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"abstract": "Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its related disease (COVID-19) continue to represent a challenge for humans. To date, vaccination programs have represented an opportunity to navigate the pandemic. However, the advent of new genetic COVID-19 variants has increased more attention representing a worrying threat not only for not vaccinated but also for vaccinated people as virus infections have been shown also in the last ones. Herein, we report different clinical cases and radiological findings of COVID-19 pneumonia in six fully vaccinated patients. Two patients had a history of Rituximab therapy for follicular lymphoma and with persistent positivity for SARS-CoV-2 on nasopharyngeal/oropharyngeal (NP/OP) swabs and with moderate pneumonia on the chest computed tomography (CT). One patient who resulted to be positive to delta variant 8 days after the second vaccination dose, died shortly after. Two patients were hospitalized due to the worsening of fever and dyspnea in presence of mild pneumonia on CT. In one patient mild pneumonia was found on the chest-CT performed after a lipothymic episode associated with chest pain and positive NP/OP swab tested for SARS-CoV-2. These data suggested that in fully vaccinated people, caution should be preserved, and the use of masks and social distancing should be continued in all closed environments. However, further clinical trials should be done to better understand how various factors can influence vaccine immunogenicity as the presence of virus mutations, age factors, and the presence of an immunocompromised state.",
"affiliations": "Department of Radiology, San Giuseppe Moscati Hospital, Contrada Amoretta, 83100 Avellino, Italy.;Radiology Unit, \"Cotugno Hospital\", Naples, Via Quagliariello 54, 80131 Naples, Italy.;Pediatric Neurology Unit, Fondazione Policlinico Universitario \"A. Gemelli\", IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.;Pharmacology Department, \"Frangipane\" Hospital, ASL Avellino, Via V. Emanuele, 83031 Ariano Irpino, Italy.;Department of Radiology, San Giuseppe Moscati Hospital, Contrada Amoretta, 83100 Avellino, Italy.;Radiology Unit, \"Frangipane\" Hospital, ASL Avellino, Via V. Emanuele, 83031 Ariano Irpino, Italy.;Department of Radiology, San Giuseppe Moscati Hospital, Contrada Amoretta, 83100 Avellino, Italy.",
"authors": "Brogna|Barbara|B|0000-0002-8037-7689;Bignardi|Elio|E|0000-0002-9484-6968;Brogna|Claudia|C|;Capasso|Chiara|C|;Gagliardi|Giuliano|G|0000-0001-5897-9539;Martino|Alberigo|A|;Musto|Lanfranco Aquilino|LA|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/medicina57090891",
"fulltext": "\n==== Front\nMedicina (Kaunas)\nMedicina (Kaunas)\nmedicina\nMedicina\n1010-660X\n1648-9144\nMDPI\n\n10.3390/medicina57090891\nmedicina-57-00891\nCase Report\nCOVID-19 Pneumonia in Vaccinated Population: A Six Clinical and Radiological Case Series\nhttps://orcid.org/0000-0002-8037-7689\nBrogna Barbara 1*†\nhttps://orcid.org/0000-0002-9484-6968\nBignardi Elio 2†\nBrogna Claudia 34\nCapasso Chiara 5\nhttps://orcid.org/0000-0001-5897-9539\nGagliardi Giuliano 1\nMartino Alberigo 6\nMusto Lanfranco Aquilino 1\nDi Micco Pierpaolo Academic Editor\n1 Department of Radiology, San Giuseppe Moscati Hospital, Contrada Amoretta, 83100 Avellino, Italy; giuliano.gagliardi@hotmail.it (G.G.); musto.lanfranco@gmail.com (L.A.M.)\n2 Radiology Unit, “Cotugno Hospital”, Naples, Via Quagliariello 54, 80131 Naples, Italy; dr.eliobignardi@alice.it\n3 Pediatric Neurology Unit, Fondazione Policlinico Universitario “A. Gemelli”, IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; claudiabrogna@yahoo.it\n4 Neuropsychiatric Unit, ASL Avellino, Via Degli Imbimbo 10/12, 83100 Avellino, Italy\n5 Pharmacology Department, “Frangipane” Hospital, ASL Avellino, Via V. Emanuele, 83031 Ariano Irpino, Italy; chiara.ftvz@gmail.com\n6 Radiology Unit, “Frangipane” Hospital, ASL Avellino, Via V. Emanuele, 83031 Ariano Irpino, Italy; albmart@libero.it\n* Correspondence: brognabarbara1@gmail.com\n† These authors contributed equally to this work.\n\n27 8 2021\n9 2021\n57 9 89107 8 2021\n26 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its related disease (COVID-19) continue to represent a challenge for humans. To date, vaccination programs have represented an opportunity to navigate the pandemic. However, the advent of new genetic COVID-19 variants has increased more attention representing a worrying threat not only for not vaccinated but also for vaccinated people as virus infections have been shown also in the last ones. Herein, we report different clinical cases and radiological findings of COVID-19 pneumonia in six fully vaccinated patients. Two patients had a history of Rituximab therapy for follicular lymphoma and with persistent positivity for SARS-CoV-2 on nasopharyngeal/oropharyngeal (NP/OP) swabs and with moderate pneumonia on the chest computed tomography (CT). One patient who resulted to be positive to delta variant 8 days after the second vaccination dose, died shortly after. Two patients were hospitalized due to the worsening of fever and dyspnea in presence of mild pneumonia on CT. In one patient mild pneumonia was found on the chest-CT performed after a lipothymic episode associated with chest pain and positive NP/OP swab tested for SARS-CoV-2. These data suggested that in fully vaccinated people, caution should be preserved, and the use of masks and social distancing should be continued in all closed environments. However, further clinical trials should be done to better understand how various factors can influence vaccine immunogenicity as the presence of virus mutations, age factors, and the presence of an immunocompromised state.\n\nSARS-CoV-2\nCOVID-19 vaccines\nCOVID-19 pneumonia\nimmunocompromised state\ncase reports\n==== Body\npmc1. Introduction\n\nThe pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its related disease (COVID-19) represents a major challenge for humans. To date, COVID-19 has caused more than 3 million deaths, leading to economic troubles in several countries [1,2,3,4].\n\nCOVID-19 has a multisystem involvement affecting not only the lungs but also the cardiovascular, nervous, and gastrointestinal systems. In adults, and especially in children, COVID-19 has led to a multisystem inflammatory syndrome [1,2,3,4].\n\nDifferent means of virus transmission have been reported. COVID-19 transmission can occur through direct contact from one person to another by coughing, sneezing, and inhaling infected droplets, or by contact with oral and nasal mucosa or conjunctival mucosa after touching an infected surface [5]. COVID-19 transmission has also been reported to follow the fecal-oral route [3].\n\nAsymptomatic individuals with COVID-19 infection can be a source for the virus transmission [6].\n\nTo date, reverse-transcription polymerase chain reaction (RT-PCR) testing is considered to be the gold standard tool to diagnose or screen for COVID-19. Chest imaging is currently indicated in suspected cases to support rapid medical triage in the presence of high pretest probability [7]. CT is mainly useful in suspected cases of COVID-19 pneumonia with the presence of comorbidities [8,9]. Different pharmacological approaches, including antibiotics, corticosteroids, and immunomodulant therapies, have been used with different gradings of clinical responses depending on the severity of the disease [10]. In addition, monoclonal antibodies, recently approved by the Food and Drug Administration (FDA), have been used to treat symptomatic people in both the adult and pediatric populations in an emergency stage [11].\n\nVaccination against SARS-CoV-2 is considered the most efficient solution. Vaccination programs have been approved worldwide, aiming to reduce morbidity and mortality, especially in frail people. Today, there are several vaccines against the novel coronavirus. Some of these vaccines have been quickly approved by the European Medicines Agency (EMA) and FDA, including the Pfizer mRNABNT162b2, Moderna mRNA -1273, Vaxzevria (ChAdOx1-S; AstraZeneca), and Johnson and Johnson vaccines [12,13,14]. These vaccines have demonstrated high efficacy in clinical trials [15,16]. However, concerns remain regarding the rapid spread of new virus variants and the increasing number of new cases in countries with high percentages of vaccinated people [17,18,19,20]. We report six different cases of COVID-19 pneumonia in fully vaccinated patients.\n\n2. Case #1\n\nA 71-year-old man with a history of hypertension received a full dose of the Vaxzevria vaccine (ChAdOx1-S; AstraZeneca) (first dose on 1 April and second dose on 24 June). Three days after the second dose, he reported cough and fever. However, after 8 days (on 2 July), he visited the emergency room of our hospital due to the worsening of symptoms, including fever and dyspnea.\n\nOn admission, the patient’s nasopharyngeal/oropharyngeal (NP/OP) swab tested positive with the detection of the Delta variant. On laboratory examination, he showed a lymphocyte count in the lower range (1100/µL; normal value range 800–5000/µL), an elevation of the D-Dimer level (4810 ng/mL; normal value < 250 ng/mL), and a mild elevation of the C-reactive Protein (CRP, 2.12 mg/dL; normal value < 0.5). The other laboratory values were within the normal range. On admission, the Saturation oxygen level (SO2) was at 88% with PO2/FiO2 290.\n\nA chest Computed tomography (CT) performed in the emergency department showed a typical central and peripheral distribution of ground-glass opacity (GGO) COVID-19 pneumonia. The CT-SS score [21] showed a value of 13/20 (Figure 1).\n\nThe serology, performed with an immunoassay (LiaisonXL), confirmed the presence of SARS-CoV-2 S1/S2 IgM associated with SARS-CoV-2 anti-spike IgG (2080 BAU/mL) (<33.80 BAU/mL: Absent) (>33.80 BAU/mL: presence), which was related to the previous vaccination.\n\nTreatment with dexamethasone (6mg once daily with intravenous administration for 10 days) and conventional oxygen therapy was started, together with low molecular weight heparin (LMWE) at 4000 IU (twice daily with a subcutaneous administration for 10 days).\n\nOne week later (on 9 July), another chest CT was performed due to the worsening of the patient’s symptoms with SO2 at 76% and PO2/FiO2 190.\n\nThe chest CT showed extended pneumonia, with an evolution in a crazy paving pattern and consolidation areas (CT-SS 16/20) (Figure 1). The patient died 5 days later.\n\n3. Case #2\n\nA 51-year-old woman with a history of follicular lymphoma in remission in September 2020, and with a previous SARS-CoV-2 infection in November 2020, received only one dose (according to the current evidence) [22,23] of the Pfizer mRNABNT162b vaccine on 7 April 2021. The patient had been undergoing treatment with rituximab since September 2020. However, the patient never developed an immune response to SARS-CoV-2 as confirmed by serology, and she had shown a persistent mild positivity on RT-PCR for SARS-CoV-2 since the day of vaccination. A few days after the vaccination, her clinical condition worsened, with dyspnea, fever, and a SO2 of 96%. One week after the vaccination, she visited the emergency room of a tertiary hospital and underwent a chest computed tomography (CT). The chest CT showed multilobe areas of ground glass (GGO) in a peripheral and central distribution in the acute phase. The patient’s RT-PCR for SARS-CoV-2 continued to be positive. After 2 months, on 7 June, she visited the emergency room of our hospital for the worsening of dyspnea and fever. On admission, another NP/OP swab tested positive for SARS-CoV-2 without the detection of any variants. Her SO2 was at 90%. A chest CT was performed in the emergency department, showing GGO in a peripheral and central distribution with a CT-SS of 9/20 (Figure 2).\n\nOn laboratory examination, she showed a low level of hemoglobin (Hb) (9.5 g/dL; normal range 13.0–16.5), a lower white blood count (2400/µL; normal value range 4300–10,800/µL), a mild elevation of the D-Dimer level (1.43 mg/L; normal value < 0.5), an elevation of the C-reactive Protein (CRP, 11.41 mg/dL; normal value < 0.5) and an elevation of lactate dehydrogenase enzyme (LDH, 360 IU/L; normal value 125–220). The other laboratory values were within the normal range. Serology showed the absence of anti-spike IgG despite the previous vaccination. Treatment with dexamethasone (4 mg once daily with intravenous administration for 10 days) and conventional oxygen therapy was started (1 L/min) with SO2 at 97%, together with low molecular weight heparin (LMWE) 4000 IU (twice daily with a subcutaneous administration for 10 days).\n\nThe patient’s NP/OP swabs continued to test positive for SARS-CoV-2 on 11 and 15 June. Another chest CT was repeated on 17 June, which showed an evolution of some GGO areas in consolidative areas with the same CT-SS. However, the chest CT also showed some new GGO areas in the left superior lobe (Figure 3).\n\nThe patient’s saturation level was at 97%, and her clinical condition remained stable. Thus, the patient was discharged. However, 15 days later (on 3 July), the patient returned to our emergency room for the worsening of dyspnea.\n\nOn admission, another NP/OP swab tested positive. The chest CT continued to show GGO areas, although the CT-SS remained stable (Figure 4). Treatment with ceftriaxone (1 g once daily with intravenous administration) was started, along with prednisone (25 mg once daily with oral administration for 10 days).\n\nHer clinical conditions improved again, and the patient was discharged. However, her RT-PCR for SARS-CoV-2 remained positive.\n\n4. Case #3\n\nA 53-year-old woman with a history of follicular lymphoma and undergoing treatment with rituximab was fully vaccinated with the COVID-19 mRNA-1273 Pfizer vaccine (first dose on 4 March and second dose on 26 March). About 30 days after vaccination (on 28 April), she tested positive for SARS-CoV-2, and she was also treated with antibody monoclonal therapy. After that, she continued to show three consecutive positive results for SARS-CoV-2 on RT-PCR (on 8, 16, and 20 May) and negative results on 27 May and 21 June. However, on 1 July, she visited the emergency room of our hospital with fever and dyspnea with SO2 at 90%. On admission, she tested positive for SARS-CoV-2 on the NP/OP swab without the detection of any variants. The chest CT showed GGO areas with a peripheral and central distribution and a CT-SS of 11/20 (Figure 5).\n\nOn laboratory examination, she showed a mild low-level white blood count (5100/µL), an increased value of LDH (658 IU/L), an increased level of CRP (8.50 mg/dL), and mild higher values of aspartate transaminases (AST) (55 IU/L; normal value range 5–34) and alanine transaminases (ALT) (101 IU/L; normal value range 0–55). The patient also showed a mild elevation of the D-Dimer level (1.11 mg/dL). The other laboratory values were within the normal limits. The serology, performed with an immunoassay (LiaisonXL), found only the presence of SARS-CoV-2 anti-spike IgG (200 BAU/mL), which was related to the previous vaccination.\n\nTreatment with dexamethasone (4 mg once daily with intravenous administration for 10 days) with intravenous remdesivir (200 mg on day 1 followed by 100 mg for 4 days) and conventional oxygen therapy (1 L/min) was started with SO2 at 96%, together with LMWE 4000 IU (once daily with a subcutaneous administration for 10 days).\n\nTwo days after her hospital admission, another OP/NP swab was repeated, which continued to test positive for SARS-CoV-2. However, her clinical conditions improved, and she showed two consecutive negative RT-PCR results on 9 and 13 July. Therefore, the patient was discharged. However, she returned to the emergency room of our hospital on 21 July. She tested positive Sars-CoV-2 on the OP/NP swab performed in the emergency room. The chest CT continued to show GGO, mainly in the inferior lobes with a CT-SS of 9/20 (Figure 6).\n\nTreatment with meropenem (3 g/day given as three doses) and methylprednisolone (1 mg/kg daily for 3 days), followed by prednisone (25 mg once daily with oral administration for 10 days), was prescribed. The patient’s clinical conditions and dyspnea improved. However, she continued to experience fever (38.5 °C) and to test positive for SARS-CoV-2 on the OP/NP swabs on 23, 26, and 3 August with negative results on 11 August and 14 August. Another chest CT has been repeated on 7 August showing new areas of GGO, especially in the superior lobes (Figure 7). Therefore, treatment with immunoglobulin was started with a resolution of some of the previous GGO on the chest CT control made a week later on 14 August. Therefore, the patient has been discharged.\n\n5. Case #4\n\nAn 80-year-old man received a full dose of the COVID-19 mRNA-1273 Pfizer vaccine (first dose on 11 March and second dose on 1 April). In addition, his wife was fully vaccinated. However, on 6 July, the patient started to experience cough, dyspnea, and fever.\n\nSeven days later, his clinical condition worsened, and he visited the emergency room of our hospital. His fever was very high (39.5 °C).\n\nOn admission, an NP/OP swab tested positive for SARS-CoV-2. The patient denied any contact with individuals who had tested positive for COVID-19. No Delta variant was detected. On laboratory examination, he showed mild lymphopenia (830/µL; normal value range 800–5000/µL) and a mild lower hemoglobin value (11.1 mg/dL). The other laboratory values were within the normal ranges.\n\nOn admission, the SO2 was at 89% with PO2/FiO2 300.\n\nA chest CT showed some small consolidation areas in a peripheral posterior distribution typical of COVID-19 pneumonia, with a CT-SS score of 5/20 (Figure 8).\n\nThe serology, performed with an immunoassay (LiaisonXL), showed the absence of SARS-CoV-22 S1/S2 IgM and the presence of SARS-CoV-2 anti-spike IgG (322 BAU/mL) related to the previous vaccination.\n\nTreatment with dexamethasone (6 mg once daily with intravenous administration for 10 days) and conventional oxygen therapy was started, together with LMWE 2000 IU (once daily with a subcutaneous administration for 10 days).\n\nAnother NP/OP swab was repeated on 16 July, and the patient continued to test positive for SARS-CoV-2. On 16 July, SO2 was at 95%, PO2/FiO2 320.\n\nHowever, the patient’s clinical condition remained stable.\n\n6. Case #5\n\nA 63-year-old woman visited the emergency department of our hospital on 30 July with fever and dyspnea with also thoracic pain. She had a history of previous uterine cancer treated with surgery 10 years before. She had already tested positive for SARS-CoV-2 on 21 July 2021 on an OP/NP swab conducted by an authorized laboratory. She was also fully vaccinated with the COVID-19 mRNA-1273 Pfizer vaccine (first dose on 22 April and second dose on 14 May). She was treated with an oral administration of azithromycin (500 mg 1 cp once daily) for 3 days by her family doctor. However, 2 days before hospital admission, she reported nausea and vomiting. At the time of hospital admission, an NP/OP swab tested positive for SARS-CoV-2, however, without the detection of any variants. The woman reported that her relatives, including her husband and daughter, were also fully vaccinated against COVID-19, and they had also tested positive for SARS-CoV-2. Her daughter reported recent contact with her boyfriend, who had also tested positive for SARS-CoV-2 prior to the daughter’s COVID-19 infection. The daughter’s boyfriend was also fully vaccinated. On hospital admission, during laboratory examination, the woman showed mild elevations in CRP (3.98 mg/dL), LDH (309 IU/L), and the D-dimer (0.51 mg/L). The other laboratory values were within the normal range. Her SO2 level was at 94%. However, due to also to the history of previous uterine cancer and the presence of dyspnea a chest CT was made in an emergency. On the chest CT, some GGO areas were found in a peripheral distribution, suggesting COVID-19 pneumonia with a CT-SS of 5/20 (Figure 9). No serology for SARS-CoV-2 was performed. Treatment with ceftriaxone (1 g once daily with intravenous administration) was started, together with dexamethasone (4 mg once daily with intravenous administration) and LMWE 4000 IU (once daily with a subcutaneous administration). The patient’s clinical conditions improved, and she was discharged after 3 days.\n\n7. Case #6\n\nA 61-year-old man received a full dose of the COVID-19 mRNA-1273 Pfizer vaccine (first dose on 22 April and second dose on 14 May). The patient had a history of hyperintensive cardiopathy and a previous cerebral hemorrhage (in 2018). However, on 7 July, he came to the emergency department of our hospital for a lipothymic episode. He did not present a confused state, and he also reported chest pain. He did not report a history of fever.\n\nHowever, on admission, an NP/OP swab tested positive for SARS-CoV-2 without the detection of any variants. The patient denied any contact with individuals who had tested positive for COVID-19.\n\nOn laboratory examination, the patient showed a mild low level of hemoglobin (Hb, 12 g/dL), a low level of platelet counts (129.000/µL; normal values 150.000–400.000/µL), a mild elevation of D-Dimer levels (1.28 mg/L), and a mild elevation of CRP (3.02 mg/dL). The other laboratory values were within the normal limits. His SO2 level was at 95%. Brain and chest CT scans were performed in the emergency department. No acute lesions were detected on the brain CT, but some GGO with consolidation areas were found on the chest CT on the left inferior lobes with a mild pleural effusion (Figure 10). Treatment with prednisone (25 mg once daily with oral administration for 10 days) was started, together with LMWE 4000 IU (once daily with a subcutaneous administration for 10 days). However, the patient’s OP/NP continued to test positive on 18 and 21 of July, but the patient’s clinical conditions remained stable. Thus, the patient was discharged.\n\n8. Discussion\n\nThe approved vaccines developed by Pfizer and Moderna use mRNA technology, while the approved formulations by AstraZeneca and Johnson and Johnson contain DNA delivered within non-replicating recombinant adenovirus (AdV) vector systems [24]. These COVID-19 vaccines have demonstrated high efficacy at preventing symptomatic disease, as shown by clinical trials [15,16]. The effectiveness of the BNT162b2 vaccine in reducing infection, severe disease, hospitalization, and death with COVID-19 patients has been reported in Israel [16,25]. The ChAdOx1 nCoV-19 trial found an efficacy against symptomatic disease of 76% at 22–90 days after at least one standard dose [15,26,27]. The efficacy of the vaccine further increases after the second dose [16,28].\n\nHowever, some genetic variants, such as the Delta variant, have emerged more recently. To date, only limited data on these variants are available in vaccinated people. Emerging studies have shown that two-dose administration resulted in efficacy against variants, such as the Delta variant [28,29]. In contrast, one dose was not shown to be protective [30]. Indeed, Williams et al. [30] reported that 8/21 residents and 14/21 staff members that had previously received a single dose of the Vaxzevria vaccine were infected by the Delta variant, but none of them died. On the other hand, in our cases, the only patient that died was affected by COVID-19 pneumonia related to the Delta variant.\n\nHowever, our patient was older than the cases described by Williams et al. [30] and he manifested the first symptoms related to Covid-19 infection three days after the second dose of vaccination, in a not fully protective state. Indeed, the protective effect of the second dose vaccines is usually observed after 14 days of vaccination, as has been reported in the literature [31]. For this reason, case 1 may have been infected by SARS-CoV-2 some days after the vaccination\n\nHowever, COVID-19 pneumonia has been rarely described in fully vaccinated patients and there are no yet ongoing clinical trials in these people categories. Surprisingly, so far, we have found only two described clinical cases [32,33].\n\nAll our cases after available SARS-CoV-2 2 vaccination presented with clinical and radiological findings of typical COVID-19 with different grading of severity infection, probably related to timing and different response to vaccination. In three patients (cases 4–6), we found only mild COVID-19 pneumonia. Our results show that vaccination can be protective against the aggressive form of COVID-19 pneumonia. In fact, in our case 4, a fully vaccinated old patient developed only mild COVID-19 pneumonia. In case 6, the detection of RT-PCR positivity for SARS-CoV-2 and of GGO on the chest CT scan were not expected and interpreted as an incidental finding because the patient came to the emergency room for a lipothymic episode that is not a typical finding of COVID-19 pneumonia presentation. The patient did not present fever or dyspnea. However syncopal or pre-syncopal episodes have been also reported as the only initial symptoms of COVID-19 infection [34].\n\nWe should highlight that pneumonia also in mild presentation has been not yet reported in fully vaccinated patients and our 5 cases have been not detected any variants but only in one case.\n\nTherefore, full vaccination is important to protect individuals from severe disease.\n\nHowever, mild symptoms with RT-PCR positivity have also been reported in fully vaccinated patients, suggesting that patients, even if asymptomatic, may still be become infected and transmit the live virus from the upper airway [35,36]. In fact, in our case 5, the patient has been infected by her full vaccinated relatives.\n\nTherefore, the use of masking and social distancing should be also continued in vaccinated people especially in all closed environments [36] and isolation recommendations should be considered even for the fully vaccinated if in contact with suspected cases of COVID-19.\n\nIn addition, our reports raised the question related to the oncologic patient that became affected by COVID-19 even if in presence of vaccination. Two patients among our cases affected by lymphoma treated with rituximab therapy presented with COVID-19 pneumonia infection after vaccination: in case 2, SARS-CoV-2 serology was not detected whereas in case 3, only the presence of SARS-CoV-2 anti-spike IgG was detected.\n\nThese data suggested that is also important to monitor the typical clinical status related to oncologic patients. Indeed, an immunocompromised state and the age-related decline of the immune response can compromise the vaccination efficacy [31,37].\n\nIt has been also reported that the use of the anti-CD20 antibody rituximab, with or without chemotherapy, is typically associated with impaired humoral responses to influenza vaccines [38]. Similar cases are emerging with SARS-CoV-2 vaccines [39,40,41,42,43]. Rituximab is associated with B cell 141 depletion for up to 78 weeks following use. On the other hand, patients with non-Hodgkin lymphomas (NHLs) are associated with disease-related immunodeficiency, which may render these patients especially susceptible to SARS-CoV-2 infection [39]. Immunocompromised patients likely acquire different clades of SARS-CoV-2 45 infection. Moreover, they cannot respond to the Sars-Cov-2 vaccines [42,43]. Alshukairi et al. [42] recently described the case of a 51-year-old female patient with a history of follicular non-Hodgkin’s lymphoma and rituximab therapy. The patient did not develop immunity after SARS-CoV-2 infection and did not respond to the mRNA COVID-19 vaccine. This case is very similar to two of our reported cases. However, in our two cases, the patients continued to test positive for SARS-CoV-2. Patients in an immunocompromised state should be always protected primarily in their own environment (e.g., hospitals and wards where this population meets there should be constantly testing to avoid inter-patient transmission).\n\nTherefore, it is important to also consider the serology after the COVID-19 vaccination. Not all people, especially those that are immunocompromised, develop a protective immune response after vaccination [31,37,41]. On the other hand, we should also consider that the age-related decline in immunity can reduce the prophylactic efficacy of vaccinations. Muller et al. [44] reported that 31.3% of the study’s elderly subjects had no detectable neutralizing antibodies after vaccination in contrast to the younger subjects. Therefore, to reduce virus transmission, we believe that it is important to continue applying the same rules, such as the use of masks, to all people, including vaccinated people. We also recommend individuating the rapid tracking of the virus with RT-PCR in mild symptomatic vaccinated patients and monitoring the immune response through the serology state, as not all people respond to the SARS-CoV-2 vaccination. In addition, the development of quicker RT-PCR for SARS-CoV-2 with major sensitivity and specificity can be useful to fight and contain the pandemic [45]. Brotons et al. [45], proposed a direct RT-PCR on self-collected raw saliva as a rapid method of screening, with a sensitivity and specificity, respectively, of 95.7% and 100.0%. We believe that caution should be preserved because some factors can influence vaccine immunogenicity as age factors and the presence of an immunocompromised state. On the other end, emergent researches also raised the question to consider the possibility of Acute enhancement disease (ADE) in presence of virus variants even if this phenomenon has been not fully demonstrated in the clinical trials [31,46]. Future clinical trials and studies in vitro and animal models should be done to better understand this mechanism.\n\n9. Conclusions\n\nAfter the establishment of the vaccine as the primary and most efficient tool of counter fighting the pandemic, it is expected not to offer 100% protection. Our cases highlight that fully vaccinated patients can also be affected by COVID-19 pneumonia in a mild form. Not all people develop an effective immune response, and an individual’s immune response depends on their immunocompromised state. Therefore, monitoring the serology state, as well as the use of masks and social distancing, should be continued in environments with high percentages of vaccinated people.\n\nThe continuous updating of COVID-19 vaccines should also be considered [47]. Furthermore, further clinical trials should be done to better understand how various factors can influence vaccine immunogenicity as the presence of virus mutations, age factors, and the presence of an immunocompromised state.\n\nAcknowledgments\n\nThe authors would like to thank all the patients presented in the study who made their data available.\n\nAuthor Contributions\n\nConceptualization B.B., E.B. and C.B.; methodology, B.B. and C.B.; software, B.B., E.B. and G.G.; validation, C.B., B.B., L.A.M. and E.B.; formal analysis, B.B., C.B., E.B., C.C., G.G. and A.M.; original draft preparation, B.B.; writing—review and editing, C.C. and C.B.; visualization, E.B., C.C., G.G., A.M. and L.A.M.; project administration, B.B. and C.B. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe authors comply with international and national ethical standards. All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki.\n\nInformed Consent Statement\n\nInformed consent was obtained from the patients to publish this paper.\n\nData Availability Statement\n\nData sharing is not applicable.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 (a,b) The basal CT with GGO in a typical peripheral and posterior distribution of COVID-19 pneumonia with a CT-SS of 13/20. (c,d) The chest CT performed 1 week later, showing more extensive pneumonia with a CT-SS of 16/20.\n\nFigure 2 Chest CT performed in the emergency department on 7 June, showing GGO areas with a peripheral and central distribution in a typical presentation of COVID-19 pneumonia in a multifocal involvement. (a,b) GGO areas in the superior lobes, (c) the middle and left superior lobes, and (d) the inferior lobes.\n\nFigure 3 Chest CT performed on 17 June. (a,b) Some new GGO areas in the left superior lobe with the disappearance of the GGO areas in the superior lobe. (c,d) An evolution in crazy paving and the consolidation of some previous GGO in the middle and inferior lobes.\n\nFigure 4 Chest CT performed on 3 July, showing in the image (a) that some GGO areas remained bilaterally present in the superior lobe and in the image (b) in the middle and inferior lobe with a multifocal distribution.\n\nFigure 5 Chest CT performed in the emergency room on 1 July. (a) Some GGO in the left superior lobe, (b) in the right superior lobe, (c) the middle and right lobe, and (d) the inferior lobes.\n\nFigure 6 Chest CT was performed on 21 July. (a) The resolution of some GGO in the superior lobe. However, GGO continued to be present in the inferior lobe, as shown in (b).\n\nFigure 7 Chest CT performed on 7 August (a) showing some new GGO in the superior lobes and also in the middle and inferior lobes (b). On the chest CT performed a week later was visible the resolution of some GGO (c,d).\n\nFigure 8 Chest CT performed 13 July showing some small consolidation areas with a peripheral and posterior distribution in the superior lobes (a), part of the superior ad inferior lobes (b) and at the basal level of the inferior lobes (c).\n\nFigure 9 Chest CT performed on 21 July showing some central and peripheral GGO with interstitial thickness and multifocal distribution in the superior lobes (a), in the middle and inferior lobes (b) and in the inferior lobes (c).\n\nFigure 10 Some GGO and consolidation located at the peripheral and posterior inferior lobes, with some consolidation and small pleural effusion (a,b) were incidentally found on the chest CT performed on 7 July for thoracic pain in a patient who tested positive for SARS-CoV-2 and who came to the emergency room for a lipothymic episode.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Gulati A. Pomeranz C. Qamar Z. Thomas S. Frisch D. George G. Summer R. DeSimone J. Sundaram B. A comprehensive review of manifestations of novel coronaviruses in the context of deadly COVID-19 global pandemic Am. J. Med. Sci. 2020 360 5 34 10.1016/j.amjms.2020.05.006 32620220\n2. Bellocchio L. Bordea I.R. Ballini A. Lorusso F. Hazballa D. Isacco C.G. Malcangi G. Inchingolo A.D. Dipalm G. Inchingolo F. Environmental Issues and Neurological Manifestations Associated with COVID-19 Pandemic: New Aspects of the Disease? Int. J. Environ. Res. Public Health 2020 17 8049 10.3390/ijerph17218049\n3. Brogna B. Brogna C. Petrillo M. Conte A.M. Benincasa G. Piscopo M. SARS-CoV-2 detection in fecal sample from a patient with typical findings of COVID-19 pneumonia on CT but negative to multiple SARS-CoV-2 RT-PCR tests on oropharyngeal and nasopharyngeal swab samples Medicina 2021 57 290 10.3390/medicina57030290 33804646\n4. Wang J.G. Zhong Z.J. Li M. Fu J. Su Y.H. Ping Y.M. Xu Z.J. Li H. Chen Y.H. Huang Y.L. Coronavirus Disease 2019-Related Multisystem Inflammatory Syndrome in Children: A Systematic Review and Meta-Analysis Biochem. Res. Int. 2021 2021 5596727 10.1155/2021/5596727 34336288\n5. Manigandan S. Wu M.T. Ponnusamy V.K. Raghavendra V.B. Pugazhendhi A. Brindhadevi K. A systematic review on recent trends in transmission, diagnosis, prevention and imaging features of COVID-19 Process Biochem. 2020 98 233 240 10.1016/j.procbio.2020.08.016 32843849\n6. Johansson M.A. Quandelacy T.M. Kada S. Prasad P.V. Steele M. Brooks J.T. Slayton R.B. Biggerstaff M. Butler J.C. SARS-CoV-2 transmission from people without COVID-19 symptoms JAMA Netw. Open 2021 4 e2035057 10.1001/jamanetworkopen.2020.35057 33410879\n7. Rubin G.D. Ryerson C.J. Haramati L.B. Sverzellati N. Kanne J.P. Raoof S. Schluger N.W. Volpi A. Yim J.-J. Martin I.B.K. The role of chest imaging in patient management during the COVID-19 pandemic: A multinational consensus statement from the Fleischner Society Chest 2020 158 106 116 10.1016/j.chest.2020.04.003 32275978\n8. Revel M.P. Parkar A.P. Prosch H. Silva M. Sverzellati N. Gleeson F. Brady A. COVID-19 patients and the radiology department—Advice from the European Society of Radiology (ESR) and the European Society of Thoracic Imaging (ESTI) Eur. Radiol. 2020 30 4903 4909 10.1007/s00330-020-06865-y 32314058\n9. Akl E.A. Blaži’c I. Yaacoub S. Frija G. Chou R. Appiah J.A. Fatehi M. Flor N. Hitti E. Jafri H. Use of Chest Imaging in the Diagnosis and Management of COVID-19: A WHO Rapid Advice Guide Radiology 2021 298 E63 E69 10.1148/radiol.2020203173 32729811\n10. Chilamakuri R. Agarwal S. COVID-19: Characteristics and therapeutics Cells 2021 10 206 10.3390/cells10020206 33494237\n11. Jahanshahlu L. Rezaei N. Monoclonal antibody as a potential anti-COVID-19 Biomed. Pharm. 2020 129 110337 10.1016/j.biopha.2020.110337 32534226\n12. U.S. Food and Drug Administration Pfizer-BioNTech COVID-19 Vaccine Available online: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/pfizer-biontech-covid-19-vaccine/ (accessed on 11 December 2020)\n13. European Medicine Agency COVID-19 Vaccines: Key Facts Available online: https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/vaccines-covid-19/covid-19-vaccines-key-facts (accessed on 21 December 2020)\n14. U.S. Food and Drug Administration JANSSEN COVID-19 Vaccine Available online: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine (accessed on 11 March 2021)\n15. Voysey M. Clemens S.A.C. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. Angus B. Baillie V.L. Barnabas S.L. Bhorat Q.E. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: An interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Lancet 2021 397 99 111 10.1016/S0140-6736(20)32661-1 33306989\n16. Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. Perez J.L. Marc G.P. Moreira E.D. Zerbini C. Safety and Efficacy of the BNT162b2 mRNA Covid19 Vaccine N. Engl. J. Med. 2020 383 2603 2615 10.1056/NEJMoa2034577 33301246\n17. Burki T.K. Lifting of COVID-19 restrictions in the UK and the Delta variant Lancet Respir. Med. 2021 9 e85 10.1016/S2213-2600(21)00328-3 34265238\n18. Lustig Y. Zuckerman N. Nemet I. Atari N. Kliker L. Regev-Yochay G. Sapir E. Mor O. Alroy-Preis S. Mendelson E. Neutralising capacity against Delta (B. 1.617. 2) and other variants of concern following Comirnaty (BNT162b2, BioNTech/Pfizer) vaccination in health care workers, Israel Eurosurveillance 2021 26 2100557 10.2807/1560-7917.ES.2021.26.26.2100557\n19. Bleier B.S. Ramanathan M. Jr. Lane A.P. COVID-19 vaccines may not prevent nasal SARS-CoV-2 infection and asymptomatic transmission Otolaryngol.–Head Neck Surg. 2021 164 305 307 10.1177/0194599820982633 33320052\n20. Aschwanden C. Five reasons why COVID herd immunity is probably impossible Nature 2021 591 520 522 10.1038/d41586-021-00728-2 33737753\n21. Chung M. Bernheim A. Mei X. Zhang N. Huang M. Zeng X. Cui J. Xu W. Yang Y. Fayad Z.A. CT Imaging Features of 2019 Novel Coronavirus (2019-nCoV) Radiology 2020 295 202 207 10.1148/radiol.2020200230 32017661\n22. Levi R. Azzolini E. Pozzi C. Ubaldi L. Lagioia M. Mantovani A. Rescigno M. One dose of SARS-CoV-2 vaccine exponentially increases antibodies in recovered individuals with symptomatic COVID-19 J. Clin. Investig. 2021 131 e149154 10.1172/JCI149154\n23. Krammer F. Srivastava K. Alshammary H. Amoako A.A. Awawda M.H. Beach K.F. Bermúdez-González M.C. Bielak D.A. Carreño J.M. Chernet R.L. Antibody responses in seropositive persons after a single dose of SARS-CoV-2 mRNA vaccine N. Engl. J. Med. 2021 384 1372 1374 10.1056/NEJMc2101667 33691060\n24. Teijaro J.R. Farber D.L. COVID-19 vaccines: Modes of immune activation and future challenges Nat. Rev. Immunol. 2021 21 195 197 10.1038/s41577-021-00526-x 33674759\n25. Dagan N. Barda N. Kepten E. Miron O. Perchik S. Katz M.A. Hernán M.A. Lipsitch M. Reis B. Balicer R.D. BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting N. Engl. J. Med. 2021 384 1412 1423 10.1056/NEJMoa2101765 33626250\n26. Ramasamy M.N. Minassian A.M. Ewer K.J. Flaxman A.L. Folegatti P.M. Owens D.R. Voysey M. Aley P.K. Angus B. Babbage G. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): A single-blind, randomised, controlled, phase 2/3 trial Lancet 2021 396 1979 1993 10.1016/S0140-6736(20)32466-1 33220855\n27. Voysey M. Clemens S.A.C. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. Angus B. Baillie V.L. Barnabas S.L. Bhorat Q.E. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: A pooled analysis of four randomised trials Lancet 2021 397 881 889 10.1016/S0140-6736(21)00432-3 33617777\n28. Chodick G. Tene L. Patalon T. Gazit S. Ben Tov A. Cohen D. Muhsen K. The effectiveness of the TWO-DOSE BNT162b2 vaccine: Analysis of real-world data Clin. Infect. Dis. 2021 4 e2115985 10.1001/jamanetworkopen.2021.15985\n29. Bernal J.L. Andrews N. Gower C. Gallagher E. Simmons R. Thelwall S. Stowe J. Tessier E. Groves N. Dabrera G. Effectiveness of COVID-19 vaccines against the B. 1.617. 2 (Delta) variant N. Engl. J. Med. 2021 385 585 594 10.1056/NEJMoa2108891 34289274\n30. Williams S.V. Vusirikala A. Ladhani S.N. De Olano E.F.R. Iyanger N. Aiano F. Stoker K. Rao G.G. John L. Patel B. An outbreak caused by the SARS-CoV-2 Delta (B. 1.617. 2) variant in a care home after partial vaccination with a single dose of the COVID-19 vaccine Vaxzevria, London, England, April 2021 Eurosurveillance 2021 26 2100626 10.2807/1560-7917.ES.2021.26.27.2100626 34240699\n31. Cheng Z. Xue M. Zheng P. Lyu J. Zhan Z. Hu H. Zhang Y. Zhang X. Sun B. Factors Affecting the Antibody Immunogenicity of Vaccines against SARS-CoV-2: A Focused Review Vaccines 2021 9 869 10.3390/vaccines9080869 34451994\n32. Mohamed E. Coyle P. Kumar T.S. Molokhia A. Harris T. Cardiac arrest secondary to Covid19 pneumonia post full vaccination Am. J. Emerg. Med. 2021 49 257 10.1016/j.ajem.2021.06.027 34171719\n33. Patrinos A. Komninos D. Dimouli K. Kartsonakis A. Serpanos D. Kalogeropoulos G. Dimitropoulou D. Case Report: An immunocompromised, vaccine breakthrough COVID-19 patient with pneumonia F1000Research 2021 10 540 10.12688/f1000research.53089.1\n34. Ebrille E. Lucciola M.T. Amellone C. Ballocca F. Orlando F. Giammaria M. Syncope as the presenting symptom of COVID-19 infection HeartRhythm Case Rep. 2020 6 363 366 10.1016/j.hrcr.2020.04.015 32373465\n35. Vignier N. Bérot V. Bonnave N. Peugny S. Ballet M. Jacoud E. Michaud C. Gaillet M. Djossou F. Epelboin L. Early Release-Breakthrough Infections of SARS-CoV-2 Gamma Variant in Fully Vaccinated Gold Miners, French Guiana EID J. 2021 27 1080 6059 10.3201/eid2710.211427\n36. Brown C.M. Vostok J. Johnson H. Burns M. Gharpure R. Sami S. Sabo R.T. Hall N. Foreman A. Schubert P.L. Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings—Barnstable County, Massachusetts, July 2021 MMWR Morb. Mortal. Wkly. Rep. 2021 70 1059 1062 10.15585/mmwr.mm7031e2 34351882\n37. Lord J.M. The effect of aging of the immune system on vaccination responses Hum. Vaccines Immunother. 2013 9 1364 1367 10.4161/hv.24696 23584248\n38. Yri O.E. Torfoss D. Hungnes O. Tierens A. Waalen K. Nordøy T. Dudman S.G. Kilander A. Wader K.F. Østenstad B. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment Blood 2011 118 6769 6771 10.1182/blood-2011-08-372649 22058114\n39. Marcacci G. Fiorentino G. Volzone F. Falcone U. Parrella R. Donnarumma D. D’Ovidio S. Annunziata A. Micallo G. Portella G. Atypical COVID-19 dynamics in a patient with mantle cell lymphoma exposed to rituximab Infect. Agents Cancer 2021 16 1 6 10.1186/s13027-021-00376-1\n40. Bonelli M.M. Mrak D. Perkmann T. Haslacher H. Aletaha D. SARS-CoV-2 vaccination in rituximab-treated patients: Evidence for impaired humoral but inducible cellular immune response Ann. Rheum. Dis. 2021 10.1136/annrheumdis-2021-220408\n41. Chilimuri S. Mantri N. Zahid M. Sun H. COVID-19 vaccine failure in a patient on rituximab therapy Rheumatol. Adv. Pr. 2021 5 rkab038 10.1093/rap/rkab038 34159292\n42. Alshukairi A.N. El-Kafrawy S.A. Dada A. Yasir M. Yamani A.H. Saeedi M.F. Aljohaney A. AlJohani N.I. Bahaudden H.A. Alam I. Re-infection with different SARS-CoV-2 clade and prolonged viral shedding in a patient with hematopoietic stem cell transplantation: SARS-CoV-2 Re-infection with different clade Int. J. Infect. Dis. 2021 110 267 271 10.1016/j.ijid.2021.07.036 34289407\n43. Bose G. Galetta K. Reactivation of SARS-CoV-2 after Rituximab in a Patient with Multiple Sclerosis Mul. Scler. Relat. Disord. 2021 52 102922 10.1016/j.msard.2021.102922\n44. Müller L. Andrée M. Moskorz W. Drexler I. Walotka L. Grothmann R. Ptok J. Hillebrandt J. Ritchie A. Schaal H. Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination MedRxiv 2021 10.1101/2021.03.03.21251066\n45. Brotons P. Perez-Argüello A. Launes C. Torrents F. Subirats M.P. Saucedo J. Claverol J. Garcia-Garcia J.J. Rodas G. Fumado V. Validation and implementation of a direct RT-qPCR method for rapid screening of SARS-CoV-2 infection by using non-invasive saliva samples Int. J. Infect. Dis. 2021 110 363 370 10.1016/j.ijid.2021.07.054 34320412\n46. Yahi N. Chahinian H. Fantini J. Infection-enhancing anti-SARS-CoV-2 antibodies recognize both the original Wuhan/D614G strain and Delta variants. A potential risk for mass vaccination? J. Infect. 2021 10.1016/j.jinf.2021.08.010\n47. Tao K. Tzou P.L. Nouhin J. Bonilla H. Jagannathan P. Shafer R.W. SARS-CoV-2 Antiviral Therapy Clin. Microbiol. Rev. 2021 34 e00109 e00121 10.1128/CMR.00109-21\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1010-660X",
"issue": "57(9)",
"journal": "Medicina (Kaunas, Lithuania)",
"keywords": "COVID-19 pneumonia; COVID-19 vaccines; SARS-CoV-2; case reports; immunocompromised state",
"medline_ta": "Medicina (Kaunas)",
"mesh_terms": "D000086382:COVID-19; D005334:Fever; D006801:Humans; D058873:Pandemics; D000086402:SARS-CoV-2",
"nlm_unique_id": "9425208",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34577814",
"pubdate": "2021-08-27",
"publication_types": "D002363:Case Reports",
"references": "34159292;33804646;34212838;32843849;34265238;33674759;33220855;33617777;32620220;34451994;33320052;33301246;32275978;33306989;32017661;33895693;33410879;33737753;34171719;33626250;34289407;33139595;33956667;34336288;34320412;34319150;32314058;33494237;33958323;23584248;34240699;34078415;34289335;33691060;34351882;33906236;34289274;32373465;32534226;34384810;33999127;32729811;22058114",
"title": "COVID-19 Pneumonia in Vaccinated Population: A Six Clinical and Radiological Case Series.",
"title_normalized": "covid 19 pneumonia in vaccinated population a six clinical and radiological case series"
} | [
{
"companynumb": "IT-PFIZER INC-202101375887",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Many drugs have been reported to cause thrombotic microangiopathy (TMA), often described as thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS). We recently established criteria to evaluate the evidence for a causal association of a drug with TMA and then we systematically reviewed all published reports of drug-induced TMA (DITMA) to determine the level of evidence supporting a causal association of the suspected drug with TMA. On the basis of this experience, we used these evaluation criteria to assess the Oklahoma TTP-HUS Registry patients who had been previously categorized as drug-induced, 1989-2014. We also reviewed the experience of the BloodCenter of Wisconsin with testing for drug-dependent antibodies reactive with platelets and neutrophils in patients with suspected immune-mediated DITMA, 1988-2014. Among 58 patients in the Oklahoma Registry previously categorized as drug-induced (15 suspected drugs), 21 patients (three drugs: gemcitabine, pentostatin, quinine) had evidence supporting a definite association with TMA; 19 (90%) of the 21 patients had quinine-induced TMA. The BloodCenter of Wisconsin tested 40 patients with suspected DITMA (eight drugs); drug-dependent antibodies, supporting a definite association with TMA, were identified in 30 patients (three drugs: oxaliplatin, quinine, vancomycin); 28 (93%) of the 30 patients had quinine-induced TMA. Combining the data from these two sources, 51 patients (five drugs) have been identified with evidence supporting a definite association with TMA. DITMA was attributed to quinine in 47 (92%) of these 51 patients.",
