohio State University College of Medicine, Columbus, USA \n2 \nInternal Medicine, Saint Vincent Hospital, Worcester, USA \n3 \nNephrology and Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, USA \nDeepali Pandey drdeepalipandey05@gmail.com21 1 2020 1 2020 12 1 e671927 12 2019 21 1 2020 Copyright © 2020, Scheetz et al.2020Scheetz et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/26007-pulmonary-presentation-of-kaposi-sarcoma-in-a-renal-transplant-recipientRenal transplant patients on immunosuppression are at risk for malignancy. One form of malignancy that commonly affects this population is Kaposi-sarcoma. Kaposi-sarcoma is a human herpesvirus-8 (HHV-8)-driven process classically associated with skin lesions in immunocompromised patients. The pulmonary system may be involved in disseminated disease. In this case, a renal transplant patient was re-admitted with acute hypoxic respiratory failure and hemoptysis of an unclear etiology. Following a broad workup, HHV-8 PCR and a lymph node biopsy confirmed pulmonary Kaposi-sarcoma. Workup for multicentric Castleman disease was negative. The patient was treated with liposomal doxorubicin, ganciclovir, and prednisone. Her immunosuppression was changed to sirolimus and she is scheduled to complete six cycles of liposomal doxorubicin.\n\nkaposi sarcomarenal transplanthhv-8The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nSolid organ transplant recipients on immunosuppression are at increased risk for malignancy [1]. Specifically, renal transplant patients are about three times more likely to develop cancer, including skin cancer, lip cancer, post-transplant lymphoproliferative disease, anogenital cancer, renal cell carcinoma, and Kaposi-sarcoma. Malignancy may present with nonspecific signs including thrombocytopenia and generalized lymphadenopathy. These signs, however, may also be seen in autoimmune and infectious processes, making diagnosis challenging. We present here a diagnostic dilemma of a case of a pulmonary presentation of Kaposi-sarcoma (KS) in a kidney transplant recipient.\n\nCase presentation\nA 43-year-old female with end-stage renal disease secondary to type two diabetes mellitus, status-post renal transplant one year prior, on tacrolimus and myfortic, was admitted with acute hypoxic respiratory failure (new oxygen requirement of eight liters per minute). She had two similar admissions within two months and was treated for community-acquired pneumonia and volume overload. CT scan during those admissions showed bilateral nodular infiltrates, diffuse lymphadenopathy (hilar, mediastinal, inguinal, and axillary), and moderate pleural and pericardial effusions. She was discharged with plans for an outpatient lymph node biopsy if an eight-week follow-up CT-chest did not show improvement. During this encounter, her respiratory status worsened to require high-flow-oxygen and she developed hemoptysis. Her initial CT scan presentation was similar (Figure 1A, 1B). An extensive workup was negative for infectious (pan-culture, immunocompromised respiratory panel, Epstein-Barr virus [EBV], cytomegalovirus [CMV], BK, Pneumocystis jiroveci pneumonia [PJP], adenovirus, fungitell, HIV, streptococcus pneumonia, and legionella) and autoimmune (antinuclear antibody [ANA], double stranded DNA [dsDNA], antineutrophil cytoplasmic antibody [ANCA], anti-glomerular basement membrane [GBM]) etiologies. She was non-responsive to diuretics and broad-spectrum antibiotics. A thoracentesis and bronchoscopy were consistent with an exudative process, narrowing the differential to autoimmune, infectious, or malignant processes with concern for diffuse alveolar hemorrhage (DAH). An axillary lymph node biopsy showed HHV-8+ KS. Further history revealed one month of a violaceous skin rash and gingival lesion. HHV-8 polymerase chain reaction (PCR) quantity was 87,572. A positron emission tomography (PET) scan for staging showed extensive lymphadenopathy (Figure 2A-2D) [2]. Workup for multicentric Castleman disease (MCD) and hemophagocytic lymphohistiocytosis (HLH) was negative. Endobronchial ultrasound-guided biopsy of a hypermetabolic subcarinal lymph node showed a spindle cell tumor consistent with Kaposi-sarcoma but not multicentric Castleman disease. Bronchoscopy at this time showed lesions consistent with pulmonary KS (Figure 3A, 3B) [3]. We treated her with liposomal doxorubicin, ganciclovir, and prednisone. We changed the immunosuppression to sirolimus given previous literature showing the benefit of mTOR inhibitors in KS. She responded well to treatment and was weaned off oxygen. She will continue on sirolimus and complete six cycles of liposomal doxorubicin.\n\nFigure 1 Chest CT of upper lungs (A) and lower lungs (B) showing multifocal bronchopneumonia (oval), moderate right and small left partially loculated pleural effusions (arrow), and enlarged mediastinal and bilateral hilar lymph nodes (arrowhead). Bilateral axillary and supraclavicular lymph nodes were also enlarged.\nFigure 2 Positron emission tomography (PET) scan for staging of Kaposi-sarcoma.\nBilateral axillary lymphadenopathy (A), subcarinal lymphadenopathy (B), uptake in the transplanted kidney (C), bilateral inguinal lymphadenopathy (D).\n\nFigure 3 Bronchoscopy showing erythematous patches (A) and purpuric lesions (B) in the airways consistent with Kaposi-sarcoma.\nDiscussion\nRenal transplant patients on immunosuppression are at risk for developing Kaposi-sarcoma [1]. This has been reported to occur as soon as four months post-transplant [4]. The initial presentation classically involves a violaceous skin rash. This rash, however, may be small, hidden, or misdiagnosed, leading to a delay in diagnosis. In this case, a violaceous gingival lesion had previously been documented but not seen as a mucocutaneous sign of malignancy. Kaposi-sarcoma may disseminate to involve visceral organs including the lungs, gastrointestinal tract, lymph nodes, or transplanted kidney [5,6]. Pulmonary Kaposi-sarcoma may be fatal if untreated. In renal transplant patients, Kaposi-sarcoma has been shown to advance rapidly and early staging with a PET scan may expedite diagnosis and initiation of treatment [7].\n\nThe patient’s thrombocytopenia, generalized lymphadenopathy, exudative pleural fluid, and bronchoscopic findings were consistent with malignancy, infection, or an autoimmune process presenting as diffuse alveolar hemorrhage. This complicated therapeutic decision making, as management of infection or malignancy is diametrically opposite to the management of an autoimmune process. Malignancy and infection require a reduction of immunosuppression, whereas diffuse alveolar hemorrhage requires intensification of immunosuppression.\n\nIn this case, an excisional biopsy earlier in the hospital course may have expedited the diagnosis. During a previous hospitalization, an inpatient lymph node biopsy was not warranted due to improving clinical status and the patient was scheduled for an outpatient lymph node biopsy. During this encounter, however, the inpatient lymph node biopsy was indicated due to generalized lymphadenopathy of unclear etiology and worsening clinical status [8]. A study has shown that inpatient excisional biopsies may lead to quicker diagnoses in hematologic disease, but outpatient ones are more cost-effective [9]. In immunocompromised patients, a high index of suspicion is required to prompt a full skin exam and potentially earlier inclusion of an excisional lymph node biopsy.\n\nThe immunosuppression regimen should be reconsidered after a diagnosis of Kaposi-sarcoma in a renal transplant patient. Calcineurin inhibitors may be associated with Kaposi-sarcoma, and the reduction of immunosuppression in renal transplant patients may result in tumor regression. On the other hand, the mTOR inhibitor sirolimus has been shown to prevent the progression of Kaposi-sarcoma in renal transplant patients [10]. The patient’s immunosuppression was changed to sirolimus following this diagnosis.\n\nIn HHV-8+ patients, consideration of multicentric Castleman disease is warranted [11]. The treatment for pulmonary Kaposi-sarcoma is liposomal doxorubicin, whereas the treatment for Kaposi-sarcoma associated multicentric Castleman disease is rituximab and liposomal doxorubicin [12,13]. Although the patient had clinical and laboratory findings concerning for multicentric Castleman disease, the diagnostic lymph node biopsy confirmed the presence of HHV-8 but did not show characteristic changes of MCD. As a result, she was treated with liposomal doxorubicin but not rituximab.\n\nConclusions\nKaposi-sarcoma often presents as a skin lesion and lymphadenopathy. This case highlights a rare initial presentation of Kaposi-sarcoma with pulmonary symptoms. A high index of suspicion in the immunocompromised population (solid organ transplant, HIV) and early diagnosis can improve survival.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nPart of this work was presented as a poster at the Ohio State University Wexner Medical Center Hospital Medicine Symposium 2019.\n==== Refs\nReferences\n1 Cancer after kidney transplantation in the United States Am J Transplant Kasiske BL Snyder JJ Gilbertson DT Wang C 905 913 4 2004 15147424 \n2 The AJCC 8th edition staging system for soft tissue sarcoma of the extremities or trunk: a cohort study of the SEER database J Natl Compr Canc Netw Cates JM 144 152 16 2018 29439175 \n3 Bronchoscopic and radiologic features of Kaposi's sarcoma involving the respiratory system Chest Zibrak JD Silvestri RC Costello P Marlink R Jensen WA Robins A Rose RM 476 479 90 1986 3489584 \n4 Kaposi's sarcoma in the early post-transplant period in a kidney transplant recipient Nefrología Ercan Z Demir ME Merhametsiz O Yayar O Ulas T Ayli MD 751 868 33 2013 24241361 \n5 Pulmonary Kaposi's sarcoma: clinical findings and results of therapy Am J Med Gill PS Akil B Colletti P 57 61 87 1989 2472743 \n6 Disseminated Kaposi's sarcoma—A missed diagnosis J Emerg Med Armstrong MB Thurber J 520 523 47 2014 25256409 \n7 A challenging case of rapid progressive Kaposi sarcoma after renal transplantation: diagnostics by FDG PET/CT Medicine Reuter S Vrachimis A Huss S Wardelmann E Weckesser M Pavenstädt H 0 93 2014 \n8 Peripheral lymphadenopathy: approach and diagnostic tools Iran J Med Sci Mohseni S Shojaiefard A Khorgami Z Alinejad S Ghorbani A Ghafouri A 158 170 39 2014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993046/ 24753638 \n9 Time to diagnosis and associated costs of an outpatient vs inpatient setting in the diagnosis of lymphoma: a retrospective study of a large cohort of major lymphoma subtypes in Spain BMC Cancer Bosch X Sanclemente-Ansó C Escoda O 276 18 2018 29530002 \n10 Sirolimus for Kaposi's sarcoma in renal-transplant recipients N Engl J Med Stallone G Schena A Infante B 1317 1323 352 2005 15800227 \n11 Concurrent and fatal HHV-8 positive multicentric Castleman's disease and Kaposi's sarcoma in a HIV negative kidney transplant recipient: 1714 Transplantation Guglielmo N Melandro F Sandri GL 832 94 2012 https://journals.lww.com/transplantjournal/Fulltext/2012/11271/Concurrent_and_Fatal_HHV_8_Positive_Multicentric.1630.aspx \n12 Liposomal doxorubicin in pulmonary Kaposi's sarcoma: improved survival as compared to patients without liposomal doxorubicin Eur J Med Res Grünaug M Bogner JR Loch O Goebel FD 13 19 3 1998 https://europepmc.org/article/med/9512962 9512962 \n13 Treatment of Kaposi sarcoma herpesvirus-associated multicentric Castleman disease Hematol Oncol Clin North Am Lurain K Yarchoan R Uldrick TS 75 88 32 2018 29157621\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(1)",
"journal": "Cureus",
"keywords": "hhv-8; kaposi sarcoma; renal transplant",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e6719",
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"pmid": "32104640",
"pubdate": "2020-01-21",
"publication_types": "D002363:Case Reports",
"references": "29157621;29530002;3489584;15800227;24753638;9512962;2472743;25256409;15147424;29439175;24241380;25192485",
"title": "Pulmonary Presentation of Kaposi-Sarcoma in a Renal Transplant Recipient.",
"title_normalized": "pulmonary presentation of kaposi sarcoma in a renal transplant recipient"
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"companynumb": "US-ACCORD-175328",
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"abstract": "OBJECTIVE\nTo describe our initial experience of \"off-clamp, non-renorrhaphy\" laparoscopic partial nephrectomy (OCNR-LPN) with perirenal fat and Gerota's fascia reapproximation technique.\n\n\nMETHODS\nBetween August 2012 and March 2013, 24 consecutive patients underwent OCNR-LPN at our institution. After the renal mass excision, biologic hemostatics such as FLOSEAL™ and TISSEEL™ (both from Baxter Healthcare Corp., Deerfield, IL) were used, and the perirenal fat and Gerota's fascia were sutured for reapproximation.\n\n\nRESULTS\nAll 24 consecutive patients underwent OCNR-LPN successfully. The warm ischemic time for all cases was 0 minute. Thirteen patients were noted to have a low (4-6) RENAL nephrometry score (RNS), and 11 patients had a moderate (7-9) RNS. The mean tumor size among this cohort was 2.9 (range, 1.2-6.0) cm, and the mean estimated blood loss was 243 (range, 50-700) mL. The mean hospital stay was 6.9 (range, 5-10) days. The mean percentage of postoperative estimated glomerular filtration rate change increased by 0.9%. No positive surgical margins were noted, and 2 patients with Grade III complication by the Clavien-Dindo classification were treated by endoscopic or radiological intervention.\n\n\nCONCLUSIONS\nOCNR-LPN with the perirenal fat and Gerota's fascia reapproximation technique is feasible. Our initial experience with OCNR-LPN demonstrates encouraging results of minimal renal function loss and complications.",
"affiliations": "Department of Urology, Kosin University Gospel Hospital , Busan, Korea.",
"authors": "Kim|Taek Sang|TS|;Oh|Jeong Hyun|JH|;Rhew|Hyun Yul|HY|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1089/lap.2013.0333",
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"issue": "24(5)",
"journal": "Journal of laparoendoscopic & advanced surgical techniques. Part A",
"keywords": null,
"medline_ta": "J Laparoendosc Adv Surg Tech A",
"mesh_terms": "D000038:Abscess; D000328:Adult; D000368:Aged; D057868:Anastomotic Leak; D000900:Anti-Bacterial Agents; D004322:Drainage; D000071938:Fasciotomy; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D010535:Laparoscopy; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D011183:Postoperative Complications; D016896:Treatment Outcome; D052096:Warm Ischemia",
"nlm_unique_id": "9706293",
"other_id": null,
"pages": "339-44",
"pmc": null,
"pmid": "24742352",
"pubdate": "2014-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "\"Off-clamp, non-renorrhaphy\" laparoscopic partial nephrectomy with perirenal fat and Gerota's fascia reapproximation: initial experience and perioperative outcomes.",
"title_normalized": "off clamp non renorrhaphy laparoscopic partial nephrectomy with perirenal fat and gerota s fascia reapproximation initial experience and perioperative outcomes"
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"abstract": "A 59-year-old Asian man presented to our emergency department with hypogastrium pain, loss of appetite, and diarrhea. On admission, he was hypotensive and jaundiced. Laboratory test results revealed thrombocytopenia, hypercreatininemia, and hyperbilirubinemia. Color Doppler sonography showed no blood flow in the right and left branches of the portal vein, which seemed similar to biliary obstruction. Enhanced computed tomography showed portal vein thrombi, consistent with pylephlebitis; a broad-spectrum antibiotic and an anticoagulant were administered.\n\n\n\nThe patient died of multiple organ failure 22 h post-admission. An autopsy revealed suppurative thrombi in the portal vein, multiple liver abscesses, and diverticulitis in the sigmoid colon.\n\n\n\nPylephlebitis, a rare complication of intra-abdominal infections, is associated with high rates of morbidity and mortality. Ultrasonography findings mimic those of biliary obstruction. Enhanced computed tomography is useful for diagnosing this condition.",
"affiliations": "Tertiary Emergency Medical Center Tokyo Metropolitan Bokutoh Hospital Sumida-ku Tokyo Japan.;Tertiary Emergency Medical Center Tokyo Metropolitan Bokutoh Hospital Sumida-ku Tokyo Japan.;Tertiary Emergency Medical Center Tokyo Metropolitan Bokutoh Hospital Sumida-ku Tokyo Japan.;Tertiary Emergency Medical Center Tokyo Metropolitan Bokutoh Hospital Sumida-ku Tokyo Japan.",
"authors": "Kashiura|Masahiro|M|0000-0002-1989-656X;Sugiyama|Kazuhiro|K|;Akashi|Akiko|A|;Hamabe|Yuichi|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ams2.205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2052-8817",
"issue": "3(4)",
"journal": "Acute medicine & surgery",
"keywords": "Cholestasis; intra‐abdominal infections; sepsis; thrombophlebitis; ultrasonography",
"medline_ta": "Acute Med Surg",
"mesh_terms": null,
"nlm_unique_id": "101635464",
"other_id": null,
"pages": "404-406",
"pmc": null,
"pmid": "29123823",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": "11045699;8942542;18680244;18341508;23817997;11316205;20864076;23759294;16685012",
"title": "Diverticulitis-induced pylephlebitis possibly misdiagnosed as biliary duct obstruction.",
"title_normalized": "diverticulitis induced pylephlebitis possibly misdiagnosed as biliary duct obstruction"
} | [
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"companynumb": "JP-PFIZER INC-2018348613",
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"abstract": "Purpose of this study was to evaluate the efficacy of switching to pegaptanib monotherapy for persistent cases of exudative age-related macular degeneration (AMD).Out of 296 eyes of 296 patients treated with ranibizumab or ranibizumab combined with photodynamic therapy (PDT), 50 eyes of 50 AMD patients were found to be resistant to these treatments. Over a 12-month period, intravitreal pegaptanib (IVP) 0.3 mg was administered at intervals of 6 weeks until the exudation disappeared prospectively. All patients were examined with the following tests: best-corrected visual acuity (BCVA) and central retinal thickness (CRT), determined at the initial visit, before the first IVP (baseline), and at 12 months. The factors responsible for achieving dry macula with IVP were examined statistically.The rate of persistent cases with intravitreal ranibizumab (IVR) and/or PDT was 17.0%. The mean number of IVPs administered was 5.4 (range, 2-9). Logarithm of the minimal angle of resolution BCVA at 12 months was stable or improved by ≥ 0.3 in 49 eyes (98.0%), with a significant improvement noted between the baseline and final BCVA (P=0.01, paired t test). The CRT (mean ± standard deviation) was 446.9 ± 150.6 µm at the initial visit, 414.5 ± 146.5 µm at baseline, and 318.7 ± 99.0 µm at 12 months. There was a significant decrease in the mean CRT between the measurements at baseline and at 12 months after the first IVP (P=0.002, Bonferroni correction). At 12 months, the exudative change was completely resolved in 27 eyes (54.0%) and reduced in 21 eyes (42.0%). The number of previous IVR treatments was significantly correlated with dry macula at 12 months.After switching therapy to pegaptanib in persistent cases of AMD, most patients maintained or improved their BCVA and exhibited a positive treatment response at 12 months.",
"affiliations": "Department of Ophthalmology (CS, AO, MK, SM, AY), Kagawa University Faculty of Medicine, Kagawa; and Department of Ophthalmology (FS), Okayama University Medical School, Okayama, Japan.",
"authors": "Shiragami|Chieko|C|;Ono|Aoi|A|;Kobayashi|Mamoru|M|;Manabe|Saki|S|;Yamashita|Ayana|A|;Shiraga|Fumio|F|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; C495058:pegaptanib; D000069579:Ranibizumab",
"country": "United States",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2531944110.1097/MD.0000000000000116001165800ArticleObservational StudyEffect of Switching Therapy to Pegaptanib in Eyes With the Persistent Cases of Exudative Age-Related Macular Degeneration Shiragami Chieko MDOno Aoi MDKobayashi Mamoru MDManabe Saki COYamashita Ayana MDShiraga Fumio MDSahin. Alparslan Department of Ophthalmology (CS, AO, MK, SM, AY), Kagawa University Faculty of Medicine, Kagawa; and Department of Ophthalmology (FS), Okayama University Medical School, Okayama, Japan.Correspondence: Chieko Shiragami, Department of Ophthalmology, Kagawa University Faculty of Medicine, 1750-1 Ikenobe Miki-cho, Kagawa 7610793, Japan (e-mail: chappi@kms.ac.jp).10 2014 10 10 2014 93 18 e11622 7 2014 15 8 2014 15 8 2014 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins2014This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nPurpose of this study was to evaluate the efficacy of switching to pegaptanib monotherapy for persistent cases of exudative age-related macular degeneration (AMD).\n\nOut of 296 eyes of 296 patients treated with ranibizumab or ranibizumab combined with photodynamic therapy (PDT), 50 eyes of 50 AMD patients were found to be resistant to these treatments. Over a 12-month period, intravitreal pegaptanib (IVP) 0.3 mg was administered at intervals of 6 weeks until the exudation disappeared prospectively. All patients were examined with the following tests: best-corrected visual acuity (BCVA) and central retinal thickness (CRT), determined at the initial visit, before the first IVP (baseline), and at 12 months. The factors responsible for achieving dry macula with IVP were examined statistically.\n\nThe rate of persistent cases with intravitreal ranibizumab (IVR) and/or PDT was 17.0%. The mean number of IVPs administered was 5.4 (range, 2–9). Logarithm of the minimal angle of resolution BCVA at 12 months was stable or improved by ≥0.3 in 49 eyes (98.0%), with a significant improvement noted between the baseline and final BCVA (P = 0.01, paired t test). The CRT (mean ± standard deviation) was 446.9 ± 150.6 µm at the initial visit, 414.5 ± 146.5 µm at baseline, and 318.7 ± 99.0 µm at 12 months. There was a significant decrease in the mean CRT between the measurements at baseline and at 12 months after the first IVP (P = 0.002, Bonferroni correction). At 12 months, the exudative change was completely resolved in 27 eyes (54.0%) and reduced in 21 eyes (42.0%). The number of previous IVR treatments was significantly correlated with dry macula at 12 months.\n\nAfter switching therapy to pegaptanib in persistent cases of AMD, most patients maintained or improved their BCVA and exhibited a positive treatment response at 12 months.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nIntravitreal agents have been used to clinically treat exudative age-related macular degeneration (AMD). Agents used include pegaptanib sodium (Macugen; Valeant Pharmaceuticals/Pfizer Inc, New York, NY), which is an RNA aptamer that targets vascular endothelial growth factor1,2 (VEGF)165, and ranibizumab (Lucentis; Genentech Inc, South San Francisco, CA), which is a monoclonal antibody fragment that binds with all VEGF-A isoforms over a period of several years.3,4 In pivotal trials, ranibizumab was shown to provide significant improvement of the mean visual acuity as compared with the control therapy for AMD.3,4 It has been suggested that these results may be related to a mechanism of action in which ranibizumab binds to all VEGF-A isoforms.3–6\n\nEven though ranibizumab is usually administered for AMD, it is not uncommon for patients receiving this treatment to frequently develop tachyphylaxis.7,8 Keane et al9 first reported finding possible tachyphylaxis after AMD treatments. Their report concluded that even though the neurosensory retinal edema and subretinal fluid showed an early reduction to nadir after intravitreal ranibizumab (IVR) therapy, there was attenuation of the effect on the retina over time, which suggested possible tachyphylaxis. Several published studies have demonstrated that aflibercept was effective for reducing the exudation that resulted in tachyphylaxis due to ranibizumab during the treatment of wet AMD.10–12 These studies additionally reported that switching the therapy to aflibercept was only effective for reducing exudation and decreasing the central retinal thickness (CRT). This change in therapy did not lead to an improvement in the visual function.\n\nThe most important endpoint for wet AMD treatment should be not only the improvement or long-term maintenance of the visual function, but also the reduction of the exudation. The selection of further treatment depends on many factors, including the activity of recurrent choroidal neovascularization (CNV), presence of geographic atrophy (GA), and prior treatments, as well as individual patient considerations. Up until now, there have been no reports that have evaluated switching persistent wet AMD patients to pegaptanib monotherapy from other anti-VEGF agents. Therefore, the aim of the current study was to investigate the outcome and effect of switching persistent AMD cases resistant to ranibizumab, and/or combined photodynamic therapy (PDT), to pegaptanib monotherapy.\n\nPATIENTS AND METHODS\nBetween April 2010 and April 2012, we prospectively reviewed 296 eyes of 296 patients treated with ranibizumab or ranibizumab combined with PDT. A total of 50 eyes of 50 AMD patients were found to be resistant to these treatments.\n\nBefore starting pegaptanib monotherapy, all 296 patients received 3 initial consecutive monthly IVR injections followed by pro re nata. PDT-combined therapy with 3 monthly loading doses was performed for most of the polypoidal choroidal vasculopathy (PCV) and retinal angiomatous proliferation (RAP) patients.\n\nDespite an initial good response to the IVR treatment, optical coherence tomography (OCT) showed thickening of the macular exudate, and there was deterioration of the visual function in 50 of the patients. Over a 12-month period, intravitreal pegaptanib (IVP) 0.3 mg was administered at 6 week intervals until the exudative lesions resolved. Because there were not so many persistent AMD cases resistant to ranibizumab and/or combined PDT in this case series, all patients were examined for the effect of switching to pegaptanib monotherapy without establishing the control group.\n\nAll patients were examined with the following tests: best-corrected visual acuity (BCVA), fundus color photography and fluorescein angiography (FA) using the Topcon TRC-50DX fundus camera (Topcon, Tokyo, Japan), indocyanine green angiography (ICGA), and OCT using a Spectralis/Heidelberg Retina Angiograph 2 (Heidelberg Engineering, Heidelberg, Germany), at the initial visit, baseline, and at every subsequent visit during the 12-month follow-up period. CRT between the inner limiting membrane and Bruch membrane was measured by Spectralis. Lesion type, location, and activity of the CNV at the initial visit were determined using FA and ICGA.\n\nDuring the study period, OCT was used to monitor the resolution and recurrence of fluid in the eyes as the pegaptanib therapy was started and stopped. Patients were usually treated when OCT imaging indicated evidence of recurrent fluid.\n\nStatistical analyses were performed to compare the BCVA at the initial visit and immediately before the first IVP (baseline) with the BCVA at 12 months (paired t test). Analyses were also performed to compare the CRT between the initial visit, baseline, and at 12 months (Bonferroni correction). Moreover, the CRT was compared between baseline and 12 month for each type of AMD (paired t test). Multiple logistic regression analysis was performed in order to determine whether there was a significant association between the independent variables (which included age, previous treatments, and duration of disease) and the dependent variable (achieving dry macula at 12 months after baseline). A P value <0.05 was considered significant except for Bonferroni correction. The statistical analyses were carried out using SPSS Statistics version 21 (IBM SPSS, Inc, Chicago, IL).\n\nThis study was conducted in accordance with the Declaration of Helsinki. The study protocol and the subject-informed consent document were approved by the institutional review board/ethics committee at Kagawa University Faculty of Medicine. All patients gave their written, informed consent prior to participating.\n\nRESULTS\nThe clinical characteristics and clinical data for the 50 AMD patients who were switched to pegaptanib monotherapy are summarized in Table 1. The patients’ ages ranged from 61 to 90 years (mean, 77.7 years). Of the 50 AMD cases, 21 eyes were typical AMD (t-AMD), 23 eyes were PCV, and 6 eyes was RAP. FA findings at the initial visit were classified as occult with no classic lesions (7 eyes, 14.0%), minimally classic lesions (27 eyes, 54.0%), and predominantly classic lesions (16 eyes, 32.0%). Of the 296 eyes treated with IVR or PDT combined therapy, 50 eyes (16.9%) developed resistance after an initial positive morphological response to ranibizumab. On average, these patients each received a total of 7.1 ± 3.0 injections of ranibizumab (range, 4–14 injections) and underwent PDT for a total of 0.68 ± 0.65 times.\n\nTable 1 Baseline Clinical Characteristics of Persistent Cases of AMD in Patients Treated With Pegaptanib Monotherapy\n\nVisual Outcomes\nLogarithm of the minimal angle of resolution (logMAR) BCVA was improved by ≥0.3 in 9 eyes, stable in 40 eyes, and worsened by ≥0.3 in 1 eye at 12 months. The BCVA was stable or improved by ≥0.3 in 49 eyes (98.0%). As for the breakdown according to the type of AMD that logMAR BCVA improved by ≥0.3, there was 3 eyes (14.3%) in t-AMD, 4 eyes (17.4%) in PCV, and 2 eyes (50%) in RAP. The logMAR BCVA (mean ± standard deviation) was 0.53 ± 0.44 at the initial visit, 0.63 ± 0.41 at baseline and 0.56 ± 0.42 at 12 months. There was a significant improvement between the baseline and final BCVA (P = 0.011, paired t test) (Figure 1A).\n\nFIGURE 1 (A) Mean change in logMAR VA (whole type of AMD cases). This plot graph shows the changes in the mean BCVA in logMAR units at the initial visit, baseline, and at 12 months. The error bar values indicate the standard deviation. The logMAR BCVA (mean ± standard deviation) was 0.53 ± 0.44 at the initial visit, 0.63 ± 0.41 at baseline, and 0.56 ± 0.42 at 12 months. A significant improvement was seen between the baseline and the BCVA at the last visit (∗P = 0.01, paired t test). (B) Mean change in logMAR VA (each type of AMD cases). \nP value indicates the statistical correlation of logMAR BCVA between baseline and 12 months (paired t test). AMD = age-related macular degeneration, BCVA = best-corrected visual acuity, logMAR = logarithm of the minimal angle of resolution, NS = not significant, PCV = polypoidal choroidal vasculopathy, RAP = retinal angiomatous proliferation, t-AMD = typical AMD, VA = visual acuity.\n\nIn each type of AMD, the mean logMAR BCVA was improved from baseline to 12 months but not significant statistically (Figure 1B).\n\nRetreatment Rate\nThe mean number of IVP treatments during the 12-month study period was 5.42 ± 2.30 (range, 2–9).\n\nCRT Outcomes\nThe CRT (mean ± standard deviation) was 446.9 ± 150.6 µm at the initial visit, 414.5 ± 146.7 µm at baseline, and 318.7 ± 100.0 µm at 12 months. Although there was a significant decrease in the CRT at 12 months when compared with the initial visit and baseline measurements (P < 0.016, Bonferroni correction), there were no significant differences between the initial visit and baseline values (Figure 2A).\n\nFIGURE 2 (A) Mean change in CRT (whole type of AMD cases). Box plots show the CRT at the initial visit, baseline, and at 12 months. The CRT (mean ± standard deviation) was 446.9 ± 150.6 μm at the initial visit, 414.5 ± 146.5 μm at baseline, and 317.1 ± 99.1 μm at 12 months. A significant improvement in the CRT was seen between the initial visit and the measurements at 12 months (∗P < 0.001) and between the baseline and the measurements at 12 months (∗∗P = 0.002) (Bonferroni correction). (B) Mean change in CRT (each type of AMD cases). \nP value indicates the statistical correlation of CRT between baseline and 12 months (paired t test). AMD = age-related macular degeneration, CRT = central retinal thickness, NS = not significant, PCV = polypoidal choroidal vasculopathy, RAP = retinal angiomatous proliferation, t-AMD = typical AMD.\n\nIn each type of AMD, the mean CRT significantly decreased from baseline to 12 months (P < 0.05, paired t test, Figure 2B).\n\nAnatomic Improvement\nAt baseline, cystoid macular edema (CME) was observed in 23 eyes, whereas serous retinal detachment (SRD) was observed in 50 eyes and pigment epithelial detachment (PED) in 29 eyes. The exudative change completely resolved in 27 eyes (52%), decreased in 21 eyes (42%), and worsened in 2 eyes (6%) at 12 months (Figure 3). There was complete resolution of CME in 10 eyes (43.5%), SRD in 41 eyes (82.0%), and PED in 19 eyes (65.5%) at 12 months.\n\nFIGURE 3 The bar graph shows the change of the exudative lesion from the baseline to 12 months for 50 eyes with AMD, switched from ranibizumab and/or combined PDT to pegaptanib monotherapy. The exudative lesion disappeared completely in 52%, decreased in 42%, and worsened in 6%. AMD = age-related macular degeneration, PDT = photodynamic therapy.\n\nFactors for Achieving Dry Macula With IVP\nAlthough previous treatment of PDT had no influence on achieving dry macula at 12 months for the patients switched to IVP monotherapy (P = 0.39, Mann–Whitney U test), there was a significant correlation for the number of IVRs (P = 0.014, Mann–Whitney U test). Multiple logistic regression analysis revealed that the number of IVRs was significantly associated with achieving dry macula at 12 months (P = 0.027), whereas the absence of CME at baseline tended to be associated with dry macula (P = 0.064, Table 2).\n\nTable 2 Multiple Logistic Regression Model of Variables Associated With Achieving Dry Macula at 12 Months After Baseline\n\nAdverse Events and Complications\nThere were no serious adverse events related to the treatment. In addition, there were no complications such as inflammation, increased intraocular pressure, severe vision loss, endophthalmitis, or systemic thromboembolic events that developed during the study.\n\nCase Reports\nCase 1\nThe patient was a 74-year-old man with PCV who was resistant to the treatment with ranibizumab-combined PDT (Figure 4).\n\nFIGURE 4 In case 1, the patient was a 74-year-old man with PCV who was resistant to the treatment with ranibizumab-combined PDT. Subfoveal polypoidal lesion and vascular network was showed on early phase ICGA (A). The OCT revealed PED and SRD (B). Although the exudative lesion disappeared after 3 IVR-combined PDT (C), the PED and SRD recurred after 4 additional IVR (D). After that, ranibizumab was switched to pegaptanib; there was complete resolution of the PED and SRD (E). ICGA = indocyanine green angiography, IVR = intravitreal ranibizumab, OCT = optical coherence tomography, PCV = polypoidal choroidal vasculopathy, PDT = photodynamic therapy, PED = pigment epithelial detachment, SRD = serous retinal detachment.\n\nAt the initial visit, the BCVA was 20/60 in his left eye. Subfoveal polypoidal lesion and vascular network were showed on early phase ICGA (Figure 4A). The OCT revealed PED and SRD (Figure 4B), and the CRT was 407 µm.\n\nAlthough the exudative lesion disappeared after 3 IVR-combined PDT (Figure 4C), the PED and SRD were increased gradually after 4 additional IVR administrations (Figure 4D). Even though BCVA was maintained at 20/60, the CRT increased to 523 µm at 12 months after the last IVR. Thus, the patient’s anti-VEGF agent was switched from ranibizumab to pegaptanib (baseline).\n\nAfter the switch, the patient underwent pegaptanib monotherapy 3 times (performed at 6-week intervals). At 12 months after the baseline observations, there was complete resolution of the PED and SRD, BCVA increased to 20/50, and CRT dramatically decreased to 226 µm (Figure 4E).\n\nCase 2\nThe patient was a 90-year-old woman with t-AMD who was resistant to the treatment with ranibizumab monotherapy (Figure 5).\n\nFIGURE 5 In case 2, the patient was a 90-year-old woman with t-AMD who was resistant to the treatment with ranibizumab monotherapy. The FA showed minimally classic CNV (A, early phase; B, late phase), and OCT revealed the presence of SRD, small PED, and CME (C). The exudative lesion almost resolved after 9 IVRs at 12 months (D). At 3 months after the last IVR, because there was exacerbation of the CME (E), ranibizumab was switched to pegaptanib. At 12 months after baseline, there was complete resolution of the CME (F). AMD = age-related macular degeneration, CNV = choroidal neovascularization, CME = cystoid macular edema, CRT = central retinal thickness, FA = fluorescein angiography, IVR = intravitreal ranibizumab, OCT = optical coherence tomography, RD = subretinal detachment, PED = pigment epithelial detachment, SRD = serous retinal detachment, t-AMD = typical AMD.\n\nAt the initial visit, the BCVA was 20/20 and the CRT was 442 µm in her left eye. FA showed minimally classic CNV (Figure 5A, early phase; Figure 5B, late phase) and OCT revealed the presence of SRD, small PED, and CME (Figure 5C).\n\nThe exudative lesion almost resolved after 9 times IVR at 12 months (Figure 5D). Three months after the last IVR, there was exacerbation of the CME, OCT showed the CRT increased to 394 µm (Figure 5E), and her BCVA decreased to 20/40. Thus, the patient’s anti-VEGF agent was switched from ranibizumab to pegaptanib. After the switch, the patient underwent pegaptanib monotherapy 6 times (performed at 6-week intervals). At 12 months after the baseline observations, the CME completely resolved, BCVA improved to 20/20, and the CRT dramatically decreased to 285 µm (Figure 5F).\n\nDISCUSSION\nIn the present study, pegaptanib appears to have been strongly effective in those patients who did not respond to frequent IVR and/or multiple PDT therapy. In patients who achieved dry macula at 12 months after switching to pegaptanib, there was a significant association with the number of IVR treatments, but not with the number of PDT procedures. The reason why persistent exudative lesions exist in wet AMD in spite of continued IVR monotherapy and/or combined PDT therapy may be because of the tachyphylaxis that occurs with IVR.\n\nA retrospective study showed that anti-VEGF tachyphylaxis appeared in 38% of the AMD patients given bevacizumab, whereas 19% exhibited tachyphylaxis following treatment with ranibizumab.7 In a second retrospective review of 976 patients, the rate of tachyphylaxis was found to be 2%.8 In our current study, the rate of persistent cases, which may have been because of tachyphylaxis that occurred with the ranibizumab, was 17.0%.\n\nThe reason why pegaptanib is effective in patients with AMD who have developed tachyphylaxis to repeated ranibizumab administrations may be because of the impact of intraocular VEGF165, in particular, on the pathological condition. During the initial period when the drug continued to be effective, ranibizumab may have adequately inhibited VEGF-A and been able to block or slow the pathological angiogenesis. Thus, the main stalk cells of CNV may be almost completely occluded by the VEGF121 blockade caused by ranibizumab. However, if its ability to completely suppress VEGF-A wanes due to drug tolerance, the VEGF165 blockade of pegaptanib may be sufficient by itself to affect the induction of the remaining tip cells of CNV. Given the fact that pegaptanib proved to be effective in the present cases, we conjectured that VEGF165, in particular, was able to affect the patient’s condition. In fact, animal experiments and studies in humans have demonstrated the importance of VEGF165, which is both soluble and insoluble.13–16 In angiogenesis, both soluble and insoluble isoforms are known to be necessary for sprouting. Because the amount of VEGF165 is significantly greater than that seen for other VEGF isoforms, including VEGF121, this isoform is thought to play a central role in angiogenesis. Thus, this may explain why pegaptanib, which only inhibits VEGF165, is effective for ranibizumab-resistant AMD. Moreover, the fact that pegaptanib is immunologically lenient because it is an aptamer and not an antibody might also be a factor in its action.\n\nThe other reason why pegaptanib is effective in AMD patients who developed tolerance and stopped responding to repeated administrations of ranibizumab may be because of the growth factor, platelet-derived growth factor (PDGF). This growth factor is involved in a variety of different mechanisms of action, such as being responsible for pericyte recruitment and survival.17,18 Furthermore, pericytes confer anti-VEGF resistance.19 Because Pfizer’s internal data have shown that pegaptanib has a weak binding ability with PDGF, if pericytes are the source of resistance for the anti-VEGF therapy in neovascular AMD, this suggests there would be a better result when anti-PDGF and anti-VEGF therapies are combined.\n\nSupport of this postulate comes from the 2012 American Academy of Ophthalmology Annual Meeting at which phase 2b study results for anti-PDGF and anti-VEGF combination therapy were presented. Although this is just 1 theory, these results suggest that the anti-PDGF effect of pegaptanib could be beneficial for treating patients exhibiting ranibizumab tolerance.\n\nOverall, these previous results suggest that pegaptanib, which targets VEGF165 and PDGF, can be of benefit when switching from ranibizumab. Additionally, in patients who show evidence of tachyphylaxis following treatment with ranibizumab for AMD, pegaptanib might be a better alternative to either bevacizumab or aflibercept, which bind to all VEGF-A isoforms.\n\n“Angiogenic” events include sprouting morphogenesis and cell growth, which involves splitting, remodeling, and stabilization.19–22 At the cellular level, angiogenesis involves at least 2 distinct cell types, endothelial cells and supporting cells. In addition, it also requires a number of different cellular functions, such as migration, proliferation, cell survival, differentiation, and specialization. During angiogenesis, VEGF plays a key role in most, if not all, of these morphogenic events.\n\nThe cellular mechanisms that guide the pattern for vascular sprouting include the graded distribution of VEGF and the sequential steps that involve the induction of a tip cell by VEGF, polarization of a tip cell with rapid directed migration, and proliferation of the stalk cells. The proliferation of the stalk cells is primarily associated with VEGF121, whereas the induction and polarization of a tip cell15,16 are strongly associated with VEGF165.\n\nAlthough the issue of VEGF-dependent ocular homeostasis is yet to be examined clinically, preclinical data have suggested that during ischemic conditions, VEGF121 may play an essential retinal neuroprotective role.22 This previous study additionally determined that VEGF121, which is the isoform spared by pegaptanib, was required for neuroprotection. When there was sustained inhibition of all of the VEGF-A isoforms, this ultimately led to a progressive loss of the retinal ganglion cells. Moreover, it has been proposed that the pan-VEGF blockade, especially the VEGF121 blockade, may be responsible for increasing the GA for AMD, thereby resulting in a poor visual prognosis.23–26 In a recent report, that evaluated the 7-year outcomes for ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON databases, macular atrophy was detected by fundus autofluorescence in 98% of the eyes, with a mean area26 of 9.4 mm2. This report determined that the area of atrophy was significantly correlated with poor visual outcome (P < 0.001). The development of macular atrophy leading to GA may be related to the frequency of pan-VEGF-A blockade treatments.23,24,26\n\nIn this study, the patient group was not homogeneous, both AMD and PCV patients were included. In spite of this difference, similar treatment effect was archived for any type of AMD.\n\nIn conclusion, switching patients from ranibizumab to pegaptanib may be able to help maintain or improve the visual function by preventing recurrence of CNV activity in AMD patients who develop tolerance to ranibizumab. The most beneficial properties of pegaptanib use appear to be the maintenance of normal retinal function and the prevention of GA, as pegaptanib does not cause pan-VEGF-A blockage. Larger and long-term observational studies will need to be undertaken in order to definitively determine the efficacy of switching anti-VEGF therapeutic agents in patients with AMD.\n\nAbbreviations: AMD = age-related macular degeneration, BCVA = best-corrected visual acuity, CME = cystoid macular edema, CNV = choroidal neovascularization, CRT = central retinal thickness, FA = fluorescein angiography, GA = geographic atrophy, ICGA = indocyanine green angiography, IVP = intravitreal pegaptanib, IVR = intravitreal ranibizumab, logMAR = logarithm of the minimal angle of resolution, OCT = optical coherence tomography, PCV = polypoidal choroidal vasculopathy, PDGF = platelet-derived growth factor, PDT = photodynamic therapy, PED = pigment epithelial detachment, RAP = retinal angiomatous proliferation, SRD = serous retinal detachment, t-AMD = typical AMD, VEGF = vascular endothelial growth factor.\n\nCS and AY contributed with study conception and design; CS, AY, AO, MK, and SM contributed with data acquisition; CS contributed with analysis and interpretation of the data; CS and FS contributed with drafting and revising the article; CS contributed with the final approval.\n\nThe authors have no funding to disclose.\n\nThe authors have no proprietary interest in any aspect of this study.\n==== Refs\nReferences\n1 Apte RS Modi M Masonson H ; Macugen AMD Study Group . Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration . Ophthalmology . 2007 ;114 :1702 –1712 .17509689 \n2 Takeda AL Colquitt J Clegg AJ \nPegaptanib and ranibizumab for neovascular age-related macular degeneration: a systematic review . Br J Ophthalmol . 2007 ;91 :1177 –1182 .17475698 \n3 Rosenfeld PJ Brown DM Heier JS \nRanibizumab for neovascular age-related macular degeneration . N Engl J Med . 2006 ;355 :1419 –1431 .17021318 \n4 Boyer DS Antoszyk AN Awh CC ; MARINA Study Group . Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration . Ophthalmology . 2007 ;114 :246 –252 .17270674 \n5 The CATT Research Group . Ranibizumab and Bevacizumab for neovascular age-related macular degeneration . N Engl J Med . 2011 ;1 –13 .\n6 Regillo CD Brown DM Abraham P \nRandomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1 . Am J Ophthalmol . 2008 ;145 :239 –248 .18222192 \n7 Gasperini JL Fawzi AA Khondkaryan A \nSwitching anti-VEGF drugs may address most cases of tachyphylaxis to anti-VEGF therapy . Br J Ophthalmol . 2012 ;96 :14 –20 .21791509 \n8 Eghøj MS Sørensen TL \nTachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab . Br J Ophthalmol . 2012 ;96 :21 –23 .21733918 \n9 Keane PA Liakopoulos S Ongchin SC \nQuantitative subanalysis of optical coherence tomography after treatment with ranibizumab for neovascular age-related macular degeneration . Invest Ophthalmol Vis Sci . 2008 ;49 :3115 –3120 .18408176 \n10 Cho H Shah CP Weber M \nAflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab . Br J Ophthalmol . 2013 ;97 :1032 –1035 .23766432 \n11 Ho VY Yeh S Olsen TW \nShort-term outcomes of aflibercept for neovascular age-related macular degeneration in eyes previously treated with other vascular endothelial growth factor inhibitors . Am J Ophthalmol . 2013 ;156 :23 –28 .23664153 \n12 Heussen FM Shao Q Ouyang Y \nClinical outcomes after switching treatment from intravitreal ranibizumab to aflibercept in neovascular age-related macular degeneration . Graefes Arch Clin Exp Ophthalmol . 2014 ;252 :909 –915 .24362854 \n13 Soker S Gollamudi-Payne S Fidder H \nInhibition of vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation by a peptide corresponding to the exon 7-encoded domain of VEGF165 . J BiolChem . 1997 ;272 :31582 –31588 .\n14 Ishida S Usui T Yamashiro K \nVEGF164 is proinflammatory in the diabetic retina . Invest Ophthalmol Vis Sci . 2003 ;44 :2155 –2162 .12714656 \n15 Ruhrberg C Gerhardt H Golding M \nSpatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis . Genes Dev . 2002 ;16 :2684 –2698 .12381667 \n16 Gerhardt H \nVEGF and endothelial guidance in angiogenic sprouting . Organogenesis . 2008 ;4 :24124 –24126 .\n17 Benjamin LE Hemo I Keshet E \nA plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF . Development . 1998 ;125 :1591 –1598 .9521897 \n18 Lindahl P Johansson BR Levéen P \nPericyte loss and microaneurysm formation in PDGF-B-deficient mice . Science . 1997 ;277 :242 –245 .9211853 \n19 Reinmuth N Liu W Jung YD \nInduction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival . FASEB J . 2001 ;15 :1239 –1241 .11344100 \n20 Hoffman BB Taylor P \nNeurotransmission: the autonomic and somatic motor nervous systems . In: Goodman LS Hardman JG Limbird LE eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics . 10th ed \nNew York : McGraw-Hill ; 2001 :115 –154 .\n21 Risau W \nMechanisms of angiogenesis . Nature . 1997 ;386 :671 –674 .9109485 \n22 Nishijima K Ng YS Zhong L \nVascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury . Am J Pathol . 2007 ;171 :53 –67 .17591953 \n23 Altaweel MM \nV.I.S.I.O.N. Study Group . Effects of intravitreal injection of pegaptanib on the retinal pigment epithelium and optic nerve . Invest Ophthalmol Vis Sci . 2007 ;48 :E-3369 .\n24 Saint-Geniez M Kurihara T Sekiyama E \nAn essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris . PNAS . 2009 ;106 :18751 –18756 .19841260 \n25 Sunness JS Gonzalez-Baron J Applegate CA \nEnlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration . Ophthalmology . 1999 ;106 :1768 –1779 .10485549 \n26 Rofagha S Bhisitkul RB Boyer DS ; for the SEVEN-UP Study Group . Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP) . Ophthalmology . 2013 ; 120 :2292 –2299 .23642856\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "93(18)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; D003131:Combined Modality Therapy; D057915:Drug Substitution; D005122:Exudates and Transudates; D005260:Female; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D010778:Photochemotherapy; D011446:Prospective Studies; D011859:Radiography; D000069579:Ranibizumab; D012160:Retina; D012163:Retinal Detachment; D041623:Tomography, Optical Coherence; D017211:Treatment Failure; D014792:Visual Acuity",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e116",
"pmc": null,
"pmid": "25319441",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "17021318;21733918;12381667;18408176;21791509;23766432;24362854;17591953;23664153;19841260;18222192;17270674;17509689;10485549;9211853;11344100;17475698;23642856;9521897;12714656;9395496;9109485;21526923;19337404",
"title": "Effect of switching therapy to pegaptanib in eyes with the persistent cases of exudative age-related macular degeneration.",
"title_normalized": "effect of switching therapy to pegaptanib in eyes with the persistent cases of exudative age related macular degeneration"
} | [
{
"companynumb": "JP-ROCHE-2195408",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "OBJECTIVE\nWe report the first comparison between rituximab (RTX) and either MMF or CYC pulses in the treatment of active LN.\n\n\nMETHODS\nFifty-four patients with active LN received three methylprednisolone pulses for 3 consecutive days followed by oral prednisone and RTX 1 g at days 3 and 18 (17 patients) or MMF 2-2.5 g/day (17 patients) or six CYC pulses (0.5 g every fortnight) (20 patients). At 4 months MMF, AZA or ciclosporin were associated to prednisone as a consolidation/maintenance therapy in all groups. The outcomes of the three groups were compared at 3 and 12 months.\n\n\nRESULTS\nPatients in the RTX group were older, had a longer duration of SLE and LN, had more renal flares, had higher activity and had higher chronicity indexes at renal biopsy than the other two groups. Four patients in each group had acute renal dysfunction and ∼50% had nephrotic syndrome. At 3 months, proteinuria was reduced by 50% in 58.8% of patients on RTX, in 64.7% on MMF and in 63.1% on CYC. At 12 months, complete remission was present in 70.6% of patients on RTX, in 52.9% on MMF, and in 65% on CYC. Partial remission was reached in 29.4% on RTX, 41.2% on MMF, and 25% on CYC.\n\n\nCONCLUSIONS\nRTX seems to be at least as effective as MMF and CYC pulses in inducing remission. Considering that patients treated with RTX had more negative renal prognostic factors, this drug should be considered a viable alternative for the treatment of active LN.",