"affiliations": "Department of Biostatistics and Epidemiology, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.",
"authors": "Reese|Jessica A|JA|;Bougie|Daniel W|DW|;Curtis|Brian R|BR|;Terrell|Deirdra R|DR|;Vesely|Sara K|SK|;Aster|Richard H|RH|;George|James N|JN|",
"chemical_list": "D000906:Antibodies; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D015649:Pentostatin; D014640:Vancomycin; D011803:Quinine; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.23960",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "90(5)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000554:Ambulatory Care Facilities; D000906:Antibodies; D003841:Deoxycytidine; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D009825:Oklahoma; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D015649:Pentostatin; D011697:Purpura, Thrombotic Thrombocytopenic; D011803:Quinine; D012042:Registries; D057049:Thrombotic Microangiopathies; D014640:Vancomycin; D014922:Wisconsin",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "406-10",
"pmc": null,
"pmid": "25639727",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "11126885;23729372;11747383;12210813;12637323;14671503;14744847;1979368;7977300;17687133;24529995;25119611;25414441;10620564;11072960;10440915;9867731;19505260;20530792;23302815;11389025",
"title": "Drug-induced thrombotic microangiopathy: Experience of the Oklahoma Registry and the BloodCenter of Wisconsin.",
"title_normalized": "drug induced thrombotic microangiopathy experience of the oklahoma registry and the bloodcenter of wisconsin"
} | [
{
"companynumb": "US-MYLANLABS-2015M1042472",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PENTOSTATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTrastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combine trastuzumab (T), a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), and a cytotoxic molecule derived from maytansine (DM1).\n\n\nMETHODS\nWe report the first case of T-DM1-associated pleural and pericardial effusions three weeks after the second course of T-DM1 in a patient with breast cancer. Drug-induced pleural and pericardial effusions was implicated in the absence of other etiologies. The Naranjo Scale indicated a probable drug-induced adverse reaction.Management & outcome: The patient fully recovered after thoracentesis and discontinuation of T-DM1. The patient has reported no side effect after the sixth course of trastuzumab.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case in the literature of bilateral pleural and pericardial effusions in a patient treated with T-DM1. The successful initiation of treatment with trastuzumab following withdrawal of T-DM1 suggests that emtansine played a role in the development of bilateral pleural and pericardial effusions. We hypothesize that the patient's condition was a result of a local inflammatory reaction to emtansine by direct toxicity.",
"affiliations": "Pharmacy Department, Centre Georges-François Leclerc, Dijon, France.;Regional Pharmacovigilance Centre of Burgundy, University Hospital of Dijon, Dijon, France.;Medical Oncology Department, Centre Georges-François Leclerc, Dijon, France.;Medical Oncology Department, Centre Georges-François Leclerc, Dijon, France.;Regional Pharmacovigilance Centre of Burgundy, University Hospital of Dijon, Dijon, France.;Regional Pharmacovigilance Centre of Burgundy, University Hospital of Dijon, Dijon, France.;Pharmacovigilance Centre of Rouen, University Hospital of Rouen, Rouen, France.;Pharmacy Department, Centre Georges-François Leclerc, Dijon, France.",
"authors": "Lombardi|Jeffrey|J|https://orcid.org/0000-0001-6619-8839;Lory|Pauline|P|;Martin|Nils|N|;Mayeur|Didier|D|;Combret|Sandrine|S|;Grandvuillemin|Aurélie|A|;Boulay|Charlène|C|;Schmitt|Antonin|A|https://orcid.org/0000-0002-3132-7730",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/10781552211015772",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Pleural effusions; adverse drug reaction; oncology; pericardial effusion; trastuzumab-emtansine",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "10781552211015772",
"pmc": null,
"pmid": "34000917",
"pubdate": "2021-05-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Trastuzumab-emtansine induced pleural and pericardial effusions.",
"title_normalized": "trastuzumab emtansine induced pleural and pericardial effusions"
} | [
{
"companynumb": "FR-PFIZER INC-2021642417",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Histamine is involved in various physiological functions like sleep-wake cycle and stress regulation. The histamine N-methyltransferase (HNMT) enzyme is the only pathway for termination of histamine neurotransmission in the central nervous system. Experiments with HNMT knockout mice generated aggressive behaviours and dysregulation of sleep-wake cycles. Recently, seven members of two unrelated consanguineous families have been reported in whom two different missense HNMT mutations were identified. All showed severe intellectual disability, delayed speech development and mild regression from the age of 5 years without, however, any dysmorphisms or congenital abnormality. A diagnosis of mental retardation, autosomal recessive 51 was made. Here, we describe a severely mentally retarded adolescent male born from second cousins with a homozygous mutation in HNMT. His phenotypic profile comprised aggression, delayed speech, autism, sleep disturbances and gastro-intestinal problems. At early age, regression occurred. Treatment with hydroxyzine combined with a histamine-restricted diet resulted in significant general improvement.",
"affiliations": "Centre of Excellence for Neuropsychiatry, Vincent Van Gogh Institute, Venray, The Netherlands wmaverhoeven@planet.nl.;Centre of Excellence for Neuropsychiatry, Vincent Van Gogh Institute, Venray, The Netherlands.;Department of Hospital Pharmacy, VieCuri Medical Centre, Venlo, The Netherlands.;Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.",
"authors": "Verhoeven|Willem M A|WMA|;Egger|Jos I M|JIM|;Janssen|Paddy K C|PKC|;van Haeringen|Arie|A|",
"chemical_list": "D006919:Hydroxyzine; D006632:Histamine; D006637:Histamine N-Methyltransferase",
"country": "England",
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"doi": "10.1136/bcr-2020-235972",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2020-235972\n10.1136/bcr-2020-235972\nRare Disease\n1506\n1523\n1560\n1375\n1325\n80\n159\n1561\n1345\nCase reportAdult male patient with severe intellectual disability caused by a homozygous mutation in the HNMT gene\nVerhoeven Willem M A 12 Egger Jos I M 13 Janssen Paddy K C 45 van Haeringen Arie 6 1 Centre of Excellence for Neuropsychiatry, Vincent Van Gogh Institute, Venray, The Netherlands\n2 Department of Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands\n3 Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands\n4 Department of Hospital Pharmacy, VieCuri Medical Centre, Venlo, The Netherlands\n5 Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands\n6 Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands\nCorrespondence to Professor Willem M A Verhoeven; wmaverhoeven@planet.nl\n2020 \n12 12 2020 \n12 12 2020 \n13 12 e23597228 9 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article 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. See: http://creativecommons.org/licenses/by-nc/4.0/.Histamine is involved in various physiological functions like sleep–wake cycle and stress regulation. The histamine N-methyltransferase (HNMT) enzyme is the only pathway for termination of histamine neurotransmission in the central nervous system. Experiments with HNMT knockout mice generated aggressive behaviours and dysregulation of sleep–wake cycles. Recently, seven members of two unrelated consanguineous families have been reported in whom two different missense HNMT mutations were identified. All showed severe intellectual disability, delayed speech development and mild regression from the age of 5 years without, however, any dysmorphisms or congenital abnormality. A diagnosis of mental retardation, autosomal recessive 51 was made. Here, we describe a severely mentally retarded adolescent male born from second cousins with a homozygous mutation in HNMT. His phenotypic profile comprised aggression, delayed speech, autism, sleep disturbances and gastro-intestinal problems. At early age, regression occurred. Treatment with hydroxyzine combined with a histamine-restricted diet resulted in significant general improvement.\n\npsychiatry (drugs and medicines)metabolic disordersgeneticstherapeutic indicationsspecial-featureunlocked\n==== Body\nBackground\nBrain histamine, formed from the essential amino acid L-histidine, is a neurotransmitter and involved in several physiological functions like sleep–wake cycles, stress response and appetite. Two different enzymes are responsible for its inactivation, that is, diamine oxidase (DAO) and histamine N-methyltransferase (HNMT), located in chromosome 2q22.1 (OMIM: 605238). DAO, also known as histaminase, is mainly expressed in the digestive tract and to a lesser extent in the kidneys and placenta, which indicates that this enzyme metabolises histamine in the peripheral organs but not in the central nervous system (CNS). In contrast, HNMT is widely expressed in the CNS, kidney and liver and catalyses the transfer of a methyl group from S-adenosyl-L-methionine to histamine, yielding N-methylhistamine and S-adenosyl-L-homocysteine (figure 1). Thus, inactivation of histamine by HNMT is the only well-known pathway for the termination of neurotransmission action in the mammalian CNS.\n\nFigure 1 Enzymatic activity of histamine N-methyltransferase (HNMT). HNMT catalyses the transfer of a methyl group from S-adenosyl-L-methionine to histamine, yielding N-methylhistamine and S-adenosyl-L-homocysteine (figure provided by PKCJ).\n\nAs reported by several investigators, genetic single nucleotide polymorphisms of HNMT may play a role in a variety of human brain disorders such as Parkinson’s disease,1–3 and attention deficit disorder,4 although that it is still not elucidated whether alterations in HNMT are primarily or secondarily involved.5 In addition, lowered histamine levels in cerebrospinal fluid have repeatedly been reported in patients with narcolepsy and other disorders with excessive daytime sleepiness.6 7 Finally, it is not clear whether polymorphisms of HNMT are also associated with gastrointestinal diseases.8\n\nAnimal experiments with HNMT knockout (KO) mice have demonstrated that HNMT deficiency enhances brain histamine concentrations indeed. As a consequence, the histamine KO mice showed high aggressive behaviours and experienced dysregulation of sleep–wake cycles.9 10\n\nIn recent years, a very limited number of patients have been described with a genetically caused deficiency of HNMT. One patient, aged 23 years, with a deletion at 2q22.1q22.3 encompassing among others the HNMT gene showed a clinical picture characterised by severe intellectual disability and several somatic anomalies related to other deleted genes.11 Apart from this patient, two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively, have been reported.12 The Turkish family with its background in Iraq had a total of nine children of whom four (two boys and two girls) showed profound to severe intellectual disability and speech was limited to single words. The condition was milder in the males as compared with the females and none of them had any neurological problems nor dysmorphisms, autism or congenital anomalies of any kind. All affected members showed mild regression from the age of 5 years. The Kurdish family with its origin in Iraq had seven children of whom three (two boys and one girl) presented with severe intellectual disability and delayed speech development. Similarly, these patients had no dysmorphisms or any congenital malformations. Exome sequencing identified two different homogeneous missense HNMT mutations. In both families with affected members, ranged in age from 13 years to 35 years, a diagnosis of non-syndromic autosomal intellectual disability was established that was named mental retardation, autosomal recessive 51 (MRT51; OMIM: 616739). These observations indicate that histamine modulates brain development and that HNMT plays an important role in human neurodevelopment.\n\nHere, we describe in detail an adolescent male with severe intellectual disability from a family of second generation consanguinity in whom exome sequencing finally yielded a homogenous mutation in the HNMT gene.\n\nCase presentation\nEarly development\nThe patient is a 23-year-old severely intellectually disabled native Dutch man born from consanguineous parents in that the paternal grandmother of the patients’ father was a sister of the paternal grandmother of the patient’s mother. Father and mother are, therefore, second cousins. The patient was born after his mother had five miscarriages and one healthy son. Pregnancy and delivery were uncomplicated and during his first 2 years, development of speech, motor function and sociality were normal, although that he suffered from recurrent upper airway infections. Thereafter, however, global deterioration with loss of previously acquired capacities, especially language, became apparent and severe aggressive behavioural problems occurred. Moreover, it was no longer possible to make normal contact. Aged 3, at a specialised outpatient department for child and adolescent psychiatry, a diagnosis of autism spectrum disorder was made, at that time also called childhood disintegrative disorder. One year later, the patient was referred to a child neurology clinic for evaluation of his developmental regression. Somatic and neurological examination disclosed no abnormalities nor were there any dysmorphisms. Laboratory tests of relevant haematological and chemical parameters as well as extensive investigations, including MRI scanning of the brain, were all normal and a diagnosis of autistic retardation was made. In subsequent years, genetic, neurological, metabolic, ophthalmological and dermatological examinations were performed as well as a second MRI of the brain under general anaesthesia. Again, no aetiological explanation could be found for his developmental delay and the diagnosis of autistic retardation was confirmed. Because of his aggressive behaviour with temper tantrums, he stayed during daytime at an activity centre of an institute for people with intellectual disabilities where several short-lasting pharmacological interventions were tried that all had to be stopped because of increase of disinhibited and aggressive behaviours (promethazine, methylphenidate and phenobarbital) or motor side effects (risperidone). Apart from challenging behaviours, there were persistent sleep disturbances as well as intermittent urine incontinence and diarrhoea.\n\nFirst neuropychiatric referral\nAt the age of 12, he was referred for specialised neuropsychiatric evaluation to the first author. Behavioural observation revealed clear ritualistic, stereotyped and autistic traits with mood instability necessitating structured individual guidance in all situations to avoid overestimation with subsequent challenging and aggressive behaviours. He could not read, write, calculate or tell the time. Somatic and neurological examination showed no abnormalities and there were no dysmorphisms. Weight, height and head circumference were in accordance with his biological age. Relevant haematological and biochemical parameters were all normal. The patient communicated with simple few word sentences, body language and pictorial signs. As assessed with the Vineland Adapative Behaviour Scale (VABS13) developmental age scores on the domains of communication, motor skills, socialisation and daily activities were 19 months, 42 months, 11 months and 24 months, respectively, corresponding with severe intellectual disability. At that time, he was treated by his mother with homeopathic compounds of which one also contained a very low dose of promethazine. For behavioural control, two times per day 0.4 mg haloperidol was added. To elucidate the aetiology of his severe intellectual disability, single nucleotide polymorphism (SNP) array analysis was performed that showed no abnormalities. Subsequently, specialised neuropsychiatric assistance was no longer needed.\n\nIntermediate period\nAged 14, the patient developed severe headache, vomiting, neck flexion, urine incontinence and unstable gait on which haloperidol was discontinued. Since these symptoms worsened, multiple brain imaging was performed that demonstrated a brain tumour in the fossa posterior. He subsequently underwent fossa posterior craniotomy and a benign right-sided cerebellar haemangioblastoma was successfully removed (see figure 2 for preoperative MRI image of the brain and CT scanning 2 years later). Neurofibromatosis type I and Von Hippel-Lindau syndrome were genetically excluded. Thereafter, the patient functioned on his premorbid level without any neurological symptoms and returned to his parent’s home and continued during daytime the structured activity programme at his former institute for people with intellectual disabilities. Severe sleeping problems, intermittent urine incontinence and diarrhoea were still present. To improve his sleeping pattern, the treating physician prescribed 2 mg zuclopenthixol. Since no significant changes in his behaviour repertoire could be expected, neuropsychiatric consultation was not requested. However, at the age of 19, trio-based exome sequencing demonstrated a homozygous pathogenic nonsense variant in the first exon of the HNMT gene (g.138722149C>T:NM_006895.2:c.88C>T(p.Gln30*)) leading to a premature stop codon, which was confirmed by Sanger sequencing. Both parents were shown to be heterozygous carrier of this variant. Figure 3 shows the Sanger sequencing electropherograms of the index patient and his parents. These findings corresponded with a diagnosis of MRT51. Because of this finding, he was referred again for specialised neuropsychiatric evaluation.\n\nFigure 2 (A) Aged 14 years. Preoperative T2-weighted-Fluid-Attenuated Inversion Recovery (FLAIR T2) MRI image of the brain showing right-sided cerebellar cystic tumour (cerebellar haemangioblastoma) with slight peritumoral oedema and a maximum cross-section of 56 mm, leading to compression of the fourth ventricle and slight displacement to the left (enhancing mural nodule and supratentorial obstructive hydrocephalus not visible). (B) Aged 16 years. CT scan image of the brain showing small residual cyst only with cross-section of 20 mm without any compression of the fourth ventricle.\n\nFigure 3 Sanger sequencing electropherogram of the index patient, and his parents showing in the grey field the homozygous mutations of the index patient (C replaced by T).\n\nSecond neuropychiatric referral\nAt examination, aged 19, a similar behavioural repertoire was present as during the first consultation, aged 12, in that he still displayed autistic, ritualistic and challenging behaviours with aggressive acts and self injuries. Active language was restricted to single words or short and simple sentences. Somatic and neurological examination disclosed no abnormalities. Height (172 cm) and weight (70 kg) were in accordance with his current biological age. Relevant haematological (eg, white blood cell count and thrombocytes) and biochemical parameters (eg, vitamin status, thyroid and liver parameters, glucose and lipid spectrum) were all normal still. Pharmacological treatment comprised two times per day 40 mg pipamperone, irregularly combined with 15 mg mirtazepine or 7.5 mg midazolam to improve his sleep pattern. Also, two times per day 20 mg omeprazole was prescribed. Again, psychological assessment was performed. Social and emotional development as measured with the Dutch scale for emotional development in people with intellectual disability (ESSEON-R14) corresponded with a developmental age of 12 months and 18 months, respectively. As assessed with the VABS, developmental age scores on the domains of communication, daily activities and socialisation were 23 months, 23 months and 15 months, respectively, being not significantly different from those as established previously. With the Dutch scale for social life skills (SRZ15), a developmental age of 2–3 years was established, corresponding with a cognitive level of 2–4 years, enhancing the risk of overestimation. He was then referred to a university outpatient department for child and adolescent psychiatry where the diagnosis of autism was confirmed. Subsequently, he attended the outpatient department of clinical pharmacology for treatment advice.\n\nTreatment\nBecause of the demonstrated homozygous mutation in the HNMT gene resulting in the complete absence of a functional HNMT, treatment with the antihistaminergic drug hydroxyzine in a daily dose of 25 mg and a histamine-restricted diet was prescribed. Since their efficacy was doubtful, it was advised to stop the use of psychotropics as mentioned before with the exception of omeprazole.\n\nOutcome and follow-up\nUntil now, aged 23, treatment with 25 mg hydroxyzine in combination with a histamine-restricted diet resulted in normalisation of the patient’s sleep–wake cycle, significant reduction of aggression, improvement of speech and receptive language capacities, and complete continence for urine and faeces. The patient (figure 4) still lives at his parents’ home following, like in previous years, during daytime an activity programme at the same institute for people with intellectual disabilities.\n\nFigure 4 Picture of the patient without any dysmorphic features: (A and B) aged 17 years and (C and D) aged 23 years.\n\nDiscussion\nHere, a 23-year-old severely intellectually disabled Dutch male patient born from second cousins is described in whom trio-based exome sequencing demonstrated a homozygous mutation in the HNMT gene matching a diagnosis of MRT51. Apart from one male patient with a homozygous mutation of the HNMT gene but without any phenotypic description (DECIPHER (324 002)), to the best of our knowledge, this is the first patient with this genetic syndrome after the publication of seven individuals from two unrelated families of Turkish and Kurdish descent, respectively.12 Like in the affected members of these two families, also in our patient, global regression occurred around the age of 4 years, most pronounced regarding speech and language, in the absence of any dysmorphic features or congenital anomalies. Although not explicitly mentioned in the description of the patient histories of the two unrelated families from Turkish and Kurdish descent, it can be assumed that in all, like in our patient, a diagnosis of autism could have been made.\n\nUnfortunately, in the publication of Heidari and coworkers, no information is given about either sleep pattern and intestinal problems or advised treatment regimen. In the here described patient, treatment with the antihistaminergic compound hydroxyzine in combination with a histamine-restricted diet resulted in normalisation of sleep pattern, complete continence, improvement of active speech and a significant reduction of aggressive challenging behaviours.\n\nIn conclusion, the behavioural phenotype of HNMT-associated MRT51 may comprise not only regression with loss of earlier achieved capacities around the middle of the first decade, but also autism, dysregulation of sleep–wake cycle and intestinal problems. The latter two may be effectively treated with the antihistaminergic compound hydroxyzine in combination with a histamine-restricted diet. Because of the attained marked and long-lasting improvement of this patients’ general functioning, in retrospect, the earlier postulated regression hypothesis may have to be reconsidered.\n\nPatient’s perspective\nWe, the parents of the described patient, have seen a significant improvement in general functioning after the diagnosis was established and our son started the medication in combination with the histamine-restricted diet. He is now much calmer, sleeps well, shows no more aggression and has become completely potty-trained. It is also noticeable that he has pleasure again in his activities within the daily activity centre. Finally, we as well as his institutional supervisors can make with simple terms much better contact with him. We are very happy with all these positive developments.\n\nLearning points\nMedical professionals should consider whole exome sequencing as the starting point for aetiological investigation.\n\nBrain histamine is crucial in physiological functions like sleep and stress regulation.\n\nHistamine N-methyltransferase deficiency is associated with aggressive behaviours and mental retardation, autosomal recessive 51.\n\nAntihistaminergic compounds that pass the blood–brain barrier such as hydroxyzine, combined with a histamine-restricted diet, normalise sleep pattern, reduce levels of challenging behaviour and ameliorate communication.\n\nWritten informed consent was obtained from the parents for publication of the case history of the patient; the parents also kindly provided the picture of the patient at present age. The patient was referred by the Centre for Consultation and Expertise, region West. The authors are indebted to the staff members of the Gemiva-SVG Institute for people with intellectual disabilities, location Zoeterwoude, for their careful observations of the behavioural status of the patient and the psychological assessments. For subsequent advises about treatment, the patient was referred to the outpatient department of clinical pharmacology at the Erasmus Medical Centre Rotterdam. MRI and CT images were reevaluated and selected by Dr GA Hoffland, (neuro)radiologist at the VieCuri Medical Centre, Venlo, the Netherlands.\n\nContributors: WMAV and JIME conceptualised and designed the study and reviewed the literature. WMAV assessed the patient, acquired the data and discussed the initial findings. WMAV and JIME reported the case history and drafted the manuscript. PKCJ commented on the literature review, initially evaluated the manuscript and created the figure showing the histamine neurotransmission process. AvH interpreted the genetic data and provided the Sanger electropherogram as well as the picture of the patient aged 17 (A and B). PKCJ and AvH critically reviewed the manuscript. All authors read and approved the final version of the manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Parental/guardian consent obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Agúndez JAG , Luengo A , Herráez O , et al \nNonsynonymous polymorphisms of histamine-metabolising enzymes in patients with Parkinson's disease\n. Neuromolecular Med \n2008 ;10 :10 –16\n. 10.1007/s12017-007-8017-7 17985251 \n2 Palada V , Terzić J , Mazzulli J , et al \nHistamine N-methyltransferase Thr105Ile polymorphism is associated with Parkinson's disease\n. Neurobiol Aging \n2012 ;33 :836.e1 –836.e3\n. 10.1016/j.neurobiolaging.2011.06.015 \n3 Yang X , Liu C , Zhang J , et al \nAssociation of histamine N-methyltransferase Thr105Ile polymorphism with Parkinson's disease and schizophrenia in Han Chinese: a case-control study\n. PLoS One \n2015 ;10 :e0119692. 10.1371/journal.pone.0119692 25768024 \n4 Stevenson J , Sonuga-Barke E , McCann D , et al \nThe role of histamine degradation gene polymorphisms in Moderating the effects of food additives on children's ADHD symptoms\n. Am J Psychiatry \n2010 ;167 :1108 –15\n. 10.1176/appi.ajp.2010.09101529 20551163 \n5 Yoshikawa T , Nakamura T , Yanai K \nHistamine N-methyltransferase in the brain\n. Int J Mol Sci \n2019 ;20 :737\n10.3390/ijms20030737 \n6 Nishino S , Sakurai E , Nevsimalova S , et al \nDecreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls\n. Sleep \n2009 ;32 :175 –80\n. 10.1093/sleep/32.2.175 19238804 \n7 Bassetti CL , Baumann CR , Dauvilliers Y , et al \nCerebrospinal fluid histamine levels are decreased in patients with narcolepsy and excessive daytime sleepiness of other origin\n. J Sleep Res \n2010 ;19 :620 –3\n. 10.1111/j.1365-2869.2010.00819.x 20846244 \n8 Maintz L , Novak N \nHistamine and histamine intolerance\n. Am J Clin Nutr \n2007 ;85 :1185 –96\n. 10.1093/ajcn/85.5.1185 17490952 \n9 Thakkar MM \nHistamine in the regulation of wakefulness\n. Sleep Med Rev \n2011 ;15 :65 –74\n. 10.1016/j.smrv.2010.06.004 20851648 \n10 Naganuma F , Nakamura T , Yoshikawa T , et al \nHistamine N-methyltransferase regulates aggression and the sleep-wake cycle\n. Sci Rep \n2017 ;7 :15899. 10.1038/s41598-017-16019-8 29162912 \n11 Mulatinho MV , de Carvalho Serao CL , Scalco F , et al \nSevere intellectual disability, omphalocele, hypospadia and high blood pressure associated to a deletion at 2q22.1q22.3: case report\n. Mol Cytogenet \n2012 ;5 :30. 10.1186/1755-8166-5-30 22686481 \n12 Heidari A , Tongsook C , Najafipour R , et al \nMutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability\n. Hum Mol Genet \n2015 ;24 :5697 –710\n. 10.1093/hmg/ddv286 26206890 \n13 De Bildt A , Kraijer D \nDutch adaptation of the vineland adaptive behavior scale of sparrow, Balla and Cicchetti . Leiden, The Netherlands : PITS , 2003 .\n14 Hoekman J , Miedema A , Otten B , et al \nESSEON-R schaal voor Het social-emotioneel ontwikkelingsniveau . Amsterdam : Hogrefe , 2014 .\n15 Kraijer DW , Kema GN , de Bildt AA \nSociale Redzaamheidsschaal voor zwakzinnigen (SRZ . Amsterdam : Harcourt Test Publishers , 2004 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "genetics; metabolic disorders; psychiatry (drugs and medicines); therapeutic indications",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000374:Aggression; D001921:Brain; D006632:Histamine; D006637:Histamine N-Methyltransferase; D006720:Homozygote; D006801:Humans; D006919:Hydroxyzine; D008607:Intellectual Disability; D008297:Male; D009154:Mutation; D012890:Sleep; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101526291",
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"pmid": "33310825",
"pubdate": "2020-12-12",
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"title": "Adult male patient with severe intellectual disability caused by a homozygous mutation in the HNMT gene.",
"title_normalized": "adult male patient with severe intellectual disability caused by a homozygous mutation in the hnmt gene"
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"abstract": "The dismal prognosis of pediatric acute myeloid leukemia (AML) relapsing after hematopoietic stem cell transplantation (HSCT) requires exploration of novel strategies to prevent relapse. Azacitidine (AZA) maintenance therapy could potentially reduce the recurrence rate post HSCT. Here, we presents the cases of three children with high-risk AML post HSCT who were treated with low-dose AZA maintenance therapy, demonstrating the feasibility of this therapy. Currently, all three are in complete remission for 13-41 months despite their high-risk characteristics. Our encouraging data warrant larger prospective studies to assess the efficacy and safety of low-dose AZA maintenance therapy post HSCT for pediatric patients with high-risk AML.",
"affiliations": "Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.;Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Kobe, Japan.",
"authors": "Tamura|Akihiro|A|0000-0001-7710-827X;Ishida|Toshiaki|T|;Saito|Atsuro|A|;Yamamoto|Nobuyuki|N|;Yokoi|Takehito|T|;Uemura|Suguru|S|;Nino|Nanako|N|;Fujiwara|Takahiro|T|;Tahara|Teppei|T|;Nakamura|Sayaka|S|;Kozaki|Aiko|A|;Kishimoto|Kenji|K|0000-0002-5495-8498;Hasegawa|Daiichiro|D|;Kosaka|Yoshiyuki|Y|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27284",
"fulltext": null,
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"issn_linking": "1545-5009",
"issue": "65(10)",
"journal": "Pediatric blood & cancer",
"keywords": "acute myeloid leukemia; azacitidine; pediatric; post hematopoietic stem cell transplantation",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D060046:Maintenance Chemotherapy; D008297:Male; D009364:Neoplasm Recurrence, Local; D012074:Remission Induction; D012189:Retrospective Studies",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27284",
"pmc": null,
"pmid": "29893458",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low-dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high-risk pediatric acute myeloid leukemia.",
"title_normalized": "low dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high risk pediatric acute myeloid leukemia"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1070688",
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"occurcountry": "JP",
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{
"abstract": "OBJECTIVE\nTo report three cases of convexity subarachnoid hemorrhage (cSAH) after acute ischemic stroke and review the relevant literature.\n\n\nBACKGROUND\ncSAH is an unusual presentation and the association with acute ischemic stroke has only infrequently been reported.\n\n\nMETHODS\nCase series with retrospective review of the clinical presentation and neuroimaging features of patients who presented with cSAH and acute ischemic stroke.\n\n\nRESULTS\nWe describe three cases of cSAH who presented with ipsilateral acute ischemic stroke. Two patients had ipsilateral ICA stenosis, with one patient developing cSAH after ICA stenting. The third patient developed cSAH in setting of small distal cortical ischemic lesions with normal cranial vasculature. None of these patients had evidence for cerebral amyloid angiopathy on magnetic resonance imaging-gradient echo (MRI-GRE) sequence. All our patients remained clinically stable with limited neurological deficit at the time of discharge.\n\n\nCONCLUSIONS\nWe report three more cases linking cSAH with ischemic strokes. All of our patients had good outcome with minimal neurological deficit. cSAH should remain in differential diagnosis and early complication of acute ischemic stroke.",
"affiliations": "Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine and Jackson Memorial Hospital, Miami, FL, USA.;Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine and Jackson Memorial Hospital, Miami, FL, USA.;Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine and Jackson Memorial Hospital, Miami, FL, USA. Electronic address: skoch@med.miami.edu.",
"authors": "Usmani|N|N|;Ahmad|F U|FU|;Koch|S|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0022-510X",
"issue": "348(1-2)",
"journal": "Journal of the neurological sciences",
"keywords": "Convexity subarachnoid hemorrhage; Extracranial vaso-occlusive disease; Ischemic stroke",
"medline_ta": "J Neurol Sci",
"mesh_terms": "D000368:Aged; D002545:Brain Ischemia; D002540:Cerebral Cortex; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke; D013345:Subarachnoid Hemorrhage",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Convexity subarachnoid hemorrhage in ischemic stroke.",
"title_normalized": "convexity subarachnoid hemorrhage in ischemic stroke"
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"abstract": "Enteral tubes are necessary for certain patients; however, medication absorption can be affected by this route of administration potentially resulting in decreased efficacy. All first-line treatments for Hepatitis C Virus (HCV) infection are only available as tablets and may have decreased absorption if administered via an enteral tube. This report describes the first case of a pegylated interferon and ribavirin treatment-experienced patient who successfully achieved HCV cure after 12 weeks of elbasvir/grazoprevir administered via percutaneous gastrostomy tube. We further review the available pharmacokinetic and clinical literature regarding administration via enteral feeding tubes for all first-line direct-acting antivirals (DAAs). The literature suggests that crushed administration can be considered for DAAs in patients with gastric access. However, caution should be exercised in patients with extragastric enteral tubes and in those with altered gastrointestinal tract anatomy.",
"affiliations": "Division of Infectious Diseases, The Miriam Hospital, Providence, RI, USA.;Department of Pharmacy, Maine Medical Center, Portland, ME, USA.;Division of Infectious Diseases, The Miriam Hospital, Providence, RI, USA.;Infectious Diseases, Essentia Health and St. Mary's Medical Center, Duluth, MN, USA.",
"authors": "Shah|Rajeev B|RB|0000-0003-0725-1809;Garrett|Katy L|KL|;Brotherton|Amy L|AL|;Noska|Amanda J|AJ|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1002/phar.2531",
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"issn_linking": "0277-0008",
"issue": "41(7)",
"journal": "Pharmacotherapy",
"keywords": "direct-acting antivirals; elbasvir; grazoprevir; hepatitis C virus; percutaneous endoscopic gastrostomy tube",
"medline_ta": "Pharmacotherapy",
"mesh_terms": null,
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "634-640",
"pmc": null,
"pmid": "33934388",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Elbasvir/grazoprevir administered for 12 weeks via percutaneous endoscopic gastrostomy tube achieves sustained virologic response: A case report and a review of the literature.",
"title_normalized": "elbasvir grazoprevir administered for 12 weeks via percutaneous endoscopic gastrostomy tube achieves sustained virologic response a case report and a review of the literature"
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"abstract": "Liposarcoma has been subclassified histologically into well-differentiated, myxoid, pleomorphic, and dedifferentiated types. The dedifferentiated type generally shows poorer prognosis than the well-differentiated type. Because of its rarity, the clinicopathological features and clinical outcomes of primary mediastinal dedifferentiated liposarcoma remain unclear.\n\n\n\nFive patients with primary mediastinal dedifferentiated liposarcoma were treated at Shinshu University Hospital between January 2012 and August 2017. We investigated the clinical characteristics, including age, gender, radiographic findings, pathological status, and clinical and treatment outcomes.\n\n\n\nFour of the five patients initially underwent radical surgical resection. One patient was disease-free after surgery, but the remaining three patients developed local recurrence in the mediastinum after surgical resection. Two of these patients underwent repeat surgical resection, resulting in long survival (60 and 40 months, respectively), while the other underwent proton beam therapy and showed no evidence of recurrence as of 17 months after treatment. The remaining patient was treated with chemotherapy using doxorubicin because of advanced inoperable disease, but failed to show a response and died within a month of the initiation of chemotherapy. Although the maximum standardized uptake values on fluorodeoxyglucose-computed tomography were relatively low, there was a slight positive relation between these values and the Ki-67-positive ratio in the tumor.\n\n\n\nAggressive treatment by surgical resection should be considered for mediastinal dedifferentiated liposarcoma, even in cases with local recurrence.",
"affiliations": "Department of Breast, Endocrine and Thoracic Surgery, Shinshu University, Matsumoto, Japan.;Department of Breast, Endocrine and Thoracic Surgery, Shinshu University, Matsumoto, Japan.;Department of Breast, Endocrine and Thoracic Surgery, Shinshu University, Matsumoto, Japan.;Department of Breast, Endocrine and Thoracic Surgery, Shinshu University, Matsumoto, Japan.;Department of Breast, Endocrine and Thoracic Surgery, Shinshu University, Matsumoto, Japan.;Department of Breast, Endocrine and Thoracic Surgery, Shinshu University, Matsumoto, Japan.;Department of Breast, Endocrine and Thoracic Surgery, Shinshu University, Matsumoto, Japan.;Department of Dentistry and Oral Surgery, Shinshu University, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University, Matsumoto, Japan.;Department of Laboratory Medicine, Shinshu University, Matsumoto, Japan.",
"authors": "Miura|Kentaro|K|0000-0001-6736-4712;Hamanaka|Kazutoshi|K|;Matsuoka|Shunichiro|S|0000-0001-9351-5000;Takeda|Tetsu|T|;Agatsuma|Hiroyuki|H|;Hyogotani|Akira|A|;Ito|Ken-Ichi|KI|;Nishimaki|Fumihiro|F|;Koizumi|Tomonobu|T|0000-0002-5182-0960;Uehara|Takeshi|T|",
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"doi": "10.1111/1759-7714.12888",
"fulltext": "\n==== Front\nThorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 10.1111/1759-7714.12888TCA12888Original ArticleOriginal ArticlesPrimary mediastinal dedifferentiated liposarcoma: Five case reports and a review Mediastinal dedifferentiated liposarcomaK. Miura et al.Miura Kentaro https://orcid.org/0000-0001-6736-4712kmiura@shinshu-u.ac.jp \n1\nHamanaka Kazutoshi \n1\nMatsuoka Shunichiro https://orcid.org/0000-0001-9351-5000\n1\nTakeda Tetsu \n1\nAgatsuma Hiroyuki \n1\nHyogotani Akira \n1\nIto Ken‐ichi \n1\nNishimaki Fumihiro \n2\nKoizumi Tomonobu https://orcid.org/0000-0002-5182-0960\n3\nUehara Takeshi \n4\n\n1 \nDepartment of Breast, Endocrine and Thoracic Surgery\nShinshu University\nMatsumoto\nJapan\n\n2 \nDepartment of Dentistry and Oral Surgery\nShinshu University\nMatsumoto\nJapan\n\n3 \nDepartment of Comprehensive Cancer Therapy\nShinshu University\nMatsumoto\nJapan\n\n4 \nDepartment of Laboratory Medicine\nShinshu University\nMatsumoto\nJapan\n* Correspondence\n\nKentaro Miura, Department of Breast, Endocrine and Thoracic Surgery, Shinshu University, 3‐1‐1 Asahi, Matsumoto 390‐8621, Japan.\n\nTel: +81 263 37 2783\n\nFax: +81 263 37 3024\n\nEmail: kmiura@shinshu-u.ac.jp\n17 10 2018 12 2018 9 12 10.1111/tca.2018.9.issue-121733 1740 24 7 2018 05 9 2018 06 9 2018 © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background\nLiposarcoma has been subclassified histologically into well‐differentiated, myxoid, pleomorphic, and dedifferentiated types. The dedifferentiated type generally shows poorer prognosis than the well‐differentiated type. Because of its rarity, the clinicopathological features and clinical outcomes of primary mediastinal dedifferentiated liposarcoma remain unclear.\n\nMethods\nFive patients with primary mediastinal dedifferentiated liposarcoma were treated at Shinshu University Hospital between January 2012 and August 2017. We investigated the clinical characteristics, including age, gender, radiographic findings, pathological status, and clinical and treatment outcomes.\n\nResults\nFour of the five patients initially underwent radical surgical resection. One patient was disease‐free after surgery, but the remaining three patients developed local recurrence in the mediastinum after surgical resection. Two of these patients underwent repeat surgical resection, resulting in long survival (60 and 40 months, respectively), while the other underwent proton beam therapy and showed no evidence of recurrence as of 17 months after treatment. The remaining patient was treated with chemotherapy using doxorubicin because of advanced inoperable disease, but failed to show a response and died within a month of the initiation of chemotherapy. Although the maximum standardized uptake values on fluorodeoxyglucose‐computed tomography were relatively low, there was a slight positive relation between these values and the Ki‐67‐positive ratio in the tumor.\n\nConclusion\nAggressive treatment by surgical resection should be considered for mediastinal dedifferentiated liposarcoma, even in cases with local recurrence.\n\nDedifferentiated liposarcomalocal recurrencemediastinum source-schema-version-number2.0component-idtca12888cover-dateDecember 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.3 mode:remove_FC converted:03.12.2018\n==== Body\nIntroduction\nLiposarcoma commonly occurs in the retroperitoneum or thigh, while primary mediastinal liposarcoma is rare and only a few cases have been reported to date.1, 2, 3, 4, 5, 6, 7, 8, 9 Liposarcoma has been subclassified histologically into well‐differentiated, myxoid, pleomorphic, and dedifferentiated types according to the 2012 National Comprehensive Cancer Network classification of liposarcoma.6 Chen et al. reported that the dedifferentiated type has poorer prognosis than the well‐differentiated type in intrathoracic liposarcoma, including lesions of lung, pleura, or mediastinum origin.6 However, the clinicopathological characteristics of dedifferentiated liposarcoma remain unclear because of its rarity, especially when originating from the mediastinum. We encountered five cases of primary mediastinal dedifferentiated liposarcoma in our institute. Herein, we summarize the clinicopathological characteristics and outcomes of our cases, and conduct a review of the relevant literature.\n\nMethods\nPatients\nThe data of five patients with mediastinal dedifferentiated liposarcoma treated at Shinshu University Hospital between January 2012 and August 2017 were included in this study.\n\nWe investigated patient characteristics, including age, gender, tumor characteristics, pathological status, and outcomes. During follow‐up, chest computed tomography (CT) was performed at least once every six months. Overall survival (OS) was defined as the interval from initial surgery or the commencement of chemotherapy to death or the last follow‐up date (September 2017). Recurrence‐free survival (RFS) was calculated from the date of surgery to the date of recurrence.\n\nThe institutional research ethics committee approved the study (No. 3395, Shinshu University School of Medicine).\n\nLiterature review\nWe searched the PubMed database for studies published between 2002 and 2016 using the keywords: dedifferentiated liposarcoma, mediastinum, or mediastinal.\n\nResults\nCase presentations\nCase 1\nA 45‐year‐old‐woman visited our hospital after an abnormality was detected on chest CT screening. She had no symptoms and no past history. The chest CT scan showed a tumor measuring 121 × 82 × 58 mm extending from the cervical region to the middle mediastinum with homogenous low density (Fig 1a). Fluoro‐2‐deoxyglucose positron emission tomography (FDG‐PET)‐CT revealed positive accumulation (maximum standardized uptake value [SUVmax] 1.93). Surgical resection via the cervical approach was performed followed by video‐assisted thoracic surgery (VATS) on the right side. The tumor was completely resected and the patient had an uncomplicated postoperative course. A diagnosis of dedifferentiated liposarcoma was made, and Ki‐67 immunostaining was < 10%. Chest CT showed solitary local recurrence in the middle mediastinum 51 months after surgical resection (Fig 1b). As no other recurrent lesions were detected on FDG‐PET‐CT, repeat surgical resection was performed by right‐side thoracotomy. The pathological findings of the resected tumor were the same as those of the primary tumor. Although adjuvant therapy was not performed, the patient has shown no signs of recurrence 12 months after repeat surgery.\n\nFigure 1 Chest computed tomography scans in Case 1 (a) preoperatively and (b) at recurrence. A 121 × 82 × 58 mm tumor was observed extending from the cervical region to the middle mediastinum with homogenous low density. Solitary local recurrence was observed in the middle mediastinum 51 months after surgery.\n\nCase 2\nA 62‐year‐old woman with no symptoms visited our hospital after an abnormality was detected on CT screening. Chest CT showed a tumor measuring 66 × 88 mm in the middle mediastinum with homogenous density (Fig 2a). FDG‐PET‐CT revealed positive accumulation (SUVmax 2.5); mediastinal liposarcoma was suspected based on the radiographic findings. Surgical resection was performed via median sternotomy, and as much tumor and peripheral fat tissue were resected as possible. Histopathologically, the tumor was diagnosed as dedifferentiated liposarcoma. Ki‐67 immunostaining was approximately 20%. Adjuvant therapy was not performed. After 28 months, tumor recurrence was detected on chest CT (Fig 2b), and proton beam therapy was performed. No evidence of recurrence has been observed as of 17 months after radiotherapy.\n\nFigure 2 Chest computed tomography scans in Case 2 (a) preoperatively and (b) at recurrence. A 66 × 88 mm tumor was observed in the middle mediastinum with homogenous density. Tumor recurrence was detected in the posterior mediastinum after 28 months.\n\nCase 3\nAn 81‐year‐old man with an anterior mediastinum tumor detected on chest CT during follow‐up of autoimmune pancreatitis was referred to our hospital. Chest CT showed a tumor measuring 66 × 30 mm in the anterior mediastinum, with heterogeneous low and high‐density components (Fig 3a). FDG‐PET‐CT revealed positive accumulation in the solid component (SUVmax 9.2) and anterior mediastinal liposarcoma was suspected. Sternotomy was performed and the tumor was completely resected without composite resection of other great vessels or organs. The resected tumor was diagnosed as dedifferentiated liposarcoma. Atypical cells were detected in the peripheral fat tissue, which showed low density on chest CT. The positive ratio of Ki‐67 immunostaining was 50%. After 28 months, follow‐up chest CT showed recurrent tumors behind the sternum. Repeat surgical resection was performed, but local recurrence was observed after eight months (Fig 3b). Radiotherapy was performed and the disease was well controlled.\n\nFigure 3 Chest computed tomography (CT) scans in Case 3 (a) preoperatively and (b) at recurrence. A 66 × 30 mm tumor was observed in the anterior mediastinum, which had heterogeneous areas of low and high density. After 28 months, follow‐up chest CT showed recurrent tumors behind the sternum.\n\nTypical pathological and immunohistological findings are shown in ***Figure 4. Hematoxylin and eosin staining in case 3 revealed spindle tumor cells proliferate with fibrous stroma. Immunohistochemical analysis was positive for CKD4 and slightly positive for MDM2.\n\nFigure 4 Histopathological findings in Case 3. Hematoxylin and eosin staining revealed spindle tumor cells proliferate with fibrous stroma. Immunohistochemical analysis was positive for CDK4 and slightly positive for MDM2.\n\nCase 4\nA 75‐year‐old man visited our hospital after an abnormal shadow was detected on chest X‐ray screening. He did not exhibit any symptoms but chest CT showed a huge tumor in the posterior mediastinum projecting on either side of the intrathoracic space (Fig 5). The esophagus was surrounded by the tumor. The tumor was suspected to be mediastinal liposarcoma and radical surgical resection was performed by bilateral thoracotomy. First, left‐side complete VATS was performed. The tumor was smooth with only mild adhesion between the tumor and lung, aorta, and diaphragm. Leaving only adhesion around the esophagus, surgery was performed on the right side with a 20 cm post lateral incision. Like the left side, the extent of adhesion between the tumor and surrounding tissue was minimal. The tumor surrounded the esophagus, as determined on preoperative chest CT. However, there was no invasion of the esophagus, and it was relatively easy to peel the tumor off the esophagus. The tumor was removed en bloc and complete resection was performed. The tumor was diagnosed as dedifferentiated liposarcoma and the rate of positive Ki‐67 immunostaining was 3%. Chest CT has shown no recurrence in three months.\n\nFigure 5 Preoperative computed tomography scan in Case 4. A huge tumor was detected in the posterior mediastinum, which projected on either side of the intrathoracic space. The esophagus was surrounded by the tumor.\n\nCase 5\nA 78‐year‐old man visited our hospital because of rapidly progressing hoarseness and dyspnea over a three‐month period. Chest CT showed a giant tumor in the middle and posterior mediastinum extensively surrounding the trachea (Fig 6). As radiographic findings were suspicious for mediastinal liposarcoma, chemotherapy with doxorubicin (60 mg/m2) was immediately commenced. However, it was not effective and he died two weeks later as a result of respiratory failure. Post‐mortem pathological examination revealed that the tumor was dedifferentiated liposarcoma but had not directly invaded the esophagus, trachea, or great vessels.\n\nFigure 6 Chest computed tomography scan of Case 5 at the first visit. A giant tumor was observed in the middle and posterior mediastinum extensively surrounding the trachea.\n\nSummary of five cases\nThe clinical characteristics, treatment, and outcomes of the five cases presented are summarized in Table 1. Four patients were treated by surgical resection: cervical resection and right‐side VATS (1 patient), bilateral thoracotomy with thoracoscopy (1 patient), and sternotomy (2 patients). Three of these four patients developed recurrence after surgical resection: two underwent repeat resection, while the remaining patient underwent heavy particle radiotherapy. Only one patient had chemotherapy as initial treatment using adriamycin. There was a weak positive association between SUVmax and Ki‐67 positive ratio. All five cases were French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade 2.\n\nTable 1 Summary of our five cases\n\nCase\tAge\tGender\tLocation\tSymptom\tTumor size (cm)\tSUVmax\tKi‐67 (%)\tFNCLCC grade\tInitial treatment\tSurgical approach\tRecurrence\tRFS (months)\tTreatment for recurrence\tOS\tOS status\t\n1\t45\tF\tMiddle\tNone\t12.7\t1.9\t< 10\t2\tSurgery\tCervical approach, right sided VATS\tYes\t51\tSurgery\t60\tAlive\t\n2\t62\tF\tSuperior\tNone\t12\t2.5\t20\t2\tSurgery\tSternotomy\tYes\t28\tRT\t48\tAlive\t\n3\t84\tM\tAnterior\tNone\t6.6\t9.2\t50\t2\tSurgery\tSternotomy\tYes\t27\tSurgery\t40\tAlive\t\n4\t75\tM\tPosterior\tNone\t20\t2.0\t3\t2\tSurgery\tBilateral thoracotomy\tNo\t3\t—\t3\tAlive\t\n5\t78\tM\tMiddle\tDyspnea, Hoarseness\t11\t5.1\t40\t2\tChemo (Doxorubicin)\t—\t—\t—\t—\t0.5\tDead\t\nChemo, chemotherapy; FNCLCC, French Federation Nationale des Centres de Lutte Contre le Cancer; OS, overall survival; FRS, recurrence‐free survival; RT, radiotherapy; SUVmax, maximum standardized uptake value; VATS, video‐assisted thoracoscopic surgery.\n\nLiterature review\nNineteen cases of mediastinal dedifferentiated liposarcoma have been published in the English language literature, including our five cases (Table 2). The mean age of patients was 63.3 ± 13.2 and there was no difference in the gender ratio. The reports presented details of symptoms in 13 patients: seven complained of some symptoms, while the other six were asymptomatic and their tumors were discovered by chance. The most common symptom was dyspnea, followed by dysphagia and hoarseness. The tumor was located in the posterior mediastinum in more than half of the cases, followed by the anterior, middle, and superior mediastinum.\n\nTable 2 Literature review of 19 cases published between 2002 and 2016, including our five cases\n\nAuthors\tNo. ofpatients\tAge\tGender\tLocation\tSymptom\tTumor size (cm)\tInitial treatment\tSurgical approach\tRecurrence\tRFS (months)\tTreatment for recurrence\tOS\tOS status\t\nBoland et al.4\n\t5\t68\tM\tPosterior\tUnknown\tUnknown\tSurgery\tUnknown\tYes\t48\tUnknown\t72\tAlive\t\n\t\t63\tF\tAnterior\tUnknown\tUnknown\tSurgery\tUnknown\tYes\t24\tUnknown\t34\tDead\t\n\t\t47\tF\tMiddle\tUnknown\tUnknown\tSurgery\tUnknown\tNo\t60\tUnknown\t60\tAlive\t\n\t\t71\tF\tPosterior\tUnknown\tUnknown\tSurgery (incomplete)\tUnknown\tResidual\t12\tUnknown\t12\tAlive\t\n\t\t76\tF\tAnterior\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t\nOrtega et al.5\n\t3\t75\tM\tPosterior\tWeight loss, dyspnea\t14\tSurgery\tUnknown\tYes\tUnknown\tUnknown\t6\tAlive\t\n\t\t66\tM\tPosterior\tChest pain, dysphagia, malaise\t9\tSurgery\tUnknown\tNo\tUnknown\t—\t24\tAlive\t\n\t\t53\tF\tPosterior\tDysphagia\t23\tSurgery\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t\nChen et al.6\n\t1\t64\tM\tUnknown\tUnknown\t6\tSurgery\tUnknown\tNo\t12\t—\t12\tAlive\t\nFukai et al.7\n\t1\t56\tM\tAnterior\tNone\t16.5\tSurgery\tSternotomy\tNo\t36\t—\t36\tAlive\t\nHamanaka et al.1\n\t1\t74\tM\tPosterior\tDry cough\t11\tSurgery\tLateral thoracotomy\tNo\t8\t—\t8\tAlive\t\nCoulibaly et al.8\n\t1\t34\tF\tPosterior\tDyspnoea\t20\tSurgery\tLateral thoracotomy\tYes\t15\tSurgery (incomplete)\t114\tDead\t\nNarasimman et al.9\n\t1\t48\tM\tPosterior\tNone\t15\tSurgery\tLateral thoracotomy\tNo\t12\t—\t12\tAlive\t\nHirai et al.3\n\t1\t64\tM\tAnterior\tHoarseness\t6.5\tSurgery\tSternotomy\tNo\t14\t—\t14\tAlive\t\nMiura et al.\t5\t45\tF\tMiddle\tNone\t12.7\tSurgery\tCervical approach, right sided VATS\tYes\t51\tSurgery\t60\tAlive\t\n\t\t62\tF\tSuperior\tNone\t12\tSurgery\tSternotomy\tYes\t28\tRT\t48\tAlive\t\n\t\t84\tM\tAnterior\tNone\t6.6\tSurgery\tSternotomy\tYes\t27\tSurgery\t40\tAlive\t\n\t\t75\tM\tPosterior\tNone\t20\tSurgery\tBilateral thoracotomy\tNo\t3\t—\t3\tAlive\t\n\t\t78\tM\tSuperior\tDyspnea, Hoarseness\t11\tChemo (Doxorubicin)\t—\t—\t—\t—\t0.5\tDead\t\nChemo, chemotherapy; OS, overall survival; FRS, recurrence‐free survival; RT, radiotherapy; SUVmax, maximum standardized uptake value; VATS, video‐assisted thoracoscopic surgery.\n\nDiscussion\nWe report five cases of mediastinal dedifferentiated liposarcoma and present some important clinical issues. First, three of four cases treated with radical surgical resection developed local recurrence within a few years after treatment, despite complete resection. However, repeat surgical resection or radiotherapy was effective for the local recurrence and the patients showed relatively long‐term survival. In contrast, one patient received doxorubicin chemotherapy, which was not effective, and died within a month (Case 5). Therefore, we suggest that complete resection should be initially considered in cases of primary mediastinum dedifferentiated liposarcoma. In addition, repeat surgical resection should be considered in cases of local recurrence. Radiation therapy may be effective to control recurrent lesions.\n\nThere have been a number of case reports regarding mediastinal dedifferentiated liposarcoma;1, 2, 3, 6, 7, 8, 9 however, few reports refer to long‐term prognosis. Coulibaly et al. reported a case of recurrent dedifferentiated liposarcoma of the mediastinum involving the lung and pleura.8 The patient showed recurrence 15 months after primary mediastinal tumor resection. Repeat surgical resection of the local recurrent tumor was incomplete, and the patient was administered adjuvant radiotherapy (60 Gy). Eight years later, a second recurrence occurred in the pleura and lung, and the patient died after three months. Chen et al. studied 23 cases of primary intrathoracic liposarcoma, including lesions in the mediastinum, pleura, and lung.6 They reported poor OS and RFS in the dedifferentiated type compared to the well‐differentiated type, and two of four cases relapsed despite radical surgical resection. Chen et al. concluded that it is essential to ensure complete resection of the primary intrathoracic liposarcoma to cure the disease. However, the growth pattern of liposarcoma tends to be expansive rather than infiltrative. Patients often complain of few symptoms until the tumor grows very large, which may be one reason for incomplete resection. Four of our surgical patients, particularly Case 4, exhibited no symptoms despite having large tumors surrounding the trachea, esophagus, or great vessels.\n\nThe median RFS period of the three cases in our study was 35 months and all developed local recurrence in the mediastinum. Two patients underwent repeat surgical resection. However, one patient showed second local recurrence in the mediastinum and was treated with heavy particle radiotherapy. Another patient with recurrence received proton beam therapy, and was followed up for 17 months without a second recurrence. Only four cases of recurrence were found in the literature review, and showed recurrence a few years after the first surgical treatment.4, 5, 8 Other reports did not refer to recurrence or the follow‐up period was relatively short; therefore long‐term prognosis after surgery is unclear. According to literature review, we speculate that there is no relationship between the tumor site and clinicopathological features, including prognosis.1, 2, 3, 4, 5, 6, 7, 8, 9\n\n\nBased on the previous reports included in our review, complete surgical resection is the best method to cure mediastinal dedifferentiated liposarcoma.1, 3, 4, 5, 6, 7, 8, 9 En bloc resection should be attempted in such cases if possible. All of our surgical cases underwent en bloc resection without breaking the tumor capsule. Adhesion between the tumor and surrounding tissue was relatively weak, and there was no invasion to any surrounding organs. In addition, during autopsy of Case 5, direct invasion to the esophagus, trachea, or great vessels was not observed, suggesting that surgical resection should be considered as initial treatment. As much of the tumor and peripheral fat tissue should be removed as possible, although it is difficult to perform complete resection of fat tissue near the thyroid or thymus. In fact, atypical cells were found in the peripheral fat tissue in our four surgical cases. We consider adjuvant radiotherapy to be effective because radiotherapy to locally recurrent lesions was effective in this study, although its efficacy has not been established in dedifferentiated liposarcoma.\n\nChemotherapy is generally ineffective for liposarcoma. Jones et al. examined the differential sensitivity of liposarcoma subtypes to chemotherapy, and reported that myxoid liposarcoma was relatively chemosensitive compared to dedifferentiated or well‐differentiated liposarcoma, and the response rate of dedifferentiated liposarcoma to first‐line chemotherapy was only 25% (doxorubicin, 8%; doxorubicin plus ifosfamide, 17%).10 The microtubule growth inhibitor, eribulin, has recently been approved for the treatment of advanced liposarcoma. Setola et al. reported that eribulin was highly effective in advanced liposarcoma.11 The efficacy of chemotherapy against mediastinal liposarcoma has not been established. However, new developed agents should be evaluated in future clinical studies for use in the treatment of dedifferentiated liposarcoma. Dedifferentiated liposarcoma has genetic abnormalities with high‐level amplifications of chromosome 12q14‐15, including the MDM2 and CDK4 cell cycle oncogenes. Novel therapies targeted at the gene products of chromosome 12 are being tested in clinical trials.12\n\n\nIn 1984, the French Federation of Cancer Centers Sarcoma Group proposed the FNCLCC grading system, which reflects the malignancy of soft tissue tumors.13 Our five cases were FNCLCC grade 2. Relationships between mediastinal dedifferentiated liposarcoma prognosis and the FNCLCC grading system remain unclear, thus further data is needed.\n\nWe evaluated Ki‐67 immunostaining and SUVmax in five patients who underwent surgical treatment. SUVmax results were relatively low, but the two parameters showed a positive association and may be useful as prognostic factors. However, the number of cases reviewed in our study was small, thus long‐term prognosis, clinicopathological features, and the optimal choice of treatment remain unclear. Further studies of larger patient samples would likely clarify the relationship between these biomarkers and the clinicopathological features of mediastinal dedifferentiated liposarcoma.\n\nWe would like to emphasize that aggressive treatment by surgical resection should initially be considered for mediastinal dedifferentiated liposarcoma. In addition, we suggest that repeat surgical resection or radiotherapy are appropriate treatment choices for locally relapsed mediastinal dedifferentiated liposarcoma.\n\nDisclosure\nNo authors report any conflict of interest.\n==== Refs\nReferences\n1 \n\nHamanaka \nK \n, \nOhashi \nM \n, \nNakamura \nT \n. Primary mediastinal dedifferentiated liposarcoma resected by lateral thoracotomy with video‐assisted thoracoscopic surgery . J Surg Case Rep \n2016 \n10.1093/jscr/rjv163 \n\n2 \n\nMani \nVR \n, \nOfikwu \nG \n, \nSafavi \nA \n. Surgical resection of a giant primary liposarcoma of the anterior mediastinum . J Surg Case Rep \n2015 \n10.1093/jscr/rjv126 \n\n3 \n\nHirai \nS \n, \nHamanaka \nY \n, \nMitsui \nN \n, \nUegami \nS \n, \nMatsuura \nY \n. Surgical resection of primary liposarcoma of the anterior mediastinum . Ann Thorac Cardiovasc Surg \n2008 ; 14 : 38 –41 .18292740 \n4 \n\nBoland \nJM \n, \nColby \nTV \n, \nFolpe \nAL \n. Liposarcomas of the mediastinum and thorax: A clinicopathologic and molecular cytogenetic study of 24 cases, emphasizing unusual and diverse histologic features . Am J Surg Pathol \n2012 ; 36 : 1395 –403 .22895273 \n5 \n\nOrtega \nP \n, \nSuster \nD \n, \nFalconieri \nG \n\net al\nLiposarcomas of the posterior mediastinum: Clinicopathologic study of 18 cases . Mod Pathol \n2015 ; 28 : 721 –31 .25475695 \n6 \n\nChen \nM \n, \nYang \nJ \n, \nZhu \nL \n, \nZhou \nC \n, \nZhao \nH \n. Primary intrathoracic liposarcoma: A clinicopathologic study and prognostic analysis of 23 cases . J Cardiothorac Surg \n2014 ; 9 : 119 .24993036 \n7 \n\nFukai \nR \n, \nFukumura \nY \n, \nSuzuki \nK \n. A dedifferentiated liposarcoma of the anterior mediastinum . Int J Clin Oncol \n2009 ; 14 : 174 –7 .19390952 \n8 \n\nCoulibaly \nB \n, \nBouvier \nC \n, \nPayan \nMJ \n, \nThomas \nP \n. Recurrent dedifferentiated liposarcoma of mediastinum involving lung and pleura . Interact Cardiovasc Thorac Surg \n2009 ; 9 : 741 –2 .19589790 \n9 \n\nNarasimman \nS \n, \nJasjit \nSN \n, \nNavarasi \nSR \n, \nPremnath \nN \n. A dedifferentiated large posterior mediastinal liposarcoma ‐ An incidental finding successfully resected . Med J Malaysia \n2016 ; 71 : 201 –2 .27770120 \n10 \n\nJones \nRL \n, \nFisher \nC \n, \nAl‐Muderis \nO \n, \nJudson \nIR \n. Differential sensitivity of liposarcoma subtypes to chemotherapy . Eur J Cancer \n2005 ; 41 : 2853 –60 .16289617 \n11 \n\nSetola \nE \n, \nNoujaim \nJ \n, \nBenson \nC \n, \nChawla \nS \n, \nPalmerini \nE \n, \nJones \nRL \n. Eribulin in advanced liposarcoma and leiomyosarcoma . Expert Rev Anticancer Ther \n2017 ; 17 : 717 –23 .28621163 \n12 \n\nThway \nK \n, \nJones \nRL \n, \nNoujaim \nJ \n, \nZaidi \nS \n, \nMiah \nAB \n, \nFisher \nC \n. Dedifferentiated liposarcoma: Updates on morphology, genetics, and therapeutic strategies . Adv Anat Pathol \n2016 ; 23 : 30 –40 .26645460 \n13 \n\nTrojani \nM \n, \nContesso \nG \n, \nCoindre \nJM \n\net al\nSoft‐tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system . Int J Cancer \n1984 ; 33 : 37 –42 .6693192\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1759-7706",
"issue": "9(12)",
"journal": "Thoracic cancer",
"keywords": "Dedifferentiated liposarcoma; local recurrence; mediastinum",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001706:Biopsy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008080:Liposarcoma; D008297:Male; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D060787:Neoplasm Grading; D000072078:Positron Emission Tomography Computed Tomography; D014057:Tomography, X-Ray Computed; D047368:Tumor Burden",
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"pages": "1733-1740",
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"pmid": "30329218",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "26724326;27770120;18292740;26410831;26645460;25475695;24993036;19390952;6693192;28621163;22895273;19589790;16289617",
"title": "Primary mediastinal dedifferentiated liposarcoma: Five case reports and a review.",
"title_normalized": "primary mediastinal dedifferentiated liposarcoma five case reports and a review"
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"abstract": "BACKGROUND\nSorafenib is an oral multikinase inhibitor that targets tumor cell angiogenesis and proliferation. Drug-associated cutaneous adverse events, such as alopecia and hand-foot skin reaction, occur frequently. Sorafenib-related side effects affecting hair, nails, and skin are summarized and the characteristics of sorafenib-treated patients who developed acneiform facial lesions are reviewed to present the clinical features of these individuals.\n\n\nMETHODS\nA man with sorafenib-associated facial acneiform lesions mimicking those of chloracne is described.\n\n\nCONCLUSIONS\nPubMed was used to search the following terms, separately and in combination: acne, acneiform eruption, chloracne, cutaneous adverse events, hepatocellular carcinoma, renal cell carcinoma, skin side effects, and sorafenib. Inclusion criteria for selecting papers to be reviewed included case reports and studies that described cutaneous and mucosal adverse side effects associated with sorafenib. All papers fulfilling inclusion criteria were reviewed and relevant manuscripts, along with their reference citations, were evaluated. Five patients-a woman with liver epithelioid hemangioendothelioma, three men with metastatic renal cell carcinoma, and a man with hepatocellular carcinoma-have developed sorafenib-associated facial acneiform eruption. The eruption typically occurred after 4 weeks of treatment at a dose of 400 mg twice daily. The lesions presented as either papules and pustules (2 patients) or, similar in appearance and distribution to chloracne, only open and closed comedones (3 patients). The sorafenib-associated facial acneiform eruption partially improved after initiating topical antibiotics, keratolytics, and/or retinoids; however, progressive improvement or resolution occurred after lowering the daily dose or discontinuation of sorafenib.\n\n\nCONCLUSIONS\nSorafenib-associated facial acneiform eruption is a rarely occurring cutaneous adverse event that has only been observed in five individuals. The skin lesions usually presented after 4 weeks of sorafenib (at a dose of 400 mg twice daily) treatment. The morphology and distribution of the lesions mimicked those of chloracne in three of the patients. Two of the patients also had other drug-related skin side effects. Topical acne-directed therapy was only partially effective in clearing the lesions; lowering the dose or discontinuation of sorafenib resulted in progressive improvement or resolution of the facial acneiform eruption.",
"affiliations": "Division of Dermatology, University of California San Diego, 10991 Twinleaf Court, Twinleaf Court, California, 92131-3643, USA, mitehead@gmail.com.",
"authors": "Cohen|Philip R|PR|",
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"doi": "10.1007/s13555-014-0067-9",
"fulltext": "\n==== Front\nDermatol Ther (Heidelb)\nDermatol Ther (Heidelb)\nDermatology and Therapy\n2193-8210\n2190-9172\nSpringer Healthcare Heidelberg\n\n25539704\n67\n10.1007/s13555-014-0067-9\nCase Report\nSorafenib-Associated Facial Acneiform Eruption\nCohen Philip R. mitehead@gmail.com\n\nDivision of Dermatology, University of California San Diego, 10991 Twinleaf Court, Twinleaf Court, California 92131-3643 USA\n25 12 2014\n25 12 2014\n3 2015\n5 1 7786\n3 11 2014\n© The Author(s) 2014\nIntroduction\n\nSorafenib is an oral multikinase inhibitor that targets tumor cell angiogenesis and proliferation. Drug-associated cutaneous adverse events, such as alopecia and hand–foot skin reaction, occur frequently. Sorafenib-related side effects affecting hair, nails, and skin are summarized and the characteristics of sorafenib-treated patients who developed acneiform facial lesions are reviewed to present the clinical features of these individuals.\n\nCase Report\n\nA man with sorafenib-associated facial acneiform lesions mimicking those of chloracne is described.\n\nDiscussion\n\nPubMed was used to search the following terms, separately and in combination: acne, acneiform eruption, chloracne, cutaneous adverse events, hepatocellular carcinoma, renal cell carcinoma, skin side effects, and sorafenib. Inclusion criteria for selecting papers to be reviewed included case reports and studies that described cutaneous and mucosal adverse side effects associated with sorafenib. All papers fulfilling inclusion criteria were reviewed and relevant manuscripts, along with their reference citations, were evaluated. Five patients—a woman with liver epithelioid hemangioendothelioma, three men with metastatic renal cell carcinoma, and a man with hepatocellular carcinoma—have developed sorafenib-associated facial acneiform eruption. The eruption typically occurred after 4 weeks of treatment at a dose of 400 mg twice daily. The lesions presented as either papules and pustules (2 patients) or, similar in appearance and distribution to chloracne, only open and closed comedones (3 patients). The sorafenib-associated facial acneiform eruption partially improved after initiating topical antibiotics, keratolytics, and/or retinoids; however, progressive improvement or resolution occurred after lowering the daily dose or discontinuation of sorafenib.\n\nConclusions\n\nSorafenib-associated facial acneiform eruption is a rarely occurring cutaneous adverse event that has only been observed in five individuals. The skin lesions usually presented after 4 weeks of sorafenib (at a dose of 400 mg twice daily) treatment. The morphology and distribution of the lesions mimicked those of chloracne in three of the patients. Two of the patients also had other drug-related skin side effects. Topical acne-directed therapy was only partially effective in clearing the lesions; lowering the dose or discontinuation of sorafenib resulted in progressive improvement or resolution of the facial acneiform eruption.\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1007/s13555-014-0067-9) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nAcne\nAcneiform eruption\nChloracne\nCutaneous adverse events\nHepatocellular carcinoma\nRenal cell carcinoma\nSkin side effects\nSorafenib\nissue-copyright-statement© Springer Healthcare 2015\n==== Body\nIntroduction\n\nSorafenib is an oral multikinase inhibitor that is currently approved for the treatment of hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. In addition to frequently occurring alopecia and hand–foot skin reactions, other common adverse skin effects related to sorafenib include desquamative ‘rash’ and erythematous eruption, seborrheic dermatitis-like facial erythema, stomatitis, subungual splinter hemorrhages, and xerosis [1–4]. A unique cutaneous reaction after initiating treatment with sorafenib—a facial acneiform eruption—is described in a man with hepatocellular carcinoma and the characteristics of other patients with this rare sorafenib-induced cutaneous adverse event are reviewed to present the clinical features of these individuals.\n\nCase Report\n\nA 79-year-old Asian man presented for evaluation of facial acneiform lesions of 2½ months duration. He also had experienced scalp and eyebrow hair loss, an itchy facial rash, peeling of his fingertips and painful lesions on feet, and dry skin. His medical history was significant for hepatitis B (genotype B) and he had been receiving entecavir 0.5 mg daily for the past 9 months, since December 2013; his most recent polymerase chain reaction quantitative hepatitis B viral load in August 2014 was <20 (undetectable). He had no exposure to aromatic hydrocarbons.\n\nFour months earlier, in May 2014, his alpha fetoprotein level was elevated (20.8 ng/mL, normal <15 ng/ml). A magnetic resonance imaging exam of his abdomen revealed several hepatic lesions consistent with hepatocellular carcinoma. On June 26, 2014 he was started on sorafenib 400 mg twice daily. Within 6 weeks after initiating treatment with sorafenib, his alpha fetoprotein had decreased to 15 ng/ml.\n\nWithin 9 days after starting sorafenib, he noted new lesions on his face and behind his ears. Subsequently, he developed a red facial rash and began to lose hair on his scalp and eyebrows. Shortly thereafter, within a month after initiating treatment, he developed generalized xerosis with hand and foot lesions.\n\nCutaneous examination of his face showed a chloracne-like eruption consisting predominantly closed comedones not only on his malar cheeks, but also on his ears, preauricular area and postauricular skin. In addition, there were several non-inflammatory small cystic lesions and occasional open comedones. There were no inflammatory papules (Fig. 1).Fig. 1 Distant (a) and closer (b) views of left side of the face of a 79-year-old Asian man show numerous closed comedones and non-inflammatory small cystic lesions on the malar cheeks, the preauricular area and the ears; occasional open comedones are also noted, but are not inflammatory papules. A closer view of the left postauricular area (c) also shows several closed comedones. The lesions appeared 9 days after he started sorafenib (400 mg twice daily) for the treatment of his hepatocellular carcinoma. The morphology and distribution of the facial acneiform lesions mimic those of chloracne\n\nThe forehead, glabella region, and paranasal malar area also showed a pruritic seborrheic dermatitis-like eruption consisting of erythema with superficial scaling on the supraorbital ridges. There was loss of the eyebrows and partial alopecia of the scalp. There was also inflammation of the seborrheic keratoses on his chest and back and xerosis was diffusely present.\n\nHand–foot skin reaction was also present. Asymptomatic peeling of the distal fingertips was observed. Also, painful hyperkeratotic plaques were present on the plantar pressure areas of both feet.\n\nTopical therapy for the acneiform eruption included topical clindamycin 1% solution twice daily, followed by tretinoin 0.025% cream in the evenings. Desonide 0.05% cream twice daily was initiated for the seborrheic dermatitis-like eruption. Betamethasone dipropionate 0.05% cream (under plastic occlusion in the evening) was applied to the hands and feet twice daily. A moisturizing cream was applied to the body once daily.\n\nThe patient returned after 1 month; 10 days earlier his family had decided to discontinue the sorafenib because he was tolerating it poorly. His seborrheic dermatitis-like eruption and facial pruritus had completely cleared and his hand–foot skin reaction was nearly resolved. The chloracne-like facial eruption had partially improved; however, since multiple closed comedones still persisted, his topical therapy with clindamycin solution and tretinoin cream was continued. His oncologist is restaging him and considering other therapeutic options or possibly restarting sorafenib at a lower dose.\n\nDiscussion\n\nSorafenib targets tumor cell angiogenesis and proliferation by inhibiting multiple kinases including c-Kit protein, FMS-like tyrosine kinase 3, platelet-derived growth factor beta, Raf kinase, RET receptor tyrosine kinase, and vascular endothelial growth factor receptors 2 and 3 [2, 5]. The hair, nails, and skin of patients treated with sorafenib are potentially also affected by the drug (Table 1) [2–4, 6–53]. In contrast to a significant percentage—ranging from a reported 24–91%—of patients receiving epidermal growth factor receptor inhibitors (such as cetuximab, erlotinib, and gefitinib) who develop a diffuse papulopustular acneiform eruption, sorafenib-associated acneiform facial eruption has seldom been observed [37–39].Table 1 Cutaneous adverse events associated with sorafenib\n\nFrequently occurring events\t\n Alopecia [2, 4, 6–9]\t\n Hand-foot skin reaction [2–4, 6, 8–16]\t\nCommon occurring events\t\n Erythematous eruption on trunk [2, 15, 17]\t\n ‘Rash’/desquamation [3, 4, 6, 9]\t\n Seborrheic dermatitis-like facial erythema [2, 8, 9, 15, 16, 18, 19]\t\n Stomatitis [2, 7]\t\n Subungual splinter hemorrhage [2, 8, 9, 16, 20]\t\n Xerosis [2, 7, 9, 21]\t\nUncommon occurring events\t\n Actinic keratoses [22]\t\n Erythema multiforme [23–28]\t\n Follicular-based erythematous papules [15, 21]\t\n Inflammation of actinic keratoses [29]\t\n Inflammation of seborrheic keratoses [30]\t\n Keratoacanthoma and squamous cell carcinoma [22, 31, 32]\t\n Keratosis pilaris-like lesions [30]\t\n Plaques: dyskeratotic or keratotic [22, 33]\t\n Pruritus [9, 34, 35]\t\n Psoriasiform eruption [36]\t\n Warts, warty papules and nodules [10, 22]\t\nRarely occurring events\t\n Acneiform eruption [37–43]\t\n Angioedema [21]\t\n Cheilitis [15, 44]\t\n Epidermal cyst on face [2, 16, 19, 30]\t\n Erythema marginatum hemorrhagicum [45]\t\n Genital (labial and scrotal) eczema [2, 15]\t\n Eruptive melanocytic nevi [30, 46, 47]\t\n Leukocytoclastic vasculitis [30, 48]\t\n Nonpigmented fixed drug eruption [49]\t\n Perforating folliculitis [21, 50]\t\n Spiny follicular hyperkeratosis eruption [39, 51]\t\n Ultraviolet radiation recall (dermatitis) [52]\t\n Yellow skin [53]\t\n\nPubMed was used to search the following terms, separately and in combination: acne, acneiform eruption, chloracne, cutaneous adverse events, hepatocellular carcinoma, renal cell carcinoma, skin side effects, and sorafenib. Inclusion criteria for selecting papers to be reviewed included case reports and studies that described cutaneous and mucosal adverse side effects associated with sorafenib. All papers fulfilling inclusion criteria were reviewed and relevant manuscripts, along with their reference citations, were evaluated.\n\nSeveral reports discuss acneiform eruptions in patients who have received sorafenib. However, three of the patients had developed epidermal cysts on their face [2, 9, 16]. In addition, a critical review of other studies showed that the observed lesions were either secondary to another drug [42] or may not have actually been acne [40, 41] or were not distinguished from other cutaneous adverse events [43].\n\nTo the best of my knowledge, including the patient in this report, a drug-related acneiform facial eruption has only been described in five individuals who were treated with sorafenib (Table 2) [37–39]. The patients include a 42-year-old woman with liver epithelioid hemangioendothelioma and 4 men, ranging from 51 to 79 years of age (median, 58 years old), with either metastatic renal cell carcinoma (3 patients) or hepatocellular carcinoma (1 patient). The dose of sorafenib ranged from 600 mg daily (1 patient) to 800 mg (1 patient for 1 day) twice daily; the other 3 patients were receiving 400 mg twice daily.Table 2 Characteristics of patients with sorafenib-associated facial acneiform facial eruptions\n\nACE acneiform eruption, BID twice daily, BP benzoyl peroxide, Ca cancer, Ca-L chloracne-like, C case, Clin clindamycin 1% solution twice daily, CR current report, EES erythromycin, FAL facial acneiform lesions, Flu fluocinonide cream, HCC hepatocellular carcinoma, HFSR hand–foot skin reaction, ISK inflamed seborrheic keratosis, LEH liver epithelioid hemangioendothelioma, Met metronidazole, mRC metastatic renal carcinoma, mRCC metastatic renal cell carcinoma, NS not stated, OSAL other sites of acneiform lesions, OSCAE other sorafenib-associated cutaneous adverse events, prog progression, Pt patient, QD daily, SD-LE seborrheic dermatitis-like eruption, SFFH spiny filiform follicular hyperkeratosis, soraf sorafenib, Sp-l sandpaper-like skin texture, Tret 0.025% tretinoin 0.025% cream each evening, Tret 0.05% tretinoin 0.05% cream each evening, + present, − absent\n\naThe facial acneiform lesions were located on bilateral malar cheeks and postauricular areas\n\nbThe facial acneiform lesions were located on the nose and bilateral malar cheeks, temples, and postauricular areas\n\ncThe facial acneiform lesions were located on bilateral malar cheeks, preauricular areas, ears, and postauricular areas\n\ndNumber of weeks on sorafenib prior to appearance of acneiform eruption\n\neA skin biopsy of an acneiform lesion showed milia-like cyst with a sparse lymphocytic inflammatory dermal infiltrate\n\nfThe patient did not return for follow-up examination\n\nThree of the patients had symptoms associated with their acneiform lesions: pain or a burning sensation, pruritus, and an increase in facial oiliness. Three of the patients also had acneiform lesions located on other areas of the body: scalp, neck, axillae and arms, genital area, and the upper back, chest and/or trunk. The facial lesions appeared within 9 days to 8 weeks (median, 4 weeks) after starting treatment with sorafenib; indeed, the patient in this report developed his acneiform eruption within the first 2 weeks after starting sorafenib.\n\nThe acneiform lesions appeared as papules and pustules for two of the patients. However, the lesions of the currently reported patient were predominantly monomorphic closed comedones. In addition, similar to two of the other patients whose acneiform eruption consisted of open and closed comedones, his facial lesions also had features in common with those observed in chloracne—particularly the development of lesions behind the ears, the absence of inflammatory papules, and the occurrence of non-inflammatory small cystic lesions [54].\n\nThe current patient also had several other drug-related cutaneous reactions: alopecia, hand–foot skin reactions, inflammation of seborrheic keratoses, seborrheic dermatitis-like facial eruption, and generalized xerosis. The 52-year-old man with metastatic renal cell carcinoma sorafenib-related facial acneiform eruption also developed other adverse cutaneous events from the drug including another rarely reported eruption: sandpaper-like skin texture associated with spiny filiform follicular hyperkeratosis [39]. Analogous to patients who have developed papulopustular eruptions after receiving epidermal growth factor receptor inhibitors [55], investigators have suggested that the development of skin eruptions (such as ‘rash’ and hand–foot skin reaction) to sorafenib is associated with successful antitumor activity of the drug [3, 17, 35, 45, 56]. Indeed, similar to other sorafenib-treated patients who developed therapy-associated cutaneous adverse events, the development of drug-induced skin effects in the current patient was associated with a favorable response of his hepatocellular carcinoma to sorafenib: a decrease of his alpha fetoprotein tumor marker.\n\nFour of the patients received topical therapy for their acneiform facial eruption; these included benzoyl peroxide, clindamycin, erythromycin, fluocinonide, isotretinoin, and metronidazole. One patient also received oral tetracycline. Although there was a variable degree of improvement following these interventions, either lowering the sorafenib daily dose or discontinuing the drug was consistently associated with partial or complete resolution of the facial eruption. Indeed, one patient’s lesions cleared when his sorafenib was discontinued for a surgical procedure and subsequently recurred when the drug was restarted.\n\nConclusion\n\nSorafenib is an oral multikinase inhibitor associated with the potential development of several cutaneous adverse events in patients treated with the drug. Alopecia and hand–foot reaction were frequently occurring events; indeed, appearance of the latter has been associated with a successful antitumor activity of the drug. In contrast, the development of a facial acneiform eruption was a rarely observed sorafenib-associated side effect that has only been described in five patients—a woman with liver epithelioid hemangioendothelioma, three men with metastatic renal cell carcinoma, and a man with hepatocellular carcinoma. The sorafenib dose ranged from 600 mg daily to 800 mg twice daily; most of the patients were receiving 400 mg twice daily. The eruption typically appeared about 4 weeks after starting sorafenib treatment; however, it was noted as early as 9 days or as late as 2 months after therapy had been initiated. Whereas two of the patients presented with papules and pustules, the other three individuals only had open and closed comedones, the appearance and distribution of which were similar to those observed in persons with chloracne. Topical antibiotics, keratolytics, and retinoids resulted in partial improvement; however, lowering the daily dose or discontinuation of sorafenib promoted progressive improvement or resolution of the facial acneiform eruption.\n\nElectronic supplementary material\n\nSupplementary material 1 (PDF 197 kb)\n\nNo funding or sponsorship was received for this study or publication of this article. The author meets the ICMJE criteria for authorship for this manuscript, takes responsibility for the integrity of the work as a whole, and has given final approval for the version to be published.\n\nConflict of interest\n\nDr. Philip R. Cohen declares no conflict of interest.\n\nCompliance with ethical guide lines\n\nInformed consent was obtained from the patient for being included in the study and for the publication of photographs. This article does not contain any studies with human subjects performed by the author.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\n==== Refs\nReferences\n\n1. Scandurra G Aiello RA Ali M Taibi E Sano MV Todaro FM La Rocca R Licciardello P Caruso M Appropriate management of cutaneous adverse events maximizes compliance with sorafenib treatment: a single center experience Future Oncol 2012 8 609 615 10.2217/fon.12.35 22646774\n2. Lee WJ Lee JL Chang SE Lee MW Kang YK Choi JH Moon KC Koh JK Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib Br J Dermatol 2009 161 1045 1051 10.1111/j.1365-2133.2009.09290.x 19558553\n3. Vincenzi B, Santini D, Russo A, Addeo R, Guiliani F, Montella L, Rizzo S, Venditti O, Frezza AM, Caraglia M, Colucci G, Del Prete S, Tonini G. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist. 2010;15:85–92 (PMID = 20051477).\n4. Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505–12 (PMID = 16636341).\n5. Wozel G, Sticherling M, Schon MP: Cutaneous side effects of inhibition of VEGF signal transduction. J DutschDermatolGes 2010;8:243-9 (PMID = 19832927).\n6. Pragasam V, Verma R, Vasudevan B. Sorafenib and sunitinib: a dermatologist’s perspective. Indian Dermatol Online J. 2014;5(1):1–3 (PMID = 24616845).\n7. Ishak RS, Aad SA, kyel A, Farhat FS. Cutaneous manifestations of anti-angiogenic therapy in oncology: review with focus on VEGF inhibitors. Crit Rev Oncol Hematol. 2014;90:152–64 (PMID = 24355408).\n8. Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, Wechsler J, Lhomme C, Escudier B, Boige V, Armand JP, Le Chevalier T. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005;6:491–500. (PMID = 15992698).\n9. Robert C, Mateus C, Spatz A, Wechsler J, Escudier B. Dermatologic symptoms associated with the multikinase inhibitor sorafenib. J Am Acad Dermatol. 2009;60:299–305 (PMID = 19028406).\n10. Curry JL, Torres-Cabala CA, Kim KB, Tetzlaff MT, Duvic M, Tsai KY, Hong DS, Prieto VG. Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions. Int J Dermatol. 2014;53:376–84 (PMID = 2387947).\n11. McLellan B, Kerr H. Cutaneous toxicities of the multikinase inhibitors sorafenib and sunitinib. Dermatol Ther. 2011;24:396–400 (PMID = 21910797).\n12. Scandurra G, Aiello RA, Ali M, Taibi E, Sano MV, Todaro FM, LaRocca R, Licciardello P, Caruso M. Appropriate management of cutaneous adverse events maximizes compliance with sorafenib treatment: a single-center experience. Future Oncol. 2012;8:609–15 (PMID = 22646774).\n13. Lipworth AD, Robert C, Zhu AX. Hand–foot syndrome (hand–foot skin reaction, palmar–plantar erythrodysesthesia): focus on sorafenib and sunitinib. Oncology. 2009;77:257–271 (PMID = 19923864).\n14. Yang CH, Lin WC, Chuang CK, Chang YC, Pang ST, Lin YC, Kuo TT, Hsieh JJ, Chang JWC. Hand–foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol. 2008;158:592–596 (PMID = 18070211).\n15. Maddox JS, Kung EF, Petronic-Rosic V, Sethi A. Cutaneous drug eruptions induced by sorafenib: a case series. J Drugs Dermatol. 2008;7:891–893 (PMID = 19112807).\n16. Autier J, Mateus C, Wechsler J, Spatz A, Robert C. Cutaneous side effects of sorafenib and sunitinib. Ann Dermatol Venereol. 2008;135(7):148–53 [quiz 7, 154 (PMID = 18342102)].\n17. Galan Brotons A, Borras-Biasco J, Rosique-Robles JD, Vicent Verge JM, Castera MDE. Generalized erythematous skin eruptions induced by sorafenib: cutaneous toxicity and treatment outcome. Clin Transl Oncol. 2008;10:844–6 (PMID = 19068457).\n18. Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol. 2008;58:545–70 (PMID = 18342708).\n19. Autier J, Escudier B, Wechsler J, Spatz A, Robert C. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol. 2008;144:886–92 (PMID = 18645140).\n20. Robert C, Faivre S, Raymond E, Armand JP, Escudier B. Subungual splinter hemorrhages: a clinical window to inhibition of vascular endothelial growth factor receptors? [letter] Ann Intern Med. 2005;143:313–4 (PMID = 16103482).\n21. Wolber C, Udvardi A, Tatzreiter G, Schneeberger A, Volc-Platzer B. Perforating folliculitis, angioedema, hand–foot syndrome—multiple cutaneous side effects in a patient treated with sorafenib. J Dtsch Dermatol Ges. 2009;7:449–52 (PMID = 19178612).\n22. Williams VL, Cohen PR, Stewart DJ. Sorafenib-induced premalignant and malignant skin lesions. Int J Dermatol. 2011;50:396–402 (PMID = 21413947).\n23. MacGregor JL, Silvers DN, Grossman ME, Sherman WH: Sorafenib-induced erythema multiforme. [letter] J Am Acad Dermatol. 2007;56:527–28 (PMID = 17241689).\n24. Lewin J, Farley-Loftus R, Pomeranz MK. Erythema multiforme-like drug reaction to sorafenib. J Drug Dermatol 2011;10:1462–3 (PMID = 22134572).\n25. Bilac C, Muezzinoglu T, Ermertcan AT, Kayhan TC, Temeltas G, Ozturkcan S, Temiz P. Sorafenib-induced erythema multiforme in metastatic renal carcinoma. Cutan Ocul Toxicol. 2009;28:90–2 (PMID = 19514932).\n26. Bilac C, Muezzinoglu T, Ermertcan AT, Kayhan TC, Temeltas G, Ozturkcan S, Temiz P. Sorafenib = induced erythema multiforme in metastatic renal cell carcinoma. Cutan Ocul Toxicol. 2009;28:90–92 (PMID = 19514932).\n27. Ikeda M, Fujita T, Mii S, Tanabae K-I, Tabata K-I, Matsumoto K, Satoh T, Iwamura M. Erythema multiforme induced by sorafenib for metastatic renal cell carcinoma. Jpn J Clin Oncol. 2012;42:820–4 (PMID = 22782962).\n28. Ikeda M, Fujita T, Amoh Y, Mii S, Matsumoto K, Iwamura M. Stevens-Johnson syndrome induced by sorafenib for metastatic renal cell carcinoma. Urol Int. 2013;91:482–3 (PMID = 239649404).\n29. Lacouture ME, Desai A, Soltani K, Petronic-Rosic V, Laumann AE, Ratain MJ, Stadlert WM. Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin Exp Dermatol. 2006;31:783–5 (PMID = 16824050).\n30. Kong HH, Turner ML. Array of cutaneous adverse effects associated with sorafenib. J Am Acad Dermatol. 2009;61:360–1 (PMID = 19615549).\n31. Cohen PR: Development of cutaneous premalignant lesions and malignant tumors in patients receiving sorafenib [comment on invasive squamous cell carcinoma and sorafenib in a black patient]. JAMA Dermatol. http://archderm.jamanetwork.com/article.aspx?articleid=426443. Posted Feb 13, 2011. Accessed Nov 30, 2014.\n32. Hong DS, Reddy SB, Prieto VG, Wright JJ, Tannir NM, Cohen PR, Diwan AH, Evans HL, Kurzrock R. Multiple squamous cell carcinomas of the skin after therapy with sorafenib combined with tipifarnib. Arch Dermatol. 2008;144:779–82 (PMID = 18559769).\n33. Chappell JA, Burkemper NM, Semchyshyn N. Localized dyskeratotic plaque with milia associated with sorafenib. J Drug Dermatol. 2009;8:573–6 (PMID = 19537383).\n34. Ensslin CJ, Rosen AC, Wu S, Lacouture ME. Pruritus in patients treated with targeted cancer therapies: systematic review and meta-analysis. J Am Acad Dermatol. 2013;69:708–20 (PMID = 23981682).\n35. Bauer C, Przybilla B, Rueff F. Severe cutaneous reaction to sorafenib: induction of tolerance. Acta Derm Venereol. 2008;88:627–8 (PMID = 19002355).\n36. Diamantis ML, Chon SY. Sorafenib-induced psoriasiform eruption in a patient with metastatic thyroid carcinoma. J Drugs Dermatol. 2010;9:169–71 (PMID = 20214183).\n37. Fleta-Asin B, Vano-Galvan S, Ledo-Rodriguez A, Truchuelo-Diez M, Jaen-Olasolo P. Facial acneiform rash associated with sorafenib. Dermatol Online .J 2009;15(4):7 (PMID = 19450400).\n38. Pickert A, Hughes M, Wells M. Chloracne-like drug eruption associated with sorafenib. J Drug Dermatol. 2011;10:1331–4 (PMID = 22052319).\n39. Joncas V, Sammour R, Krasny M, Bouffard D, Provost N. A distinctive cutaneous reaction to sorafenib and a multikinase inhibitor. Int J Dermatol. 2008;47:767–9 (PMID = 18613894).\n40. Porta C, Paglino C, Imarisio I, Bonomi L. Uncovering Pandora’s vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitnib. Clin Exp Med. 2007;7:127–34 (PMID = 18188524).\n41. Alexandrescu DT, Vaillant JG, Dasanu CA. Effect of treatment with a colloidal oatmeal lotion on the acneform eruption induced by epidermal growth factor receptor and multiple tyrosine-kinase inhibitors. Clin Exp Dermatol. 2007;32:71–4 (PMID = 17034418).\n42. Duran I, Hotte SJ, HirteH, Chen EX, MacLean M, Turner S, Duan L, Pond GR, Lathia C, Walsh S, Wright JJ, Dancey J, Siu LL. Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors. Clin Cancer Res. 2007;13:4849-57 (PMID = 17699864).\n43. Ji YX, Zhang ZF, Lan KT, Nie KK, Geng CX, Liu SC, Zhang L, Zhuang XJ, Zou X, Sun L, Zhang ZC. Sorafenib in liver function impaired advanced hepatocellular carcinoma. Chin Med Sci J. 2014;29:7–14 (PMID = 24698672).\n44. Hotte SJ, Hirte HW: BAY 43-9006. early clinical data inpatients with advanced solid malignancies. Cur Pharm Des. 2002;8:2249–53 (PMID = 12369852).\n45. Rubsam K, Flaig MJ, Ruzicka T, Prinz JC: Erythema marginatum hemorrhagicum: a unique side effect of sorafenib. [letter] J Am AcadDermatol 2011;64:1194-1196 (PMID = 21571189).\n46. Kong HH, Sibaud V, Chanco Turner ML, et al. Sorafenib-induced eruptive melanocytic lesions. Arch Dermatol. 2008;144:820–2 (PMID = 18559790).\n47. Bennani-Lahlou M, Mateus C Escudier B, Massard C, Soria JC, Spatz A, Robert C. Eruptive nevi associated with sorafenib treatment. Ann Dermatol Venereol. 2008;135:672–4 (PMID = 18929917).\n48. Chung NM, Gutierrez M, Turner ML. Leukocytoclastic vasculitis masquerading as hand–foot syndrome in a patient treated with sorafenib. Arch Dermatol. 2006;142:1510–11 (PMID = 17116852).\n49. Tanabe K, Amoh Y, Mii S, Eto H, Iwamura M, Kasuoka K. Non-pigmented fixed drug eruption induced by sorafenib. Acta Derm Venereol 2010;90:307 (PMID = 20526556).\n50. Pichler M, Carriere C, Mazzoleni G, Kluge R, Eisendle K. Acne inversa-like lesions associated with the multi-kinase inhibitor sorafenib. Clin Exp Dermatol. 2014;39:232–3 (PMID = 24330088).\n51. Franck N, Barete S, Moguelet P, Blanchet B, Carlotti A, Ropert S, Avril MF, Frances C, Billemont B, Goldwasser F. Spiny follicular hyperkeratosis eruption: a new cutaneous adverse effect of sorafenib. [letter] J Clin Oncol. 2010;28:e640–2 (PMID = 20855839).\n52. Magne N, Chargari C, Auberdiac P, Moncharmont C, Merrouche Y, Spano J-P. Ultraviolet recall dermatitis reaction with sorafenib. Invest New Drugs. 2011;29:1111–3 (PMID = 20567994).\n53. Dasanu C, Cutcher J, Alexandrescu D. Yellow skin discoloration associated with sorafenib use for treatment of metastatic renal cell carcinoma. South Med J. 2007;100:328–30 (PMID = 17396743).\n54. Panteleyev AA, Bickers DR. Dioxin-induced chloracne—reconstructing the cellular and molecular mechanisms of a classic environmental disease. Exp Dermatol. 2006;15:705–30 (PMID = 16881967).\n55. Perez-Soler R. Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer. 2006;8 Suppl 1:S7–14 (PMID = 17239291).\n56. Shomura M, Kagawa T, Shiraishi K, Hirose S, Arase Y, Koizumi J, Mine T. Skin toxicity predicts efficacy to sorafenib in patients with advanced hepatocellular carcinoma. World J Hepatol. 2014;6:670–6 (PMID = 25276283).\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": null,