"affiliations": "Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy. gmoroni@policlinico.mi.it.;Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy.;Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy.;Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy.;Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy.;Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy.;Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy.;Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy.;Divisione di Nefrologia & Dialisi, IRCCS Fondazione Ca' Granda, Ospedale Maggiore, Mangiagalli, Regina Elena, Divisone di Nefrologia e Immunologia clinica, Ospedale San Carlo Borromeo, Dipartimento di Reumatologia, Unita' Operativa di Day Hospital, Istituto G. Pini and Dipartimento di Reumatologia, Istituto G. Pini and IRCCS Istituto Auxologico Italiano, Milano, Italy.",
"authors": "Moroni|Gabriella|G|;Raffiotta|Francesca|F|;Trezzi|Barbara|B|;Giglio|Elisa|E|;Mezzina|Nicoletta|N|;Del Papa|Nicoletta|N|;Meroni|Pierluigi|P|;Messa|Piergiorgio|P|;Sinico|Alberto Renato|AR|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D007166:Immunosuppressive Agents; D000069283:Rituximab; D003520:Cyclophosphamide; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/ket462",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "53(9)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "cyclophosphamide pulse therapy; lupus nephritis; mycophenolate therapy; rituximab therapy; systemic lupus erythematosus",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "1570-7",
"pmc": null,
"pmid": "24505125",
"pubdate": "2014-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study.",
"title_normalized": "rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis a clinical observational study"
} | [
{
"companynumb": "IT-BAXTER-2014BAX060426",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Langerhans cell sarcoma (LCS) is a rare neoplastic proliferation of Langerhans cells with a poor prognosis. Owing to its rarity, standard treatment for LCS has not been established to date. Here, we report a case of LCS occurring in multiple lymph nodes in the right cervix in which remission is maintained by autologous hematopoietic stem cell transplantation (auto-HSCT) after surgical resection. A 58-year-old male presented with enlarged right submandibular lymph nodes. Positron-emission tomography/computed tomography (PET/CT) revealed multiple lymphadenopathies in his right cervix. We performed a lymph node biopsy, and he was diagnosed with LCS. We selected the CHOP regimen as the first-line chemotherapy; however, rapid disease progression was observed soon after the first cycle of the therapy. The neck dissection was performed on day 16 of the CHOP therapy. As the residual tumor was suspected, we started the second-line chemotherapy with a combination of etoposide, cisplatin, ifosfamide, and gemcitabine; complete remission was confirmed by PET/CT. Subsequently, the patient was administered high-dose chemotherapy with auto-HSCT. After 2 years of auto-HSCT, complete remission has been maintained. Although there is no report of auto-HSCT for LCS, it could be an effective therapeutic tool for the disease.",
"affiliations": "Department of Hematology, Osaka City General Hospital.;Department of Hematology, Osaka City General Hospital.;Department of Hematology, Osaka City General Hospital.;Department of Hematology, Osaka City General Hospital.;Department of Hematology, Osaka City General Hospital.;Department of Hematology, Osaka City General Hospital.;Department of Hematology, Osaka City General Hospital.;Department of Hematology, Osaka City General Hospital.;Department of Pathology, Osaka City General Hospital.;Department of Pathology, Osaka City General Hospital.;Department of Otorhinolaryngology, Osaka City General Hospital.;Department of Hematology, Osaka City General Hospital.",
"authors": "Fuseya|Hoyuri|H|;Nakao|Takafumi|T|;Tsutsumi|Minako|M|;Nakaya|Yosuke|Y|;Horiuchi|Mirei|M|;Yoshida|Masahiro|M|;Yoshimura|Takuro|T|;Hayashi|Yoshiki|Y|;Fukushima|Hiroko|H|;Inoue|Takeshi|T|;Aiba|Tsunemasa|T|;Yamane|Takahisa|T|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.60.314",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "60(4)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Auto-HSCT; Langerhans cell sarcoma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D054752:Langerhans Cell Sarcoma; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D011239:Prednisolone; D012074:Remission Induction; D014182:Transplantation, Autologous; D014750:Vincristine",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "314-318",
"pmc": null,
"pmid": "31068562",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Durable remission of Langerhans cell sarcoma attained by autologous hematopoietic stem cell transplantation following surgical resection.",
"title_normalized": "durable remission of langerhans cell sarcoma attained by autologous hematopoietic stem cell transplantation following surgical resection"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-224484",
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"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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"abstract": "The somatotropic axis is intricately involved in normal sleep, as evidenced by the fact that hypothalamic growth hormone-releasing hormone (GHRH) has sleep promoting effects and pituitary growth hormone (GH) release is strongly associated with slow-wave sleep (SWS). Abnormalities in the somatotropic axis, such as GH deficiency of hypothalamic or pituitary origin, result in an alteration of normal sleep patterns which may explain the fatigue reported in these individuals. Sleep disorders such as narcolepsy, in which individuals abnormally enter rapid eye movement (REM) sleep at sleep onset are also associated with an altered GHRH circadian rhythm and abnormal GH secretion. While few studies are available, this review explores what is known about sleep abnormalities in GH deficiency, the effect of treatment on sleep in patients with GH deficiency, and GH secretion in narcolepsy. Emerging evidence suggests a hypothalamic link between narcolepsy and GH secretion. We also describe the unique constellation of isolated idiopathic GH deficiency and severe excessive sleepiness in adopted Nicaraguan siblings, one of which has narcolepsy and the other idiopathic hypersomnia.",
"affiliations": "Indiana University School of Medicine, Riley Hospital for Children, Fellow, Endocrinology and Diabetes, 705 Riley Hospital Drive, Room 5960, Indianapolis, IN 46202, USA, E-mail: agohil@iu.edu.;Indiana University School of Medicine, Riley Hospital for Children, Endocrinology and Diabetes, 705 Riley Hospital Drive, Room 5960, Indianapolis, IN 46202, USA.",
"authors": "Gohil|Anisha|A|;Eugster|Erica|E|",
"chemical_list": "D019382:Human Growth Hormone; D013007:Growth Hormone-Releasing Hormone",
"country": "Israel",
"delete": false,
"doi": "10.17458/per.vol17.2019.ge.ghdeficiencyandsleepiness",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1565-4753",
"issue": "17(1)",
"journal": "Pediatric endocrinology reviews : PER",
"keywords": "Growth Hormone Deficiency; Idiopathic Hypersomnia; Narcolepsy; Slow-wave Sleep",
"medline_ta": "Pediatr Endocrinol Rev",
"mesh_terms": "D002648:Child; D004393:Dwarfism, Pituitary; D013007:Growth Hormone-Releasing Hormone; D019382:Human Growth Hormone; D006801:Humans; D009290:Narcolepsy; D000077260:Sleepiness",
"nlm_unique_id": "101202124",
"other_id": null,
"pages": "41-46",
"pmc": null,
"pmid": "31599135",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15135771;12374492;16817827;11106980;572007;19998868;7397291;457840;3227222;1445594;8476038;1361964;24816469;12453828;10973318;4307378;2595174;27707443;8848933;4302913;14161512;11055430;1592893;17969461;2106091;9779515;20332249;5675428;8300049;15090035;25406443;8772566;23447518;981985;21464567;467171;15358440;30556659;26716917;28247315;8779943;15132732",
"title": "Growth Hormone Deficiency and Excessive Sleepiness: A Case Report and Review of the Literature.",
"title_normalized": "growth hormone deficiency and excessive sleepiness a case report and review of the literature"
} | [
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"companynumb": "US-PFIZER INC-2019503775",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SOMATROPIN"
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{
"abstract": "OBJECTIVE\nTo compare the efficacy and safety of scheduled low-dose haloperidol versus placebo for the prevention of delirium (Intensive Care Delirium Screening Checklist ≥ 4) administered to critically ill adults with subsyndromal delirium (Intensive Care Delirium Screening Checklist = 1-3).\n\n\nMETHODS\nRandomized, double-blind, placebo-controlled trial.\n\n\nMETHODS\nThree 10-bed ICUs (two medical and one surgical) at an academic medical center in the United States.\n\n\nMETHODS\nSixty-eight mechanically ventilated patients with subsyndromal delirium without complicating neurologic conditions, cardiac surgery, or requiring deep sedation.\n\n\nMETHODS\nPatients were randomly assigned to receive IV haloperidol 1 mg or placebo every 6 hours until delirium occurred (Intensive Care Delirium Screening Checklist ≥ 4 with psychiatric confirmation), 10 days of therapy had elapsed, or ICU discharge.\n\n\nRESULTS\nBaseline characteristics were similar between the haloperidol (n = 34) and placebo (n = 34) groups. A similar number of patients given haloperidol (12/34 [35%]) and placebo (8/34 [23%]) developed delirium (p = 0.29). Haloperidol use reduced the hours per study day spent agitated (Sedation Agitation Scale ≥ 5) (p = 0.008), but it did not influence the proportion of 12-hour ICU shifts patients spent alive without coma (Sedation Agitation Scale ≤ 2) or delirium (p = 0.36), the time to first delirium occurrence (p = 0.22), nor delirium duration (p = 0.26). Days of mechanical ventilation (p = 0.80), ICU mortality (p = 0.55), and ICU patient disposition (p = 0.22) were similar in the two groups. The proportion of patients who developed corrected QT-interval prolongation (p = 0.16), extrapyramidal symptoms (p = 0.31), excessive sedation (p = 0.31), or new-onset hypotension (p = 1.0) that resulted in study drug discontinuation was comparable between the two groups.\n\n\nCONCLUSIONS\nLow-dose scheduled haloperidol, initiated early in the ICU stay, does not prevent delirium and has little therapeutic advantage in mechanically ventilated, critically ill adults with subsyndromal delirium.",
"affiliations": "1School of Pharmacy, Northeastern University, Boston, MA.2Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada.3Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, Boston, MA.4Department of Psychiatry, Tufts Medical Center, Boston, MA.5Department of Pharmacy, Tufts Medical Center, Boston, MA.6Research Design Center and Biostatistics Research Center, Tufts Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA.",
"authors": "Al-Qadheeb|Nada S|NS|;Skrobik|Yoanna|Y|;Schumaker|Greg|G|;Pacheco|Manuel N|MN|;Roberts|Russel J|RJ|;Ruthazer|Robin R|RR|;Devlin|John W|JW|",
"chemical_list": "D014150:Antipsychotic Agents; D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1097/CCM.0000000000001411",
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"issn_linking": "0090-3493",
"issue": "44(3)",
"journal": "Critical care medicine",
"keywords": null,
"medline_ta": "Crit Care Med",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D003128:Coma; D016638:Critical Illness; D003693:Delirium; D004311:Double-Blind Method; D005260:Female; D006220:Haloperidol; D006801:Humans; D007362:Intensive Care Units; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011595:Psychomotor Agitation; D012121:Respiration, Artificial; D014481:United States",
"nlm_unique_id": "0355501",
"other_id": null,
"pages": "583-91",
"pmc": null,
"pmid": "26540397",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "11430542;25369558;11511942;15082703;1959406;8659621;8844239;10446827;15559753;16181163;17404704;17933157;18074477;18191684;18291021;19188334;19446324;19786862;19915454;20095068;20142454;20375300;20833940;21926597;22323509;22067628;22436797;22784203;22941208;23040282;23269131;22596087;24261644;24401069;24461612;24394627;24815803;23327295;25402299;25251759;25289932",
"title": "Preventing ICU Subsyndromal Delirium Conversion to Delirium With Low-Dose IV Haloperidol: A Double-Blind, Placebo-Controlled Pilot Study.",
"title_normalized": "preventing icu subsyndromal delirium conversion to delirium with low dose iv haloperidol a double blind placebo controlled pilot study"
} | [
{
"companynumb": "US-JNJFOC-20160303132",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPostpartum deep vein thrombosis is a unique condition in diagnosis and treatment. Rivaroxaban, a novel oral anticoagulant, is indicated for acute deep vein thrombosis, but limited data have been reported for postpartum women. Catheter-directed thrombolysis is a common procedure for treating acute deep vein thrombosis, but it is rarely used for postpartum patients, especially after more than 3 months.\nA 31-year-old Asian woman suffered from progressive erythematous swelling and local heat of the left lower limb after twin delivery.\nVenous duplex ultrasound examination showed thrombus formation in the left femoral vein and popliteal vein with reduced compressibility. After standard treatment of novel oral anticoagulant therapy for 4 months, we observed only partial improvement of the symptoms, and the condition deteriorated after her ordinary activities.\n\n\nMETHODS\nVenography was performed and a large amount of thrombus lining from left femoral vein to left iliac vein was noted with total occluded left common iliac vein. After catheter-directed thrombolysis and balloon dilatation, better flow was regained and her symptoms improved completely after procedure.\n\n\nRESULTS\nDuring a 1-year follow-up without medication, the patient did not complain about leg swelling, exercise aggravation, or any other post-thrombotic symptoms.\n\n\nCONCLUSIONS\nPregnancy seems to be a transient provoking factor for deep vein thrombosis, but it is sometimes refractory even during the postpartum period.Follow-up imaging studies should be encouraged to confirm the vessel condition, particularly for applying down-titration or discontinuation strategies of medication.Catheter-directed thrombolysis could be considered as an alternative method for postpartum iliofemoral deep vein thrombosis. Postpartum women usually have favorable functional status and lower bleeding risk.Rivaroxaban is a favorable choice for deep vein thrombosis, but its use in postpartum women is still controversial, and evidence of its effectiveness is not available. Thus, endovascular intervention can be a relatively safe therapy, in addition to anticoagulation therapy for premenopausal patients with recurrent deep vein thrombosis.",
"affiliations": "Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital.;Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital.",
"authors": "Chen|Po-Wei|PW|;Liu|Ping-Yen|PY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000016052",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31192964MD-D-18-0983010.1097/MD.0000000000016052160523400Research ArticleClinical Case ReportPostpartum deep vein thrombosis resolved by catheter-directed thrombolysis A case reportChen Po-Wei MD, MSabLiu Ping-Yen MD, PhDab∗NA. a Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospitalb Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.∗ Correspondence: Ping-Yen Liu, Division of Cardiology, Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng-Li Road, Tainan City 70403, Taiwan (e-mail: larry@mail.ncku.edu.tw).6 2019 14 6 2019 98 24 e160528 1 2019 25 4 2019 24 5 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nPostpartum deep vein thrombosis is a unique condition in diagnosis and treatment. Rivaroxaban, a novel oral anticoagulant, is indicated for acute deep vein thrombosis, but limited data have been reported for postpartum women. Catheter-directed thrombolysis is a common procedure for treating acute deep vein thrombosis, but it is rarely used for postpartum patients, especially after more than 3 months.\n\nPatient concerns:\nA 31-year-old Asian woman suffered from progressive erythematous swelling and local heat of the left lower limb after twin delivery.\n\nDiagnoses:\nVenous duplex ultrasound examination showed thrombus formation in the left femoral vein and popliteal vein with reduced compressibility. After standard treatment of novel oral anticoagulant therapy for 4 months, we observed only partial improvement of the symptoms, and the condition deteriorated after her ordinary activities.\n\nInterventions:\nVenography was performed and a large amount of thrombus lining from left femoral vein to left iliac vein was noted with total occluded left common iliac vein. After catheter-directed thrombolysis and balloon dilatation, better flow was regained and her symptoms improved completely after procedure.\n\nOutcomes:\nDuring a 1-year follow-up without medication, the patient did not complain about leg swelling, exercise aggravation, or any other post-thrombotic symptoms.\n\nLessons:\nPregnancy seems to be a transient provoking factor for deep vein thrombosis, but it is sometimes refractory even during the postpartum period.\n\nFollow-up imaging studies should be encouraged to confirm the vessel condition, particularly for applying down-titration or discontinuation strategies of medication.\n\nCatheter-directed thrombolysis could be considered as an alternative method for postpartum iliofemoral deep vein thrombosis. Postpartum women usually have favorable functional status and lower bleeding risk.\n\nRivaroxaban is a favorable choice for deep vein thrombosis, but its use in postpartum women is still controversial, and evidence of its effectiveness is not available. Thus, endovascular intervention can be a relatively safe therapy, in addition to anticoagulation therapy for premenopausal patients with recurrent deep vein thrombosis.\n\nKeywords\ncatheter-directed thrombolysispostpartumthrombosisvenous thrombosisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nVenous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism, is a common disorder with an annual incidence of approximately 1 case per 1000 persons.[1] Nearly two-thirds of VTE episodes manifest as DVT and one-third as pulmonary embolism with or without DVT. The background risk factors for VTE must be explored to determine whether it is modifiable. Pregnancy and the puerperium are two of the most well-established provoked factors for VTE.[2] However, the treatment strategy for such patients remains uncertain.\n\nDuring the third trimester and during the first 2 weeks following delivery, women have a relatively high risk of VTE, which is the leading cause of maternal death in Western countries.[3] The subjective clinical assessment of DVT is usually difficult during pregnancy, with a limited number of women having the opportunity to complete the diagnosis confirmed using objective exams. In general, women have bilateral leg edema developed at the third trimester, even lasting to the postpartum period, thus masking the signs of DVT over the legs. In addition, bed rest and hormonal therapy during pregnancy are often prescribed for symptomatic relief, and these management methods may increase the risk of DVT. With multiple reversible risk factors for DVT in such patients, the physiological response of the pregnancy process remains the most inevitable and easily ignored factor for hypercoagulopathy.[3]\n\nCurrent guidelines recommend the use of subcutaneous low-molecular-weight heparin, rather than intravenous unfractionated heparin or vitamin K antagonists, for women during pregnancy.[3] Notably, anti-Xa inhibitors, which are among the novel oral anticoagulant (NOAC), are not currently recommended for pregnant women.[2,3] Their use in postpartum women is also controversial, and evidence of their effectiveness in such women is not available. In this paper, we report a case of a postpartum woman diagnosed as having DVT with possible NOAC treatment failure, who was rescued using catheter-directed thrombolysis.\n\n2 Patient information and clinical findings\nA 31-year-old Asian woman was found to have twin pregnancy during her first gravida. She initially presented frequent vaginal bleeding, and her obstetrician prescribed oral progesterone at a dosage of 300 to 400 mg per day (Utrogestan) and intramuscular progesterone at a dosage of 125 mg/amp per week (Progeston Depot-s) since her 8th week of gestation. However, because of early uterine contraction and cervical incontinence, she started to take additional ritodrine at 10 mg 6 times daily (Yutopar) and rectal indomethacin since her 18th week of gestation. After Mcdonald cerclage was performed at the 21st week of gestation, she restricted her daily activities at home and rested in bed most of the time, following her obstetrician's advice. A cesarean section was then arranged at the 32nd week due to frequent uterine contractions. However, progressive erythematous swelling and local heat of the left lower limb were found on the 14th day after delivery. In addition, she denied dyspnea, chest pain, fever, chills, cough, and hemoptysis.\n\nVenous duplex ultrasound examination showed thrombus formation in the left femoral vein and popliteal vein with reduced compressibility. Under the impression of DVT with VTE, a regimen of rivaroxaban (15 mg) twice daily was prescribed after discussion by mode of shared decision making with families and patient herself.\n\nAfter oral anticoagulation therapy with additional medical compression stocking, her leg swelling was ameliorated gradually 3 days later. On the basis of current clinical trial and treatment guidelines, we switched the regimen to rivaroxaban (20 mg) once daily after 21 days.\n\nAfter 3 months of anticoagulation therapy, we observed only partial improvement of the symptoms, and the condition deteriorated after her ordinary activities. Repeated venous duplex ultrasound examination revealed residual thrombus in the left femoral vein. For further evaluation and management, we performed invasive venous angiography.\n\n3 Interventions\nVenography was performed through the left popliteal vein after popliteal vein cannulation under ultrasound guidance. We observed a large amount of thrombus lining from the femoral vein to the iliac vein. We also found total occlusion along the external iliac vein to the inferior vena cava (IVC) with abundant collateral vessels (Fig. 1). The infusion catheter was then inserted for catheter-directed thrombolysis with urokinase (60000 IU/h), concomitant with systemic heparinization.\n\nFigure 1 Procedure day 1. Venogram obtained from the left popliteal vein showed thrombus formation in the left iliofemoral vein and total occlusion in the left common iliac vein (Fig. 1).\n\nTwenty-four hours following venography, we observed residual thrombosis with poor antegrade flow in the main trunk. Subsequently, percutaneous transluminal angioplasty was performed from the common femoral vein to the common iliac vein after IVC filter placement. An infusion catheter for catheter-directed thrombolysis with the same dosage for 1 more day was arranged because of the residual thrombosis (Fig. 2).\n\nFigure 2 Procedure day 2. After catheter-directed thrombolysis and balloon dilatation, residual thrombus was still noted with collateral veins (Fig. 2A). Residual stenosis was noted in the proximal part of the external iliac vein (Fig. 2B).\n\nAfter 2 days of thrombolysis and balloon dilatation, final venography revealed improved antegrade main-trunk flow with less than 30% residual luminal area narrowing (Fig. 3). The patient felt free of symptoms completely after endovascular intervention.\n\nFigure 3 Procedure day 3. After 1 more day of catheter-directed thrombolysis and larger balloon dilatation, improved main-trunk flow of femoral vein was noted (Fig. 3A). Residual stenosis in the proximal part of the external iliac vein improved with more favorable flow (Fig. 3B).\n\n4 Follow-up and outcomes\nOne month after the intervention, IVC filter retrieval was arranged, and patent iliac-femoral venous flow was confirmed by a subsequent venography procedure (Fig. 4). Six months later, a patent femoral vein without remarkable thrombus was noted through venous duplex ultrasound examination, and oral anticoagulation therapy was discontinued. During a 1-year follow-up without medication, the patient did not complain about leg swelling, exercise aggravation, or any other post-thrombotic symptoms.\n\nFigure 4 After 2 weeks, follow-up venography was performed before IVC filter retrieval.\n\n5 Discussion\nCatheter-directed thrombolysis is a common procedure for acute DVT, but it is rarely used for postpartum patients, especially after more than 3 months. Herein, we report a case of a postpartum woman initially diagnosed as having DVT with possible NOAC treatment failure, who was eventually rescued using catheter-directed thrombolysis 5 months later.\n\nBased on the guideline for VTE in Taiwan, pregnancy-related VTE is a specific issue; nevertheless, no recommendations are available for postpartum VTE.[4] The European Society of Cardiology guideline in 2014 recommend that anticoagulant treatment for pregnancy-related VTE should be administered for at least 6 weeks after delivery and with a minimum overall treatment duration of 3 months.[2] Furthermore, warfarin can be administered to breast-feeding women, but NOAC is not mentioned for the postpartum period in the current guidelines.[2,4]\n\nThe EINSTEIN-DVT trial, a phase III randomized controlled study, established an approved indication about rivaroxaban for the treatment of acute DVT.[5] However, pregnant patients have almost always been excluded in clinical trials, including the EISTEIN-DVT study, although the EISTEIN-DVT study protocol did not clearly restrict postpartum patients. The study enrolled 6 postpartum patients, representing 0.3% of the rivaroxaban treatment group, but no subgroup analysis was available.[5] Current guidelines recommend 3 to 6 months of anticoagulant therapy for women with provoked factors for VTE.[2,4] However, no suggestion is available for those with NOAC treatment failure. Furthermore, catheter-directed thrombolysis is reserved for patients with massive iliac-femoral DVT or anticoagulation therapy failure.[6]\n\nOur patient was diagnosed as having DVT 14 days immediately after delivery. Her possible provoked factors included hormonal drugs, immobilization, and pregnancy, especially twin pregnancy. After smooth delivery, these provoked factors were completely corrected. On the basis of current guidelines, 3 months of anticoagulation therapy should be recommended.[2] Moreover, the patient's symptoms improved just after rivaroxaban use; no more invasive procedure was considered initially. However, her symptoms recurred as leg swelling, which was aggravated after walking or standing and relieved after resting or raising the leg. After the failure of compression stocking, catheter-directed thrombolysis was considered as an alternative method for treating chronic DVT, and this procedure was safe for the patient who had favorable functional status and low bleeding risk. Eventually, follow-up venography showed not only one blood clot above the knee but also a total occluded lesion in the common iliac vein.\n\nNo randomized controlled trials have tested the comparative effectiveness and safety of pharmacomechanical thrombectomy in the management of patients with DVT.[6] In addition, in previous case series, catheter-directed thrombolysis was safe and effective for acute iliofemoral DVT in the postpartum period.[7] However, there are only a few reported pregnancy-provoked cases of patients who received endovascular intervention because of anticoagulation therapy failure after 3 to 6 months.[7–9]\n\nThis case provides several clinical implications. First, pregnancy seems to be a transient provoking factor, but it is sometimes refractory even during the postpartum period. Second, follow-up imaging studies should be encouraged to confirm the vessel condition, particularly for applying down-titration or discontinuation strategies of medication. Third, catheter-directed thrombolysis could be considered as an alternative method for treating postpartum iliofemoral DVT. Postpartum women usually have favorable functional status and lower bleeding risk. Rivaroxaban is a favorable choice for DVT, but its use in postpartum women is still controversial, and evidence of its effectiveness is not available. Thus, endovascular intervention can be a relatively safe therapy, in addition to anticoagulation therapy for premenopausal patients with recurrent DVT.\n\nAuthor contributions\nConceptualization: Po-Wei Chen, Ping-Yen Liu.\n\nData curation: Po-Wei Chen.\n\nProject administration: Po-Wei Chen.\n\nResources: Po-Wei Chen.\n\nSupervision: Ping-Yen Liu.\n\nWriting – original draft: Po-Wei Chen.\n\nWriting – review & editing: Po-Wei Chen.\n\nPo-Wei Chen orcid: 0000-0003-2300-0698.\n\nAbbreviations: DVT = deep vein thrombosis, IVC = inferior vena cava, NOAC = novel oral anticoagulant, VTE = venous thromboembolism.\n\nWritten informed consent was obtained from this patient for publication of this case history and associated images.\n\nThe authors have no conflicts of interest or financial disclosures to declare.\n==== Refs\nReferences\n[1] White RH \nThe epidemiology of venous thromboembolism . Circulation \n2003 ;107 23 Suppl 1 :I4–8 .12814979 \n[2] Konstantinides SV Torbicki A Agnelli G \n2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism . Eur Heart J \n2014 ;35 : 3033-69, 69a-69k .\n[3] Bates SM Middeldorp S Rodger M \nGuidance for the treatment and prevention of obstetric-associated venous thromboembolism . J Thromb Thrombolysis \n2016 ;41 :92–128 .26780741 \n[4] Wang K-L Chu P-H Lee C-H \nManagement of venous thromboembolisms: Part I. The consensus for deep vein thrombosis . Acta Cardiologica Sinica \n2016 ;32 :1–22 .27122927 \n[5] Robertson L Kesteven P McCaslin JE \nOral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis . Cochrane Database Syst Rev . 2015 (6 ):CD010956 .\n[6] Robertson L McBride O Burdess A \nPharmacomechanical thrombectomy for iliofemoral deep vein thrombosis . Cochrane Database Syst Rev \n2016 ;11 :CD011536.27814432 \n[7] Srinivas BC Patra S Nagesh CM \nCatheter-directed thrombolysis in management of postpartum lower limb deep venous thrombosis - A case series . Indian Heart J \n2015 ;67 Suppl 3 :S67–70 .26995437 \n[8] Keragala CB Cummins KD Goergen SK \nIsolated iliac vein thrombosis in pregnancy . Intern Med J \n2015 ;45 :460–1 .25827515 \n[9] Bloom AI Farkas A Kalish Y \nPharmacomechanical catheter-directed thrombolysis for pregnancy-related iliofemoral deep vein thrombosis . J Vasc Interv Radiol \n2015 ;26 :992–1000 .25899048\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "98(24)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D002404:Catheterization; D005260:Female; D005268:Femoral Vein; D006801:Humans; D007084:Iliac Vein; D049590:Postpartum Period; D011644:Puerperal Disorders; D015912:Thrombolytic Therapy; D020246:Venous Thrombosis",
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"pmid": "31192964",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Postpartum deep vein thrombosis resolved by catheter-directed thrombolysis: A case report.",
"title_normalized": "postpartum deep vein thrombosis resolved by catheter directed thrombolysis a case report"
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"abstract": "Pyoderma gangrenosum (PG) is a rare, debilitating, inflammatory skin disease associated with a variety of systemic diseases. Because of its rarity, PG is treated with miscellaneous immunosuppressive agents as there is no US Food and Drug Administration-approved standardized treatment approach. We present four patients with PG treated with tofacitinib in the context of the six existing cases in the literature. Tofacitinib appeared to be beneficial in the small sample of patients (n = 10) who failed an average of four other systemic therapies. The majority of patients had classic PG located on the legs (80%, 8/10), while 20% of cases (2/10) were peristomal. The most common comorbidity was inflammatory bowel disease (78%, 7/9). There were no negative treatment results and 40% (4/10) of patients had complete healing of their ulcers, while the other 60% (6/10) had marked clinical improvement. From our observation, tofacitinib appears to be a promising steroid-sparing adjuvant treatment in patients with refractory PG who have failed on other systemic therapies.",
"affiliations": "Department of Dermatology, Oregon Health and Science University, Portland, OR, USA.;Department of Dermatology, Central State Medical Academy, Moscow, Russia.;Department of Mohs Micrographic and Reconstructive Surgery, Epiphany Dermatology, Austin, TX, USA.;Department of Dermatology, Oregon Health and Science University, Portland, OR, USA.;Department of Dermatology, Virginia Commonwealth University, Richmond, VA, USA.",
"authors": "Orfaly|V E|VE|https://orcid.org/0000-0001-6438-2384;Kovalenko|I|I|;Tolkachjov|S N|SN|https://orcid.org/0000-0003-0725-1649;Ortega-Loayza|A G|AG|;Nunley|J R|JR|",
"chemical_list": "D003879:Dermatologic Agents; D007166:Immunosuppressive Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C479163:tofacitinib",
"country": "England",
"delete": false,
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"issn_linking": "0307-6938",
"issue": "46(6)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D007868:Leg Dermatoses; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D017511:Pyoderma Gangrenosum; D011743:Pyrimidines; D054047:Surgical Stomas; D016896:Treatment Outcome",
"nlm_unique_id": "7606847",
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"pages": "1082-1085",
"pmc": null,
"pmid": "33864685",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tofacitinib for the treatment of refractory pyoderma gangrenosum.",
"title_normalized": "tofacitinib for the treatment of refractory pyoderma gangrenosum"
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"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
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"abstract": "Baclofen is a gamma-aminobutyric acid type B receptor agonist used as an anti-craving agent for treatment of alcohol dependence. It has gained popularity in the recent times because it is well tolerated even in patients with hepatic impairments. Herein we are summarizing the latest literature about baclofen induced hypomania and are reporting a case of baclofen abuse because of its mood elevating property in a patient of alcohol dependence with comorbid major depressive disorder. Literature review and case study of a 36-year-old male with alcohol dependence with comorbid major depressive disorder was prescribed with tablet baclofen as an anti-craving agent along with antidepressant medicines. The patients who did not improve with conventional antidepressant therapy started feeling better in terms of his mood symptoms on taking tablet baclofen. Owing to the mood elevating property he started abusing baclofen. Despite its safety profile in hepatic impairment, one must be very cautious in prescribing baclofen because of its mood altering property which may account for its abuse potentiality.",
"affiliations": "Department of Psychiatry, Assam Medical College and Hospital, Dibrugarh, Assam, India.;Department of Psychiatry, Assam Medical College and Hospital, Dibrugarh, Assam, India.",
"authors": "Ghosh|Soumitra|S|;Bhuyan|Dhrubajyoti|D|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2017.15.2.187",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2844956910.9758/cpn.2017.15.2.187cpn-15-187Case ReportBaclofen Abuse due to Its Hypomanic Effect in Patients with Alcohol Dependence and Comorbid Major Depressive Disorder Ghosh Soumitra Bhuyan Dhrubajyoti Department of Psychiatry, Assam Medical College and Hospital, Dibrugarh, Assam, \nIndiaAddress for correspondence: Dhrubajyoti Bhuyan, MD, Department of Psychiatry, Assam Medical College and Hospital, Dibrugarh, Assam 786002, India, Tel: +91-9435030212, Fax: +91-373-2302952, E-mail: dr.dhrubajyoti@gmail.com5 2017 31 5 2017 15 2 187 189 18 3 2016 18 5 2016 19 5 2016 Copyright © 2017, Korean College of Neuropsychopharmacology2017This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Baclofen is a gamma-aminobutyric acid type B receptor agonist used as an anti-craving agent for treatment of alcohol dependence. It has gained popularity in the recent times because it is well tolerated even in patients with hepatic impairments. Herein we are summarizing the latest literature about baclofen induced hypomania and are reporting a case of baclofen abuse because of its mood elevating property in a patient of alcohol dependence with comorbid major depressive disorder. Literature review and case study of a 36-year-old male with alcohol dependence with comorbid major depressive disorder was prescribed with tablet baclofen as an anti-craving agent along with antidepressant medicines. The patients who did not improve with conventional antidepressant therapy started feeling better in terms of his mood symptoms on taking tablet baclofen. Owing to the mood elevating property he started abusing baclofen. Despite its safety profile in hepatic impairment, one must be very cautious in prescribing baclofen because of its mood altering property which may account for its abuse potentiality.\n\nBaclofenAlcoholismTreatment-resistant depressive disorderBaclofen abuse\n==== Body\nINTRODUCTION\nBaclofen is a gamma-aminobutyric acid type B (GABA-B) receptor agonist used primarily in the treatment of spasticity and in recent years it has gained popularity as an anti-craving medicine for the treatment of alcohol dependence syndrome.1,2)\n\nThe anti-craving and anti-reward effects of baclofen are attributed to its agonist effect on GABA-B receptors in the ventral tegmental area, which are reported to control the activity of mesolimbic dopamine neurons, one of the major pathways in the regulation of the reinforcing properties of drugs of addiction.3,4)\n\nBaclofen is found to be effective and well tolerated by patients with hepatic impairment also. A provisional evidence of dose-response effect has been demosntarted by Addolorato et al.5) with 20 mg three times a day (TDS) dose found to be more effective than 10 mg TDS in suppression of carving for alcohol. There have been individual case reports of using baclofen in a much higher dose, i.e. 270 mg/day for suppressing the craving for alcohol. However there is no systematic study on the use of higher doses.6,7)\n\nHowever recently published case reports have shown several serious safety concerns which includes drowsiness, seizure vulnerability, risk for triggering specific pharmacologic withdrawal syndrome and intoxication.8–11)\n\nBaclofen has previously been reported for inducing behavioural disinhibition and manic like symptoms.1,2) Due to its mood elevating property its abuse potentiality cannot be ruled out.\n\nHere we are presenting a case of baclofen abuse in a patient with alcohol dependence with comorbid major depressive disorder who reported to have used baclofen in order to overcome his depression.\n\nCASE\nA 36 years old Hindu, literate married male patient from urban background took treatment for alcohol dependence and recovered well. He was prescribed with baclofen 30 mg daily. He was better but often on, he used to drink alcohol along with his medication baclofen. On enquiry he was found to be having moderate depression with sleep problem for last 1 year. He was prescribed with mirtazepine 15 mg daily at bedtime and lorazepam 2 mg. He continued for two months but there was no significant improvement. Therefore he was prescribed with escitalopram 20 mg daily along with the previous medication. He was continuing for months but still there was no improvement. He was always complaining of sleep problem in spite of all those medications. So he was prescribed with quetiapine 100 mg daily along with mirtazepine 15 mg, escitalopram 20 mg, lorazepam 2 mg, and baclofen 20 mg daily. Patient remained sober and off alcohol. He was continuing all those medication without much improvement of his depression. So he discontinued coming for checkup. On the next visit when he came after seven months he revealed that he was only taking mirtazepine 15 mg, lorazepam 2 mg and whenever he takes baclofen 80 mg daily along with those medication he feels much better. His family member also gave history that whenever he takes baclofen 80 mg and sometimes more than that dose his confidence increases becomes irritable and angry. He remains euphoric and sleeps less; remain restless most of the time. But his work function remains same without deterioration. On understanding his change of behavior after abusing baclofen 80 mg they stopped baclofen but immediately the patient becomes depressed like before. It means the patient was having hypomanic switch on taking 80 mg of baclofen. Interestingly during his hypomanic phase he never took alcohol which is most probably for taking baclofen which is an anti-craving drug for alcohol.\n\nDISCUSSION\nThere have been many case reports depicting manic or hypomanic episode resulting from use of baclofen.1,2) The mood elevating property of baclofen has not been properly known. However it is postulated that mood altering property of baclofen may be due to its GABA-B receptor agonist action which results—(a) acceleration of noradrenaline turnover by changing post synaptic receptor density and (b) up regulation of serotonin (5HT2) receptor thereby leading to diminished liberation of serotonin.12)\n\nTo our knowledge, abusing baclofen due to it mood elevating property has not been reported till date in literature. Herein we are reporting such a case. Our patient who did not show any improvement on antidepressant medicines reported to have felt better in terms of his mood state whenever he takes baclofen. The patient may be regarded as a case of resistant depression as per the criteria. He reported that whenever he takes higher doses of baclofen his confidence increases becomes irritable and angry. This indicates that mood elevating property of baclofen is dose dependant. Hypomania/mania symptom checklist (HCL-32) by Angst et al.13) was applied and the score was found to be 12. Naranjo algorithm14) was also applied to ascertain the occurrence of such hypomanic symptoms in the patients and the results are shown in Table 1.15)\n\nIn our case the score was 7 which means hypomania is probably related to baclofen use and because of it he has started abusing baclofen.\n\nBaclofen has in recent time gained popularity as an anti-craving agent due to its safety profile in hepatic compromised patients. However, one must be very cautious in using it because of its abuse potential due to its mood elevating property. One possible positive outcome of this report may be that it may be a potential area of research to find out whether baclofen can be used in the treatment of resistant depression.\n\nTable 1 The Naranjo adverse drug reaction probability scale and its responses\n\nThe Naranjo adverse drug reaction probability scale; To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score\tYes\tNo\tDo not know\tScore\t\n1. Are there previous conclusive reports on this reaction?\t+1\t0\t0\t+1\t\n2. Did the adverse event occur after the suspected drug was administered?\t+2\t−1\t0\t+2\t\n3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?\t+1\t0\t0\t+1\t\n4. Did the adverse reaction reappear when the drug was re-administered?\t+2\t−1\t0\t+2\t\n5. Are there alternative causes (other than the drug) that could have on their own caused the reaction?\t−1\t+2\t0\t−1\t\n6. Did the reaction reappear when a placebo was given?\t−1\t+1\t0\t0\t\n7. Was the blood detected in the blood (or other fluids) in concentrations known to be toxic?\t+1\t0\t0\t0\t\n8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?\t+1\t0\t0\t+1\t\n9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?\t+1\t0\t0\t+1\t\n10. Was the adverse event confirmed by any objective evidence?\t+1\t0\t0\t0\t\nTotal\t\t\t\t7\t\nThe adverse drug reaction is assigned to a probability category from the total score as follows: definite if the overall score is 9 or greater, probable for a score of 5–8, possible for 1–4 and doubtful if the score is 0.15)\n==== Refs\nREFERENCES\n1 Geoffroy PA Auffret M Deheul S Bordet R Cottencin O Rolland B Baclofen-induced manic symptoms: case report and systematic review Psychosomatics 2014 55 326 332 10.1016/j.psym.2014.02.003 24751117 \n2 Silva JV Pinheiro J Mota J Baclofen-induced manic episode - a case report IJCNMH 2015 2 Suppl 1 59 \n3 Addolorato G Caputo F Capristo E Domenicali M Bernardi M Janiri L Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study Alcohol Alcohol 2002 37 504 508 10.1093/alcalc/37.5.504 12217947 \n4 Colombo G Addolorato G Agabio R Carai MA Pibiri F Serra S Role of GABA(B) receptor in alcohol dependence: reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics Neurotox Res 2004 6 403 414 10.1007/BF03033315 15545024 \n5 Addolorato G Leggio L Ferrulli A Cardone S Bedogni G Caputo F Baclofen Study Group Dose-response effect of baclofen in reducing daily alcohol intake in alcohol dependence: secondary analysis of a randomized, double-blind, placebo-controlled trial Alcohol Alcohol 2011 46 312 317 10.1093/alcalc/agr017 21414953 \n6 Ameisen O Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician Alcohol Alcohol 2005 40 147 150 10.1093/alcalc/agh130 15596425 \n7 Bucknam W Suppression of symptoms of alcohol dependence and craving using high-dose baclofen Alcohol Alcohol 2007 42 158 160 10.1093/alcalc/agl091 17172256 \n8 Franchitto N Pelissier F Lauque D Simon N Lançon C Self-intoxication with baclofen in alcohol-dependent patients with co-existing psychiatric illness: an emergency department case series Alcohol Alcohol 2014 49 79 83 10.1093/alcalc/agt169 24226812 \n9 Pommier P Debaty G Bartoli M Viglino D Carpentier F Danel V Severity of deliberate acute baclofen poisoning: a nonconcurrent cohort study Basic Clin Pharmacol Toxicol 2014 114 360 364 10.1111/bcpt.12161 24138484 \n10 Lee TH Chen SS Su SL Yang SS Baclofen intoxication: report of four cases and review of the literature Clin Neuropharmacol 1992 15 56 62 10.1097/00002826-199202000-00008 1576599 \n11 Rolland B Jaillette E Carton L Bence C Deheul S Saulnier F Assessing alcohol versus baclofen withdrawal syndrome in patients treated with baclofen for alcohol use disorder J Clin Psychopharmacol 2014 34 153 156 10.1097/JCP.0000000000000054 24346755 \n12 Bartholini G GABA receptor agonists: pharmacological spectrum and therapeutic actions Med Res Rev 1985 5 55 75 10.1002/med.2610050103 2984490 \n13 Angst J Adolfsson R Benazzi F Gamma A Hantouche E Meyer TD The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients J Affect Disord 2005 88 217 233 10.1016/j.jad.2005.05.011 16125784 \n14 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n15 Zaki SA Adverse drug reaction and causality assessment scales Lung India 2011 28 152 153 10.4103/0970-2113.80343 21712934\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "15(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Alcoholism; Baclofen; Baclofen abuse; Treatment-resistant depressive disorder",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "187-189",
"pmc": null,
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"pubdate": "2017-05-31",
"publication_types": "D002363:Case Reports",
"references": "17172256;24138484;2984490;21712934;12217947;15545024;16125784;15596425;7249508;24346755;24751117;24226812;21414953;1576599",
"title": "Baclofen Abuse due to Its Hypomanic Effect in Patients with Alcohol Dependence and Comorbid Major Depressive Disorder.",
"title_normalized": "baclofen abuse due to its hypomanic effect in patients with alcohol dependence and comorbid major depressive disorder"
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"companynumb": "IN-SAOL THERAPEUTICS-2017SAO01078",
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"activesubstancename": "QUETIAPINE"
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"abstract": "OBJECTIVE\nReport a case of central diabetes insipidus (DI) associated with ketamine infusion.\n\n\nMETHODS\nA 2-year-old girl with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and stable hypertrophic cardiomyopathy was admitted to the pediatric intensive care with pneumonia. She subsequently developed respiratory failure and required intubation. Continuous ketamine infusion was used for the sedation and facilitation of mechanical ventilation. Shortly after infusion of ketamine, the patient developed DI and responded appropriately to vasopressin.\n\n\nCONCLUSIONS\nThe Naranjo adverse drug reaction probability scale indicated a probable relationship between the development of central DI and ketamine. The most likely mechanism involves ketamine's antagonist action on N-methyl-d-aspartate receptors, resulting in inhibition of glutamate-stimulated arginine vasopressin release from the neurohypophysis.\n\n\nCONCLUSIONS\nThis is the second case report of ketamine-induced central DI and the only report in children. Clinicians who sedate children with continuous ketamine infusions should monitor patients for developing signs and symptoms of DI by measuring serum sodium and urine output prior to, during, and after ketamine infusion in order to make a timely diagnosis of this potentially serious complication.",
"affiliations": "Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Division of Endocrinology and Diabetes, Emory University School of Medicine, Atlanta, GA, USA sarah.hatab@emory.edu.;Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Division of Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA, USA.;Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Division of Endocrinology and Diabetes, Emory University School of Medicine, Atlanta, GA, USA.;Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA Division of Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, USA, USA.",
"authors": "Hatab|Sarah Z|SZ|;Singh|Arun|A|;Felner|Eric I|EI|;Kamat|Pradip|P|",
"chemical_list": "D000777:Anesthetics; D007649:Ketamine; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063991:Mitochondrial Trifunctional Protein",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014549991",
"fulltext": null,
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"issn_linking": "1060-0280",
"issue": "48(12)",
"journal": "The Annals of pharmacotherapy",
"keywords": "children; diabetes insipidus and ketamine",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D015094:3-Hydroxyacyl CoA Dehydrogenases; D000777:Anesthetics; D009202:Cardiomyopathies; D002312:Cardiomyopathy, Hypertrophic; D002675:Child, Preschool; D003919:Diabetes Insipidus; D005260:Female; D006801:Humans; D007649:Ketamine; D008052:Lipid Metabolism, Inborn Errors; D017240:Mitochondrial Myopathies; D063991:Mitochondrial Trifunctional Protein; D009422:Nervous System Diseases; D012121:Respiration, Artificial; D012206:Rhabdomyolysis",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1642-5",
"pmc": null,
"pmid": "25225198",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient central diabetes insipidus induced by ketamine infusion.",
"title_normalized": "transient central diabetes insipidus induced by ketamine infusion"
} | [
{
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{
"abstract": "BACKGROUND\nThe aim of our study was to evaluate feasibility, toxicity profile and local control of salvage intensity modulated radiotherapy (IMRT) delivered with simultaneous integrated boost (SIB) associated or not to concomitant weekly cisplatin in patients affected by NSCLC with mediastinal nodal recurrence after surgery. Patterns of recurrence, outcomes and prognostic factors were assessed.\n\n\nMETHODS\nFourteen consecutive patients received 25 fractions of 50Gy/2Gy to the elective nodal stations and boost up to 62.5Gy/2.5Gy to the macroscopic lymph node metastases. Concomitant weekly cisplatin (40 mg/m2) was administered to 8 (57.1%) patients.\n\n\nRESULTS\nFive (35.7%) patients experienced grade 2 pneumonitis and 5 (35.7%) patients had grade 2 esophagitis. One case of grade 3 pneumonitis occurred and was successfully treated with antibiotics and steroids with no sequelae. No patient recurred locally in the boost volume (local control 100%). Loco-regional control was 79% with 3 patients that developed nodal recurrence principally marginal to the elective volume. Seven patients developed distant metastases. Median PFS was 7 months. The nodal involvement of station 7 was associated to a significantly lower median metastasis-free survival (4 months vs. not reached, p = 0.036).\n\n\nCONCLUSIONS\nSalvage radiotherapy with IMRT-SIB is a feasible and a well-tolerated treatment option for mediastinal recurrent NSCLC after surgery. The role of more intensified radiation regimens and association to systemic therapy remain to be evaluated in larger cohorts.",