"issue": "5(1)",
"journal": "Dermatology and therapy",
"keywords": null,
"medline_ta": "Dermatol Ther (Heidelb)",
"mesh_terms": null,
"nlm_unique_id": "101590450",
"other_id": null,
"pages": "77-86",
"pmc": null,
"pmid": "25539704",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": "23969404;20855839;19002355;19450400;17239291;24616845;17396743;22134572;23879247;19068457;20051477;18070211;17116852;18559769;17241689;19923864;19112807;16636341;18929917;18559790;25276283;22052319;23981682;19558553;16824050;18188524;15992698;24330088;17699864;18342708;24355408;19178612;20567994;24698672;18342102;21571189;21910797;16103482;19537383;18613894;12369852;22782962;18645140;17034418;21413947;19028406;20526556;19832927;16881967;19514932;19615549;20214183;22646774",
"title": "Sorafenib-associated facial acneiform eruption.",
"title_normalized": "sorafenib associated facial acneiform eruption"
} | [
{
"companynumb": "US-BAYER-2015-003343",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
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{
"abstract": "In Clozapine users constipation is among the reported side effects including agranulocytosis and myocarditis with prevalence rates ranging from 14% to 60%. In extreme cases this may lead to bowel obstruction and paralytic ileus which, if not detected and treated early, may lead to mortality up to 30%. We report the first case of hepatic outflow block secondary to compression of the liver by a distended colon upstream an impacted fecaloma in a 47-year old schizophrenic man treated by clozapine. Emergency sub-total colectomy was performed for pan-colonic ischemia. Surgery relieved the liver outflow block and was followed by uneventful outcome. Patients receiving clozapine should undergo routine laxatives and monitoring in order to limit the risk of clozapine-related ileus and bowel ischemia.",
"affiliations": "Henri Mondor Hospital, Department of Hepato-Pancreato-Biliary and Liver Transplantation.",
"authors": "Osseis|Michael|M|;Lim|Chetana|C|;Lahat|Eylon|E|;Doussot|Alexandre|A|;Salloum|Chady|C|;Azoulay|Daniel|D|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "Japan",
"delete": false,
"doi": "10.5582/ddt.2015.01067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1881-7831",
"issue": "9(6)",
"journal": "Drug discoveries & therapeutics",
"keywords": null,
"medline_ta": "Drug Discov Ther",
"mesh_terms": "D014150:Antipsychotic Agents; D006502:Budd-Chiari Syndrome; D003024:Clozapine; D005244:Fecal Impaction; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia",
"nlm_unique_id": "101493809",
"other_id": null,
"pages": "422-3",
"pmc": null,
"pmid": "26781928",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatic venous outflow block caused by compressive fecaloma in a schizophrenic patient treated with clozapine.",
"title_normalized": "hepatic venous outflow block caused by compressive fecaloma in a schizophrenic patient treated with clozapine"
} | [
{
"companynumb": "FR-WATSON-2016-02540",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Autoimmune haemolytic anaemia (AIHA) is an uncommon condition characterized by increased destruction of erythrocytes associated with reticulocytosis in the great majority of cases. We present the case of a 68-year-old woman with jaundice and malaise. Investigation revealed AIHA with reticulocytopenia. The patient failed to respond to prednisolone or to rituximab. Azathioprine and epoetin beta were subsequently started, the prednisolone dose was increased, and the patient began to respond after 1 month. In AIHA, reticulocytopenia is a very rare presentation and a sign of great severity and poor outcome. The scarcity of therapeutic options in refractory cases poses a major challenge for physicians.\nAutoimmune haemolytic anaemia is a rare disorder characterized by decompensated acquired haemolysis caused by the host's immune system acting against its own red cell antigens.Concomitant presentation with reticulocytopenia is very rare and a sign of great severity and poor outcome.Treatment options in refractory cases still greatly rely on individual experience and expert opinion.",
"affiliations": "Internal Medicine Department, Centro Hospitalar do Baixo Vouga, Aveiro, Portugal.;Haematology Department, Centro Hospitalar do Baixo Vouga, Aveiro, Portugal.;Internal Medicine Department, Centro Hospitalar do Baixo Vouga, Aveiro, Portugal.;Internal Medicine Department, Centro Hospitalar do Baixo Vouga, Aveiro, Portugal.;Internal Medicine Department, Centro Hospitalar do Baixo Vouga, Aveiro, Portugal.",
"authors": "Aveiro|Marcelo|M|;Ferreira|Gisela|G|;Matias|Carla|C|;Oliveira|Ana|A|;Rodrigues|Tatiana|T|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_002112",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2284-2594",
"issue": "7(12)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Haemolytic anaemia; azathioprine; reticulocytopenia",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "002112",
"pmc": null,
"pmid": "33457372",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "28005293;25963403;3814817;4177973;26819490;22851939;7411826;1570541;6509884;18314434;25232059;28360039",
"title": "Hard-To-Treat Idiopathic Refractory Autoimmune Haemolytic Anaemia with Reticulocytopenia.",
"title_normalized": "hard to treat idiopathic refractory autoimmune haemolytic anaemia with reticulocytopenia"
} | [
{
"companynumb": "PT-CELLTRION INC.-2021PT000915",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
... |
{
"abstract": "Catastrophic antiphospholipid syndrome (CAPS) involves sudden multiorgan dysfunction from thrombosis due to antibodies that cause platelet activation and endothelial dysfunction. Treatment variably combines anticoagulation, corticosteroid use, therapeutic plasma exchange (TPE), and high-dose intravenous immunoglobulin (IVIG). A 42-year-old male with antiphospholipid syndrome (APS) presented with severe thrombocytopenia, encephalopathy, cardiac ischemia, and acral purpuric cutaneous lesions. CAPS was identified and he received heparin infusion, methylprednisolone, and IVIG. On day 7 he developed new purpuric lesions on his right foot despite detectable arterial pulses representing new microthrombosis refractory to IVIG. He was treated with TPE which resolved the right foot ischemia and eventually his CAPS. To our knowledge, this is the first patient with CAPS reported that failed initial treatment with IVIG and subsequently had excellent response to TPE. Our observations also support recent literature indicating that onset of thrombocytopenia in APS is a warning of progression to CAPS requiring treatment escalation.",
"affiliations": "Department of Medicine, McMaster University, Hamilton, Canada.;Department of Medicine, McMaster University, Hamilton, Canada.;Department of Medicine, McMaster University, Hamilton, Canada.;Department of Medicine, McMaster University, Hamilton, Canada.",
"authors": "James|Tyler E|TE|;Martin|Leslie J|LJ|;Warkentin|Theodore E|TE|https://orcid.org/0000-0002-8046-7588;Crowther|Mark A|MA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09537104.2020.1802414",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-7104",
"issue": "32(6)",
"journal": "Platelets",
"keywords": "Catastrophic antiphospholipid syndrome; high-dose intravenous immunoglobulin; microvascular; therapeutic plasma exchange; thrombocytopenia; thrombosis",
"medline_ta": "Platelets",
"mesh_terms": null,
"nlm_unique_id": "9208117",
"other_id": null,
"pages": "828-831",
"pmc": null,
"pmid": "32762580",
"pubdate": "2021-08-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Catastrophic antiphospholipid syndrome refractory to high-dose intravenous immunoglobulin responsive to therapeutic plasma exchange.",
"title_normalized": "catastrophic antiphospholipid syndrome refractory to high dose intravenous immunoglobulin responsive to therapeutic plasma exchange"
} | [
{
"companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2021-23525",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "Clinically significant extrauterine twin-twin transfusion syndrome in conjoined twins is rare and carries a high risk of perinatal mortality. The ensuing postnatal imbalance in circulation across connecting vessels results in hypovolemia in the donor and hypervolemia in the recipient. Data on management and treatment are sparse especially in the setting of a single ventricle congenital heart defect. We present a case of a pair of omphalopagus conjoined twins, one with a single ventricle physiology (Twin B), who developed twin-twin transfusion syndrome shortly after birth. The resulting pathophysiology in the setting of a single ventricle congenital heart defect created added layers of complexity to their management and expedited surgical separation. Shunting from Twin B to Twin A-with an anatomically normal heart-resulted in mal-perfusion and rapid deterioration jeopardizing the health of both twins. In the preoperative course, steps taken to medically optimize the twins prior to surgery and the anesthetic considerations are detailed in this report.",
"affiliations": "Division of Pediatric Anesthesiology, Children's Health System of Texas, Dallas, TX, USA.;Division of Pediatric Anesthesiology, Children's Health System of Texas, Dallas, TX, USA.;Division of Pediatric Anesthesiology, Children's Health System of Texas, Dallas, TX, USA.;Division of Pediatric Anesthesiology, Children's Health System of Texas, Dallas, TX, USA.;Division of Pediatric Surgery, Children's Health System of Texas, Dallas, TX, USA.;Division of Pediatric Surgery, Children's Health System of Texas, Dallas, TX, USA.;Division of Pediatric Anesthesiology, Children's Health System of Texas, Dallas, TX, USA.;Division of Pediatric Cardiology, UT Southwestern Medical Center, Dallas, TX, USA.;Division of Pediatric Anesthesiology, Children's Health System of Texas, Dallas, TX, USA.",
"authors": "Kiss|Edgar|E|https://orcid.org/0000-0002-5690-0409;Chehab|Sarah|S|;Moreno Duarte|Ingrid|I|https://orcid.org/0000-0001-7965-7934;Khan|Umar|U|;Schindel|David|D|;Pandya|Samir|S|;Ullah|Sana|S|;Ochoa|Courtney|C|;Zabala|Luis M|LM|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1111/pan.14276",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "31(11)",
"journal": "Paediatric anaesthesia",
"keywords": "congenital heart disease; conjoined twins; twin-twin transfusion",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D005260:Female; D005330:Fetofetal Transfusion; D006330:Heart Defects, Congenital; D006801:Humans; D011247:Pregnancy; D014428:Twins, Conjoined",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "1255-1258",
"pmc": null,
"pmid": "34390085",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Twin-twin transfusion syndrome complicated by single ventricle physiology: A case report.",
"title_normalized": "twin twin transfusion syndrome complicated by single ventricle physiology a case report"
} | [
{
"companynumb": "US-PFIZER INC-202101446531",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MILRINONE"
},
"drugadditional": null,
... |
{
"abstract": "Fluid and salt retention have been described as a side effect of tacrolimus therapy. We report a case of unexplained massive fluid retention with pleural effusion and ascites in the immediate post-transplant period. The patient recovered immediately on conversion from tacrolimus to sirolimus.",
"affiliations": "Department of Nephrology, SB Hospital, Thanjavur, Tamil Nadu, India.;Department of Urology, SB Hospital, Thanjavur, Tamil Nadu, India.;Department of Urology, SB Hospital, Thanjavur, Tamil Nadu, India.",
"authors": "Nayagam|L S|LS|;Vijayanand|B|B|;Balasubramanian|S|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0971-4065.133024",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-24-31810.4103/0971-4065.133024Case ReportMassive pleural effusion in a renal transplant recipient on tacrolimus Nayagam L. S. Vijayanand B. 1Balasubramanian S. 1Department of Nephrology, SB Hospital, Thanjavur, Tamil Nadu, India1 Department of Urology, SB Hospital, Thanjavur, Tamil Nadu, IndiaAddress for correspondence: Dr. L. S. Nayagam, SB Hospital, Medical College Road, Rajappa Nagar, Thanjavur - 613 007, Tamil Nadu, India. E-mail: lsnayagam@yahoo.co.inSep-Oct 2014 24 5 318 320 Copyright: © Indian Journal of Nephrology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Fluid and salt retention have been described as a side effect of tacrolimus therapy. We report a case of unexplained massive fluid retention with pleural effusion and ascites in the immediate post-transplant period. The patient recovered immediately on conversion from tacrolimus to sirolimus.\n\nFluid retentionsirolimustacrolimus\n==== Body\nIntroduction\nTacrolimus is the calcineurin inhibitor (CNI) of choice for maintenance immunosuppression in kidney transplant recipients. The major drawbacks of tacrolimus are its narrow therapeutic window, unpredictable bioavailability and nephrotoxicity. Fluid and sodium retention are reported rarely. Here, we report a patient who developed significant fluid retention including third space collection in the immediate post-transplant period and showed dramatic improvement on conversion to sirolimus.\n\nCase Report\nA 51-year-old female patient was admitted with rapidly progressive renal failure 3 years ago. She had proteinuria and microhematuria. Antinuclear antibodies were positive. Complement levels were normal and anti-double stranded deoxyribonucleic acid antibodies and antineutrophil cytoplasmic antibodies were negative. Hepatitis B surface antigen, hepatitis C virus (HCV) antibodies and enzyme-linked immunosorbent assay for human immunodeficiency virus were negative. Ultrasonogram showed normal kidney size. However kidney biopsy showed only chronic changes with fibrous crescents. She was started on maintenance hemodialysis and oral prednisolone for arthralgia. She was on hemodialysis for next 30 months along with alternate day prednisolone 5 mg/day. She became anti-HCV positive a year later. Liver functions were normal and there was no evidence of chronic liver disease and portal hypertension on ultrasonogram and upper gastrointestinal endoscopy. She was not considered for interferon therapy. She was euthyroid on thyroxine replacement (100 μg/day) at the time of transplantation. There was no edema prior to transplantation and she was at her dry weight on the day of transplantation. She was started on tacrolimus 0.1 mg/kg/day, mycophenolate mofetil 500 mg b.d. and prednisolone 20 mg/day. She had received pulse methyl prednisolone 1 g on day and 500 mg for the next 2 days. Induction antibodies were not given. Trough tacrolimus level on post-operative day 2 was 12.1 ng/ml. Graft started functioning immediately and creatinine had dropped to 1.6 mg/dl on day 2 and 1.4 mg/dl on day 4. Patient developed breathlessness (relieved on lying to the left side), pedal edema, abdominal distension and swelling of upper limbs (more on the left side) 4 days after transplantation. Urine output was 2 l/day. Creatinine stabilized between 1.4 and 1.7 mg/dl. There was no proteinuria and serum albumin was 3.2 g. Twenty four hour urine protein estimation done 2 days after the onset of symptoms was 300 mg/day. Echocardiography showed normal left ventricular function, mild pericardial effusion and there was no suggestion of pulmonary embolism. She remained euthyroid. Chest X-ray showed a massive left pleural effusion [Figure 1]. Computed tomography scan showed a massive left pleural effusion with complete collapse of left lung, moderate right pleural effusion and massive ascites. She was transfused two units of packed cells and 100 ml of 20% human albumin along with diuretics. She was maintained on a negative fluid balance. Anasarca persisted in spite of these measures. Urine output remained between 2 and 3 l/day and serum creatinine 10 days after transplantation was 1.4 mg/dl. Intercostal tube drainage of left pleural effusion was carried out. Pleural fluid was clear, transudative and pleural fluid adenosine deaminase was normal. Tacrolimus dose was reduced from 4.5 mg/day to 3.5 mg/day following which the trough level came down to 11.9 ng/ml. There was no improvement in fluid overload and right pleural effusion started worsening. A diagnosis of fluid retention secondary to tacrolimus was suspected and 6 days after the onset of fluid retention tacrolimus was stopped. She was started on sirolimus with a maintenance dose of 2 mg/day. Her trough sirolimus level was 6.54 ng/ml. Patient's edema started decreasing 48 h after stopping tacrolimus. Urine output improved to 3.5-4 l/day and creatinine stabilized around 1.4 mg/dl. Intercostal tube drainage was removed 3 days later and there was significant improvement in right pleural effusion and ascites also. Chest X-ray showed a complete resolution of pleural effusion [Figure 2]. Patient has not developed fluid retention during the 7 months of follow-up. At the last follow-up, patient's serum creatinine was 1.4 mg/dl and there was no proteinuria.\n\nFigure 1 Chest X-ray on post-transplant day 5 showing a massive left pleural effusion\n\nFigure 2 Chest X-ray 3 days after conversion to sirolimus\n\nDiscussion\nNephrotoxicity is the major limiting factor, with tacrolimus therapy often dictating the optimal dosage regime of the drug. Nephrotoxicity manifests in many ways such as oliguria, increased serum creatinine, hyperkalemia, fluid and salt retention.[12] Lowering the dosage of tacrolimus generally, but not always, reduces the toxic effects. However reduction in dosage is associated with risk of under immunosuppression and acute rejection. Fluid retention manifesting as peripheral edema, ascites and pleural effusion has been reported in 20-30% of patients receiving tacrolimus for liver transplant.[13] The incidence of peripheral edema and ascites was less than 15% and pleural effusion was 35% in the European FK 506 Multicenter Liver Study Group.[4] The incidence of fluid retention is similar for cyclosporine. There has not been any case report of significant pleural effusion, necessitating intercostal tube drainage, with tacrolimus. Most of the time fluid retention improves with dose reduction. However, our patient did not respond to reduction in dosage. Conversion from CNIs to sirolimus has been a standard practice for CNI nephrotoxicity. Hence in our patient, we considered the possibility of tacrolimus induced pleural effusion and shifted her to sirolimus and the patient showed immediate response.\n\nIn summary, we report a case of massive pleural effusion and ascites induced by tacrolimus in the immediate post-transplant period and which rapidly improved after conversion to sirolimus.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Spencer CM Goa KL Gillis JC Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation Drugs 1997 54 925 75 9421697 \n2 BeDell LS Mosby's Complete Drug Reference Physicians GenRX 1997 7th ed St. Louis, MO Mosby 145 8 \n3 Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft. rejection European FK506 Multicentre Liver Study Group Lancet 1994 344 423 8 7520105 \n4 A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation The U.S. Multicenter FK Liver Study Group. 6 Li The US Multicenter FK506 Liver Study Group N Engl J Med 1994 331 1110 5 7523946\n\n",
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"keywords": "Fluid retention; sirolimus; tacrolimus",
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"affiliations": "From the *Division of Cardiac Surgery, †Division of Hematology, Department of Medicine, ‡Department of Oncology, §Department of Epidemiology and Biostatistics, ¶Department of Medical Imaging, Schulich School of Medicine and Dentistry, and ∥Division of Cardiovascular and Thoracic Surgery, University of Western Ontario, London, ON Canada.",
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"abstract": "Peritoneal dialysis (PD) is a form of therapy for end-stage kidney disease (ESKD), and peritonitis is a known complication. Mycobacterium (M) species associated peritonitis in PD patients is uncommon. Our experience of managing PD associated peritonitis caused by M abscessus in a middle-aged man with ESKD due to focal segmental glomerulosclerosis is shared in this article with a review of the literature on this condition.\n\n\n\nA 49-year old man presented to our unit with symptoms of peritonitis and cloudy PD effluent. Initial analysis of PD fluid showed Gram stain was negative, with no organism grown. Empirical PD peritonitis treatment with intra-peritoneal antibiotics did not improve his symptoms and he required intravenous antibiotics, PD catheter removal and a switch to haemodialysis. Cultures of the PD fluid later grew M abscessus, and the antibiotic regimen was changed appropriately, leading to clinical improvement.\n\n\n\nM abscessus associated peritonitis in PD patients is rare. It needs to be borne in mind when clinical improvement is not seen with standard broad-spectrum antibiotics, especially in situations where the PD fluid is initially deemed to be culture negative. PD fluid samples should be sent for acid-fast bacillus and if detected, should be further analysed with genome-wide sequencing to confirm the species of the Mycobacterium. Prompt removal of the catheter with peritoneal washout is critical for clinical improvement.",
"affiliations": "South West Thames Renal & Transplantation Unit, Epsom & St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton, Surrey, SM5 1AA, UK.;Department of Microbiology, Epsom & St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton, Surrey, SM5 1AA, UK.;Department of Microbiology, Epsom & St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton, Surrey, SM5 1AA, UK.;South West Thames Renal & Transplantation Unit, Epsom & St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton, Surrey, SM5 1AA, UK.;South West Thames Renal & Transplantation Unit, Epsom & St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton, Surrey, SM5 1AA, UK. Nephr0nite@gmail.com.",
"authors": "Jheeta|Anup Singh|AS|;Rangaiah|Jayakeerthi|J|;Clark|John|J|;Makanjuola|David|D|;Somalanka|Subash|S|0000-0002-1547-5127",
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"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369 BioMed Central London \n\n2146\n10.1186/s12882-020-02146-4\nCase Report\nMycobacterium abscessus - an uncommon, but important cause of peritoneal dialysis-associated peritonitis – case report and literature review\nJheeta Anup Singh 1 Rangaiah Jayakeerthi 2 Clark John 2 Makanjuola David 1 https://orcid.org/0000-0002-1547-5127Somalanka Subash Nephr0nite@gmail.com 1 1 grid.419496.7South West Thames Renal & Transplantation Unit, Epsom & St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton, Surrey, SM5 1AA UK \n2 grid.419496.7Department of Microbiology, Epsom & St Helier University Hospitals NHS Trust, Wrythe Lane, Carshalton, Surrey, SM5 1AA UK \n17 11 2020 \n17 11 2020 \n2020 \n21 49127 7 2020 2 11 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\nPeritoneal dialysis (PD) is a form of therapy for end-stage kidney disease (ESKD), and peritonitis is a known complication. Mycobacterium (M) species associated peritonitis in PD patients is uncommon. Our experience of managing PD associated peritonitis caused by M abscessus in a middle-aged man with ESKD due to focal segmental glomerulosclerosis is shared in this article with a review of the literature on this condition.\n\nCase presentation\nA 49-year old man presented to our unit with symptoms of peritonitis and cloudy PD effluent. Initial analysis of PD fluid showed Gram stain was negative, with no organism grown. Empirical PD peritonitis treatment with intra-peritoneal antibiotics did not improve his symptoms and he required intravenous antibiotics, PD catheter removal and a switch to haemodialysis. Cultures of the PD fluid later grew M abscessus, and the antibiotic regimen was changed appropriately, leading to clinical improvement.\n\nConclusion\nM abscessus associated peritonitis in PD patients is rare. It needs to be borne in mind when clinical improvement is not seen with standard broad-spectrum antibiotics, especially in situations where the PD fluid is initially deemed to be culture negative. PD fluid samples should be sent for acid-fast bacillus and if detected, should be further analysed with genome-wide sequencing to confirm the species of the Mycobacterium. Prompt removal of the catheter with peritoneal washout is critical for clinical improvement.\n\nKeywords\nPeritoneal dialysisCatheterPeritonitisMycobacterium abscessusissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPeritoneal dialysis is used for managing end-stage kidney disease (ESKD). It requires access to the peritoneal space by way of a percutaneous tunnelled dialysis catheter. Infective complications of peritoneal dialysis (PD) include catheter exit-site infection (ESI), catheter tunnel infection (TI) and peritonitis. Peritonitis can be particularly severe and can lead to PD failure and discontinuation of PD. [1] Early recognition of infections, prompt microbiological diagnosis, and establishing appropriate treatment are therefore essential. An essential factor that determines a successful outcome in such cases is anti-microbial susceptibility testing to guide appropriate therapy. PD related peritonitis is most commonly caused by gram-positive aerobes such as coagulase-negative Staphylococci and Staphylococcus aureus, or gram-negative aerobes such as Pseudomonas aeruginosa [2]. Reports of PD related peritonitis caused by Mycobacterium species are relatively rare, although their incidence has been well documented [3, 4]. Nontuberculous mycobacteria (NTM) are members of the genus Mycobacterium but are significantly different from other members of the same genus, e.g., M.tuberculosis and M.leprae. NTM related PD peritonitis is emerging as a diagnostic and therapeutic challenge in the management of PD peritonitis, with comparatively higher rates of PD catheter loss and PD failure compared to other organisms [5]. Consensus on the management of NTM related PD peritonitis does not currently exist, possibly because of the paucity of reported cases. We describe what is to our knowledge the first reported case in the UK of PD related peritonitis secondary to the NTM species Mycobacterium abscessus.\n\nCase presentation\nA 49-year-old male of Afro-Caribbean origin with a background of hypertension, type 2 diabetes mellitus, high body mass index of 40 and ESKD secondary to focal and segmental glomerulosclerosis (FSGS) diagnosed in 2007 and received only 1 month of corticosteroids. He presented to our PD unit with mild abdominal discomfort and cloudy PD effluent in July 2019. He had been on PD for 4 years and had experienced one previous episode of PD peritonitis caused by Staphylococcus aureus requiring catheter replacement 2 years ago. The PD regimen consisted of automated peritoneal dialysis [APD] of 8.5 h duration with 5 cycles of 3 l fills. The dialysate fluid consisted of 1.36% glucose concentration of 10 l and 2.27% glucose concentration of 5 l with extraneal (Icodextrin 7.5%) solution as a last fill of 1.7 l. He also received an Opti exchange of 2.0 l of 1.36% solution in the evenings.\n\nHe was clinically and haemodynamically stable with mild abdominal discomfort as his symptom. Serum inflammatory markers showed a white cell count [WCC] of 6.0 × 106/L and a C-reactive protein [CRP] of 80.7 mg/L (normal range < 5 mg/L). Microscopy of the PD fluid showed a WCC of 155 x 106cells/L and a total eosinophil count of 1 × 106 cells/L, but the Gram stain was negative. Empirical broad-spectrum intra-peritoneal antibiotics (Vancomycin and Gentamicin) were commenced. On day 5, he developed worsening abdominal pain. On examination, his blood pressure was 158/100 mmHg; heart rate 90/min, temperature 37.5 °C. His abdomen was tender on palpation. There was no evidence of PD catheter exit site infection or any tunnel infection. The CRP was 456.9 mg/L, and WCC was 12.3 × 106/L. He was admitted to the renal unit and treatment was escalated to intravenous Gentamicin and Vancomycin, and subsequently to intravenous Meropenem on day 7 in view of persistent symptoms and raised inflammatory markers. He underwent rapid PD fluid exchanges to help relieve abdominal pain. On day 8, his CRP was 534 mg/L, WCC was 20.5 × 106/L with a temperature of 39.8 °C. He underwent emergency surgical PD catheter removal with peritoneal washout. Intra-operative findings did not reveal any bowel perforation. A haemodialysis catheter was inserted, and regular haemodialysis (HD) was commenced. On day 8, acid-fast bacilli [AFB] were grown from the PD fluid sample, which was confirmed by the National Mycobacterium Reference Laboratory through whole-genome sequencing to be Mycobacterium abscessus. In view of this, he was commenced on quadruple therapy with intravenous Amikacin, Clarithromycin, Tigecycline and Imipenem with cilastatin. He developed new QTc prolongation on the electrocardiogram (ECG) on day 16, which was attributed to Clarithromycin, so this was therefore discontinued. Furthermore, he developed acute hepatic impairment which resolved following cessation of Tigecycline on day 26.\n\nHe remained clinically well on dual therapy with intravenous Amikacin and Imipenem and was discharged on day 35 (Fig. 1). A peripherally inserted central venous catheter was placed, to facilitate daily intravenous antibiotics as an outpatient. He continued on antibiotics for a total of 5 months. Linezolid was added during the last 6 weeks of therapy. He had a regular review by the Audiologists, but in spite of close monitoring to maintain the Amikacin levels within the therapeutic range, he has sustained a degree of sensorineural hearing loss.\nFig. 1 Timeline of inpatient stay\n\n\n\nDiscussion and conclusion\nM.abscessus is a nontuberculous mycobacterium (NTM). It is one of the most clinically relevant, rapidly growing mycobacteria, which are environmental organisms that usually grow in culture within 1 week. M. abscessus has been frequently isolated from water, soil, domestic and wild animals [6]. Although not highly virulent, M.abscessus is known to cause disseminated infection in immunocompromised hosts, and bacteraemia can occur in the context of dialysis catheter use [7]. It is a well-documented cause of pulmonary infection in patients with structural lung disease such as cystic fibrosis, and can cause skin and soft tissue infections in hospitalised post-surgical patients [8, 9].\n\nDiagnosis\nThe diagnosis of NTM and M.abscessus PD peritonitis can be challenging. NTM can cause culture-negative infection, and it is interesting to note that in 4 out of 16 reported cases, the development of PD peritonitis was preceded by catheter replacement for the management of what was deemed to be culture-negative ESI or TI [3, 10, 11]. Clinicians should, therefore be vigilant with regards to possible NTM infection in patients with culture-negative PD peritonitis, particularly in the context of non-responsiveness to standard anti-microbial therapy [5, 12].\n\nOur patient was diabetic and on PD for his kidney failure. The presence of end-stage renal failure (ESRF) is associated with impairment of the innate and adaptive immune system [13]. Diabetes mellitus was present in 27.5% of cases of NTM related PD peritonitis in one systematic review, suggesting that metabolic disease may pre-dispose to NTM infection [5]. M.abscessus has a predisposition to create biofilms, colonise and infect catheters [7]. Consequently, all previously documented cases of M.abscessus PD peritonitis have required catheter removal for effective source control (Table 1). The intrinsic resistance of M.abscessus to classical anti-tuberculous drugs as well as most other available broad-spectrum antibiotics limits the choice of options for therapy [20] and poses a significant challenge with regards to treatment.\nTable 1 Summary of previously reported cases of M.abscessus PD peritonitis\n\nCase number\tAge: sex\tDuration of PD\tTime to culture\tPositive AFB stain\tRemoval of PD catheter\tAntibiotics and duration\tClinical outcome\tPrior ESI, TI or abdominal intervention prior.\tCountry of reported case\t\n1 [14]\t67 M\t12 months\t\t\tY\tAmikacin, Clarithromycin (3 months)\tConverted to HD\t\tUSA\t\n2 [12]\t70 M\t36 months\t9 days\tN\tY\tAmikacin, Clarithromycin\n\nClarithromycin stopped (hepatic impairment)\n\n\tConverted to HD. Died 6 weeks into treatment, acute coronary syndrome.\tY - Umbilical hernia repair\tChina\t\n3 [12]\t50 M\t6 months\t6 days\tN\tY\tCiprofloxacin, Clarithromycin (3 months)\tConverted to HD\tY – culture negative ESI\tIndia\t\n4 [12]\t56 M\t36 months\t8 days\tN\tY\tAmikacin, Clarithromycin\tConverted to HD.\n\nRe-admission with catheter related infection and sepsis 2 weeks after discharge.\n\nDied from acute coronary syndrome.\n\n\tY- Pseudomonas\n\nESI\n\n\tChina\t\n5 [12]\t60 M\t46 months\t6 days\tY\tY\tAmikacin (6 weeks)\n\nClarithromycin (3 months)\n\nAmikacin stopped as developed sensorineural hearing loss.\n\n\tTemporarily converted to HD. Re-established on PD after 3 months.\tN\tChina\t\n6 [15]\t60F\t60 months\t6 days\tY\tY\tAmikacin, Clarithromycin (8 weeks)\tConverted to HD\tY – accidental removal of Tenckhoff catheter\tSaudi\t\n7 [15]\t64F\t12 months\t4 days\tY\tY\tClarithromycin (12 weeks)\tConverted to HD\tN\tSaudi\t\n8 [16]\t39F\t60 months\tNot disclosed\tNot disclosed\tY\tMeropenem (4 weeks), Amikacin (8 weeks), Cefoxitin (28 weeks)\tConverted to HD.\n\nIntra-abdominal collection requiring drainage.\n\n\tRecurrent P.aeruginosa ESI 2004–2007\tHong Kong\t\n9 [16]\t45 M\t3 months\tNot disclosed\tNot disclosed\tY\tAmikacin (4 weeks), Azithromycin 6 weeks) Moxifloxacin (20 weeks)\tTemporarily converted to HD. Re-established on PD after 9 months.\tN\tHong Kong\t\n10 [17]\t49 M\tNot disclosed\tNot disclosed\tNot disclosed\tY\tCephazolin, Gentamicin\tConverted to HD. Died after 5 months (sclerosing peritonitis)\t\tAustralia\t\n11 [17]\t40F\tNot disclosed\tNot disclosed\tNot disclosed\tY\tAmikacin, Cefoxitin, Vancomycin, Gentamicin, Flucloxacillin\tConverted to HD\t\tAustralia\t\n12 [17]\t65 M\tNot disclosed\tNot disclosed\tNot disclosed\tY\tClarithromycin, Vancomycin, Ticarcillin and clavulanic acid, Gentamicin\tConverted to HD\t\tAustralia\t\n13 [18]\t44F\t96 months\t28 days\tY\tY\tClarithromycin (165 days), Amikacin (68 days), Meropenem (165 days), Levofloxacin (111 days)\tConverted to HD. Died after 8 months (renal haemorrhage and retroperitoneal infection).\tY – Catheter replacement for refractory exit site infection.\n\nCommenced on anti-tuberculous drugs post AFB.\n\n\tTaiwan\t\n14 [18]\t58F\t60 months\t10 days (treatment commenced day 3)\tY\tY\tClarithromycin (165 days), Amikacin (50 days), Imipenem (70 days), Ciprofloxacin (217 days), Doxycycline (180 days).\tConverted to HD.\n\nAbscess formation in abdominal wall requiring debridement × 2.\n\n\tY – Catheter replacement 3 weeks prior for tunnelled line infection.\tTaiwan\t\n15 [11]\t51F\t14 months\tNot disclosed\tY\tY\tClarithromycin (7 weeks)\n\nCiprofloxacin (3 weeks)\n\nAmikacin (3 weeks)\n\n\tConverted to HD. Disseminated cutaneous infection requiring surgical debridement\tY – PD catheter replacement 8 days prior (persistent culture neg. Tunnel infection)\tJapan\t\n16 [19]\t56 M\t\t33 days\tN\tY\tImipenem (4 weeks)\n\nClarithromycin (6 months)\n\n\tConverted to HD.\n\nInfection post catheter insertion.\n\n\tY – Re-insertion of PD catheter (refractory ESI and TI presumed to be methicillin resistant coagulase negative staphylococcus)\tJapan\t\n\n\nA systematic review of 57 cases of NTM PD peritonitis found that the time from onset of symptoms to the initiation of appropriate treatment was 4 weeks [5]. This delay is multi-factorial. Firstly, the available data do not demonstrate any factor unique to M.abscessus PD peritonitis compared with more common organisms. The symptoms and signs are indistinguishable from conventional PD peritonitis or tuberculous peritonitis [4, 21]. All cases of M.abscessus PD peritonitis first received empirical antibiotics and in one case, subsequently received anti-tuberculous therapy following a positive acid-fast bacillus (AFB) stain [22]. Secondly, the utility of AFB staining in such cases is debatable, as the sensitivity of this test is not high enough [23]. In one particular study, AFB staining was positive in only four out of 10 cases of M.abscessus peritonitis [4]. Most centres do not perform AFB staining routinely as it does not distinguish between tuberculous mycobacteria and NTM, thus providing no further information regarding anti-microbial sensitivities [24, 25]. As a consequence, the diagnosis is reliant on bacterial culture alone, which leads to delays in the initiation of appropriate treatment and may likely result in worse outcome in such cases [26].\n\nTreatment\nThe management of M.abscessus PD peritonitis is complex. Catheter removal appears to be essential to recovery in the acute setting, with long term management reliant on anti-microbial therapy [12, 17]. M.abscessus is a multi-drug resistant organism, and as a consequence, the antibiotic choices are limited. One report investigated resistance and susceptibility criteria of M.abscessus in various published cases and showed that resistance rates for Quinolones, Doxycycline and Imipenem, were considerably high, while resistance rates for Cefoxitin (15.1%) and Amikacin (7.7%) were low. Clarithromycin showed variable resistance rates ranging from 0 to 38%. As a consequence, treatment should be based on the susceptibility profile of the bacterium isolated from individual patients [18].\n\nIt has been recommended that non-pulmonary M.abscessus infection should be treated for between 4 and 6 months [27]. There is no consensus, however, for the optimal duration of the treatment for M.abscessus PD peritonitis and this is reflected in the variability of treatment regimens observed in the reported cases, where treatment duration ranged from 7 weeks to 28 weeks with a variety of drug combinations used based on individual sensitivities.\n\nThe challenges posed by the administration of long-term antibiotics should also be recognised. In our case, quadruple therapy was not tolerated due to the development of hepatic impairment with Tigecycline and QTc prolongation with Clarithromycin. Similar complications were observed in previous cases with Amikacin (sensorineural hearing loss) and Clarithromycin (hepatic impairment) [12]. The optimal duration of anti-microbial therapy is unclear at present but is likely to be at least 4 months [27].\n\nOverall, outcomes from M.abscessus PD peritonitis appear to be worse than for conventional organisms. A 10-year retrospective cohort study of PD peritonitis in an Australian population found that the risk of catheter removal varied between < 20 to > 40% depending on the causative organism [17]. The risk of changing over to HD was estimated to be between 5 to 20% [1]. In previously reported cases of M.abscessus PD peritonitis, 100% of patients were converted to HD [6]. In only two of these cases were the patients successfully converted back to PD, suggesting that the risk of PD failure is higher with M.abscessus infection compared with conventional organisms.\n\nIn summary, we present, to our knowledge, the first reported case of M.abscessus PD peritonitis in the United Kingdom. It was managed with catheter removal, a prolonged course of intravenous broad-spectrum antibiotics and conversion to HD. Clinicians should have a high index of suspicion of M.abscessus in cases of non-resolving PD related infections, or culture-negative peritonitis. Catheter removal appears to be essential for clinical recovery, and the switch to HD may be permanent.\n\nAbbreviations\nAFBAcid-fast bacillus\n\nCRPC-reactive protein\n\nECGElectrocardiogram\n\nESIExit-site infection\n\nESKDEnd-stage kidney disease\n\nHDHaemodialysis\n\nM abscessusMycobacterium abscessus\n\nM.tuberculosisMycobacterium tuberculosis\n\nM.lepraeMycobacterium leprae\n\nNTMNontuberculous mycobacteria\n\nPDPeritoneal dialysis\n\nTITunnel infection\n\nUKUnited Kingdom\n\nWCCWhite cell count\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nnone.\n\nAuthors’ contributions\nAuthors have provided substantial contributions to the concept, design of the work; the acquisition, and analysis, interpretation of data and the contributions to the drafting of the original manuscript and its subsequent revisions. All authors have read and have approved the submitted version and any substantially modified version that involves the author’s contribution to the document. The authors have agreed to be personally accountable for the author’s contributions and to ensure that the questions related to the accuracy or integrity of any part of the work, even ones in which the authors are not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. The individual author’s contributions are declared below:- ASJ - looked after the patient, substantially contributed to the acquisition, analysis of the data and the preparation of the manuscript. JR – contributed substantially to the analysis of the data, design and the preparation of the manuscript. JC - contributed substantially to the analysis of the data, design and the preparation of the manuscript. DM – Looked after the patient, substantially contributed to the acquisition, analysis and interpretation of the data, in addition to the preparation of the manuscript. SS- Looked after the patient. Substantial contribution to the acquisition and interpretation of the data, design and concept of the manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for the publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal. The same has been uploaded on the submission site.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Htay H Cho Y Pascoe EM Darssan D Nadeau-Fredette AC Hawley C Center effects and peritoneal Dialysis peritonitis outcomes: analysis of a National Registry Am J Kidney Dis 2018 71 6 814 821 10.1053/j.ajkd.2017.10.017 29289475 \n2. Li PKT Szeto CC Piraino B de Arteaga J Fan S Figueiredo AE ISPD peritonitis recommendations: 2016 update on prevention and treatment Peritoneal Dialysis Int Multimed Inc 2016 36 481 508 10.3747/pdi.2016.00078 \n3. Rohit A Abraham G Peritoneal dialysis related peritonitis due to mycobacterium Spp.: a case report and review of literature J Epidemiol Global Health Elsevier Ltd 2016 6 243 248 10.1016/j.jegh.2016.06.005 \n4. Karayaylali I Seyrek N Akpolat T Ateş K Ozener C Yilmaz ME The prevalence and clinical features of tuberculous peritonitis in CAPD patients in Turkey, report of ten cases from multi-centers Ren Fail 2003 25 5 819 827 10.1081/JDI-120024296 14575289 \n5. Song Y Wu J Yan H Chen J Peritoneal dialysis-associated nontuberculous mycobacterium peritonitis: a systematic review of reported cases Nephrol Dial Transplant 2012 27 4 1639 1644 10.1093/ndt/gfr504 21891775 \n6. Ding LW Lai CC Lee LN Hsueh PR Abdominal nontuberculous mycobacterial infection in a University Hospital in Taiwan from 1997 to 2003 J Formos Med Assoc 2006 105 5 370 376 10.1016/S0929-6646(09)60132-7 16638646 \n7. El Helou G Viola GM Hachem R Han XY Raad II Rapidly growing mycobacterial bloodstream infections Lancet Infect Dis 2013 13 166 174 10.1016/S1473-3099(12)70316-X 23347634 \n8. Broda A Jebbari H Beaton K Mitchell S Drobniewski F Comparative drug resistance of Mycobacterium abscessus and M. chelonae isolates from patients with and without cystic fibrosis in the United Kingdom J Clin Microbiol 2013 51 1 217 223 10.1128/JCM.02260-12 23135941 \n9. Shields RK Clancy CJ Minces LR Shigemura N Kwak EJ Silveira FP Epidemiology and outcomes of deep surgical site infections following lung transplantation Am J Transplant 2013 13 8 2137 2145 10.1111/ajt.12292 23710593 \n10. Mooren VHJF Bleeker MWP van Ingen J Hermans MHA Wever PC Disseminated mycobacterium abscessus infection in a peritoneal dialysis patient IDCases. 2017 9 6 7 10.1016/j.idcr.2017.05.001 28529886 \n11. Kameyama H Mori Y Kimura T Sugishita C Adachi T Sonomura K A case report of mycobacterium abscessus peritonitis in a peritoneal dialysis patient Ther Apher Dial 2007 11 6 449 451 10.1111/j.1744-9987.2007.00526.x 18028172 \n12. Renaud CJ Subramanian S Tambyah PA Lee EJC The clinical course of rapidly growing nontuberculous mycobacterial peritoneal dialysis infections in Asians: a case series and literature review Nephrology. 2011 16 2 174 179 10.1111/j.1440-1797.2010.01370.x 21272129 \n13. Kato S Chmielewski M Honda H Pecoits-Filho R Matsuo S Yuzawa Y Aspects of immune dysfunction in end-stage renal disease Clin J Am Soc Nephrol 2008 3 1526 1533 10.2215/CJN.00950208 18701615 \n14. Slagle K, Oblack D. Mycobacterium abscessus peritonitis: a case report. Clin Lab Sci. 1998:206–8 [cited 2020 May 3] Available from: https://pubmed.ncbi.nlm.nih.gov/10182108/.\n15. Siddiqi N, Sheikh I. Peritonitis caused by mycobacterium abscesses in patients on continuous ambulatory peritoneal dialysis. Saudi J Kidney Dis Transpl. 2012:321–4 [cited 2020 May 3] Available from: https://pubmed.ncbi.nlm.nih.gov/22382227/.\n16. Lo MW Mak SK Wong YY Lo KC Chan SF Tong GMW Atypical mycobacterial exit-site infection and peritonitis in peritoneal dialysis patients on prophylactic exit-site gentamicin cream Perit Dial Int 2013 33 3 267 272 10.3747/pdi.2011.00184 23032088 \n17. Jiang SH Roberts DM Clayton PA Jardine M Nontuberculous mycobacterial PD peritonitis in Australia Int Urol Nephrol 2013 45 5 1423 1428 10.1007/s11255-012-0328-4 23180442 \n18. Yang TK Lee JJ Lu PL Kuo HT Kuo MC Chen HC Peritoneal dialysis-associated peritonitis caused by mycobacterium abscessus Perit Dial Int 2015 35 3 369 371 10.3747/pdi.2014.00012 26015424 \n19. Yoshimura R Kawanishi M Fujii S Yamauchi A Takase K Yoshikane K Peritoneal dialysis-associated infection caused by Mycobacterium abscessus: a case report BMC Nephrol 2018 19 1 341 10.1186/s12882-018-1148-2 30497395 \n20. Nessar R Cambau E Reyrat JM Murray A Gicquel B Mycobacterium abscessus: a new antibiotic nightmare J Antimicrob Chemother 2012 67 4 810 818 10.1093/jac/dkr578 22290346 \n21. Ram R Swarnalatha G Akpolat T Dakshinamurty KV Mycobacterium tuberculous peritonitis in CAPD patients: a report of 11 patients and review of literature Int Urol Nephrol 2013 45 1129 1135 10.1007/s11255-012-0311-0 23143752 \n22. Yang T-K, Lee J-J, Lu P-L, Kuo H-T, Kuo M-C, Chen H-C. Peritoneal dialysis-associated peritonitis caused by mycobacterium abscessus. 2015;35(3):369–371. Available from: http://10.0.14.163/pdi.2014.00012.\n23. Caulfield AJ Wengenack NL Diagnosis of active tuberculosis disease: from microscopy to molecular techniques J Clin Tuberculosis Other Mycobacterial Dis Elsevier Ltd 2016 4 33 43 10.1016/j.jctube.2016.05.005 \n24. Chakravorty S Sen MK Tyagi JS Diagnosis of extrapulmonary tuberculosis by smear, culture, and PCR using universal sample processing technology J Clin Microbiol 2005 43 9 4357 4362 10.1128/JCM.43.9.4357-4362.2005 16145077 \n25. Shu CC Wang JT Wang JY Yu CJ Lee LN Mycobacterial peritonitis: difference between nontuberculous mycobacteria and Mycobacterium tuberculosis Clin Microbiol Infect 2012 18 3 246 252 10.1111/j.1469-0691.2011.03547.x 21631640 \n26. Esther CR Hoberman S Fine J Allen S Culbreath K Rodino K Detection of rapidly growing mycobacteria in routine cultures of samples from patients with cystic fibrosis J Clin Microbiol 2011 49 4 1421 1425 10.1128/JCM.02379-10 21289148 \n27. Griffith DE Aksamit T Brown-Elliott BA Catanzaro A Daley C Gordin F An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases Am J Respir Crit Care Med 2007 175 4 367 416 10.1164/rccm.200604-571ST 17277290\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "21(1)",
"journal": "BMC nephrology",
"keywords": "Catheter; Mycobacterium abscessus; Peritoneal dialysis; Peritonitis",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D000073358:Mycobacterium abscessus; D010530:Peritoneal Dialysis; D010538:Peritonitis; D006435:Renal Dialysis",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "491",
"pmc": null,
"pmid": "33203375",
"pubdate": "2020-11-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "22290346;23135941;14575289;22382227;28529886;23032088;27443487;16638646;21272129;30497395;23710593;17277290;31723686;21289148;27282851;21891775;23143752;18701615;18028172;23347634;29289475;23180442;26015424;21631640;16145077",
"title": "Mycobacterium abscessus - an uncommon, but important cause of peritoneal dialysis-associated peritonitis - case report and literature review.",
"title_normalized": "mycobacterium abscessus an uncommon but important cause of peritoneal dialysis associated peritonitis case report and literature review"
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"abstract": "Buprenorphine maintenance therapy patients frequently have severe postoperative pain due to buprenorphine-induced hyperalgesia and provider use of opioids with limited efficacy in the presence of buprenorphine. The authors report good-to-excellent pain management in 4 obstetric patients using nonopioid analgesics, regional anesthesia, continuation of buprenorphine, and use of opioids with high μ receptor affinity.",
"affiliations": "From the *Department of Surgery, Garrett Regional Medical Center, Oakland, Maryland; and †Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri.",
"authors": "Leighton|Barbara L|BL|;Crock|Lara W|LW|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D000069479:Buprenorphine, Naloxone Drug Combination; D009292:Narcotic Antagonists",
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"doi": "10.1213/ANE.0000000000002498",
"fulltext": "\n==== Front\nAnesth AnalgAnesth. AnalgANEAnesthesia and Analgesia0003-29991526-7598Lippincott Williams & Wilkins 0004510.1213/ANE.0000000000002498Chronic Pain MedicineBrief ReportCase Series of Successful Postoperative Pain Management in Buprenorphine Maintenance Therapy Patients Leighton Barbara L. MD*Crock Lara W. MD, PhD†From the * Department of Surgery, Garrett Regional Medical Center, Oakland, Maryland; and † Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri.Address correspondence to Barbara L. Leighton, MD, Department of Surgery, Garrett Regional Medical Center, 114 Markwood Dr, Oakland, MD 21550. Address e-mail to bleighton@gcmh.com.11 2017 20 10 2017 125 5 1779 1783 18 8 2017 Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.2017This 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.Buprenorphine maintenance therapy patients frequently have severe postoperative pain due to buprenorphine-induced hyperalgesia and provider use of opioids with limited efficacy in the presence of buprenorphine. The authors report good-to-excellent pain management in 4 obstetric patients using nonopioid analgesics, regional anesthesia, continuation of buprenorphine, and use of opioids with high μ receptor affinity.\n\nOPEN-ACCESSTRUE\n==== Body\nThe population of patients receiving chronic buprenorphine maintenance therapy (BMT) is large and includes many pregnant women. Most BMT patients are maintained on 1 of 2 sublingual preparations: Suboxone (Indivior Inc, Richmond, VA), a combination of buprenorphine and naloxone, or Subutex, which is solely buprenorphine. Pregnant illicit opioid users with poor access to BMT clinics may also use illicit buprenorphine to manage their own opiate withdrawals. Buprenorphine, an opioid with a long serum half-life and active metabolites, binds tightly to the μ-opioid receptor, and there is a ceiling to the analgesia buprenorphine can provide.1–7 Consequently, parturients who present for cesarean delivery or tubal ligation while receiving BMT may have severe postoperative pain.6,7\n\nMultimodal, rather than opioid-only, analgesia is generally preferable. There are 4 options for preoperative buprenorphine management: (1) continue buprenorphine and add additional postoperative buprenorphine,8 (2) continue baseline buprenorphine and add traditional opioids with high μ receptor affinity,9 (3) reduce the baseline buprenorphine preoperatively,10 or (4) discontinue buprenorphine and start a traditional opioid preoperatively.11–13 This last approach is not practical for many obstetric BMT surgical patients. First, buprenorphine has a half-life of 24–60 hours, so patients presenting for urgent or emergent surgery do not have time preoperatively to achieve complete washout. Second, patients fearing a relapse of their opiate addiction may refuse to abstain from buprenorphine. Third, many obstetricians refuse to ask their pregnant patients to abstain from buprenorphine because they fear unmonitored and untreatable fetal withdrawal symptoms. A multimodal approach to BMT patients was recently described by Anderson et al.14 We utilized a similar multimodal approach in the 4 obstetric cases described.\n\nEach patient gave written permission for the authors to publish this case series.\n\nCASE DESCRIPTIONS\nA 22-year-old Gravida 2, Para 1 healthy parturient presented for an elective repeat cesarean delivery. Her only medication was buprenorphine/naloxone (Suboxone) 8 mg/2 mg twice daily. The patient was placed in a seated position, and we inserted a paramedian epidural catheter at T10–11, then inserted a 25-gauge Whitacre spinal needle at L2–3, and injected hyperbaric bupivacaine 15 mg and epinephrine 0.1 mg. The anesthetic level was T4 bilaterally, and the patient was comfortable during the cesarean delivery. Postoperatively, we continued Suboxone 8 mg/2 mg twice daily. We initiated a patient-controlled epidural infusion of bupivacaine 0.0625% at 4 mL/h with a bolus dose of 2 mL and a lockout interval of 30 minutes. The patient also received scheduled ketorolac 30 mg intravenously (IV) every 6 hours for 4 doses, then scheduled ibuprofen 800 mg per os every 8 hours. The patient was able to maintain 5-second leg lifts 5 hours postoperatively and was able to move to a chair with assistance 8 hours postoperatively. One day after surgery, the patient could ambulate without assistance. She received an average of bupivacaine 5 mL/h during the first 24 hours and an average of 4 mL/h during the second 24 hours after the cesarean delivery. Her maximum pain scores were 1/10 during the first 24 hours and 0/10 during the second 24 hours after cesarean delivery. At 48 hours, we stopped the epidural infusion and observed the patient for 2 hours. Her pain score remained 0/10, so we removed the epidural catheter and continued the ibuprofen and the buprenorphine/naloxone (Suboxone).\n\nA 23-year-old Gravida 2, Para 1 healthy parturient presented in active labor for urgent repeat cesarean delivery. The patient was on a waiting list for a BMT clinic. While waiting, she illicitly purchased and consumed buprenorphine 4 mg 3 times daily. In the seated position, we performed a combined spinal–epidural anesthetic at L2–3. We injected bupivacaine 15 mg intrathecally and placed a lumbar epidural catheter for postoperative pain relief. The anesthetic level was T3 bilaterally, and the patient was comfortable during the cesarean delivery. We initiated a patient-controlled epidural infusion of bupivacaine 0.0625% at 10 mL/h with a bolus dose of 2 mL and a lockout interval of 15 minutes. We initiated buprenorphine 4 mg every 8 hours. The patient also received scheduled ketorolac 30 mg IV every 6 hours for 4 doses, and then scheduled ibuprofen 800 mg per os every 8 hours. The patient was comfortable with pain scores of 3 to 4/10 for the first 24 hours. Then a mechanical pump problem stopped the infusion and the patient’s pain score increased to 10/10. Comfort and a pain score of 2/10 returned with an epidural bolus of 10 mL bupivacaine 0.25%. We continued the epidural infusion for a second day. We then discontinued the epidural infusion. The patient’s pain remained mild 2 hours later, when we removed the epidural catheter. The main adverse effect with this lumbar epidural analgesia was leg weakness. While the epidural was infusing, the patient required the assistance of 2 nurses to ambulate. The patient was discharged on ibuprofen.\n\nA 34-year-old Gravida 6, Para 5 parturient presented in early labor for repeat cesarean delivery. The patient denied substance abuse. We induced spinal anesthesia with bupivacaine 13.5 mg, fentanyl 25 µg, and morphine 0.1 mg. Intraoperatively, the urine drug screen returned positive for buprenorphine. The patient then admitted to buying illicit buprenorphine and consuming 4 mg every other day. The patient declined our offer to place a thoracic epidural for postoperative pain control. Three hours after surgery, the patient rated her pain as intolerable and reported her pain score as 10/10. We started a hydromorphone IV patient-controlled analgesia (PCA) infusion with a dose of 0.1 mg, lockout of 10 minutes, and maximum hourly dose of 0.6 mg. She received 1.9 mg of hydromorphone over the first 24 hours. The patient also received scheduled ketorolac 30 mg IV every 6 hours for 4 doses, and then scheduled ibuprofen 800 mg per os every 8 hours. After the start of the PCA hydromorphone, the patient’s highest pain score was 5/10. The hydromorphone PCA was discontinued on the second postoperative day, with no increase in pain scores. The patient was discharged on ibuprofen.\n\nA healthy 25-year-old Gravida 2, Para 2 parturient presented 14 hours postpartum for bilateral tubal ligation. Her only medication was buprenorphine 4 mg/day, which she purchased illicitly while waiting for an appointment at a BMT clinic. The patient was seated during intrathecal injection of bupivacaine 15 mg and sufentanil 10 µg. We obtained a T8 sensory level, and the patient was comfortable during the operation. Three hours postoperatively, the patient rated her pain as 4 to 5/10. She received ketorolac 30 mg IV, and her pain decreased to 1 to 2/10. We continued the scheduled ketorolac 30 mg IV every 6 hours and administered buprenorphine 4 mg/day while the patient was in the hospital. The patient’s pain score was 2/10 or lower for the next 24 hours, when she was discharged on acetaminophen and diclofenac.\n\nDISCUSSION\nPatients receiving buprenorphine generally have higher opioid use and worse pain control after cesarean delivery than opioid-naive patients.6,7 Published surgical case reports document high postoperative opioid requirements and poor pain control whether or not buprenorphine is held preoperatively (Table 1).7,9,11–13,15–19 Our cesarean delivery patients have had the best analgesia with the least leg weakness when we utilized postoperative thoracic epidural analgesia, as illustrated in case 1.\n\nTable 1. Case Reports Describing Postoperative Analgesia in Patients Receiving Buprenorphine\n\nBuprenorphine is an agonist at both the μ-opioid (Ki= 0.2157 nM) and the nociceptin (opioid receptor-like 1) (Ki= 285 nM) receptors, and an antagonist at the κ-opioid and δ-opioid receptors.2,20 Buprenorphine binds more tightly to the μ-opioid receptor (ie, has a lower Ki or equilibrium inhibition constant) than most commonly used μ-opioid agonists (Table 2).3 Opioids with low Ki values have greater binding affinity at the μ receptor but not necessarily greater potency than other opioids. We believe that better analgesia in BMT patients can be achieved by using opioids with Ki values close to the Ki of buprenorphine (such as sufentanil or hydromorphone) rather than opioids that bind more weakly to the μ-opioid receptor (Table 2). High-dose hydromorphone was used successfully in several published case reports.11,16 However, other authors have reported pain control ranging from poor-to-excellent with the use of hydromorphone, fentanyl, or morphine (Table 1). Some authors report poor pain control until discontinuation of the buprenorphine.17,18 Factors other than opioid-binding properties, such as the preoperative buprenorphine dose, the nature of the surgery, and the use of regional anesthesia and nonopioid pain control adjuvants, are also important to consider during postoperative pain management.\n\nTable 2. μ-Opioid Receptor Binding Affinities (Ki) for Commonly Used Opioids and Antagonists\n\nActivation of the nociceptin receptor antagonizes the analgesia provided by activation of the μ-opioid receptor. Because of this, the pain relief provided by increasing doses of buprenorphine creates a bell-shaped curve in mice, with the greatest analgesia at moderate buprenorphine doses and less pain relief at higher doses.20 Morphine does not have this ceiling effect.20 The buprenorphine dose associated with maximum postoperative analgesia has not been determined in BMT patients. However, a nonoperative study in opioid-addicted volunteers reported maximum buprenorphine analgesia at a daily dose of 4 to 8 mg.21\n\nHeroin addicts and patients maintained on either methadone or buprenorphine exhibit hyperalgesia, as measured by withdrawal latency in the cold pressor test, when compared to opioid-naive controls.22,23 This hyperalgesia dissipates very slowly with opioid abstinence; chronic pain patients still demonstrated hyperalgesia 121 ± 23 weeks after discontinuation of methadone or buprenorphine.23\n\nIn the described cases, patients reached a point 48–72 hours after surgery beyond which they needed only buprenorphine and nonsteroidal anti-inflammatory agents for pain control. Thus, outpatient full agonist opioids may not be needed for many BMT patients after cesarean delivery or postpartum tubal ligation. Outpatient Suboxone can only be prescribed by physicians specifically licensed to do so. Therefore, we did not provide outpatient prescriptions for Suboxone. Ketamine and dexmedetomidine have been successfully added to multimodal analgesia in BMT patients.18,19 We did not use either drug but encourage other clinicians to consider doing so.\n\nThe American Academy of Pediatrics supports breastfeeding in BMT patients.24 The concentrations of buprenorphine and its metabolites are low in human milk and are low or undetectable in the plasma of 14-day-old breastfeeding infants of BMT patients.25 The incidence of neonatal abstinence syndrome is lower in infants of mothers receiving methadone or buprenorphine who are breastfed than in those who are fed formula.26\n\nIn summary, because of the high affinity of buprenorphine for the µ receptor, activation of the nociceptin receptor, and buprenorphine-induced hyperalgesia, BMT patients have severe postoperative pain more frequently than opioid-naive patients. However, good-to-excellent postoperative pain control can be achieved in many obstetric buprenorphine patients if supplemental opioids are carefully chosen and regional anesthesia is used appropriately.\n\nDISCLOSURES\nName: Barbara L. Leighton, MD.\n\nContribution: This author helped care for all 4 patients, obtained consent for publication from the patients, wrote the first draft of the article, and did the final editing of the manuscript.\n\nName: Lara W. Crock, MD, PhD.\n\nContribution: This author helped review the literature summarized in Table 1, created Table 1, and prepared an intermediate draft of the article.\n\nThis manuscript was handled by: Honorio T. Benzon, MD.\n\nFunding: None.\n\nThe authors declare no conflicts of interest.\n\nReprints will not be available from the authors.\n==== Refs\nREFERENCES\n1. Lutfy K Cowan A \nBuprenorphine: a unique drug with complex pharmacology. \nCurr Neuropharmacol . 2004 ;2 :395 402 .18997874 \n2. Brown SM Holtzman M Kim T Kharasch ED \nBuprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. \nAnesthesiology . 2011 ;115 :1251 1260 .22037640 \n3. Volpe DA McMahon Tobin GA Mellon RD \nUniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs. \nRegul Toxicol Pharmacol . 2011 ;59 :385 390 .21215785 \n4. Poisnel G Quentin T Barré L Coquerel A Debruyne D \nCompetitive displacement binding assay on rat brain sections and using a beta-imager: application to mu-opioid ligands. \nJ Neurosci Methods . 2006 ;154 :60 67 .16423409 \n5. Chen KY Chen L Mao J \nBuprenorphine-naloxone therapy in pain management. \nAnesthesiology . 2014 ;120 :1262 1274 .24509068 \n6. Meyer M Paranya G Keefer Norris A Howard D \nIntrapartum and postpartum analgesia for women maintained on buprenorphine during pregnancy. \nEur J Pain . 2010 ;14 :939 943 .20444630 \n7. Jones HE O’Grady K Dahne J \nManagement of acute postpartum pain in patients maintained on methadone or buprenorphine during pregnancy. \nAm J Drug Alcohol Abuse . 2009 ;35 :151 156 .19462298 \n8. Book SW Myrick H Malcolm R Strain EC \nBuprenorphine for postoperative pain following general surgery in a buprenorphine-maintained patient. \nAm J Psychiatry . 2007 ;164 :979 .\n9. Kornfeld H Manfredi L \nEffectiveness of full agonist opioids in patients stabilized on buprenorphine undergoing major surgery: a case series. \nAm J Ther . 2010 ;17 :523 528 .19918165 \n10. Greenwald MK Comer SD Fiellin DA \nBuprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy. \nDrug Alcohol Depend . 2014 ;144 :1 11 .25179217 \n11. Chern SY Isserman R Chen L Ashburn M Liu R \nPerioperative pain management for patients on chronic buprenorphine: a case report. \nJ Anesth Clin Res . 2013 ;3 :1000250 .24307971 \n12. Israel JS Poore SO \nThe clinical conundrum of perioperative pain management in patients with opioid dependence: lessons from two cases. \nPlast Reconstr Surg . 2013 ;131 :657e 658e .\n13. Harrington CJ Zaydfudim V \nBuprenorphine maintenance therapy hinders acute pain management in trauma. \nAm Surg . 2010 ;76 :397 399 .20420250 \n14. Anderson TA Quaye ANA Ward EN Wilens TE Hilliard PE Brummett CM \nTo stop or not, that is the question: acute pain management for the patient on chronic buprenorphine. \nAnesthesiology . 2017 ;126 :1180 1186 .28511196 \n15. Hansen LE Stone GL Matson CA Tybor DJ Pevear ME Smith EL \nTotal joint arthroplasty in patients taking methadone or buprenorphine/naloxone preoperatively for prior heroin addiction: a prospective matched cohort study. \nJ Arthroplasty . 2016 ;31 :1698 1701 .26899477 \n16. McCormick Z Chu SK Chang-Chien GC Joseph P \nAcute pain control challenges with buprenorphine/naloxone therapy in a patient with compartment syndrome secondary to McArdle’s disease: a case report and review. \nPain Med . 2013 ;14 :1187 1191 .23647815 \n17. Huang A Katznelson R de Perrot M Clarke H \nPerioperative management of a patient undergoing Clagett window closure stabilized on Suboxone® for chronic pain: a case report. \nCan J Anaesth . 2014 ;61 :826 831 .24985936 \n18. Brummett CM Trivedi KA Dubovoy AV Berland DW \nDexmedetomidine as a novel therapeutic for postoperative pain in a patient treated with buprenorphine. \nJ Opioid Manag . 2009 ;5 :175 179 .19662927 \n19. Macintyre PE Russell RA Usher KA Gaughwin M Huxtable CA \nPain relief and opioid requirements in the first 24 hours after surgery in patients taking buprenorphine and methadone opioid substitution therapy. \nAnaesth Intensive Care . 2013 ;41 :222 230 .23530789 \n20. Lutfy K Eitan S Bryant CD \nBuprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. \nJ Neurosci . 2003 ;23 :10331 10337 .14614092 \n21. Walsh SL Preston KL Bigelow GE Stitzer ML \nAcute administration of buprenorphine in humans: partial agonist and blockade effects. \nJ Pharmacol Exp Ther . 1995 ;274 :361 372 .7542336 \n22. Compton P Charuvastra VC Ling W \nPain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. \nDrug Alcohol Depend . 2001 ;63 :139 146 .11376918 \n23. Wachholtz A Gonzalez G \nCo-morbid pain and opioid addiction: long term effect of opioid maintenance on acute pain. \nDrug Alcohol Depend . 2014 ;145 :143 149 .25456326 \n24. Sachs HC ; Committee on Drugs . The transfer of drugs and therapeutics into human breast milk: an update on selected topics. \nPediatrics . 2013 ;132 :e796 e809 .23979084 \n25. Jansson LM Spencer N McConnell K \nMaternal buprenorphine maintenance and lactation. \nJ Hum Lact . 2016 ;32 :675 681 .27563013 \n26. Welle-Strand GK Skurtveit S Jansson LM Bakstad B Bjarkø L Ravndal E \nBreastfeeding reduces the need for withdrawal treatment in opioid-exposed infants. \nActa Paediatr . 2013 ;102 :1060 1066 .23909865\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0003-2999",
"issue": "125(5)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000328:Adult; D016362:Analgesia, Obstetrical; D016058:Analgesia, Patient-Controlled; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D000069479:Buprenorphine, Naloxone Drug Combination; D017604:Cesarean Section, Repeat; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D009292:Narcotic Antagonists; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D059408:Pain Management; D010147:Pain Measurement; D058748:Pain Perception; D017288:Pain Threshold; D010149:Pain, Postoperative; D011247:Pregnancy; D013246:Sterilization, Tubal; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "1779-1783",
"pmc": null,
"pmid": "29049122",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24509068;7542336;23979084;23542298;20420250;14614092;20444630;25456326;23530789;22037640;27563013;21215785;16423409;25179217;19918165;24985936;26899477;19662927;11376918;28511196;24307971;23647815;23909865;17541066;18997874;19462298",
"title": "Case Series of Successful Postoperative Pain Management in Buprenorphine Maintenance Therapy Patients.",
"title_normalized": "case series of successful postoperative pain management in buprenorphine maintenance therapy patients"
} | [
{
"companynumb": "US-MYLANLABS-2017M1073541",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe foremost side effects of anti-PD-1 therapy are immune related and pancreatitis associated with nivolumab treatment has been rarely reported.\n\n\nMETHODS\nThe patient was treating with subcutaneous insulin because of nivolumab induced diabetes mellitus. A patient was diagnosed metastatic renal cell carcinoma and treated with nivolumab. Diabetes mellitus and pancreatitis, which are immune-related adverse events were observed in the patient.\nAfter the diagnosis of nivolumab induced immune pancreatitis methylprednisolone 2 mg/kg per day intravenously started. After steroid treatment, the patient's complaints regressed, amylase and lipase levels began to decline.\n\n\nCONCLUSIONS\nThis case report highlights the possibility of different immune-related adverse events that can affect pancreas in all patients which were treated with ICIs.",
"affiliations": "Medical Oncology Department, Bakırköy Sadi Konuk Training and Research Hospital, İstanbul, Turkey.;SamsunTraining and Research Hospital Samsun, Samsun, Samsun 55090 Turkey.",
"authors": "Yilmaz|Mesut|M|https://orcid.org/0000-0003-1466-3887;Baran|Ahmet|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/10781552211028636",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "28(1)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Nivolumab; diabetes mellitus; immune related adverse event; pancreatitis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "255-258",
"pmc": null,
"pmid": "34250849",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Two different immune related adverse events occured at pancreas after nivolumab in an advanced RCC patient.",
"title_normalized": "two different immune related adverse events occured at pancreas after nivolumab in an advanced rcc patient"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-323569",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUNITINIB"
},
"druga... |
{
"abstract": "Babesiosis is an increasingly recognized disease which may benefit from therapeutic apheresis (Category II/Grade 2C). Vulnerable populations include the splenectomized, those aged >50, those with malignancies, and the immunocompromised. In the setting of parasite levels > 10%, significant anemia, renal impairment, pulmonary compromise, or hepatic dysfunction, RBC exchange can rapidly reduce parasite burdens and decrease the bioavailability of proinflammatory cytokines. No previous report has shown such a rapid rebound in parasitemia despite adequate organism removal. Herein, we report a case of severe babesiosis in a splenectomized 56 year old male with a past medical history significant for benign multiple sclerosis. Following a week of flu-like symptoms, the patient presented to an outside hospital with anemia, elevated bilirubin, thrombocytopenia, and 15% of his RBCs containing Babesia forms on a peripheral smear. Despite initiation of appropriate antimicrobials, subsequent transfer to our facility revealed worsening parasitemia (25%), tachypnea, and hypoxia. An emergent two volume RBC exchange was performed, resulting in 15% post-exchange parasitemia. Twelve hours later, the parasitic burden had climbed to 30%. A second RBC exchange reduced the parasite burden to 1.5%. His post-procedural course was significant for diminishing periodic increases in parasitemia despite continued antimicrobial therapy. Rapid increases in parasitic burden following RBC exchanges can occur and post-procedural surveillance of parasitemia should be closely monitored to expedite additional exchanges.",
"affiliations": "Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Transfusion Medicine Service, Lebanon, New Hampshire, 03756.;Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Transfusion Medicine Service, Lebanon, New Hampshire, 03756.;Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Transfusion Medicine Service, Lebanon, New Hampshire, 03756.",
"authors": "Alquist|Caroline R|CR|;Szczepiorkowski|Zbigniew M|ZM|;Dunbar|Nancy|N|",
"chemical_list": "D000977:Antiparasitic Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21492",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "32(4)",
"journal": "Journal of clinical apheresis",
"keywords": "RBC exchange; babesiosis; parasitemia",
"medline_ta": "J Clin Apher",
"mesh_terms": "D000977:Antiparasitic Agents; D001403:Babesia; D001404:Babesiosis; D001781:Blood Component Removal; D017707:Erythrocyte Transfusion; D004912:Erythrocytes; D006801:Humans; D008297:Male; D008875:Middle Aged; D018512:Parasitemia; D012008:Recurrence",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "276-278",
"pmc": null,
"pmid": "27583822",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Babesia parasitemia rebound after red blood cell exchange.",
"title_normalized": "babesia parasitemia rebound after red blood cell exchange"
} | [
{
"companynumb": "PHHY2017US132048",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Levonorgestrel-releasing intrauterine devices (LIUDs) are thought to release this progestin locally in the uterus to limit side effects. Authors here present a case of treatment-refractory hydrocephalus and pseudomeningocele (PMC), both of which fully resolved after LIUD removal.A 35-year-old woman with an implanted LIUD developed symptomatic PMC and hydrocephalus after suboccipital craniectomy for Chiari malformation type I. Over the next 8 months, she underwent ventriculoperitoneal shunt placement and two attempts at needle decompression of the fluid collection, which did not relieve her symptoms or the PMC, except for a few days at a time. Subsequently, she had her LIUD removed. Three weeks after removal of the LIUD, her symptoms as well as the fluid collection resolved completely without any further intervention. Thus, the increased intracranial pressure and associated persistence of the PMC may be partially attributed to the LIUD.This case indicates that a persistent problem (PMC and intracranial hypertension) that may be associated with the LIUD rapidly resolves after its removal. Implication of LIUDs as the cause of intracranial hypertension is still a matter of controversy. Further studies are needed to evaluate any potential causal relationship between LIUDs and intracranial hypertension, and physicians are advised to consider this scenario in their differential diagnosis.",
"affiliations": null,
"authors": "Maragkos|Georgios A|GA|;Motiei-Langroudi|Rouzbeh|R|;Filippidis|Aristotelis S|AS|;Papavassiliou|Efstathios|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3085",
"issue": null,
"journal": "Journal of neurosurgery",
"keywords": "Chiari decompression; ICP = intracranial pressure; IIH = idiopathic intracranial hypertension; LIUD = levonorgestrel-releasing intrauterine device; PMC = pseudomeningocele; VPS = ventriculoperitoneal shunt; hydrocephalus; levonorgestrel-releasing intrauterine device; pseudomeningocele",
"medline_ta": "J Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "0253357",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "30497211",
"pubdate": "2018-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intracranial hypertension after Chiari decompression resolving after removal of a levonorgestrel-releasing intrauterine device: case report.",
"title_normalized": "intracranial hypertension after chiari decompression resolving after removal of a levonorgestrel releasing intrauterine device case report"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2019GMK043685",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugaddit... |
{
"abstract": "OBJECTIVE\nImmune checkpoint inhibitor (ICI)-associated myocarditis is a rare and potentially fatal immune-related adverse event (irAE). The study aimed to observe the occurrence of myocarditis caused by ICIs.\n\n\nMETHODS\nThe clinical manifestations, diagnosis, and treatment of immune myocarditis were explored through retrospective analysis of the detailed data of typical ICI-associated myocarditis from our center and a literature review.\n\n\nRESULTS\nFrom January 1, 2018, to December 31, 2019, a total of 283 patients were treated with PD-1 or PD-L1 monoclonal antibodies (McAbs) alone or combination therapy at our center. There were 3 cases of ICI-associated myocarditis, of which the incidence rate was 1.06% (3/283); among these cases, 2 were treated with nivolumab alone, and 1 was treated with camrelizumab combined with gemcitabine. One case died on day 56 because of heart and respiratory failure, and the other died on day 34 because of tumor progression. The third case recovered after treatment. The typical clinical manifestations are palpitations, dyspnea, and fatigue. One patient had no clear symptoms. Electrocardiograms (ECG) showed grade 3 of atrioventricular block and frequent ventricular premature contraction in one case, and frequent ventricular and atrial premature contraction in the other case. Most of the cardiac biomarkers decreased or returned to normal after glucocorticoid treatment.\n\n\nCONCLUSIONS\nICI-associated myocarditis is a rare adverse event but has a high mortality rate. Early diagnosis of myocarditis and prompt glucocorticoid therapy may be helpful to improve the prognosis.",
"affiliations": "Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical College, Nanjing 210029, China; Cancer Centre of People's Liberation Army, Jinling Hospital, Nanjing 210002, China.;Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical College, Nanjing 210029, China.;Cancer Centre of People's Liberation Army, Jinling Hospital, Nanjing 210002, China. qinsk@csco.org.cn.;Cancer Centre of People's Liberation Army, Jinling Hospital, Nanjing 210002, China.;Cancer Centre of People's Liberation Army, Jinling Hospital, Nanjing 210002, China.;Cancer Centre of People's Liberation Army, Jinling Hospital, Nanjing 210002, China.;Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical College, Nanjing 210029, China. yangmin@jsinm.org.",
"authors": "Wang|Feng|F|;Sun|Xinchen|X|;Qin|Shukui|S|;Hua|Haiqing|H|;Liu|Xiufeng|X|;Yang|Liuqing|L|;Yang|Min|M|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "China",
"delete": false,
"doi": "10.21037/cco.2020.03.08",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2304-3865",
"issue": "9(2)",
"journal": "Chinese clinical oncology",
"keywords": "Immune checkpoint inhibitor (ICI); cardiac biomarker; glucocorticoid; myocarditis",
"medline_ta": "Chin Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002681:China; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008875:Middle Aged; D009205:Myocarditis; D012189:Retrospective Studies",
"nlm_unique_id": "101608375",
"other_id": null,
"pages": "16",
"pmc": null,
"pmid": "32279526",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A retrospective study of immune checkpoint inhibitor-associated myocarditis in a single center in China.",
"title_normalized": "a retrospective study of immune checkpoint inhibitor associated myocarditis in a single center in china"
} | [
{
"companynumb": "CN-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-009690",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "We report the case of a 46-year-old male abattoir worker who developed myalgias, shortness of breath, and irritability 2 weeks after sustaining a laceration to the hand with a knife at work. During his hospital evaluation for septic shock he was noted to be febrile, hypotensive, profoundly jaundiced with aseptic meningitis, and renal failure, and was diagnosed with Leptospirosis interrogans infection confirmed by serum and urine polymerase chain reaction. After standard antibiotic therapy and recovery from severe clinical illness, he developed unilateral orchitis with pyuria secondary to leptospirosis, a well-established complication in the veterinary literature, but of which we offer the first report in humans in the English literature. The case presented was also the index case that uncovered a cluster outbreak of leptospirosis in New York City during the winter of 2016-2017, involving a total of three patients who lived or worked within a block of the abattoir. Two patients survived whereas the third died of pulmonary hemorrhage shortly after seeking medical care.",
"affiliations": "Division of Infectious Diseases and Immunology, NYU School of Medicine, New York, New York.;International Rescue Committee, New York, New York.;Division of Infectious Diseases and Immunology, NYU School of Medicine, New York, New York.",
"authors": "Kupferman|Tania|T|;Coffee|Megan P|MP|;Eckhardt|Benjamin J|BJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.17-0545",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "97(6)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000003:Abattoirs; D000328:Adult; D000900:Anti-Bacterial Agents; D017809:Fatal Outcome; D005334:Fever; D006470:Hemorrhage; D006801:Humans; D007565:Jaundice; D007919:Leptospira; D007922:Leptospirosis; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D009519:New York City; D016273:Occupational Exposure; D016896:Treatment Outcome",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "1679-1681",
"pmc": null,
"pmid": "29016310",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25266477;5812537;25813883;14227167;15445302;14343833",
"title": "Case Report: A Cluster of Three Leptospirosis Cases in a New York City Abattoir and an Unusual Complication in the Index Case.",
"title_normalized": "case report a cluster of three leptospirosis cases in a new york city abattoir and an unusual complication in the index case"
} | [
{
"companynumb": "US-ZYDUS-018761",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nThe purpose of this study was to evaluate the efficacy of 3 first-line chemotherapy combination regimens for HER2-negative metastatic breast cancer (mBC).\n\n\nMETHODS\nIn this open-label, 3-arm, randomized phase II trial, patients were randomized to all-oral NORCAP (vinorelbine/capecitabine), GEMPAC (gemcitabine/paclitaxel), or GEMDOC (gemcitabine/docetaxel) as first-line chemotherapy for HER2-negative mBC. Stratification factors were center, previous (neo)adjuvant anthracycline, and age. The primary end point was disease control rate (DCR; complete or partial response, or stable disease for ≥3 months).\n\n\nRESULTS\nThe DCR was 73% (95% confidence interval [CI], 59-85) with NORCAP (36 of 49 patients), 78% (95% CI, 64-88) with GEMPAC (39 of 50 patients), and 80% (95% CI, 66-90) with GEMDOC (40 of 50 patients). Objective response rates were 33% (16 of 49 patients), 24% (12 of 50 patients), and 50% (25 of 50 patients), respectively; median progression-free survival was 7.6, 9.0, and 11.4 months, respectively. Median overall survival was 30 to 31 months with all regimens. The most common Grade ≥3 adverse event with each regimen was neutropenia (24 patients [50%], 23 patients [46%], and 43 patients [86%], respectively). The most common nonhematological Grade ≥3 adverse event was fatigue. Grade 2 alopecia occurred in 36 patients (72%) who received GEMPAC and 38 patients (76%) who received GEMDOC, but only 4 patients (8%) who received NORCAP. There was no evidence of a detrimental effect of NORCAP on quality of life.\n\n\nCONCLUSIONS\nAll-oral NORCAP is an active first-line chemotherapy regimen and might be offered as an alternative to first-line taxane-based therapy for HER2-negative mBC, particularly if patients wish to avoid alopecia or frequent intravenous administrations.",
"affiliations": "Medical Oncology and Breast Unit, European Institute of Oncology (IRCCS), Milan, and San Antonio Perrino Hospital, Brindisi, Italy. Electronic address: saverio.cinieri@ieo.it.;Breast Cancer Research Centre-WA and Curtin University, Perth, Australia.;Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.;Medical Oncology Department, ZNA Middelheim Hospital, Antwerp, Belgium.;Centre Hospitalier Universitaire de Limoges, Limoges, France.;Medical Oncology Department, Hospital Sant Pau, Barcelona, Spain.;Medical Oncology Department, CER Instituto Medico, Buenos Aires, Argentina.;Medical Oncology Department, Istituti Ospitalieri di Cremona, Cremona, Italy.;Department of Oncology, National Hospital, Bloemfontein, South Africa.;Medical Oncology Department, Regionalspital Thun, Thun, Switzerland.;Medical Affairs Oncology, Institut de Recherche Pierre Fabre, Boulogne-Billancourt Cedex, France.;Department of Medical Oncology, Gazi University School of Medicine, Gazi Hospital, Ankara, Turkey.",
"authors": "Cinieri|Saverio|S|;Chan|Arlene|A|;Altundag|Kadri|K|;Vandebroek|An|A|;Tubiana-Mathieu|Nicole|N|;Barnadas|Agusti|A|;Dodyk|Patricia|P|;Lazzarelli|Silvia|S|;Botha|Michiel|M|;Rauch|Daniel|D|;Villanova|Gustavo|G|;Coskun|Ugur|U|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D014747:Vinblastine; D000069287:Capecitabine; C056507:gemcitabine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D017239:Paclitaxel; D000077235:Vinorelbine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clbc.2016.06.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "17(2)",
"journal": "Clinical breast cancer",
"keywords": "Capecitabine; Combination chemotherapy; Oral chemotherapy; Oral vinorelbine; Taxane doublet",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000505:Alopecia; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D003841:Deoxycytidine; D018572:Disease-Free Survival; D000077143:Docetaxel; D005221:Fatigue; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009503:Neutropenia; D017239:Paclitaxel; D011788:Quality of Life; D018719:Receptor, ErbB-2; D043823:Taxoids; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "91-99.e1",
"pmc": null,
"pmid": "27756583",
"pubdate": "2017-04",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Final Results of the Randomized Phase II NorCap-CA223 Trial Comparing First-Line All-Oral Versus Taxane-Based Chemotherapy for HER2-Negative Metastatic Breast Cancer.",
"title_normalized": "final results of the randomized phase ii norcap ca223 trial comparing first line all oral versus taxane based chemotherapy for her2 negative metastatic breast cancer"
} | [
{
"companynumb": "IT-ROCHE-1927274",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
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"abstract": "Doxycycline is a broad-spectrum antibiotic belonging to the tetracycline group which acts by inhibiting bacterial protein synthesis. It is considered to be a relatively safe drug. We report a case of doxycycline-induced acute pancreatitis (DIAP) in an adult female patient who was started on the usual therapeutic dose 1 week before for acne vulgaris. The WHO causality assessment was possible, and the Naranjo scale confirmed it as \"definite\" adverse drug reaction. A brief literature review on case reports previously reporting DIAP has also been summarized.",
"affiliations": "Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ, USA.;Department of Pharmacology, St John's Medical College, Bangalore, India.",
"authors": "Rawla|Prashanth|P|;Raj|Jeffrey Pradeep|JP|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.14740/gr838w",