"affiliations": "Department of Radiation Oncology, Sant'Andrea Hospital, \"Sapienza\" University of Rome, Via di Grottarossa 1035-1039, 00189, Rome, Italy. lucanicosia.rg@gmail.com.;Department of Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.;Department of Radiation Oncology, Sant'Andrea Hospital, \"Sapienza\" University of Rome, Via di Grottarossa 1035-1039, 00189, Rome, Italy.;Department of Radiation Oncology, Sant'Andrea Hospital, \"Sapienza\" University of Rome, Via di Grottarossa 1035-1039, 00189, Rome, Italy.;Department of Radiation Oncology, Sant'Andrea Hospital, \"Sapienza\" University of Rome, Via di Grottarossa 1035-1039, 00189, Rome, Italy.;Radiation Oncology Unit, UPMC Hillman Cancer Center, San Pietro Hospital, Rome, Italy.;Department of Oncology, Radiation Oncology, University of Torino, Torino, Italy.;Department of Radiation Oncology, Sant'Andrea Hospital, \"Sapienza\" University of Rome, Via di Grottarossa 1035-1039, 00189, Rome, Italy.;Department of Radiation Oncology, Sant'Andrea Hospital, \"Sapienza\" University of Rome, Via di Grottarossa 1035-1039, 00189, Rome, Italy.",
"authors": "Nicosia|L|L|http://orcid.org/0000-0002-0731-8041;Agolli|L|L|;Reverberi|C|C|;De Sanctis|V|V|;Marinelli|L|L|;Minniti|G|G|;Di Muzio|J|J|;Valeriani|M|M|;Osti|M F|MF|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13014-018-1155-2",
"fulltext": "\n==== Front\nRadiat OncolRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central London 115510.1186/s13014-018-1155-2ResearchSalvage radiotherapy with simultaneous integrated boost in non small-cell lung cancer patients with mediastinal relapse after surgery: a pilot study http://orcid.org/0000-0002-0731-8041Nicosia L. +39 0633776160+39 0633776164lucanicosia.rg@gmail.com 1Agolli L. linda.agolli@uniklinikum-dresden.de 2Reverberi C. chiarareverberi87@gmail.com 1De Sanctis V. dsvita@gmail.com 1Marinelli L. lucamarinelli@osepdalesantandrea.it 1Minniti G. gminniti@ospedalesantandrea.itgiuseppeminniti@libero.it 34Di Muzio J. jacopo.dimuzio@gmail.com 5Valeriani M. mauval1@libero.it 1Osti M. F. mattiafosti@gmail.com 11 grid.7841.aDepartment of Radiation Oncology, Sant’Andrea Hospital, “Sapienza” University of Rome, Via di Grottarossa 1035-1039, 00189 Rome, Italy 2 Department of Radiation Oncology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany 3 0000 0004 1760 5524grid.416418.eRadiation Oncology Unit, UPMC Hillman Cancer Center, San Pietro Hospital, Rome, Italy 4 0000 0004 1760 3561grid.419543.eIRCCS Neuromed, Pozzilli (IS), Italy 5 0000 0001 2336 6580grid.7605.4Department of Oncology, Radiation Oncology, University of Torino, Torino, Italy 23 10 2018 23 10 2018 2018 13 20720 3 2018 11 10 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe aim of our study was to evaluate feasibility, toxicity profile and local control of salvage intensity modulated radiotherapy (IMRT) delivered with simultaneous integrated boost (SIB) associated or not to concomitant weekly cisplatin in patients affected by NSCLC with mediastinal nodal recurrence after surgery. Patterns of recurrence, outcomes and prognostic factors were assessed.\n\nMethods\nFourteen consecutive patients received 25 fractions of 50Gy/2Gy to the elective nodal stations and boost up to 62.5Gy/2.5Gy to the macroscopic lymph node metastases. Concomitant weekly cisplatin (40 mg/m2) was administered to 8 (57.1%) patients.\n\nResults\nFive (35.7%) patients experienced grade 2 pneumonitis and 5 (35.7%) patients had grade 2 esophagitis. One case of grade 3 pneumonitis occurred and was successfully treated with antibiotics and steroids with no sequelae. No patient recurred locally in the boost volume (local control 100%). Loco-regional control was 79% with 3 patients that developed nodal recurrence principally marginal to the elective volume. Seven patients developed distant metastases. Median PFS was 7 months. The nodal involvement of station 7 was associated to a significantly lower median metastasis-free survival (4 months vs. not reached, p = 0.036).\n\nConclusions\nSalvage radiotherapy with IMRT-SIB is a feasible and a well-tolerated treatment option for mediastinal recurrent NSCLC after surgery. The role of more intensified radiation regimens and association to systemic therapy remain to be evaluated in larger cohorts.\n\nKeywords\nMediastinal recurrent NSCLCPost-surgical relapseSalvage radiotherapyIntensity modulated radiotherapy with simultaneous integrated boostissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nSurgery is the gold standard in the treatment of resectable stage I-IIIA non small-cell lung cancer (NSCLC) with 5-years survival rates of 92% for early stage and 26% for locally advanced disease, respectively [1]. Relapse after surgery may occur in up to 50% of patients depending on the pathological stage [2] and recurrence occurs mainly in the mediastinal lymph nodes in 8–37% of cases [3, 4]. Recent data showed that the routine use of post-operative radiotherapy (PORT) after complete resection has a negative effect on survival [5], therefore, the role of mediastinal irradiation can be evaluated in the case of loco-regional relapse.\n\nTreatment options in of mediastinal recurrence could be surgery, chemotherapy, radiotherapy (RT), or a combination. Nevertheless, the best approach remains uncertain. Some studies reported long-term survival and in some cases even cure after intensive local treatment in a selected population of patients with mediastinal lymph node recurrence after surgery and no distant metastases [6–8].\n\nSystemic therapy alone is necessary, but not very efficient to contain the macroscopical active sites of disease. An aggressive local therapy such as surgery or high-dose RT is required. The reported 5-years survival in patients with loco-regional relapse/persistence treated with surgery ranged from 13 to 25% [9, 10]. Unfortunately, in patients already resected a second surgery is not always feasible. This category of patients often presents with related-symptoms and associated comorbidities; RT could represent a valid alternative comparable to surgery in terms of survival and with acceptable toxicity rates [11, 12]. Most of the studies evaluating this topic are limited from the inhomogeneous treatment schedules and the use of old irradiation techniques. The advantage of modern techniques is to escalate the dose to the tumor and improve toxicity profile in order to obtain good tumor control and better tolerance rates.\n\nWe reported feasibility, safety and local control of NSCLC patients presenting post-operative mediastinal nodal recurrence, who received salvage intensity modulated radiotherapy - simultaneous integrated boost (IMRT-SIB) with curative intent.\n\nMethods\nWe retrospectively reviewed a series of patients with NSCLC and post-operative mediastinal nodal relapse, treated with salvage IMRT-SIB associated or not to concomitant chemotherapy.\n\nPre-treatment evaluation included: physical examination, total body computed tomography (CT) scan and 18-fluordeoxyglucose positron emission/ CT (18FDG-PET/CT), both not older than 1 month, lung function test, total blood count and kidney function test.\n\nTreatment characteristics and planning\nAll patients underwent pretreatment planning CT in the supine position using a wing-board system for immobilization. Planning CT images were matched with contrast medium diagnostic CT and 18FDG-PET/CT images using automatic matching for the target volume delineation. Gross Tumor Volume (GTV) encompassed the positive mediastinal lymph nodes (PET positive and/or ≥ 10 mm). The elective clinical target volume (CTV-elective) encompassed the nodal stations based on primary tumor location: stations 2R, 4R, 7 and 10R for tumors in the superior right lobe (SRL) and middle lobe (ML); stations 4R, 7, 10R for tumors of the inferior right lobe (IRL): stations 2 L, 4 L, 5, 6, 7, 10 L for tumors in the superior left lobe (SLL); and stations: 4 L, 5, 6, 7, 10 L for tumors located in the inferior left lobe (ILL). Afterwards, GTV and CTV were expanded 5 mm and 7 mm in all directions to generate planning target volume 1 (PTV1) and PTV2, respectively.\n\nAll patients were treated with IMRT-SIB technique using multiple coplanar and non-coplanar fields. The margins were maintained small in order to avoid potential toxicities and an image guidance with kilovolt on-board cone beam CT was performed daily in order to guarantee an adequate positioning of the patients. The images from the cone-beam CT were matched to the planning CT prior to each treatment based on the initial automatic bone alignment, followed by a soft tissue/target alignment. Radiation therapy was delivered by a linear accelerator using 6-MV photon beams. The radiation treatment regimen consisted of 50Gy in 25 fractions of 2Gy each to the PTV2, with a simultaneous integrated boost of 62.5Gy in 25 fractions of 2.5Gy each on the PTV1.\n\nThe BED (biological equivalent dose 10 [BED10]) at the PTV1 was 78Gy. The dose was prescribed at the 95% isodose with normalization to the maximal dose. The treatment was administered 5 times per week for 5 weeks. Dose constraints for critical normal structures are reported in Table 1. Concomitant chemotherapy consisted in weekly cisplatin (40 mg/m2), given on days 1, 6, 11, 16, 21. Chemotherapy was not administered in cases of inadequate renal function or refusal by the patients.Table 1 Dosimetry and dose constraints to critical normal structures\n\nPTV1\tMedian 45.8 Gy (41.8–48.2Gy)\t\nPTV2\tMedian 59.8 Gy (57.3–60.1Gy)\t\nMean Lung Dose\tMedian 10.3 Gy (6–15.3Gy)\t\nBilateral lung V20\tMedian 16.45% (7.6–33.1%)\t\nIpsilateral Lung V5\tMedian 62.45% (39.9–81.1%)\t\nIpsilateral Lung V20\tMedian 28% (17.9–42.5%)\t\nControlateral Lung V5\tMedian 45.75% (2.3–69.1%)\t\nControlateral lung V20\tMedian 16.35% (0.6–48%)\t\nHeart V5\t20.2% (7.1–66.1%)\t\nHeart V30\t2.75% (0–12.3%)\t\nEsophagus V11.5\t36% (21.1–68.5%)\t\nEsophagus V18\t45.15% (27.3–69.1%)\t\nEsophagus V27\t52.35% (26.9–69.8%)\t\n\n\nFollow-up and statistics\nAll patients underwent weekly clinical evaluations and routine blood examinations during radiation therapy. Treatment-related toxicities were graded according to the CTCAE v 4.0 scale. Follow-up was performed every 3 months for the first 2 years after RT and then every 6 months afterward. A total body CT with contrast medium was performed at 1 month after RT and every 6 months afterward. A post treatment 18FDG-PET/CT was performed at 3 months after RT and if there was suspicion for tumor recurrence/progression at CT images. The local/regional recurrence was based on new evidence or marginal regrowth of the disease on follow-up CT scans and higher uptake on the 18FDG-PET/CT.\n\nStatistical analysis was performed using SPSS, version 16.0, software (SPSS, Inc., Chicago, IL). Primary end-points were toxicity and local control. Secondary end-points were pattern of failure, survivals and possible prognostic factors. Local progression-free survival (LPFS) was defined as the time to in-field or marginal regrowth of the disease or death. PFS was defined as the time to any progression or death. Metastasis-free survival (MFS) was defined as any site of distant progression (including the lungs) or death. Survivals were calculated from the date of initial RT and were estimated using the Kaplan- Meier method. Clinical prognostic factors such as age, sex, histological subtype, number and station of involved lymph nodes, PTV size, previous chemotherapy, and type of response were included in the statistical analysis. Univariate analysis was performed to determine significant prognostic factors using the log-rank test. A p-value < .05 was considered statistically significant.\n\nResults\nPatients’ characteristics\nFrom January 2014 to September 2016, 14 consecutive patients with NSCLC and post-operative mediastinal nodal relapse were treated with salvage IMRT-SIB associated or not to concomitant chemotherapy.\n\nMedian age was 68 years (range, 51–78 years). Eleven (78.5%) patients were male, 3 (21.5%) were female. Patients had ECOG (Eastern Cooperative Oncology Group Criteria) ≤2 and received no previous thoracic RT. All patients underwent surgery and mediastinal lymphadenectomy before salvage RT. Five (35.7%) patients received pre-operative chemotherapy with platinum-based regimen and 9 (34.3%) patients received subsequently platinum-based adjuvant chemotherapy. The median interval between primary surgery and mediastinal recurrence was 10 months (range, 2–18 months). Patient’s characteristics are summarized in Table 2.Table 2 Patients’ characteristics (n = 14)\n\nAge (median, years)\t68\t\nRange (years)\t51–78\t\nSex\t\n • Male\t11 (78.5)\t\n • Female\t3 (21.5)\t\nHistology\t\n • Adenocarcinoma\t12 (85.6)\t\n • Squamocellular\t2 (14.4)\t\nPathological Stage\t\n • IB\t2 (14.4)\t\n • IIA\t6 (42.8)\t\n • IIIA\t6 (42.8)\t\nNeoadjuvant Chemotherapy\t\n • Platinum-based\t5 (35.7)\t\n • No\t9 (64.3)\t\nInitial surgery\t\n • Lobectomy + LAD\t13 (92.8)\t\n • Atypical resection + LAD\t1 (7.2)\t\nAdjuvant Chemotherapy\t\n • Platinum-based\t8 (57.2)\t\n • Vinorelbine monotherapy\t1 (7.1)\t\n • No\t5 (35.7)\t\nN° of pathological nodal stations involved at diagnosis\t\n 0\t2 (14.3)\t\n 1\t6 (42.8)\t\n 2\t3 (21.5)\t\n 3\t1 (7.1)\t\n 4\t2 (14.3)\t\nLAD: lymphadenectomy\n\n\n\nLocal control and toxicity profile\nFive (35.7%) patients experienced grade 2 pneumonitis and 5 (35.7%) patients had grade 2 esophagitis. One patient developed grade 1 leucopenia and grade 2 thrombocytopenia; radiochemotherapy was prudently interrupted for 5 days until achievement of normal blood count and was subsequently continued with no other interruption or toxicity. No treatment-related deaths occurred. One (7.1%) case of G3 pneumonitis occurred and was then successfully treated with antibiotics and steroids with no sequelae. The patient had a known diagnosis of chronic obstructive pulmonary disease (COPD) and a probable reactivation of the disease could be hypothesized, also considering the retained dose constraints for the lung (V20 29.9%, MLD 15.1%). See Table 3.Table 3 Acute and late toxicity (sec. CTCAE 4.0)\n\n\tG1–2\tG3\tG4–5\t\nAcute toxicity\t\n Pneumonitis\t5 (35.7)\t1 (7.1)\t0\t\n Esophagitis\t5 (35.7)\t0\t0\t\n Nausea\t3 (21.5)\t0\t0\t\n Leukopenia\t1 (7.1)\t0\t0\t\n Thrombocytopenia\t1 (7.1)\t0\t0\t\n Fatigue\t2 (14.3)\t0\t0\t\n Skin erithema\t1 (7.1)\t0\t0\t\nLate toxicity\t\n Fibrosis\t4 (28.6)\t0\t0\t\n\n\nFive (35.7%) patients did not receive concomitant chemotherapy for inadequate kidney function or refusal. No patient recurred locally in the boost volume (local control 100%). Loco-regional control was 79% with three patients that developed nodal recurrence principally marginal to the elective volume.\n\nPatterns of relapse, survival and prognostic factors\nAfter a median follow up of 12 months (range: 3–28 months), 3 patients developed regional failure: one patient had lymph node metastases in station 7 and 5 marginal to the elective volume; 2 patients developed lymph node metastasis in station 7: in the elective irradiated volume and marginal to the elective volume, respectively. Seven patients developed distant progression: 2 patients had solitary brain metastases, one patient had diffuse lung and nodal metastases, one patient developed diffuse liver metastases, one patient had bone and brain metastases and one patient had bone metastases. See patterns of relapse in Table 4.Table 4 Patterns of recurrence and treatment\n\nPatient\tAge\tSite of Boost Volume\tCCT\tDosis SIB (Gy)\tVolume/Volume SIB (cc)\tLocal relapse (boost)\tNodal regional relapse\tDistant recurrence\tTherapy after recurrence\t\n1\t78\t2 L, 4 L, 5, 6\tYes\t50/62.5\t323.24/80\tNo\tNo\tLung, nodes\tBSC\t\n2\t55\t4R, 10R\tYes\t50/62.5\t166.48/52.43\tNo\t7\tBrain, bone\tPalliative RT\t\n3\t67\t4R, 5, 10R\tNo\t50/62.5\t213.81/14.91\tNo\tNo\t\t\t\n4\t78\trT, 10R\tNo\t50/62.5\t201.06/11.35\tNo\t7 and 5\t\tBSC\t\n5\t75\t2R, 4R, 5\tYes\t50/62.5\t402.31/98.14\tNo\tNo\t\t\t\n6\t69\t5, 6, 10 L\tNo\t50/62.5\t203.58/76.48\tNo\tNo\t\t\t\n7\t56\t10R\tYes\t50/62.5\t64.16/5.42\tNo\tNo\t\t\t\n8\t55\t2 L, 4R, 6\tYes\t50/62.5\t148.86/10.29\tNo\tNo\t\t\t\n9\t51\t2R, 4R, 5, 7, 10R\tNo\t50/62.5\t313.01/193.46\tNo\tNo\t\t\t\n10\t57\t2R, 4R, 5, 7, 10R\tNo\t50/62.5\t408.43/95\tNo\tNo\tBrain\tSRS 9 Gyx3\t\n11\t77\t7\tNo\t50/62.5\t289.92/34.99\tNo\tNo\tLiver\tBSC\t\n12\t58\t4R\tYes\t50/62.5\t141.27/95.95\tNo\tNo\tBrain\t3 SRS 20 Gy\t\n13\t69\t4R, 10R\tYes\t50/62.5\t121.91/50.37\tNo\t7\tBone\tCT\t\n14\t69\t4R\tYes\t50/62.5\t134.19/19.86\tNo\tNo\tLung, nodes\tBSC\t\nCCT: concomitant chemotherapy, SIB: simultaneous integrated boost, CT: chemotherapy, RT: radiotherapy, BSC: best supportive care, SRS: stereotactic radiosurgery\n\n\n\nAt the time of the analysis, 6 (42.8%) patients were deceased: 4 of them due to disease progression, 2 of them had a worsening of the known COPD and one died of massive thrombosis. Median PFS was 7 months (range: 3–28 months) and 1-year PFS was 39.7%. Median LPFS was 26 months (range: 3–28 months) and 1-year LPFS was 80%. Median MFS was 9 months (range: 3–28 months) and 1 year MFS was 46.3%.\n\nConcomitant chemotherapy did not significantly predict for a longer LPFS, PFS or MFS. The nodal involvement of station 7 was associated to a significantly lower median MFS (4 months vs. not reached, p = 0.036). No other significant factors were found.\n\nDiscussion\nThis is a pilot study of patients affected by NSCLC presenting with post-operative mediastinal lymph node relapse and treated with IMRT-SIB technique associated or not to weekly cisplatin. The purpose of the study was to establish the safety and feasibility of the hypofractionated RT schema. Our results are in accordance to those presented by other authors. Bae et al. [12] treated 64 patients between 1994 and 2007, with a median BED10 of 70.2 Gy (range 51.5–85.8 Gy) delivered with various fractionations and concomitant chemotherapy in 21.9% patients. Toxicity profile was characterized by one (1.6%) case of grade 4 pneumonitis and 6 (9.4%) cases of grade3 pneumonitis. Kim et al. [13] reported 5.3% and 3.5% rates of grade 3 pneumonitis and esophagitis, respectively, in 57 NSCLC patients with loco-regional relapse after surgery treated with different RT schedules (median BED10 79.2 Gy; range 58.5–84 Gy) and concomitant chemotherapy (73.7% of patients).\n\nOur treatment schedule was well tolerated, with only one case of grade 3 pneumonitis in a patient with known COPD. The use of IMRT in our population can explain the relatively low rate of severe toxicity, as compared to the higher rates (2.6–65.5%) of previous studies, where 3D-CRT, techniques or more toxic chemotherapeutic regimens were used. A summary of previous studies showing the toxicity profile, type of treatment and RT regimens is reported in Table 5.Table 5 Summary of literature on toxicity and relative doses in salvage radiotherapy for locoregional recurrent NSCLC after surgery\n\nAuthor\tType of study\tN° of patients\tTime period\tMedian FUP\tRT technique\tTreatment volume\tMedian Dose (Gy)\tConcurrent chemotherapy (n°)\tToxicity (%)\t\nKagami et al., 1998 [20]\tRetrospective\t32\t1981–1991\tn.s.\tAP-PA until 40 Gy, then opposite oblique technique\tPTV: GTV (margins n.s.)\t47.5–65\t–\tNo G3\t\nUno et al., 2005 [21]\tRetrospective\t21\t2000–2004\t2–8 months\t3D-CRT\tPTV1: uninvolved mediastinal and ipsilateral hilar lymphnodes+ 10–15 mm\nPTV2:GTV + 10 mm\t60 (46–60)\twCBDCA (7)\nwCBDCA-PTX (2)\nwCBDCA-VDS (1)\nwCBDCA-VNB (1)\nwCDDP (1)\tPneumonitis G3 (4.7)\nHematologic G3 (4.7)\nHematologic G4 (4.7)\t\nKelsey et al., 2006 [22]\tRetrospective\t29\t1991–2003\tn.s.\tn.s.\tPTV: ENI (27/29; n.s. in others)\t66 (46–74)\tNAD to RT (7)\nConcomitant (8)\tEsophagitis + stenosis G3 (6.8)\t\nBae et al., 2012\tRetrospective\t64\t1994–2007\t32 months\t3D-CRT\tPTV: GTV + 10–20 mm\tMedian BED10 70.2 (51.5–85.8)\twCDDP-PTX (12)\nCDDP-Eto q28 (2)\tPneumonitis G3 (9.4%)\nPneumonitis G4 (1.6%)\t\nBar et al., 2013 [18]\tRetrospective\t30\t1999–2007\tn.s.\t3D-CRT (43)\tn.s.\t63.5 (26–66)\tCDDP-VNL q21 (14)\nwCBDCA-PTX (7)\nCDDP-Eto q 21 (4)\nOther platinum reg. (5)\tPneumonitis G3 (7)\nPneumonitis G4 (3.5)\nEsophagitis G3 (14)\nFebrile neutropenia (14)\nEsophageal stenosis (7)\nOther G3/4 (5/1): hearing loss (2), depression (1), neuropathy (1), nausea (1), pulmonary embolus (1)\t\nLee et al., 2013 [14]\tRetrospective\t38\t2001–2009\t26.4 months\t3D-CRT\tPTV: GTV + 10 mm for the CTV + 5–15 mm\nIpsilateral hilum usually included,\tMedian BED10 74.4 (58.5–97.5)\tCDDP-Eto (9)\nCBDCA-PTX (3)\tEsophagitis G3 (2.6%)\t\nTakenada et al., 2015\tRetrospective\t35\t2000–2011\tn.s.\tn.s.\tn.s.\t60 (30–60)\tCDDP-S1 (11)\nCDDP-Tegafur-Uracil (8)\nCBDCA-VNL (10)\nOther CDDP reg. (4)\nOther CBDCA reg. (2)\tEsophagitis G3 (9)\nNeutropenia G3 (14)\nNeutropenia G4 (20)\nCardiac G3 (2)\nMiscellaneous infection (9)\nOther G3 (11)\t\nKim et al., 2017 [13]\tRetrospective\t57\t2004–2014\t53.6 months\t3D-CRT\tPTV: GTV + 5–8 mm for the CTV + 10 mm\tMedian BED10 79.2 (58.5–84)\twCDDP-PTX (40)\nCDDP-Eto q21 (2)\tPneumonitis G3 (5.3)\nEsophagitis G3 (3.5)\t\nNakamichi et al., 2017 [19]\tRetrospective\t74\t2000–2010\tn.s.\tn.s.\tLung lesions+recurrent lymphnodes+regional nodes\tMedian 60 (50–70)\tCDDP-VNL q28 (14)\nCBDCA-PTX (3)\nCDDP-PTX (1)\tRT group (56):\nPneumonitis G3 (5)\nLate pulm. Toxicity (2)\nOther non-hematologic (2)\nR-CT group (18):\nFebrile neutropenia (17)\nPneumonitis G3 (5)\nEsophagitis Ge (5)\nOther non-hematologic (5)\t\nSeol et al., 2017 [16]\tRetrospective\t31\t2008–2013\t14 months\t3D-CRT\tPTV: GTV + 10–20 mm + adjacent nodal areas (mediastinal and hilar) considered at risk+ 3–5 mm\t66 (51–66)\tNAD CT (7)\nConcomitant CT (7)\nNAD CT + R-CT (1)\nRT + Adj CT (1)\tPneumonitis G3 (3.2)\t\nNicosia et al. (present study)\tRetrospective\t14\t2014–2016\t12 months\tIMRT-SIB\tPTV1: GTV + 5 mm\nPTV2: involved nodal station + adjacent stations and hilum + 7 mm\t50 + boost 62.5\twCDDP (9)\tPneumonitis G3 (7.1)\t\nNSCLC: non-small cell lung cancer; FUP: follow-up; CT: chemotherapy; AP-PA: antero-postero parallel opposite technique; 3D-CRT: 3-dimensional conformal radiotherapy; NAD: neoadiuvant; BED: biological equivalent dose; R-CT: radio-chemotherapy; Adj: adjuvant; CBDCA: carboplatin; PTX: paclitaxel; VDS: vindesine; VNB: vinorelbine; CDDP: cisplatin; Eto: etoposide\n\n\n\nThe rationale of treating NSCLC patients with mediastinal nodal relapse retain in the oligometastatic concept: patients with limited metastatic disease may benefit from more aggressive local treatment to the macroscopical disease. Recent series suggest that survival of loco-regional recurrent NSCLC is more similar to that of stage III NSCLC than to stage IV. Therefore, it is conceivable that a dose of RT >66Gy and the addition of systemic therapy may improve local control having a favorable effect on survival [1, 14–17].\n\nBar et al. [18] treated 30 patients with different RT schedules (median dose 63.5 Gy) and platinum-based chemotherapy obtaining a response rate of 70% and 2- and 3-years overall survival (OS) of 50.8% and 38.7%, respectively. Nakamichi et al. [19] reported a series of 74 patients treated with RT alone 60 Gy (56 patients) or RT 60 Gy associated to concomitant chemotherapy (18 patients). The response rate after RT alone and combined therapy were 68% and 78%, respectively, and the use of the concomitant chemotherapy predicted for better OS and PFS. The median OS for RT alone and radiochemotherapy patients were 33.1 and 79.6 months, respectively, and the 5-years OS were 35% and 53%, respectively. Kim et al. [13] reported rates of 2-years LRFS and OS of 70.9% and 62.4%, respectively. Treatment failure globally occurred in 68.4% of patients with 8.8% of isolated in-field failure.\n\nLocal control of our series was in line with previous studies with 50% of complete response at 1-year, median LPFS of 26 months and 1- and 2-years LPFS of 80% and 40%, respectively. In-field recurrence occurred all within the 50 Gy volume, so that the dose in the boost volume seems adequate to control the macroscopical disease, even if a longer follow-up would be required.\n\nThe contribution of metastatic spread was difficult to assess in this series, also considering that the analysis of survival was beyond the intentions of this pilot study. Metastatic spread occurred in 50% of patients after a median of 9 months. This could be in accordance with two hypothesis: first of all, it was a disseminated disease from the beginning, and second of all, there was poor efficacy of the concomitant chemotherapy. We are more likely to consider the second option as more plausible, since we accurately staged all the patients before treatment with CT scan and 18FDG-PET/CT. Moreover, the systemic control of previous studies, where regimens more intensive were administered, are consistent with this hypothesis.\n\nTo our knowledge this is the first study that reported the use of IMRT-SIB in a population of mediastinal nodal recurrent NSCLC. Our preliminary data, taking into account the retrospective nature of the study, showed optimal tolerance and promising local control. A phase II study with a larger population is mandatory to assess the effect of a more intensive concomitant chemotherapy regimen that could synergize with the proposed fractionation delivered with modern and precise techniques, with the aim to improve survival and minimize side effects.\n\nConclusions\nAggressive local therapy associated to systemic therapy could be a good option in the treatment of postoperative mediastinal nodal relapse in NSCLC patients unfit to receive a second surgery. In this particular population of oligometastatic NSCLC patients, a modern radiotherapy delivered with accurate techniques and a combined systemic approach may lead to good outcome and tolerability. Better distant control might be obtained with more intensified systemic therapy and should be prospectively evaluated in a larger series.\n\nAbbreviation\n18FDG-PET18fluorodeoxyglucose-positron emission tomography\n\n3D-CRT3-dimensional conformal radiotherapy\n\nAdjAdjuvant\n\nAP-PAAntero-postero parallel opposite technique\n\nBEDBiological equivalent dose\n\nBSCBest supportive care\n\nCBDCACarboplatin\n\nCCTConcomitant chemotherapy\n\nCDDPCisplatin\n\nCOPDChronic obstructive pulmonary disease\n\nCRComplete response\n\nCTComputed tomography\n\nCTCAECommon Terminology Criteria for Adverse Events\n\nCTVClinical target volume\n\nEtoEtoposid\n\nFUPFollow-up\n\nGTVGross target volume\n\nILLInferior left lobe\n\nIMRTIntensity-modulated radiation therapy\n\nIRLInferior right lobe\n\nLPFSLocal progression-free survival\n\nMFSMetastasis-free survival\n\nMLMiddle lobe\n\nMLDMean lung dose\n\nNADNeoadiuvant\n\nNSCLCNon-small cell lung cancer\n\nOSOverall survival\n\nPFSProgression-free survival\n\nPORTPost-operative radiation therapy\n\nPTVPlanning target volume\n\nPTXPaclitaxel\n\nR-CTRadio-chemotherapy\n\nRTRadiotherapy\n\nSIBSimultaneous integrated boost\n\nSLLSuperior left lobe\n\nSRLSuperior right lobe\n\nSRSStereotactic radiosurgery\n\nVDSVindesine\n\nVNBVinorelbine\n\nAcknowledgements\nThe authors would like to thank Prof. Grace Xerri for her help in the final revision of the manuscript.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nLN analyzed and interpreted patients data, wrote the manuscript. LA analyzed data and was a major contributor in writing the manuscript. CR collected patient data and wrote Material and Methods chapter. VD Contributed to write the manuscript and LM collected patient data. GM Statistical analysis. JD revised the literature, compiled tables and revised the manuscript. MV Statistical analysis and contributor in writing the manuscript. MO Definition of protocol parameters and final revision of manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Burdett S Rydzewska L Tierney J Fisher D Parmar MKB Arriagada R Pignon JP Le Pechoux C on behalf of the PORT meta-analysis Trialists group Postoperative radiotherapy for non-small cell lung cancer Cochrane Database Syst Rev 2016 10 CD002142 27727451 \n6. Corbin KS Hellman S Weichselbaum RR Extracranial oligometastases: a subset of metastases curable with stereotactic radiotherapy J Clin Oncol 2013 31 1384 1390 10.1200/JCO.2012.45.9651 23460715 \n7. Niibe Y Hayakawa K Oligometastases and oligo-recurrence: the new era of cancer therapy Jpn JClin Oncol 2010 40 107 111 10.1093/jjco/hyp167 20047860 \n8. Huang F Wu G Yang K Oligometastasis and oligo-recurrence: more than a mirage RadiatOncol 2014 9 230 \n9. Pfannschmidt J Dienemann H Surgical treatment of oligometastatic nonsmall cell lung cancer Lung Cancer 2010 69 251 258 10.1016/j.lungcan.2010.05.003 20537426 \n10. Tanvetyanon T Robinson LA Schell MJ Strong VE Kapoor R Coit DG Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small- cell lung cancer: a systematic reviewand pooled analysis J Clin Oncol 2008 26 1142 1147 10.1200/JCO.2007.14.2091 18309950 \n11. Yamashita H Niibe Y Yamamoto T Lung stereotactic radiotherapy for oligometastases: comparison of oligorecurrence and sync-oligometastases Jpn J Clin Oncol 2016 46 687 691 10.1093/jjco/hyw047 27162324 \n12. Bae SH Ahn YC Nam H Park HC Pyo HR Shim YM Kim J Kim K Ahn JS Ahn MJ Park K High dose involved field radiation therapy as salvage for loco-regional recurrence of non-small cell lung cancer Yonsei Med J 2012 53 6 1120 1127 10.3349/ymj.2012.53.6.1120 23074111 \n13. Kim Eunji Song Changhoon Kim Mi Young Kim Jae-Sung Long-term outcomes after salvage radiotherapy for postoperative locoregionally recurrent non-small-cell lung cancer Radiation Oncology Journal 2017 35 1 55 64 10.3857/roj.2016.01928 28183160 \n14. Lee NK Moon SH Kim TH Han JY Yun T Kim HT Lee HS Kim MS Lee JM Cho KH Lee JS Prognostic value of gross tumor volume for definitive radiation therapy in patients with locoregionally recurrent non-small-cell lung cancer after surgical resection Clin Lung Cancer 2013 14 4 399 406 10.1016/j.cllc.2012.11.002 23276823 \n15. Takenaka T Takenoyama M Toyozawa R Inamasu E Yoshida T Toyokawa G Shiraishi Y Hirai F Yamaguchi M Seto T Ichinose Y Concurrent chemoradiotherapy for patients with postoperative recurrence of surgically resected non-small-cell lung cancer Clin Lung Cancer 2015 16 1 51 56 10.1016/j.cllc.2014.06.001 25038000 \n16. Seol KH Lee JE Cho JY Lee DH Seok Y Kang MK Salvage radiotherapy for regional lymph node oligo-recurrence after radical surgery of non-small cell lung cancer Thorac Cancer 2017 8 6 620 629 10.1111/1759-7714.12497 28906073 \n17. Yoon SM Shaikh T Hallman M Therapeutic management options for stage III non-small cell lung cancer World J Clin Oncol 2017 8 1 20 10.5306/wjco.v8.i1.1 28246582 \n18. Bar J Ng D Moretto P Goss GD Sun A Macrae R Laurie SA Leighl N Nicholas G Chemoradiotherapy for locoregional recurrence of non-small-cell lung cancer after surgical resection: a retrospective analysis Clin Lung Cancer 2013 14 2 200 204 10.1016/j.cllc.2012.05.008 22868221 \n19. Nakamichi S Horinouchi H Asao T Goto Y Kanda S Fujiwara Y Nokihara H Yamamoto N Ito Y Watanabe SI Ohe Y Comparison of radiotherapy and Chemoradiotherapy for Locoregional recurrence of non-small-cell lung Cancer developing after surgery Clin Lung Cancer. 2017 18 6 e441 e448 10.1016/j.cllc.2017.05.005 28583380 \n20. Kagami Y Nishio M Narimatsu N Mjoujin M Sakurai T Hareyama M Saito A Radiotherapy for locoregional recurrent tumors after resection of non-small cell lung cancer Lung Cancer 1998 20 1 31 35 10.1016/S0169-5002(98)00008-7 9699185 \n21. Uno T Isobe K Kawakami H Ueno N Kawata T Yamamoto S Sekine Y Iyoda A Iizasa T Fujisawa T Shigematsu N Ito H Dose-volume factors predicting radiation pneumonitis in patients receiving salvage radiotherapy for postlobectomy locoregional recurrent non-small-cell lung cancer Int J Clin Oncol 2006 11 1 55 59 10.1007/s10147-005-0542-5 16508730 \n22. Kelsey CR Clough RW Marks LB Local recurrence following initial resection of NSCLC: salvage is possible with radiation therapy Cancer J 2006 12 4 283 288 10.1097/00130404-200607000-00006 16925972\n\n",
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010865:Pilot Projects; D011379:Prognosis; D050397:Radiotherapy, Intensity-Modulated; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate",
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"title": "Salvage radiotherapy with simultaneous integrated boost in non small-cell lung cancer patients with mediastinal relapse after surgery: a pilot study.",
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"abstract": "Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19+ B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology.",
"affiliations": "Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK. w.qasim@ucl.ac.uk.;Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.;Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.;Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.;Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.;Cancer Institute, University College London, London WC1E 6DD, UK.;Division of Cancer Studies, Department of Haematological Medicine, King's College London, London SE5 9NU, UK.;Division of Cancer Studies, Department of Haematological Medicine, King's College London, London SE5 9NU, UK.;Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.;Sheffield Children's Hospital, Sheffield S10 2TH, UK.;Cancer Institute, University College London, London WC1E 6DD, UK.;Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.",
"authors": "Qasim|Waseem|W|;Zhan|Hong|H|;Samarasinghe|Sujith|S|;Adams|Stuart|S|;Amrolia|Persis|P|;Stafford|Sian|S|;Butler|Katie|K|;Rivat|Christine|C|;Wright|Gary|G|;Somana|Kathy|K|;Ghorashian|Sara|S|;Pinner|Danielle|D|;Ahsan|Gul|G|;Gilmour|Kimberly|K|;Lucchini|Giovanna|G|;Inglott|Sarah|S|;Mifsud|William|W|;Chiesa|Robert|R|;Peggs|Karl S|KS|;Chan|Lucas|L|;Farzeneh|Farzin|F|;Thrasher|Adrian J|AJ|;Vora|Ajay|A|;Pule|Martin|M|;Veys|Paul|P|",
"chemical_list": "D018941:Antigens, CD19; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D011948:Receptors, Antigen, T-Cell; D000071336:Transcription Activator-Like Effectors; D000074323:Alemtuzumab; D000069896:Transcription Activator-Like Effector Nucleases",
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"journal": "Science translational medicine",
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"medline_ta": "Sci Transl Med",
"mesh_terms": "D000074323:Alemtuzumab; D018941:Antigens, CD19; D000074301:CD52 Antigen; D057176:Compassionate Use Trials; D005260:Female; D000072669:Gene Editing; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D016086:Lentivirus; D009364:Neoplasm Recurrence, Local; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D011948:Receptors, Antigen, T-Cell; D012074:Remission Induction; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes; D000069896:Transcription Activator-Like Effector Nucleases; D000071336:Transcription Activator-Like Effectors; D014184:Transplantation, Homologous",
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"pmid": "28123068",
"pubdate": "2017-01-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells.",
"title_normalized": "molecular remission of infant b all after infusion of universal talen gene edited car t cells"
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"abstract": "OBJECTIVE\nTo examine neurocognitive functioning of children exposed prenatally to carbamazepine, lamotrigine, levetiracetam or valproate monotherapy.\n\n\nMETHODS\nIn a prospective observational study, children aged 6 or 7 years, identified from the European Registry of Antiepileptic Drugs and Pregnancy database in The Netherlands, were assessed using the Wechsler Intelligence Scale for Children and the developmental neuropsychological assessment. Maternal IQ was measured using Wechsler Adult Intelligence Scale. Assessors were blinded to drug exposures.\n\n\nRESULTS\nOne hundred and sixty-one children (one set of twins and 21 sibling pairs) of 139 mothers were included. As a group, children achieved average scores on neurocognitive outcomes. Children exposed to valproate (n = 22) performed lower on all six neurocognitive domains, especially language, than those exposed to carbamazepine (n = 32), lamotrigine (n = 82) or levetiracetam (n = 25). After controlling for maternal IQ and drug dose, the verbal IQ of valproate-exposed children was on average 9.1 points lower than those exposed to carbamazepine (95% confidence interval [CI] 1.3-17.0; p = 0.023), 10.3 lower than lamotrigine-exposed children (CI 3.4-17.3; p = 0.004) and 13.4 lower than levetiracetam-exposed children (CI 5.2-21.6; p = 0.002). No significant dose-effect was found. Virtually no significant differences were found between lamotrigine and levetiracetam or lamotrigine and carbamazepine exposed children.\n\n\nCONCLUSIONS\nConsistent with previous research, valproate-exposed children experienced more problems compared to three other common antiepileptic drugs, while children exposed to lamotrigine, carbamazepine or levetiracetam revealed little to no problems. This illustrates the need for systematic follow-up of prenatally exposed children, to support pre-pregnancy counseling and treatment decisions in women of reproductive age.",
"affiliations": "Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands.;Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands.;Research Institute of Child Development and Education, University of Amsterdam, 15776, 1001 NG, Amsterdam, The Netherlands.;Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands.;Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands. H.R.Rodenburg@uva.nl.",
"authors": "Huber-Mollema|Yfke|Y|http://orcid.org/0000-0003-0623-1929;van Iterson|Loretta|L|;Oort|Frans J|FJ|;Lindhout|Dick|D|http://orcid.org/0000-0001-9580-624X;Rodenburg|Roos|R|http://orcid.org/0000-0002-4288-1737",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D000077287:Levetiracetam; D014635:Valproic Acid; D000077213:Lamotrigine",
"country": "Germany",
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"doi": "10.1007/s00415-020-09764-w",
"fulltext": "\n==== Front\nJ Neurol\nJ. Neurol\nJournal of Neurology\n0340-5354 1432-1459 Springer Berlin Heidelberg Berlin/Heidelberg \n\n9764\n10.1007/s00415-020-09764-w\nOriginal Communication\nNeurocognition after prenatal levetiracetam, lamotrigine, carbamazepine or valproate exposure\nhttp://orcid.org/0000-0003-0623-1929Huber-Mollema Yfke yfke.mollema@gmail.com 12 van Iterson Loretta lviterson@sein.nl 1 Oort Frans J. F.J.Oort@uva.nl 2 http://orcid.org/0000-0001-9580-624XLindhout Dick dl@knmg.org 13 http://orcid.org/0000-0002-4288-1737Rodenburg Roos H.R.Rodenburg@uva.nl 12 1 grid.419298.f0000 0004 0631 9143Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands \n2 grid.7177.60000000084992262Research Institute of Child Development and Education, University of Amsterdam, 15776, 1001 NG Amsterdam, The Netherlands \n3 grid.7692.a0000000090126352Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands \n28 2 2020 \n28 2 2020 \n2020 \n267 6 1724 1736\n5 11 2019 14 2 2020 14 2 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Objective\nTo examine neurocognitive functioning of children exposed prenatally to carbamazepine, lamotrigine, levetiracetam or valproate monotherapy.\n\nMethods\nIn a prospective observational study, children aged 6 or 7 years, identified from the European Registry of Antiepileptic Drugs and Pregnancy database in The Netherlands, were assessed using the Wechsler Intelligence Scale for Children and the developmental neuropsychological assessment. Maternal IQ was measured using Wechsler Adult Intelligence Scale. Assessors were blinded to drug exposures.\n\nResults\nOne hundred and sixty-one children (one set of twins and 21 sibling pairs) of 139 mothers were included. As a group, children achieved average scores on neurocognitive outcomes. Children exposed to valproate (n = 22) performed lower on all six neurocognitive domains, especially language, than those exposed to carbamazepine (n = 32), lamotrigine (n = 82) or levetiracetam (n = 25). After controlling for maternal IQ and drug dose, the verbal IQ of valproate-exposed children was on average 9.1 points lower than those exposed to carbamazepine (95% confidence interval [CI] 1.3–17.0; p = 0.023), 10.3 lower than lamotrigine-exposed children (CI 3.4–17.3; p = 0.004) and 13.4 lower than levetiracetam-exposed children (CI 5.2–21.6; p = 0.002). No significant dose–effect was found. Virtually no significant differences were found between lamotrigine and levetiracetam or lamotrigine and carbamazepine exposed children.\n\nConclusions\nConsistent with previous research, valproate-exposed children experienced more problems compared to three other common antiepileptic drugs, while children exposed to lamotrigine, carbamazepine or levetiracetam revealed little to no problems. This illustrates the need for systematic follow-up of prenatally exposed children, to support pre-pregnancy counseling and treatment decisions in women of reproductive age.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s00415-020-09764-w) contains supplementary material, which is available to authorized users.\n\nKeywords\nEpilepsyPregnancyAntiepileptic drugsCognitionNeuropsychological assessmentEURAP & developmentStichting panta rhei-Rodenburg Roos issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nEpilepsy affects up to 1% of the population [1], and antiepileptic drugs (AEDs) are the main treatment. About a third of people receiving AEDs are women of reproductive age [2], and women in three to four per 1000 pregnancies take AEDs [3]. Treatment continuation during pregnancy is a must for most women with active epilepsy [4].\n\nKnowledge of AED teratogenicity has increased in the past decade [5, 6]. Children of mothers with epilepsy are at higher risk of congenital malformations and, for a number of maternal AEDs, these risks show a dose–effect relationship [7]. Increasing attention has also been paid to the long-term neurocognitive and behavioral effects of prenatal exposure to AEDs [6]. The greatest impact has been observed for valproate (VPA) [5, 6, 8, 9]. As this drug is associated with major malformations and neurocognitive effects it is no longer routinely prescribed to women with child-bearing potential [10], which has resulted in increased use of newer AEDs such as lamotrigine (LTG) and levetiracetam (LEV) [11, 12]. To date, few or no effects on neurocognition have been found with carbamazepine (CBZ) or LTG [6, 13]. However, currently available data on long-term development of prenatal LTG exposed children are fairly limited, and even less is known about possible effects of LEV [8, 14].\n\nWe examined neurocognitive functioning of children aged 6 or 7 years, prenatally exposed to monotherapy with CBZ, LTG, LEV or VPA. It was hypothesized that children exposed to VPA would have impaired neurocognitive functioning compared to children exposed to CBZ, LTG or LEV. In addition, LTG and LEV were exploratively examined as these are first choice treatments for many women with epilepsy of childbearing age.\n\nMethods\nStudy design and participants\nWe collaborated with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP) to design the Dutch EURAP & Development study [15]. EURAP & Development is a prospective observational study of children of mothers with epilepsy, with assessors blinded to drug exposures. The current study is part of a larger longitudinal study in which long-term effects of prenatal exposure to AEDs on neurocognitive and behavioral development are investigated from a family perspective [15].\n\nParticipants were mother–child pairs identified from the EURAP-NL database in The Netherlands, a national, single center pregnancy register that investigates the prevalence of major congenital malformations following prenatal exposure to AEDs. Women are enrolled by the EURAP-NL center through self-referral or by their health professional. Recruitment occurs preferably within the first 16 weeks of pregnancy—relevant for the evaluation of major malformations—facilitating prospective information about health and well-being during the pregnancy [7]. Mother–child pairs with risk factors (e.g., seizure occurrence, alcohol or nicotine use during pregnancy) assessed prenatally, after delivery, or up until 3 years of age, were eligible. Inclusion criteria were maternal CBZ, LTG, LEV or VPA monotherapy starting before conception and continuing during the entire pregnancy, and the child aged between 6.0 and 7.11 years at the neurocognitive assessment. Children were excluded if (1) the mother was unable to take care of the child (e.g., lives in foster care), (2) the child has a known chromosomal/genetic syndrome or prematurity (gestational age less than 37 weeks), or (3) there were factors other than AED exposure which significantly modified child development, such that reliable assessment was not possible.\n\nAs participants lived all across The Netherlands, the study was conducted at different locations [e.g., Heemstede (epilepsy center SEIN), Amsterdam (University of Amsterdam), Rotterdam, Zwolle and Groningen (outpatient clinics SEIN), Nijmegen (Radboud University), Eindhoven (center for child psychiatry) and Heeze (epilepsy center Kempenhaeghe)]. If travel to one of the study locations was not possible, the child assessment took place at home. All assessors (in total thirteen child psychologists, including (and under supervision of) YH-M) were (video) trained and monitored according to the test protocol, to ensure standardized procedures. Further detailed information on procedures are provided in the study protocol [15].\n\nMeasures\nGeneral information\nParents completed an online questionnaire on demographic information, developmental milestones, school performance and additional educational needs.\n\nIntelligence\nNine subtests of the Wechsler Intelligence Scale for Children (WISC-III-NL) [16] were used to assess child intelligence: picture completion; information; object assembly; similarities; block design; comprehension; coding; symbol search and digit span. The WISC-III short form assesses full-scale IQ (FSIQ), verbal IQ (VIQ), performance IQ (PIQ) and the processing speed index (PSI) [17]; parents completed the short form of the Wechsler Adult Intelligence Scale (WAIS-III-NL) [18] (seven subtests).\n\nAttention and executive functioning\nWe used the subtests auditory attention, response set, inhibition, statue, and design fluency of the developmental neuropsychological assessment (NEPSY-II-NL) [19], which allows the measurement of subcomponents of attention and executive functions. These are: inhibition of learned and automated responses; monitoring and self-regulation; alertness, selective and sustained attention; ability to establish maintain and change responses; nonverbal problem solving, planning and organizing a complex response; and production of patterns [19]. In contrast to the first edition of the NEPSY, NEPSY-II-NL does not include a visual attention task. We therefore used the Visual Sky Search task of the Test of Everyday Attention for Children (Tea-CH) [20]. With this task the child is asked to search an A3 sheet with numerous pairs of spaceships which are randomly distributed and to try to circle as many pairs of identical spaceships as quickly as possible.\n\nLanguage skills\nFrom the language domain of the NEPSY-II-NL, we assessed speeded naming, comprehension of instructions, and word generation. These subtests measure fast semantic access to, and production of, words (e.g. names of colors, shapes, or sizes); the ability to receive, process, and execute oral instructions of increasing complexity; and verbal productivity through the ability to generate words within specific semantic categories [19]. We used the Peabody Picture Vocabulary Test (PPVT-III-NL) to measure vocabulary [21]. Verbal fluency was assessed with the Lindeboom [22]. This is a short confrontational naming task where the child is asked to name rapidly 15 common pictures. The time score is used as outcome measure, with shorter times indicating better performance. To measure phonological processing (not included in the NEPSY-II-NL), we applied two short language tasks: auditory synthesis (sound blending) [23] and phoneme deletion [24].\n\nMemory and learning\nShort and long-term memory were measured with memory for faces, memory for faces delayed, memory for names, memory for names delayed and narrative memory of the NEPSY-II-NL. The subcomponents that were assessed included: encoding of facial features, as well as face discrimination and recognition; the ability to learn names of children; and the ability to remember organized verbal material, under free recall, cued recall and recognition conditions [19].\n\nFine motor skills\nFrom the Sensorimotor domain of the NEPSY-II-NL fingertip tapping, imitating hand positions, and visuomotor precision were measured for fine motor skills. The subcomponents that were assessed included the ability to imitate hand positions, to produce repetitive and sequential finger movements and to use a pencil with speed and precision [19]. Handedness was observed during the assessment.\n\nVisuospatial skills\nFrom the visuospatial processing domain of the NEPSY-II-NL, arrows and design copying were used to measure visuospatial skills. The subcomponents that were assessed included the ability to judge line orientation and the ability to copy two-dimensional geometric figures with paper and pencil [19].\n\nStatistical analyses\nData were analyzed using IBM SPSS Statistics 24. Descriptive analyses were performed for each AED taken, to describe the sample and to examine the nature and severity of neurocognitive development and the frequency of additional educational needs. All neurocognitive measures are standardized by age of the child based on population norms from the different test manuals. Some raw scores of the NEPSY-II-NL are originally standardized as percentile scores [19]. To facilitate interpretation, all NEPSY-II-NL scores were transformed to standard scores with mean 10 and standard deviation 3. Scores between 8 and 12 are considered average; scores of 7 or lower are interpreted as below average and scores of 12 or higher as above average. IQ scores (WISC-III-NL; PPVT-III-NL) have an average of 100, with scores lower than 90 interpreted clinically as below average and scores of 110 and higher classified as above average [25]. In line with DSM classifications, the statistical cut-off score of < 85 is used for percentage of children with below average intelligence [26].\n\nWe performed multiple regression analyses for each neurocognitive outcome to test the hypothesis that VPA-exposed children have impaired neurocognitive functioning compared to those exposed to the other AEDs. As LTG was the largest group, and as we also wanted to make a comparison between LTG- and LEV-exposed children (as first choice treatments for many women with epilepsy of childbearing age) and between LTG- and CBZ-exposed children, we performed additional analyses with LTG as reference group. As our sample also included a number of siblings, we conducted multilevel regression analyses to account for within family dependencies.\n\nPotential confounders were selected by assessing their relationships with the medication and outcome variables (through ANOVA with post hoc Tukey tests, Kruskal–Wallis, Chi square, Fisher’s exact tests and Pearson correlations). Variables included as potential confounders were: type of maternal epilepsy; tonic–clonic seizures during pregnancy; use of folic acid; alcohol and nicotine exposure during each trimester; breastfeeding; maternal age at delivery; maternal IQ and educational level; gestational age; gender; age at assessment; presence or absence of congenital malformations and time of inclusion in the EURAP-NL database (Table 1). Variables showing a relationship (p < 0.15) with medication and outcome measure, or that were expected to influence child development (e.g., maternal IQ) were entered one by one, each into a separate multiple regression analysis. Variables related to AED use were maternal age at delivery, gestational age, age at assessment, epilepsy type, alcohol use during the first trimester, nicotine use during each trimester, and presence of congenital malformations. As these variables were not found to be related to the outcome measure, we included only maternal IQ in the multiple regression analyses (see bivariate correlations between potential confounders and cognitive outcome measures in the supplemental material, e-Table1a). AED exposure type was entered into the model, with the VPA-exposed group as the reference group. To enable additional comparisons, we repeated the analyses with the LTG-exposed group as group of reference.Table 1 Group demographic information by antiepileptic exposure group\n\nSample size\tVPA\tCBZ\tLTG\tLEV\tp value\t\n22\t32\t82\t25\t\nMaternal characteristics: epilepsy and pregnancy information\t\n AED daily dose 1st trimester, mg/day mean (range min max)\t913.6 (500–1500)\t656.3 (200–1400)\t277.4 (50–600)\t1120.0 (250–3000)\tNA\t\n AED daily dose 3rd trimester, mg/day mean (range min max)\t940.9 (500–1500)\t656.3 (200–1600)\t334.2 (50–1000)\t1150.0 (250–2500)\t\t\n Dose changes, n (%), increased/decreased\t3 (14%)\n\n2 vs 1\n\n\t3 (9%)\n\n2 vs 1\n\n\t50 (61%)\n\n49 vs 1\n\n\t6 (24%)\n\n4 vs 2\n\n\t\t\n Maternal age at birth of baby, mean (SD)\t33 (3)\t32 (5)\t31 (4)\t32 (4)\t.018a\t\n Maternal FSIQsd, mean (SD)\t103 (14)\t100 (17)\t104 (14)\t108 (15)\t0.287a\t\n VIQs, mean (SD)\t102 (13)\t100 (16)\t102 (13)\t105 (13)\t0.548a\t\n PIQs, mean (SD)\t104 (9)\t100 (10)\t104 (9)\t106 (11)\t0.125a\t\n Maternal educationd, n (%) higher education\t12 (60%)\t14 (47%)\t41 (61%)\t14 (70%)\t0.720b\t\n Folate supplementation, n (%) yes†\t19 (91%)\t23 (77%)\t67 (82%)\t21 (84%)\t0.693c\t\n Alcohol exposure, n (%) yes\t\n First trimester\t3 (14%)\t3 (9%)\t26 (32%)\t4 (16%)\t0.036c\t\n Second and/or third trimester\t1 (5%)\t1 (3%)\t8 (10%\t0\t0.369c\t\n Nicotine exposure, n (%) yes\t\n First trimester\t6 (27%)\t3 (9%)\t3 (4%)\t1 (4%)\t0.007c\t\n Second and/or third trimester\t3 (14%)\t0\t2 (2%)\t1 (4%)\t0.064c\t\n Maternal epilepsy type, n (%)\t0.000c\t\n Generalized\t16 (73%)\t2 (6%)\t22 (27%)\t9 (36%)\t\t\n Localization-related\t4 (18%)\t28 (88%)\t52 (63%)\t15 (60%)\t\t\n Unknown\t2 (9%)\t2 (6%)\t8 (10%)\t1 (4%)\t\t\n Tonic–clonic seizures, n (%) yes\t2 (9%)\t5 (16%)\t14 (17%)\t4 (16%)\t0.843b\t\n Breastfeeding, n (%) yes\t5 (23%)\t12 (38%)\t18 (22%)\t4 (16%)\t0.261c\t\nPaternal characteristics\t\n Paternal FSIQe, mean (SD)\t108 (13)\t104 (14)\t111 (13)\t113 (11)\t0.192a\t\n VIQs, mean (SD)\t103 (16)\t104 (12)\t110 (13)\t113 (16)\t0.120a\t\n PIQs, mean (SD)\t104 (9)\t102 (10)\t105 (9)\t106 (4)\t0.429a\t\n Paternal educatione, n (%) higher education\t11 (55%)\t10 (33%)\t43 (63%)\t13 (62%)\t0.178b\t\nChild characteristics\t\n Age at assessment, months, mean (SD)\t81.5 (6.2)\t81.0 (6.1)\t82.7 (7.7)\t78.2 (5.6)\t0.051a\t\n Gestational age, weeks, mean (SD)\t40.6 (1.3)\t39.9 (1.4)\t40.0 (1.1)\t40.3 (1.1)\t0.089a\t\n Child sex, n (%) male\t11 (50%)\t15 (47%)\t42 (51%)\t15 (60%)\t0.804b\t\n Congenital malformations, n (%) yes\t5 (23%)\t4 (13%)\t4 (5%)\t1 (4%)\t0.043c\t\n Sibling, n (%) yes\t2 (9%)\t1 (3%)\t14 (17%)\t4 (16%)\t\t\n Inclusion moment EURAP-NL, n (%)\t0.812b\t\n Before 16th week pregnancy\t14 (64%)\t22 (69%)\t62 (76%)\t19 (76%)\t\t\n Between 16th week and birth\t6 (27%)\t6 (19%)\t11 (13%)\t3 (12%)\t\t\n After birth\t2 (9%)\t4 (13%)\t9 (11%)\t3 (12%)\t\t\nParental report of child needs\t\n Special education, n (%)\t2 (9%)\t0 (0%)\t3 (4%)\t0 (0%)\t0.227c\t\n Repeating a year of school, n (%)\t4 (18%)\t3 (9%)\t9 (11%)\t1 (4%)\t0.491c\t\n Additional educational needs, n (%)\t8 (36%)\t5 (16%)\t11 (13%)\t3 (12%)\t0.099c\t\n Developmental delay, n (%)\t7 (32%)\t4 (13%)\t8 (10%)\t3 (12%)\t0.088c\t\n Physiotherapy, n (%)\t10 (46%)\t9 (28%)\t21 (26%)\t7 (28%)\t0.347c\t\n Speech therapy, n (%)\t7 (32%)\t11(34%)\t24 (29%)\t4 (16%)\t0.447c\t\nAED antiepileptic drug, VPA valproate, CBZ carbamazepine, LTG lamotrigine, LEV levetiracetam, TIQs estimated total intelligence, VIQs estimated verbal intelligence, PIQs estimated performance intelligence\n\naAnalysis of variance (continuous data)\n\nbChi square\n\ncFisher exact (dichotomous data)\n\ndOne hundred and thirty-nine mothers. One mother without IQ scores\n\neOne hundred and thirty-nine fathers of which 85 with IQ scores\n\n†Appropriate use of folic acid was defined as at least 4 weeks before conception with a minimum dose of 0.4 mg/day. Three missing because of unknown start date of folic acid\n\n\n\nDose effect was included in the regression analyses as the percentage relative to the median group AED dose [100 × ((dose first trimester − median group AED dose)/median group AED dose)]. An interaction term between AED type and dose (e.g., VPA dose) was also included separately in the regression models. Correlation analyses were used to examine relationships between AED dose (CBZ, LTG, LEV, VPA) and outcome measures. We examined relationships with first trimester as well as third trimester dose.\n\nAnalyses were conducted with all available scores on the outcome variables, without imputation for missing data on outcome variables. Specific neurocognitive scores were missing on two children in the VPA-exposed group, since we only obtained information from their parents. Both children had previously been assessed within a clinical setting; we therefore included IQ scores based on the psychological report and parent information from the online questionnaire. For one mother without IQ scores, we used the average IQ in her education group.\n\nWe performed sensitivity analyses with only one child from each family (the first-born child within the study) and with only the children included in EURAP-NL before 16 weeks of gestation to avoid possible bias.\n\nData availability\nThe study protocol is available on PsyArXiv, https://doi.org/10.17605/OSF.IO/B8DYJ. Anonymized data will be restrictedly available after project completion from the corresponding author on reasonable request by a qualified investigator.\n\nResults\nParticipants\nFour hundred and five invitations to participate were sent with 173 positive responses received (42.9%). 117 families declined participation (28.9%), and 126 did not respond (31.3%) (Fig. 1). Between January 2015 and February 2018 one hundred and sixty-one children of 139 mothers (one pair of twins and 21 pairs of siblings) were included for this neurocognition study (mean age 82 months; range 72–97 months—one child was 8.1 years at assessment because of a rescheduled appointment). This was approximately 40% of the original mother–child pairs who participated in EURAP-NL. The inclusion rate per AED was VPA 37%, CBZ 28%, LTG 51%, and LEV 36%.Fig. 1 Flowchart inclusion Dutch EURAP & Development study\n\n\n\nFor the outcome variables there were few missing values (Tables 2, 3). Extra tasks to the test protocol (design fluency, word generation, visual attention, and phonological processing) were not assessed in all children, due to lack of time or motivation. Some tasks were available only for certain ages (statue and auditory synthesis at 6 years only; phoneme deletion from 6.5 years).Table 2 Means and standard deviations of full scale, verbal and performance intelligence and processing speed, and percentage of children scoring below 85, by AED group\n\nWISC-III-NL\tSample size\tVPA (22)\tCBZ (32)\tLTG (82)\tLEV (25)\tp value\t\nM (SD) range No. (%) < 85\tM (SD) range No. (%) < 85\tM (SD) range No. (%) < 85\tM (SD) range No. (%) < 85\t\nFSIQ\t161\t103.2 (14.8) 73–138 1 (4.5)\t105.3 (13.7) 70–125 3 (9.4)\t109.2 (15.0) 71–148 3 (3.7)\t110.8 (14.8) 77–136 1 (4.0)\t0.188a\t\nVIQ\t161\t100.6 (14.9) 70–126 4 (18.2)\t106.2 (14.2) 86–138 0 (0)\t109.7 (15.7) 64–150 6 (7.3)\t114.0 (13.1) 88–140 0 (0)\t0.014a\t\nPIQ\t161\t105.3 (17.0) 77–140 3 (13.6)\t102.8 (15.5) 62–127 4 (12.5)\t106.0 (14.9) 77–146 6 (7.3)\t104.4 (14.8) 73–129 3 (12.0)\t0.796a\t\nPSI\t153\t107.4 (18.6) 72–143 3 (14.3)\t108.7 (12.1) 75–137 1 (3.3)\t111.0 (14.4) 75–140 3 (3.9)\t111.2 (16.7) 69–142 1 (4.0)\t0.722a\t\nMeans are unadjusted for covariates. Test mean is 100 with a standard deviation of 15. IQ below 85 is classed as a below average performance\n\nWISC-III-NL [16] Wechsler Intelligence Scale for Children-third edition, FSIQ full scale intelligence, VIQ verbal intelligence, PIQ performance intelligence, PSI processing speed index, VPA valproate, CBZ carbamazepine, LTG lamotrigine, LEV levetiracetam, M mean, SD standard deviation\n\naAnalysis of variance (normal distribution)\n\nTable 3 Means and standard deviations by AED group for specific neurocognitive outcomes\n\nNEPSY-II-NLa, Tea-CHa, PPVT-III-NLb, Lindebooma\tSample size\tVPA (20)\tCBZ (32)\tLTG (82)\tLEV (25)\tp value\t\nAttention and executive functioning\t\n Auditory attentiong\t157\t9.8 (2.2)\t9.8 (2.7)\t9.4 (2.6)\t9.9 (2.4)\t0.790f\t\n Response setg\t148\t8.3 (3.1)\t8.9 (2.5)\t9.1 (2.2)\t9.2 (2.8)\t0.762f\t\n Inhibition—naming total errorsg\t156\t8.5 (2.3)\t8.6 (2.4)\t8.8 (2.3)\t9.3 (2.5)\t0.526f\t\n Inhibition—naming time score\t156\t9.9 (3.1)\t11.0 (2.3)\t11.4 (2.1)\t11.5 (2.4)\t0.069d\t\n Inhibition—inhibition total errorsg\t156\t8.5 (2.2)\t8.8 (2.4)\t8.9 (2.5)\t9.5 (2.2)\t0.593f\t\n Inhibition—inhibition time scoreg\t156\t8.2 (2.5)\t8.9 (2.3)\t8.9 (1.8)\t9.1 (1.9)\t0.501f\t\n Statueg\t117\t6.8 (2.0)\t8.6 (2.5)\t9.0 (3.2)h\t8.6 (2.9)\t0.052f\t\n Design fluency\t100\t9.2 (3.1)h\t11.1 (3.5)h\t11.2 (3.1)h\t11.4 (3.2)h\t0.234d\t\n Visual attentiona\t102\t11.1 (3.4)\t11.7 (3.1)h\t11.3 (2.6)h\t10.4 (3.1)\t0.610d\t\nLanguage skills\t\n Comprehension of instructions\t157\t9.2 (2.1)\t10.6 (2.3)\t11.2 (3.0)\t12.0 (3.5)\t0.004e\t\n Speeded naming time scoreg\t155\t8.2 (2.7)\t9.2 (2.5)\t9.3 (2.4)\t9.4 (2.5)\t0.313f\t\n Speeded naming total correctg\t155\t7.2 (3.1)\t8.6 (3.3)\t8.7 (3.1)\t7.8 (3.2)\t0.190f\t\n Word generation\t118\t8.9 (2.9)\t10.0 (3.1)h\t10.9 (2.5)h\t10.7 (3.2)\t0.075d\t\n Verbal fluencya—time score\t157\t9.7 (4.6)\t8.5 (4.3)\t11.1 (4.4)\t10.3 (4.6)\t0.048d\t\n Vocabulary—WBQb\t157\t105.7 (11.3)\t110.1 (10.8)\t111.0 (13.2)\t114.9 (9.8)\t0.105d\t\n Auditory synthesisc\t75\t7.3 (1.5)h\t7.0 (2.0)h\t7.2 (2.0)h\t8.3 (1.8)h\t0.118d\t\n Phoneme deletiona\t46\t9.7 (4.1)h\t10.3 (2.9)h\t10.6 (2.4)h\t9.8 (1.5)h\t0.857d\t\nMemory and learning\t\n Memory for faces\t158\t9.2 (4.0)\t11.3 (3.4)\t10.6 (2.6)\t9.9 (3.5)\t0.211e\t\n Memory for faces delayed\t157\t10.6 (4.7)\t12.1 (3.0)\t11.2 (2.5)\t11.6 (2.7)\t0.427e\t\n Memory for names\t155\t8.8 (3.0)\t8.7 (2.7)\t8.9 (2.7)\t9.8 (2.9)\t0.448d\t\n Memory for names delayed\t155\t7.7 (3.9)\t8.1 (3.6)\t8.1 (3.7)\t8.8 (4.5)\t0.778d\t\n Narrative memory—free and cuedg\t156\t9.2 (2.2)\t9.1 (2.4)\t9.4 (2.2)\t9.5 (2.4)\t0.852f\t\nFine motor skills\t\n Imitating hand positions\t155\t10.6 (3.0)\t11.2 (3.0)\t11.1 (2.5)\t11.5 (3.2)\t0.762d\t\n Fingertip tapping—repetition DH\t154\t12.0 (1.2)\t12.4 (1.3)\t11.9 (2.0)\t12.2 (1.9)\t0.556f\t\n Fingertip tapping—repetition NDH\t154\t11.7 (1.3)\t11.7 (1.1)\t11.5 (1.9)\t11.8 (1.4)\t0.946f\t\n Fingertip tapping—series DH\t151\t9.0 (3.3)\t10.5 (1.7)\t10.6 (2.1)\t10.6 (2.2)\t0.201f\t\n Fingertip tapping—series NDHg\t151\t8.4 (3.2)\t9.6 (2.3)\t9.3 (2.3)\t9.4 (2.5)\t0.624f\t\n Visuomotor precision time scoreg\t157\t9.1 (2.6)\t7.9 (2.5)\t8.0 (2.6)\t8.8 (2.6)\t0.245f\t\n Visuomotor precision total errorsg\t157\t6.5 (2.6)\t8.4 (2.1)\t8.7 (2.5)\t7.5 (2.3)\t0.004f\t\nVisuospatial skills\t\n Arrows\t155\t11.1 (3.8)\t12.2 (3.3)\t12.5 (3.1)\t12.3 (3.0)\t0.358d\t\n Design copyingg\t156\t8.3 (2.5)\t9.3 (2.2)\t9.2 (1.9)\t9.0 (2.2)\t0.293d\t\nMeans are unadjusted for covariates. Lindeboom [22]—verbal fluency task, Auditory Synthesis from “language test for children” [23]. Phoneme Deletion from “Dyslexia Screening Test” [24]\n\nNEPSY-II-NL [19] developmental neuropsychological assessment—second edition, Tea-CH [20] Test of Everyday Attention for Children, PPVT-III-NL [21] Peabody Picture Vocabulary Test—third edition, VPA valproate, CBZ carbamazepine, LTG lamotrigine, LEV levetiracetam, DH dominant hand, NDH non-dominant hand\n\naTest mean is 10 with a standard deviation of 3. Standard score 8–12 is average\n\nbTest mean is 100 with a standard deviation of 15. IQ scores between 90 and 110 are interpreted as average\n\ncDecile scores\n\ndAnalysis of variance (normal distribution)\n\neWelch (no homogeneous group)\n\nfKruskal–Wallis (skewed)\n\ngOriginal percentile score, converted to standard scores [19]; standard score between 8 and 12 are average\n\nhMore than 25% missing\n\n\n\nChildren from the four AED-exposed groups were comparable across most demographic variables (Table 1). Significant differences were found in children exposed to nicotine in the first trimester, with highest rates seen for children from the VPA-exposed group (27%). The mothers of children exposed to VPA were also slightly but significantly older at the child’s birth. Mothers who used LTG were significantly more likely to have consumed alcohol during the first trimester (32%). Epilepsy type differed significantly between groups. Mothers who used VPA significantly more often had generalized epilepsy (73%) while mothers who used CBZ significantly more often had focal epilepsy (88%). Children who were exposed to VPA had significantly more congenital malformations (23%) than those who were exposed to CBZ (13%), LTG (5%) or LEV (4%).\n\nParent-reports showed that the majority of children attended mainstream schools (Table 1). Many children, however, received additional support at school, speech therapy, or physiotherapy. VPA exposed children tended to have higher frequencies of additional educational needs (36%) but this was not significant (p = 0.099, Fisher test). No significant differences were found for rates of children with developmental delay according to type of AED, as per parent reported (p = 0.088, Fisher test).\n\nThe nature and severity of neurocognitive development\nAcross the AED groups, VPA-exposed children had the lowest unadjusted mean scores for full scale intelligence (FSIQ), Verbal intelligence (VIQ) and processing speed (PSI) (Table 2), and across most specific neurocognitive domains (Table 3).\n\nCompared to the norms, all children generally scored within the average range on neurocognitive outcome measures, except for VPA-exposed children, who performed below average on the tasks of statue and memory for names delayed. VPA-exposed children and LEV-exposed children also performed below average on speeded naming (total correct) and visuomotor precision (total errors). CBZ-exposed children performed below average on visuomotor precision (time score). On other outcome measures children performed at least low on average (standard score 8) and sometimes above average (Tables 2, 3).\n\nChildren exposed to VPA scored lower on verbal intelligence. The mean score on verbal IQ is average but the distribution of verbal IQ scores appears somewhat shifted to the left, indicating overall lowered scores when contrasted to the other AED groups (Fig. 2). Similar distributions were found for the other neurocognitive outcome measures. LEV-exposed children scored above average on verbal intelligence, comprehension of instructions and vocabulary.Fig. 2 Distribution of verbal IQ scores of exposed children across the four AED groups\n\n\n\nBecause maternal IQ is an important confounder for child IQ, we also calculated outcome variable means adjusted for maternal IQ, but this gave similar results (Table 4). Adjusted verbal IQ was for VPA 100.5 (SE 2.9; 95% CI 94–106), for CBZ 107.9 (SE 2.5; 95% CI 103–113), for LTG 109.6 (SE 2.5; 95% CI 107–113), and for LEV 112.3 (SE 2.8; 95% CI 107–118).Table 4 Adjusted means of full scale, verbal and performance intelligence and processing speed\n\nWISC-III-NL\tSample size\tVPA (22)\tCBZ (32)\tLTG (82)\tLEV (25)\t\nMeana (SE)\t95% CI\tMeana (SE)\t95% CI\tMeana (SE)\t95% CI\tMeana (SE)\t95% CI\t\nFSIQ\t161\t103.1 (2.9)\t97–109\t106.9 (2.4)\t102–112\t109.1 (1.5)\t106–112\t109.2 (2.8)\t104–115\t\nVIQ\t161\t100.5 (2.9)\t95–106\t107.9 (2.5)\t103–113\t109.6 (1.5)\t107–113\t112.3 (2.9)\t107–118\t\nPIQ\t161\t105.2 (3.2)\t99–111\t104.0 (2.6)\t99–109\t105.9 (1.6)\t103–109\t103.3 (3.0)\t97–109\t\nPSI\t153\t107.8 (3.1)\t102–114\t109.9 (2.6)\t105–115\t110.8 (1.6)\t108–114\t109.8 (2.9)\t104–116\t\nWISC-III-NL [16] Wechsler Intelligence Scale for Children-third edition, FSIQ full scale intelligence, VIQ verbal intelligence, PIQ performance intelligence, PSI processing speed index, VPA valproate, CBZ carbamazepine, LTG lamotrigine, LEV levetiracetam, SE standard error, CI confidence interval\n\naMeans are adjusted for maternal IQ (mean 104.65)\n\n\n\nLEV-exposed children frequently had a disharmonic profile—meaning a significant difference of more than 16 points between VIQ and PIQ—in favor of verbal skills (seven had VIQ > PIQ vs one who had VIQ < PIQ). In VPA-exposed children it was the opposite with more disharmonic profiles in favor of performance skills (2 VIQ > PIQ vs 4 VIQ < PIQ). For CBZ- and LTG-exposed children this was 6 vs 5 and 20 vs 10 respectively.\n\nComparison between children exposed to different antiepileptic drug types\nAfter controlling for maternal IQ, standardized dose and VPA-dose, multiple regression analyses showed that VPA-exposed children scored significantly lower on FSIQ than those exposed to LTG, and significantly lower on VIQ than CBZ-, LTG-, and LEV-exposed children. No significant differences were found for PIQ or PSI (Table 5).Table 5 Multiple regression analyses of intelligence outcomes with VPA as reference group\n\nWISC-III-NL\tVIQ\tPIQ\tFSIQ\tPSI\t\nB (SE)\t95% CI\tp value\tB (SE)\t95% CI\tp value\tB (SE)\t95% CI\tp value\tB (SE)\t95% CI\tp value\t\nConstant\t55.9 (8.7)\t38.7–73.0\t0.000\t75.2 (9.4)\t56.7–93.7\t0.000\t60.3 (8.6)\t43.3–77.3\t0.000\t71.9 (9.2)\t53.6–90.2\t0.000\t\nCBZ\t9.1 (4.0)\t1.3–17.0\t0.023*\t0.1 (4.3)\t− 8.3–8.6\t0.973\t5.6 (3.9)\t− 2.2–13.4\t0.157\t5.1 (4.2)\t− 3.3–13.5\t0.229\t\nLTG\t10.3 (3.5)\t3.4–17.3\t0.004**\t2.3 (3.8)\t− 5.3–9.8\t0.551\t7.5 (3.5)\t0.6–14.4\t0.033*\t6.3 (3.8)\t− 1.1–13.7\t0.097†\t\nLEV\t13.4 (4.2)\t5.2–21.6\t0.002**\t− 0.6 (4.5)\t− 9.5–8.3\t0.901\t7.7 (4.1)\t− 0.4–15.8\t0.064†\t4.9 (4.4)\t− 3.9–3.6\t0.275\t\nMaternal IQ\t0.4 (0.1)\t0.3–0.6\t0.000**\t0.3 (0.08)\t0.1–0.4\t0.001**\t0.4 (0.08)\t0.2–0.5\t0.000**\t0.3 (0.08)\t0.2–0.5\t0.000**\t\nDose\t0.02 (0.02)\t− 0.02–0.05\t0.417\t− 0.01 (0.02)\t− 0.05–0.03\t0.677\t0.005 (0.02)\t− 0.03–0.04\t0.774\t− 0.01 (0.01)\t− 0.05–0.02\t0.476\t\nVPA Dose\t− 0.2 (0.1)\t− 0.5–0.02\t0.071\t− 0.1 (0.1)\t− 0.4–0.1\t0.284\t− 0.2 (0.1)\t− 0.4–0.3\t0.081\t− 0.2 (0.1)\t− 0.5–0.02\t0.065\t\nDose was standardized based on the formula: [100 × ((dose 1st trimester − median AED dose)/median AED dose)]\n\nWISC-III-NL Wechsler Intelligence Scale for Children-third edition, FSIQ full scale intelligence, VIQ verbal intelligence, PIQ performance intelligence, PSI processing speed index, VPA valproate, CBZ carbamazepine, LTG lamotrigine, LEV levetiracetam, B unstandardized coefficients, SE standard error, CI confidence interval\n\n*p < 0.05\n\n**p < 0.01\n\n†p < 0.10\n\n\n\nOn specific neurocognitive domains, VPA-exposed children performed significantly lower on the following sub-scores of attention and executive functions: [statue: VPA < CBZ, LTG, LEV; inhibition naming (time score): VPA < CBZ, LTG, LEV; design fluency: VPA < LTG], language skills [comprehension of instruction: VPA < CBZ, LTG, LEV; speeded naming (total correct): VPA < LTG; word generation: VPA < LTG; vocabulary: VPA < LEV], memory and learning [memory for faces and memory for faces delayed: VPA < CBZ], fine motor skills [fingertip tapping series dominant hand: VPA < LTG; visuomotor precision (total errors): VPA < CBZ, LTG], and visuospatial skills [arrows: VPA < LTG; design copying: VPA < CBZ and LTG] (see supplemental material e-Table 5).\n\nAdditional analyses with LTG-exposed group as reference and maternal IQ, standardized dose and LTG dose as confounders, revealed virtually no significant differences between children exposed to LTG and LEV or LTG and CBZ (e-Table 6). LTG-exposed children only performed significantly better than LEV-exposed children on Visuomotor Precision (total errors; − 1.3, CI − 2.4 to − 0.2, p = 0.022) and achieved a significantly higher score on the Verbal Fluency task (Lindeboom) compared to children exposed to CBZ (− 2.3, CI − 4.2 to − 0.4, p = 0.017).\n\nAntiepileptic drug dose\nFor children exposed to LEV, LTG or CBZ no dose–effect was found. The effect of VPA dose was significant for a number of outcome measures (Statue (p = 0.032), phoneme deletion (p = 0.017), memory for names (p = 0.032), memory for names delayed (p = 0.029), and narrative memory (p = 0.025)). The association between child IQ and VPA-dose was nonsignificant. It made no difference whether we examined first trimester dose or third trimester dose, for both we found no significant relationship between cognitive outcome measures and dose.\n\nConfounding factors\nEpilepsy type differed significantly between the different types of AED used. Mothers using VPA mainly had generalized epilepsy which could suggest confounding by indication. Epilepsy type was, however, not associated with the outcome measures. The presence of convulsions during pregnancy was also not associated with the outcome measures. The presence of congenital malformations was associated with some of the outcome measures (e.g., FSIQ), but after controlling for type of AED (interaction term between malformations and AED), this was no longer significant. As expected, higher maternal IQ was associated with improved child performance on intelligence and specific neurocognitive measures (Table 5; e-Table 5). Maternal education, which we used as proxy for social economic status (SES), was also associated with child outcome measures, but because they are intercorrelated, only maternal IQ was included in the analyses. Other potential confounders have been thoroughly examined but were not found to be associated with the outcome measures (see supplemental material, e-Table1a).\n\nSensitivity analyses\nSome children shared the same mother, father, and family environment, which may cause dependency between outcome measures. Multilevel analyses, however, did not suggest significant dependency. To confirm this, we also conducted a sensitivity analysis with only one child from each family (n = 139). This yielded similar results. Sensitivity analyses with only children included before 16 weeks of gestation (n = 117) showed also similar results (not shown, available on request).\n\nDiscussion\nThis study showed differences in neurocognitive functioning between children exposed prenatally to four common AED monotherapies. Consistent with previous observational studies [5, 8, 13, 27–29], VPA-exposed children performed less-well in all neurocognitive domains than children exposed to CBZ, LTG, or LEV, especially on language skills (9–13 points lower on VIQ). A direct comparison, between the largest group of school-aged LTG-exposed children and LEV- or CBZ-exposed children, showed virtually no significant differences, after controlling for potential confounders. Children exposed to LTG, CBZ or LEV performed at average to above average levels on intelligence and specific neurocognitive functions. This is consistent with previous studies finding no or fewer problems after exposure to CBZ, LTG or LEV [5, 8, 13, 27].\n\nWe noticed that LEV-exposed children more often had disharmonic profiles which were opposite to VPA-exposed children’s profiles. LEV-exposed children appeared to have higher developmental scores than VPA-exposed children, indicating fewer problems. However, no increased intelligence was found in the previous reported study on school-aged LEV-exposed children [8]. Our group of children exposed to LEV was relatively small, so new studies using larger samples are needed to examine long-term functioning in LEV-exposed children.\n\nWe found no dose–effect for LEV, LTG or CBZ. Within the VPA-exposed group, the dose–effect for cognition (intelligence) was nonsignificant, while some other neurocognitive measures showed a dose effect for VPA. Other studies have reported that the risk of VPA is dose-related. Earlier studies indicated that differences in neurocognition cause problems at a dose of 800–1000 mg of valproate [5, 27], differences at lower doses have also been found (< 400 mg) [30], with higher doses giving rise to more problems [5, 7, 27]. Our negative finding may be due to the small sample size of the VPA-exposed group.\n\nThe dose in the third trimester appears to be particularly important for cognitive development [31]. Correlation analyses with third trimester dose showed no differences compared to first trimester dose. In particular the dose of LTG was often increased (Table 1). It is known however, that the clearance of LTG changes during pregnancy because of pharmacokinetics [32]. It would therefore be more reliable to use AED blood levels, but those were not available. We examined the median AED dose within the first trimester instead. However, we are aware that this has limitations, also because we did not have access to adherence data.\n\nFrequent convulsions during pregnancy have previously been associated with reduced cognitive functions in the child [33], but this has not been found in other studies [5, 13]. In our study there was no significant difference between mothers from the four AED groups regarding the occurrence of tonic–clonic seizures. No associations were found between tonic–clonic seizures and outcome measures. We conducted a post hoc analysis into tonic–clonic seizure frequency (with five or more seizures), but this did not reveal differences. There was also no association found for type of epilepsy.\n\nPre-conceptional folate has been associated with higher intelligence scores in children of mothers with epilepsy [5], and was recently associated with a reduced risk of autistic traits [34]. We have seen no associations between preconception folic acid use and outcomes.\n\nThe number of children with congenital malformations differed significantly between the different types of AED, with VPA-exposed children most affected. The rate of malformations within the VPA and CBZ exposed group showed to be higher than typically reported within pregnancy registers [7, 12]. When type of AED and its interaction with presence or absence of malformations was controlled for, the association between malformations and neurocognitive outcomes was, however, no longer significant.\n\nPositive associations seem to exist between breastfeeding and outcome measures [35, 36]. In our study no such association was found. This may be due to the rather small proportion of breast-fed children in our study (16–38%). Over the years (2007–2011), a slight increase in breastfeeding can been seen in our study, but most women had been advised not to breastfeed their children. For mothers with epilepsy who wish to breastfeed, the benefits are usually considered to outweigh the risks [37]. This calls for providing more accurate information about breastfeeding and AEDs to women with epilepsy [38].\n\nThis study has several strengths. First, the prospective design of the study with recruitment of mother–child pairs through the national pregnancy register (EURAP-NL). Secondly, children and their mothers and fathers were extensively assessed by assessors blinded to AED exposure type, using standardized neuropsychological measures [31]. Thirdly, a major methodological strength was the rigorous control for potential confounders, including AED-dose and maternal IQ [39]. Finally, the large size of the LTG-exposed group and inclusion of LEV-exposed children allowed us to obtain more insights into associations between these increasingly prescribed AEDs and child outcomes [8].\n\nThere also are limitations to our study. The statistical threshold (p < 0.05) used for the multiple regression analyses was uncorrected for the multitude of analyses. This gives a risk of probability capitalization. We consider, however, that the number of significantly found p-values was greater than could be expected on the basis of 5% chance. In addition, the mean differences were large across the outcome measures on the whole and support the statistical findings thereby reducing the likelihood that the findings were by chance,\n\nWe also note that pregnancy registers only reach part of the women with epilepsy. This may limit the generalization of the results to the population of mothers with epilepsy. Generalization may also be limited due to the relatively high educational level of mothers across all four exposure groups. This may mainly explain the average to above-average IQ in the children. Future studies should aim to obtain more inclusive recruitment of families from lower educational levels.\n\nThe Flynn effect may also explain in part the apparently average or above average functioning of the children. The Flynn effect is the increase in intelligence scores within a population over the years [40]. The Flynn effect may have been enhanced using the WISC-III-NL [16]. In other countries the WISC-IV or WISC-V are used, but in The Netherlands these WISC-versions were not available at the start of the study period. In other countries using a wide range of different cognitive tests and test versions, children of mothers with epilepsy score average [5, 8, 27], or below average [28, 41, 42].\n\nThe group of mothers that participated had in general well controlled seizures. This might also have caused a selection bias. Mothers with well controlled seizures may have been able to attend the assessment with more ease. We partly managed to overcome this problem because we could assess mother–child pairs at home and at regional centers.\n\nBecause the purpose of this study was a comparison between different types of AEDs monotherapy, a control group of non-exposed children was not included. Children who were exposed to AED polytherapy were also not included. More research is needed to answer related questions about respectively a comparison with non-exposed children or children exposed to different polytherapy combinations [6].\n\nThe number of children within each AED group differed, with a larger number of children exposed to LTG and a relatively smaller group of children exposed to VPA, LEV, and CBZ. The inclusion rate of children for the four AEDs, however, was similar (approximately 40%), but lowest for CBZ and highest for LTG. Our inclusion rate is comparable with other prospective observational studies [8], but not with studies with multiple follow-ups from early age on [5, 27]. The lower number of children exposed to VPA can be explained by a steady decline over the years in The Netherlands of the number of women using VPA during pregnancy paralleled by an increase in LTG or LEV monotherapy. The use of VPA is declining but for some women with epilepsy other AEDs are not a suitable choice [43]. VPA is also increasingly prescribed for psychiatric disorders [44]. More insight into contributing factors to vulnerability in VPA-exposed children is warranted. Based on current reproductive toxicological knowledge, VPA prescriptions for epilepsy in women of reproductive age may be replaced by prescriptions of AEDs with lower teratogenic profile, such as LEV or LTG [45, 46]. Meanwhile, further confirmation of these findings by future studies of neurocognitive functioning in LEV- and LTG-exposed children is required. Collaborative studies and pooling of data may facilitate this.\n\nIn summary, VPA-exposed children performed worse than children exposed to CBZ, LTG and LEV, while few differences were found within a comparison between the three other AEDs. This has implications for pre-pregnancy counseling. To date, healthcare for women with epilepsy has paid little attention to continued monitoring of children of mothers with epilepsy [47]. It is essential that children of mothers with epilepsy be followed over time. Developmental problems may then be detected in a timely manner and treated accordingly. In this study we did not consider the role of active maternal epilepsy during infant and child development. It will be worthwhile examining these aspects in future studies as they are of importance for developing interventions [48]. This may ultimately enhance the quality of life of children who have been exposed to AEDs in utero, their mothers, and their families.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.Supplementary file1 (PDF 276 kb)\n\n \n\nAcknowledgements\nThe study was funded by Stichting Panta Rhei with additional support from the Central Commission of the European Registry of Antiepileptic Drugs and Pregnancy (EURAP) as part of the Neuro Cognitive Extension Protocol (NCEP), and was supported by the Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie (Nederland). Foundations were not involved in the study design, data collection, analysis and interpretation of the data, or manuscript preparation. We thank the Central Project Commission of the European Registry of Antiepileptic Drugs and Pregnancy (EURAP, Chair: Torbjörn Tomson). We are grateful to Eija Gaily as coordinator of the European Neuro Cognitive Extension study (NCEP). We thank Eugène van Puijenbroek from The Netherlands Pharmacovigilance Centre Lareb (coordinator EURAP-NL). We thank all assessors who helped with data collection. We are also grateful to Prof. Ley Sander and Dr. Gail Bell for critically reviewing the manuscript. Lastly, we express our gratitude to all participating children and their parents.\n\nAuthor contributions\nRR designed the first draft of the neurocognition study. YH-M, LvI, DL, and RR further refined and conceptualized the study. YH-M collected the data. YH-M and FO analyzed and interpreted the data and statistical analysis conducted. YH-M drafted the manuscript and all authors contributed to the manuscript for intellectual content and approved the submitted version.\n\nCompliance with ethical standards\nConflicts of interest\nYH-M, FO, LvI and RR have no disclosures to report. DL has received—in the past (2000–2002)—research grants from Janssen-Cilag, GlaxoSmithKline, Pfizer, and The Netherlands Epilepsy Foundation, to start-up the basic EURAP study in The Netherlands.\n\nEthical standards\nThe study was approved by the Medical Ethics Committee of the Academic Medical Center (AMC: NL 45505.018.13). Prior to enrollment of the first participant, the study was registered in the Dutch trial register (https://www.trialregister.nl: NTR4800).\n\nInformed consent\nParents provided written consent for themselves and the child.\n==== Refs\nReferences\n1. Hauser W Hesdorffer D Epilepsy: frequency, causes and consequences 1990 New York Demos publications \n2. Yerby MS Pregnancy, teratogenesis, and epilepsy Neurol Clin 1994 12 749 771 10.1016/S0733-8619(18)30075-6 7845341 \n3. Lindhout D Omtzigt JGC Pregnancy and the risk of teratogenicity Epilepsia 1992 33 41 48 10.1111/j.1528-1157.1992.tb06226.x \n4. Pennell PB Pregnancy in women who have epilepsy Neurol Clin 2004 22 799 820 10.1016/j.ncl.2004.07.004 15474768 \n5. Meador KJ Baker GA Browning N Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study Lancet Neurol 2013 12 244 252 10.1016/S1474-4422(12)70323-X 23352199 \n6. Bromley R Weston J Adab N Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child Cochrane Database Syst Rev 2014 10.1002/14651858.CD010236.pub2 25354543 \n7. Tomson T Battino D Bonizzoni E Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry Lancet Neurol 2011 10 609 617 10.1016/S1474-4422(11)70107-7 21652013 \n8. Bromley RL Calderbank R Cheyne CP Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate Neurology 2016 87 1943 1953 10.1212/WNL.0000000000003157 27581218 \n9. Cohen MJ Meador KJ Browning N Fetal antiepileptic drug exposure: adaptive and emotional/behavioral functioning at age 6 years Epilepsy Behav 2013 29 308 315 10.1016/j.yebeh.2013.08.001 24012508 \n10. Harden CL Meador KJ Pennell PB Practice parameter update: management issues for women with epilepsy–focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the quality standards subcommittee and therapeutics and technology assessment subcommittee of the American Academy of Neurology and American Epilepsy Society Neurology 2009 73 133 141 10.1212/WNL.0b013e3181a6b312 19398681 \n11. Ackers R Besag FMC Wade A Changing trends in antiepileptic drug prescribing in girls of child-bearing potential Arch Dis Child 2009 94 443 447 10.1136/adc.2008.144386 19307197 \n12. Hernandez-Diaz S Smith CR Shen A Comparative safety of antiepileptic drugs during pregnancy Neurology 2012 78 1692 1699 10.1212/WNL.0b013e3182574f39 22551726 \n13. Gaily E Kantola-Sorsa E Hiilesmaa V Normal intelligence in children with prenatal exposure to carbamazepine Neurology 2004 62 28 32 10.1212/WNL.62.1.28 14718692 \n14. Shallcross R Bromley RL Cheyne CP In utero exposure to levetiracetam vs valproate development and language at 3 years of age Neurology 2014 82 213 221 10.1212/WNL.0000000000000030 24401687 \n15. Huber-Mollema Y van Iterson L Oort FJ Lindhout D Rodenburg R EURAP & Development: study protocol of a Dutch prospective observational study into fetal antiepileptic drug exposure and long-term neurocognitive, behavioral and family outcomes PsyArxiv 2018 10.31234/osf.io/b8dyj \n16. Kort W Schittekatte M Dekker P WISC-III NL Wechsler intelligence scale for children. Derde Editie NL. Handleiding en Verantwoording [Manual. Dutch Third Edition] 2005 London The Psychological Corporation \n17. van Iterson L Huber-Mollema Y Rodenburg R Augustijn P Short forms of the Wechsler Intelligence Scales for Children (wisc-iii) in paediatric epilepsy: are results reliable? Epilepsia 2015 56 98 \n18. Wechsler D WAIS-III NL. Wechsler adult intelligence scale WAIS-III. Dutch version. Manual 2005 Amsterdam Harcourt Test Publishers \n19. Korkman M Kirk U Kemp S NEPSY-II 2007 San Antonio Pearson \n20. Manly T Robertson I Anderson V Nimmo-Smith I The test of everyday attention for children (TEA-Ch) 1999 Bury, St, Edmonds Thames Valley Test Company \n21. Dunn L, Dunn L (2005) Peabody picture vocabulary test—dutch adaptation (PPVT-III-NL) (trans: Schlichting L). Hartcourt Assessment BV, Amsterdam\n22. van Iterson L de Jong PF Development of verbal short-term memory and working memory in children with epilepsy: developmental delay and impact of time-related variables. A cross-sectional study Epilepsy Behav 2018 78 166 174 10.1016/j.yebeh.2017.10.018 29128471 \n23. Van Bon W Hoekstra J Taaltests voor kinderen [language test for children] 1982 Lisse Swets & Zeitlinger \n24. Kort W Schittekatte M van den Bos K Dyslexie screening test–NL [Dutch dyslexia screening test] 2005 Antwerpen Harcourt Test Publishers \n25. Resing W Blok JB De classificatie van intelligentiescores: Voorstel voor een eenduidig systeem [Towards a uniform classification system for intelligence test scores] Psycholoog 2002 37 5 244 249 \n26. Kaldenbach Y De WISC-III anno 2006 Kind Adolesc Prakt 2006 5 100 10.1007/BF03059594 \n27. Baker GA Bromley RL Briggs M IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study Neurology 2015 84 382 390 10.1212/WNL.0000000000001182 25540307 \n28. 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Veiby G Engelsen BA Gilhus NE Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy JAMA Neurol 2013 70 1367 10.1001/jamaneurol.2013.4290 24061295 \n37. Harden CL Beneficial or neutral effect of breastfeeding on cognitive outcomes in children of mothers with epilepsy? JAMA Pediatr 2014 168 699 700 10.1001/jamapediatrics.2014.420 24934300 \n38. Van Ness PC Breastfeeding in women with epilepsy JAMA Neurol 2013 70 1357 1358 10.1001/jamaneurol.2013.4348 24061233 \n39. Nadebaum C Anderson V Vajda F Neurobehavioral consequences of prenatal antiepileptic drug exposure Dev Neuropsychol 2012 37 1 29 10.1080/87565641.2011.589483 22292829 \n40. Shenk D What is the Flynn effect, and how does it change our understanding of IQ?: What is the Flynn effect Wiley Interdiscip Rev Cogn Sci 2017 8 e1366 10.1002/wcs.1366 \n41. Thomas SV Sukumaran S Lukose N Intellectual and language functions in children of mothers with epilepsy Epilepsia 2007 10.1111/j.1528-1167.2007.01376.x 18329997 \n42. Kasradze S Gogatishvili N Lomidze G Cognitive functions in children exposed to antiepileptic drugs in utero—study in Georgia Epilepsy Behav 2017 66 105 112 10.1016/j.yebeh.2016.10.014 28038386 \n43. Thomas RH Valproate: life-saving, life-changing Clin Med 2018 18 s1 s8 10.7861/clinmedicine.18-2-s1 \n44. Murphy S Bennett K Doherty CP Prescribing trends for sodium valproate in Ireland Seizure 2016 36 44 48 10.1016/j.seizure.2016.01.019 26896815 \n45. Tomson T Marson A Boon P Valproate in the treatment of epilepsy in girls and women of childbearing potential Epilepsia 2015 56 1006 1019 10.1111/epi.13021 25851171 \n46. European Medicines Agency New measures to avoid valproate exposure in pregnancy endorsed 2018 London EMA \n47. Lawther L Dolk H Sinclair M Morrow J The preconception care experiences of women with epilepsy on sodium valproate Seizure 2018 59 82 89 10.1016/j.seizure.2018.05.003 29778017 \n48. Huber-Mollema Y van Iterson L Sander JW Exposure to antiepileptic drugs in pregnancy: the need for a family factor framework Epilepsy Behav 2018 10.1016/j.yebeh.2018.06.043 30030084\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0340-5354",
"issue": "267(6)",
"journal": "Journal of neurology",
"keywords": "Antiepileptic drugs; Cognition; EURAP & development; Epilepsy; Neuropsychological assessment; Pregnancy",
"medline_ta": "J Neurol",
"mesh_terms": "D000927:Anticonvulsants; D002220:Carbamazepine; D002648:Child; D002657:Child Development; D060825:Cognitive Dysfunction; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D009426:Netherlands; D009483:Neuropsychological Tests; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies; D012042:Registries; D014635:Valproic Acid; D014888:Wechsler Scales",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "1724-1736",
"pmc": null,
"pmid": "32112258",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "15474768;25354543;27581218;24012508;19398681;19307197;14718692;29128471;16029946;31782407;17996637;15491979;29279889;24934501;24061295;24934300;22292829;18329997;28038386;26896815;25851171;29778017;30030084",
"title": "Neurocognition after prenatal levetiracetam, lamotrigine, carbamazepine or valproate exposure.",
"title_normalized": "neurocognition after prenatal levetiracetam lamotrigine carbamazepine or valproate exposure"
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"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
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"activesubstancename": "LEVETIRACETAM"
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{
"abstract": "T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy with a median survival of the patients of less than two years. Besides characteristic chromosomal translocations, frequent mutations affect the ATM gene, JAK/STAT pathway members, and epigenetic regulators. We here performed a targeted mutation analysis for 40 genes selected from a RNA sequencing of 10 T-PLL in a collection of 28 T-PLL, and an exome analysis of five further cases. Nonsynonymous mutations were identified in 30 of the 40 genes, 18 being recurrently mutated. We identified recurrently mutated genes previously unknown to be mutated in T-PLL, which are SAMHD1, HERC1, HERC2, PRDM2, PARP10, PTPRC, and FOXP1. SAMHD1 regulates cellular deoxynucleotide levels and acts as a potential tumor suppressor in other leukemias. We observed destructive mutations in 18% of cases as well as deletions in two further cases. Taken together, we identified additional genes involved in JAK/STAT signaling (PTPRC), epigenetic regulation (PRDM2), or DNA damage repair (SAMHD1, PARP10, HERC1, and HERC2) as being recurrently mutated in T-PLL. Thus, our study considerably extends the picture of pathways involved in molecular pathogenesis of T-PLL and identifies the tumor suppressor gene SAMHD1 with ~20% of T-PLL affected by destructive lesions likely as major player in T-PLL pathogenesis.",
"affiliations": "Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. patricia.johansson@uk-essen.de.;Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;Lead Discovery Center GmbH, Dortmund, Germany.;Lead Discovery Center GmbH, Dortmund, Germany.;Center for Drug Discovery, Department of Pediatrics, Emory Center for AIDS Research, Emory University, Children's Healthcare of Atlanta, Atlanta, GA, USA.;Center for Drug Discovery, Department of Pediatrics, Emory Center for AIDS Research, Emory University, Children's Healthcare of Atlanta, Atlanta, GA, USA.;Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Kiel, Germany.;Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;Institute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Kiel, Germany.;Department of Molecular Therapy in Haematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.;Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.",
"authors": "Johansson|Patricia|P|;Klein-Hitpass|Ludger|L|;Choidas|Axel|A|;Habenberger|Peter|P|;Mahboubi|Bijan|B|;Kim|Baek|B|;Bergmann|Anke|A|;Scholtysik|René|R|;Brauser|Martina|M|;Lollies|Anna|A|;Siebert|Reiner|R|;Zenz|Thorsten|T|;Dührsen|Ulrich|U|;Küppers|Ralf|R|;Dürig|Jan|J|",
"chemical_list": "D009363:Neoplasm Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1038/s41408-017-0036-5",