"fulltext": "\n==== Front\nGastroenterology ResGastroenterology ResElmer PressGastroenterology Research1918-28051918-2813Elmer Press 10.14740/gr838wCase ReportDoxycycline-Induced Acute Pancreatitis: A Rare Adverse Event Doxycycline-Induced Acute PancreatitisRawla Prashanth acRaj Jeffrey Pradeep b\na Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ, USA\nb Department of Pharmacology, St John’s Medical College, Bangalore, Indiac Corresponding Author: Prashanth Rawla, Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ, USA. Email: rawlap@gmail.com8 2017 31 8 2017 10 4 244 246 10 4 2017 25 4 2017 Copyright 2017, Rawla et al.2017This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Doxycycline is a broad-spectrum antibiotic belonging to the tetracycline group which acts by inhibiting bacterial protein synthesis. It is considered to be a relatively safe drug. We report a case of doxycycline-induced acute pancreatitis (DIAP) in an adult female patient who was started on the usual therapeutic dose 1 week before for acne vulgaris. The WHO causality assessment was possible, and the Naranjo scale confirmed it as “definite” adverse drug reaction. A brief literature review on case reports previously reporting DIAP has also been summarized.\n\nDoxycyclinePancreatitisDrug-induced pancreatitis\n==== Body\nIntroduction\nDoxycycline is a broad-spectrum antibiotic belonging to the antibiotic drug class of tetracyclines which are bacteriostatic to a broad spectrum of both aerobic and anerobic gram-positive and gram-negative bacteria. It acts by inhibiting the bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome and preventing the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. Doxycycline is unique in the sense that it does not undergo metabolism and is excreted unchanged in the urine and bile. It also does not require a dose modification in renal impairment. The common side effects of tetracycline groups of drugs are gastrointestinal side effects and bone and teeth deposits. Whereas the less common ones include photosensitivity, renal toxicity and hepatic toxicity in patients with impaired kidney functions. These side effects are even less frequent in patients who use newer tetracycline like the doxycycline, tigecycline and minocycline [1]. Here we present an interesting case of a female adult patient who was diagnosed with doxycycline-induced acute pancreatitis (DIAP).\n\nCase Report\nA 52-year-old adult female who is a known patient of fibromyalgia and spondylolisthesis at the lumbar vertebral levels L2, 3, 4 for the last 3 years presented with a 3-day history of acute onset very severe epigastric pain increasing in severity with time since onset. At presentation, the patient reported a score of 10 on a pain rating scale of 10. The quality of the pain was sharp, and it was radiating to the back with mild relief on bending forward. There were no known aggravating factors. The pain was associated with nausea and non-bilious vomiting with no traces of blood. The patient denied any similar episodes in the past and has no history of alcohol consumption. She has a history of cholecystectomy done 2 years back for abdominal pain, but the gallbladder was apparently devoid of any gallstones.\n\nAn ultrasound and a computed tomography of the abdomen and blood workup were performed to determine the cause of pain. At admission, the serum lipase levels were elevated to > 1,600 IU/L (laboratory reference level 10 - 53 IU/L). An ultrasound of the abdomen revealed a normal common bile duct with its diameter of 5.4 mm (Fig. 1). The abdomen CT findings were also consistent with the diagnosis of acute pancreatitis wherein there was stranding in the retroperitoneum and the abdominal mesentery with trace fluid in the perihepatic and pelvic space. There was edema of the head and body of the pancreas with peripancreatic edema but without any pancreatic pseudocyst. The remaining findings were unremarkable with no intrahepatic or extrahepatic biliary dilatation, patent mesenteric blood vessels and normal spleen and adrenal glands (Fig. 2). Further workup was done to look for other less frequent causes of pancreatitis. A magnetic resonance cholangiopancreatography (MRCP) was done which did not reveal any gallstones or sludge in the common bile duct (Fig. 3). IgG4 levels were normal thus ruling out autoimmune pancreatitis. Triglycerides were within the normal limits, and viral hepatitis panel was negative. At this stage, a possibility of drug-induced acute pancreatitis was considered. The patient was on oxycodone 5 mg twice daily for fibromyalgia and gabapentin 600 mg three times daily for neuropathic pain for the last 3 years. She also gave a recent history of being prescribed doxycycline 100 mg twice daily by her dermatologist for worsening acne. The patient had been taking doxycycline regularly for the past 7 days. Since the patient was doing all right with oxycodone and gabapentin for a longer time, it was considered that doxycycline would be the most probable cause for the patient’s condition. However, all three drugs were stopped immediately. By then, the serum lipase levels began to fall. It was 1,140 IU/L the second day, 347 IU/L the third day and 111 IU/L on day 4.\n\nFigure 1 Ultrasound abdomen done on day 1. Yellow arrow shows common bile duct diameter within normal limits of 5.4 mm. \n\nFigure 2 Computed tomography of the abdomen done on day 1. Yellow arrow shows edema in body of pancreas with pancreatic fluid and stranding consistent with acute pancreatitis. Black arrow head shows prior cholecystectomy. \n\nFigure 3 Magnetic resonance cholangiopancreatography done on day 2. Yellow arrow shows common bile duct measures 5.5 mm in diameter, no CBD stones. White arrow head shows no obstruction in pancreatic duct. \n\nThe patient was started on enteral feeding when her nausea subsided. However, her abdominal pain persisted. Due to her constant and severe abdominal pain, a repeat abdomen CT was done on day 6 which showed a little necrosis of 6 mm in the head of the pancreas. The patient was managed conservatively with IV fluids and parenteral morphine. After the repeat abdomen CT was done, the patient was rechallenged with oxycodone and gabapentin, and the lipase levels were found to be normal. As the patient’s condition improved, oral feeding was started and was subsequently discharged.\n\nDiscussion\nAcute pancreatitis is a life-threatening condition with an incidence of 45 per 100,000 people annually [2]. Drug-induced pancreatitis (DIP) is a very rare entity. The estimated incidence ranges from 0.1% to 5.3% in human immunodeficiency negative individuals [3, 4]. A retrospective study from Germany in 1993 reported the incidence of DIP to be 1.4% [5]. The study from the Czech Republic in 2010 reported that among 170 cases of acute pancreatitis, 5.3% were DIP [4]. Thus, the exact incidence of DIP is very hard to determine, and of this, doxycycline to be reported as a causative drug has been exceedingly rare [6]. A PubMed search which was performed using the MeSH terms “Doxycycline” AND “Pancreatitis” shortlisted just two case reports reporting definite DIAP [6, 7]. There were two other case reports reporting probable DIAP [8, 9]. The case reported by Ocal et al [8] had concomitant use of ornidazole and a much higher dose of doxycycline (500 mg twice daily). While the other case reported by Moy and Kapila [9] had other causes of pancreatitis namely highly uncontrolled diabetes mellitus (HbA1c: 15.5%) and diabetic ketoacidosis which are more common than DIP. Thus, it is evident that DIAP is a rare condition.\n\nThe diagnosis of DIAP was a diagnosis of exclusion after all other common causes such as biliary disease and alcoholism were ruled out. In our patient, there were few more concomitant drugs used for other co-morbidities. Since the patient was on these medications for more than 3 years, it was unlikely that they caused pancreatitis. However, these drugs were also stopped and later rechallenged after 6 days of stopping which proved harmless as confirmed by the normal serum lipase levels. Hence we believe that our case is one of the well-proven cases of DIAP with a well corroborating temporal association of the use of a drug. The mechanism by which it causes pancreatitis is largely unknown. However, because of the rarity, it may be considered as an idiosyncratic reaction [6].\n\nAccording to the WHO causality assessment, doxycycline is the “probable” cause for DIP as de-challenge was positive and re-challenge was not done. According to the Naranjo algorithm, the adverse drug reaction (ADR) was classified as “definite” ADR with a score of 9 (2 points each for an adverse event occurring after doxycycline was administered and other causes being ruled out. One point each for the availability of previous conclusive reports of DIAP, an improvement on stopping the drug, less severe when the dose was decreased, and pancreatitis confirmed objectively with imaging and blood tests) [10]. According to the Schumock and Thornton preventability scale, the ADR was unpreventable [11] and based on the Hartwig and Siegel severity assessment scale, the severity of the reaction is placed at level 5 which involves withholding of the suspected drug and a prolonged hospital stay by at least 1 day with admission in the intensive care unit [10].\n\nConclusion\nDoxycycline is a well-studied drug with a good safety profile, and food and drug administration (FDA) approved it for multidisciplinary clinical uses like the treatment of a wide variety of bacterial infections including acne vulgaris and periodontitis. Here, we report a rare case of DIAP. It is important that the physician keeps such rare adverse events in mind and have a high degree of suspicion to tackle the crisis effectively. To conclude, drug should be entertained as a possible etiology of idiopathic pancreatitis when other common causes are ruled out keeping in mind the vastly expanding pharmacotherapy in the recent times.\n\nFunding Support\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nConflicts of Interest\nThe authors do not have any conflicts of interest to disclose.\n\nFinancial Disclosure\nNone.\n\nAuthor Contributions\nStudy design, drafting, critical revisions and final approval by PR and JPR.\n==== Refs\nReferences\n1 Rang HP Ritter JM Flower RJ Henderson G Rang & Dales Pharmacology 8th ed Elsevier Ltd 2016 632 634 \n2 Yadav D Lowenfels AB The epidemiology of pancreatitis and pancreatic cancer Gastroenterology 2013 144 6 1252 1261 10.1053/j.gastro.2013.01.068 23622135 \n3 Balani AR Grendell JH Drug-induced pancreatitis : incidence, management and prevention Drug Saf 2008 31 10 823 837 10.2165/00002018-200831100-00002 18759507 \n4 Vinklerova I Prochazka M Prochazka V Urbanek K Incidence, severity, and etiology of drug-induced acute pancreatitis Dig Dis Sci 2010 55 10 2977 2981 10.1007/s10620-010-1277-3 20499176 \n5 Lankisch PG Droge M Gottesleben F Drug induced acute pancreatitis: incidence and severity Gut 1995 37 4 565 567 10.1136/gut.37.4.565 7489946 \n6 Inayat F Virk HU Yoon DJ Riaz I Drug-Induced Pancreatitis: A Rare Manifestation of Doxycycline Administration N Am J Med Sci 2016 8 2 117 120 10.4103/1947-2714.174348 27042611 \n7 Wachira JK Jensen CH Rhone K Doxycycline-induced pancreatitis: a rare finding S D Med 2013 66 6 227 229 23923680 \n8 Ocal S Selcuk H Korkmaz M Unal H Yilmaz U Acute pancreatitis following doxycycline and ornidazole coadministration JOP 2010 11 6 614 616 21068497 \n9 Moy BT Kapila N Probable doxycycline-induced acute pancreatitis Am J Health Syst Pharm 2016 73 5 286 291 10.2146/ajhp150298 26896500 \n10 Srinivasan R Ramya G Adverse Drug Reaction-Causality Assessment Int J Res Pharm Chem 2011 1 3 606 612 \n11 Schumock GT Thornton JP Focusing on the preventability of adverse drug reactions Hosp Pharm 1992 27 6 538 10118597\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1918-2805",
"issue": "10(4)",
"journal": "Gastroenterology research",
"keywords": "Doxycycline; Drug-induced pancreatitis; Pancreatitis",
"medline_ta": "Gastroenterology Res",
"mesh_terms": null,
"nlm_unique_id": "101519422",
"other_id": null,
"pages": "244-246",
"pmc": null,
"pmid": "28912911",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports",
"references": "7489946;23923680;26896500;20499176;23622135;10118597;18759507;27042611;21068497",
"title": "Doxycycline-Induced Acute Pancreatitis: A Rare Adverse Event.",
"title_normalized": "doxycycline induced acute pancreatitis a rare adverse event"
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"activesubstancename": "DOXYCYCLINE"
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"abstract": "Background: An important cause of treatment failure to antiretroviral therapy (ART) is the potential interaction between the antiretroviral (ARV) drugs and co-prescribed drugs used concomitantly for the treatment of opportunistic infections and co-morbid ailments in HIV-infected patients. Objectives: The study evaluated potential clinically significant drug interactions (CSDIs) occurring between recommended ART regimens and their co-prescribed non-antiretroviral drugs (CPD) Method: This study was carried out in a large HIV treatment centre (APIN clinic) in a Nigerian teaching hospital, in Lagos Nigeria, caring for over 20,000 registered patients. Electronic Medical Records (EMR) of 500 patients who received treatment between 2005 and 2015, were selected using systematic random sampling, reviewed retrospectively, and evaluated for potential CSDIs using Liverpool HIV Pharmacology Database and other similar databases. Results: Majority of patients, 421 (84%) were at risk of CSDIs, of which 410, (82%) were moderate and frequently involved co-trimoxazole + zidovudine (or stavudine) /lamivudine (386, 77.2%) and NNRTIs or PIs + artemisinin-based combination therapies (ACTs) [296, 59.2%]. Age (p=0.131), sex (p=0.316) and baseline CD4+ cell counts (p>0.05) were not significantly associated with CSDIs. The interactions, however, were significantly associated with the development of antiretroviral treatment failure (p <0.001) which occurred in nearly a third (139; 27.8%) of the patients. Conclusion: There is a high prevalence of CSDIs between ART and CPDs most of which were categorized as moderate. Further studies are required to evaluate the pharmacokinetic and clinical relevance of these interactions.",
"affiliations": "University of Lagos. oreagbai@yahoo.com.",
"authors": "Oreagba|Ibrahim Adekunle|IA|;Usman|Sikiru Olatunji|SO|;Oshikoya|Kazeem Adeola|KA|;Akinyede|Akinwumi|A|;Agbaje|Esther|E|;Opanuga|Oluranti|O|;Akanmu|Sulaiman|S|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "Australia",
"delete": false,
"doi": "10.22374/1710-6222.26.1.1",
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"issn_linking": "2561-8741",
"issue": "26(1)",
"journal": "Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharmacologie clinique",
"keywords": null,
"medline_ta": "J Popul Ther Clin Pharmacol",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections; D006784:Hospitals, Teaching; D006801:Humans; D008297:Male; D008875:Middle Aged; D009549:Nigeria; D015995:Prevalence; D012189:Retrospective Studies; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "101530023",
"other_id": null,
"pages": "e1-e19",
"pmc": null,
"pmid": "31002484",
"pubdate": "2019-01-22",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinically Significant Drug-Drug Interaction in a Large Antiretroviral Treatment Centre in Lagos, Nigeria.",
"title_normalized": "clinically significant drug drug interaction in a large antiretroviral treatment centre in lagos nigeria"
} | [
{
"companynumb": "NG-JNJFOC-20190801712",
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"activesubstancename": "DARUNAVIR"
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{
"abstract": "Eptifibatide is a glycoprotein (GP) IIb/IIIa inhibitor used mostly in the treatment of acute coronary syndrome (ACS). The GP IIb/IIIa antagonists occupy the fibrinogen binding site at the GP IIb/IIIa and block thrombocyte aggregation independent of the initial activation pathway. Severe thrombocytopenia has been reported with eptifibatide use. Thrombocytopenia after ACS can have multiple etiologies. Human immunodeficiency virus (HIV) infection has also been implicated in immune-mediated thrombocytopenia. In this manuscript, we report a case of acute severe thrombocytopenia secondary to eptifibatide use in a patient with a history of HIV infection who presented with an ST elevation myocardial infarction. We also review the differential diagnosis and suggest management strategies in this challenging clinical scenario.",
"affiliations": "VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TENNESSEE.;UNIVERSITY OF LOUISVILLE, LOUISVILLE, KENTUCKY.;UNIVERSITY OF LOUISVILLE, LOUISVILLE, KENTUCKY.",
"authors": "Bhatia|Nirmanmoh|N|;Sawyer|Robert D|RD|;Ikram|Sohail|S|",
"chemical_list": "D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000077542:Eptifibatide",
"country": "United States",
"delete": false,
"doi": "10.14797/mdcj-13-4-248",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1947-6108",
"issue": "13(4)",
"journal": "Methodist DeBakey cardiovascular journal",
"keywords": "acute coronary syndrome; eptifibatide; thrombocytopenia",
"medline_ta": "Methodist Debakey Cardiovasc J",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000328:Adult; D001792:Blood Platelets; D004562:Electrocardiography; D000077542:Eptifibatide; D005260:Female; D006801:Humans; D010455:Peptides; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017713:Platelet Transfusion; D012307:Risk Factors; D000072657:ST Elevation Myocardial Infarction; D015607:Stents; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "101508600",
"other_id": null,
"pages": "248-252",
"pmc": null,
"pmid": "29744018",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10502237;12200368;24564943;23788287;16425959;11514371;14969621;15720965;11545770;11551503;11914001;18008040",
"title": "Eptifibatide-Induced Profound Thrombocytopenia After Percutaneous Intervention for Acute Coronary Syndrome: A Challenging Clinical Scenario.",
"title_normalized": "eptifibatide induced profound thrombocytopenia after percutaneous intervention for acute coronary syndrome a challenging clinical scenario"
} | [
{
"companynumb": "US-ACCORD-067523",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "BACKGROUND\nThe left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (DCM) and the treatment with carvedilol in infants with severe heart failure remain poorly understood.\n\n\nMETHODS\nWe reviewed the medical records of 5 infants around 12 months old referred to our hospital with severe heart failure due to DCM. Increased left ventricular fractional shortening (LVFS) by more than 10% and the percent of normal of left ventricular end-diastolic dimension (%LVDd) less than 120% were defined as LVRR in this study.\n\n\nRESULTS\nDCM onset ranged from 8 to 16 months. Initial treatment of their acute heart failure was successful in all 5 but 4 patients relapsed despite the usual dose of carvedilol (induction 0.02-maintenance 0.4mg/kg/day), and developed worsening heart failure. Brain natriuretic peptide (BNP) levels which increased again after the acute treatment had fallen subsequent to discontinuing or decreasing carvedilol. Over 24 months, LVFS had increased from 11±2% (mean±SD) to 34±5% (p<0.05), and %LVDd decreased from 149±27% to 108±11% (p<0.05).\n\n\nCONCLUSIONS\nLVRR was found at 2 years after the onset of DCM. Usual dose induction of carvedilol therapy can sometimes worsen heart failure after successful initial conventional treatment for the acute heart failure in DCM. Close control of carvedilol treatment may determine the prognosis of infantile DCM around 12 months old. It is prudent to increase low-dose carvedilol slowly corresponding with the BNP level.",
"affiliations": "Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan. Electronic address: etsuda@ncvc.go.jp.;Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan.",
"authors": "Tsuda|Etsuko|E|;Negishi|Jun|J|;Noritake|Kanae|K|;Iwasa|Toru|T|;Abe|Tadaaki|T|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D020097:Natriuretic Peptide, Brain",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0914-5087",
"issue": "67(2)",
"journal": "Journal of cardiology",
"keywords": "Brain natriuretic peptide; Carvedilol; Dilated cardiomyopathy; Heart failure; Left ventricular reverse remodeling",
"medline_ta": "J Cardiol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D002311:Cardiomyopathy, Dilated; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure; D006801:Humans; D007223:Infant; D008297:Male; D020097:Natriuretic Peptide, Brain; D011379:Prognosis; D011412:Propanolamines; D012189:Retrospective Studies; D013997:Time Factors; D020257:Ventricular Remodeling",
"nlm_unique_id": "8804703",
"other_id": null,
"pages": "147-52",
"pmc": null,
"pmid": "26572957",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Left ventricular reverse remodeling with infantile dilated cardiomyopathy and pitfalls of carvedilol therapy.",
"title_normalized": "left ventricular reverse remodeling with infantile dilated cardiomyopathy and pitfalls of carvedilol therapy"
} | [
{
"companynumb": "JP-CIPLA LTD.-2017JP04829",
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drugadditional": null,
... |
{
"abstract": "Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898-164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3-like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures.",
"affiliations": "Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.;Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.;Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.;Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.;Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.;Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.;Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.;Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA.",
"authors": "Chandrasekar|Indira|I|;Tourney|Anne|A|;Loo|Kamela|K|;Carmichael|Jason|J|;James|Kiely|K|;Ellsworth|Katarzyna A|KA|;Dimmock|David|D|;Joseph|Maries|M|0000-0002-6392-795X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.62185",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "185(7)",
"journal": "American journal of medical genetics. Part A",
"keywords": "NPRL3 gene; NPRL3 gene variant; hemimegalencephaly; infantile epilepsy; infantile epileptic encepahlopathy; intractable neonatal seizures",
"medline_ta": "Am J Med Genet A",
"mesh_terms": null,
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "2126-2130",
"pmc": null,
"pmid": "33749980",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hemimegalencephaly and intractable seizures associated with the NPRL3 gene variant in a newborn: A case report.",
"title_normalized": "hemimegalencephaly and intractable seizures associated with the nprl3 gene variant in a newborn a case report"
} | [
{
"companynumb": "US-UCBSA-2021033006",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "The aim of the nationwide retrospective matched cohort study was to evaluate health service utilization and medical costs between patients with schizophrenia who received long-acting injectable (LAI) risperidone and those who took risperidone orally. Data were sourced from the 2008 to 2013 Psychiatric Inpatient Medical Claim Dataset in Taiwan. The sample selection process was performed by propensity score matching. Finally, there were 691 patients in the exposed cohort and 1382 patients in the unexposed cohort. Each patient was individually followed for a 1-year period. Two-part models and generalized estimating equations were used to evaluate health service utilization and direct medical costs of patients. Analytical results showed that patients receiving LAI risperidone had used outpatient services significantly more, had greater hospital admissions, and had shorter lengths of stay than those who took risperidone orally. Furthermore, compared with their counterparts in the unexposed group, patients in the exposed group had incurred higher medical costs because of costs incurred from increased utilization of outpatient service and hospital admissions, under the special context of the healthcare system in Taiwan, a single-payer universal health coverage system with low copayment rates. In summary, this study suggested that patients with schizophrenia treated with LAI risperidone had shorter lengths of stay, higher medical costs largely because of increased utilization of outpatient service and hospital admissions, compared with those who took risperidone orally.",
"affiliations": "School of Health Care Administration, Taipei Medical University, Taipei, Taiwan.;Department of Health Administration, Governors State University, University Park, Illinois, USA.;School of Health Care Administration, Taipei Medical University, Taipei, Taiwan.;School of Health Care Administration, Taipei Medical University, Taipei, Taiwan.;School of Health Care Administration, Taipei Medical University, Taipei, Taiwan.",
"authors": "Fan|Szu-Jui|SJ|;Lu|Ning|N|;Chang|Hui-Chih|HC|;Tang|Chao-Hsiun|CH|;Huang|Kuo-Cherh|KC|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": "10.1097/YIC.0000000000000213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1315",
"issue": "33(4)",
"journal": "International clinical psychopharmacology",
"keywords": null,
"medline_ta": "Int Clin Psychopharmacol",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D002648:Child; D015331:Cohort Studies; D003362:Cost-Benefit Analysis; D005260:Female; D006296:Health Services; D006760:Hospitalization; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018967:Risperidone; D012559:Schizophrenia; D013624:Taiwan; D055815:Young Adult",
"nlm_unique_id": "8609061",
"other_id": null,
"pages": "204-212",
"pmc": null,
"pmid": "29489495",
"pubdate": "2018-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Health service utilization and medical costs among patients with schizophrenia receiving long-acting injectable risperidone versus oral risperidone: a nationwide retrospective matched cohort study in Taiwan.",
"title_normalized": "health service utilization and medical costs among patients with schizophrenia receiving long acting injectable risperidone versus oral risperidone a nationwide retrospective matched cohort study in taiwan"
} | [
{
"companynumb": "TW-JNJFOC-20180414858",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
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"abstract": "Overall survival in a phase III study for metastatic pancreatic cancer has significantly improved with gemcitabine (GEM) plus nab-paclitaxel. However, to date, there is limited data on the efficacy and safety of its use for patients with locally advanced (LA) or borderline resectable pancreatic cancer (BRPC). Here, we investigated the efficacy and safety of first-line GEM plus nab-paclitaxel for LA or BRPC. We retrospectively analysed consecutive patients with pathologically confirmed, untreated LA or BRPC who started receiving first-line GEM plus nab-paclitaxel. A total of 30 patients (LA, n = 22; BRPC, n = 8) were analysed. Twelve patients (40%) without distant metastasis received additional chemoradiotherapy using S-1. Laparotomy was performed on 8 patients and 6 (20%; LA, n = 3; BR, n = 3) achieved R0 resection. Objective response rate was 44.8%. For all patients, median progression-free survival and overall survival were 14.8 and 29.9 months, respectively. Median overall survival for LA was 24.1 months with a 2-year survival rate of 50.8%. The most frequently observed grade 3 or 4 toxicities were neutropenia (73%) and biliary infection (13%). First-line GEM plus nab-paclitaxel was well-tolerated and feasible with an encouraging survival for LA or BRPC.",
"affiliations": "Division of Gastroenterology, Chiba Cancer Centre, Chiba, Japan.;Division of Gastroenterology, Chiba Cancer Centre, Chiba, Japan. kentarosudo9@yahoo.co.jp.;Division of Gastroenterology, Chiba Cancer Centre, Chiba, Japan.;Division of Gastroenterology, Chiba Cancer Centre, Chiba, Japan.;Division of Radiation Oncology, Chiba Cancer Centre, Chiba, Japan.;Division of Hepatobiliary and Pancreatic Surgery, Chiba Cancer Centre, Chiba, Japan.;Division of Gastroenterology, Chiba Cancer Centre, Chiba, Japan.;Division of Gastroenterology, Chiba Cancer Centre, Chiba, Japan.",
"authors": "Tsujimoto|Akiko|A|;Sudo|Kentaro|K|;Nakamura|Kazuyoshi|K|;Kita|Emiri|E|;Hara|Ryusuke|R|;Takayama|Wataru|W|;Ishii|Hiroshi|H|;Yamaguchi|Taketo|T|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1038/s41598-019-52486-x",
"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 5248610.1038/s41598-019-52486-xArticleGemcitabine plus nab-paclitaxel for locally advanced or borderline resectable pancreatic cancer Tsujimoto Akiko 1Sudo Kentaro kentarosudo9@yahoo.co.jp 1Nakamura Kazuyoshi 1Kita Emiri 1Hara Ryusuke 2Takayama Wataru 3Ishii Hiroshi 1Yamaguchi Taketo 11 Division of Gastroenterology, Chiba Cancer Centre, Chiba, Japan 2 Division of Radiation Oncology, Chiba Cancer Centre, Chiba, Japan 3 Division of Hepatobiliary and Pancreatic Surgery, Chiba Cancer Centre, Chiba, Japan 7 11 2019 7 11 2019 2019 9 1618714 3 2019 18 10 2019 © The Author(s) 2019Open 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/.Overall survival in a phase III study for metastatic pancreatic cancer has significantly improved with gemcitabine (GEM) plus nab-paclitaxel. However, to date, there is limited data on the efficacy and safety of its use for patients with locally advanced (LA) or borderline resectable pancreatic cancer (BRPC). Here, we investigated the efficacy and safety of first-line GEM plus nab-paclitaxel for LA or BRPC. We retrospectively analysed consecutive patients with pathologically confirmed, untreated LA or BRPC who started receiving first-line GEM plus nab-paclitaxel. A total of 30 patients (LA, n = 22; BRPC, n = 8) were analysed. Twelve patients (40%) without distant metastasis received additional chemoradiotherapy using S-1. Laparotomy was performed on 8 patients and 6 (20%; LA, n = 3; BR, n = 3) achieved R0 resection. Objective response rate was 44.8%. For all patients, median progression-free survival and overall survival were 14.8 and 29.9 months, respectively. Median overall survival for LA was 24.1 months with a 2-year survival rate of 50.8%. The most frequently observed grade 3 or 4 toxicities were neutropenia (73%) and biliary infection (13%). First-line GEM plus nab-paclitaxel was well-tolerated and feasible with an encouraging survival for LA or BRPC.\n\nSubject terms\nPancreatic cancerChemotherapyissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nLocally advanced (LA) or borderline resectable pancreatic cancer (BRPC) are subsets of PC which account for about 30–40% of all patients1,2. Patterns of disease progression and survival outcomes differ from those with metastatic disease1,3. To date, systemic chemotherapy, combined or not with chemoradiotherapy (CRT), represents the standard treatment for LAPC4. In addition, neoadjuvant therapy followed by surgical resection is the preferred option in BRPC, despite a lack of high-level evidence5.\n\nHowever, it remains unclear what is the best first-line therapy in LA or BRPC patients. Up to the early 2010s, CRT or gemcitabine (GEM)-based systemic chemotherapy were the mainstay in the treatment of LAPC. However, it has been shown that those conventional therapies provided limited survival benefits, having a reported median survival of 8–17 months6–12. Consequently, it is urgent to develop more effective therapies.\n\nIn a large-scale, international phase III study for metastatic pancreatic cancer (MPACT), it has been shown that GEM plus nab-paclitaxel significantly improved both overall survival and progression-free survival (PFS) compared to GEM alone13. Additionally, an improved radiographic response was observed (23% vs. 7%, P < 0.001). As stated in the National Comprehensive Cancer Network (NCCN) guidelines of pancreatic adenocarcinoma, GEM plus nab-paclitaxel is currently accepted as an option in the management of LA or BRPC5. However, to date, there is limited data available on the safety and efficacy of its use for this population. To address this issue, we retrospectively investigated the efficacy and safety of first-line GEM plus nab-paclitaxel for LA or BRPC in the present study.\n\nResults\nPatients\nA total of 196 patients with pancreatic cancer started chemotherapy at the division of Gastroenterology of Chiba Cancer Centre between January 2015 and August 2017 (Fig. 1). Of the 196 patients, 47 patients had LA or BR disease at the initiation of chemotherapy. Of these, 17 patients were excluded due to receiving other treatment (n = 15), starting GEM plus nab-paclitaxel at the referring hospital (n = 1) or lack of pathologic confirmation (n = 1). Thus, 30 patients with LA unresectable (n = 22) and BRPC (n = 8) were eligible for the study (Fig. 1). Table 1 shows the baseline characteristics of the study population. The median age was 67 years. All patients had a good performance status (PS) of 0 or 1. The primary tumour was located in the head of the pancreas in 18 patients (60%) and it was in the body/tail in 12 (40%). Biliary drainage was required prior to treatment initiation in 16 patients (53%). Specifically, 14 patients underwent endoscopic biliary stent placement and 2 underwent choledochojejunostomy. The median tumour size was 44 mm. Median serum CA19–9 concentration was 160 U/mL.Figure 1 Consort Diagram.\n\nTable 1 Patient characteristics. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; BR, borderline resectable; LA, locally advanced; SMA, superior mesenteric artery; CA, celiac axis; HA, hepatic artery; SMV, superior mesenteric vein; PV, portal vein.\n\n\tn or median (range)\t\nn\t30\t\n\nGender\n\t\nMale\t14\t\nFemale\t16\t\nMedian Age, years (range)\t67 (47–75)\t\n\nECOG PS\n\t\n0\t16\t\n1\t14\t\n\nSite of primary tumour\n\t\nHead\t18\t\nBody or tail\t12\t\n\nBiliary drainage\n\t\nStent\t14\t\nBypass\t2\t\nMedian tumour size, mm (range)\t44 (25–88)\t\n\nResectability\n\t\nBR\n\nLA\n\n\t8\n\n22\n\n\t\nVessel invasion, (%)\t\nSMA\t24 (80%)\t\nCA\t15 (50%)\t\nHA\t18 (60%)\t\nSMV/PV\t25 (83.3%)\t\nCA19–9 (U/mL), median [range]\t160 [<2–44074]\t\n\n\nTreatment\nFigure 1 summarizes the treatment for all the patients. The initial doses of GEM or nab-paclitaxel were reduced by more than 10% in 4 patients (13.3%) because of repeated biliary tract infection (n = 1), patient’s wish (n = 1), co-existing disease (n = 1) or physician’s discretion (n = 1). The remaining patients (n = 26) started GEM plus nab-paclitaxel at standard dosage. Treatment was terminated due to adverse events (AEs) in 2 patients. The median duration for first-line GEM plus nab-paclitaxel was 5.4 months (range: 1.4–25.8 months). In total, 90% (n = 27) of the patients required dose modification (dose reduction, n = 12; treatment schedule modification, n = 3; both, n = 12) owing to the development of toxicity. Forty-three percent of the patients had dose reduction of GEM and 80% had dose reduction of nab-paclitaxel. Of the 30 patients, 12 (40%) received S-1-based CRT after the first-line GEM plus nab-paclitaxel, followed by maintenance chemotherapy using GEM plus nab-paclitaxel (n = 4), S-1 alone (n = 5) or GEM plus S-1 (n = 1). The median duration from the start of GEM plus nab-paclitaxel to CRT initiation was 6 months (range, 2.8–8.5 months). The median duration from the completion of CRT to the start of maintenance chemotherapy was 2.5 weeks (range, 1.1–4 weeks).\n\nSafety\nAll the patients (n = 30) were evaluable for AEs. Table 2 shows Grade 3 or 4 AEs observed during the first-line GEM plus nab-paclitaxel. The most common Grade 3 or 4 AE were neutropenia (73% of the patients), followed by biliary infection (13% of patients). All the patients who developed biliary infection had pancreatic head tumour and had undergone biliary stent placement. Among these patients, one patient developed acute cholecystitis during chemotherapy with GEM plus nab-paclitaxel. Repeated biliary tract infection after biliary stent placement was the main cause of acute cholecystitis. The patient required percutaneous gallbladder drainage followed by elective cholecystectomy. Biliary tract infection in other patients was mainly induced by stent occlusion, and this was managed by stent replacement and antibiotic treatment.Table 2 Grade 3 or 4 adverse events.\n\n\tn (%)\t\nWhite blood cell decreased\t5 (17%)\t\nNeutrophil count decreased\t22 (73%)\t\nFebrile neutropenia\t0\t\nAnaemia\t2 (7%)\t\nAnorexia\t1 (3%)\t\nNausea\t1 (3%)\t\nBiliary tract infection\t4 (13%)\t\nPneumonitis\t1 (3%)\t\nLung infection\t1 (3%)\t\nHaematuria\t1 (3%)\t\nFatigue\t0\t\nPeripheral neuropathy\t0\t\nDiarrhoea\t0\t\n\n\nFurthermore, two patients had additional AEs. One patient developed interstitial lung disease, likely induced by GEM, the other developed pneumocystis pneumonia. Both patients recovered with conservative therapy. We did not observe cases of febrile neutropenia or treatment-related death.\n\nResponse\nTwenty-nine patients were evaluable for radiographic response. One patient was excluded from the evaluation of objective response due to the lack of a measurable lesion. During chemotherapy with GEM plus nab-paclitaxel, 13 patients (44.8%) achieved a partial response, 15 (51.7%) had stable disease and 1 (3.4%) developed disease progression. Among the 15 patients with stable disease, 2 showed a partial response after additional CRT. Therefore, 15 patients (51.7%) achieved a partial response following multimodal treatment using GEM plus nab-paclitaxel.\n\nOverall, 8 patients (26.7%; BR, n = 4; LA, n = 4) underwent laparotomy with a curative intent (Fig. 1). Three patients with BRPC received GEM plus nab-paclitaxel as neoadjuvant therapy, and they underwent either pancreatoduodenectomy (n = 2) or distal pancreatectomy (n = 1) at 2.2–5.6 months after treatment initiation. They all achieved R0 resection. Further, one patient with BRPC who showed partial response after receiving first-line GEM plus nab-paclitaxel therapy underwent laparotomy at 24.4 months after treatment initiation. However, this patient was found to be inoperable owing to peritoneal dissemination. Three patients with LAPC who showed significant radiographic response underwent either pancreatoduodenectomy (n = 2) or distal pancreatectomy (n = 1) at 6.1–10.2 months after treatment initiation. They all achieved R0 resection. Of note, one patient treated with additional CRT showed a pathologic complete response. Another patient with LAPC underwent laparotomy at 3.4 months after treatment initiation, but this patient was found to be inoperable owing to liver metastasis.\n\nSurvival\nThe median follow-up length for censored cases was 25.2 months (range: 6.9–35.3 months). Disease progression was observed in 19 patients. The median PFS for all treated patients (n = 30) was 14.8 months (95% CI, 11.4–24.4) (Fig. 2A). Specifically, median PFS for LA (n = 22) and BRPC patients (n = 8) was 12.4 months (95% CI, 8.9–20.3) and 24.4 months (95% CI, 11.4–NA), respectively (Fig. 2B).Figure 2 (A) Progression-free survival for all patients (n = 30) and (B) for LA (n = 22) and BR (n = 8) patients. (C) Overall survival curves of all patients (n = 30) and (D) LA (n = 22) and BR (n = 8) patients. (E) Overall survival for resected (n = 6) and non-resected (n = 24) patients.\n\n\n\nFor all treated patients (n = 30), the median overall survival was 29.9 months (95% CI, 20.1–NA) with a 2-year survival rate of 65.1% (95% CI, 43.4–80.2%) (Fig. 2C). For LA patients (n = 22), median overall survival and survival rate at 2 years were 24.1 months (95% CI, 17.9–NA) and 50.8% (95% CI, 26.1–71%), respectively (Fig. 2D). The median overall survival of BR patients (n = 8) was not reached (Fig. 2D). The median overall survival for 24 patients who did not undergo pancreatectomy was 24.9 months (95% CI, 18.6–NA) with a 2-year survival rate of 58% (95% CI, 34.4–75.7%) (Fig. 2E).\n\nDiscussion\nThere is limited data available as to the efficacy and safety of GEM plus nab-paclitaxel in patients with LA or BRPC. Gulhati et al. assessed the use of first-line GEM plus nab-paclitaxel for the treatment of localised pancreatic cancer in a large case series (n = 99)14. In that study, most of the patients (81%) received biweekly doses of GEM plus nab-paclitaxel. The median survival of all the patients, including those with resectable pancreatic cancer (n = 45), was 18 months, but specific survival data for patients with BR (n = 14) or LAPC (n = 40) have not been presented.\n\nIn the present study, we demonstrated that first-line GEM plus nab-paclitaxel was feasible. Additionally, we showed that this line of treatment is associated with an encouraging survival outcome for this population. Median overall survival of patients treated with GEM plus nab-paclitaxel (all patients, 29.9 months; LA patients, 24.1 months) appeared to be better than for patients treated with conventional therapies (e.g. upfront CRT or GEM-based systemic chemotherapy) (8–17 months) (Table 3)6–12. Furthermore, median overall survival of 24 patients (80%) treated with non-surgical treatment alone reached 24.9 months.Table 3 Clinical studies of conventional CRT or GEM based chemotherapy for LAPC. Abbreviations: P II, phase II study; P III, phase III study; GEM, gemcitabine; CRT, chemoradiotherapy; RT, radiation therapy; PFS, progression-free survival; TTP, time to progression; MST, median survival time; NA, not available.\n\nAuthor\tdesign\tCRT or systemic chemotherapy\tn\tResponse rate\tPFS or TTP\n(months)\tMST\n(months)\tref.\t\nIshii\tP II\t5-FU + RT (50.4 Gy)\t20\t10%\t4.9\t10.3\t6\t\nSudo\tP II\tS-1 + RT (50.4 Gy)\t34\t41%\t8.7\t16.8\t7\t\nOkusaka\tP II\tGEM + RT (50.4 Gy)\t42\t21%\t4.4\t9.5\t8\t\nLoehrer\tP III\tGEM + RT (50.4 Gy)\n\nGEM\n\n\t34\n\n37\n\n\t6%\n\n5%\n\n\t6.0\n\n6.7\n\n\t11.1\n\n9.2\n\n\t9\t\nChauffert\tP III\t5-FU + Cisplatin + RT (60 Gy)\n\nGEM\n\n\t59\n\n60\n\n\tNA\n\nNA\n\n\t14%a\n\n32%a\n\n\t8.6\n\n13.0\n\n\t10\t\nIshii\tP II\tGEM\t50\tNA\t6.0\t15.0\t11\t\nUeno\tP III\tGEM + S-1\n\nGEM\n\nS-1\n\n\t68\n\n66\n\n68\n\n\tNA\n\nNA\n\nNA\n\n\tNA\n\nNA\n\nNA\n\n\t15.9\n\n12.7\n\n13.8\n\n\t12\t\naOne-year progression-free survival.\n\n\n\nIt is possible that a better patient selection positively influenced the survival outcomes in the present study. However, previously published studies have shown similar survival outcomes by assessing FOLFIRINOX or GEM plus nab-paclitaxel regimens for LA or BRPC (Table 4)14–17. FOLFIRINOX has also shown a significant improvement of overall survival compared to GEM alone in metastatic pancreatic cancer18. Importantly, both in our study and in previously published data, a multimodal approach centring on potent systemic therapies was employed. Following the use of systemic chemotherapy, 40–80% of patients received CRT and 20–40% underwent surgical resection (Table 4). Such data indicate that multimodal treatment using these novel regimens provide significant survival benefits (median overall survival, 20–30 months). Limited evidence supports this strategy and the clinical significance of CRT is still controversial. However, we believe that the improved survival outcomes warrant further investigation.Table 4 Published studies assessing GEM plus nab-paclitaxel or FOLFIRINOX for LA or BRPC. Abbreviations: FOLFIRINOX, fluorouracil, leucovorin, irinotecan and oxaliplatin; GEM, gemcitabine; PAXG, GEM, nab-paclitaxel, capecitabine and cisplatin; BR, borderline resectable; LA, locally advanced; CRT, chemoradiotherapy; PFS, progression-free survival; MST, median survival time.\n\nAuthor\tDesign\tTreatment\tn\tBR/LA\tCRT\tR0/1 resection\tPFS\n(months)\tMST\n(months)\tref.\t\nSuker\tMeta-analysis\tFOLFIRINOX\t315\t0/315\t64%a\t26%b\t15.0\t24.2\t15\t\nStein\tPhase II\tFOLFIRINOX\t31\t11/20\t55%\t42%\t17.8\t26.6\t16\t\nGulhati\tretrospective\tGEM + nab-paclitaxel\t99\t45c/14/40\t45%\t15%\t11.0d\t18\t14\t\nReni\tRandomised phase II\tPAXG\n\nGEM + nab-paclitaxel\n\n\t26\n\n28\n\n\t10/16\n\n15/13\n\n\t88%\n\n57%\n\n\t31%\n\n32%\n\n\t12.5\n\n9.9\n\n\t20.7\n\n19.1\n\n\t17\t\nCurrent study\tretrospective\tGEM + nab-paclitaxel\t30\t8/22\t40%\t20%\t14.8\t29.9\t\t\naPooled proportion of patients who received any radiation therapy in a random-effects model.\n\nbPooled proportion of patients who had resection in a random-effects model.\n\ncPotentially resectable.\n\ndMetastatic disease-free survival.\n\n\n\nObjective response rate of GEM plus nab-paclitaxel (44.8%) was higher than conventional regimens for LAPC (5–41%) (Table 3). These results are consistent with those of the phase I/II study of GEM plus nab-paclitaxel for metastatic pancreatic cancer reported by Ueno et al. The authors showed that 69% of the patients (18 out of 26) underwent >30% shrinkage of pancreatic tumour19. In the era of neoadjuvant or conversion strategy for localised pancreatic cancer, first-line chemotherapy with higher response rate represents an attractive option.\n\nIn the present study, we found that first-line GEM plus nab-paclitaxel was well-tolerated and feasible in patients with LA or BRPC. The most common Grade 3 or 4 toxicity was neutropenia. However, patients rarely developed life-threatening infections or febrile neutropenia. The frequency of biliary tract infection (13%) was comparable to those observed in our previous prospective study (20%)20. The most common non-haematological toxicity was peripheral neuropathy in prospective studies13,19. In contrast, none of the patients developed grade 3 or more peripheral neuropathy in this study, possibly because the dosage of nab-paclitaxel was reduced or its administration was temporally discontinued when grade 2 peripheral neuropathy was observed.\n\nThe present study had some limitations. The main one is its retrospective nature. Thus, no standardized indication of pancreatectomy after induction of GEM plus nab-paclitaxel in BRPC was available. Furthermore, additional CRT was not performed according to predefined criteria. Radiographic evaluation was not performed according to the protocol specified duration. Consequently, objective response rate and PFS were biased. Finally, we enrolled a small number of patients, and the sample size was not calculated based on any statistical hypotheses.\n\nThe present study has an important fundamental strength. It included patients who started receiving first-line GEM plus nab-paclitaxel for LA or BRPC at our institution in a consecutive manner. We analysed all the treated patients, whether or not they received CRT or pancreatectomy based on an intention-to-treat basis. Furthermore, to avoid selection bias, we excluded from the study those patients who were referred from other institutions after the introduction of GEM plus nab-paclitaxel. Thus, the present study can provide precise data on survival outcomes of first-line GEM plus nab-paclitaxel for LA or BRPC in clinical practice.\n\nIn conclusion, our results demonstrate that first-line GEM plus nab-paclitaxel was well-tolerated and feasible in patients with LA or BRPC. Using a multimodal approach, we observed good survival outcomes (median survival of 29.9 months in all patients and 24.1 months in patients with LA). Although the study is limited by its retrospective nature with a small sample size, these results were better than those of patients treated with conventional therapies (e.g. upfront CRT or GEM-based chemotherapy). Further prospective studies are warranted to elucidate the effectiveness of first-line GEM plus nab-paclitaxel in a large cohort of patients.\n\nMaterials and Methods\nPatients\nWe reviewed medical records of consecutive patients with PC who started chemotherapy at the division of Gastroenterology of Chiba Cancer Centre between January 2015 and August 2017. The following are the selection criteria of the study population: (1) Patients who started receiving first-line GEM plus nab-paclitaxel in our institution; (2) Pathologically confirmed pancreatic adenocarcinoma; (3) No prior chemotherapy or radiotherapy for PC; and (4) LA unresectable or BRPC, based on the NCCN clinical practice guidelines in oncology version 2.201821.\n\nPatients who were referred from other institutions after the introduction of GEM plus nab-paclitaxel were excluded to avoid selection bias.\n\nTreatment\nPatients received intravenous nab-paclitaxel 125 mg/m2 followed by intravenous GEM 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. According to the patient’s condition, GEM or nab-paclitaxel’s doses were modified at the physician’s discretion. Treatment was continued until the patient showed disease progression or unacceptable adverse events.\n\nFor patients who did not develop distant metastasis, we performed CRT using S-1 on the physician’s discretion following a minimum of a 2-week washout period of GEM plus nab-paclitaxel. Further contraindications for additional CRT included tumour invasion to the gastrointestinal tract, huge tumours, massive lymph adenopathy or ascites. We performed S-1-based CRT as reported previously7,20. In brief, a total dose of 50.4 Gy was delivered in 28 fractions. S-1 was administered twice a day on days 1 to 14 and 22 to 35. The daily S-1 dose was determined according to body surface area (BSA) as follows: BSA < 1.25 m2, 80 mg/day; 1.25 m2 ≤ BSA < 1.50 m2, 100 mg/day; and 1.50 m2 ≤ BSA, 120 mg/day. Maintenance chemotherapy was started after CRT until the patient showed disease progression or unacceptable adverse events, as reported previously7,20.\n\nIndication for surgery was determined at the hepatobiliary pancreatic cancer board of Chiba Cancer Centre. Based on the radiographic findings and patient’s conditions, indication for surgery required consensus among radiologists, surgeons, pathologists and medical oncologists.\n\nAssessment\nWe evaluated the PS according to the ECOG (Eastern Cooperative Oncology Group) criteria. We assessed AEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. In the present study, we investigated AEs during first-line GEM plus nab-paclitaxel. We did not include AEs observed during maintenance chemotherapy after CRT. Radiographic responses were evaluated according to Response Evaluation Criteria in Solid Tumours, version 1.1.\n\nStatistical analysis\nPFS was defined as the time between the date of treatment initiation and the date of disease progression or death. Overall survival was defined as the time between the date of treatment initiation and the date of death due to any cause. We used the Kaplan–Meier method to estimate the PFS and overall survival. The EZR ver. 1.35 software (https://cran.r-project.org/web/packages/RcmdrPlugin.EZR/index.html) was used to perform statistical analyses22.\n\nEthics statement\nThe ethical review board of Chiba Cancer Centre approved the study. We performed the study in compliance with the 1964 Helsinki declaration and its later amendments and with the ethical guidelines for medical research by the Ministry of Health, Labour and Welfare of Japan. For this type of study (retrospective, non-invasive, observational study), written informed consent is not required. We used our institutional official website as an opt-out method.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe would like to thank all patients involved in this study. We would like to thank Enago (www.enago.jp) for the English language review.\n\nAuthor contributions\nThe study was designed by K.S. and A.T. Data collection was performed by K.S., A.T., K.N., E.K., R.H. and W.T. Statistical analysis was performed by K.S. and A.T. Data analysis and interpretation was performed by K.S., A.T., K.N., E.K., H.I. and T.Y. K.S. and T.A. wrote the manuscript. H.I. and T.Y. revised the manuscript. All authors reviewed the manuscript.\n\nData availability\nThe datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nCompeting interests\nHiroshi Ishii reports honoraria from Yakult Honsha, Taiho Pharmaceutical, Eisai, TOWA and Teijin Pharma, and a consulting role for Ono Pharmaceutical, outside the submitted work. Other authors declare no conflict of interest.\n==== Refs\nReferences\n1. Coveler AL Herman JM Simeone DM Chiorean EG Localized pancreatic cancer: multidisciplinary management Am Soc Clin Oncol Educ Book 2016 35 e217 e226 10.1200/EDBK_160827 27249726 \n2. Shaib WL Contemporary management of borderline resectable and locally advanced unresectable pancreatic cancer Oncologist 2016 21 178 187 10.1634/theoncologist.2015-0316 26834159 \n3. Sultana A Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy Br J Cancer 2007 96 1183 1190 10.1038/sj.bjc.6603719 17406358 \n4. Balaban EP Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline J Clin Oncol 2016 34 2654 2668 10.1200/JCO.2016.67.5561 27247216 \n5. Tempero MA Pancreatic adenocarcinoma, version 2.2017, NCCN Clinical Practice Guidelines in Oncology J Natl Compr Canc Netw 2017 15 1028 1061 10.6004/jnccn.2017.0131 28784865 \n6. Ishii H Protracted 5-fluorouracil infusion with concurrent radiotherapy as a treatment for locally advanced pancreatic carcinoma Cancer 1997 79 1516 1520 10.1002/(SICI)1097-0142(19970415)79:8<1516::AID-CNCR11>3.0.CO;2-0 9118032 \n7. Sudo K Phase II study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer Int J Radiat Oncol Biol Phys 2011 80 119 125 10.1016/j.ijrobp.2010.01.027 20605363 \n8. Okusaka T Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer Br J Cancer 2004 91 673 677 10.1038/sj.bjc.6602001 15226765 \n9. Loehrer PJ Sr Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial J Clin Oncol 2011 29 4105 4112 10.1200/JCO.2011.34.8904 21969502 \n10. Chauffert B Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study Ann Oncol 2008 19 1592 1599 10.1093/annonc/mdn281 18467316 \n11. Ishii H Phase II study of gemcitabine chemotherapy alone for locally advanced pancreatic carcinoma: JCOG0506 Jpn J Clin Oncol 2010 40 573 579 10.1093/jjco/hyq011 20185458 \n12. Ueno H Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study J Clin Oncol 2013 31 1640 1648 10.1200/JCO.2012.43.3680 23547081 \n13. Von Hoff DD Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine N Engl J Med 2013 369 1691 1703 10.1056/NEJMoa1304369 24131140 \n14. Gulhati P First-Line Gemcitabine and Nab-Paclitaxel Chemotherapy for Localized Pancreatic Ductal Adenocarcinoma Ann Surg Oncol 2019 26 619 627 10.1245/s10434-018-6807-9 30324485 \n15. Suker M FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis Lancet Oncol 2016 17 801 810 10.1016/S1470-2045(16)00172-8 27160474 \n16. Stein SM Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer Br J Cancer 2016 114 737 743 10.1038/bjc.2016.45 27022826 \n17. Reni M A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma Eur J Cancer 2018 102 95 102 10.1016/j.ejca.2018.07.007 30149366 \n18. Conroy T FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 364 1817 1825 10.1056/NEJMoa1011923 21561347 \n19. Ueno H Phase I/II study of nab-paclitaxel plus gemcitabine for chemotherapy-naive Japanese patients with metastatic pancreatic cancer Cancer Chemother Pharmacol 2016 77 595 603 10.1007/s00280-016-2972-3 26842789 \n20. Sudo K Phase II study of induction gemcitabine and S-1 followed by chemoradiotherapy and systemic chemotherapy using S-1 for locally advanced pancreatic cancer Cancer Chemother Pharmacol 2017 80 195 202 10.1007/s00280-017-3350-5 28597040 \n21. NCCN Clinical Practice Guidelines in Oncology version 2.2018 July 10, 2018. Available at, https://www.nccn.org/professionals/physician_gls/default.aspx.\n22. Kanda Y Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics Bone Marrow Transplant 2013 48 452 458 10.1038/bmt.2012.244 23208313\n\n",