"fulltext": "\n==== Front\nBlood Cancer JBlood Cancer JBlood Cancer Journal2044-5385Nature Publishing Group UK London 293521813610.1038/s41408-017-0036-5ArticleSAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia Johansson Patricia +49 (0)201-723-85845patricia.johansson@uk-essen.de 12Klein-Hitpass Ludger 2Choidas Axel 3Habenberger Peter 3Mahboubi Bijan 4Kim Baek 4Bergmann Anke 5Scholtysik René 2Brauser Martina 2Lollies Anna 2Siebert Reiner 56Zenz Thorsten 78Dührsen Ulrich 1Küppers Ralf 28Dürig Jan 181 Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 2 0000 0001 2187 5445grid.5718.bInstitute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany 3 0000 0004 0542 0426grid.474028.dLead Discovery Center GmbH, Dortmund, Germany 4 0000 0004 0371 6071grid.428158.2Center for Drug Discovery, Department of Pediatrics, Emory Center for AIDS Research, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA USA 5 0000 0001 2153 9986grid.9764.cInstitute for Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig Holstein, Kiel, Germany 6 grid.410712.1Institute of Human Genetics, University of Ulm and University Hospital of Ulm, Ulm, Germany 7 0000 0001 0328 4908grid.5253.1Department of Molecular Therapy in Haematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany 8 0000 0004 0492 0584grid.7497.dGerman Cancer Consortium (DKTK), Heidelberg, Germany 19 1 2018 19 1 2018 1 2018 8 1 1128 6 2017 5 10 2017 12 10 2017 © The Author(s) 2018Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy with a median survival of the patients of less than two years. Besides characteristic chromosomal translocations, frequent mutations affect the ATM gene, JAK/STAT pathway members, and epigenetic regulators. We here performed a targeted mutation analysis for 40 genes selected from a RNA sequencing of 10 T-PLL in a collection of 28 T-PLL, and an exome analysis of five further cases. Nonsynonymous mutations were identified in 30 of the 40 genes, 18 being recurrently mutated. We identified recurrently mutated genes previously unknown to be mutated in T-PLL, which are SAMHD1, HERC1, HERC2, PRDM2, PARP10, PTPRC, and FOXP1. SAMHD1 regulates cellular deoxynucleotide levels and acts as a potential tumor suppressor in other leukemias. We observed destructive mutations in 18% of cases as well as deletions in two further cases. Taken together, we identified additional genes involved in JAK/STAT signaling (PTPRC), epigenetic regulation (PRDM2), or DNA damage repair (SAMHD1, PARP10, HERC1, and HERC2) as being recurrently mutated in T-PLL. Thus, our study considerably extends the picture of pathways involved in molecular pathogenesis of T-PLL and identifies the tumor suppressor gene SAMHD1 with ~20% of T-PLL affected by destructive lesions likely as major player in T-PLL pathogenesis.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nT-cell prolymphocytic leukemia (T-PLL) is a rare leukemia with an aggressive disease course and a median survival of the patients of less than 2 years. Leukemic cells are characterized by expression of pan-T-cell markers with the unique feature of CD4 and CD8 co-expression in 25% of cases. A CD4+CD8− phenotype is observed in 60% of patients, whereas a CD4−CD8+ phenotype is rare (~15%)1,2. Most T-PLL carry typical genetic alterations, namely inv(14)(q11q32), t(14;14)(q11;q32), or, less often, t(X;14)(q28;q11). These alterations, involving the TCRAD locus on chromosome 14q11, cause overexpression of the oncogenes TCL1A on chromosome 14q32 or MTCP1 on chromosome Xq283–6. Other frequent genetic lesions involve chromosome 8 (idic(8p), t(8;8)(p21;q11), trisomy 8q), and the ATM gene on chromosome 11 (11q2.23). ATM is deleted or mutated in up to 70% of cases7–9. Further recurrent deletions or losses occur on chromosomes 12p13 (CDKN1B), 6q, 17p13.1 (TP53 locus), and 22q10. Sequencing analyses identified recurrent mutations in members of the JAK/STAT signaling pathway, as well as in epigenetic regulators7,11–14. Recent next-generation sequencing studies included whole-genome and exome sequencing7 as well as targeted deep sequencing13,14.\n\nWe characterized T-PLL by RNA sequencing, targeted capture sequencing, and whole-exome sequencing (WES) for somatic mutations, and by single-nucleotide polymorphism (SNP) arrays for detection of genomic imbalances in candidate regions. We identified recurrent mutations in SAMHD1 in 6/33 cases (18%). Copy number losses were observed in two more patients. Other genes that exhibited recurrent mutations and/or copy number alterations were HERC2, HERC1, PRDM2, PARP10, PTPRC, and FOXP1.\n\nMaterials and methods\nPatients and samples\nPatient samples were obtained from archived material of the participating institutions. Patients were diagnosed between 2005 and 2012 in accordance with the WHO 2008 classification2. The study was approved by the ethical review committees of the Universities of Duisburg-Essen and Kiel (14-6080-BO and B295/11). All patients provided written informed consents according to the Declaration of Helsinki. The detection of an inv(14)/t(14;14) or t(X;14) by cytogenetic analysis and/or detection of TCL1 or MTCP1 breakpoints by FISH was required for inclusion into the study. Clinical data of 33 study patients are summarized in Table 1. Standard clinical criteria were applied for initiation of therapy15. RNA sequencing data and copy number analyses were assessed for 10 patients. As control, we sequenced T-cell RNA from five healthy donors. CD3+ T cells were enriched by magnetic cell separation (Miltenyi Biotech, Bergisch Gladbach). For 28 samples, including the 10 with RNA-sequencing analysis, DNA capture sequencing was performed. WES was carried out for five additional T-PLL. The assignment of samples and experiments is given in Supplementary Table 1.Table 1 Clinical patient data\n\n\nPatient ID\n\t\nSex\n\t\nAge at diagnosis (years)\n\t\nGenetic group\n\t\nT-PLL Immunophenotype\n\t\nSAMHD1 status\n\t\nAbsolute WBC count at diagnosis (10\n9\n/L)\n\t\nAbsolute lymph. count at diagnosis (10\n9\n/L)\n\t\nOther sites of involvement (except blood and BM)\n\t\nType of Treatment*\n\t\nAllogenic transplant\n\t\nCR at any time\n\t\nOverall survival (months)\n\t\nDeath\n\t\nComorbidity\n\t\n\n1\n\tF\t74\tinv(14)/t(14;14)\tCD4+\tLoss\t719\t62.7\tNone\t1; 2; 3; 4\tNo\tNo\t34\tYes\tPrior T-PLL: Cervical carcinoma (radiotherapy, CR); immunoblastic lymphoma (CTX, CR)\t\n\n2\n\tF\t64\tt(X;14)\tCD4+\tMutated\t17.3\t8.5\tSkin\t1; 2; 4\tNo\tNo\t18\tYes\tRheumatoid arthritis; myociadial inf.; renal insuff, Std. III\t\n\n3\n\tM\t62\tinv(14)/t(14;14)\tCD4+\tMutated\t148\t121\tSpleen, liver, lymph nodes, skin\t1; 2; 3; 4\tNo\tNo\t7\tYes\tNone\t\n\n4\n\tM\t69\tinv(14)\tCD4+\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tNo\tNo\t0\tYes\tn.a.\t\n\n5\n\tM\t75\tinv(14)\tCD8+\tWT\t830\t730\tSpleen, liver, lymph nodes\t1; 2; 3; 4\tNo\tYes\t33\tYes\tPonsinfarction right; vasculare leukencephalopathie; hypertension; kidney-surgery right; polyneuropathy\t\n\n6\n\tF\t41\tt(X;?)\tCD4+\tWT\t102\t91\tSpleen, lymph nodes, mediastinal\t1; 2; 4\tyes\tno\t12\tYes\tNone\t\n\n7\n\tF\t51\tt(14;14)\tCD8+\tWT\t11.8\t8\tSpleen, liver, lymph nodes\t1; 2; 3; 4\tYes\tYes\t16\tYes\tDiabetes mellitus; hypertension; adiposity; bronchial asthma\t\n\n8\n\tM\tn.a.\tt(X;14)\t\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t33\tYes\tn.a.\t\n\n10\n\tM\t82\tinv(14)\tCD4+\tWT\t32\t28\tSpleen\t1; 2; 4\tNo\tNo\t5\tYes\tHypertension; renal insuff.; depression; prior to T-PLL: Prostate cancer\t\n\n11\n\tF\t62\tinv(14)\tCD4+/CD8+\tLoss\t34\t30\tSpleen\t1; 2; 3; 4\tYes\tNo\t21\tYes\tHypertension; diabetes mellitus; ulcerative colitis\t\n\n12\n\tM\t57\tinv(14)\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n13\n\tF\t53\tinv(14)\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n15\n\tF\t78\tt(X;14)\tCD4+\tMutated\tn.a.\tn.a.\tn.a.\tn.a.\tNo\tn.a.\t21\tYes\tn.a.\t\n\n16\n\tM\t47\tinv(14)\tn.a.\tMutated\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n17\n\tM\t48\tinv(14)\tCD4+\tWT\t22\t17.6\tNone\t1; 2; 3; 4\tNo\tNo\t20\tn.a.\tn.a.\t\n\n18\n\tM\tn.a.\tn.a.\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n19\n\tF\t54\tn.a.\tn.a.\tWT\t181\tn.a.\tLymph nodes\t1; 2; 3; 4\tYes\tYes\t158\tNo\tNone\t\n\n20\n\tF\t55\tn.a.\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n21\n\tM\tn.a\tn.a.\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n22\n\tF\t69\tinv(14)\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n24\n\tM\tn.a\tt(14;14)\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n25\n\tF\t76\tinv(14)\tCD4+\tWT\t118\t106\tSpleen, lymph nodes\t3\tNo\tYes\t30\tNo\tCLL\t\n\n26\n\tM\tn.a.\tinv(14)\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n28\n\tF\tn.a.\tinv(14)\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n29\n\tM\tn.a.\tinv(14)\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n30\n\tF\tn.a.\tt(X;14)\tn.a.\tWT\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n31\n\tF\tn.a.\tinv(14)\tCD4+\tMutated\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\tn.a.\t\n\n33\n\tF\t64\tinv(14)\tCD4+\tWT\t30.2\t28.4\tSpleen, liver\t3\tNo\tNo\t17\tNo\tChronic HepC infection, liver cirrhosis; diabetes mellitus; renal insuff.; hypertension; heart insuff.; pulmonary hypertension; atrial fibrillation\t\n\n34\n\tM\t71\tn.a.\tCD4+\tWT\t76\t68\tSkin\t3\tYes\tYes\t13\tYes\tHypertension\t\n\n35\n\tM\t76\tinv(14)\tCD4+\tWT\t407\t387\tSpleen\t3\tNo\tNo\t19\tNo\tHypertension; hyperuricemia\t\n\n36\n\tM\t70\tt(X;14)\tCD8+\tUPD\t185\t180\tSpleen, liver, lymph nodes,\t3; 4\tYes\tYes\t8\tYes\tHypertension; diabetes mellitus; renal insuff.\t\n\n37\n\tM\t74\tinv(14)\tCD4+\tMutated\t53\t44\tLymph nodes, skin\t4\tNo\tNo\t51\tNo\tM. Bechterew, psoriasis\t\n\n38\n\tF\t74\tinv(14)\tCD4+\tWT\t79\t72\tSkin\t1; 2; 3; 4\tNo\tYes\t29\tYes\tHypertension\t\nWT wildtype, WBC white blood cell, Lymph. lymphocyte, BM bone marrow, CR complete remission, n.a. not available.\n\n*Type of treatment:\n\n1 alkylators (chlorambucile, etc.),\n\n2 purine analogs (Fludarabine, Pentostatin, etc.),\n\n3 Anti-CD52 antibody (Alemtuzumab),\n\n4 others\n\n\n\nTumor cell enrichment\nDetails are given in the supplementary methods.\n\nRNA and DNA isolation\nRNA and DNA were extracted from 1–2 × 107 enriched tumor cells per sample. Details are given in the supplementary methods.\n\nTranscriptome sequencing\nSample libraries were prepared from RNA of isolated cells of 10 patients and five healthy blood donors. RNA sequencing (RNA-Seq) was performed on the HiSeq 2500 system with 2 × 101 bp paired-end reads (Illumina). Duplicate reads were removed and reads were quality filtered. Mutations were considered only if the particular position was covered at least 20-fold. For exclusion of polymorphisms, the dbSNP database was used. In general, single nucleotide variants were excluded if they matched i) a 1000 genomes entry and/or ii) exhibited an annotated variant allele frequency (VAF) above 1% and/or iii) occurred in one or more healthy donor samples. Filtering against healthy donor samples was performed to exclude sequencing artefacts. Database version dbSNP137 was used for data evaluation. Expression analysis of RNA-Seq data was performed with Partek Genomics Suite software, version 6.6; 2016 (Partek Inc., St. Louis, MO, USA)16. Further details are given in the supplementary methods. Data are available under GEO accession number GSE100882.\n\nTargeted capture sequencing\nTo validate candidate mutations in genes identified by RNA-Seq, we selected 40 genes for which capture oligonucleotides for all coding exons of the respective genes were designed (Fig. 1). Further information is given in the supplementary methods. All variant calls originating from positions covered with less than 20 reads were removed. We excluded variants with less than 20% VAF and analyzed non-synonymous variants only. Polymorphisms were excluded as indicated above. Database version dbSNP137 was used for evaluation of capture sequencing data. Data are available under SRA accession number SRP111041.Fig. 1 Distribution of mutated genes in the T-PLL cohort analyzed by targeted capture sequencing and WES\nMutated genes are indicated as black fields for the 33 T-PLL that carried at least one mutated gene. * indicate the five cases for which results are generated by WES. Not listed are 10 genes without any mutations, which are BCL11B, CBL, CUX1, ETV6, JAK1, MTOR, RUNX1, SUZ12, VOPP1, and ZRSR2\n\n\n\nWhole-exome sequencing\nFor five T-PLL samples WES was performed. SNPs with entries in the 1000 genomes project17 were removed. We eliminated mutations if the respective position was covered with less than 20 reads. Only non-synonymous mutations were considered. We excluded variants with a VAF below 20%. Database version dbSNP147 was used for data evaluation. Data are available under SRA accession number SRP111041.\n\nAmplification and sequence analysis of mutations\nTo verify candidate mutations detected in SAMHD1 by targeted capture sequencing or WES, we selected the respective mutated positions in this gene for three SAMHD1-mutated T-PLL. For all three cases, non-tumor DNA extracted from CD14+ and CD19+ cells was available. After PCR, amplicons were analyzed by Sanger sequencing (ABI3130 Genetic Analyzer; Applied Biosystems, Life Technologies). Primer sequences are available from the authors upon request.\n\nCopy number analysis\nCopy number variation (CNV) analysis was carried out on Affymetrix SNP 6.0 microarrays (n = 10) and CytoScan HD arrays (n = 4; Affymetrix, Santa Clara, CA, USA). Further details are given in the supplementary information.\n\nWestern blotting\nFor analysis of SAMHD1, equal amounts of protein lysates were separated by SDS-PAGE and transferred to a nitrocellulose membrane. Details are found in the supplementary information.\n\nQuantitative reverse transcription PCR\nRNA was transcribed into cDNA with the high-capacity cDNA reverse transcription kit (Applied Biosystems). Details are given in the supplementary methods.\n\nCell viability assay\nFor determination of the number of metabolically active cells, the CellTiter-Glo LuminescenT-cell Viability Assay (Promega, Fitchburg, WI, USA), which is based on quantification of ATP, was used. Details are described in the supplementary methods.\n\nDetermination of cellular dNTP content\nTo obtain intracellular dNTPs, cell pellets prepared from 2 × 106 cells of seven T-PLL samples comprising four SAMHD1 mutated and three wild-type samples as well as three CD3+ MACS-enriched healthy donor samples were lysed. The extraction and quantitative measurement of intracellular dNTPs were conducted as reported previously18.\n\nResults\nIdentification of mutations in T-PLL by RNA and DNA sequencing\nOutline of the experimental design\nFor identification of recurrent mutations in T-PLL, we first performed RNA-Seq analysis of isolated tumor cells of 10 cases. We then selected 40 candidate genes from this analysis and studied them for somatic mutations in an extended cohort of 28 patients with a targeted DNA capture sequencing approach. Five additional T-PLL were analyzed by WES. For both DNA-sequencing analyses, we excluded mutations with low coverage (read counts < 20) at a respective position and occurring only at subclonal levels, as mutation detection is less reliable in these instances. The cutoff for subclonality was set to 20%. Polymorphisms were excluded (see Materials and Methods section).\n\nTranscriptome sequencing\nIn the RNA-Seq analysis of 10 T-PLL, we obtained an average number of 9.5 million reads on the target region after quality filtering and duplicate removal. Focusing on variants with high sequence quality scores, we selected all genes carrying non-synonymous mutations and fulfilling the following criteria: (i) mutations in a gene in at least two T-PLL and (ii) a quality score of 1000, which is the highest possible value. The score is calculated as the −10log10 of the p value given by the AVADIS software. The 40 genes fulfilling the criteria (Fig. 1) were subjected to further analyses on the DNA level.\n\nCapture sequencing\nAll coding exons of the 40 candidate genes selected from the RNA-Seq analysis were studied by a targeted deep sequencing approach in a total of 28 T-PLL, including the 10 samples on which RNA-Seq was performed. The average sequence coverage for the target region in the capture approach was 151, with 97% of target-region nucleotides covered at least 20 times. Twenty-nine of the forty genes (73%) showed non-synonymous mutations (Fig. 1). Most mutations appeared with VAF of 40–60%, indicating that they are clonal heterozygous mutations (Fig. 2; but note that SNVs with VAF below 20% were filtered out). Two genes (ATM and SAMHD1) showed several mutations with VAF between 90 and 100%, suggesting either homozygous or hemizygous clonal mutations. Ten of the forty genes selected from the RNA-Seq analysis were not found to be mutated in the targeted sequencing (and also not in a WES of five further cases, see below). The discrepancy to the RNA-Seq data is mainly due to the fact that we applied more stringent selection criteria in the DNA analysis (e.g., VAF ≥ 20%). Moreover, not all mutations identified by RNA-Seq were validated in the targeted sequencing approach, indicating some false-positive results in the RNA-Seq analysis, or that some alleles with subclonal mutations were preferentially transcribed.Fig. 2 Variant allele frequencies of 18 mutated genes carrying at least two mutations\nVariant allele frequencies below 20% are not considered. Depicted are all mutations per gene. Bars indicate mean and S.D.\n\n\n\nWES\nFive further T-PLL were analyzed by WES. On average, the target region of the exome was covered 75 times across all samples. Overall 88% of nucleotides were covered at least 20 times. After applying the above-mentioned filtering criteria, we first focused on the 40 genes selected for targeted sequencing. Ten of the forty genes (25%), namely ATM, FOXP1, HERC1, HERC2, JAK3, NOTCH1, PARP10, PRMT2, SAMHD1, and STAT5B, showed non-synonymous mutations (Fig. 1). Analyzing the complete WES data, we identified several previously unreported recurrently mutated genes (Supplementary Table 2). Three T-PLL displayed mutations in the ryanodine receptor 3 gene, RYR3, namely two replacement mutations and one splice site mutation. RYR3 can release calcium from the endoplasmic reticulum. PARN was mutated in two T-PLL. It encodes a poly(A)-specific ribonuclease, which degrades poly(A) tails of mRNAs. PCLO, coding for the piccolo presynaptic cytomatrix protein, was mutated in two T-PLL. This gene is also frequently mutated in diffuse large B-cell lymphomas19,20. One T-PLL also carried a mutation in the IL2RG gene, which is known to be recurrently mutated in T-PLL7.\n\nCombining capture (n = 28) and WES data (n = 5), we observed in total mutations in 30 of the 40 genes (75%). ATM was the most frequently mutated gene, with 76% of cases harboring ATM mutations (Fig. 1), in line with prior studies9. Other genes known to be mutated in T-PLL7,13,14 were also recurrently mutated in our cohort, including JAK3 (27% of cases mutated) and STAT5B (12%). Mutations in genes encoding epigenetic regulators, including four members of the KMT2 lysine-methyltransferase family, were observed in 3–9% of cases, and overall in 6 of the 33 cases. Mutations in other epigenetic regulators occurred at lower frequencies compared to previous reports, e.g., BCOR and TET2 each in only 3% of cases (Fig. 1), whereas in prior studies, they were mutated in up to 9% and up to 17% of T-PLL, respectively7,13,14.\n\nWe also identified recurrently mutated genes known to be involved in tumorigenesis of various hematologic malignancies, but which have not been described in T-PLL yet. These are SAMHD1, HERC1, HERC2, PRDM2, PARP10, PTPRC, and FOXP1, which could be assigned to distinct functional categories (Fig. 1).\n\nBesides ATM, the group of mutated genes related to DNA damage/repair included SAMHD1 as the second most frequently mutated gene, which was mutated in 18% of cases. The pattern and distribution of these mutations are depicted in Figs. 1 and 3. SAMHD1 encodes a dGTP-activated triphosphohydrolase, which regulates the cellular dNTP pool. Inactivating mutations in SAMHD1, which lead to increased dNTP levels, promote tumor cell survival. In our cohort, the majority of SAMHD1 mutations are frameshift or nonsense mutations. Three of six mutated cases with four SAMHD1 mutations could be used for verification studies by PCR and Sanger sequencing. All SAMHD1 mutations observed in the next-generation sequencing approaches were confirmed. The pattern and distribution of these mutations are depicted in Fig. 3. An analysis of corresponding non-tumor DNA of these patients confirmed the somatic origin of three of the four mutations, whereas in the patient with two SNVs in the gene one of these was also detected in the non-tumor DNA, indicating that this is a germline variant. To test for mutual exclusivity of SAMHD1 mutations with other recurrent mutations, we performed a contingency analysis, which revealed a significant negative association between ATM and SAMHD1 mutations (Fisher’s exact test, p = 0.02).Fig. 3 Pattern and distribution of mutations in SAMHD1\nDepicted are all mutations. The missense mutation in brackets was also observed in hematopoietic non-tumor cells of a female patient carrying two SAMHD1 mutations. The scale indicates the numbering of the amino acids. SAM sterile alpha motif, HDc Histidine (H)-Aspartate (D) containing\n\n\n\nThe genes HERC2 and HERC1, which are mutated in 12 and 9% of T-PLL, respectively, encode for E3 ubiquitin protein ligases. In both genes, we observed replacement mutations distributed along the whole length of the gene. HERC2 and HERC1 function as DNA repair genes21. HERC1 is recurrently mutated in T-cell acute lymphoblastic leukemias (T-ALL)22.\n\nPARP10, encoding the mono-ADP-ribosyltransferase PARP10, is mutated in 3/33 cases (9%). Two mutations lead most likely to loss of the protein or impaired protein function as they are a nonsense mutation and a missense mutation in the ubiquitin-interacting motif, which is part of the catalytic domain of the protein23. PARP10 is recruited to stalled replication forks and mediates cellular resistance to DNA damage, thereby promoting genomic stability24.\n\nThe most frequently mutated gene in the group of epigenetic regulators is PRDM2, with 12% of T-PLL harboring mutations. It is a member of a nuclear histone/protein methyltransferase superfamily and described as tumor suppressor gene, mutated in several types of cancers25,26. Microsatellite-instable tumors show frequent frameshift mutations of PRDM227. Three of four mutations are predicted to change the amino-acid sequence in the coiled-coil domain of the protein. The lysine-methyltransferase genes KMT2B and KMT2E are mutated in three cases each (9%). All mutations are missense mutations, dispersed along the gene. KMT2B, mutated in several cancers28, is a methyltransferase, while KMT2E, which was initially grouped to the KMT2 family and is also mutated in various cancers29, seems to lack intrinsic histone methyltransferase activity.\n\nPTPRC, encoding CD45, is expressed on all human hematopoietic cells, and has, among other functions, a role in inhibiting JAK/STAT signaling. A downregulation of CD45 is reported in T-ALL carrying PTPRC mutations30. We observed replacement mutations in PTPRC in 9% of cases. Two of three mutations were located in the catalytic protein tyrosine phosphatase domain. CD45 protein expression measured by FACS was slightly reduced in two of the three mutated cases (not shown).\n\nFinally, 9% of T-PLL in our cohort carried mutations in FOXP1, encoding a ubiquitously expressed transcription factor and essential regulator in human CD4+ T cells31,32. All mutations, including missense and nonsense mutations, are located in the forkhead domain, which mediates monomeric DNA binding33.\n\nCopy number variations\nTo identify gains and losses in this T-PLL cohort, we performed genome-wide CNV analyses for 14 patients (Table 2). Besides already known CNV, we identified several previously unknown gains and losses as well as uniparental disomies (UPDs) for the 40 genes of interest (Table 2). Two of fourteen (14%) patients displayed losses of the SAMHD1 locus at 20q11. In addition, we identified two further patients carrying UPDs involving SAMHD1. None of these four patients had a point mutation or small indel in SAMHD1. For HERC2, HERC1, FOXP1, and PRDM2, no copy number alterations were observed.Table 2 Copy number variations and UPDs for 40 selected genes\n\n\nArray\n\t\nSNP 6.0\n\t\nCytoHD\n\t\n\nGene\n\t\nChr\n\t\nT-PLL 1\n\t\nT-PLL 8\n\t\nT-PLL 2\n\t\nT-PLL 7\n\t\nT-PLL 10\n\t\nT-PLL 4\n\t\nT-PLL 38\n\t\nT-PLL 11\n\t\nT-PLL 5\n\t\nT-PLL 3\n\t\nT-PLL 33\n\t\nT-PLL 34\n\t\nT-PLL 35\n\t\nT-PLL 36\n\t\nARID4B\t1\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nJAK1\t1\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nMTOR\t1\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nPRDM2\t1\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nPTPRC\t1\t\t\t\tUPD 4.7 Mb\t\t\t\t\t\t\t\t\t\t\t\nCEBPZ\t2\t\t\t\t\t\t\t\t\t\tGain 46.6 Mb\t\t\t\t\t\nFOXP1\t3\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nFBXW7\t4\tGain 7.6 Mb\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nTET2\t4\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nWHSC1\t4\t\t\tLoss 1.8 Mb\t\t\t\t\t\t\t\t\t\t\t\t\nTNIP1\t5\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nBCLAF1\t6\t\t\t\t\tLoss 66 Mb\tUPD 104 Mb\t\t\t\tLoss 4.1 Mb\t\t\t\t\t\nCUX1\t7\t\t\t\t\tGain 2.8 Mb\tGain 10.2 Mb\t\t\t\tGain 0.8 Mb\t\t\t\t\t\nKMT2C\t7\tLoss 4 Mb\t\tLoss 1.3 Mb\t\tUPD 8.1 Mb\tGain 5.8 Mb\t\t\t\tLoss 3.9 Mb\t\t\t\tLoss 14.7 Mb\t\nKMT2E\t7\t\t\t\t\tGain 0.6 Mb\tGain 1.6 Mb\t\t\t\tGain 3.5 Mb\t\t\t\tLoss 0.4 Mb\t\nVOPP1\t7\t\t\t\t\t\tGain 9.2 Mb\t\t\t\t\t\t\t\t\t\nPARP10\t8\tGain 2.2 Mb\tGain 5.2 Mb\t\t\tGain 4.3 Mb\tGain 34 Mb\tGain 7.1 Mb\tGain 2.2 Mb\t\t\tGain 93.1 Mb\tGain 27.2 Mb\tGain 88.3 Mb\tGain 58 Mb\t\nNOTCH1\t9\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nUSP20\t9\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nATM\t11\tLoss 8.8 Mb\tLoss 2.2 Mb\t\t\tLoss 7.1 Mb\t\tLoss 7.2 Mb\tLoss 7.1 Mb\tUPD 74.4 Mb\t\tLoss 25.4 Mb\t\tLoss 9 Mb\tGain mosaic 51.3 Mb\t\nCBL\t11\t\t\t\t\tLoss 6.2 Mb\t\t\tLoss 10.4 Mb\tUPD 74.4 Mb\t\tLoss 25.4 Mb\t\t\tGain mosaic 51.3 Mb\t\nCCDC88B\t11\t\t\t\t\t\t\t\t\tUPD 74.4 Mb\t\t\t\t\t\t\nDDB2\t11\t\tLoss 2.5 Mb\t\t\t\t\tLoss 1 Mb\t\tLoss 3.5 Mb\t\t\t\t\t\t\nETV6\t12\t\t\t\tLoss 2.8 Mb\tLoss 3.3 Mb\t\t\tLoss 2.3 Mb\t\t\t\tLoss mosaic 4.5 Mb\t\t\t\nHIP1R\t12\t\t\t\t\tUPD 84.4 Mb\t\t\t\t\t\t\t\t\t\t\nKMT2D\t12\t\t\t\t\tUPD 84.4 Mb\t\t\t\t\t\t\t\t\t\t\nRPLP0\t12\t\t\t\t\tUPD 84.4 Mb\t\t\t\t\t\t\t\t\t\t\nBCL11B\t14\tGain 3.4 Mb\tGain 4.2 Mb\t\t\t\t\t\t\tGain 18.5 Mb\t\t\t\t\tGgain 66.7 Mb\t\nHERC1\t15\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nHERC2\t15\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nSTAT5B\t17\t\t\t\t\t\tUPD 50.7 Mb\t\t\t\tGain 0.2 Mb\t\t\t\t\t\nSUZ12\t17\t\t\t\t\t\tUPD 50.7 Mb\t\t\t\t\t\t\t\t\t\nJAK3\t19\t\t\t\t\t\t\t\t\tUPD 19.5 Mb\t\t\t\t\t\t\nKMT2B\t19\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nSAMHD1\t20\tLoss 1.9 Mb\t\t\t\t\t\t\tLoss 2 Mb\t\t\t\t\t\t\t\nPRMT2\t21\t\t\t\t\t\t\t\t\t\tGain 0.1 Mb\t\t\t\t\t\nRUNX1\t21\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nEP300\t22\t\t\t\t\t\t\t\tLoss 1.5 Mb\t\t\tGain 21.9 Mb\t\t\t\t\nBCOR\tX\t\t\t\t\t\t\t\t\t\t\tLoss mosaic 56.8 Mb\t\t\t\t\nZRSR2\tX\t\t\t\t\t\t\t\t\t\t\tLoss mosaic 56.8 Mb\t\t\t\t\nChr chromosome, UPD uniparental disomy, Mb megabases\n\n\n\nIn the region containing PTPRC, UPDs were observed in 3/14 patients (21%). None of these patients displayed other PTPRC mutations. Recurrent gains were observed in BCL11B in 4/14 patients (29%). The role of BCL11B, which is a main maturation factor of T cells34,35, in hematologic malignancies is still discussed. In T-ALL it is reported as either a tumor suppressor or oncogene36,37.\n\nSAMHD1 protein expression is reduced in T-PLL carrying mutations or gene losses\nAs most mutations in SAMHD1 were destructive or caused loss of one allele, we analyzed whether these genetic lesions affected RNA and/or protein expression of SAMHD1. Quantitative real-time reverse transcription PCR showed variable mRNA levels of SAMHD1 in nine T-PLL analyzed (Fig. 4a). Three T-PLL with SAMHD1 point mutations or a deletion were among the five T-PLL with lowest transcript levels. However, there was no strict correlation between SAMHD1 mRNA levels and presence of mutations. More importantly, western blot analysis of 12 T-PLL revealed that T-PLL without genetic lesions in SAMHD1 had strong protein expression, comparable to normal peripheral blood CD4+ and CD8+ T cells, whereas three of the four mutated cases had hardly detectable levels, and one case slightly reduced levels (Fig. 4b). A similarly low expression was observed for cases with losses and even for one case with a UPD (Fig. 4b).Fig. 4 SAMHD1 mRNA and protein expression in T-PLL\na mRNA expression levels (−ΔCT values) for SAMHD1 of T-PLL with mutated or deleted SAMHD1 (affected) compared to T-PLL with wild-type SAMHD1 (unaffected). Samples with mutated or deleted SAMHD1 have a lower SAMHD1 mRNA expression. GAPDH was used as internal reference. Bars indicate mean and S.D. b. Protein expression levels of 12 T-PLL samples. Samples with mutated SAMHD1 or losses show lower SAMHD1 protein expression compared to WT samples. β-actin served as loading control. mut mutated, WT wild type, UPD uniparental disomy, ACTB Actin beta\n\n\n\nT-PLL cells carrying SAMHD1 mutations do not respond differently to cytarabine in vitro\nSAMHD1 reduces cytarabine (Ara-C) toxicity in acute myeloid leukemia cells38. Ara-CTP, which is the active triphosphate metabolite of Ara-C, is hydrolyzed by SAMHD1 as its direct substrate, which results in reduction of Ara-C levels. Hence, in cells with inactive SAMHD1, the cytotoxic activity of Ara-C is potentiated38. On the other hand, SAMHD1 may potentially also decrease cell sensitivity to AraC, namely due to the increase of cellular dCTP as competitor of AraCTP. The net outcome may depend on cell types. Although Ara-C is not particularly effective in T-PLL39, we tested drug toxicity to determine a potential effect of Ara-C in cases with SAMHD1 mutations. We performed cell viability assays on thawed viably cryopreserved T-PLL cells after treatment with Ara-C and a number of other cytotoxic agents in different concentrations (Table 3). However, we observed no difference in the IC50 values between cells with low or high SAMHD1 protein expression, indicating that Ara-C is not cytotoxic for T-PLL cells, even not in those with low SAMHD1 expression (Fig. 5). The response of SAMHD1 mutant cases was not improved for any of the drugs tested. When analyzing the cases for the five most frequent mutations occurring in this cohort, we observed next to Ara-C non-responsiveness that SAMHD1 mutant cases neither responded to fludarabine nor clofarabine. By contrast, four of the ATM mutated cases responded well to fludarabine and clofarabine (Table 3). Each of the four cases carried non-synonymous mutations that were predicted to be destructive for ATM protein function by at least 5/7 prediction tools. Two of the cases additionally showed deletions of the second ATM allele. Hence, although the functional impairment of ATM in these cases could not be experimentally validated, it seems that in these T-PLL, ATM mutations are not linked to resistance against fludarabine or clofarabine.Table 3 Cell viability assay\n\n\t\nIC50 (µM)\n\t\n\nCompound name\n\t\nT-PLL_2\n\t\nT-PLL_3\n\t\nT-PLL_10\n\t\nT-PLL_11\n\t\nT-PLL_7\n\t\nT-PLL_36\n\t\nT-PLL_5\n\t\nT-PLL_25\n\t\nT-PLL_34\n\t\nT-PLL_37\n\t\nT-PLL_35\n\t\nMean\n#\n\t\nCytarabine\t16.095\t\n1.875\n\t\n3.212\n\t29.91\t14.727\t\n3.897\n\t29.91\t\n7.761\n\t\n2.034\n\t24.826\t6.233\t8.3\t\nFludarabine\t29.91\t29.91\t0.468\t29.91\t29.91\t0.76\t25.828\t\n39.91\n\t0.241\t29.91\t0.363\t6.4\t\nClofarabine\t29.91\t29.91\t0.046\t29.91\t29.91\t0.225\t29.91\t29.91\t0.372\t29.91\tNA\t6.2\t\nCyclophosphamide\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.9\t\nPrednisone\tND\tND\tND\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.91\t29.9\t\nDoxorubicine\t0.226\t\n2.523\n\t3.535\t4.011\t4.208\t4.532\t5.645\t\n1.935\n\t\n2.061\n\t0.553\t5.439\t2.3\t\n\nSAMHD1 status\n\tMutated\tMutated\tWT\tLoss\tWT\tLoss (UPD)\tWT\tWT\tWT\tMutated\tWT\t\t\n\nATM status\n\tWT\tWT\tMutated/loss\tMutated\tMutated\tMutated/gain\tMutated\tWT*\tMutated\tWT*\tMutated/loss\t\t\n\nJAK3 status\n\tWT\tMutated\tWT\tWT\tWT\tMutated\tMutated/UPD\t*\tWT\tMutated*\tWT\t\t\n\nHERC2 status\n\tMutated\tWT\tWT\tWT\tWT\tWT\tWT\t*\tWT\t*\tWT\t\t\n\nFOXP1 status\n\tWT\tWT\tWT\tWT\tWT\tWT\tWT\t*\tMutated\t*\tWT\t\t\nNA not available, ND not determined, WT wild type, UPD uniparental disomy.\n\n*No copy number status available;\n\n#calculated as geometric mean\n\nFig. 5 Lack of toxic effects of cytarabine on T-PLL cells\nIC50 values for cytarabine of 12 T-PLL samples separated into SAMHD1 affected (n = 4) and SAMHD1 unaffected (n = 7) cases. Bars indicate mean and S.D.\n\n\n\nCorrelating SAMHD1 mutations to clinical data, we observed no differences between mutated and unmutated cases in terms of age at diagnosis, genetic group, T-PLL immunophenotype, absolute white blood cell count, and absolute lymphocyte count at diagnosis, sites of involvement or response to therapy (Table 1).\n\nIntracellular dNTP levels of SAMHD1-mutated T-PLL are elevated compared to SAMHD1 wild-type and healthy blood donor-derived CD3+ samples\nIntracellular dNTP levels measured from 2 × 106 cells of four SAMHD1-mutated samples revealed detectable levels, whereas no dNTPs were detected in three T-PLL SAMHD1 wild-type samples and three healthy donor-derived CD3+ samples, using the same cell numbers for analysis (Fig. 6). The dNTP levels did not correlate with the size of the SAMHD1 mutant clone. The contingency analysis revealed a significant difference between SAMHD1-mutated and unmutated samples (p = 0.0048, two-tailed Fisher’s exact test).Fig. 6 dATP levels of T-PLL and healthy donor samples\nDisplay of dATP levels from dNTP measurement from 2 × 106 cells. Samples 1–4: T-PLL with SAMHD1 mutations. Samples 5–7: T-PLL with wild-type SAMHD1. Samples 8–10: healthy donor-derived CD3+ T cells. In samples 5–10 the dNTP levels were not detectable\n\n\n\nDiscussion\nT-PLL is characterized by inversions or translocations involving the TCL1 gene or the MTCP1 gene, along with one of the TCR loci3–6. Further genetic lesions involved in T-PLL pathogenesis involve ATM7–9, members of the JAK/STAT signaling pathway, and epigenetic regulators7,11,12,40.\n\nWe focused here on 40 candidate genes selected from an exploratory RNA-Seq analysis. Formally, we cannot exclude that a few alterations identified in the RNA or DNA analyses are not somatic mutations but represent germline variants, because for most cases non-tumor RNA or DNA was not available. However, our stringent filtering against known polymorphisms, the occurrence of distinct non-synonymous mutations for recurrently mutated genes, and the direct experimental verification for the somatic origin of three of four tested SAMHD1 mutations together argue that the vast majority of events described here are indeed somatic mutations. Overall, our results confirm previously reported data from our12 and other groups7 and furthermore reveal novel recurrently altered genes in T-PLL (Fig. 1).\n\nMost recurrently altered genes encode proteins with functions in DNA damage/repair. This category included HERC2 and HERC1, the latter of which has been previously reported as recurrently mutated in up to 13% of patients with T-ALL22. We observed nonsense and missense mutations in the ubiquitin-interacting motif of PARP10. As PARP10 deficiency leads to severe DNA repair defects41, these mutations may disturb DNA repair in T-PLL. Ten of fourteen patients (71%) displayed gains involving the PARP10 gene. Such gains are in a considerable number of cases occurring due to formation of an isochromosome i(8q). While the point mutations observed in PARP10 likely have functional consequences, it remains unclear whether these gains translate into higher protein levels and hence functional alterations.\n\nA further gene in the category of DNA damage/repair is SAMHD1, which is mutated in 6/33 (18%) of cases and, moreover, is affected by deletions in two further cases. SAMHD1 encodes a dGTP-activated triphosphohydrolase, which regulates the cellular dNTP pool42. Inactivating mutations in SAMHD1 can promote tumor cell survival as they lead to increased dNTP levels42. SAMHD1 is recurrently mutated in CLL, and the protein is supposed to act as a tumor suppressor43. Most mutations we observed in SAMHD1 are frameshift or nonsense mutations. In several cases, the high VAF of mutations indicates biallelic destruction of the gene. SAMHD1 is highly expressed in monocytes, macrophages, dendritic cells, and resting T cells44,45. In T-PLL, we observed variable SAMHD1 protein expression levels, but in general protein expression of wild-type SAMHD1 was comparable to resting normal CD4+ and CD8+ T cells (Fig. 4b). By contrast, T-PLL cases carrying SAMHD1 mutations or losses showed hardly any SAMHD1 protein, further validating the destructive nature of the mutations (Fig. 4b). We also observed downregulation of SAMHD1 protein in four T-PLL cases not carrying mutations or losses in the coding region of this gene (data not shown). In these cases, epigenetic silencing might occur, although at the group level we did not observe hypermethylation of the SAMHD1 promotor by comparing over 50 T-PLL to normal T-cell subsets (data not shown; to be published elsewhere). Thus, the situation in T-PLL is different from that of CD4 T cells of patients with Sézary syndrome in which the SAMHD1 promotor is hypermethylated46,47. We did not observe a stringent correlation between SAMHD1 protein and mRNA expression (Fig. 4a), which hints toward a regulation of gene expression on different levels. Notably, in the present cohort SAMHD1 mutations are significantly negatively associated with ATM mutations (Fisher’s exact test, p = 0.02). Hence, SAMHD1 inactivation may be an alternative lesion to loss of ATM function to impede proper DNA repair in T-PLL cells. The observation that SAMHD1 mutant cases did not show differences to wild-type cases regarding clinical data might be explained by the relatively low number of cases analyzed, but even more by the aggressive nature of T-PLL and short survival of patients with this disease, so that moderate alterations of tumor cell physiology do not translate into a significant change of clinical outcome.\n\nSAMHD1 regulates dNTP homeostasis by decreasing intracellular dNTP levels. In T-PLL, we observed elevated dNTP levels in SAMHD1-mutated cases compared to SAMHD1 wild-type cases and CD3+ T cells from healthy donors, confirming that mutant SAMHD1 is not able to regulate dNTP levels in T-PLL (Fig. 6). Nucleoside analogs, which are used as therapeutic agents against leukemias, are incorporated into the DNA by a competitive mechanism. It was supposed that in leukemias SAMHD1 mutations causing loss of the proteins’ tumor-suppressive function could lead to enhanced drug efficacy48,49. However, for patients with acute myeloid leukemia it was observed that Ara-CTP, the active metabolite of cytarabine, is a direct substrate of SAMHD1. Hence, intact SAMHD1 reduces Ara-C levels, whereas impaired SAMHD1 protein leads to more effective drug responses38.\n\nAlthough Ara-C is not generally effective in T-PLL, we analyzed whether T-PLL with SAMHD1 mutations or deletions show an increased sensitivity toward cytarabine. However, this was not observed (Fig. 5). Testing of further nucleoside analogs including Fludarabine and other drugs showing cytotoxic effects in T-PLL also revealed no increased sensitivity in SAMHD1 mutant cases toward any of the drugs (Table 3). Therefore, we conclude that the disturbance of the dNTP pool caused by SAMHD1 mutations in T-PLL leads to a benefit for the tumor cells, since increased intracellular dNTPs promote cell cycle progression, proliferation, and survival of the cells. Regarding the non-responsiveness to drugs, in T-PLL further regulatory mechanisms are likely playing a major role in this context, reflecting the overall drug resistance of these tumor cells.\n\nIn the present cohort, PRDM2 is the most frequently mutated gene among those involved in epigenetic regulation. PRDM2 is frequently inactivated by mutations in colorectal cancer cell lines and in relapsed bladder cancer25,26. The amino-acid changing mutations we observed, occurring in the coiled-coil domain of the protein, lead most likely to an impaired function, potentially resulting in tumor cell advantage. We also validate the occurrence of mutations in other epigenetic regulators, namely members of the KMT2 family, BCOR, and TET2.\n\nPTPRC, encoding CD45, is recurrently mutated in T-ALL, leading to downregulation of the protein30. Two of three mutations we observed were located in the catalytic protein tyrosine phosphatase domain, suggesting functional consequences. CD45 negatively regulates JAK/STAT signaling by dephosphorylation of all four JAKs50. Therefore, mutations in PTPRC can enhance the already constitutively activated JAK/STAT signaling in T-PLL12.\n\nFOXP1 is a ubiquitously expressed transcription factor and essential regulator in human CD4+ T cells32. Main mechanisms leading to FOXP1 protein overexpression in cancers are translocations, amplifications, or the repression of miRNAs normally downregulating FOXP1 translation51. All three replacement mutations observed in our T-PLL cohort are located in the DNA-binding forkhead domain, with unclear consequences. Notably, however, in other T-cell lymphoproliferative disorders FOXP1 expression is constitutionally repressed32. Clearly, the role of FOXP1 alterations in T-PLL requires further investigations.\n\nNovel recurrently mutated genes identified by WES included the ryanodine receptor 3 gene RYR3, PARN, coding for a poly(A)-specific ribonuclease and PCLO, encoding the piccolo presynaptic cytomatrix protein. RYR3 releases calcium from the endoplasmic reticulum. Intracellular calcium homeostasis plays an important role in cell metabolism, therefore a disturbed calcium metabolism caused by mutations in RYR3 or overexpression of RYR3 may be oncogenic, as reported for several cancers52. As the point mutations we observed are not located in already described domains, their impact is unclear. However, the observation of a fourfold higher expression of the RYR3 gene in T-PLL compared to normal CD3+ T cells (p = 0.026) is in line with altered RYR3 expression in several cancer types52. PARN was already described as a potential tumor-suppressor gene53. Two missense mutations are located directly in front and behind a coiled-coil region of PARN, which may alter its function. PCLO is recurrently mutated or targeted by copy number gains in diffuse large B-cell lymphomas19,20. We identified one missense and one frameshift mutation, and two copy number gains in two further patients. These seemingly contradictory findings (inactivating frameshift mutation vs. increased gene dosage by copy gain) warrant further investigations.\n\nIn conclusion, we identified novel recurrently mutated genes in T-PLL, including PTPRC, regulating the JAK/STAT pathway, epigenetic regulators like PRDM2 and HERC1/2, and genes involved in DNA damage response and DNA repair like SAMHD1, which has most likely a tumor-suppressor function in T-PLL.\n\nElectronic supplementary material\n\nSupplementary Methods\n\n \nSupplementary Table S1\n\n \nSupplementary Table S2\n\n \n\n\nElectronic supplementary material\n\nSupplementary Information accompanies this paper at 10.1038/s41408-017-0036-5.\n\nAcknowledgements\nWe thank Michael Möllmann and Sabine Senkel for expert technical assistance. We thank the Imaging Center Essen (IMCES). We thank the technicians in the Baek Kim Laboratory. This work was supported by a research grant provided from the Dr. Werner Jackstädt-Stiftung, by the Deutsche Krebshilfe (70112112), by National Institutes of Health to B. Kim (GM104198 and AI049781), and by the Deutsche Forschungsgemeinschaft (KU1315/9-2). R.S. is supported through SFB 1074/2 B09*. P.J. is supported by IFORES.\n\nAuthors’ contributions\nP.J. and L.K.H. performed the sequencing experiments. A.C. and P.H. performed the cell viability assays. A.B. und R.Sie provided samples and performed genetic and epigenetic analyses. B.M. and B.K. performed dNTP measurements. R.Sch and L.K.H. processed all sequencing data. P.J., M.P. prepared cells from healthy donors and patients. P.J. and A.L. performed the protein analyses. T.Z., J.D., and P.J. designed the study. P.J. and R.K. interpreted data and wrote the manuscript. All authors read, edited, and approved the manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Dungarwalla M Matutes E Dearden CE Prolymphocytic leukaemia of B- and T-cell subtype: a state-of-the-art paper Eur. J. Haematol. 2008 80 469 476 10.1111/j.1600-0609.2008.01069.x 18331594 \n2. Swerdlow S. H. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn (IARC Press, Lyon, 2008).\n3. de Oliveira FM Translocations t(X;14)(q28; q11) and t(Y;14)(q12;q11) in T-cell prolymphocytic leukemia Int. J. Lab. Hematol. 2009 31 453 456 10.1111/j.1751-553X.2008.01036.x 18294235 \n4. Fisch P Forster A Sherrington PD Dyer MJ Rabbitts TH The chromosomal translocation t(X;14)(q28; q11) in T-cell pro-lymphocytic leukaemia breaks within one gene and activates another Oncogene 1993 8 3271 3276 8247530 \n5. Madani A Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations Blood 1996 87 1923 1927 8634440 \n6. Stern MH MTCP-1: a novel gene on the human chromosome Xq28 translocated to the T-cell receptor alpha/delta locus in mature T-cell proliferations Oncogene 1993 8 2475 2483 8361760 \n7. Kiel MJ Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia Blood 2014 124 1460 1472 10.1182/blood-2014-03-559542 24825865 \n8. Stankovic T Taylor AM Yuille MR Vorechovsky I Recurrent ATM mutations in T-PLL on diverse haplotypes: no support for their germline origin Blood 2001 97 1517 1518 10.1182/blood.V97.5.1517 11243240 \n9. Stilgenbauer S Biallelic mutations in the ATM gene in T-prolymphocytic leukemia Nat. Med. 1997 3 1155 1159 10.1038/nm1097-1155 9334731 \n10. Dürig J Combined single nucleotide polymorphism-based genomic mapping and global gene expression profiling identifies novel chromosomal imbalances, mechanisms and candidate genes important in the pathogenesis of T-cell prolymphocytic leukemia with inv(14)(q11q32) Leukemia 2007 21 2153 2163 10.1038/sj.leu.2404877 17713554 \n11. Bellanger D Recurrent JAK1 and JAK3 somatic mutations in T-cell prolymphocytic leukemia Leukemia 2014 28 417 419 10.1038/leu.2013.271 24048415 \n12. Bergmann AK Recurrent mutation of JAK3 in T-cell prolymphocytic leukemia Genes. Chromosomes Cancer 2014 53 309 316 10.1002/gcc.22141 24446122 \n13. Lopez C Genes encoding members of the JAK-STAT pathway or epigenetic regulators are recurrently mutated in T-cell prolymphocytic leukaemia Br. J. Haematol. 2016 173 265 273 10.1111/bjh.13952 26917488 \n14. Stengel A Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker Genes. Chromosomes Cancer 2016 55 82 94 10.1002/gcc.22313 26493028 \n15. Dearden C Management of prolymphocytic leukemia Hematol. Am. Soc. Hematol. Educ. Program. 2015 2015 361 367 \n16. PartekInc. Partek® Genomics Suite® Revision 5.0 (Partek Inc, St. Louis, 2016).\n17. Auton A A global reference for human genetic variation Nature 2015 526 68 74 10.1038/nature15393 26432245 \n18. Diamond TL Macrophage tropism of HIV-1 depends on efficienT-cellular dNTP utilization by reverse transcriptase J. Biol. Chem. 2004 279 51545 51553 10.1074/jbc.M408573200 15452123 \n19. Lohr JG Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing Proc. Natl. Acad. Sci. USA 2012 109 3879 3884 10.1073/pnas.1121343109 22343534 \n20. Mareschal S Whole exome sequencing of relapsed/refractory patients expands the repertoire of somatic mutations in diffuse large B-cell lymphoma Genes. Chromosomes Cancer 2016 55 251 267 10.1002/gcc.22328 26608593 \n21. Sanchez-Tena S Cubillos-Rojas M Schneider T Rosa JL Functional and pathological relevance of HERC family proteins: a decade later Cell. Mol. Life Sci. 2016 73 1955 1968 10.1007/s00018-016-2139-8 26801221 \n22. Neumann M Mutational spectrum of adult T-ALL Oncotarget 2015 6 2754 2766 10.18632/oncotarget.2218 25595890 \n23. Ame JC Spenlehauer C de Murcia G The PARP superfamily Bioessays 2004 26 882 893 10.1002/bies.20085 15273990 \n24. Nicolae CM The ADP-ribosyltransferase PARP10/ARTD10 interacts with proliferating cell nuclear antigen (PCNA) and is required for DNA damage tolerance J. Biol. Chem. 2014 289 13627 13637 10.1074/jbc.M114.556340 24695737 \n25. Mouradov D Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer Cancer Res. 2014 74 3238 3247 10.1158/0008-5472.CAN-14-0013 24755471 \n26. Wu S Novel variants in MLL confer to bladder cancer recurrence identified by whole-exome sequencing Oncotarget 2016 7 2629 2645 26625313 \n27. Piao Z Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability Cancer Res. 2000 60 4701 4704 10987271 \n28. Rao RC Dou Y Hijacked in cancer: the KMT2 (MLL) family of methyltransferases Nat. Rev. Cancer 2015 15 334 346 10.1038/nrc3929 25998713 \n29. Zhang X., Novera W., Zhang Y., Deng L. W. MLL5 (KMT2E): structure, function, and clinical relevance. Cell Mol. Life Sci. (2017).\n30. Porcu M Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia Blood 2012 119 4476 4479 10.1182/blood-2011-09-379958 22438252 \n31. Durek P Epigenomic profiling of human CD4+ T-cells supports a linear differentiation model and highlights molecular regulators of memory development Immunity 2016 45 1148 1161 10.1016/j.immuni.2016.10.022 27851915 \n32. Garaud S FOXP1 is a regulator of quiescence in healthy human CD4+ T-cells and is constitutively repressed in T-cells from patients with lymphoproliferative disorders Eur. J. Immunol. 2017 47 168 179 10.1002/eji.201646373 27861791 \n33. Clark KL Halay ED Lai E Burley SK Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5 Nature 1993 364 412 420 10.1038/364412a0 8332212 \n34. Avram D Califano D The multifaceted roles of Bcl11b in thymic and peripheral T-cells: impact on immune diseases J. Immunol. 2014 193 2059 2065 10.4049/jimmunol.1400930 25128552 \n35. Satterwhite E The BCL11 gene family: involvement of BCL11A in lymphoid malignancies Blood 2001 98 3413 3420 10.1182/blood.V98.12.3413 11719382 \n36. Gutierrez A The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia Blood 2011 118 4169 4173 10.1182/blood-2010-11-318873 21878675 \n37. Kraszewska MD BCL11B, FLT3, NOTCH1 and FBXW7 mutation status in T-cell acute lymphoblastic leukemia patients Blood Cells Mol. Dis. 2013 50 33 38 10.1016/j.bcmd.2012.09.001 23040356 \n38. Schneider C SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia Nat. Med. 2017 23 250 255 10.1038/nm.4255 27991919 \n39. Dearden C How I treat prolymphocytic leukemia Blood 2012 120 538 551 10.1182/blood-2012-01-380139 22649104 \n40. Bergmann A. K. et al. DNA methylation profiling of pediatric B-cell lymphoblastic leukemia with KMT2A rearrangement identifies hypomethylation at enhancer sites. Pediatr. Blood Cancer64(2017).\n41. Shahrour MA PARP10 deficiency manifests by severe developmental delay and DNA repair defect Neurogenetics 2016 17 227 232 10.1007/s10048-016-0493-1 27624574 \n42. Ballana E Este JA SAMHD1: at the crossroads of cell proliferation, immune responses, and virus restriction Trends Microbiol. 2015 23 680 692 10.1016/j.tim.2015.08.002 26439297 \n43. Rossi D SAMHD1: a new gene for CLL Blood 2014 123 951 952 10.1182/blood-2013-12-545384 24526775 \n44. Descours B SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells Retrovirology 2012 9 87 10.1186/1742-4690-9-87 23092122 \n45. Laguette N SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx Nature 2011 474 654 657 10.1038/nature10117 21613998 \n46. de Silva S Promoter methylation regulates SAMHD1 gene expression in human CD4+ T-cells J. Biol. Chem. 2013 288 9284 9292 10.1074/jbc.M112.447201 23426363 \n47. de Silva S Downregulation of SAMHD1 expression correlates with promoter DNA methylation in Sezary syndrome patients J. Invest. Dermatol. 2014 134 562 565 10.1038/jid.2013.311 23884314 \n48. Clifford R SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage Blood 2014 123 1021 1031 10.1182/blood-2013-04-490847 24335234 \n49. Ballana E SAMHD1 specifically affects the antiviral potency of thymidine analog HIV reverse transcriptase inhibitors Antimicrob. Agents Chemother. 2014 58 4804 4813 10.1128/AAC.03145-14 24913159 \n50. Irie-Sasaki J CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling Nature 2001 409 349 354 10.1038/35053086 11201744 \n51. Katoh M Katoh M Human FOX gene family (Review) Int. J. Oncol. 2004 25 1495 1500 15492844 \n52. Cui C Merritt R Fu L Pan Z Targeting calcium signaling in cancer therapy Acta Pharm. Sin. B 2017 7 3 17 10.1016/j.apsb.2016.11.001 28119804 \n53. Maragozidis P Alterations of deadenylase expression in acute leukemias: evidence for poly(a)-specific ribonuclease as a potential biomarker Acta Haematol. 2012 128 39 46 10.1159/000337418 22614729\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2044-5385",
"issue": "8(1)",
"journal": "Blood cancer journal",
"keywords": null,
"medline_ta": "Blood Cancer J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D015461:Leukemia, Prolymphocytic, T-Cell; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; D015398:Signal Transduction",
"nlm_unique_id": "101568469",
"other_id": null,
"pages": "11",
"pmc": null,
"pmid": "29352181",
"pubdate": "2018-01-19",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27624574;28188343;27991919;21878675;26432245;22649104;26917488;23884314;28119804;26625313;25998713;18331594;26493028;9334731;22614729;24526775;22438252;10987271;25128552;25595890;24913159;27851915;24755471;23040356;15273990;24048415;8634440;11243240;26801221;22343534;26637744;11201744;8332212;15492844;26608593;27861791;8361760;24695737;18294235;27786413;17713554;15452123;24335234;8247530;11719382;21613998;23426363;26439297;23092122;24446122;24825865",
"title": "SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia.",
"title_normalized": "samhd1 is recurrently mutated in t cell prolymphocytic leukemia"
} | [
{
"companynumb": "DE-SA-2018SA032714",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": null,
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{
"abstract": "Despite unprecedented results of anti-programmed death protein (ligand) 1 (PD-(L)1) immune checkpoint inhibitor in the oncology's armamentarium, immune-related adverse events (irAEs) represent a therapeutic hurdle. Currently, there is no consensual recommendation on a routinely monitored biomarker to early detect irAE. Biological markers such as serum creatine phosphokinase (CPK) are commonly used to measure muscular tissue injury. The potential of routine serum CPK monitoring to predict cardiac or neuromuscular irAE in patients treated with immunotherapy remains unknown.\n\n\n\nIn this retrospective study between January 2016 and December 2018 at Gustave Roussy Cancer Campus, 1151 cancer patients treated with anti-PD-(L)1 immunotherapy were systematically monitored with serum CPK measurements before each immunotherapy cycle. We considered significant CPK increases according to Common Terminology Criteria for Adverse Events v5.0 (CTCAEV5) of grade ≥2 severity. Comparisons were performed in patients with immune-related CPK (ir-CPK) elevations symptomatic versus asymptomatic.\n\n\n\nOverall, 53 of 1151 (4.6%) patients showed a CPK increase. Elevations of CPK were deemed to be immunotherapy-related in 31 of 1151 (2.7%) patients. Among them, 12 of 31 (38.7%) patients experienced symptomatic cardiac or neuromuscular irAE, whereas the other 19 of 31 (61.3%) patients remained asymptomatic. In patients with symptomatic irAE, the mean ir-CPK level was higher compared with asymptomatic patients (1271 versus 771 UI/L, P value = 0.02). In the asymptomatic group, all patients experienced a spontaneous resolution of the ir-CPK increase, and none required medical intervention.\n\n\n\nMost patients with immune-related CPK increase remained asymptomatic. The CPK serum increase did not alter the clinical management of asymptomatic patients. The results of this study did not support a significant clinical interest for a systematic routine CPK monitoring in patients amenable to anti-PD-(L)1 immunotherapy.",
"affiliations": "Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France; Centre de Recherche Du Centre Hospitalier de Montréal (CRCHUM), Université de Montréal, Montréal, Canada.;Department of Cardiology, Saint Antoine Hospital, Assistance Publique-Hôpitaux de Paris, UNICO-GRECO Cardio-oncology Program, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Department of Biology, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Centre de Recherche Du Centre Hospitalier de Montréal (CRCHUM), Université de Montréal, Montréal, Canada.;Department of Pharmacy, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Department of Neurology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Department of Oncology, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Department of Oncology, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Department of Oncology, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Department of Oncology, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France.;Clinical Immunology Department, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, 94270, Le Kremlin Bicêtre, France; Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (IDMIT/IMVA-HB), UMR1184, 94270, Le Kremlin Bicêtre, France.;Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, F-94805, Villejuif, France. Electronic address: Jean-marie.michot@gustaveroussy.fr.",
"authors": "Hajem|Samia|S|;Ederhy|Stéphane|S|;Champiat|Stéphane|S|;Troalen|Frédéric|F|;Nolin-Lapalme|Alexis|A|;Berhoune|Malik|M|;Cauquil|Cécile|C|;Martin-Romano|Patricia|P|;Baldini|Capucine|C|;Laparra|Ariane|A|;Vuagnat|Perrine|P|;Hollebecque|Antoine|A|;Mateus|Christine|C|;Besse|Benjamin|B|;Naltet|Charles|C|;Robert|Caroline|C|;Marabelle|Aurélien|A|;Massard|Christophe|C|;Lambotte|Olivier|O|;Michot|Jean-Marie|JM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2021.08.045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "157()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Anti-PD-L1 immunotherapy; Anti-PD1 immunotherapy; Creatine phosphokinase (CPK); Immune checkpoint inhibitor; Immune-related adverse events; Immune-related myocarditis; Immune-related myositis; Patient monitoring",
"medline_ta": "Eur J Cancer",
"mesh_terms": null,
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "383-390",
"pmc": null,
"pmid": "34571335",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Absence of significant clinical benefit for a systematic routine creatine phosphokinase measurement in asymptomatic patients treated with anti-programmed death protein (ligand) 1 immune checkpoint inhibitor to screen cardiac or neuromuscular immune-related toxicities.",
"title_normalized": "absence of significant clinical benefit for a systematic routine creatine phosphokinase measurement in asymptomatic patients treated with anti programmed death protein ligand 1 immune checkpoint inhibitor to screen cardiac or neuromuscular immune related toxicities"
} | [
{
"companynumb": "FR-009507513-2111FRA003189",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nExtracorporeal treatments such as hemodialysis and plasma exchange are lifesaving measures in the treatment of drug poisoning. This treatment method generally is not used for severe cutaneous and systemic drug reactions.\n\n\nMETHODS\nHere, we describe three cases wherein hemodialysis therapy was instrumental in reversing the adverse drug reaction.\n\n\nRESULTS\nIn the cases of severe cutaneous drug reactions reviewed, patients presented with linear immunoglobulin A bullous dermatosis, acute generalized exanthematous pustulosis, and toxic epidermal necrolysis. Salvage treatment with hemodialysis therapy drastically influenced the course of disease, resulting in remission.\n\n\nCONCLUSIONS\nThis novel and highly effective treatment option is not considered in current algorithms for adverse drug reactions. Hence, in addition to the rarity of these reactions, the main limitation of the study is the small number of patients. Hemodialysis can substantially alter the prognosis and, in some cases, be a lifesaving treatment for patients with severe adverse cutaneous drug reaction associated with systemic toxicity.",
"affiliations": "Department of Dermatology, Mayo Clinic, Rochester, MN, USA.;Department of Dermatology, Mayo Clinic, Rochester, MN, USA.;Department of Dermatology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.",
"authors": "El-Azhary|Rokea A|RA|;Wang|Michael Z|MZ|;Wentworth|Ashley B|AB|;Hickson|LaTonya J|LJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ijd.13837",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "57(2)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D016879:Salvage Therapy; D012872:Skin Diseases, Vesiculobullous; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "177-182",
"pmc": null,
"pmid": "29165802",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27772642;26927288;24007192;24696106;26674736;27854302;27496039;23232549;27779083;21670191;26551508;27886905;25986310;24599767;26050528;27134114;21410610;26833523;24998037;27554629;27656858;28084022",
"title": "Treatment of severe drug reactions by hemodialysis.",
"title_normalized": "treatment of severe drug reactions by hemodialysis"
} | [
{
"companynumb": "US-QILU PHARMACEUTICAL CO.LTD.-QLU-000422-2018",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
... |
{
"abstract": "Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near-normal patient life-expectancy; however, quality of life and aggravation of existing co-morbidities have posed new treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective 'real-world practice' review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow-up of 27·3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow-up. Seventy-six patients eventually discontinued LD TKI and the two-year treatment-free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.",
"affiliations": "Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.;Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.;Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.;Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.;Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.;Imperial Molecular Pathology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.;Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.;Imperial Molecular Pathology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.;Imperial Molecular Pathology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.;Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.;Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.;Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.",
"authors": "Claudiani|Simone|S|0000-0003-3686-7610;Apperley|Jane F|JF|;Szydlo|Richard|R|;Khan|Afzal|A|;Nesr|George|G|0000-0001-7147-843X;Hayden|Chloe|C|;J Innes|Andrew|A|0000-0003-0918-8882;Dominy|Kathy|K|;Foskett|Pierre|P|;Foroni|Letizia|L|;Khorashad|Jamshid|J|0000-0002-6961-7311;Milojkovic|Dragana|D|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; C406060:abl-bcr fusion protein, human; C471992:bosutinib; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "193(2)",
"journal": "British journal of haematology",
"keywords": "CML; TFR; TKI; dose-reduction; low dose",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds; D015897:Comorbidity; D000069439:Dasatinib; D000084862:Drug Tapering; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011788:Quality of Life; D011804:Quinolines; D012074:Remission Induction; D012189:Retrospective Studies; D012449:Safety; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "346-355",
"pmc": null,
"pmid": "33368155",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia.",
"title_normalized": "tki dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia"
} | [
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"abstract": "The development of perianal ulcers related to the use of a hemorrhoidal ointment has not been reported in the literature. We describe a series of 11 patients who were treated for perianal ulcers in 10 Spanish hospitals after they used the same ointment containing the active ingredients triamcinolone acetonide, lidocaine, and pentosan polysulfate sodium. No prior or concomitant conditions suggesting an alternative cause for the condition could be identified, and after the patients stopped using the ointment, their ulcers cleared completely in 8 weeks on average. This case series shows the damage that can be caused by an over-the-counter pharmaceutical product used without medical follow-up. It also illustrates the need to ask patients with perianal ulcers about any topical agents used before the lesions appeared.",
"affiliations": "Servicio de Dermatología, Hospital Universitari Sagrat Cor, Barcelona, España. Electronic address: marindidac@gmail.com.;Servicio de Dermatología, Hospital Universitari Sagrat Cor, Barcelona, España.;Servicio de Dermatología, Hospital Universitario Infanta Leonor, Madrid, España.;Servicio de Dermatología, Hospital Universitario de Fuenlabrada, Madrid, España.;Servicio de Dermatología, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, España.;Servicio de Dermatología, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, España.;Departamento de Dermatología, Hospital Universitario La Princesa, Madrid, España.;Sección de Dermatología, Complejo Hospitalario de Zamora, Zamora, España.;Departamento de Dermatología, Hospital Universitario Ramón y Cajal, Madrid, España.;Unidad de Enfermedades Infecciosas, Hospital Universitario de Burgos, Burgos, España.;Servicio de Dermatología, Hospital Universitario de Burgos, Burgos, España.;Servicio de Dermatología, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, España.;Sección de Dermatología, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, España.;Sección de Dermatología, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, España.;Servicio de Dermatología, Área Integrada de Talavera de la Reina, Toledo, España.;Clínica Dermalar, Santiago de Compostela, España.",
"authors": "Marín-Piñero|D|D|;Iglesias-Sancho|M|M|;Company-Quiroga|J|J|;Martínez-Moran|C|C|;Perez-Feal|P|P|;Vazquez-Osorio|I|I|;Rodriguez-Jiménez|P|P|;Sánchez-Estella|J|J|;Suárez-Valle|A|A|;Buzón-Martín|L|L|;Martín-Saez|E|E|;García-Rodiño|S|S|;Sáez-Vicente|A|A|;Arranz-Sánchez|D M|DM|;Cervigón-González|I|I|;Del Rio|E|E|",
"chemical_list": null,
"country": "Spain",
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"doi": "10.1016/j.ad.2021.02.002",
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"journal": "Actas dermo-sifiliograficas",
"keywords": "Corticoide tópico; Hemorrhoidal ointment; Lidocaine; Lidocaína; Pentosan polysulfate sodium; Pentosano polisulfato sódico; Perianal ulcer; Pomada antihemorroidal; Topical steroid; Úlcera perianal",
"medline_ta": "Actas Dermosifiliogr (Engl Ed)",
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"pages": null,
"pmc": null,
"pmid": "33636161",
"pubdate": "2021-02-23",
"publication_types": "D002363:Case Reports",
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"title": "Multiple Perianal Ulcers Related to Use of a Hemorrhoidal Ointment With the Active Ingredients Triamcinolone Acetonide, Lidocaine, and Pentosan Polysulfate Sodium: A Series of 11 Spanish Patients.",
"title_normalized": "multiple perianal ulcers related to use of a hemorrhoidal ointment with the active ingredients triamcinolone acetonide lidocaine and pentosan polysulfate sodium a series of 11 spanish patients"
} | [
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"activesubstancename": "TRIAMCINOLONE ACETONIDE"
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"abstract": "Nocardiosis is an uncommon infection, however it needs to be included in the differential diagnosis, especially in immunocompromised hosts. Central nervous system (CNS) nocardiosis, in particular, is an even rarer entity with a higher mortality. This is a case of CNS Nocardia infection with an atypical presentation that was initially concerning for metastatic disease. In an immunocompromised patient with CNS findings, atypical infectious processes need to be considered. In a patient with concomitant pulmonary findings, an evaluation for Nocardia should be pursued as the lungs are the primary route of entry for this organism. Treatment typically involves a sulfonamide with secondary antibiotic agent, however a combination using meropenem has proved effective here.",
"affiliations": "Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.;Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.;Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.;Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.",
"authors": "Patel|Hamel|H|;Patel|Bijal|B|;Jadeja|Sonal|S|;Isache|Carmen|C|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.idcr.2019.e00652",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30291-410.1016/j.idcr.2019.e00652e00652ArticleCentral nervous system nocardiosis masquerading as metastatic brain lesions Patel Hamel Patel Bijal Jadeja Sonal Isache Carmen Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, FL, United States01 10 2019 2019 01 10 2019 18 e006526 7 2019 26 9 2019 26 9 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Nocardiosis is an uncommon infection, however it needs to be included in the differential diagnosis, especially in immunocompromised hosts. Central nervous system (CNS) nocardiosis, in particular, is an even rarer entity with a higher mortality. This is a case of CNS Nocardia infection with an atypical presentation that was initially concerning for metastatic disease. In an immunocompromised patient with CNS findings, atypical infectious processes need to be considered. In a patient with concomitant pulmonary findings, an evaluation for Nocardia should be pursued as the lungs are the primary route of entry for this organism. Treatment typically involves a sulfonamide with secondary antibiotic agent, however a combination using meropenem has proved effective here.\n\nKeywords\nN. farcinicaNocardiaCentral nervous system (CNS)ImmunocompromisedAbscessPulmonary\n==== Body\nIntroduction\nNocardia spp. is an aerobic, gram-positive, weakly acid-fast, branching rod-shaped bacteria that is widely found in the environment, i.e. soil. Infections in humans occurs either by inhalation or by direct inoculation of skin. Cell-mediated immunity plays a significant role in eliminating this infection in immunocompetent individuals. A defect in these host defenses, which can occur in patients with AIDS, certain malignancies, organ transplant, immunosuppressive therapy, etc., predisposes a patient to develop localized or systemic infection [4]. A severe form of this represents central nervous system (CNS) involvement, such as meningitis or brain abscess, which can manifest in a variety of ways including headaches, seizures, and focal neurological deficits [1]. However, because it can have a more insidious presentation, CNS nocardiosis is often mistaken for neoplasia. We report a case of CNS Nocardiosis in a patient who presented with new onset headaches and lethargy and was found to have multiple brain lesions in the setting of chronic prednisone therapy.\n\nCase report\nWe report the case of a 54-year-old African-American female who presented to the emergency department with a new headache and altered mental status. She has a medical history of cirrhosis secondary to suspected hepatic sarcoidosis (on chronic prednisone) and hypertension. Computed tomography (CT) imaging of her head showed mass lesions in bilateral cerebellar hemispheres and left orbital frontal lobe concerning for metastatic disease as well as mild obstructive hydrocephalus of the fourth ventricle. During her hospital stay, the patient became increasingly more lethargic requiring intubation and transfer to the neuro-critical care unit. Chest CT showed bilateral lower lobe pulmonary opacities and calcified nodules. Subsequent CT of her abdomen and pelvis were unremarkable for any masses or lesions. Patient underwent aspiration of the larger right cerebellar mass. Acid-fast bacterial culture of aspirate resulted in growth of Nocardia farcinica. She was started on intravenous trimethoprim-sulfamethoxazole (TMP-SMX) and meropenem per Infectious Disease specialist recommendations. She was successfully extubated after receiving a short course of steroid therapy to reduce vasogenic cerebral edema. The patients’ lethargy began showing improvement with continued antibiotic therapy which was evident by day 3. After the initial two weeks, TMP-SMX was switched to intravenous ciprofloxacin due to the development of severe pancytopenia. Ciprofloxacin therapy was chosen based on susceptibility testing from the isolated Nocardia farcinica (Fig. 1). Meropenem was continued. She was treated with intravenous meropenem and ciprofloxacin for 6 more weeks (for a total of 8 weeks), followed by oral ciprofloxacin and sulfadiazine to complete a one year course of treatment. Her chronic prednisone therapy was weaned due to her immunocompromised state which likely predisposed her to develop this infection. Magnetic resonance imaging of her brain done after the first two months of treatment revealed near complete resolution of right cerebellar lesion (Fig. 2), interval resolution of left frontal periventricular lesion, and no evidence of any new lesion. Patient was followed up in clinic and she successfully completed the planned one year course of antibiotics without any lasting deficits or symptoms.Fig. 1 Nocardia Farcinica Susceptibility Chart.\n\nFig. 1Fig. 2 MRI Brain – T2 Axial.\n\nImaging prior to biopsy: 3.4 cm peripherally enhancing cystic lesion of right cerebellum with marked surrounding vasogenic edema and mass effect with partial effacement of the fourth ventricle\n\nImaging after 2 months of antibiotic therapy: Significant interval improvement of right cerebellar lesion, now with 0.6 cm enhancing nodule\n\nFig. 2\n\nDiscussion\nNocardia species are saprophytic aerobic actinomycetes found commonly worldwide in soil, where they contribute to the decay of organic matter. While greater than 50 Nocardia species have been identified, most systemic disease involves N. cyriacigeorgica, N. farcinica, N. pseudobrasiliensis, and species in the N. transvalensis and N. nova complexes [5]. Greater than 90% of cases of pulmonary or disseminated disease occur in individuals with deficient cell-mediated immunity, particularly those with lymphoma, transplantation, AIDS, or on glucocorticoid therapy [5]. They are thought to follow inhalation of fragmented bacterial mycelia. The most common form of nocardial disease is in the respiratory tract. In half of all cases of pulmonary nocardiosis, disease also appears outside the lungs, the most common site being the brain [5].\n\nCentral nervous system Nocardia infections typically present as meningitis or subacute abscess. Brain abscesses are typically supra-tentorial, often multi-loculated, and may be single or multiple. When occurring in isolation, Nocardia brain abscess presents as a slowly progressive mass lesion, with a reported mortality rate of 55% in immunocompromised patients and 20% in immunocompetent patients; these rates increase to 66% with multiple abscesses [2,3]. N. farcinica is a significant cause of disseminated disease among Nocardia species and is highly drug resistant. Initial treatment is typically with dual intravenous antibiotic therapy. Usually, a clinical response is seen within 1 week if on appropriate antibiotic therapy. Surgical intervention should be pursued if the patient demonstrates clinical deterioration or no improvement with susceptibility based antibiotic therapy. Therapy can be switched to oral agents after 3–6 weeks depending on clinical course, with a total duration of 6–12 months.\n\nSulfonamides are the drugs of choice, with the combination of TMP-SMX being the primary therapy in mild to moderate cases. Multi-agent intravenous therapy is recommended by infectious disease experts in severe disease, including disseminated or CNS disease. Amikacin or imipenem are typically added as the second agent, because there is more clinical experience with these agents and appear to be the most active agents in vitro and in animal models [10]. Some reports show TMP-SMX having less than 2% resistance in the United States [7], but other studies demonstrate substantial prevalence of resistance patterns in certain Nocardia isolates [8]. This highlights the importance of obtaining susceptibility testing in order to select efficacious therapy early and to have alternative options in the situation of resistance, drug toxicity, or other contraindication. In patients unable to receive TMP-SMX due to hematologic toxicity, N. farcinica species can alternately be treated with amikacin, ciprofloxacin, imipenem, and linezolid [5]. For Nocardia farcinica, lowest rates of antibiotic resistance are with linezolid (0%), amikacin (2.9%), TMP-SMX (5.4%), minocycline (9.4%) and imipenem (19.5%) [9]. As demonstrated in Fig. 1, typical susceptibility patterns of this organism include majority being susceptible to amikacin, most to sulfonamides, and resistance against aminoglycosides and third generation cephalosporins.\n\nThis case highlights the importance of susceptibility testing to guide therapy when the patient developed an adverse reaction as well as the successful use of atypical antibiotic regimens with meropenem. Meropenem, like imipenem, has good CSF penetration, similar pharmacokinetics, and is associated with a lower incidence of seizures. It has good in vitro activity against several Nocardia species, although one study found that meropenem was less active than imipenem against N. farcinica and N. nova (11). There are only a few reports using meropenem in combination with other antibiotics to treat nocardiosis, however efficacy has been varying. In our patient the combination of meropenem/TMP-SMX and meropenem/ciprofloxacin both proved to be effective treatments for CNS Nocardia Farcinica. In addition data suggests higher resistance to sulfadiazine therapy without the TMP component, but ciprofloxacin and sulfadiazine was also efficacious here.\n\nOur case of Nocardia farcinica brain abscesses had a presentation that was initially concerning for metastatic brain lesions in an immunocompromised patient receiving prednisone therapy. It is important to distinguish between non-infectious brain tumors and Nocardia abscess as administration of corticosteroids can contribute to rapid progression of infection, possibly through inhibition of capsule formation [6]. Corticosteroids can however still be used, with caution, to reduce significant cerebral edema and mass effect [6]. In a patient with host defense defects who presents with brain imaging concerning for metastatic disease and lung imaging suggestive of pneumonia, evaluation for disseminated Nocardia infection should be done, to prevent any delay in diagnosis and treatment of this condition with high associated mortality. Patients should be appropriately diagnosed and treated, then followed carefully for at least six months after completion of therapy with repeat brain imaging to document resolution of lesions.\n\nAuthor statement\nHamel Patel: conceptualization, resources, writing – original draft; writing – reviewing and editing.\n\nBijal Patel: resources, writing - original draft; writing – reviewing and editing.\n\nSonal Jadeja: writing – reviewing and editing.\n\nCarmen Isache: writing – reviewing and editing.\n==== Refs\nReferences\n1 Fellows G.A. Kalsi P.S. Martin A.J. Nocardia farcinica brain abscess in a patient without immunocompromise Br J Neurosurg 21 3 2007 301 303 17612924 \n2 Iannotti C.A. Hall G.S. Procop G.W. Tuohy M.J. Staugaitis S.M. Weil R.J. Solitary Nocardia farcinica brain abscess in an immunocompetent adult mimicking metastatic brain tumor: Rapid diagnosis by pyrosequencing and successful treatment Surg Neurol. 72 1 2009 74 79 18514285 \n3 Mamelak A.N. Obana W.G. Flaherty J.F. Nocardia brain abscess: treatment strategies and factors influencing outcome Neurosurgery 35 4 1994 622 631 7808604 \n4 Beaman B.L. Beaman L. Nocardia species: host-parasite relationships Clin Microbiol Rev. 7 2 1994 213 264 8055469 \n5 Longo J.L. Nocardiosis and actinomycosis. Harrisons principles of internal medicine vol 1 2018 McGraw-Hill Education New York 1322 1326 \n6 Mamelak A.N. Mamalpam T. Obana W.G. Improved management of multiple brain abscesses: a combined surgical and medical approach Neurosurgery 36 1 1995 76 86 7708172 \n7 McTaggart L.R. Doucet J. Witkowska M. Richardson S.E. Antimicrobial susceptibility among clinical Nocardia species identified by multilocus sequence analysis Antimicrob Agents Chemother. 59 1 2015 269 25348540 \n8 Uhde K.B. Pathak S. McCullum I. Jr Antimicrobial-resistant Nocardia isolates, United States, 1995-2004 Clin Infect Dis. 51 2010 1445 1448 21058914 \n9 Lebeaux D. Antibiotic susceptibility testing and species identifications of Nocardia isolates: a retrospective analysis of data from a French expert laboratory Clin Microbiol Infect. 25 April 4 2019 489 495 29933049 \n10 Schlaberg R. Fisher M.A. Hanson K.E. Susceptibility profiles of Nocardia isolates based on current taxonomy Antimicrob Agents Chemother. 58 2014 795 800 24247124\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "18()",
"journal": "IDCases",
"keywords": "Abscess; Central nervous system (CNS); Immunocompromised; N. farcinica; Nocardia; Pulmonary",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00652",
"pmc": null,
"pmid": "31720223",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "21058914;24247124;17612924;7708172;18514285;25348540;8055469;7808604;29933049",
"title": "Central nervous system nocardiosis masquerading as metastatic brain lesions.",
"title_normalized": "central nervous system nocardiosis masquerading as metastatic brain lesions"
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{
"companynumb": "US-TEVA-2019-US-1149706",
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"activesubstancename": "PREDNISONE"
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"abstract": "Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic syndrome that strikes previously healthy children aged 3-15 years and has an unknown pathogenesis and few treatments. These children experience a nonspecific febrile illness that is followed by prolonged refractory status epilepticus. Although the etiology is unknown, FIRES has a biphasic presentation, with the acute phase beginning as seizure activity lasting 1-12 weeks, then followed by the chronic phase, which is characterized by refractory seizures that cluster every 2-4 weeks, and may continue to be multifocal and independent. Treatment of FIRES is difficult, typically unresponsive to antiepileptic drugs. Some children resolve temporarily with drug-induced burst suppression comas. Other therapies such as a ketogenic diet have limited benefit. The outcome varies with the length of the acute phase and is usually poor, with up to 30% of cases ending in death and 66-100% of survivors having intellectual disability. The authors present a case of a 6-year-old child presenting with FIRES and refractory status epilepticus, which continued despite multidrug therapy. The patient underwent immunomodulatory therapy with the eventual resolution of status, but she developed a chronic, moderately severe encephalopathy, including intractable epilepsy. This case highlights the challenges of FIRES and the potential of immunomodulatory therapies for children with this disorder.",
"affiliations": "a Neurodiagnostics and Sleep Science Program , University of North Carolina, Chapel Hill , Chapel Hill , North Carolina.;a Neurodiagnostics and Sleep Science Program , University of North Carolina, Chapel Hill , Chapel Hill , North Carolina.;b Department of Neurology, School of Medicine , University of North Carolina , Chapel Hill, Chapel Hill , North Carolina.;b Department of Neurology, School of Medicine , University of North Carolina , Chapel Hill, Chapel Hill , North Carolina.",
"authors": "Fox|Kristy|K|;Wells|Mary Ellen|ME|;Tennison|Michael|M|;Vaughn|Bradley|B|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1080/21646821.2017.1355181",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2164-6821",
"issue": "57(3)",
"journal": "The Neurodiagnostic journal",
"keywords": "Febrile infection-related epilepsy syndrome (FIRES); ketogenic diet; prolonged refractory status epilepticus; refractory status epilepticus; status epilepticus",
"medline_ta": "Neurodiagn J",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D002648:Child; D002675:Child, Preschool; D055423:Diet, Ketogenic; D004569:Electroencephalography; D004827:Epilepsy; D006801:Humans; D003294:Seizures, Febrile; D013226:Status Epilepticus; D013577:Syndrome",
"nlm_unique_id": "101573167",
"other_id": null,
"pages": "224-233",
"pmc": null,
"pmid": "28898171",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Febrile Infection-Related Epilepsy Syndrome (FIRES): A Literature Review and Case Study.",
"title_normalized": "febrile infection related epilepsy syndrome fires a literature review and case study"
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"abstract": "OBJECTIVE\nData on kidney transplant outcomes for pediatric patients with end-stage renal disease (ESRD) secondary to anti-neutrophil cytoplasmic antibody glomerulonephritis (ANCA GN), particularly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), is limited. We describe our experience of kidney transplantation in pediatric ANCA GN patients.\n\n\nMETHODS\nWe performed a retrospective review of patients with ANCA GN who developed ESRD and were transplanted at a single center between the years 2000 and 2014.\n\n\nRESULTS\nSince 2000, there were seven pediatric patients with ANCA GN (four MPA) transplanted. Mean age at ANCA GN diagnosis was 11.8 ± 2.8 (range, 7.2-15.4) years. All seven were ANCA (three anti-PR3/four anti-MPO) positive. Estimated glomerular filtration rate (eGFR) at diagnosis was 11.7 ± 6.3 ml/min/1.73 m2. All received steroids and cyclophosphamide and three (23.3%) received plasma exchange. Six were dialysis dependent by 6 months post diagnosis. Time from diagnosis to transplant was 30 ± 12 (range, 17-48) months. Six of the seven received a deceased donor transplant. All patients received induction therapy and standard maintenance immunosuppression post transplant. Median duration of follow-up post transplantation was 27 months (range, 13-88 months). Median eGFR at last follow-up was 77 ml/min/1.73 m2 (range, 7.9-83.5). One patient lost her transplant to acute cellular rejection following non-adherence to immunosuppression after 21 months of stable transplant function. No patient had recurrence of vasculitis, either renal or extra-renal.\n\n\nCONCLUSIONS\nShort-term patient and allograft survival in pediatric patients with ESRD secondary to ANCA GN seems excellent, with no recurrence of vasculitis post transplant in this small cohort.",
"affiliations": "Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. damien.noone@sickkids.ca.;Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.;Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.",
"authors": "Noone|Damien|D|http://orcid.org/0000-0003-3385-6174;Yeung|Rae S M|RSM|;Hebert|Diane|D|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-017-3749-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "32(12)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Anti-neutrophil cytoplasmic antibody; Children; Glomerulonephritis; Outcome; Survival; Transplant",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D002648:Child; D005260:Female; D005921:Glomerulonephritis; D006801:Humans; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "2343-2350",
"pmc": null,
"pmid": "28766066",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": "11431216;23846462;23421384;24118474;12743792;21682926;17530684;25147157;12496506;10504506;25324359;18762796;24257368;19536079;19602476;25917555;19054820;23223225;23467258;16252100;23453993;8419611;21508899;23349331;23100606;20516028;26371598;25550447;20394635;16322081;20616173;19158356",
"title": "Outcome of kidney transplantation in pediatric patients with ANCA-associated glomerulonephritis: a single-center experience.",
"title_normalized": "outcome of kidney transplantation in pediatric patients with anca associated glomerulonephritis a single center experience"
} | [
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"companynumb": "CA-APOTEX-2018AP005970",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",... |
{
"abstract": "Objective The aim of this study was to examine the clinical features, treatment and outcome of systemic lupus erythematosus (SLE) patients in our centre who presented with lupus pneumonitis as the initial manifestation. Methods We performed a retrospective review of all patients who presented with lupus pneumonitis during the initial SLE manifestation from March 2006 to March 2015. Results There were a total of five patients in our study who presented with fever and cough as the main clinical features. All patients had pulmonary infiltrates on chest radiographs. High-resolution computed tomography, which was performed in two patients, showed ground glass opacities with patchy consolidations bilaterally. All patients received high-dose steroids, 80% received intravenous cyclophosphamide and 60% received intravenous immunoglobulin. Two patients died from severe lupus pneumonitis within 2 weeks of admission despite treatment with ventilation, steroids, cyclophosphamide and intravenous immunoglobulin. Conclusions Acute lupus pneumonitis is an uncommon presentation of SLE. Mortality in this case series is 40%.",
"affiliations": "1 Department of Medicine, Sarawak General Hospital, Sarawak, Malaysia.;1 Department of Medicine, Sarawak General Hospital, Sarawak, Malaysia.;2 Radiology Department, University Malaysia Sarawak, Sarawak, Malaysia.",
"authors": "Wan|S A|SA|;Teh|C L|CL|;Jobli|A T|AT|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D013256:Steroids; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1177/0961203316646461",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "25(13)",
"journal": "Lupus",
"keywords": "Lupus pneumonitis; systemic lupus erythematosus",
"medline_ta": "Lupus",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003520:Cyclophosphamide; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008180:Lupus Erythematosus, Systemic; D011014:Pneumonia; D013902:Radiography, Thoracic; D012189:Retrospective Studies; D013256:Steroids; D055815:Young Adult",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "1485-1490",
"pmc": null,
"pmid": "27125293",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lupus pneumonitis as the initial presentation of systemic lupus erythematosus: case series from a single institution.",
"title_normalized": "lupus pneumonitis as the initial presentation of systemic lupus erythematosus case series from a single institution"
} | [
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"companynumb": "MY-PFIZER INC-2015320516",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
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{
"abstract": "Although ruxolitinib contributes to immunomodulation and can lead to severe infections, it seems a feasible treatment strategy for patients with polycythemia vera and myelofibrosis after liver transplantation.",
"affiliations": "Department of Internal Medicine I Rheinische Friedrich-Wilhelms University Bonn Bonn Germany.;Department of Internal Medicine I Rheinische Friedrich-Wilhelms University Bonn Bonn Germany.;Department of Internal Medicine III Rheinische Friedrich-Wilhelms University Bonn Bonn Germany.;Department of Internal Medicine I Rheinische Friedrich-Wilhelms University Bonn Bonn Germany.;Department of Internal Medicine I Rheinische Friedrich-Wilhelms University Bonn Bonn Germany.;Department of Internal Medicine I Rheinische Friedrich-Wilhelms University Bonn Bonn Germany.",
"authors": "Dold|Leona|L|https://orcid.org/0000-0002-7677-3347;Lutz|Philipp|P|;Heine|Annkristin|A|;Weismüller|Tobias J|TJ|;Strassburg|Christian P|CP|;Spengler|Ulrich|U|",
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"country": "England",
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"doi": "10.1002/ccr3.4782",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4782\nCCR34782\nCase Report\nCase Reports\nRuxolitinib for treatment of polycythemia vera and myelofibrosis in patients after liver transplantation\nDOLD et al.\nDold Leona https://orcid.org/0000-0002-7677-3347\n1 2 leona.dold@ukbonn.de\n\nLutz Philipp 1 2\nHeine Annkristin 3\nWeismüller Tobias J. 1\nStrassburg Christian P. 1\nSpengler Ulrich 1 2\n1 Department of Internal Medicine I Rheinische Friedrich‐Wilhelms University Bonn Bonn Germany\n2 German Centre of Infection Research (DZIF) Partner site Cologne‐Bonn Bonn Germany\n3 Department of Internal Medicine III Rheinische Friedrich‐Wilhelms University Bonn Bonn Germany\n* Correspondence\nLeona Dold, Department of Internal Medicine I, Universityhospital Bonn, Venusberg Campus 1, D ‐ 53105 Bonn, Germany.\nEmail: leona.dold@ukbonn.de\n\n05 9 2021\n9 2021\n9 9 10.1002/ccr3.v9.9 e0478231 7 2021\n20 1 2021\n15 8 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nAlthough ruxolitinib contributes to immunomodulation and can lead to severe infections, it seems a feasible treatment strategy for patients with polycythemia vera and myelofibrosis after liver transplantation.\n\nPatients after liver transplantation have an increased risk to develop hematologic neoplasia. Information how to treat these patients in the context of immunosuppression is sparse. Here, we report two patients with polycythemia vera (PV) and myelofibrosis (MF) on ruxolitinib after liver transplantation.\n\nliver transplantation\nmyelofibrosis\npolycythemia vera\nruxolitinib\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:05.09.2021\nDoldL, LutzP, HeineA, WeismüllerTJ, StrassburgCP, SpenglerU. Ruxolitinib for treatment of polycythemia vera and myelofibrosis in patients after liver transplantation. Clin Case Rep. 2021;9 :e04782. 10.1002/ccr3.4782\n\nFunding information\n\nWe did not receive any financial support for this report\n==== Body\npmc1 INTRODUCTION\n\nRuxolitinib (Jakavi®), an inhibitor of Janus kinase 1 and 2, enables efficient therapy of myeloproliferative disease such as polycythemia vera (PV) and myelofibrosis (MF) by reducing spleen size and constitutional symptoms. However, ruxolitinib is a potent immunomodulator and thus might contribute to the high risk of infectious complications due to long‐term immunosuppression after liver transplantation.1 Clinical information on outcomes and risks of ruxolitinib therapy after liver transplantation is limited, although myeloproliferative neoplasms after liver transplantation have been described in some cases.2, 3 Compared with the general population, solid organ transplant recipients have an elevated risk for myeloid neoplasms, with a 7.2‐fold increase for polycythemia vera.4 The incidence of polycythemia vera is about 12 cases/100,000 person‐years at all ages, while it is only 5 cases/100,000 person‐years for ages 50–64. However, risk of death is not significantly increased following the diagnosis of polycythemia vera after solid organ transplantation.4\n\nHere, we report on two patients who developed progressive myeloproliferative disease after liver transplantation and therefore were treated with ruxolitinib.\n\n2 PATIENT 1\n\nTen years after liver transplantation for acute liver failure of unknown origin, a 49‐year‐old female patient on mycophenolic acid (3 × 360 mg/day) and tacrolimus (1.5 mg/day) developed JAK2 V617F positive polycythemia vera. CBC at diagnosis was leukocytes, 5.1 G/L (ref. range: 3.9–10.2); erythrocytes, 6.74 T/L (ref. range: 3.9–5.2); hemoglobin, 16.8 g/dl (ref. range: 12–15.4); HKT, 50.1% (ref. range: 35.5–45.5); platelets, 306 G/L (ref. range: 150–370); and LDH: 310 U/L (ref. range: 250). The patient had a DIPPS Score of 1 at the time of diagnosis. PV was at first treated with acetylsalicylic acid and intermittent phlebotomy. After 3 years, the patient's platelet counts and hemoglobin levels dropped, and a second bone marrow biopsy confirmed progression to post‐PV myelofibrosis. However, being afraid of potential side effects, our patient refused therapy with ruxolitinib and therefore was continued on acetylsalicylic acid alone. Two months later, urinary outflow obstruction was diagnosed by ultrasound and a surgical pyeloplasty was advised. Again, the patient was afraid of complications and refused surgery, accepting the increased risk to develop urinary tract infections.\n\nSubsequently, her health tremendously deteriorated further: Her enlarged spleen reached a size of 22 cm in length in MRI and she became increasingly weaker so that she was barely able to walk. MPN‐TSS score was then 60 (out of 100). Finally, she agreed to start treatment with 10 mg bid ruxolitinib. Within the next 6 months her general health rapidly improved, she gained 22 pounds in weight, spleen size decreased to 17 cm, and platelet counts normalized. Intermittent facial edema and eye redness were the only side effects attributed to ruxolitinib. CBC after treatment initiation with ruxolitinib steadily improved to leukocytes, 5.75 G/L (Ref. range: 3.9–10.2); erythrocytes, 5.4 T/L (Ref. range: 3.9–5.2); hemoglobin, 13.0 g/dl (ref. range: 12–15.4); HKT, 41% (ref. range: 35.5–45.5); and platelets: 203 G/L (ref. range: 150–370). MPN‐TSS score improved to 37 (out of 100). However, the patient developed bacterial pneumonia, treated successfully with a course of piperacillin/tazobactam for 7 days, and two episodes of cystitis responding well to oral fosfomycin. Despite the infections, ruxolitinib was continued without interruption, and the patient made a rapid recovery after each infection.\n\n18 months later, the patient developed leukocytosis of 25.8 G/L (ref. range 3.6–10.5 G/L) and erythrocytosis of 6.8 T/L (ref. range 3.85–5.2 G/L). A CT scan of the chest revealed mild residual changes after pneumonia in her basal lung sections, but a meticulous workup did not provide any evidence to support infection (CRP = 0.6 mg/L, ref. range: 0–3 mg/L). Thus, the leukocytosis and the erythrocytosis was attributed to the hematologic malignancy rather than infection. Consequently, the dose of ruxolitinib was increased to 15 mg bid. Blood counts and general health improved immediately once more, so that ruxolitinib has been continued at the higher dose. Since then, the patient experienced five further episodes of cystitis, which rapidly responded to oral antibiotic treatment. During the entire post‐transplant observation period, her immunosuppressive regimen remained unchanged, because the patient was afraid of transplant rejection. Overall, the patient was followed until today for 33 months after initiation of ruxolitinib.\n\n3 PATIENT 2\n\nThis young female patient had to undergo three liver transplantations because of recurrent thrombotic events. The first transplantation was performed due to Budd‐Chiari syndrome at the age of 19 years. The second transplantation was needed to treat focal nodular hyperplasia with partial thrombosis of the liver veins at the age of 38. A third transplantation was needed shortly thereafter owing to acute occlusion of the portocaval anastomosis. Myeloproliferative disease was suspected but was not confirmed over the next 16 years, although clinical and lab investigations were done repeatedly. Likewise, an underlying coagulopathy was not detected. In order to prevent further thrombotic complications, she received phenprocoumon (target range: INR of 2.5–3). Despite her history with recurrent thromboses the patient continued smoking (14 py, 30 cig/day).\n\nHer initial immunosuppressive medication after liver transplantation comprised ciclosporin and prednisone, which was changed to tacrolimus (Prograf) and mycophenolate at age 25, and switched again to daily sirolimus 1 mg and prednisolone 2.5 mg at the age of 28, because she developed calcineurin inhibitor (CNIs)‐induced kidney injury.\n\nAt the age of 44, a kidney tumor in the right kidney combined with thrombosis of the inferior vena cava (VCI) was identified during a routine follow‐up MRI. The kidney tumor was removed and was classified as moderately differentiated renal cell carcinoma (pT1a, L0, V0, R0, Pn0). A radiologic attempt to recanalize the VCI closure failed and phenprocoumon was continued (target range: INR of 2.5–3).\n\nSix months later, hemoglobin steadily increased to 19.8 g/dl (Ref. range 12–15.4 g/dl). At this time leukocytes were 10.9 G/L (ref. range: 3.9–10.2), erythrocytes >8.9 T/L (ref. range: 3.9–5.2), HKT 58% (ref. range 35.5–45), and platelets 180 G/L (ref. range: 150–370). LDH was increased to 519 U/L (ref. range: 250). The erythropoietin level was decreased to 2 mIU/ml (ref. range 4.3–29.0). Now, JAK2 V617F positive polycythemia vera was confirmed for the first time by genetic testing and bone marrow biopsy. Molecular studies identified an ETV6 deletion, and next generation sequencing also showed JAK2 V617F mutation and DNMT3A S770L mutation in 70% and 40% of cells, respectively. Bone marrow histology revealed moderate reticulin fiber fibrosis and collagen fiber fibrosis (M2).\n\nAs a first therapeutic step, her high hematocrit was lowered by phlebotomies. Next, ruxolitinib 15 mg bid was initiated. Progressive pancytopenia developed so that the dose was reduced to 10 mg once daily. At this lower dosage, the patient still had reduced hemoglobin and platelet counts, which however remained stable. Her splenomegaly declined from 20 to 14 cm in diameter measured by ultrasound and the patient reported a good clinical recovery and stable general well‐being. Finally, ruxolitinib was given in two divided daily doses of 5 mg, which further improved tolerability. Immunosuppression was continued with daily 1 mg sirolimus and 2.5 mg prednisolone. Thus far, this patient has not suffered from any infectious complications. CBC after treatment initiation improved to leukocytes 6.02 G/L (ref. range: 3.9–10.2), erythrocytes 5.1 T/L (ref. range: 3.9–5.2), hemoglobin 13.2 g/dl (ref. range: 12–15.4), HKT 40% (ref. range: 35.5–45.5), and platelets 100 G/L (Ref. range: 150–370). The patient has been followed on ruxolitinib treatment since 19 months so far.\n\n4 DISCUSSION\n\nMalignancies are the most frequent cause of mortality in adult liver transplant recipients.5 Myeloproliferative neoplasms after liver transplantation have been described but seem to be rather rare events3 and underlying hematologic etiologies may become unmasked only several years after liver transplantation in patients with Budd‐Chiari syndrome and thrombotic hepatic diseases, as is illustrated in our second patient. Nevertheless, data on treatment of PV and MF are lacking for patients after liver transplantation. Of note, in a cohort of 17 patients with liver transplantation for Budd‐Chiari syndrome, 12 patients (71%) had detectable evidence of an underlying myeloproliferative disorder. These patients were treated with warfarin, hydroxyurea, and aspirin.6 Treatment of myeloproliferative neoplasms in patients after organ transplantation is hampered by the fact that the alternative use of interferons would probably induce organ rejection. On the other hand, the longtime hydroxyurea promotes the development of secondary malignancies, additive to the risk caused by the long‐term immunosuppression for organ transplantation. Both hydroxyurea and interferon are poorly effective in relieving symptoms and the effects on splenomegaly are moderate, while ruxolitinib is effective in controlling the hematocrit, reduction of spleen size, and improving symptoms.7 Since both of our patients had splenomegaly and constitutional symptoms, we preferred a therapy with ruxolitinib.\n\nThere are no known direct interactions between immunosuppressive agents used in liver transplant recipients and ruxolitinib. Nevertheless, an increased risk for infectious complications must be assumed given that ruxolitinib, which can be used for the treatment of graft versus host disease, has profound immunomodulatory effects.8 In the clinical settings it remains unclear, how to adjust long‐term immunosuppression after solid organ transplantation when ruxolitinib must be administered.\n\nThe randomized, double‐blind and placebo‐controlled study COMFORT‐I and ‐II demonstrate that ruxolitinib relieves symptoms and improves survival. Accordingly, in our two patients occurred astonishing improvements in clinical presentation and quality of life after treatment with ruxolitinib was started. However, one of our patients experienced more frequent episodes of cystitis in the context of an anatomic predisposition, and pneumonia as infectious complications under ruxolitinib. In the COMFORT‐I study, sepsis (2.6%) and pneumonia (1.9%) were the leading adverse events contributing to death in the ruxolitinib arm.9 Of note, it has been shown that ruxolitinib decreases the function of dendritic cells, NK cells and T cells as important players of immune control.10, 11\n\nThere is no data on how immunosuppression in solid organ recipient should be adjusted in concomitant treatment with ruxolitinib to avoid infectious complications. Given that both ruxolitinib and mycophenolate display strong antiproliferative properties, the increased frequency of infections in patient 1 may be related to this combination. However, the patient declined to at least reduce the dose of mycophenolate.\n\nOur patients were regularly monitored for any infections, and we strongly recommend to follow this strategy when ruxolitinib has to be prescribed after liver transplantation, taking into account published clinical experience is still limited to few patients with rather short observation periods.\n\nTaken together, our patients confirm a positive treatment response of myeloproliferative disease to ruxolitinib, leading to a rapid relief of symptoms and improved quality of life. These clinical observations suggest a favorable balance between risks and benefits in patients after liver transplantation who may need ruxolitinib therapy for severe progressive PV and MF. Thus, we hope that our case series will stimulate more reports on the use of ruxolitinib in solid organ transplantation to establish optimal concomitant immunosuppression regimens and monitoring intervals.\n\nCONFLICT OF INTEREST\n\nAll authors declare no conflict of interest.\n\nAUTHOR CONTRIBUTIONS\n\nLD, PL, and AH provided medical care and collected all data. TJW, CPS, and US helped with preparation of the manuscript. LD wrote the manuscript. All authors read and approved the final manuscript.\n\nETHICAL APPROVAL\n\nThe authors have no ethical conflicts to disclose.\n\nACKNOWLEDGEMENTS\n\nInformed consent was obtained from both patients.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing not applicable – no new data generated.\n==== Refs\nREFERENCES\n\n1 HeineA, BrossartP, WolfD. Ruxolitinib is a potent immunosuppressive compound: is it time for anti‐infective prophylaxis? Blood. 2013;122 :3843‐3844.24288410\n2 QuinlanSC, MortonLM, PfeifferRM, et al. Increased risk for lymphoid and myeloid neoplasms in elderly solid‐organ transplant recipients. Cancer Epidemiol Biomarkers Prev. 2010;19 :1229‐1237.20406959\n3 WuB, IngersollK, JugR, et al. Myeloid neoplasms following solid organ transplantation: clinicopathologic studies of 23 cases. Am J Clin Pathol. 2017;149 :55‐66.29228125\n4 MortonLM, GibsonTM, ClarkeCA, et al. Risk of myeloid neoplasms after solid organ transplantation. Leukemia. 2014;28 :2317‐2323.24727673\n5 FungJJ, JainA, KwakEJ, KusneS, DvorchikI, EghtesadB. De novo malignancies after liver transplantation: a major cause of late death. Liver Transpl. 2001;7 :S109‐S118.11689783\n6 MelearJM, JurczakW, StrausDJ, et al. Hematologic aspects of liver transplantation for Budd‐Chiari syndrome with special reference to myeloproliferative disorders. Transplantation. 2002;74 :1090‐1095.12438952\n7 VannucchiAM, KiladjianJJ, GriesshammerM, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372 :1670‐1671.\n8 Escamilla GomezV, García‐GutiérrezV, López CorralL, et al. Ruxolitinib in refractory acute and chronic graft‐versus‐host disease: a multicenter survey study. Bone Marrow Transplant. 2020;55 :641‐648.31700138\n9 VerstovsekS, MesaRA, GotlibJ, et al. Long‐term treatment with ruxolitinib for patients with myelofibrosis: 5‐year update from the randomized, double‐blind, placebo‐controlled, phase 3 COMFORT‐I trial. J Hematol Oncol. 2017;10 :55.28228106\n10 HeineA, HeldSAE, DaeckeSN, et al. The JAK‐inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122 :1192‐1202.23770777\n11 SchonbergK, RudolphJ, WolfD. NK cell modulation by JAK inhibition. Oncoscience. 2015;2 :677‐678.26425655\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(9)",
"journal": "Clinical case reports",
"keywords": "liver transplantation; myelofibrosis; polycythemia vera; ruxolitinib",
"medline_ta": "Clin Case Rep",
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"pages": "e04782",
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"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "31700138;26425655;28228106;23770777;12438952;25901432;24727673;29228125;24288410;11689783;20406959",
"title": "Ruxolitinib for treatment of polycythemia vera and myelofibrosis in patients after liver transplantation.",
"title_normalized": "ruxolitinib for treatment of polycythemia vera and myelofibrosis in patients after liver transplantation"
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"abstract": "Gastrointestinal neuroendocrine neoplasms were recently reclassified into the 2019 World Health Organization schema into well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Among these, gastric MiNENs are exceedingly rare and often metastasize quickly without diagnostic clues. We present a refractory gastric MiNEN with unique presenting features. This case highlights the clinical spectrum of these tumors, the importance of accurate histochemical interpretation, and clinical management in the absence of formalized guidelines. Future therapies looking at novel targets and palliative symptom relief are needed.",
"affiliations": "Department of Internal Medicine, Michigan State University at Hurley Medical Center, Flint, MI.;Department of Internal Medicine, Michigan State University at Hurley Medical Center, Flint, MI.;Department of Internal Medicine, Michigan State University at Hurley Medical Center, Flint, MI.;New York Institute of Technology College of Osteopathic Medicine, Glen Head, NY.;Division of Hematology, Department of Internal Medicine, Duke University, Durham, NC.;Department of Internal Medicine, Michigan State University at Hurley Medical Center, Flint, MI.;Division of Gastroenterology, Department of Internal Medicine, Emory University, Atlanta, GA.",
"authors": "Deliwala|Smit S|SS|;Ponnapalli|Anoosha|A|;Gakhal|Inderdeep|I|;Modi|Viraj|V|;Haykal|Tarek|T|;Bachuwa|Ghassan|G|;Chawla|Saurabh|S|",