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"mesh_terms": "D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007813:Laparotomy; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D015996:Survival Rate",
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"title": "Gemcitabine plus nab-paclitaxel for locally advanced or borderline resectable pancreatic cancer.",
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"abstract": "A 65-year-old male presented to our institution with acute-onset headache. Imaging studies demonstrated a mass in the region of the pineal gland, with subsequent histopathology findings being consistent with large B cell lymphoma. The patient was treated with methotrexate, but ultimately did not survive. Primary central nervous system (CNS) lymphoma rarely involves the pineal gland, but should be considered in the differential diagnosis of pineal gland tumors in the appropriate clinical setting.",
"affiliations": "Department of Radiology, University of Rochester Medical Center, Rochester, New York, USA.;Department of Radiology, University of Rochester Medical Center, Rochester, New York, USA.;Department of Pathology, University of Rochester Medical Center, Rochester, New York, USA.",
"authors": "Gupta|Akshya|A|;Johnson|Mahlon|M|;Hussain|Ali|A|",
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"fulltext": "\n==== Front\nJ Clin Imaging SciJ Clin Imaging SciJCISJournal of Clinical Imaging Science2156-75142156-5597Medknow Publications & Media Pvt Ltd India JCIS-5-5110.4103/2156-7514.166350Case ReportPineal Gland Lymphoma: Case Report and Literature Review Gupta Akshya Johnson Mahlon Hussain Ali 1Department of Radiology, University of Rochester Medical Center, Rochester, New York, USA1 Department of Pathology, University of Rochester Medical Center, Rochester, New York, USAAddress for correspondence: Dr. Akshya Gupta, 601 Elmwood Avenue, Box 648, Rochester - 14642, New York, USA. E-mail: Akshya_Gupta@urmc.rochester.edu2015 30 9 2015 5 5119 6 2015 20 8 2015 Copyright: © 2015 Journal of Clinical Imaging Science2015This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.A 65-year-old male presented to our institution with acute-onset headache. Imaging studies demonstrated a mass in the region of the pineal gland, with subsequent histopathology findings being consistent with large B cell lymphoma. The patient was treated with methotrexate, but ultimately did not survive. Primary central nervous system (CNS) lymphoma rarely involves the pineal gland, but should be considered in the differential diagnosis of pineal gland tumors in the appropriate clinical setting.\n\nLymphomapineal glandhydrocephalus\n==== Body\nINTRODUCTION\nPrimary central nervous system (CNS) lymphoma is a relatively uncommon malignancy, accounting for approximately 6% of all malignant CNS neoplasms.[1] They typically occur in middle-aged and older adults, although it can be seen more commonly in younger patients with human immunodeficiency virus (HIV) or transplant recipients. More than 90% of primary CNS lymphomas are of the diffuse large B-cell variety.[1] Most of these lesions appear hyperdense on a non-contrast enhanced computed tomography (CT) scan and tend to demonstrate restricted diffusion on magnetic resonance imaging (MRI), given their high cellularity. This is the eighth reported case of CNS lymphoma involving the pineal gland in the literature.[234567]\n\nCASE REPORT\nA 65-year-old male presented with a 2-week history of worsening headache and double vision. Initial non-contrast head CT demonstrated a homogeneous hyperdense mass in the pineal gland region with mild hydrocephalus, but no calcification or hemorrhage [Figure 1]. Contrast MRI was performed, which demonstrated a homogeneously enhancing mass involving the pineal gland, with increased perfusion with corresponding low apparent diffusion coefficient values [Figure 2]. The mass was hypointense on T1-weighted images and isointense to mildly hyperintense compared to brain parenchyma on T2-weighted images. Leptomeningeal enhancement was identified near the supraoptic recess and along the cerebellar velum [Figure 3].\n\nFigure 1 65-year-old male presented with headache and was later diagnosed with pineal gland lymphoma. Axial non-contrast CT of the head demonstrates a homogeneously hyperdense mass (arrow) in the pineal gland region. There are no calcifications or hemorrhage identified.\n\nFigure 2 65-year-old male presented with headache and was later diagnosed with pineal gland lymphoma. (a) Axial T1 post-contrast MRI image of the head demonstrates a homogeneously enhancing mass (arrow) in the region of the pineal gland. (b) Axial MRI diffusion-weighted imaging (DWI) sequence demonstrates increased signal (arrow). (c) The corresponding axial apparent diffusion coefficient (ADC) map demonstrates low ADC values (arrow).\n\nFigure 3 65-year-old male presented with headache and was later diagnosed with pineal gland lymphoma. (a) Axial T2 FLAIR MR image demonstrates the pineal gland mass (arrow) as isointense to mildly hyperintense to brain parenchyma. (b) Sagittal T1-weighted MR image demonstrates that the mass is hypointense. (c) Sagittal T1 post-contrast MR image again shows the enhancing pineal gland mass (arrowhead) as well as leptomeningeal enhancement near the supraoptic recess (arrow) and cerebellar velum.\n\nA transventricular endoscopic biopsy was performed. Cerebrospinal fluid sampling was not obtained unfortunately. The histopathology showed a hypercellular tumor with high nuclear/cytoplasmic ratio, but no pineocytomatous or Homer Wright rosettes or papillary architecture [Figure 4]. The nuclei had coarse chromatin, notches, and occasional nucleoli. The tumor appeared to involve the pineal parenchyma. Focal necrosis was found. No rhabdomyoblasts or strap cells were found. Mitoses were noted and Ki-67 labeled the majority of cells. Tumor cells exhibited vimentin, CD45, extensive CD20, CD79a, and nuclear PAX 5 reactivity. In situ hybridization showed kappa, but no lambda light chain hybridization. Scattered small lymphocytes showed CD3 immunoreactivity. There was focal granular synaptophysin, but no neuron specific enolase (NSE), glial fibrillary acidic protein (GFAP), beta tubulin, Cam 5.2, thyroid transcription factor (TTF-1), CD99, pancytokeratin, myogenin, or neurofilament immunoreactivity. A diagnosis of large B cell lymphoma was made.\n\nFigure 4 65-year-old male presented with headache and was later diagnosed with pineal gland lymphoma. (a) Hematoxylin and eosin staining at magnification (40×) demonstrates malignant lymphoma with coarse chromatin, nucleoli (arrow), and mitoses. (b) Diaminobenzidene chromagen at magnification (40×) demonstrates tumor cells (arrow) extensively exhibiting CD20 reactivity. (c) Diaminobenzidene chromagen at magnification (40×) demonstrates tumor cells (arrow) exhibiting extensive CD79a, but no neural, myogenic, or epithelial marker immunoreactivity.\n\nAt the time of biopsy, a ventricular drain was placed. Patient's symptoms resolved and the drain was subsequently removed after trial of clamping. Staging chest, abdomen, and pelvis CT exams revealed no other areas of lymphomatous involvement. The patient was discharged home in stable condition, but presented to the emergency department 1 week later with worsening hydrocephalus and headache. At this time, the patient underwent ventriculoperitoneal shunt placement for management of his hydrocephalus and received one cycle of high-dose methotrexate. However, he developed severe hypotension and acute kidney injury 2 months after his diagnosis and was re-admitted to the hospital, with repeat non-contrast head CT showing enlargement of the mass. Given his multiple medical comorbidities and evidence of disease progression, the patient and his family elected to pursue comfort care measures.\n\nDISCUSSION\nPrimary CNS lymphoma accounts for approximately 6% of all malignant CNS neoplasms.[1] They can affect both immunocompetent and immunocompromised patients, although patients who are immunocompromised typically present at a younger age. There is a predilection for the periventricular white matter and basal ganglia, and they can present as either solitary or multiple mass lesions. Pathologically, most are high-grade B-cell lymphomas.\n\nOn non-contrast CT, most masses are hyperdense, given the high cellularity, and surrounding edema is common. Calcifications and necrosis are considered less common. Contrast enhancement is typically homogeneous, but can have a more variable appearance in immunocompromised patients. On MRI, although these lesions can appear hypointense to gray matter on T1-weighted imaging and hypointense to isointense on T2-weighted imaging, the hallmark is restricted diffusion due to the increased cellularity.[16] Enhancement is typically homogeneous.\n\nPrimary CNS lymphoma has rarely been found to involve the pineal gland, with seven cases reported in the literature. Headache was one of the most common presenting symptoms in these patients, although symptoms include cranial nerve and cauda equina syndrome, focal neurologic deficits, fever, diplopia, altered mental status, and seizure.[7] The average age at diagnosis was 40 years, and only one female patient has been reported. B-cell lymphoma has been the most common pathologic diagnosis, with cases including large B cell lymphoma, malignant B cell lymphoma, immunoblastic lymphoma, and anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK-1 positive ALCL).[7] There has been a single case of malignant T cell lymphoma and one case providing no additional detail to the diagnosis of lymphoma. Imaging features in these cases most commonly included hydrocephalus and relatively homogeneously enhancing lesions identified on MRI.\n\nThe imaging findings in this particular case were typical of highly cellular tumor with leptomeningeal involvement, given the hyperdense mass on non-contrast CT and restricted diffusion with contrast enhancement on MRI. A histologic diagnosis is essential prior to beginning invasive treatment, as the imaging characteristics of pineal lymphoma are not necessarily pathognomonic. Other differential considerations for a tumor in the pineal region with these imaging characteristics include pineoblastoma, germ cell tumor, and metastatic disease. Pineoblastoma is a pediatric diagnosis with masses typically appearing more heterogeneous and with peripheral calcifications. Germ cell tumors are also typically diagnosed at a younger age and are associated with calcification. While metastatic disease may fit the imaging pattern and patient age seen in our case, a primary malignancy was not identified.\n\nOur patient was treated with high-dose methotrexate, which has been shown to increase survival in patients with primary CNS lymphoma. The addition of rituximab to this regimen has also been shown to improve remission rates and progression-free survival; however, our patient decompensated and progressed prior to initiation of this therapy.[8]\n\nCONCLUSION\nPrimary CNS lymphoma is an uncommon primary CNS malignancy, and rarely involves the pineal gland. However, in the appropriate clinical context and with relevant imaging findings, lymphoma should be in the differential diagnosis of a pineal gland mass. Prompt diagnosis and treatment are essential to improve survival in these patients.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAvailable FREE in open access from: http://www.clinicalimagingscience.org/text.asp?2015/5/1/51/166350\n==== Refs\nREFERENCES\n1 Partovi S Karimi S Lyo JK Esmaeili A Tan J Deangelis LM Multimodality imaging of primary CNS lymphoma in immunocompetent patients Br J Radiol 2014 87 20130684 24646184 \n2 Amagasa M Kawase M Sato S Yuda F Spinal malignant lymphoma appearing after radiation and chemotherapy of a pineal region tumor Surg Neurol 1996 45 169 71 \n3 Grimoldi N Tomei G Stankov B Lucini V Masini B Caputo V Neuroendocrine, immunohistochemical, and ultrastructural study of pineal region tumors J Pineal Res 1998 25 147 58 9745983 \n4 Karikari IO Thomas KK Lagoo A Cummings TJ George TM Primary cerebral ALK-1-positive anaplastic large cell lymphoma in a child. Case report and literature review Pediatr Neurosurg 2007 43 516 21 17992044 \n5 Pantanowitz L Freedman SJ Dezube BJ Joseph JT November 2002: A 72-year-old woman with a pineal gland mass Brain Pathol 2003 13 235 6 239 12744478 \n6 Schwingel R Reis F Zanardi V Queiroz L França M Jr Atypical sites of lymphoma in the central nervous system Arq Neuropsiquiatr 2011 69 566 7 21755144 \n7 Yoshida T Tezuka Y Hirosawa T Umeki H Obara H Sueyoshi T Pineal malignant B-cell lymphoma with lower cranial nerve involvement Intern Med 2014 53 1205 8 24881750 \n8 Holdhoff M Ambady P Abdelaziz A Sarai G Bonekamp D Blakeley J High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma Neurology 2014 83 235 9 24928128\n\n",
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"keywords": "Lymphoma; hydrocephalus; pineal gland",
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"title": "Pineal Gland Lymphoma: Case Report and Literature Review.",
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"abstract": "BACKGROUND\nCardiac dysrhythmias, other than sinus tachycardia, rarely occur with salicylate poisoning. When dysrhythmias do occur, they are typically a terminal event.\n\n\nMETHODS\nA 45-year-old woman presented an unknown amount of time after an intentional ingestion of aspirin and acetaminophen. On presentation her vital signs were T 39 degrees C, P 125 beats/minute, R 26 breaths/minute, and BP 153/79 mmHg. She was initially obtunded, but minutes after presentation had a generalized tonic-clonic seizure lasting approximately two minutes, which ceased after 2 mg of intravenous lorazepam. She was sedated, intubated and treated with sodium bicarbonate. Her peak salicylate concentration was 152 mg/dL. Her course was complicated by seizures and dysrhythmias, including monomorphic ventricular tachycardia and Torsades de Pointes. With bicarbonate therapy, hemodialysis, and veno-venous hemofiltration, she survived neurologically intact.\n\n\nCONCLUSIONS\nThe etiology of these dysrhythmias is likely multifactorial. Metabolic derangements typically encountered with severe salicylism, including insensible water losses, respiratory alkalosis, and metabolic acidosis, may contribute. Iatrogenic causes, especially sodium bicarbonate therapy, may cause hypokalemia, hypocalcemia, and hypomagnesemia. Additionally, animal data suggests that high salicylate concentrations may have direct deleterious effects on the electrophysiology of cardiac cells, specifically by its action on the SA node and on the action potential of atria and Purkinje fibers.\n\n\nCONCLUSIONS\nNon-fatal ventricular dysrhythmias associated with salicylate toxicity are rare in patients who survive. The causes of dysrhythmias in salicylate may include electrolyte abnormalities and a direct effect of salicylate on myocardial membrane permeability.",
"affiliations": "University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.",
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"chemical_list": "D014151:Anti-Anxiety Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen; D008140:Lorazepam; D001241:Aspirin",
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"mesh_terms": "D000082:Acetaminophen; D014151:Anti-Anxiety Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001145:Arrhythmias, Cardiac; D001241:Aspirin; D005260:Female; D006440:Hemofiltration; D006801:Humans; D008140:Lorazepam; D008875:Middle Aged; D013406:Suicide, Attempted; D016896:Treatment Outcome; D018754:Ventricular Dysfunction",
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"title": "Non-fatal ventricular dysrhythmias associated with severe salicylate toxicity.",
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"abstract": "OBJECTIVE\nTo investigate the developmental effects of clozapine and other atypical antipsychotics on infants who were exposed to as fetus.\n\n\nMETHODS\nThe developmental progress of 33 infants who were exposed to clozapine as fetus was compared to 30 infants who were exposed to risperidone, olanzapine or quetiapine as fetus by assessing Apgar scoring, birth weight at birth, body weight, height, and the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at months 2, 6 and 12 of age. Five subscale scores of BSID-III including cognitive, language, motor, social-emotional, and adaptive behavior were also compared. Student's t test and Chi-square analysis were used as appropriate. Repeated measurements were evaluated by analysis of covariance.\n\n\nRESULTS\nOf the 63 infants, 58 (92.1%) completed a 12-month study period. At the age of 2 and 6 months, mean adaptive behavior scores of BSID-III were significantly lower in clozapine-exposed infants than infants who exposed to other atypical antipsychotic at 2 and 6 months of age. More clozapine-exposed infants had delayed development (defined as the subscale score of <85) for adaptive behavior at 2 and 6 months of age. There was no difference between the two groups for cognitive, language, motor, social and emotional at 2, 6 and 12 months of age. More infants who were exposed to clozapine as fetus (25 of 33, 75.8%) had disturbed sleep and a labile state than those who were exposed to other atypical antipsychotics (8 of 30, 26.7%) during 2 months of age (P<0.001).\n\n\nCONCLUSIONS\nThese results suggest that clozapine has more adaptive behavior effects on infants who were exposed to as a fetus than other atypical antipsychotics at 2 and 6 months of age.\n\n\nBACKGROUND\nClinicalTrials.gov NCT01479400.",
"affiliations": "Institute of Mental Health of The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road, Changsha 410011, Hunan, P.R. China; Brains Hospital of Hunan Province, 427# Renmin Middle Road (3 Duan), Changsha 410007, Hunan, P.R. China.;Institute of Mental Health of The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road, Changsha 410011, Hunan, P.R. China.;Department of Obstetrical of The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road,Changsha 410011, Hunan, P.R. China.;Institute of Mental Health of The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road, Changsha 410011, Hunan, P.R. China.;Institute of Mental Health of The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road, Changsha 410011, Hunan, P.R. China.;Institute of Mental Health of The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road, Changsha 410011, Hunan, P.R. China.",
"authors": "Shao|Ping|P|;Ou|Jianjun|J|;Peng|Mei|M|;Zhao|Jingping|J|;Chen|Jindong|J|;Wu|Renrong|R|",
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"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2590951310.1371/journal.pone.0123373PONE-D-14-25925Research ArticleEffects of Clozapine and other Atypical Antipsychotics on Infants Development Who Were Exposed to as Fetus: A Post-Hoc Analysis Antipsychotics and Infant-DevelopmentShao Ping \n1\n\n2\nOu Jianjun \n1\nPeng Mei \n3\nZhao Jingping \n1\nChen Jindong \n1\n*Wu Renrong \n1\n*\n1 \nInstitute of Mental Health of The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road, Changsha 410011, Hunan, P.R. China\n\n2 \nBrains Hospital of Hunan Province, 427# Renmin Middle Road (3 Duan), Changsha 410007, Hunan, P.R. China\n\n3 \nDepartment of Obstetrical of The Second Xiangya Hospital, Central South University, 139# Renmin Middle Road,Changsha 410011, Hunan, P.R. China\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: RW JZ JC. Performed the experiments: PS JO MP. Analyzed the data: RW JO. Contributed reagents/materials/analysis tools: PS JO. Wrote the paper: PS.\n\n* E-mail: wurenrong2013@163.com (RRW); chenjd269@163.com (JDC)24 4 2015 2015 10 4 e01233732 8 2014 23 2 2015 © 2015 Shao et al2015Shao 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.Objective\nTo investigate the developmental effects of clozapine and other atypical antipsychotics on infants who were exposed to as fetus.\n\nMethod\nThe developmental progress of 33 infants who were exposed to clozapine as fetus was compared to 30 infants who were exposed to risperidone, olanzapine or quetiapine as fetus by assessing Apgar scoring, birth weight at birth, body weight, height, and the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at months 2, 6 and 12 of age. Five subscale scores of BSID-III including cognitive, language, motor, social-emotional, and adaptive behavior were also compared. Student’s t test and Chi-square analysis were used as appropriate. Repeated measurements were evaluated by analysis of covariance.\n\nResults\nOf the 63 infants, 58 (92.1%) completed a 12-month study period. At the age of 2 and 6 months, mean adaptive behavior scores of BSID-III were significantly lower in clozapine-exposed infants than infants who exposed to other atypical antipsychotic at 2 and 6 months of age. More clozapine-exposed infants had delayed development (defined as the subscale score of <85) for adaptive behavior at 2 and 6 months of age. There was no difference between the two groups for cognitive, language, motor, social and emotional at 2, 6 and 12 months of age. More infants who were exposed to clozapine as fetus (25 of 33, 75.8%) had disturbed sleep and a labile state than those who were exposed to other atypical antipsychotics (8 of 30, 26.7%) during 2 months of age (P<0.001).\n\nConclusion\nThese results suggest that clozapine has more adaptive behavior effects on infants who were exposed to as a fetus than other atypical antipsychotics at 2 and 6 months of age.\n\nTrial Registration\nClinicalTrials.gov NCT01479400\n\n\nThis work was supported by the National Natural Science Foundation of China (Grant No.81371481 to RRW). The funder 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. Additional data are available upon request to Ren-Rong Wu (wurenrong2013@163.com), Institute of Mental Health of The Second Xiangya Hospital, Central South University.Data Availability\nAll relevant data are within the paper. Additional data are available upon request to Ren-Rong Wu (wurenrong2013@163.com), Institute of Mental Health of The Second Xiangya Hospital, Central South University.\n==== Body\nIntroduction\nFemale reproductive health safety and the development effect of antipsychotics on fetus has become a growing focus of concern for women who need antipsychotic treatments during their reproductive years. Majority schizophrenia women need antipsychotic treatment during the pregnancy, because non-adherence to antipsychotic treatments in patients with schizophrenia can cause relapse and poor treatment response [1–2]. It is well known that the consequence of relapse may increase personal suffering and family and societal burden [2–4].\n\nClozapine is very popularly used for female patients with schizophrenia in China. Usually, it is suggested that pregnant women who require treatment with clozapine should switch to one of other atypical antipsychotics because the newer atypical antipsychotics do not have some of the side effects of clozapine. But, some patients do not respond to treatment with other atypical antipsychotics. However, there is sparse data on the reproductive safety of the currently available newer compounds. Up to now, most information about atypical antipsychotics on reproductive safety and the effects on infant development come from case reports, case series, and retrospective studies [5–7]. Very few studies compared the difference effects on infants’ development for clozapine and other atypical antipsychotics.\n\nSo, there is urgent need of longitudinal prospective studies to assess the effects using atypical antipsychotics during pregnancy on infant’s development, especially neurodevelopment. Because, the prospective study was undertaken to evaluate the effect of clozapine and other atypical antipsychotics on infant development including neurobehavioral development after mothers were treated with atypical antipsychotics throughout their pregnancy. The progress of neurobehavioral development was evaluated by the Bayley Scales of Infant Development (BSID), third edition (Bayley-III) [8], a widely used measure to determine infant developmental delay. This scale has the potential to provide more clinically useful information relating to early development.\n\nThe aim of this post-hoc investigation was to assess the developmental effects of clozapine and other atypical antipsychotics on infants who were exposed to as fetus.\n\nMethods\nThis study used data from our original prospective, case-controlled study of effects of prenatal exposure to atypical antipsychotics on postnatal development, which was conducted between October 2007 and December 2010.\n\nParticipants\nSchizophrenia women with singleton pregnancies at more than 38 weeks’ were approached by study research assistants to inquire whether they could participate in the study when they gave birth in the department of obstetrical/gynecology of the Second Xiangya Hospital, Central South University, China, between October 2007 and December 2010. They were given information about the study, and if they agree to participate, they needed provide written informed consent. All enrolled pregnancy women completed a detailed questionnaire with questions regarding demographic characteristics, history of antipsychotic treatment and pregnancy outcomes which were gotten from participants, family members and medical records.\n\nWomen were assessed for schizophrenia by using the Structured Clinical Interview of DSM-IV Axis I Disorders [9], Clinical Version and were diagnosed in accordance with criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) [10] during screening. Women who were identified as schizophrenia and having taking a targeted antipsychotic agent- clozapine, olanzapine, risperidone, or quetiapine alone throughout the pregnancy were recruited to be the exposed group. All expectant mothers were excluded from the study if they had evidence of liver or renal dysfunction, diabetes mellitus or cardiovascular diseases during their pregnancy.\n\nThe study was approved by the ethics committee of the Second Xiangya Hospital, and all participants provided written informed consent in accordance with National Health and Medical Research Council guidelines.\n\nMeasures\nAll infants were followed for 12 months after birth. Baseline assessments included demographics and a comprehensive medical history for the mother and the birth weight, height and Apgar score at 1 and 5 minutes after birth [11] for the newborn. The assessment of infant development included body weight, height, and neurobehavioral development measurements at 2, 6 and 12 months of age.\n\nThe Bayley-III including cognitive, language, motor, social-emotional, and adaptive-behavior domains may discriminate specific development deficits caused by antipsychotics. The cognitive scale evaluates abilities, such as sensorimotor development, exploration and manipulation, object relatedness, concept formation, memory, and simple problem solving. The language scale is a composite of receptive communication (verbal comprehension, vocabulary) and expressive communication (babbling, gesturing, and utterances), and the motor scale evaluates both gross and fine motor functioning.\n\nThe Bayley-III was assessed by one psychologist who is blind to the status of the child. Parent-report questionnaires were incorporated into the Bayley-III to assess social-emotional and adaptive behavior. The raw scores for each of the scales were standardized to a mean of 100 with an SD of 15 (range, 50–150). The standardized scores were also classified into the categories of accelerated performance (>115), within normal limits (85–115), and delayed performance (<85).\n\nThe primary outcome was the difference of cognitive score between the infants who exposed to clozapine or other atypical antipsychotics. The major secondary outcomes included the differences of birth weight, height, and the percentage of developmental delay and scores of language, motor, social-emotional, adaptive-behavior between the two groups.\n\nStatistical Analysis\nAll analyses were conducted using the Statistical Package for Social Sciences, version 11.5 (SPSS Inc, Chicago, Illinois). Continuous variables were described by summary statistics such as means and standard deviations. Categorical variables were described by using frequencies and percentages. Student’s t test and Chi-square analysis were used as appropriate to evaluate between-group differences in baseline characteristics and changes in the scale scores from baseline to endpoint. The main strategy involved analysis of covariance (ANCOVA) with repeated measurements with corresponding baseline values as covariates. Analyses designed to compare groups were performed for all enrolled infants (Intent-To-Treat (ITT) analyses using the last observation carried forward method for missing data). The difference was considered statistically significant if a 2-tailed p value was less than 0.05.\n\nResults\nMaternal characteristics and pregnancy outcomes\nAs shown in Table 1, 63 newborns enrolled in this study. No infant had malformation. For all infants’ mothers, they received the treatment of clozapine (n = 33), risperidone (n = 16), olanzapine (n = 8), and quetiapine (n = 6) alone without using any benzodiazepines and mood stabilizers during the pregnancy. The duration of their illness and antipsychotic treatment before pregnancy were significantly longer in the clozapine group than the other atypical antipsychotic group (3.8 vs. 2.7 years and 2.8 vs. 1.9 years, P<0.001, respectively). Moreover, 54.5% of clozapine women had a BMI>23.9kg/m2 (the normal range, 18.5–23.9 Moreover, 54.5% of clozapine women had a BMI>23.9kg/m2 (the normal range, 18.5–23.9 kg/m2), compared with 26.7% of the other atypical antipsychotic women in pre-pregnancy (P = 0.025).\n\n10.1371/journal.pone.0123373.t001Table 1 Comparison of maternal characteristics and pregnancy outcomes between clozapine group and other atypical antipsychotics group.\nCharacteristic\tClozapine group (n = 33)\tOther atypical antipsychotics group (n = 30)\tTest statistics\t\nP value\t\nAge, mean (SD), y\t31.5 (4.9)\t29.8 (3.7)\t1.654\t0.078\t\nGestational age at birth, mean (SD), week\t39.0 (0.5)\t38.9 (0.5)\t0.795\t0.430\t\nDuration of illness, mean (SD), y\t3.8 (0.8)\t2.7 (1.0)\t4.964\t<0.001\t\nDuration of antipsychotic treatment, mean (SD), y\t2.8 (0.7)\t1.9 (0.6)\t5.012\t<0.001\t\nSmoking during pregnancy\t1 (3.0)\t1 (3.3)\t0.005\t0.945\t\nUnplanned pregnancy, n (%)\t18 (54.5)\t15 (50.0)\t0.130\t0.718\t\nNo take vitamin or folic acid during pregnancy, n (%)\t8 (24.2)\t7 (23.3)\t0.007\t0.933\t\nLiving arrangements, n (%)\t\t\t1.861\t0.394\t\n Married\t29 (87.9)\t29(96.7)\t\t\t\n Single\t1(3.9)\t0 (0)\t\t\t\n Divorced\t3 (7.9)\t1 (3.3)\t\t\t\nOccupation, n (%)\t\t\t2.170\t0.538\t\n Homemaker\t12 (36.4)\t10 (33.3)\t\t\t\n Work part-time\t2 (6.1)\t3(10.0)\t\t\t\n Work full-time\t3 (9.1)\t6 (20.0)\t\t\t\n unemployed\t16 (48.5)\t11 (36.7)\t\t\t\nBody mass index >23.9 (pre-pregnancy), n (%)\t18 (54.5)\t8 (26.7)\t5.039\t0.025\t\nDiabetes during pregnancy, n (%)\t2 (6.1)\t1 (3.3)\t0.258\t0.612\t\nHypertension during pregnancy, n (%)\t2 (6.1)\t1 (3.3)\t0.258\t0.612\t\nBreast feeding more than one month, n (%)\t5 (15.2)\t5(16.7)\t0.027\t0.869\t\nInfant male sex\t16 (48.5)\t15 (50.0)\t0.014\t0.904\t\nFive (7.9%) mothers (3 taking clozapine, 1 taking risperidone, and 1 taking quetiapine) relapsed, and the rest were stable during the pregnancy. Only 10 mothers breastfed their infants more than one month. For the 10 breast-feeding mothers, 5 mothers took clozapine, 2 took quetiapine, 2 took olanzapine and 1 took risperidone. There were no statistical differences in other maternal characteristics such as the mean gestational age at birth, complications during delivery and the rates of neonatal complications et al. between the two groups (Table 1). The mean dosage of clozapine, risperidone, olanzapine and quetiapine were 178.03mg, 2.06mg, 7.81mg and 550.00 mg, respectively (Table 2). The medication adherence was defined as having taken more than 80% of the study drug dose prescribed for that period. In this study 93% of mothers in both groups took 80% or more of their medications without difference between the two groups throughout the pregnancy.\n\n10.1371/journal.pone.0123373.t002Table 2 The information for antipsychotics using.\nAntipsychotics\tMinimum dosage (mg)\tMaximum dosage (mg)\tMean (mg)\tSD (mg)\t\nClozapine (n = 33)\t75.00\t450.00\t178.03\t70.37\t\nRisperidone (n = 16)\t1.00\t4.00\t2.06\t0.85\t\nOlanzapine (n = 8)\t5.0\t10.00\t7.81\t2.48\t\nQuetiapine (n = 6)\t400.00\t600.00\t550.00\t83.67\t\nInfant developments between the two groups\nOf the 63 infants, all were assessed at birth and at 2 months of age, 60 infants at 6 months of age and 58 infants at 12 months of age. The ratio of female and male infant gender was not significantly different between the two groups.\n\nWeight and height development\nAs shown in Table 3, there were not significant differences between the two groups in the Apgar score at 5 minutes after birth, the percentage of low birth weight (less than 2.5kg), as well as the weight and height at birth, 2, 6, and 12 months of age. However, the the Apgar score at 1 minutes was higher in the clozapine group than the other atypical antipsychotic group (8.6 vs. 8.3, p = 0.030).\n\n10.1371/journal.pone.0123373.t003Table 3 The infants developments between clozapine and other atypical antipsychotic groups\na\n.\nVariables\tClozapine group (n = 33)\tOther atypical antipsychotics group (n = 30)\tTest statistics\t\nP value\t\n Birth weight, kg\t3.2 (0.7)\t3.3 (0.6)\t0.831\t0.409\t\n Low birth weight, n (%)\t3 (9.0)\t5 (16.7)\t0.814\t0.367\t\n Birth height, cm\t51.2 (0.8)\t50.8 (1.1)\t1.312\t0.195\t\n Apgar Scoring at 1 minute\t8.6 (0.5)\t8.3 (0.6)\t2.222\t0.030\t\n Apgar Scoring at 5 minute\t9.6 (0.5)\t9.4 (0.5)\t1.370\t0.176\t\n2 months of age\t\t\t\t\t\n Weight, kg\t5.3 (0.7)\t5.0 (0.6)\t1.750\t0.085\t\n Height, cm\t59.1 (1.1)\t58.6 (1.4)\t1.565\t0.123\t\n Cognitive scale\t89.8 (5.1)\t90.6 (7.7)\t0.438\t0.663\t\n Language scale\t93.4 (6.7)\t94.8 (8.3)\t0.743\t0.460\t\n Motor scale\t90.8 (5.9)\t90.0 (5.3)\t0.542\t0.590\t\n Social-emotional scale\t95.7 (10.0)\t95.0 (9.1)\t0.288\t0.774\t\n Adaptive behavior scale\t89.1 (8.9)\t96.3 (7.6)\t3.419\t0.001\t\n6 months of age\t\t\t\t\t\n Weight, kg\t8.0 (0.9)\t7.9 (0.5)\t0.165\t0.869\t\n Height, cm\t67.5 (2.2)\t67.3 (2.3)\t0.382\t0.704\t\n Cognitive scale\t98.2 (8.0)\t98.7 (9.3)\t0.209\t0.835\t\n Language scale\t95.0 (5.3)\t95.8 (8.2)\t0.446\t0.657\t\n Motor scale\t99.5 (7.9)\t102.2 (9.3)\t1.248\t0.217\t\n Social-emotional scale\t100.2 (10.1)\t99.0 (10.3)\t0.472\t0.638\t\n Adaptive behavior scale\t94.8 (9.9)\t100.5 (6.8)\t2.613\t0.011\t\n12 months of age\t\t\t\t\t\n Weight, kg\t10.0 (0.8)\t10.1 (0.6)\t0.241\t0.810\t\n Height, cm\t74.8 (2.2)\t75.5 (2.6)\t1.125\t0.265\t\n Cognitive scale\t100.7 (8.5)\t100.2 (7.3)\t0.295\t0.769\t\n Language scale\t97.4 (6.3)\t96.4 (6.5)\t0.616\t0.540\t\n Motor scale\t101.7 (8.1)\t100.9 (7.9)\t0.380\t0.705\t\n Social-emotional scale\t102.0 (8.5)\t102.1 (10.9)\t0.027\t0.979\t\n Adaptive behavior scale\t98.3 (9.4)\t96.3 (7.6)\t0.372\t0.712\t\n\naData are expressed as mean (SD).\n\nNeurobehavioral development of the two groups\nMean adaptive-behavior scores of Bayley-III were lower in the clozapine group than the other atypical antipsychotic group at 2 and 6 months of age, but this difference disappeared at 12 months of age. At 2, 6 and 12 months of age, mean scores of Bayley-III cognitive, motor, social-emotional and language scales did not differ between the two groups (Table 3).\n\nMore exposed clozapine infants met the criteria for delayed development (score was <85) in the adaptive-behavior domain compared with those in the other atypical antipsychotic group at 2 and 6 months of age, and this difference disappeared at 12 months of age (Table 4). However, the delayed development percentage of cognitive, language, motor and social-emotional did not differ between the two groups at 2, 6 and 12 months of age (Table 4).\n\n10.1371/journal.pone.0123373.t004Table 4 The proportion of infants with delayed development defined as below 85 standard scores of the Bayley-III in infants who have fetal exposure to clozapine versus those in other atypical antipsychotics group\na\n.\nVariables\tClozapine group (n = 33)\tOther atypical antipsychotics group (n = 30)\tTest statistics\t\nP value\t\nCognitive scale\t\t\t\t\t\n2 months of age\t6 (18.2)\t5 (16.7)\t0.025\t0.874\t\n6 months of age\t4 (12.1)\t3 (10.0)\t0.072\t0.789\t\n12 months of age\t4 (12.1)\t2 (6.7)\t0.543\t0.461\t\nLanguage scale\t\t\t\t\t\n2 months of age\t6 (18.2)\t4 (13.3)\t0.277\t0.599\t\n6 months of age\t4 (12.1)\t4 (13.3)\t0.021\t0.885\t\n12 months of age\t4 (12.1)\t4 (13.3)\t0.021\t0.885\t\nMotor sacle\t\t\t\t\t\n2 months of age\t7 (21.2)\t5 (16.7)\t0.211\t0.646\t\n6 months of age\t4 (12.1)\t3 (10.0)\t0.072\t0.789\t\n12 months of age\t3 (9.1)\t3 (10.0)\t0.015\t0.902\t\nSocial-emotional scale\t\t\t\t\t\n2 months of age\t6 (18.2)\t7 (23.3)\t0.255\t0.614\t\n6 months of age\t6 (18.2)\t6 (20.0)\t0.034\t0.854\t\n12 months of age\t4 (12.1)\t5 (16.7)\t0.265\t0.607\t\nAdaptive scale\t\t\t\t\t\n2 months of age\t18 (54.5)\t5 (16.7)\t9.727\t0.002\t\n6 months of age\t10 (30.3)\t3 (10.0)\t3.955\t0.047\t\n12 months of age\t7 (21.2)\t2 (6.7)\t2.715\t0.099\t\n\naData was expressed as No. (%)\n\nMore clozapine-exposed infants (25 of 33, 75.8%) had disturbed sleep and labile state (depending on parents’ reports) than infants who were exposed to other atypical antipsychotics during 2 months of age (8 of 30, 26.7%) (χ2 = 15.182, P<0.001). However, the 5 breast feeding infants who were exposed to clozapine were stable and had regular living during 2 months of age. At 6 and 12 months of age, there were not any differences in disturbed sleep and labile state between the two groups.\n\nDiscussion\nIn this longest perspective study for the effects of clozapine and other atypical antipsychotics on infant’s neurodevelopment, we found that more infants who exposed to clozapine as fetus had adaptive-behavior development delay at 2 and 6 months of age than those exposed to other atypical antipsychotics. Meanwhile, infants exposed to clozapine had more disturbed sleep and labile state at 2 months of age. But all these differences disappeared after 6 months of age. These findings indicated that clozapine should have more effects on the infant’s adaptive-behavior development and these effects will not last for more than 6 months of age.\n\nOur results were consistent with some case reports and few studies [8, 12], but not others [5–7]. Mendhekar [13] reported that an infant had delayed speech acquisition until 5 years old when the mother was taking clozapine during pregnancy and breast feeding period, but in our study we did not find any difference for language development between the two groups. Also many case reports indicate that there are not any developmental problems for infants exposed to antipsychotics during pregnancy. The inconsistency might be due to the methodology used for case reports. No case reports had used a standard measurement for assessing infants’ development like Bayley-III. All previous case studies depend on parents’ reports. Our results showed that the structure of the new Bayley-III had the potential to provide more clinically useful information relating to early development, improving our capacity to discriminate specific developmental problems and helping to target early intervention programs to more specific areas of weakness, and may be a more sensitive outcome measure for clinical trials [14–15].\n\nMeanwhile, for these infants who were exposed to clozapine as fetus, in this post-hoc analysis we found 5 breast feeding infants who were exposed to clozapine were more stable and had regular living than those without breast feeding.These findings should be related with clozapine withdrawal syndrome. The 5 breast feeding infants have not clozapine withdrawal syndrome as clozapine can be in the breast milk. Case report has found that clozapine may induce withdrawal syndromes and newborns withdrawal of clozapine can increase the risk of convulsive and hypotonia [16]. Althouigh we did not find the withdrawal syndromes for other antipsychotics. Gilad O et al [17] reported that 10% of newborns that had withdrawal of olanzapine had withdrawal symptoms. So, we recommend that the pregnant women taking clozapine should decrease their dosage of clozapine in the last two months of pregnancy to prevent withdrawal syndrome in the infants. In terms of breast feeding, no conclusions can be drawn about the risk/benefit profile of the majority of antipsychotics in breast-feeding. In general, clozapine and olanzapine should be avoided during breast-feeding, because clozapine should be considered contraindicated for its liability of inducing potential life-threatening events in the infant, and olanzapine seems to be associated with an increased risk of inducing extrapyramidal reactions in the breast-fed babies [18]. Conversely, in patients who need to continue antipsychotic therapy during breast-feeding, it is suitable to maintain the previous pharmacologic regimen, if known to be effective.\n\nThe response of the mother and fetus/neonate to antipsychotics is determined by the distribution and elimination of the antipsychotic within and between the mother and fetus. All psychotropic medications diffuse across the placenta, which exposes the fetus to some degree of risk [19]. Newport et al [20] found that olanzapine has high placental passage ratio, and followed by haloperidol, risperidone, and quetiapine. It has been shown that neonates who are exposed to olanzapine had higher tendencies to have low birth weight and admission to the neonatal intensive care unit. However, we did not find more olanzpine exposed infants had low birth weight. But we found that more clozapine exposed schizophrenic mothers had a body mass index >23.9 kg/m2, and longer duration of illness and antipsychotic treatment than those exposed to other atypical antipsychotics. These should be related to weight gain induced by clozapine. Moreover, clozapine is very popularly prescribed for chronic schizophrenia patients in China.\n\nThe antipsychotic dosages of mothers were lower than acute schizophrenic patients, but the same as stable patients. The choice of antipsychotic dosage should be based on the general effectiveness profile of each agent. In pregnancy, physiological changes may result in reduced plasma protein binding, an increase in the apparent volume of distribution, and more rapid metabolic and renal clearance of certain drugs [20]. Therefore the dosages of antipsychotics may need to be altered during pregnancy. We think it should be better to supervise the serum concentration of antipsychotics and change the dosage depending on the serum concentration.\n\nAs we have reported [21], when compared to control participants, the delayed neurodevelopment appeared to be short-term, suggesting that the potential “harmful” effects of atypical antipsychotics on infant’s development are in the first 12 months of life.\n\nThe study has some limitations and the first is that the sample size was small. Therefore, the data might be not representative. We only reported the neurodevelopment of 63 infants who were exposed to antipsychotics throughout their mothers’ pregnancy and it gives some evidences for clinicians when they weigh the risks and benefits of continuous antipsychotics treatment for pregnant schizophrenia women. Second, we have not evaluated the antipsychotic concentration of the placenta. So we do not know the relationship between the antipsychotic concentration and the delayed neurodevelopment of infants. Third, we only observed the neurodevelopment at 12 months of age in infants, and do not know about the neurodevelopment of infants after 1 years old. Fourth, we did not evaluate the difference between infants who were experienced fetal-exposure to antipsychotics and control infants who were not fetal-exposure to antipsychotics. Lastly, in the study we cannot find the effect of antipsychotic on the early pregnancy outcomes such as abortion. In the future, we will do some prospective studies to examine the effect of antipsychotics on pregnancy outcomes and neonatal development. 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The cost of relapse in patients with schizophrenia in the European SOHO (Schizophrenia Outpatient Health Outcomes) study . Prog Neuropsychopharmacol Biol Psychiatry \n2009 (5); 33 : 835 –841 . 10.1016/j.pnpbp.2009.03.034 \n19351551 \n5 \nDuran A , Ugur MM , Turan S , Emul M . Clozapine use in two women with schizophrenia during pregnancy . J Psychopharmacol \n2008 ; 22 (1 ):111 –113 . 10.1177/0269881107079171 \n18187538 \n6 \nGupta N , Grover S . Safety of clozapine in 2 successive pregnancies . Can J Psychiatry \n2004 ; 49 (12 ):863 \n15679212 \n7 \nLin HC , Chen IJ , Chen YH , Lee HC , Wu FJ . Maternal schizophrenia and pregnancy outcome: does the use of antipsychotics make a difference? \nSchizophr Res \n2010 ; 116 (1 ): 55 –60 . 10.1016/j.schres.2009.10.011 \n19896335 \n8 \nBayley N. \nBayley Scales of Infant and Toddler Development , Third Edition \nSan Antonio, TX : Psychological Corporation ; 2005 .\n9 \nFirst MB , Spitzer RL , Gibbon M: Structured Clinical Interview for DSM-IV Axis I Disorders- Clinician Version (SCID-CV) . Washington, DC : American Psychiatry Press ; 1997 \n\n10 \nAmerican Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders (4th ed ). Washington, DC : American Psychiatric Association ; 1994 \n\n11 \nGentile S . Infant safety with antipsychotic therapy in breast-feeding: a systematic review . J Clin Psychiatry \n2008 ; 69 (4 ):666 –673 .\n18370569 \n12 \nMcKenna K , Koren G , Tetelbaum M , Wilton L , Shakir S , Diav-Citrin O , et al\nPregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study . J Clin Psychiatry \n2005 ; 66 (4 ):444 –49 ; quiz 546.\n15816786 \n13 \nMendhekar DN . Possible delayed speech acquisition with clozapine therapy during pregnancy and lactation . J Neuropsychiatry Clin Neurosci \n2007 ; 19 (2 ):196 –197 .\n17431071 \n14 \nMsall ME . Measuring outcomes after extreme prematurity with the Bayley-III Scales of infant and toddler development: a cautionary tale from Australia . Arch Pediatr Adolesc Med \n2010 ; 164 (4 ):391 –393 . 10.1001/archpediatrics.2010.25 \n20368495 \n15 \nRobertson CM , Hendson L , Biggs WS , Acton BV . Application of the Flynn effect for the Bayley III Scales . Arch Pediatr Adolesc Med \n2010 ; 164 (11 ):1072 –1073 . 10.1001/archpediatrics.2010.199 \n21041604 \n16 \nNguyen HN , Lalonde P . Clozapine and pregnancy . Encephale \n2003 ; 29 (2 ):119 –124 .\n14567163 \n17 \nGilad O , Merlob P , Stahl B , Klinger G . Outcome of infants exposed to olanzapine during breastfeeding .Breastfeed Med \n2011 ; 6 (2 ):55 –58 . 10.1089/bfm.2010.0027 \n21034242 \n18 \nMucklow JC . The fate of drugs in pregnancy . Clin Obstet Gynaecol \n1986 ; 13 (2 ):161 –175 .\n3731662 \n19 \nAnderson GD . Pregnancy-induced changes in pharmacokinetics: a mechanistic- based approach . Clin Pharmacokinet \n2005 ; 44 (10 ): 989 –1008 .\n16176115 \n20 \nNewport DJ , Calamaras MR , DeVane CL , Donovan J , Beach AJ , Winn S , et al\nAtypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes . Am J Psychiatry \n2007 ; 164 (8 ):1214 –1220 .\n17671284 \n21 \nPeng M , Gao K , Ding Y , Ou J , Calabrese JR , Wu R , et al\nEffects of prenatal exposure to atypical antipsychotics on postnatal development and growth of infants: a case-controlled, prospective study . Psychopharmacology (Berl) . 2013 \n8 ;228 (4 ):577 –84 . 10.1007/s00213-013-3060-6 \n23559219\n\n",