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"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253\nWolters Kluwer Maryland, MD\n\nACGCR-20-1055\n10.14309/crj.0000000000000569\n00013\nCase Report\nStomach\nWhen Variants Collide: An Unusual Presentation of Metastatic Gastric Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm\nDeliwala Smit S. MD 1\nPonnapalli Anoosha MD 1aponnap1@hurleymc.com\n\nGakhal Inderdeep MD 1igakhal1@hurleymc.com\n\nModi Viraj BS 2vmodi03@nyit.edu\n\nHaykal Tarek MD 3tarek.haykal@duke.edu\n\nBachuwa Ghassan MD, MS, MHSA, FACP, AGSF 1gbachuw2@hurleymc.com\n\nChawla Saurabh MD, FACG 4saurabh.chawla@emory.edu\n\n1 Department of Internal Medicine, Michigan State University at Hurley Medical Center, Flint, MI\n2 New York Institute of Technology College of Osteopathic Medicine, Glen Head, NY\n3 Division of Hematology, Department of Internal Medicine, Duke University, Durham, NC\n4 Division of Gastroenterology, Department of Internal Medicine, Emory University, Atlanta, GA\nCorrespondence: Smit S. Deliwala, MD (Deliwal1@msu.edu).\n4 2021\n27 4 2021\n8 4 e0056902 9 2020\n03 12 2020\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nABSTRACT\n\nGastrointestinal neuroendocrine neoplasms were recently reclassified into the 2019 World Health Organization schema into well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Among these, gastric MiNENs are exceedingly rare and often metastasize quickly without diagnostic clues. We present a refractory gastric MiNEN with unique presenting features. This case highlights the clinical spectrum of these tumors, the importance of accurate histochemical interpretation, and clinical management in the absence of formalized guidelines. Future therapies looking at novel targets and palliative symptom relief are needed.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\n\nThe neuroendocrine cells of the gastrointestinal tract produce numerous hormones with effects on acid secretion, motility, pancreatic stimulation, and storage.1 Neuroendocrine neoplasms (NENs) are epithelial overgrowths confined to neuroendocrine differentiation. In 2019, the World Health Organization released a significant update and reclassified the digestive system tumors. It divides NENs into well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, or mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). This classification largely depends on molecular profiling, histochemical analysis, and proliferation markers such as Ki-67 and the mitotic index.2 Traditionally, gastric tumors display a hyperplasia-dysplasia-neoplasia sequence under hypergastrinemia states; however, neuroendocrine carcinomas have demonstrated unique tumorigenesis from endocrine cells.3 NENs are underestimated, and clinical data lack because these patients are often excluded from clinical trials. This places importance on the reporting of newly diagnosed MiNENs that often require a multidisciplinary consensus to design the most optimal treatment strategy.4 Over the years, these groups of digestive tumors have undergone frequent classification changes because more sophisticated immunohistochemical methods are used. Although pathologists have recognized this entity for quite some time, there seems to be a lag in its clinical understanding as its presentation occurs late. We present an exceedingly rare case of a gastric MiNEN presenting with atypical features not noted previously in the literature. This case aims to broaden the clinical understanding of this tumor, highlighting its paraneoplastic and locoregional effects.\n\nCASE REPORT\n\nA 59-year-old woman presented to her primary care physician with dizziness, fatigue, anorexia, bloating, and hoarseness for months despite lifestyle measures and omeprazole. She had a history of hypertension and a family history significant for cardiovascular disease. She never used tobacco products, alcohol, or illicit substances. She began workup with an abdominal ultrasound that revealed a 2.2-cm solid lesion in the liver but was lost to follow-up until she presented to the emergency department with complaints of abdominal pain, anorexia, night sweats, and recurrent near syncopal episodes.\n\nOn arrival, she was hypotensive to 77/34 mm/hg, normocardic to 83 beats per minute, afebrile, tachypneic, and not requiring supplemental oxygen. She appeared ill, dehydrated, and uncomfortable unable to stand for extended periods without feeling dizzy. After a fluid bolus, repeated blood pressure was 94/67 mm Hg with a heart rate of 98 beats/min. Complete blood counts and metabolic panels were unremarkable. Reviewing her history from centralized electronic records, the mass on her ultrasound prompted a magnetic resonance imaging, which revealed numerous lesions in the liver and bulky adenopathy along the stomach, pancreas, and gastrohepatic ligaments (Figure 1). A coronal computed tomography scan revealed a tortuous inferior vena cava (IVC) with surrounding mass effect with the left renal vein being compressed by para-aortic nodes, while the IVC was wrapped by anterior and posterior lymph nodes (Figure 2). No biliary or ductal abnormalities were noted. Symptoms were controlled with esomeprazole, prophylactic low-molecular-weight heparin, ondansetron, prochlorperazine, and frequent hydration to the extent tolerable. An esophagogastroduodenoscopy revealed a 4-cm ulcerative mass at the gastroesophageal junction extending into the fundus, with biopsy revealing an MiNEN with sheets of high-grade tumor cells and glands with underlying squamous epithelium (Figure 3). Helicobacter pylori staining was negative, and gastrin was not obtained because of the nature of the diagnosis. Liver biopsy confirmed metastatic MiNEN with medium to large tumor cells and scattered adenocarcinoma of gastric origin (Figure 4).\n\nFigure 1. Abdominal magnetic resonance imaging reveals the index hepatic lesion measuring 2.8 × 2.7 cm and thickening of the lesser curvature of the stomach.\n\nFigure 2. Abdominal and pelvic coronal computed tomography revealing the 2.8 × 2.7-cm index lesion of the liver and a distorted inferior vena cava vasculature from anterior and posterior lymph node compression (arrowhead) with left para-aortic lymph nodes compressing the left renal vein.\n\nFigure 3. Esophagogastroduodenoscopy revealing a 4-cm large ulcerative mass extending into the gastric fundus.\n\nFigure 4. Histopathology of the liver, revealing high-grade tumor cells, with rare tumor cells having moderate cytoplasm and occasional nucleoli (hematoxylin and eosin stain, 40× magnification).\n\nOn disclosing her results, the patient decided to go back home to pursue staging, molecular profiling, and candidacy for clinical trials, ultimately undergoing palliative chemotherapy with carboplatin and etoposide. After assessing fit, she received a chest port to initiate chemotherapy with carboplatin 750-mg and etoposide 220-mg infusions, pretreated with aprepitant 130 mg, ondansetron 8 mg, and dexamethasone 12 mg. Despite 2 cycles over 2–3 months and relief in stomach pain, repeat imaging revealed diffuse osseous metastatic involvement of the thoracolumbar spine and pelvis. Hopeful for life prolongation, the next treatment line was initiated with capecitabine 1,000 mg twice a day from days 1–14 and temozolomide 400 mg on days 10–14. During subsequent outpatient visits, she was found to be repeatedly hypotensive, with increasing occurrences of presyncope. After ruling out other etiologies, interventional radiology was consulted for IVC stent placement, although it was decided that chemotherapy would continue, with the possibility of stent placement if adequate tumor shrinkage was not achieved. During a subsequent admission for renal failure and severe thrombocytopenia, her hemodynamics and course rapidly worsened, eventually passing away in hospice care.\n\nDISCUSSION\n\nThe unique element of our case remains the rarity of this tumor and its atypical clinical presentation, often seen in advanced stages. MiNENs have an overall poor prognosis presenting with metastatic and paraneoplastic components at the time of diagnosis. Gastric MiNENs constitute a small fraction of digestive tumors, most commonly affecting men in their fifth or sixth decade.4,5 The most extensive report on MiNEN trends comes from the Surveillance, Epidemiology, and End Results registry between 1975 and 2016. It reports an incidence of 5.6%, mostly in the appendix, colon, cecum, rectum, or small intestine.5 Compared with other tumors, gastric MiNENs are discovered at advanced stages, and very little is known about them.\n\nOur patient experienced recurrent dizziness, intolerance to standing for prolonged periods, and presyncope consistent with orthostatic hypotension, and alternative causes were ruled out, including anemia, volume depletion, and arrhythmia. Autonomic failure seemed less likely due to her response in heart rate. We attributed her symptoms to IVC compression by extensive lymphadenopathy consistent with IVC syndrome, a presentation consistent with the literature.6–8 A similar case of IVC compression has been described, eluding to the propensity of these tumors to metastasize in a disorganized way risking compression of vital structures.7\n\nRecommendations for therapy guidance, surveillance patterns, and treatment duration are lacking, placing precedence on isolated reports.9 The challenge for pathologists remains to identify both elements because it has prognostic implications.10 In most cases, the neuroendocrine component is represented by small or large cell NEC, which in itself renders a poor prognosis, while the non-neuroendocrine component is represented by carcinoma of the primary site.7,11 A recent systematic review noted that the neuroendocrine component determines the clinical trajectory. Most diagnostic and therapeutic data come from advanced cases, while isolated reports achieving success with long-term survival are sparse.11,12 The general approach in patients identified with a metastatic spread at diagnosis is palliative chemotherapy initiation with combination cisplatin or carboplatin with etoposide before deterioration limits chemotherapy. These tumors respond to platinum-based regimens, often administered for 4 cycles, while surgical metastasectomy offers no further benefit.6 In a multinetwork cohort, platinum-based regimens demonstrated higher efficacy than folinic acid, fluorouracil, and irinotecan and folinic acid, fluorouracil, and oxaliplatin regimens for progression-free and median overall survival. Platinum-based therapy is highly individualized but often administered as cisplatin 25 mg/m2 on days 1–3 or carboplatin 300 mg/m2 followed by etoposide 100 mg/m2 on days 1–3 every 21 days.13\n\nInterestingly, a 3-drug regimen derived from small-cell lung cancer models consisting of paclitaxel, carboplatin, and etoposide reflected a longer median survival, with nearly 25% of patients alive at 3 years.14 Despite the study limitations and unvalidated paclitaxel benefits in this setting, any benefit in outcome must be explored in these aggressive tumors. Future research looking into novel molecular targets is vital in quelling its progression. Equally important are therapies that provide palliative symptom relief, especially in tumors that have a mass effect on vital structures.3,15,16 In conclusion, through this report, we want to highlight the formation of a rare mixed neuroendocrine-non-neuroendocrine neoplasm and its unique presentation.17\n\nDISCLOSURES\n\nAuthor contributions: S. Deliwala wrote the manuscript and is the article guarantor. A. Ponnapalli, I. Gakhal, and V. Modi edited the manuscript. T. Haykal, G. Bachuwa, and S. Chawla edited the manuscript and revised it for intellectual content.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n\n1. Gunawardene AR Corfe BM Staton CA . Classification and functions of enteroendocrine cells of the lower gastrointestinal tract. Int J Exp Pathol 2011;92 (4 ):219–31.21518048\n2. Nagtegaal ID Odze RD Klimstra D . The 2019 WHO classification of tumours of the digestive system. Histopathology 2020;76 (2 ):182–8.31433515\n3. Domori K Nishikura K Ajioka Y Aoyagi Y . Mucin phenotype expression of gastric neuroendocrine neoplasms: Analysis of histopathology and carcinogenesis. Gastric Cancer 2014;17 (2 ):263–72.23828549\n4. Frizziero M Chakrabarty B Nagy B . Mixed neuroendocrine non-neuroendocrine neoplasms: A systematic review of a controversial and underestimated diagnosis. J Clin Med 2020;9 (1 ):273.\n5. Shi H Qi C Meng L . Do neuroendocrine carcinomas and mixed neuroendocrine–non-neuroendocrine neoplasm of the gastrointestinal tract have the same prognosis? A SEER database analysis of 12,878 cases. Ther Adv Endocrinol Metab 2020;11 (6 ):204201882093830.\n6. Yun M Kim GH Lee SY . Hypotension due to compression of the inferior vena cava by intrathoracic herniation of peritoneal fat during laparoscopic surgery: A case report. Anesth Pain Med 2018;13 (1 ):72–6.\n7. Patel SA . The inferior vena cava (IVC) syndrome as the initial manifestation of newly diagnosed gastric adenocarcinoma: A case report. J Med Case Rep 2015;9 (1 ):204.26411979\n8. Koratala A Bhatti V . An unusual cause of syncope. Intern Emerg Med 2017;12 (5 ):717–9.27796703\n9. Qin J Lu H . Combined small-cell lung carcinoma. Onco Targets Ther 2018;11 :3505–11.29950855\n10. Ishida M Sekine S Fukagawa T . Neuroendocrine carcinoma of the stomach: Morphologic and immunohistochemical characteristics and prognosis. Am J Surg Pathol 2013;37 (7 ):949–59.23759931\n11. Uccella S La Rosa S . Looking into digestive MiNENs: Subtypes, prognosis and predictive factors. Histopathology 2020;77 (5 ):700–17.32538468\n12. Kanazawa Y Kikuchi M Imai Y Katakami N Kaihara S Shinohara S . Successful treatment of a mixed neuroendocrine-nonneuroendocrine neoplasm of the colon with metastases to the thyroid gland and liver. Case Rep Otolaryngol 2020;2020 :5927610.32099708\n13. Walter T Tougeron D Baudin E . Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: Are they really heterogeneous? Insights from the FFCD-GTE national cohort. Eur J Cancer 2017;79 :158–65.28501762\n14. Hainsworth JD Spigel DR Litchy S Greco FA . Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: A minnie pearl cancer research network study. J Clin Oncol 2006;24 (22 ):3548–54.16877720\n15. La Rosa S Marando A Furlan D . Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: Insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers. Am J Surg Pathol 2012;36 (4 ):601–11.22314183\n16. Brountzos EN Binkert CA Panagiotou IE . Clinical outcome after intrahepatic venous stent placement for malignant inferior vena cava syndrome. Cardiovasc Intervent Radiol 2004;27 (2 ):129–36.15259806\n17. Minaya-Bravo AM Garcia Mahillo JC Mendoza Moreno F . Large cell neuroendocrine: Adenocarcinona mixed tumour of colon: Collision tumour with peculiar behaviour. What do we know about these tumours? Ann Med Surg 2015;4 (4 ):399–403.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "8(4)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00569",
"pmc": null,
"pmid": "34476269",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "16877720;23759931;28501762;29950855;32099708;27796703;15259806;26635955;31433515;32670540;31963850;26411979;23828549;22314183;21518048;32538468",
"title": "When Variants Collide: An Unusual Presentation of Metastatic Gastric Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm.",
"title_normalized": "when variants collide an unusual presentation of metastatic gastric mixed neuroendocrine non neuroendocrine neoplasm"
} | [
{
"companynumb": "US-009507513-2205USA007481",
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"occurcountry": "US",
"patient": {
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"activesubstancename": "TEMOZOLOMIDE"
},
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... |
{
"abstract": "Neonatal abstinence syndrome (NAS) which is observed in 55-94% of the newborns from opioids-taking mothers produces deleterious neurological symptoms. Various pharmacological therapies have been investigated in neonates with NAS. This article reviews all studies on NAS treatment to analyze the duration of treatment, length of hospitalization and possible drug adverse effects. The search was limited to the randomized clinical trials which examined the treatments of neonates with NAS. Scientific databases including PubMed, Cochrane Library, ISI Web of Science, Embase and Scopus were systematically searched. Retrieved articles were reviewed by two researchers and evaluated using the JADAD scoring system. Finally, the treatment duration, hospitalization length and drug side-effects were extracted. Methadone, buprenorphine and clonidine were found more effective than morphine. Diluted tincture of opium (DTO) in combination with phenobarbital or clonidine was significantly more effective than DTO alone. Clonidine was a significantly better adjunctive therapy than phenobarbital in reducing morphine treatment days. No significant difference was observed between morphine and DTO effectiveness. Deciding the optimal regimen to manage symptomatic NAS, as a single or an adjunct therapy is not possible based on the literature, due to the low quality, small size and short-term treatment considered in the published studies. Graphical abstract Process of selecting trials included in the present systematic review.",
"affiliations": "Department of Nursing and Midwifery, Razi School of Nursing and Midwifery, Kerman University of Medical Sciences, Kerman, Iran.;Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.;Mother and Child Welfare Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.;Cardiac Anesthesia Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.;Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.;Department of Medical and Toxicological Critical Care, Paris-Diderot University, INSERM UMRS-1144, Paris, France.;Center of Toxicology Science & Research, Medical School, University of Crete, Heraklion, Crete, Greece.;Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.;Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. raminrezaee1983@gmail.com.",
"authors": "Ghazanfarpour|Masumeh|M|;Najafi|Mona Najaf|MN|;Roozbeh|Nasibeh|N|;Mashhadi|Mohamadghasem Etemadi|ME|;Keramat-Roudi|Atefeh|A|;Mégarbane|Bruno|B|;Tsatsakis|Aristidis|A|;Moghaddam|Mohammad Mobin Miri|MMM|;Rezaee|Ramin|R|http://orcid.org/0000-0001-7567-6142",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D003000:Clonidine; D008691:Methadone",
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40199-019-00266-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1560-8115",
"issue": "27(1)",
"journal": "Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences",
"keywords": "Clonidine; Methadone; Morphine; Neonatal abstinence syndrome; Neonatal passive addiction; Neonatal withdrawal syndrome; Opioid; Opium; Withdrawal",
"medline_ta": "Daru",
"mesh_terms": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D003000:Clonidine; D004359:Drug Therapy, Combination; D006801:Humans; D007231:Infant, Newborn; D007902:Length of Stay; D008691:Methadone; D009357:Neonatal Abstinence Syndrome; D058850:Opiate Substitution Treatment; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101125969",
"other_id": null,
"pages": "423-431",
"pmc": null,
"pmid": "31093953",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": "10103095;10609351;12032522;14649563;15210660;15537850;15607839;15613582;18435873;18694901;18806056;19398463;20925688;21124750;21170166;23949834;25183042;25357093;25624389;25976238;26712409;28468518;29913015;30071529;30205091;3293868;7068937;8721797",
"title": "Therapeutic approaches for neonatal abstinence syndrome: a systematic review of randomized clinical trials.",
"title_normalized": "therapeutic approaches for neonatal abstinence syndrome a systematic review of randomized clinical trials"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-05578",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "We investigated, in a real-life setting, the prognostic relevance of previous primary treatment (radical prostatectomy [RP] or external beam radiotherapy [EBRT]) on overall survival for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (223Ra).\n\n\n\nIn the present multicenter retrospective study, we enrolled 275 consecutive patients. The demographic and clinical data and mCRPC characteristics were recorded and evaluated at baseline and at the end of treatment or progression. 223Ra was administered according to the current label authorization until disease progression or unacceptable toxicity. We divided the whole cohort into 2 groups: those who had undergone primary radical prostatectomy or ablative radiotherapy (RP/EBRT) and those who had not received previous primary treatment (NO).\n\n\n\nOf the 275 patients, 128 (46.5%) were alive and undergoing monitoring at the last follow-up examination, 103 (37.4%) had stopped treatment because of disease progression or the onset of comorbidities, and 147 (53.5%) had died during the study period. Of the 275 patients, 132 were in the RP/EBRT group (48%), of whom 93 had undergone RP and 76 had undergone ablative EBRT, and 143 patients were in the NO group (52%). The data showed a clear advantage for the patients in the RP/EBRT group compared with those in the NO group, with an estimated median survival of 18 versus 11 months, respectively (P < .001). The results from the multivariate analysis corroborated this trend, with a hazard ratio of 0.7 (P = .0443), confirming the better outcome for the RP/EBRT group.\n\n\n\nPrevious radical treatment provides a protective role for patients with mCRPC undergoing 223Ra treatment.",
"affiliations": "Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: viviana.frantellizzi@uniroma1.it.;Unit of Nuclear Medicine, Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo, Italy.;Unit of Nuclear Medicine, \"Spirito Santo\" Hospital, Pescara, Italy.;Unit of Nuclear Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.;Unit of Nuclear Medicine, Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo, Italy.;Department of Urology, \"Villa Stuart\" Private Hospital, Rome, Italy.;Unit of Nuclear Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.;PhD Program in Morphogenesis and Tissue Engineering, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.;Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza University of Rome, Rome, Italy.",
"authors": "Frantellizzi|Viviana|V|;Costa|Renato|R|;Mascia|Manlio|M|;Spanu|Angela|A|;Farcomeni|Alessio|A|;Licari|Maria|M|;Cindolo|Luca|L|;Nuvoli|Susanna|S|;Pontico|Mariano|M|;De Vincentis|Giuseppe|G|",
"chemical_list": "D011868:Radioisotopes; C581106:radium Ra 223 dichloride; D011883:Radium",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clgc.2019.10.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "18(3)",
"journal": "Clinical genitourinary cancer",
"keywords": "(223)Ra; Ablative radiotherapy; Overall survival; RT; Radical prostatectomy",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001918:Brachytherapy; D003131:Combined Modality Therapy; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011468:Prostatectomy; D064129:Prostatic Neoplasms, Castration-Resistant; D065840:Protective Factors; D011868:Radioisotopes; D011883:Radium; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "185-191",
"pmc": null,
"pmid": "32173355",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Primary Radical Prostatectomy or Ablative Radiotherapy as Protective Factors for Patients With mCRPC Treated With Radium-223 Dichloride: An Italian Multicenter Study.",
"title_normalized": "primary radical prostatectomy or ablative radiotherapy as protective factors for patients with mcrpc treated with radium 223 dichloride an italian multicenter study"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020134792",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPrimary cutaneous diffuse large B-cell lymphoma (PCLBCL) represents a rare subtype among primary cutaneous B-cell lymphoma exhibiting a characteristic genetic background, an aggressive clinical course and a high relapse rate under different therapeutic regimen. Therefore, PCLBCL has a rather restricted prognosis.\n\n\nMETHODS\nFour patients with PCLBCL were treated at our institution with age- and toxicity-adapted first-line immunochemotherapy with rituximab and modified CHOP (cyclophosphamid, vincristin, liposomal doxorubicin, prednisolon). On relapse, the same regimen with R-CHOP or different antineoplastic strategies (radiation, polychemotherapy, immunotherapy, stem cell transplantation) were applied. Toxicity, clinical response and overall survival was documented.\n\n\nRESULTS\nUnder this regimen, clinical response to modified R-CHOP was achieved in all patients with tolerable toxicity - however, being characterized by a rapid disease progression with inconsistent response towards the subsequent therapeutic armentarium and unsecure impact on overall survival.\n\n\nCONCLUSIONS\nSo far, it is still unknown, if an extensive multimodal therapy for PBLBCL improves overall survival. Immunochemotherapy with R-CHOP currently represents the most effective treatment.",
"affiliations": "Department of Dermatology, University Clinic of Würzburg, Germany. wobser_m@klinik.uni-wuerzburg.de",
"authors": "Wobser|Marion|M|;Kneitz|Hermann|H|;Bröcker|Eva-Bettina|EB|;Becker|Jürgen Christian|JC|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Germany",
"delete": false,
"doi": "10.1111/j.1610-0387.2010.07578.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1610-0379",
"issue": "9(3)",
"journal": "Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG",
"keywords": null,
"medline_ta": "J Dtsch Dermatol Ges",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007866:Leg; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011241:Prednisone; D012878:Skin Neoplasms; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101164708",
"other_id": null,
"pages": "204-11",
"pmc": null,
"pmid": "21122066",
"pubdate": "2011-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary cutaneous diffuse large B-cell lymphoma, leg-type, treated with a modified R-CHOP immunochemotherapy - diagnostic and therapeutic challenges.",
"title_normalized": "primary cutaneous diffuse large b cell lymphoma leg type treated with a modified r chop immunochemotherapy diagnostic and therapeutic challenges"
} | [
{
"companynumb": "DE-TEVA-2020-DE-1209014",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "We report a case of Cryptococcus neoformans pulmonary infection complicated by empyema in a 79-year-old man with diffuse large B-cell lymphoma treated with R-CHOP and ibrutinib. A literature review identified 25 cases of cryptococcal pleural disease published since 1980. Most cases were caused by the C. neoformans species in immunocompromised hosts with an exudative pleural effusion and lymphocyte-predominant infiltrate. The cryptococcal antigen test was often positive when pleural fluid and serum were tested. The outcome was favourable in most cases with antifungal therapy and either thoracocentesis or surgical resection. We also identified 40 cases of opportunistic infections, most commonly aspergillosis, cryptococcosis and Pneumocystis jirovecii pneumonia, in patients treated with ibrutinib. In vitro studies indicate Bruton tyrosine kinase inhibition impairs phagocyte function and offer a mechanism for the apparent association between ibrutinib and invasive fungal infections.",
"affiliations": "Infectious Diseases and Microbiology, Concord Repatriation General Hospital, Concord, New South Wales, Australia.;Infectious Diseases and Microbiology, Concord Repatriation General Hospital, Concord, New South Wales, Australia.",
"authors": "Swan|Christopher David|CD|;Gottlieb|Thomas|T|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000935:Antifungal Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C571759:R-CHOP protocol; C068538:liposomal amphotericin B; C551803:ibrutinib; D000069283:Rituximab; D014750:Vincristine; D000666:Amphotericin B; D004317:Doxorubicin; D003520:Cyclophosphamide; D015725:Fluconazole; D000225:Adenine; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-224786",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "cryptococcosis; cryptococcus; empyema; pleural infection; tyrosine kinase inhibitor",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000225:Adenine; D000368:Aged; D000666:Amphotericin B; D058846:Antibodies, Monoclonal, Murine-Derived; D000935:Antifungal Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003520:Cyclophosphamide; D004317:Doxorubicin; D016724:Empyema, Pleural; D015725:Fluconazole; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D010880:Piperidines; D011241:Prednisone; D011720:Pyrazoles; D011743:Pyrimidines; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30021735",
"pubdate": "2018-07-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "28377877;25747471;23782158;23825946;27456945;28013480;28815693;2021155;16616071;16896431;29592982;1735305;25637383;28156016;27096597;28792175;23820392;29186341;2325190;7620032;28552327;26395579;10533638;28480254;3816325;19180728;24643864;16230188;24881631;28714866;28554246;25903044;6992663;8302429;24985132;7410903;25573991;23509356;27637985;28184982;26059948;1561905;9678688;14732801;29181420;2752835;27503501;19761731;27956157;8365820;27703818;11812896;19407434;19015612;28229118",
"title": "Cryptococcus neoformans empyema in a patient receiving ibrutinib for diffuse large B-cell lymphoma and a review of the literature.",
"title_normalized": "cryptococcus neoformans empyema in a patient receiving ibrutinib for diffuse large b cell lymphoma and a review of the literature"
} | [
{
"companynumb": "AU-MYLANLABS-2018M1061918",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Tacrolimus has been used in pregnant organ recipients for >20 years, and the relationship between fetal complications and the amount of tacrolimus crossing the placenta is still controversial. We report the case of a kidney transplant recipient who used tacrolimus and gave birth to an offspring that developed, shortly after birth, an acute kidney injury caused by tacrolimus exposure, which was detected by measuring tacrolimus levels in the umbilical vein, as well as in maternal blood. Even if whole-blood levels of tacrolimus are within the therapeutic range throughout pregnancy, the amount of tacrolimus could reach toxic levels.",
"affiliations": "Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.;Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.;Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.;Department of Nephrology, Ankara University School of Medicine, Ankara, Turkey.",
"authors": "Aktürk|Serkan|S|;Sadioğlu|Rezzan Eren|RE|;Şengül|Şule|Ş|;Keven|Kenan|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfz093",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfz093sfz093TransplantationAcute kidney injury in an infant of a kidney allograft recipient Aktürk Serkan Sadioğlu Rezzan Eren Şengül Şule Keven Kenan \nDepartment of Nephrology, Ankara University School of Medicine, Ankara, TurkeyCorrespondence and offprint requests to: Rezzan Eren Sadioğlu; E-mail: rezzanerensadioglu@gmail.com2 2020 08 8 2019 08 8 2019 13 1 123 124 24 2 2019 25 6 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nTacrolimus has been used in pregnant organ recipients for >20 years, and the relationship between fetal complications and the amount of tacrolimus crossing the placenta is still controversial. We report the case of a kidney transplant recipient who used tacrolimus and gave birth to an offspring that developed, shortly after birth, an acute kidney injury caused by tacrolimus exposure, which was detected by measuring tacrolimus levels in the umbilical vein, as well as in maternal blood. Even if whole‐blood levels of tacrolimus are within the therapeutic range throughout pregnancy, the amount of tacrolimus could reach toxic levels.\n\nfetal exposurekidney transplantationplacental transferpregnancytacrolimus\n==== Body\nBACKGROUND\nTacrolimus is used in solid organ transplant recipients as an immunosuppressive agent that blocks T cell activation during pregnancy. The incidence of major structural malformations in cases of fetal exposure to immunosuppressants during pregnancy is not much higher than that in the general population. However, intrauterine growth restriction, low birthweight, reversible renal dysfunction and hyperkalaemia have been reported in offspring of kidney transplant recipients [1]. \n\nCASE REPORT\nA 31-year-old woman with a history of Goodpasture’s syndrome received a living related kidney allograft. The maintenance immunosuppressive therapy comprised mycophenolate mofetil (MMF 1000 mg daily), tacrolimus (Prograf® 3 mg daily) and methylprednisolone (5 mg daily). Five years later, the patient expressed the wish to get pregnant. Her blood pressure (BP) was in the normal range. Her serum creatinine (sCr) level was 1.04 mg/dL, estimated glomerular filtration rate 71 mL/min/1.73 m2 and urine protein:creatinine ratio (PCR) <1 g/g; graft functions had also been stable over the last 2 years. Accordingly, tacrolimus and methylprednisolone treatment were continued, but MMF was replaced with azathioprine 75 mg daily. Pregnancy was confirmed at week 6 of gestation. Tacrolimus trough levels (TTLs) were kept between 4 and 7 ng/mL, with an average tacrolimus dose of 4.57, 9.53 and 9 mg/day in early, mid and late pregnancy, respectively. The patient received regular obstetric care during the entire course of pregnancy. The gestational period was uneventful until gestational week 21 when the patient developed hypertension and proteinuria (PCR: 2.8 g/g). BP increased to 150/100 mmHg and was well controlled with α-methyldopa 750 mg daily. An elective Caesarean section (CS) was performed at week 36 of pregnancy. The patient’s sCr level was 2.34 mg/dL the day before the CS. In order to assess for fetal exposure to tacrolimus, whole‐blood samples were obtained from both maternal blood (4 h after tacrolimus dosing) and the umbilical cord vein at the time of delivery (Figure 1).\n\n\nFIGURE 1 Whole‐blood tacrolimus levels of maternal, umbilical cord venous and newborn blood samples.\n\nA female newborn weighing 2450 g was delivered. The Apgar (Appearance, Pulse, Grimace, Activity, Respiration) scores were 7 and 8 at 1 and 5 min, respectively. The newborn was transferred to the neonatal intensive care unit (NICU) for close monitoring. Reduced urine output (0.3 mL/kg/h) and elevated blood urea nitrogen (BUN) and sCr levels were suggestive of acute kidney injury (AKI). Creatinine level was 1.6 mg/dL (normal range: 0.24–0.85 mg/dL) on admission to the NICU (12 h after birth). Urinalysis was negative for protein. The newborn received 60–80 mL/kg of enteral fluid and nutrition daily. Renal ultrasonography revealed two normal kidneys. On day 3 after birth, the tacrolimus level was measured to determine whether the AKI was due to drug toxicity. Whole‐blood tacrolimus, creatinine and potassium levels were 4.2 ng/mL, 1.3 mg/dL and 4.9 mEq/L, respectively. On day 5 after birth, urine output increased from 0.3 to 1.6 mL/kg/h. BUN and sCr levels regressed to the normal range (BUN: 8 mg/dL; creatinine: 0.42 mg/dL). At the 6-month post-partum follow-up visit, the infant was doing well, with no proteinuria and a normal creatinine level of 0.41 mg/dL. \n\nDISCUSSION\nTo date, data on maternal and fetal tacrolimus transfer kinetics and the effects of tacrolimus exposure through maternal-to-fetal transfer on fetal development are limited [1]. \n\nIn the first case report on placental transfer of tacrolimus, tacrolimus levels from the umbilical vein and newborn’s blood were reported to be 8.1 and 6.4 ng/mL, respectively. While the mother’s TTL on hospital admission for urgent CS was 6.5–7.6 ng/mL, the TTL at the time of delivery was not stated. In addition, indometacin administration to treat patent ductus arteriosus in the neonate makes it difficult to directly associate the AKI with tacrolimus toxicity [2]. \n\nZheng et al. investigated whole-blood, plasma and unbound tacrolimus concentrations in maternal and umbilical cord blood samples in eight solid organ transplant recipients. Mean tacrolimus concentrations in maternal and umbilical cord venous blood were 9.0 ± 3.4 ng/mL and 6.6 ± 1.8 ng/mL, respectively. Mean tacrolimus concentrations at the time of delivery in umbilical cord venous blood were 71% of maternal concentrations [3]. The authors suggested this decrease could be explained by several mechanisms protecting the fetus against drug toxicity, including the molecular weight of tacrolimus. Another possible mechanism is P-glycoprotein, which acts as a membrane carrier for tacrolimus on placental syncytiotrophoblasts. A further important mechanism involves molecular binding of tacrolimus to erythrocytes, accounting for 85–95% of unbound drug in blood. Since haematocrit levels in the umbilical vein are higher, the amount of free drug delivered to the fetus is reduced. \n\nCYP3A7 is a major cytochrome P450 enzyme in the fetal liver, and its efficacy in tacrolimus metabolism is significantly less than that of CYP3A4. However, in the post-partum period, CYP3A7 is replaced with CYP3A4. Accordingly, blood levels of tacrolimus in newborns are reduced by about 15% per day [4].\n\nIn our case, the average tacrolimus dose used was 7.6 mg/day and TTLs were maintained at around 4–7 ng/mL during the entire pregnancy. Maternal tacrolimus levels at delivery across cases are hard to compare because they depend on the time interval between tacrolimus dosing and blood sampling, which, in the present case, was 4 h. Tacrolimus levels in umbilical cord venous blood were 26% of maternal levels at the time of delivery in our case. We believe this difference in levels could be explained by the various mechanisms mentioned earlier, of which the most likely could involve P-glycoprotein, which, as the drug level increases, might become hyperactive in order to protect the fetus from drug toxicity. In our report, there was no nephrotoxic exposure, except for that of tacrolimus. \n\nAs also described by Hebert et al., measurement of plasma or unbound tacrolimus concentrations in pregnant transplant recipients might better reflect the active form of the drug, rather than measurement of whole‐blood concentrations [5].\n\nIn conclusion, tacrolimus should be considered as a potential cause of AKI in infants of kidney transplant recipients on treatment with the immunosuppressant.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES \n1 \nMcKay DB , Josephson MA. \nPregnancy after kidney transplantation . Clin J Am Soc Nephrol 2008 ; 3 : S117e25 18308999 \n2 \nResch B , Mache CJ , Windhager T \net al\nFK 506 and successful pregnancy in a patient after renal transplantation . Transplant Proc 1998 ; 30 : 163 –164 9474990 \n3 \nZheng S , Easterling TR , Hays K \net al\nTacrolimus placental transfer at delivery and neonatal exposure through breast milk . Br J Clin Pharmacol 2013 ; 76 : 988 –996 23528073 \n4 \nDe Wildt SN , Kearns GL , Leeder JS \net al\nCytochrome P450 3A: ontogeny and drug disposition . Clin Pharmacokinet 1999 ; 37 : 485 –505 10628899 \n5 \nHebert MF , Zheng S , Hays K \net al\nInterpreting tacrolimus concentrations during pregnancy and postpartum . Transplantation 2013 ; 95 : 908 –915 23274970\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "13(1)",
"journal": "Clinical kidney journal",
"keywords": "fetal exposure; kidney transplantation; placental transfer; pregnancy; tacrolimus",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "123-124",
"pmc": null,
"pmid": "32082563",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": "9474990;10628899;18308999;23274970;23528073",
"title": "Acute kidney injury in an infant of a kidney allograft recipient.",
"title_normalized": "acute kidney injury in an infant of a kidney allograft recipient"
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"abstract": "Tumour lysis syndrome (TLS) is a life-threatening complication wherein massive tumour cell lysis results in severe metabolic abnormalities. TLS generally follows chemotherapy of rapidly proliferating haematological malignancies; spontaneous TLS and TLS from treatment of solid tumours are infrequently reported. We present a rare case of TLS following treatment of a large gastrointestinal stromal tumour (GIST) in a 63- year-old man. Imatinib was started for tumour size reduction prior to surgical intervention and in 5 days the patient developed metabolic derangements consistent with TLS. Imatinib was held and fluids, allopurinol and rasburicase were started. All metabolic abnormalities resolved in 3 days. Imatinib was restarted, and he eventually underwent surgical intervention. This is the second case demonstrating successful reinitiation of imatinib following TLS when treating GIST. We highlight the importance of risk factor assessment and need for pre-emptive therapy to prevent TLS when using tyrosine kinase inhibitor therapy.",
"affiliations": "Med One Hospitalist Internal Medicine, Riverside Methodist Hospital, Columbus, Ohio, USA.;Internal Medicine, Riverside Methodist Hospital, Columbus, Ohio, USA.;Internal Medicine, Riverside Methodist Hospital, Columbus, Ohio, USA.",
"authors": "Ondecker|Juliann|J|;Kordic|Geno|G|;Jordan|Kim|K|http://orcid.org/0000-0003-4969-603X",
"chemical_list": "D047428:Protein Kinase Inhibitors; C469709:rasburicase; D000493:Allopurinol; D000068877:Imatinib Mesylate; D014503:Urate Oxidase",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226647",
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"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "gastroenterology; tyrosine kinase inhibitor; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000493:Allopurinol; D003937:Diagnosis, Differential; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D012307:Risk Factors; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome; D014503:Urate Oxidase",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567109",
"pubdate": "2018-11-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25002953;25195963;29333308;18728705;21717109;15384972;25031988;18274611;11287975;27993406;22174597;12655435;17687160;19885836;10636102;25876990",
"title": "Tumour lysis syndrome: a rare side effect of imatinib therapy for GIST.",
"title_normalized": "tumour lysis syndrome a rare side effect of imatinib therapy for gist"
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"abstract": "Visceral Leishmaniasis (VL) is an opportunistic infection amongst HIV-infected people in several endemic countries, and the clinical management of this co-infection poses several challenges. Here we describe a co-infected patient in India who failed to respond to miltefosine monotherapy and subsequently relapsed following two further (different) regimens of liposomal amphotericin B. He was then successfully treated with a combination of 30 mg/kg liposomal amphotericin B and 14 days of 100mg/day oral miltefosine.",
"affiliations": "Department of Medicine and Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India. Electronic address: shalom_patole@yahoo.co.uk.;Médecins Sans Frontières, New Delhi, India.;Department of Medicine and Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India.",
"authors": "Patole|Shalom|S|;Burza|Sakib|S|;Varghese|George M|GM|",
"chemical_list": "D000981:Antiprotozoal Agents; C068538:liposomal amphotericin B; D010767:Phosphorylcholine; C039128:miltefosine; D000666:Amphotericin B",
"country": "Canada",
"delete": false,
"doi": null,
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"issn_linking": "1201-9712",
"issue": "25()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "HIV infection; Relapse; Treatment; Visceral leishmaniasis",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000981:Antiprotozoal Agents; D023241:Antiretroviral Therapy, Highly Active; D060085:Coinfection; D015658:HIV Infections; D006801:Humans; D007194:India; D007898:Leishmaniasis, Visceral; D008297:Male; D010767:Phosphorylcholine; D012008:Recurrence; D016896:Treatment Outcome",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "204-6",
"pmc": null,
"pmid": "24927662",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple relapses of visceral leishmaniasis in a patient with HIV in India: a treatment challenge.",
"title_normalized": "multiple relapses of visceral leishmaniasis in a patient with hiv in india a treatment challenge"
} | [
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"companynumb": "IN-GILEAD-2014-0110777",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "EMTRICITABINE"
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{
"abstract": "Background: Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm diagnosed in young children, characterized by somatic or germline mutations that lead to hyperactive RAS signaling. The only curative option is hematopoietic stem cell transplantation (HSCT). Recent data showing that aberrant DNA methylation plays a significant role in pathogenesis and correlates with clinical risk suggest a possible benefit of hypomethylating agents (HMA) in JMML treatment. Aim: The aim is to report the results of HMA-based therapy with 5-azacytidine (AZA) in three JMML patients treated in a single center, non-participating in EWOG-MDS study. Methods: The diagnosis and treatment response were evaluated according to international consensus criteria. AZA 75 mg/m2 intravenous (i.v.) was administered once daily on days 1-7 of each 28-day cycle. All patients were monitored for hematologic response, spleen size, and evolution of extramedullary disease. Targeted next generation sequencing (NGS) were performed after the 3rd AZA cycle and before SCT to evaluate the molecular alterations and genetic response. Results: Three patients diagnosed with JMML were treated with AZA (off-label indication) in Pediatric Department of Fundeni Clinical Institute, Bucharest, Romania between 2017 and 2019. There were two females and one male with median age 11 months, range 2-16 months. The cytogenetic analysis showed normal karyotype in all patients. Molecular analysis confirmed KRAS G13D mutation in two patients and NRAS G12D mutation in one patient. The clinical evaluation showed important splenomegaly and hepatomegaly in all 3 pts. One patient received AZA for early relapse after haploidentical HSCT and the other two patients received upfront AZA, as bridging therapy before HSCT. After HMA therapy, 2/3 patients achieved clinical partial response (cPR), 1/3 had clinical stable disease (cSD) and all had genetic stable disease (gSD) after 3 cycles and were able to receive the planned HSTC. One patient achieved clinical and genetic complete response before HSCT. During 22 cycles of AZA there were only four adverse events but only one determined dose reduction and treatment delay. Conclusion: Our data show that AZA monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT.",
"affiliations": "Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.;Department of Stem Cell Transplantation, Coltea Hospital, Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.;Cellular and Molecular Pathology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania.;Cellular and Molecular Pathology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania.;Molecular Virology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania.;Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.;Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.;Molecular Virology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania.;Personal Genetics-Medical Genetics Center, Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.",
"authors": "Marcu|Andra|A|;Colita|Andrei|A|;Radu|Letitia Elena|LE|;Jercan|Cristina Georgiana|CG|;Bica|Ana Maria|AM|;Asan|Minodora|M|;Coriu|Daniel|D|;Tanase|Alina Daniela|AD|;Diaconu|Carmen C|CC|;Mambet|Cristina|C|;Botezatu|Anca|A|;Pasca|Sergiu|S|;Teodorescu|Patric|P|;Anton|Gabriela|G|;Gurban|Petruta|P|;Colita|Anca|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.00484",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00484\nOncology\nCase Report\nSingle-Center Experience With Epigenetic Treatment for Juvenile Myelomonocytic Leukemia\nMarcu Andra 12† Colita Andrei 34† Radu Letitia Elena 12 Jercan Cristina Georgiana 12 Bica Ana Maria 1 Asan Minodora 1 Coriu Daniel 14 Tanase Alina Daniela 15 Diaconu Carmen C. 6 Mambet Cristina 6 Botezatu Anca 7 Pasca Sergiu 8 Teodorescu Patric 910 Anton Gabriela 7 Gurban Petruta 11 Colita Anca 12* 1Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania\n2Department of Pediatrics, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania\n3Department of Stem Cell Transplantation, Coltea Hospital, Bucharest, Romania\n4Department of Hematology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania\n5Department of Hematology, Titu Maiorescu University of Medicine, Bucharest, Romania\n6Cellular and Molecular Pathology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania\n7Molecular Virology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania\n8Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania\n9Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania\n10Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj Napoca, Romania\n11Personal Genetics-Medical Genetics Center, Bucharest, Romania\nEdited by: Liren Qian, Sixth Medical Center of PLA General Hospital, China\n\nReviewed by: Alina-Andreea Zimta, Iuliu Haţieganu University of Medicine and Pharmacy, Romania; Gabriel Ghiaur, Johns Hopkins Medicine, United States\n\n*Correspondence: Anca Colita ancacolita@yahoo.comThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work and share first authorship\n\n\n09 4 2020 \n2020 \n10 48412 2 2020 17 3 2020 Copyright © 2020 Marcu, Colita, Radu, Jercan, Bica, Asan, Coriu, Tanase, Diaconu, Mambet, Botezatu, Pasca, Teodorescu, Anton, Gurban and Colita.2020Marcu, Colita, Radu, Jercan, Bica, Asan, Coriu, Tanase, Diaconu, Mambet, Botezatu, Pasca, Teodorescu, Anton, Gurban and ColitaThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm diagnosed in young children, characterized by somatic or germline mutations that lead to hyperactive RAS signaling. The only curative option is hematopoietic stem cell transplantation (HSCT). Recent data showing that aberrant DNA methylation plays a significant role in pathogenesis and correlates with clinical risk suggest a possible benefit of hypomethylating agents (HMA) in JMML treatment.\n\nAim: The aim is to report the results of HMA-based therapy with 5-azacytidine (AZA) in three JMML patients treated in a single center, non-participating in EWOG-MDS study.\n\nMethods: The diagnosis and treatment response were evaluated according to international consensus criteria. AZA 75 mg/m2 intravenous (i.v.) was administered once daily on days 1–7 of each 28-day cycle. All patients were monitored for hematologic response, spleen size, and evolution of extramedullary disease. Targeted next generation sequencing (NGS) were performed after the 3rd AZA cycle and before SCT to evaluate the molecular alterations and genetic response.\n\nResults: Three patients diagnosed with JMML were treated with AZA (off-label indication) in Pediatric Department of Fundeni Clinical Institute, Bucharest, Romania between 2017 and 2019. There were two females and one male with median age 11 months, range 2–16 months. The cytogenetic analysis showed normal karyotype in all patients. Molecular analysis confirmed KRAS G13D mutation in two patients and NRAS G12D mutation in one patient. The clinical evaluation showed important splenomegaly and hepatomegaly in all 3 pts. One patient received AZA for early relapse after haploidentical HSCT and the other two patients received upfront AZA, as bridging therapy before HSCT. After HMA therapy, 2/3 patients achieved clinical partial response (cPR), 1/3 had clinical stable disease (cSD) and all had genetic stable disease (gSD) after 3 cycles and were able to receive the planned HSTC. One patient achieved clinical and genetic complete response before HSCT. During 22 cycles of AZA there were only four adverse events but only one determined dose reduction and treatment delay.\n\nConclusion: Our data show that AZA monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT.\n\njuvenile myelomonocytic leukemiamutationepigeneticsmethylationazacytidinehematopoietic stem cell transplantation\n==== Body\nIntroduction\nJuvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative/myelodysplastic neoplasm of early infancy and childhood defined by an excessive production of mature and immature myeloid cells, predominantly of monocytic and granulocytic lineages (1, 2). Therapeutic approaches range from watchful monitoring to allogeneic hematopoietic stem cell transplantation (HSCT) performed in early stages (3). Clinical symptoms result from hematopoietic insufficiency and leukemic infiltration of various organs, such as spleen, liver, skin, lung, and gastrointestinal tract (4). Conventional cytogenetics studies indicate monosomy 7 in up to 25% of JMML patients and other abnormalities in 10% of cases. However, a normal karyotype is diagnosed in about two-thirds of patients (5–7). Strikingly, many JMML children with a normal karyotype exhibit an elevated level of fetal hemoglobin (HbF) (8).\n\nThe genetic landscape of JMML is dominated by somatic or germline mutations that lead to hyperactive RAS signaling (9). Five molecular alterations of RAS pathway were described in association with five JMML genetic subtypes, that have distinct clinical and hematological features (1). Three subtypes, covering 55–60% of patients, involve heterozygous somatic activating mutations in PTPN11, NRAS, and KRAS genes (1, 9). The other two subtypes (20–30% of JMML cases) occur in patients with underlying constitutional diseases caused by germline mutations in the RAS pathways (RASopathies): neurofibromatosis type 1 (NF1) and Noonan-like “CBL syndrome,” respectively. Hematological disorders develop due to the acquired loss of heterozygosity of the constitutionally affected NF1 or CBL tumor suppressor genes in the hematopoietic progenitors (4, 10, 11). In rare cases of JMML that lack the above-mentioned mutations, heterozygous somatic RRAS mutations have been reported as disease drivers (12). In addition to RAS pathway mutations, whole-exome sequencing has identified secondary molecular events in ~50% of patients. These alterations, including also mutations in epigenetic regulation genes (EZH2, ASXL1, DNMT3A), might impact clinical outcome and therapeutic decisions (1). Interestingly, JMML displays a unique linear pattern of disease progression. As shown previously, all mutations present at diagnosis are acquired by a single dominant clone that is consistently detected at relapse. Also, Stieglietz et al. have reported that the number of somatic mutations identified at diagnosis influences the survival rate, while the type of RAS pathway mutations that does not represent an independent prognostic factor (13).\n\nAberrant DNA methylation is another factor related to adverse clinical outcome in JMML patients. European Working Group on MDS in Childhood (EWOG-MDS) published in 2011 a study on 127 JMML patients, evaluating DNA methylation at 14 loci through quantitative mass spectrometry, describing CpG island hypermethylation in the BMP4, CALCA, CDKN2B, or RARB promoter regions as being the best predictor of relapse after HSCT (14). Similarly, different other studies showed that DNA hypermethylation is connected to clinical risk (15–18). Recently, three JMML epigenetic subgroups based on DNA methylation profiling were identified. The low methylation cluster is defined by the presence of Noonan syndrome, CBL mutations and the majority of NRAS mutations, having a favorable outcome. The intermediate methylation cluster consists of patients with numeric aberration of chromosome seven (monosomy) and somatic KRAS mutations. The high methylation subgroup includes patients displaying somatic PTPN11 mutation, low platelet count, elevated HbF, and diagnosis established after the age of two. This subgroup was specifically associated with a higher rate of disease relapse and dismal prognosis (2).\n\nThe aberrant DNA methylation patterns described in JMML create a premise for the clinical use of hypomethylating agents, such as 5-azacytosine (azacytidine) and 2′-deoxy-5-azacytidine (decitabine). Once entering the cell, azacytidine is activated through consecutive ATP-dependent phosphorylation steps. Eighty to ninety percentage of azacytidine is incorporated into RNA leading to apoptosis (19) 10–20% of azacytidine is integrated into DNA, permanently inhibiting DNA methyltransferase, suppressing its function, and causing its degradation. Methylation marks are lost during DNA replication, reversing silenced tumor suppressor genes and recovering proliferation, and apoptosis control (20–22). Azacytidine induces specific immune responses through azacytidine-induced immune genes and inhibition of regulatory T cells (23–25).\n\nCase Presentations\nTwo girls and one boy, median age 11 months, range 2–16 months, were diagnosed and treated with azacytidine (off label indication) in the Pediatric Department of Fundeni Clinical Institute, Bucharest, Romania, between 2017 and 2019. On admission, mean hemoglobin (Hb) was 8,8 g/dl (range 7,1–10,2 g/dl), mean white blood cell (WBC) count was 22,576 × 109/L (range 19,75–28,21 × 109/L), mean monocyte count was 7,1 × 109/L (range 6,2–8,4 × 109/L) and mean platelet count was 65 × 109/L (range 46–77 × 109/L). All patients presented with blasts in the bone marrow 4–15% (mean 10%), while only 1 patient presented with 5% myeloid blasts in peripheral blood. The cytogenetic analysis showed normal karyotype, while targeted next-generation sequencing (NGS) revealed KRAS G13D mutation in two patients and NRAS G12D mutation in one patient. All patients had important splenomegaly, with mean spleen size of 7 cm (range 3–10 cm) under the costal margin and hepatomegaly with mean liver size of 5 cm (range 4–8 cm) under costal margin. One patient received azacytidine for early relapse after hematopoietic stem cell transplantation (HSCT) and the other two received upfront azacytidine, as bridging therapy before HSCT (Table 1).\n\nTable 1 Response to azacytidine in children with JMML.\n\n\tDisease status\tSex\n\nAge\n\n(months)\tCytogenetics\tMutational group\tNo. of AZA cycles\tConcomitant\n\ntreatment\tResponse after 3rd AZA\tResponse before HSCT\tHSCT\n\nnumber type\tStatus\n\nPost-transplant\tFollow-up (months)\t\n\t\t\t\t\t\t\tClinic\tGenetic\tClinic\tGenetic\t\t\t\t\nCase 1\tRelapse after 1st HSCT\tM\n 11\t46, XY\n FISH−7/del7q negative\tNRAS\t8\t6MP\tcPR\tgSD\tcPR\tgSD\t2\n Haplo\n MUD\tAlive\n gCR\t46\t\nCase 2\tDe novo JMML\tF\n 2\t46, XX\n FISH−7/del7q negative\tKRAS\t8\tno\tcPR\tgSD\tcCR\tgCR\t1\nMUD\tAlive\n gCR\t14\t\nCase 3\tDe novo JMML\tF\n 16\t46, XX\n FISH−7/del7q negative\tKRAS\t6\tno\tcSD\tgSD\tcPD\tgSD\t1\nMSD\tAlive\n gSD\t12\t\n6MP, 6 mercaptopurin; cPR, clinical partial remission; cSD, clinical stable disease; cCR, clinical complete remission; cPD, clinical progressive disease; gCR, genetic complete response; gSD, genetic stable disease; MUD, matched unrelated donor; MSD, matched sibling donor; mo, month; F, female; M, male; haplo, haploidentical HSCT.\n\nJMML diagnosis and therapy response were evaluated according to international consensus criteria (Table 2) (26). Azacytidine 75 mg/m2 i.v. was administered once daily, on days 1–7 of each 28-day cycle. All patients were monitored for hematologic response, spleen size, and evolution of extramedullary disease. NGS at diagnosis and real-time PCR were performed in order to identify the molecular alterations and assess the genetic response after first three cycles and pre-HSCT. Patients were monitored for adverse events (AEs).\n\nTable 2 Variables for evaluation of response to therapy in JMML (26).\n\nVariables for response\t\tDefinition of response\tDefinition of disease\n\nprogression or relapse\n\n(applicable to all patients)\t\n\tAssessment of CR and PR is feasible if the following are present before therapy\tCR\tPR\tPD\t\n1) WBC count\t>20 × 109/L\t3.0–15.0 × 109/L\tDecreased by ≥50% over pre-treatment but still over >15 × 109/L\tIncrease by ≥50% and ≥20 × 109/L\t\n2) Myeloid and erythroid precursors and blasts in PB*\t≥5%\t0–1%\tDecreased by ≥50% over pre-treatment but still ≥ 2%\tIncrease from the baseline: <5%: ≥50% increase and ≥5%≥5%: ≥50% increase of total % of myeloid and erythroid precursors and blasts\t\n3) Platelet count\t<100 × 109/L\t≥100 × 109/L\tFor patients starting with ≥ 20 × 109/L platelets: absolute increase of ≥30 × 109/L For patients starting with <20 × 109/L platelets: increase by ≥100% and >20 × 109/L\tDevelopment of transfusion dependency or, if patients have the baseline of the platelet count ≥30 × 109/L, decrease by ≥100% and <100 × 109/L\t\n4) BM blasts\t≥5%\t<5%\tDecreased by ≥50% over pre-treatment but still ≥5% baseline\tIncrease from baseline; <5%: ≥50% increase and ≥5%≥5%: ≥50% increaseof BM blasts\t\n5) Spleen size\n Clinical evaluation\t≥2 cm under\tNo splenomegaly\t50% decrease by cm under the costal margin\tIncrease by ≥100% if baseline <4cm from under the costal margin≥50% if baseline 5-10 cm>30% if baseline >10 cm\t\nUltrasonography\tLength of spleen≥150% of upper limit of normal range\tNo splenomegaly\t>25% decrease by length, but still splenomegaly\tIncrease by≥25% of length\t\n6) Extramedullary disease#\tExtramedullary leukemic infiltration\tNo evidence of extramedullary leukemic infiltration in any organ\t\tWorsening or new lesions of extramedullary leukemic infiltration\t\n7) Cytogenetic response\tSomatic cytogenetic abnormality detected\tNormal karyotype\t\tReappearance or additional acquirement of cytogeneticabnormalities\t\n8) Molecular response\tSomatic genetic anomalies detected**\tAbsence of somatic genetic anomalies\t\tReappearance or additional acquirement of JMML-specificsomatic gene abnormalities\t\n9) Chimerism response (only for patients after HSCT)\t>15% autologous cells after allo-HSCT\tComplete donor chimerism\t\t50% increase and >5% increase of autologous cells and >5%\t\nCR, complete response; PR, partial response; PD, progressive disease; WBC, white blood cell; PB, peripheral blood; BM, bone marrow.\n\n* Myeloid precursors include promyelocytes, myelocytes and metamyelocytes. The myeloid and erythroid precursors and blasts in PB are given as percentage of the total nucleated cells in PB (WBC including erythroblasts).\n\n** In NF-1, PTPN11, NRAS, KRAS, or CBL, thus the mutations are thought to be initiating. In patients with germ-line NF-1, PTPN11 or CBL mutation, only acquired mutations can be evaluated for response and relapse after therapy. The germ-line mutation remains even if patients achieved complete molecular response.\n\n# Extramedullary disease includes infiltration of skin, lung, and, very rarely, cranial nerves or central nervous system.\n\nThe first case is of an 11-month-old boy diagnosed with NRAS-JMML, treated with 6-mercaptopurine and low-dose cytarabine, while searching for an HLA compatible donor for an allogeneic HSCT. Since the donor was not available at clearance timepoint and considering the emergency for transplantation, he underwent a haploidentical HSCT (haplo HSCT) from his father, with melphalan-fludarabine conditioning regimen, post-transplant cyclophosphamide, and immunosuppressive therapy for graft-vs. -host disease (GvHD) prophylaxis. After engraftment, the chimerism analysis performed on day +19 showed mixed results (53% chimerism from donor). Despite stopping immunosuppression and infusion of donor lymphocytes (DLI), followed by skin and gastrointestinal grade 4 GvHD and severe lung disease, there was a progressive loss of donor cells. Therapy with azacytidine was initiated while a new work-up for second HSCT was started. The infant achieved clinical partial remission (cPR) after three courses of azacytidine and maintained the same status after eight courses. After 1 year, a 9/10 unrelated donor HSCT was performed, with busulfan-cyclophosphamide-melphalan-ATG conditioning. Chimerism analysis on day +24 showed 100% donor cells. He is now at 2 years after 2nd transplant, with very good clinical condition, no chronic GvHD, normal blood count, full donor chimerism, and full immune recovery.\n\nThe second case is of a 2-month-old girl diagnosed with KRAS-JMML, who was started in first line therapy with azacytidine. She tolerated azacytidine courses very well, without hematological toxicities. After three courses, she obtained cPR (normal WBC, absent myeloid/erythroid precursors or blasts in PB, normal PLT count, no blasts in BM, more than 50% reduction in spleen and liver size) and complete clinical remission (cCR) after eight courses. Targeted next-generation sequencing (NGS) revealed the presence of KRAS G13D mutation with 21% variant allele frequency (VAF) at diagnosis. Molecular monitoring by real-time PCR indicated a decrease of mutational load after three courses and genetic complete remission (gCR) after eight courses. 10/10 MUD HSCT, with thiotepa-treosulfan-fludarabine-ATG conditioning has been performed.\n\nThe third case is of a 16-month-old girl with KRAS-JMML, who was started on upfront azacytidine. The patient's first clinical and hematological abnormalities were noted at 6 months, but the diagnosis was made 10 months later, when she presented with massive hepato-splenomegaly and respiratory manifestations due to leukemic infiltration. Targeted NGS at diagnosis identified KRAS G13D mutation with a VAF of 38%. She received six courses of azacytidine as bridging therapy for matched sibling donor HSCT. Evaluation after first three courses showed clinical stable disease (cSD) (normal WBC, no blasts in PB or in the BM, but the patient still presented massive hepato-splenomegaly, and thrombocytopenia). She developed pneumonia complicated with lung abscess and received antibiotic treatment for 28 days, with 2 weeks delay in azacytidine administration, and loss of therapeutic response. After six courses of azacytidine we noted clinical progressive disease (cPD) based on the development of platelet transfusion dependency and increase of spleen size after initial reduction. The molecular monitoring confirmed gSD. Matched sibling donor HSCT with thiotepa-treosulfan-fludarabine conditioning has been performed.\n\nWe report 4 AEs (fever CTCAE grade 4 – 1 patient, diarrhea CTCAE grade 2 - 2 patients, urticaria and rash grade 2 CTCAE - 1 patient) during 22 cycles of azacytidine, with dose reduction for one course and delay for the next course because of pneumonia. The hematologic monitoring during azacytidine cycles showed normal Hb value, normal WBC, and differential count for all patients, as well as normal PLT count for two of them after the first three courses. No hematologic toxicities were reported in our series (Figure 1). All AEs were managed with standard supportive care and without modifications or delay in azacytidine treatment.\n\nFigure 1 Hematology parameters in dynamics for the patients. Case 2: At diagnosis: KRAS G13D mutation with 21% variant allele frequency (VAF). Molecular monitoring by NGS after 3 courses of therapy indicated a decrease of mutational load to 12%. Molecular monitoring by NGS after 8 courses of therapy indicated complete molecular remission. After HSCT: complete molecular remission. Case 3: At diagnosis: KRAS G13D mutation with a VAF of 38%. Molecular monitoring by NGS after 3 courses of therapy: mutational load 37.5%. Molecular monitoring by NGS at the end of therapy: VAF 35.2%. After HSCT: VAF 2.5%.\n\nDiscussions\nTreatment with HMA aims for clinical and hematological response, transfusion independency, and prolonged survival after HSCT, azacytidine being one of the most used agents. Acknowledging its tolerable toxicity and cytoreductive activity, azacytidine becomes a suitable choice for bridging treatment before HSCT, as well as strategy for second HSCT or palliation (27). JMML is challenging and difficult to treat, the only curative option being HSCT. In its absence, the median survival time from diagnosis is <1year (28).\n\nThe published data on HMA therapy in relapsed patients after transplantation is limited to three cases. Cseh et al. (27) reported that azacytidine is correlated with partial response during three cycles in one patient, but all three patients eventually progressed and died. Still, we report a NRAS-JMML patient who relapsed after haploidentical HSCT and didn't respond to DLI, despite severe, grade 4 GvHD. He received eight cycles of azacytidine with clinical partial response. After 2nd unrelated HSCT, the patient obtained complete remission, with full donor chimerism. He is alive, fully recovered at 2 years after the 2nd transplant and, in our knowledge, is the first patient showing a favorable response to azacytidine in relapse after HSCT.\n\nFurlan et al. (29) reported a JMML patient with monosomy 7 and KRAS mutation who received upfront azacytidine. Good clinical response was documented, with regression of splenomegaly, and monocyte count after the first course of treatment and disappearance of molecular alterations after cycle five (for monosomy 7) and seven (for KRAS mutation). The eight courses of azacytidine were followed by allogeneic HSCT with complete remission and disease-free survival at 5 years follow-up. Consequently, further trials were open to evaluate remission response at three cycles of therapy and to establish the remission persistence until transplantation. Cseh et al. (27) mentioned three complete clinical, cytogenetic and/or molecular remissions out of nine patients with JMML who received azacytidine before HSCT. Two of the patients had somatic PTPN11 mutation and one had KRAS mutation, thus showing that certain patients respond to this treatment. Although azacytidine may induce complete clinical, cytogenetic and/or molecular remission before allogeneic HSCT, complete remission has not been maintained without transplant.\n\nInterim analysis of the prospective AZA-JMML-001 study evaluating upfront azacytidine in JMML (30) reported 18 patients with JMML (13 PTPN11-, 3 NRAS-, 1 KRAS-, 1 NF1-mutated), classified in DNA methylation classes (MC): high - 11, intermediate (int) – 5 or low for two patients. 11 patients (61%) were in cPR after three cycles of azacytidine, while seven had PD at same treatment stage or prior. All seven patients from the int/low MC and 4/11 from high MC achieved cPR. Seventeen patients received HSCT at a median of 58 days (37–518 days) from last azacytidine dose. Fourteen patients were leukemia-free at a median follow-up of 15.7 months (0.1–31.7 months) after HSCT. Two patients from the high MC relapsed after allograft. 16/18 patients were alive at a median follow-up of 19.8 months (2.6–37.3 months) from diagnosis. One patient discontinued HSCT prior to cycle 3 azacytidine and died from PD. One non-responder patient died from transplant-related causes.\n\nIn our case-series we rport cPR at cycle 3 azacytidine in all patients, with gSD. After eight and, respectively, six courses of HMA treatment, we report cCR for one patient, cPR for one patient and cPD for one patient, while genetic response was complete for only one patient before transplantation. Four AEs were reported during 22 cycles of azacytidine, but only one determined dose reduction and treatment delay. Regarding the failure of engraftment for the first transplant for the first patient, it should be mentioned that it was not a failure to engraft, but engraftment with mixed progressive chimerism, followed by complete receptor hematopoiesis, probably in the context of important splenomegaly.\n\nConclusions\nThe heterogeneity of disease evolution in different patients cannot be well-explained yet, though the importance of methylation groups and secondary mutations has already been established.\n\nIn accordance with international data, our patient series shows that azacytidine monotherapy is well-tolerated in patients with de novo JMML, as well as in patients with relapse after previous treatments, even transplantation. Although the long-term advantage of azacytidine before transplant remains to be fully assessed, responses show it is effective in JMML and provides clinical benefit without severe adverse events.\n\nEthics Statement\nThe study was reviewed and approved by the Ethics Committee of the Fundeni Clinical Institute. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAll authors have read and approved the manuscript and contributed to data gathering. AM, AndC, and AncC wrote the manuscript.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer A-AZ declared a shared affiliation, with no collaboration, with several of the authors, PT and SP, to the handling editor at the time of review.\n\nFunding. We gratefully acknowledge the funding from the project Competitiveness Operational Programme (COP) A1.1.4. ID: P_37_798 MyeloAL-EDiaProT, Contract 149/26.10.2016 (SMIS: 106774), MyeloAL Project.\n==== Refs\nReferences\n1. Niemayer CM \nJMML genomics and decisions\n. Hematol Am Soc Hematol Educ Program. (2018 ) 2018 :307 –12\n. 10.1182/asheducation-2018.1.307 \n2. Lipka DB Witte T Toth R Yang J Wiesenfarth M N?llke P . RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia\n. Nat. Commun . (2017 ) 8 :2126 . 10.1038/s41467-017-02177-w 29259247 \n3. Niemeyer CM Flotho C \nJuvenile myelomonocytic leukemia: who's the drive at the wheel?\n\nBlood . (2019 ) 133 :1060 –70\n. 10.1182/blood-2018-11-844688 30670449 \n4. 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(2014 ) 2 :25 . 10.3389/fped.2014.00025 24734223 \n29. Furlan I Batz C Flotho C Mohr B Lübbert M Suttorp M Niemeyer CM \nIntriguing response to azacytidine in a patient with juvenile myelomonocytic leukemia and monosomy 7\n. Blood . (2009 ) 113 :2867 –8\n. 10.1182/blood-2008-12-195693 19299654 \n30. Niemeyer CM Flotho C Lipka DB Starý J R?ssig C Baruchel A \nUpfront azacitidine (AZA) in juvenile myelomonocytic leukemia (JMML): interim analysis of the prospective AZA-JMML-001 study\n. J Clin Oncol. (2019 ) 37 (Suppl. 15 ):10031 \n10.1200/JCO.2019.37.15_suppl.10031\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "azacytidine; epigenetics; hematopoietic stem cell transplantation; juvenile myelomonocytic leukemia; methylation; mutation",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "484",
"pmc": null,
"pmid": "32328464",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25838281;26888021;17998812;25147919;25552679;30504325;24162015;14521811;17339880;9523301;24705357;29279013;19299654;21406719;21239819;24583822;24734223;26457647;30670449;20015894;18302710;25564399;27330573;19571318;29259247;26720758;27158276;26891149",
"title": "Single-Center Experience With Epigenetic Treatment for Juvenile Myelomonocytic Leukemia.",
"title_normalized": "single center experience with epigenetic treatment for juvenile myelomonocytic leukemia"
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"companynumb": "RO-MYLANLABS-2020M1052094",
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"abstract": "Immune check point inhibitor (ICI) therapy can be a potentially effective salvage treatment for anaplastic thyroid cancer (ATC) with progression despite standard of care therapies. We report a case of unresectable treatment-naïve ATC showing a dramatic and durable response to first-line pembrolizumab therapy. A 69-year-old male presented with a large, right-sided neck mass associated with compressive symptoms. A neck ultrasound showed a large, right-sided, and highly suspicious thyroid nodule. A fine needle aspiration (FNA) biopsy revealed tumor cells consistent with ATC that were positive for PD-L1, with an expression score of >95% and negative for the BRAF V600E mutation. Imaging studies were negative for distant metastases. The disease was declared surgically inoperable, and the patient declined chemotherapy/radiation therapy (XRT), but agreed to ICI therapy with intravenous pembrolizumab 200 mg every three weeks. The patient has received 25 doses of pembrolizumab to date, with rapid resolution of symptoms and a significant reduction in tumor size. He remains alive without disease progression 18 months since initial diagnosis.",
"affiliations": "Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University and Arthur G. James Cancer Center, Columbus, OH 43235, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Department of Pathology, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH, USA.;Department of Otolaryngology-Head and Neck Surgery, The Ohio State University James Cancer Hospital and Solove Research Institute, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University and Arthur G. James Cancer Center, Columbus, OH 43235, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.",
"authors": "Nabhan|Fadi|F|https://orcid.org/0000-0003-3810-0050;Kander|Elizabeth|E|;Shen|Rulong|R|;Agrawal|Amit|A|;Sukrithan|Vineeth|V|;Zhou|Ye|Y|;Goyal|Ashima|A|;Roll|Katie|K|;Shah|Manisha|M|;Konda|Bhavana|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/5521649",
"fulltext": "\n==== Front\nCase Rep Endocrinol\nCase Rep Endocrinol\nCRIE\nCase Reports in Endocrinology\n2090-6501\n2090-651X\nHindawi\n\n10.1155/2021/5521649\nCase Report\nPembrolizumab in a Patient with Treatment-Naïve Unresectable BRAF-Mutation Negative Anaplastic Thyroid Cancer\nhttps://orcid.org/0000-0003-3810-0050\nNabhan Fadi fadi.nabhan@osumc.edu\n1\nKander Elizabeth 2\nShen Rulong 3\nAgrawal Amit 4\nSukrithan Vineeth 2\nZhou Ye 2\nGoyal Ashima 2\nRoll Katie 1\nShah Manisha 2\nKonda Bhavana 2\n1Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University and Arthur G. James Cancer Center, Columbus, OH 43235, USA\n2Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA\n3Department of Pathology, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH, USA\n4Department of Otolaryngology—Head and Neck Surgery, The Ohio State University James Cancer Hospital and Solove Research Institute, Columbus, OH, USA\nAcademic Editor: Désirée Deandreis\n\n2021\n22 5 2021\n2021 55216499 2 2021\n12 5 2021\nCopyright © 2021 Fadi Nabhan et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nImmune check point inhibitor (ICI) therapy can be a potentially effective salvage treatment for anaplastic thyroid cancer (ATC) with progression despite standard of care therapies. We report a case of unresectable treatment-naïve ATC showing a dramatic and durable response to first-line pembrolizumab therapy. A 69-year-old male presented with a large, right-sided neck mass associated with compressive symptoms. A neck ultrasound showed a large, right-sided, and highly suspicious thyroid nodule. A fine needle aspiration (FNA) biopsy revealed tumor cells consistent with ATC that were positive for PD-L1, with an expression score of >95% and negative for the BRAF V600E mutation. Imaging studies were negative for distant metastases. The disease was declared surgically inoperable, and the patient declined chemotherapy/radiation therapy (XRT), but agreed to ICI therapy with intravenous pembrolizumab 200 mg every three weeks. The patient has received 25 doses of pembrolizumab to date, with rapid resolution of symptoms and a significant reduction in tumor size. He remains alive without disease progression 18 months since initial diagnosis.\n==== Body\n1. Introduction\n\nATC is a rare and aggressive cancer comprising 1.7% of all thyroid cancers [1] that disproportionately accounts for about one-half of thyroid cancer-related deaths [2]. The disease is uniformly lethal, with a median overall survival (OS) of 3-4 months [3]. However, recent reports indicate a trend towards improved survival that is attributed to the development of more effective therapies [4]. Many patients have advanced disease at the time of diagnosis, and 46% of patients had distant metastases at diagnosis in one study [5]. The frequent coexistence of ATA with well-differentiated thyroid cancer (DTC) in tumor specimens, in conjunction with the presence of several shared genomic alterations with DTC suggests that ATC can result from dedifferentiation of DTC. However, the genomic profile of ATC is more complex, and some appear to also arise without evidence of dedifferentiation from DTC [6]. Additionally, ATC has higher mutational burden and genomic disruption than DTC and poorly differentiated thyroid cancer (PDTC) reflecting the significantly higher aggressiveness [7]. Genomic disruption and the acquisition of additional mutations might make ATC an attractive target for immune check point inhibitor therapies de novo. Traditional treatment of ATC depends on the extent of disease at presentation. Stage IVA and resectable stage IVB disease are treated with surgery and external radiation with or without chemotherapy. Chemotherapy and radiation can be considered for unresectable stage IVB and stage IVC patients [2]. The recent FDA approval of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in advanced BRAF V600E mutated ATC has provided an additional treatment option for this subset of patients [8]. However, progression of disease is frequent which calls for additional therapeutic options. While immunotherapy has been tried as a salvage treatment of patients with ATC [9, 10], there is limited data on its use as a first-line therapy [11]. Here, we report such a case and review-related literature.\n\n2. Case\n\nA 69-year-old male presented with a 2-month history of dysphagia, dysphonia, pain in the right neck and right ear, and a ten-pound weight loss. Thyroid function tests were normal. A physical examination revealed a large, right-sided neck mass. Confirmed by a neck ultrasound, the mass was hypoechoic with macrocalcification and ill-defined borders measuring at least 5.5 cm. A fine needle aspiration (FNA) biopsy at an outside institution revealed malignancy best classified as primary thyroid cancer with high grade and spindle cell origin with suspicion of anaplastic thyroid cancer (ATC). The patient was then referred to our institution for further management. Laryngoscopy revealed right vocal cord paralysis. A CT scan of the neck showed a large, right thyroid lobe mass measuring 7.5 × 4.1 cm, displacing the larynx and trachea to the left and encasing the internal carotid artery by at least 180° (Figures 1 and 2 ). CT scans of the chest, abdomen, and pelvis and an MRI scan of the brain showed no definitive evidence of distant metastases. Serum thyroglobulin (Tg) level was at 41.5 ng/ml (Beckman Coulter assay with functional sensitivity of 0.1) with undetectable anti-Tg antibodies (Beckman Coulter assay with a functional sensitivity of 0.9). A repeat FNA biopsy of the right thyroid mass revealed discohesive atypical pleomorphic tumor cells consistent with ATC (Figure 3). Immunocytochemistry staining of the both FNA samples were focally positive for TTF 1, variably positive for thyroglobulin and PAX8, and negative for calcitonin, CEA, SOX-10, and p63. PD-L1 22C3 pharmDx—performed on Dako Autostainer Link 48—was positive for high PD-L1 expression with tumor proportion score (TPS) >95% (Figure 4). Molecular testing of the tumor was negative for BRAF (V600/601), KRAS (Exon 2/3/4), and NRAS mutations. Next generation sequencing of the tumor could not be done due to inadequate tissue. Liquid biopsy revealed no reportable genomic alterations. However, this was performed while the patient was on pembrolizumab treatment and not before its initiation. The tumor was deemed unresectable, and the patient declined chemotherapy and radiation therapy. Given the high PD-L1 expression, off-label intravenous pembrolizumab at 200 mg every three weeks was initiated with patient consent and absence of clinical trial accessible to the patient. One week after the first dose, the patient had significant improvement in dysphagia and resolution of pain in the right neck and ear. Restaging scans after four cycles of treatment (one cycle equaling three weeks) revealed a partial response per RECIST v 1.1 (48% decrease in the size of the tumor) (Figures 5 and 6 ). He continues to tolerate the treatment well without adverse events, except for the development of immune-mediated thyroiditis. After an initial thyrotoxic phase, the thyroiditis has progressed toward persistent hypothyroidism and has required thyroid hormone replacement therapy. The patient has received 25 doses of pembrolizumab with continued reduction in size of tumor with most recent scans performed showing approximately 66% reduction in tumor from pretherapy (Figures 7 and 8 ). The tumor has become resectable but with remaining significant potential high functional morbidity such as possible laryngopharyngectomy and tracheal and esophageal resection given its location. However, the patient continues to decline surgical therapy.\n\n3. Discussion\n\nThe evolving understanding of the pathogenesis of ATC at the molecular level has provided insight into its management. ATC differs from well-differentiated thyroid cancer by having a higher mutation burden [7]. However, as stated before, many ATC arise from dedifferentiation of DTC. Genomically, ATC is considered to be composed of three types: one that resembles papillary thyroid cancer (PTC) and has a high prevalence of the BRAF V600E mutation; second that resembles follicular thyroid cancer (FTC) and has a high prevalence of the NRAS mutation; and third that has less identifiable genes and appears to resemble hurthle cell thyroid cancer (HCTC) [12]. In ATC patients with the BRAF V600E mutation, which is estimated to be present in 41% of patients [12], the U.S. Food and Drug Administration (FDA) approved the combination of BRAF plus MEK inhibitors (dabrafenib and trametinib, respectively). Subbiah and colleagues [8] reported 16 ATC patients with the BRAF V600E mutation that were treated with dabrafenib and trametinib with an overall response rate of 69% at a median follow-up of 47 weeks.\n\nImmunotherapy has been tried as a treatment for ATC patients who have progressed on other therapies. Iyer and colleagues [9] evaluated 12 patients with ATC on combination therapy of pembrolizumab with tyrosine kinase inhibitors (TKI) where there was a progression of disease on TKI. With combination therapy and a median treatment of 5.6 months, there was a partial response in 42% (5/12) of patients and stable disease in 33% (4/12) of patients [9]. Cabanillas and colleagues [10] reported a case of a patient with ATC where pembrolizumab was used after progression of disease with chemotherapy and dabrafenib/trametinib. The treatment was for approximately ten months, with interruption due to surgery and external radiation, and the patient was alive 12 months after treatment [10]. An ongoing phase 2 study (ATLEP) of the combination of lenvatinib and pembrolizumab showed an interim response rate of 37.5% (6/16; all partial responses) with the rest experiencing stable disease [13]. A phase 2 study of spartalizumab, a PD-1 inhibitor, in ATC reported response rates of 19% (8/42) including three complete responses [14]. Another study of the combination of lenvatinib and pembrolizumab is currently ongoing (NCT04171622).\n\nTo the best of our knowledge, there is only one other reported case where ICI therapy was used as a primary treatment for a patient with inoperable and treatment-naïve ATC, with a high PD-L1 expression (60%) in tumor cells [11]. This patient had a near complete response but, however, developed grade 4 colitis after eight cycles of pembrolizumab, which required drug discontinuation, leading to subsequent progression and death 18 months after initial diagnosis [11].\n\nPD-L1 expression has been shown to be as high as 75% in patients with ATC [15]. However, it is important to note that some of the PD-L1 expression may be related to the ensuing immune response to the tumor rather than as an independent process implicated in disease progression. Yet, the association of a worse prognosis with high PD-L1 expression [16] may reflect the latter. Additionally, PD-L1 staining in cytological specimens can be more challenging than in histological ones if the tumor is heterogeneous [17]. When the tumor is homogenous, there is an evidence that the detection and quantification of PD-L1 expression shows a high degree of concordance (>90%) between cytologic and histologic specimens in non-small cell lung cancer [18]. Whether a high PD-L1 expression score is predictive of treatment response in ATC remains unclear. In the present case and another case report [10], the PD-L1 expression was >95%, while the response was irrespective of the degree of PD-L1 expression in a case series by Iyer and colleagues [9].\n\n4. Conclusion\n\nATC is an aggressive malignancy with a very low survival rate which frequently presents with distant metastases or unresectable disease [19]. This case highlights the possibility of using ICI therapy as a primary treatment modality in treatment-naïve unresectable ATC patients. However, it has yet to be determined whether ICI therapy may be used as a neoadjuvant treatment to allow for surgical intervention or if it may be used as a long-term maintenance therapy when other forms of treatment are refused or when surgery is not feasible. In addition, studies further exploring the use of ICIs as an alternative to chemoradiation are necessary. More studies of immune check point blockade in ATC [20] are in progress, and the results will provide valuable information on the optimal use of these medications in ATC.\n\nAcknowledgments\n\nDr. Manisha Shah reports research funding from Merck and Eli Lilly and Co. Dr. Konda reports research funding from Merck, Eisai, Xencor, Bristol Myers Squibb, and Eli Lilly and Co.\n\nDisclosure\n\nThis case report was presented as an abstract at the 89th annual meeting of American Thyroid Association under the following title: “Dramatic Response to Pembrolizumab in a Patient with Treatment-Naı¨ve Unresectable Anaplastic Thyroid Cancer.”\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 CT scan of the neck at presentation (axial image).\n\nFigure 2 CT scan of the neck at presentation (coronal image).\n\nFigure 3 Cytology showing atypical discohesive cells consistent with ATC.\n\nFigure 4 Immunocytochemistry staining showing strong positivity for PD-L1.\n\nFigure 5 First CT scan of the neck after the initiation of pembrolizumab, 4 doses (axial image).\n\nFigure 6 First CT scan of the neck after the initiation of pembrolizumab, 4 doses (coronal image).\n\nFigure 7 CT scan of the neck after 25 doses of pembrolizumab (axial image).\n\nFigure 8 CT scan of the neck after 25 doses of pembrolizumab (coronal image).\n==== Refs\n1 Smallridge R. C. Copland J. A. Anaplastic thyroid carcinoma: pathogenesis and emerging therapies Clinical Oncology 2010 22 6 486 497 10.1016/j.clon.2010.03.013 2-s2.0-77954760114 20418080\n2 Smallridge R. C. Ain K. B. Asa S. L. American thyroid association guidelines for management of patients with anaplastic thyroid cancer Thyroid 2012 22 11 1104 1139 10.1089/thy.2012.0302 2-s2.0-84869077150 23130564\n3 Lin B. Ma H. Ma M The incidence and survival analysis for anaplastic thyroid cancer: a SEER database analysis American Journal of Translational Research 2019 11 5888 5896 31632557\n4 Maniakas A. Dadu R. Busaidy N. L. Evaluation of overall survival in patients with anaplastic thyroid carcinoma JAMA Oncology 2020 6 9 1397 1404 32761153\n5 McIver B. Hay I. D. Giuffrida D. F. Anaplastic thyroid carcinoma: a 50-year experience at a single institution Surgery 2001 130 6 1028 1034 10.1067/msy.2001.118266 2-s2.0-0035666788 11742333\n6 Kunstman J. W. Juhlin C. C. Goh G. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing Human Molecular Genetics 2015 24 8 2318 2329 10.1093/hmg/ddu749 2-s2.0-84926511800 25576899\n7 Landa I. Ibrahimpasic T. Boucai L. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers Journal of Clinical Investigation 2016 126 3 1052 1066 10.1172/jci85271 2-s2.0-84959862166\n8 Subbiah V. Kreitman R. J. Wainberg Z. A. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer Journal of Clinical Oncology 2018 36 1 7 13 10.1200/jco.2017.73.6785 2-s2.0-85039975292 29072975\n9 Iyer P. C. Dadu R. Gule-Monroe M. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma J Immunother Cancer 2018 6 p. 68 10.1186/s40425-018-0378-y 2-s2.0-85049833645\n10 Cabanillas M. E. Ferrarotto R. Garden A. S. Neoadjuvant BRAF- and immune-directed therapy for anaplastic thyroid carcinoma Thyroid 2018 28 7 945 951 10.1089/thy.2018.0060 2-s2.0-85049923540 29742974\n11 Spalart V. Legius B. Segers K. Coolen J. Maes B. Decoster L. Dramatic response to first line single agent pembrolizumab in anaplastic thyroid carcinoma Case Rep Endocrinol 2019 2019 4 9095753 10.1155/2019/9095753\n12 Pozdeyev N. Gay L. M. Sokol E. S. Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers Clinical Cancer Research 2018 24 13 3059 3068 10.1158/1078-0432.ccr-18-0373 2-s2.0-85049372836 29615459\n13 Dierks JS C. Ruf J. Duyster J. Thomusch O. Miething C. Zielke A. The lenvatinib/pembrolizumab combination induces long lasting and complete responses in patients with metastatic anaplastic or poorly differentiated thyroid carcinoma: results from a retrospective study and first results from the prospective phase II ATLEP trial Annals of Oncology 2020 31 p. S1085\n14 Capdevila J. Wirth L. J. Ernst T. PD-1 blockade in anaplastic thyroid carcinoma Journal of Clinical Oncology 2020 38 23 2620 2627 10.1200/jco.19.02727 32364844\n15 Bastman J. J. Serracino H. S. Zhu Y. Tumor-infiltrating T cells and the PD-1 checkpoint pathway in advanced differentiated and anaplastic thyroid cancer The Journal of Clinical Endocrinology & Metabolism 2016 101 7 2863 2873 10.1210/jc.2015-4227 2-s2.0-85013254723 27045886\n16 Chintakuntlawar A. V. Rumilla K. M. Smith C. Y. Expression of PD-1 and PD-L1 in anaplastic thyroid cancer patients treated with multimodal therapy: results from a retrospective study The Journal of Clinical Endocrinology & Metabolism 2017 102 6 1943 1950 10.1210/jc.2016-3756 2-s2.0-85020482909 28324060\n17 O’Malley D. P. Yang Y. Boisot S Immunohistochemical detection of PD-L1 among diverse human neoplasms in a reference laboratory: observations based upon 62,896 cases Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc 2019 32 929 942 10.1038/s41379-019-0210-3 2-s2.0-85061473741\n18 Gosney J. R. Boothman A.-M. Ratcliffe M. Kerr K. M. Cytology for PD-L1 testing: a systematic review Lung Cancer 2020 141 101 106 10.1016/j.lungcan.2020.01.010 32007657\n19 Molinaro E. Romei C. Biagini A. Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies Nature Reviews Endocrinology 2017 13 11 644 660 10.1038/nrendo.2017.76 2-s2.0-85031324613\n20 Liotti F. Prevete N. Vecchio G. Melillo R. M. Recent advances in understanding immune phenotypes of thyroid carcinomas: prognostication and emerging therapies F1000 Research 2019 8 p. 1 10.12688/f1000research.16677.1 2-s2.0-85062718408\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-651X",
"issue": "2021()",
"journal": "Case reports in endocrinology",
"keywords": null,
"medline_ta": "Case Rep Endocrinol",
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"nlm_unique_id": "101576457",
"other_id": null,
"pages": "5521649",
"pmc": null,
"pmid": "34123437",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26878173;23130564;32761153;28324060;30854191;27045886;31632557;29615459;32007657;25576899;29742974;32364844;11742333;30760860;31885948;29072975;20418080;29996921;28707679",
"title": "Pembrolizumab in a Patient with Treatment-Naïve Unresectable BRAF-Mutation Negative Anaplastic Thyroid Cancer.",
"title_normalized": "pembrolizumab in a patient with treatment na ve unresectable braf mutation negative anaplastic thyroid cancer"
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"abstract": "BACKGROUND\nDe novo malignancy is a severe complication after liver transplantation (LT), but de novo leiomyosarcoma is extremely rare.\n\n\nMETHODS\nWe reported de novo leiomyosarcoma occurring after LT. The patient's status for Epstein-Barr virus was negative. The donor was a 21-year-old man with a central nervous system malignancy who underwent surgery. Three months later brain death occurred and his organs were donated.\n\n\nRESULTS\nLeiomyosarcoma in the recipient was detected shortly after LT. It progressed after minimization of immunosuppression and apatinib therapy, and the patient died of cachexia 17 months after LT.\n\n\nCONCLUSIONS\nDe novo leiomyosarcoma is a rare but serious event after LT, needing comprehensive management.",
"affiliations": "Liver Transplant Center, Beijing Friendly Hospital, Capital Medical University, Beijing, China.;Hepatobiliary Department and Liver Transplant Center, 302 Hospital, Beijing, 100039, China.;Hepatobiliary Department and Liver Transplant Center, 302 Hospital, Beijing, 100039, China. Electronic address: zhoust71@163.com.;Hepatobiliary Department and Liver Transplant Center, 302 Hospital, Beijing, 100039, China. Electronic address: zsun7379@yahoo.com.",
"authors": "Zhang|J|J|;Sun|Y|Y|;Gao|Y J|YJ|;Zhou|S|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.06.023",
"fulltext": null,
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"issn_linking": "0041-1345",
"issue": "52(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D017809:Fatal Outcome; D004854:Herpesvirus 4, Human; D006801:Humans; D007890:Leiomyosarcoma; D016031:Liver Transplantation; D008297:Male; D011183:Postoperative Complications; D014019:Tissue Donors; D055815:Young Adult",
"nlm_unique_id": "0243532",
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"pages": "2809-2812",
"pmc": null,
"pmid": "32674859",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leiomyosarcoma After Liver Transplantation Is Unrelated to Epstein-Barr Virus: A Case Report.",
"title_normalized": "leiomyosarcoma after liver transplantation is unrelated to epstein barr virus a case report"
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"companynumb": "CN-FRESENIUS KABI-FK202014003",
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"abstract": "OBJECTIVE\nIn 2012, tenofovir disoproxil fumarate (TDF) was approved for use in children over 2 years of age at a dose of 8 mg/kg/day, and is the WHO recommended first-line therapy for children over 10 years of age or 35 kg in weight, at 300 mg daily. Whilst postmarketing experience of paediatric TDF is limited, prior off-licence use has occurred at our centre due to its tolerability, efficacy and resistance profiles. In this article we describe a single-centre experience of TDF nephrotoxicity in children aged <16 years.\n\n\nMETHODS\nWe conducted a retrospective case-note audit of children with perinatally-acquired HIV who ever received TDF-based antiretroviral therapy.\n\n\nRESULTS\nFrom 2001 to December 2013, 70 children [39 (56 %) females] ever received TDF. Median age at the start of TDF treatment was 12 years (interquartile range 10-14). Seven (10 %) children developed asymptomatic renal tubular leak with associated hypophosphataemia (3) and hypokalaemia (1), all resulting in TDF withdrawal and biochemical resolution. Comparison of the nephrotoxic group versus the rest of the cohort showed no significant differences for age, sex, antiretroviral regimen or CD4 count. Lower weight (p = 0.05) and initial dose of TDF received (p = 0.0048) were significantly associated with TDF-induced nephrotoxicity: median dose of TDF (7.8 mg/kg/day) compared with the remainder of the cohort (6.5 mg/kg/day). Concurrent use of protease inhibitors (PIs) with TDF may be a contributing factor to the development of nephrotoxicity (odds ratio 6; 95 % CI 0.7-54; p = 0.111).\n\n\nCONCLUSIONS\nAlthough all children with TDF-associated nephrotoxicity had biochemical resolution on drug withdrawal, renal monitoring of children receiving TDF is important, especially with the co-administration of PIs. Postmarketing surveillance is essential in the paediatric setting.",
"affiliations": "The Family Clinic, Department of Paediatrics, Imperial College Healthcare NHS Trust, London, UK, yinrulim85@gmail.com.",
"authors": "Lim|Yinru|Y|;Lyall|Hermione|H|;Foster|Caroline|C|",
"chemical_list": "D019380:Anti-HIV Agents; D000068698:Tenofovir",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-015-0287-5",
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"issn_linking": "1173-2563",
"issue": "35(5)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000293:Adolescent; D019380:Anti-HIV Agents; D002648:Child; D005260:Female; D015658:HIV Infections; D006801:Humans; D007008:Hypokalemia; D017674:Hypophosphatemia; D007674:Kidney Diseases; D008297:Male; D012189:Retrospective Studies; D000068698:Tenofovir",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "327-33",
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"pmid": "25861908",
"pubdate": "2015-05",
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"references": "21799928;20299966;22269183;13130407;16863446;18171292;20673002;20139752;19273671;19209091;22301477;15090798;22878694;23249917;16291735;15738371;19842939;15076241;22892171;22313955;16260905;16773419;12942419;17661851",
"title": "Tenofovir-Associated Nephrotoxicity in Children with Perinatally-Acquired HIV Infection: A Single-Centre Cohort Study.",
"title_normalized": "tenofovir associated nephrotoxicity in children with perinatally acquired hiv infection a single centre cohort study"
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"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
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{
"abstract": "OBJECTIVE\nTo report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD).\n\n\nMETHODS\nWe performed a multicenter study of main characteristics and outcomes of anti-TNF alpha treatments [mainly infliximab (62%), and adalimumab (30%)] in 124 BD patients [48% of men; median age of 33.5 (28-40) years].\n\n\nRESULTS\nOverall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2 ± 0.5 vs 1.7 ± 2.4 before the use of anti-TNF, p < 0.0001). The prednisone dose was significantly reduced at 6 and 12 months (p < 0.0001). In multivariate analysis, retinal vasculitis was negatively associated with complete response to anti-TNF (OR = 0.33 [0.12-0.89]; p = 0.03). The efficacy and relapse free survival were similar regardless of the type of anti-TNF agent used. After a median follow-up of 21 [7-36] months, side effects were reported in 28% of patients, including infections (16.3%) and hypersensitivity reactions (4.1%). Serious adverse events were reported in 13% of cases.\n\n\nCONCLUSIONS\nAnti-TNF alpha therapy is efficient in all severe and refractory BD manifestations. Efficacy appears to be similar regardless of the anti-TNF agent used (infliximab or adalimumab).",
"affiliations": "Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière hospital, 83, boulevard de l'Hôpital, Paris 75013, France; Centre national de référence maladies systémiques et autoimmunes rares, DHU Inflammation, Immunopathologie, Biothérapie, Université Paris VI-Pierre et Marie Curie, Paris, France.;Department of Internal Medicine, Saint Eloi Hospital, Montpellier, France.;Department of Clinical Epidemiology and Biostatistics, Saint Louis Hospital, France.;Department of Internal Medicine, University Hospital, Grenoble, France.;Department of Internal Medicine, University Hospital, Toulouse, France.;Department of Rheumatology, Santa Maria Nuova Hospital, Reggio Emilia, Italy.;Department of Rheumatology, Santa Maria Nuova Hospital, Reggio Emilia, Italy.;Department of Internal Medicine, University Hospital, Lille, France.;Department of Internal Medicine, University Hospital, Dijon, France.;Department of Internal Medicine, Croix Rousse Hospital, Lyon, France.;Department of Rheumatology, University Hospital, Strasbourg, France.;Department of Internal Medicine, University Hospital, Strasbourg, France.;Department of Internal Medicine, Jean Verdier Hospital, Bondy, France.;Department of Internal Medicine, University Hospital, Rouen, France.;Department of Internal Medicine, Edouard Herriot Hospital, Lyon, France.;Department of Internal Medicine, University Hospital, Grenoble, France.;Department of Internal Medicine, E3M Institut, Pitié Salpêtrière Hospital, Paris, France.;Department of Internal Medicine, Lariboisière Hospital, Paris, France.;Department of Internal Medicine, Pitié Salpêtrière Hospital, Paris, France.;Department of Internal Medicine, Croix Saint Simon Hospital, Paris, France.;Department of Ophtalmology, Pitié Salpêtrière Hospital, Paris, France.;Department of Internal Medicine, University Hospital, Lille, France.;Department of Internal Medicine, Saint Antoine Hospital, Paris, France.;Department of Rheumatology, Kremlin Bicetre University Hospital, Kremlin Bicetre, France.;Department of Internal Medicine, Bichat Hospital, Paris, France.;Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière hospital, 83, boulevard de l'Hôpital, Paris 75013, France; Centre national de référence maladies systémiques et autoimmunes rares, DHU Inflammation, Immunopathologie, Biothérapie, Université Paris VI-Pierre et Marie Curie, Paris, France.;Department of Ophtalmology, Pitié Salpêtrière Hospital, Paris, France.;Department of Clinical Epidemiology and Biostatistics, Saint Louis Hospital, France.;Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière hospital, 83, boulevard de l'Hôpital, Paris 75013, France; Centre national de référence maladies systémiques et autoimmunes rares, DHU Inflammation, Immunopathologie, Biothérapie, Université Paris VI-Pierre et Marie Curie, Paris, France.;Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière hospital, 83, boulevard de l'Hôpital, Paris 75013, France; Centre national de référence maladies systémiques et autoimmunes rares, DHU Inflammation, Immunopathologie, Biothérapie, Université Paris VI-Pierre et Marie Curie, Paris, France. Electronic address: david.saadoun@psl.aphp.fr.",
"authors": "Vallet|H|H|;Riviere|S|S|;Sanna|A|A|;Deroux|A|A|;Moulis|G|G|;Addimanda|O|O|;Salvarani|C|C|;Lambert|M|M|;Bielefeld|P|P|;Seve|P|P|;Sibilia|J|J|;Pasquali|Jl|J|;Fraison|Jb|J|;Marie|I|I|;Perard|L|L|;Bouillet|L|L|;Cohen|F|F|;Sene|D|D|;Schoindre|Y|Y|;Lidove|O|O|;Le Hoang|P|P|;Hachulla|E|E|;Fain|O|O|;Mariette|X|X|;Papo|T|T|;Wechsler|B|B|;Bodaghi|B|B|;Rigon|M Resche|MR|;Cacoub|P|P|;Saadoun|D|D|;|||",
"chemical_list": "D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8411",
"issue": "62()",
"journal": "Journal of autoimmunity",
"keywords": "Anti-TNF; Behçet's disease; Efficacy; Safety; Vasculitis",
"medline_ta": "J Autoimmun",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D001528:Behcet Syndrome; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D008297:Male; D012008:Recurrence; D019233:Retreatment; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8812164",
"other_id": null,
"pages": "67-74",
"pmc": null,
"pmid": "26162757",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Efficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: Multicenter study of 124 patients.",
"title_normalized": "efficacy of anti tnf alpha in severe and or refractory beh et s disease multicenter study of 124 patients"
} | [
{
"companynumb": "FR-JNJFOC-20150813245",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
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