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"journal": "PloS one",
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"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001827:Body Height; D001835:Body Weight; D002657:Child Development; D003024:Clozapine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018811:Maternal Exposure; D011247:Pregnancy; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors",
"nlm_unique_id": "101285081",
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"pages": "e0123373",
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"pmid": "25909513",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Effects of Clozapine and other Atypical Antipsychotics on Infants Development Who Were Exposed to as Fetus: A Post-Hoc Analysis.",
"title_normalized": "effects of clozapine and other atypical antipsychotics on infants development who were exposed to as fetus a post hoc analysis"
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"abstract": "Anti-tumor necrosis factor alpha (anti-TNF-a) therapy has been widely used for the management of rheumatologic diseases. The most frequent adverse effects of anti-TNF-a therapy are infections and malignancies while sarcoidosis is a rare condition. On the other hand, anti-TNF-a therapy has been used in the treatment of sarcoidosis. Elucidation of this paradoxical issue is unclear. In this article, we report an ankylosing spondylitis patient who was diagnosed as sarcoidosis during the period of etanercept usage. Sarcoidosis as a possible adverse effect should be kept in mind during anti-TNF-a therapy.",
"affiliations": "Department of Rheumatology, Muğla Sıtkı Koçman University, Education And Research Hospital, Muğla, Turkey.;Department of Physical Medicine and Rehabilitation, Medical Faculty of Gazi University, Ankara, Turkey.",
"authors": "Mengi|Gönen|G|;Göğüş|Feride|F|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5606/ArchRheumatol.2017.6055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2148-5046",
"issue": "32(1)",
"journal": "Archives of rheumatology",
"keywords": "Adverse effect; anti-tumor necrosis factor alpha therapy; sarcoidosis",
"medline_ta": "Arch Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101639000",
"other_id": null,
"pages": "67-70",
"pmc": null,
"pmid": "30375550",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports",
"references": "25948363;20001207;25097790;24346918;12853521;18520114;26799429;19423648;17013853;20638761;24325385;25488782",
"title": "A Rare Adverse Effect of Anti-Tumor Necrosis Factor Alpha Therapy: Sarcoidosis.",
"title_normalized": "a rare adverse effect of anti tumor necrosis factor alpha therapy sarcoidosis"
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"activesubstance": {
"activesubstancename": "ETANERCEPT"
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{
"abstract": "We conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database on spontaneously reported adverse events to evaluate the association between anticancer drug therapy and hepatitis B infection. Reports of hepatitis B infection were retrieved from the FAERS database. The reporting odds ratio (ROR) was used to estimate the association between hepatitis B infection and various anticancer agents and drug combinations. We detected statistically significant risk signals of hepatitis B for 33 of 64 anticancer agents by ROR (26 cytotoxicity drugs and seven molecular-targeted drugs). We focused on molecular-targeted drugs and assessed the risk of hepatitis B from specific anticancer drug combinations. The frequency of hepatitis B infection was significantly high for drugs such as rituximab, bortezomib, imatinib, and everolimus. The addition of cyclophosphamide, doxorubicin, and fludarabine to drug combinations additively enhanced the frequency of hepatitis B infection. There were no reports on hepatitis B infection associated with trastuzumab or azacitidine monotherapy. However, trastuzumab-containing regimens (e.g., combinations with docetaxel or paclitaxel) were correlated with the incidence of hepatitis B infection, similar to azacitidine monotherapy. Our findings suggest that the concomitant use of anticancer drugs, such as trastuzumab, taxane, and azacitidine, may contribute to the risk of hepatitis B infection. The unique signals detected from the public database might provide clues to eliminate the threat of HBV in oncology.",
"affiliations": "Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan.;Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.;Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.;Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.;Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan.;Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.;Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.;Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.;Department of Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.;Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan.",
"authors": "Sanagawa|Akimasa|A|0000-0002-5168-3011;Hotta|Yuji|Y|0000-0002-9474-7775;Kataoka|Tomoya|T|;Maeda|Yasuhiro|Y|;Kondo|Masahiro|M|;Kawade|Yoshihiro|Y|;Ogawa|Yoshihiro|Y|;Nishikawa|Ryohei|R|;Tohkin|Masahiro|M|0000-0002-2937-8926;Kimura|Kazunori|K|0000-0002-2473-4776",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.1429",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 2966372910.1002/cam4.1429CAM41429Original ResearchClinical Cancer ResearchOriginal ResearchHepatitis B infection reported with cancer chemotherapy: analyzing the US FDA Adverse Event Reporting System A. Sanagawa et al.Sanagawa Akimasa http://orcid.org/0000-0002-5168-3011\n1\n\n2\nHotta Yuji http://orcid.org/0000-0002-9474-7775\n2\nKataoka Tomoya \n3\nMaeda Yasuhiro \n2\nKondo Masahiro \n1\nKawade Yoshihiro \n2\nOgawa Yoshihiro \n4\nNishikawa Ryohei \n4\nTohkin Masahiro http://orcid.org/0000-0002-2937-8926\n4\nKimura Kazunori http://orcid.org/0000-0002-2473-4776kkimura@med.nagoya-cu.ac.jp \n1\n\n2\n\n3\n\n1 \nDepartment of Pharmacy\nNagoya City University Hospital\nNagoya\nJapan\n\n2 \nDepartment of Hospital Pharmacy\nGraduate School of Pharmaceutical Sciences\nNagoya City University\nNagoya\nJapan\n\n3 \nDepartment of Clinical Pharmaceutics\nGraduate School of Medical Sciences\nNagoya City University\nNagoya\nJapan\n\n4 \nDepartment of Regulatory Science\nGraduate School of Pharmaceutical Sciences\nNagoya City University\nNagoya\nJapan\n* Correspondence\n\nKazunori Kimura, Department of Pharmacy, Nagoya City University Hospital, 1‐Kawasumi, Mizuho‐cho, Mizuho‐ku, Nagoya 467‐8602, Japan. Tel: +81 52 858 7404; Fax: +81 52 858 7402; E‐mail: kkimura@med.nagoya-cu.ac.jp\n16 4 2018 6 2018 7 6 10.1002/cam4.2018.7.issue-62269 2279 20 12 2017 14 1 2018 09 2 2018 © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nWe conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database on spontaneously reported adverse events to evaluate the association between anticancer drug therapy and hepatitis B infection. Reports of hepatitis B infection were retrieved from the FAERS database. The reporting odds ratio (ROR) was used to estimate the association between hepatitis B infection and various anticancer agents and drug combinations. We detected statistically significant risk signals of hepatitis B for 33 of 64 anticancer agents by ROR (26 cytotoxicity drugs and seven molecular‐targeted drugs). We focused on molecular‐targeted drugs and assessed the risk of hepatitis B from specific anticancer drug combinations. The frequency of hepatitis B infection was significantly high for drugs such as rituximab, bortezomib, imatinib, and everolimus. The addition of cyclophosphamide, doxorubicin, and fludarabine to drug combinations additively enhanced the frequency of hepatitis B infection. There were no reports on hepatitis B infection associated with trastuzumab or azacitidine monotherapy. However, trastuzumab‐containing regimens (e.g., combinations with docetaxel or paclitaxel) were correlated with the incidence of hepatitis B infection, similar to azacitidine monotherapy. Our findings suggest that the concomitant use of anticancer drugs, such as trastuzumab, taxane, and azacitidine, may contribute to the risk of hepatitis B infection. The unique signals detected from the public database might provide clues to eliminate the threat of HBV in oncology.\n\nCancer chemotherapydata miningFDA Adverse Event Reporting Systemhepatitis B virussignal detectionJSPS KAKENHI16H00574 source-schema-version-number2.0component-idcam41429cover-dateJune 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.1.1 mode:remove_FC converted:20.06.2018\n\nCancer Medicine \n2018 ; 7(6):2269 –2279 \n29663729\n==== Body\nIntroduction\nIn recent years, many cytotoxic and molecular‐targeted anticancer drugs have been developed, increasing the complexity of chemotherapy. Nearly 400 million people are infected with the hepatitis B virus (HBV) worldwide 1, 2 and at a risk for virus reactivation by immunosuppressive therapy for various diseases 3, 4. Chemotherapy‐induced hepatitis B reactivation is well known and can result in fulminant hepatic failure or death or both 5. Thus, prior to the initiation of immunosuppressive events (e.g., chemotherapy), HBV screening is recommended in the national and international guidelines 4, 6, 7, 8, 9. However, several cost‐effectiveness analyses have concluded that the recommended level of HBV screening should depend on the cancer type 10, 11, 12. Therefore, it is important to identify anticancer drugs associated with HBV reactivation.\n\nEvaluating the risk of adverse events associated with anticancer polytherapy is difficult in general. A recent report recommended the creation of a public database for comprehensive and timely reporting of all drugs, either new or old, associated with HBV reactivation 13. Data mining is a useful method for identifying drugs that may induce adverse events (AEs) and is used by regulatory agencies and the pharmaceutical industry to screen drugs for further clinical review 14, 15, 16, 17, 18. The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database provides a powerful means for identifying potential associations between drugs and AEs 19, 20 and exploring drug–drug interactions 21. However, there are few studies analyzing this database for anticancer agents and AEs 22, 23. In this study, we analyzed FAERS database to search for clues to eliminate the threat of HBV in oncology.\n\nMethods\nData sources\nData were obtained from the FAERS website 19. Cases with missing data (drug name or adverse reactions) were excluded. For duplicate case report forms, we adopted the most recent case number 24.\n\nReorganizing drug names\nTo accurately identify and aggregate all case reports for a marketed drug, the drug name variants (including generic names, names used outside the USA, and misspellings) were grouped under a common name. Spelling errors were detected by working pharmacists. The target drug group comprised 64 anticancer drugs searchable in the medical database DrugBank 25.\n\nDefinition of an AE\nThe AEs in the FDA database were coded using preferred terms (PT) in the Medical Dictionary for Regulatory Activities (MedDRA) 26. The PT “hepatitis B” was selected as the target AE.\n\nSignal detection\nA statistically significant association with an AE was considered a signal 20. The statistical signal strength of the association between an anticancer drug or drug combination and hepatitis B infection was calculated using the reporting odds ratio (ROR) 17 and the proportional reporting ratio (PRR) 14 as indicators. ROR has higher sensitivity than PRR. Conversely, PRR has higher specificity than ROR. ROR and PRR were calculated by identifying the case reports in datasets. A signal of the drug–event combination was detected when the lower limit of 95% confidence interval (CI) of the ROR exceeded 1. A signal was defined as a PRR of 2 or more, chi‐squared value of at least 4, and three or more cases. We added a signal count to all the cells in the corresponding 2 × 2 table. In addition, we specified cases that used target drugs listed as primary and secondary suspected drugs, and calculated the statistical signal strength.\n\nEvaluation of the relationship between hepatitis B infection and multidrug chemotherapy\nAnticancer drugs with AE signals detected by ROR were termed “signal drugs.” Signal detection by ROR gives an estimate of relative signal strength, reflecting the frequency of a particular AE in association with a given drug, compared with other drugs for the same indication 27. Standard drug regimens for various cancers are listed in the NCCN Chemotherapy Order Templates 28. Concomitant patterns of signal drugs were determined from this list and checked by working pharmacists. The number of hepatitis B cases and all AEs was collected from concomitant patterns of signal drugs. The RORs of each combinatorial pattern for similar indications were calculated. The relationship between hepatitis B infection and multidrug chemotherapy was estimated from a comparison table of signal drug combinations. For a risk estimate of hepatitis B, the lower limit of 95% CI of ROR had to exceed 1. The analyses were conducted using SAS 9.4 (SAS Institute, Inc., Cary, NC).\n\nResults\nData mining\nFigure 1 shows the flowchart of data extraction. We analyzed 5,597,295 case reports received by the FDA between the first quarter of 2004 and the first quarter of 2014. After excluding duplicate reports and cases missing the drug name or adverse reaction, 4,330,807 case reports remained. The number of hepatitis B events reported during the study period was 2091. Of the hepatitis B reports, 595 (28%) lacked information on patient age. In the remaining reports, the mean age of patients with hepatitis B was 52.8 ± 16.2 years. Data on sex were missing in 228 case reports (11%); the number of male and female patients in the remaining cases was 1163 and 700, respectively.\n\nFigure 1 Flowchart illustrating data mining from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database.\n\nAnticancer drugs reported with hepatitis B events\nTables 1, 2 show the associations between chemotherapeutic drugs and reported hepatitis B events. Signals were detected for 26 of 38 cytotoxic anticancer agents and seven of 26 molecular‐targeted drugs by ROR, and for 23 of 38 cytotoxic anticancer agents, and six of 26 molecular‐targeted drugs by PRR. For dacarbazine, docetaxel (DOC), paclitaxel (PTX), and thalidomide (THAL), signals were detected only by ROR. The number of cases that used target drugs listed as primary or secondary suspected drugs, and the calculated ROR and PRR are shown in parentheses in Tables 1, 2. In the data analysis, we detected signals for busulfan and gemcitabine; however, these signals were similar to those detected for vindesine and thalidomide. It can be suggested that busulfan and gemcitabine might be associated with hepatitis B, whereas signals of vindesine and thalidomide may be specious signals. Signals of these drugs may be affected by concomitant drugs. In addition, anticancer drugs with ROR‐detected signals were classified as “signal drugs” and subjected to further analysis. We focused on combinations that included the signal‐detected molecular‐targeted drugs rituximab (Rmab), trastuzumab (Tmab), bortezomib (BOR), THAL, imatinib (GLI), everolimus (Emus), and azacitidine (AZA).\n\nTable 1 Signal detection for cytotoxicity drugs associated with hepatitis B infection\n\n\tHepatitis B events\tAll AEs\tROR\t95% CI\tPRR\t\nχ\n2\n\t\nAlkylating agents\t\nBusulfan\t5 (5)\t4428 (3345)\t2.34 (3.10)\n\t0.97–5.64 (1.29–7.46)\n\t2.34 (3.10)\n\t2.61 (5.14)\n\t\nCyclophosphamide*\n,\n†\n\t405 (328)\t41,828 (30,046)\t24.86 (26.91)\t22.30–27.77 (23.91–30.30)\t24.63 (26.63)\t7387.94 (6803.41)\t\nIfosfamide*\n,\n†\n\t17 (16)\t4358 (3739)\t8.17 (8.96)\t5.06–13.17 (5.47–14.66)\t8.14 (8.92)\t98.64 (104.03)\t\nMelphalan*\n,\n†\n\t35 (25)\t8767 (5761)\t8.42 (9.08)\t6.03–11.77 (6.12–13.48)\t8.39 (9.05)\t216.97 (168.97)\t\nDacarbazine*\n\t3 (0)\t1623 (1296)\t3.84 (4.81)\t1.24–11.92 (1.55–14.94)\t3.83 (4.80)\n\t3.76 (5.62)\n\t\nProcarbazine\t0 (0)\t1321 (1146)\t\t\t\t\t\nTemozolomide*\n,\n†\n\t15 (15)\t7090 (6371)\t4.41 (4.91)\t2.65–7.34 (2.96–8.17)\t4.41 (4.90)\t35.92 (42.51)\t\nAntimetabolites\t\nCladribine*\n,\n†\n\t6 (5)\t784 (664)\t16.01 (15.74)\t7.16–35.78 (6.52–37.99)\t15.89 (15.63)\t69.34 (54.52)\t\nFludarabine*\n,\n†\n\t76 (63)\t11,293 (8037)\t14.52 (16.83)\t11.54–18.27 (13.09–21.65)\t14.43 (16.71)\t902.68 (887.60)\t\nNelarabine\t0 (0)\t275 (260)\t\t\t\t\t\nPentostatin\t1 (0)\t539 (479)\t3.85\t0.54–27.39\t3.84\t0.22\t\nCapecitabine\t4 (3)\t26,089 (22,494)\t0.32 (0.28)\t0.12–0.84 (0.09–0.85)\t0.32 (0.28)\t5.24 (5.02)\t\nCytarabine*\n,\n†\n\t42 (34)\t12,276 (9812)\t7.23 (7.30)\t5.33–9.82 (5.20–10.25)\t7.21 (7.28)\t214.21 (175.11)\t\nFluorouracil*\n,\n†\n\t43 (37)\t23,886 (17,266)\t3.79 (4.51)\t2.80–5.13 (3.26–6.24)\t3.79 (4.50)\t83.66 (95.57)\t\nGemcitabine\t13 (12)\t16,239 (13,614)\t1.66 (1.83)\n\t0.96–2.87 (1.04–3.23)\n\t1.66 (1.83)\t2.78 (3.71)\t\nMethotrexate*\n,\n†\n\t139 (90)\t110,270 (24,737)\t2.73 (7.85)\t2.30–3.24 (6.36–9.70)\t2.73 (7.83)\t140.17 (506.75)\t\nPemetrexed\t2 (2)\t7091 (6438)\t0.59 (0.64)\t0.15–2.34 (0.16–2.57)\t0.58 (0.64)\t0.25 (0.12)\t\nAntitumor antibiotics\t\nBleomycin*\n,\n†\n\t13 (12)\t3035 (2508)\t8.96 (10.00)\t5.19–15.47 (5.66–17.67)\t8.92 (9.96)\t83.193 (87.52)\t\nDactinomycin*\n,\n†\n\t5 (4)\t1033 (905)\t10.09 (9.21)\t4.19–24.32 (3.44–24.61)\t10.05 (9.17)\t32.12 (21.49)\t\nMitomycin\t0 (0)\t1305 (1070)\t\t\t\t\t\nDaunorubicin*\n,\n†\n\t6 (6)\t4190 (3296)\t2.97 (3.78)\t1.33–6.63 (1.70–8.44)\t2.97 (3.78)\t5.99 (9.61)\t\nDoxorubicin*\n,\n†\n\t293 (240)\t28,552 (22,536)\t24.80 (25.04)\t21.91–28.07 (21.88–28.67)\t24.56 (24.79)\t5675.18 (4830.97)\t\nEpirubicin*\n,\n†\n\t28 (24)\t5817 (4578)\t10.14 (11.02)\t6.97–14.73 (7.36–16.50)\t10.09 (10.97)\t217.47 (205.37)\t\nIdarubicin*\n,\n†\n\t7 (7)\t1718 (1278)\t8.49 (11.44)\t4.04–17.87 (5.43–24.07)\t8.46 (11.38)\t38.80 (56.13)\t\nMitoxantrone*\n,\n†\n\t26 (24)\t3357 (2589)\t16.35 (19.58)\t11.09–24.11 (13.07–29.34)\t16.23 (19.41)\t352.25 (396.47)\t\nAsparaginase\t4 (4)\t3633 (3249)\t2.28 (2.55)\t0.86–6.10 (0.96–6.82)\t2.28 (2.55)\t1.74 (2.38)\t\nAntimicrotubule agents\t\nVinblastine*\n,\n†\n\t6 (5)\t1552 (1177)\t8.06 (8.85)\t3.61–17.98 (3.67–21.33)\t8.03 (8.85)\t30.14 (27.22)\t\nVincristine*\n,\n†\n\t288 (228)\t20,500 (15,484)\t34.05 (34.60)\t30.05–38.59 (30.13–39.74)\t33.59 (34.11)\t7826.67 (6501.79)\t\nVindesine*\n,\n†\n\t3 (1)\t472 (344)\t13.26 (6.04)\n\t4.26–41.30 (0.85–43.01)\n\t13.18 (6.02)\n\t22.67 (0.67)\n\t\nVinorelbine\t1 (0)\t4595 (3152)\t0.45\t0.06–3.20\t0.45\t0.23\t\nEribulin\t0 (0)\t678 (613)\t\t\t\t\t\nDocetaxel*\n\t17 (13)\t18,227 (14,161)\t1.94 (1.91)\t1.20–3.13 (1.11–3.29)\t1.94 (1.91)\t6.77 (4.71)\t\nPaclitaxel*\n\t23 (20)\t24,039 (19,372)\t1.99 (2.15)\t1.32–3.01 (1.38–3.34)\t1.99 (2.15)\n\t10.29 (11.06)\n\t\nTopoisomerase inhibitors\t\nIrinotecan*\n,\n†\n\t20 (18)\t11,671 (8802)\t3.58 (4.27)\t2.30–5.56 (2.68–6.79)\t3.57 (4.27)\t34.22 (41.42)\t\nEtoposide*\n,\n†\n\t71 (58)\t14,231 (11,331)\t10.71 (10.93)\t8.45–13.58 (8.41–14.19)\t10.66 (10.88)\t591.46 (496.34)\t\nPlatinum‐based agents\t\nCarboplatin*\n,\n†\n\t24 (19)\t21,457 (16,499)\t2.33 (2.40)\t1.56–3.49 (1.53–3.77)\t2.33 (2.40)\t16.76 (13.99)\t\nCisplatin*\n,\n†\n\t36 (34)\t22,054 (17,654)\t3.43 (4.04)\t2.46–4.77 (2.88–5.68)\t3.42 (4.04)\t58.33 (73.52)\t\nOxaliplatin\t13 (8)\t17,247 (14,114)\t1.57 (1.17)\t0.91–2.70 (0.59–2.35)\t1.57 (1.18)\t2.10 (0.07)\t\n*Signal detected by ROR; †Signal detected by PRR.\n\nThe numbers in parentheses: target drugs were listed as primary suspected drug or secondary suspected drug. Bold, change of interpretation of signal detection. AE, adverse event; ROR, reporting odds ratio; PRR, proportional reporting ratio; CI, confidence interval.\n\nJohn Wiley & Sons, LtdTable 2 Signal detection for molecular‐targeted drugs associated with hepatitis B infection\n\n\tHepatitis B events\tAll AEs\tROR\t95% CI\tPRR\t\nχ\n2\n\t\nRituximab*\n,\n†\n\t445 (427)\t33,225 (28,845)\t35.43 (38.83)\t31.89–39.36 (34.89–43.21)\t34.97 (38.27)\t11,537.76 (12,309.87)\t\nTrastuzumab*\n,\n†\n\t15 (13)\t12,113 (10,310)\t2.58 (2.62)\t1.55–4.29 (1.52–4.53)\t2.58 (2.62)\t12.84 (11.40)\t\nGemtuzumab ozogamicin\t2 (1)\t1766 (1700)\t2.35 (1.22)\t0.59–9.40 (0.17–8.66)\t2.35 (1.22)\t0.49 (0.13)\t\nBevacizumab\t15 (15)\t38,038 (35,757)\t0.82 (0.86)\t0.49–1.36 (0.52–1.44)\t0.82 (0.87)\t0.45 (0.18)\t\nCetuximab\t3 (3)\t14,789 (14,304)\t0.42 (0.43)\t0.14–1.30 (0.14–1.35)\t0.42 (0.43)\t1.86 (1.69)\t\nPanitumumab\t0 (0)\t3101 (3016)\t\t\t\t\t\nIbritumomab tiuxetan\t0 (0)\t124 (115)\t\t\t\t\t\nGefitinib\t1 (1)\t3924 (3761)\t0.53 (0.55)\t0.07–3.75 (0.08–3.91)\t0.53 (0.55)\t0.08 (0.06)\t\nImatinib*\n,\n†\n\t31 (31)\t19,945 (19,333)\t3.26 (3.36)\t2.28–4.64 (2.36–4.79)\t3.25 (3.36)\t45.46 (48.23)\t\nBortezomib*\n,\n†\n\t57 (54)\t16,693 (13,373)\t7.26 (8.59)\t5.58–9.46 (6.55–11.26)\t7.24 (8.56)\t292.40 (343.98)\t\nErlotinib\t1 (1)\t23,275 (22,676)\t0.09 (0.09)\t0.01–0.63 (0.01–0.65)\t0.09 (0.09)\t8.49 (8.20)\t\nCrizotinib\t0 (0)\t2153 (2133)\t\t\t\t\t\nSorafenib\t9 (7)\t10,944 (10,485)\t1.71 (1.38)\t0.89–3.29 (0.66–2.91)\t1.71 (1.38)\t1.96 (0.41)\t\nSunitinib\t7 (7)\t17,207 (16,569)\t0.84 (0.87)\t0.40–1.77 (0.42–1.84)\t0.84 (0.88)\t0.08 (0.03)\t\nAxitinib\t0 (0)\t1900 (1867)\t\t\t\t\t\nPazopanib\t0 (0)\t4860 (4794)\t\t\t\t\t\nNilotinib\t4 (4)\t6414 (6300)\t1.29 (1.32)\t0.48–3.45 (0.49–3.51)\t1.29 (1.32)\t0.05 (0.07)\t\nDasatinib\t1 (1)\t5280 (5033)\t0.39 (0.41)\t0.06–2.78 (0.06–2.92)\t0.39 (0.41)\t0.43 (0.36)\t\nLapatinib\t6 (5)\t8938 (8537)\t1.39 (1.21)\t0.62–3.10 (0.50–2.92)\t1.39 (1.21)\t0.33 (0.04)\t\nEverolimus*\n,\n†\n\t10 (10)\t8370 (7989)\t2.48 (2.60)\t1.33–4.62 (1.40–4.85)\t2.48 (2.60)\t7.39 (8.27)\t\nThalidomide*\n\t15 (13)\t18,373 (16,889)\t1.70 (1.60)\n\t1.02–2.82 (0.93–2.76)\n\t1.70 (1.60)\t3.59 (2.32)\t\nLenalidomide\t23 (19)\t51,724 (50,904)\t0.92 (0.77)\t0.61–1.39 (0.49–1.21)\t0.92 (0.77)\t0.09 (1.06)\t\nTemsirolimus\t2 (2)\t2905 (2802)\t1.43 (1.48)\t0.36–5.71 (0.37–5.92)\t1.43 (1.48)\t0.01 (0.02)\t\nVorinostat\t0 (0)\t1183 (1122)\t\t\t\t\t\nAfatinib\t0 (0)\t276 (272)\t\t\t\t\t\nAzacitidine*\n,\n†\n\t6 (6)\t4393 (4048)\t2.84 (3.08)\t1.27–6.33 (1.38–6.87)\t2.38 (3.08)\t5.39 (6.44)\t\n*Signal detected by ROR; †Signal detected by PRR.\n\nThe numbers in parentheses: target drugs were listed as primary suspected drug or secondary suspected drug. Bold, change of interpretation of signal detection. AE, adverse event; ROR, reporting odds ratio; PRR, proportional reporting ratio; CI, confidence interval.\n\nJohn Wiley & Sons, LtdHepatitis B reported with Rmab‐based chemotherapy for lymphoma\nTable 3 outlines the drug combinations reported for lymphoma treatment and the associated number of AE reports. Figure 2 shows the frequency of hepatitis B reported among lymphoma treatment groups; RORs were calculated from the data in Table 3, and not all combination patterns were included. However, of the 445 hepatitis B cases, 350 (78.7%) were reported with Rmab‐containing treatments.\n\nTable 3 Drug combinations and adverse events reported for lymphoma\n\n\tHepatitis B events\tAll adverse events\t\nRmab+CPA+DXR+VCR\t182\t5313\t\nRmab+CPA+VCR\t14\t722\t\nRmab+FLU+CPA\t36\t1516\t\nRmab+FLU\t9\t602\t\nRmaba\n\t109\t15,668\t\nFLU+CPA\t9\t1574\t\nFLUa\n\t6\t3274\t\na Only one signal drug.\n\nRmab, rituximab; CPA, cyclophosphamide; DXR, doxorubicin; VCR, vincristine; FLU, fludarabine.\n\nJohn Wiley & Sons, LtdFigure 2 Estimates of hepatitis B virus infection risk in chemotherapy regimens for lymphoma. Chemotherapeutic drug combinations are listed in black cells. The estimate is located at the intersection of the column‐defined combination pattern and the row‐defined combination pattern. To obtain reporting odds ratios (RORs) for comparisons in the opposing direction, the reciprocals should be taken. For hepatitis B infection risk, an ROR value below 1 favors the column‐defined combination pattern. Statistically significant estimates appear in gray cells. The numbers in the parentheses indicate 95% confidence intervals. The corresponding data are listed in Table 3.\n\nThe combination Rmab+cyclophosphamide (CPA)+doxorubicin (DXR)+vincristine (VCR) exhibited a substantially higher relevance to hepatitis B infection than other combinations. All lower limits of 95% CIs in the RORs of this drug combination in the column exceeded 1 (Fig. 2). Conversely, fludarabine (FLU) exhibited a substantially lower relevance to hepatitis B infection than other combinations; all lower limits of the 95% CIs in the row exceeded 1. Hepatitis B infection of all other drug combinations involving Rmab was reported at a higher frequency than FLU+CPA, Rmab monotherapy, and FLU monotherapy. The contribution of Rmab+FLU+CPA combination to hepatitis B infection was reported at a higher frequency than that of CPA+DXR+VCR combination. These results indicate that a specific combination may contribute more to hepatitis B infection. The combination most associated with hepatitis B infection was Rmab+CPA+DXR+VCR.\n\nHepatitis B reported with Tmab‐based chemotherapy for breast cancer\nTable 4 outlines the drug combinations reported for breast cancer treatment and the associated number of AE reports. Of the 15 hepatitis B cases, 11 (73.3%) were reported with Tmab‐containing regimens. Figure 3 shows the frequency of hepatitis B reported among breast cancer treatment groups. The frequency of hepatitis B reported for Tmab+DOC and Tmab+PTX was higher than that for Tmab monotherapy, DOC monotherapy, and PTX monotherapy. The frequency of reporting of hepatitis B for CPA+DXR+fluorouracil (5‐FU) and CPA+DXR was higher than that for the three monotherapies, whereas that of CPA+epirubicin (EPI)+5‐FU was higher than that of Tmab and DOC monotherapies. Similarly, the frequency of reporting of hepatitis B for CPA+EPI combination was higher than that of DOC monotherapy.\n\nTable 4 Drug combinations and adverse events reported for breast cancer\n\n\tHepatitis B events\tAll adverse events\t\nTmab+DOC\t3\t1232\t\nTmab+PTX\t7\t1255\t\nTmaba\n\t1\t6024\t\nDOCa\n\t1\t7819\t\nPTXa\n\t3\t7582\t\nCPA+DXR+5‐FU\t3\t366\t\nCPA+EPI+5‐FU\t2\t1079\t\nCPA+DXR\t12\t1533\t\nCPA+EPI\t1\t402\t\na Only one signal drug.\n\nTmab, trastuzumab; DOC, docetaxel; PTX, paclitaxel; CPA, cyclophosphamide; DXR, doxorubicin; 5‐FU, fluorouracil; EPI, epirubicin.\n\nJohn Wiley & Sons, LtdFigure 3 Estimates of hepatitis B infection risk in chemotherapy regimens for breast cancer. Chemotherapeutic drug combinations are listed in black cells. The estimate is located at the intersection of the column‐defined combination pattern and the row‐defined combination pattern. To obtain reporting odds ratios (RORs) for comparisons in the opposing direction, the reciprocals should be taken. For hepatitis B infection risk, an ROR value below 1 favors the column‐defined combination pattern. Statistically significant estimates appear in gray cells. The numbers in the parentheses indicate 95% confidence intervals. The corresponding data are listed in Table 4.\n\nHepatitis B reported with BOR‐ or THAL‐based chemotherapy for multiple myeloma (MM)\nTable 5 outlines the drug combinations reported for MM treatment and the associated number of AE reports. Of the 57 hepatitis B cases, 44 (77.2%) were reported with BOR‐containing treatments. Figure 4 shows the reporting frequency of hepatitis B among MM treatment groups. The reporting frequency of hepatitis B for combination therapy with BOR did not exceed the frequency for BOR monotherapy. The frequency of reporting of hepatitis B for THAL was substantially lower than that of BOR monotherapy or any drug combination, except for BOR+THAL.\n\nTable 5 Drug combinations and adverse events reported for multiple myeloma\n\n\tHepatitis B events\tAll adverse events\t\nBOR+CPA\t2\t631\t\nBOR+DXR\t2\t935\t\nBOR+L‐PAM\t3\t836\t\nBOR+THAL\t0\t802\t\nL‐PAM+THAL\t3\t803\t\nBORa\n\t37\t10,504\t\nTHALa\n\t4\t13,729\t\na Only one signal drug.\n\nBOR, bortezomib; L‐PAM, melphalan; THAL, thalidomide, CPA, cyclophosphamide; DXR, doxorubicin.\n\nJohn Wiley & Sons, LtdFigure 4 Estimates of hepatitis B infection risk in chemotherapy regimens for multiple myeloma. Chemotherapeutic drug combinations are listed in black cells. The estimate is located at the intersection of the column‐defined combination pattern and the row‐defined combination pattern. To obtain reporting odds ratios (RORs) for comparisons in the opposing direction, reciprocals should be taken. For hepatitis B infection risk, a ROR value below 1 favors the column‐defined combination pattern. Statistically significant estimates appear in gray cells. The numbers in the parentheses indicate 95% confidence intervals. The corresponding data are listed in Table 5.\n\nHepatitis B reported with GLI‐, Emus‐, or AZA‐based chemotherapy\nTable 6 shows that the prevalence of hepatitis B and other AEs calculated for GLI, Emus, and AZA monotherapies did not vary substantially from the prevalence calculated for drug combinations that included these drugs. This implies that these drugs were not used with other signal drugs and reveals that the use of these three drugs or their indications is associated with hepatitis B.\n\nTable 6 Comparison of adverse events in monotherapies and in combinations that did not include other signal drugs\n\n\tHepatitis B events\tAll adverse events\t\nGLI monotherapy\t31\t19,945\t\nGLIa\n\t31\t18,983\t\nEmus monotherapy\t10\t8370\t\nEmusa\n\t9\t7710\t\nAZA monotherapy\t6\t4393\t\nAZAa\n\t5\t4051\t\na The chemotherapy regimen included other drugs, but none were signal drugs.\n\nGLI, imatinib; Emus, everolimus; AZA, azacitidine.\n\nJohn Wiley & Sons, LtdDiscussion\nWe identified anticancer drugs associated with hepatitis B infection by conducting a comprehensive signal‐detection analysis. First, we used the PRR method to distinguish true positives from pseudo positives. However, in the PRR method, risk signals may be missed because the interpretation of signals is convoluted for AEs associated with cancer chemotherapy. Meanwhile, there is no gold standard signal‐detection method. The ROR method probably detected pseudopositives owing to its high sensitivity and potential signal–signal interactions. Therefore, we used ROR to avoid overlooking signals. The number of signals detected by ROR slightly exceeded the number detected by PRR. Some of the signal drugs detected by ROR have been reported to be associated with hepatitis B 29, 30. Hence, we performed sensitivity analysis. However, these signal drugs are not necessarily used alone in clinical settings. In cancer chemotherapy, several anticancer drugs are frequently combined. To our knowledge, no report has been published on the association between multiple‐drug anticancer therapy and risk signals in large‐scale postmarketing databases for adverse drug reactions to date. We focused on signal‐detected molecular‐targeted drug‐containing combinations, because indications for molecular‐targeted drugs are limited compared with indications for cytotoxic anticancer drugs. Tables 3, 4, 5 show that these combinations reasonably account for most hepatitis B events reported for patients receiving molecular‐targeted drugs. Cytotoxic anticancer drugs are administered in multiple combination patterns, which are difficult to track.\n\nRmab is well known as a drug associated with HBV reactivation 3, 4, 11, 13, 29, 30. Among signal drugs, Rmab has the highest ROR score. Rmab is frequently used with CPA, DXR, and VCR to treat lymphoma. The drug combination R‐CHOP (Rmab, CPA, DXR, VCR, and prednisone) is a typical regimen for lymphoma. FLU is another drug used to treat lymphoma. The ROR scores of CPA, DXR, VCR, and FLU were relatively high among the signal drugs. We suspected that Rmab affected the ROR scores of the other signal drugs. First, we analyzed the drug combinations. Second, cases that involved target signal drugs only were regarded as patients receiving multiple‐drug anticancer combination therapy. We attempted to identify key drugs associated with hepatitis B infection by subtracting the signal drugs. Signal–signal interactions and differences in risk have not been reported so far.\n\nTmab and combined‐drug regimens containing DXR, CPA, EPI, or 5‐FU are often used to treat breast cancer. Although a relationship between anthracycline and hepatitis B has been reported, Tmab treatment has not been previously linked to hepatitis B 29, 30. DOC and PTX are frequently used in conjunction with Tmab. We found that combinations of Tmab and taxane are likely to contribute to hepatitis B infection, whereas Tmab monotherapy may not. PRR did not detect signals for DOC and PTX and may lead to overlooking true positives. The addition of 5‐FU to drug combinations may not contribute to hepatitis B risk.\n\nBortezomib and thalidomide are used in treating MM. Several cases of hepatitis B infection associated with BOR have been reported 31, 32, 33. CPA, DXR, and melphalan (L‐PAM) are also used in the treatment of MM, and lenalidomide may be indicated for MM. However, we did not detect a signal for lenalidomide. We found that all drug monotherapies and polytherapies for MM conferred similar risks of hepatitis B infection, with the exception of THAL monotherapy. THAL signals were influenced by other signal drugs. PRR did not detect signals for THAL. Immunomodulatory drugs such as THAL may not pose a risk for hepatitis B infection in MM.\n\nA few cases were treated with GLI, Emus, or AZA and other signal drugs, although these drugs are usually administered alone. This suggests that the signal detected for these drugs was dependent on the target drug itself. GLI and Emus have been reported to exacerbate HBV 34, 35, whereas little is known about the risk of hepatitis B associated with AZA. AZA has been shown to increase the production of hepatitis B surface antigen in vitro 36.\n\nAs mentioned above, we found a risk of hepatitis B infection in treatments containing AZA or Tmab and taxane combinations and showed that signals detected for anticancer drugs are strongly affected by combinational drug therapy. In addition, hepatitis B risk appears to increase additively by concomitant use of some key anticancer drugs. The FAERS database is considered a valuable tool; however, the following limitations inherent to spontaneous reporting have been pointed out 17: duplicate records, missing data, misspelling of drug names, under‐reporting, over‐reporting for drugs involved in safety alerts, and reporting rate on the length of time. Reporting bias has been discussed in pharmacovigilance of oncology drugs 37. We minimized biases introduced by some limitations as much as possible through data cleaning. However, biases such as under‐reporting and reporting rate may affect the number of cases reported. The existence of indication bias may also affect the results of this study.\n\nWe must state that the PT “hepatitis B” includes lowest level terms (LLT) such as serum hepatitis, hepatitis B reactivation, hepatitis B flare, hepatitis B aggravated, viral hepatitis B, hepatitis homologous serum‐like, and HBV coinfection. From a clinical oncology standpoint, we assumed almost all hepatitis B cases that used anticancer drugs as hepatitis B reactivation or flare cases. However, analyses are generally performed at the PT level, and analyses at the LLT level should be avoided. Incidentally, the level of terms may be changed by a change request from users. In MedDRA ver.20.0 (2017 March), the term level of hepatitis B reactivation was changed from LLT to PT. Therefore, hepatitis B reactivation should be analyzed at the PT level in a voluntary reporting system. The influence of non‐anticancer drugs used concomitantly was not analyzed; these drugs may affect hepatitis B reactivation. Nuclear analogs, for instance, are known to contribute to the prevention of HBV reactivation 38. Conversely, HBV replication increases in the presence of glucocorticoid agents 39. However, drugs used to treat cancer symptoms or the side effects of treatment were not specified in our FAERS searches. Hematopoietic stem cell transplantation may contribute to the risk of hepatitis B infection in lymphoma and MM 40, 41. The prevalence of HBV infection varies across countries, regions, and institutions 6. However, geographical data were not reported in FAERS.\n\nOwing to the above limitations, the approaches using voluntary reporting systems cannot replace traditional methods. However, it is difficult to detect hepatitis B associated with cancer chemotherapy by randomized clinical trials. Conversely, the postmarketing spontaneous reporting system can generate alert signals that may not be detected in clinical trials 42. The list of potential signals of serious risks/new safety information identified from FAERS has been published 19. We cannot avoid paying attention to the information about potential signals from each regulatory authority.\n\nOur analytical method may offer a way to estimate HBV infection risk in cancer therapy. Large population‐based studies would be required to validate our risk estimates. However, FAERS is the largest repository of spontaneously reported adverse events in the world. In the analysis of rare AEs, its sensitivity is limited by the number of events reported. However, we were not able to avoid the problem of sample size and signal‐detection methods as mentioned above. We expected to find novel signals by continual surveillance using the database of each regulatory authority. Recently, it was reported that the drug–drug interactions detected from FAERS were determined by fundamental research using animal models 43. The approaches using cultured cells have also been reported 44, 45. Hence, not only epidemiological approaches but also fundamental research may be important.\n\nIn actual innovations, it is possible that the approach of this study may apply to the other rare AEs associated with cancer chemotherapy. We hope that this study based on public databases can promote researches on rare AEs associated with cancer chemotherapy and eventually affect clinical decisions or guidelines or both.\n\nConflict of Interest\nThe authors declare no conflict of interests.\n\nAcknowledgments\nThis work was supported by JSPS KAKENHI (grant number 16H00574). We would like to thank Editage (http://www.editage.jp) for English language editing.\n==== Refs\nReferences\n1 \n\nAlter , M. J. \n\n2003 \nEpidemiology of hepatitis B in Europe and worldwide . J. Hepatol. \n39 (Suppl. 1 ):S64 –S69 .14708680 \n2 \n\nWasley , A. \n, \nD. \nKruszon‐Moran \n, \nW. \nKuhnert \n, \nE. P. \nSimard \n, \nL. \nFinelli \n, \nG. \nMcQuillan \n, et al. 2010 \nThe prevalence of hepatitis B virus infection in the United States in the era of vaccination . J. Infect. Dis. \n200 :192 –201 .\n3 \n\nHwang , J. P. \n, \nJ. M. \nVierling \n, \nA. D. \nZelenetz \n, \nS. C. \nLackey \n, and \nR. \nLoomba \n. 2012 \nHepatitis B virus management to prevent reactivation after chemotherapy: a review . Support. Care Cancer \n20 :2999 –3008 .22933131 \n4 \n\nLok , A. S. \n, \nJ. W. \nWard \n, \nR. P. \nPerrillo \n, \nB. J. \nMcMahon \n, and \nT. J. \nLiang \n. 2012 \nReactivation of hepatitis B during immunosuppressive therapy: potentially fatal yet preventable . Ann. Intern. Med. \n156 :743 –745 .22586011 \n5 \n\nGupta , S. \n, \nS. \nGovindarajan \n, \nT. L. \nFong \n, and \nA. G. \nRedeker \n. 1990 \nSpontaneous reactivation in chronic hepatitis B: patterns and natural history . J. Clin. Gastroenterol. \n12 :562 –568 .2230000 \n6 \n\nWeinbaum , C. M. \n, \nI. \nWilliams \n, \nE. E. \nMast \n, \nS. A. \nWang \n, \nL. \nFinelli \n, \nA. \nWasley \n, et al. 2008 \nRecommendations for identification and public health management of persons with chronic hepatitis B virus infection . MMWR Recomm. Rep. \n57 (RR‐8 ):1 –20 .\n7 \n\nLok , A. S. F. \n, and \nB. J. \nMcMahon \n. 2009 \nAASLD Practice Guideline Update: Chronic Hepatitis B . Available at: https://www.aasld.org/sites/default/files/guideline_documents/ChronicHepatitisB2009.pdf (accessed 5 January 2016).\n8 \n\nArtz , A. S. \n, \nM. R. \nSomerfield \n, \nJ. J. \nFeld \n, \nA. F. \nGiusti \n, \nB. S. \nKramer \n, \nA. L. \nSabichi \n, et al. 2010 \nAmerican Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases . J. Clin. Oncol. \n28 :3199 –3202 .20516452 \n9 \nEuropean Association for the Study of the Liver \n. 2012 \nEASL clinical practice guidelines: management of chronic hepatitis B virus infection . J. Hepatol. \n57 :167 –185 .22436845 \n10 \n\nDay , F. L. \n, \nJ. \nKarnon \n, and \nD. \nRischin \n. 2011 \nCost‐effectiveness of universal hepatitis B virus screening in patients beginning chemotherapy for solid tumors . J. Clin. Oncol. \n29 :3270 –3277 .21788556 \n11 \n\nZurawska , U. \n, \nL. K. \nHicks \n, \nG. \nWoo \n, \nC. M. \nBell \n, \nM. \nKrahn \n, \nK. K. \nChan \n, et al. 2012 \nHepatitis B virus screening before chemotherapy for lymphoma: a cost‐effectiveness analysis . J. Clin. Oncol. \n30 :3167 –3173 .22711851 \n12 \n\nWong , W. W. \n, \nL. K. \nHicks \n, \nH. A. \nTu \n, \nK. I. \nPritchard \n, \nM. D. \nKrahn \n, \nJ. J. \nFeld \n, et al. 2015 \nHepatitis B virus screening before adjuvant chemotherapy in patients with early‐stage breast cancer: a cost‐effectiveness analysis . Breast Cancer Res. Treat. \n151 :639 –652 .25962692 \n13 \n\nLoomba , R. \n, and \nT. J. \nLiang \n. 2017 \nHepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions . Gastroenterology \n152 :1297 –1309 .28219691 \n14 \n\nEvans , S. J. \n, \nP. C. \nWaller \n, and \nS. \nDavis \n. 2001 \nUse of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports . Pharmacoepidemiol. Drug Saf. \n10 :483 –486 .11828828 \n15 \n\nvan Puijenbroek , E. P. \n, \nA. \nBate \n, \nH. G. \nLeufkens \n, \nM. \nLindquist \n, \nR. \nOrre \n, and \nA. C. \nEgberts \n. 2002 \nA comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions . Pharmacoepidemiol. Drug Saf. \n11 :3 –10 .11998548 \n16 \n\nSzarfman , A. \n, \nS. G. \nMachado \n, and \nR. T. \nO'Neill \n. 2002 \nUse of screening algorithms and computer systems to efficiently signal higher‐than‐expected combinations of drugs and events in the US FDA's spontaneous reports database . Drug Saf. \n25 :381 –392 .12071774 \n17 \n\nBate , A. \n, and \nS. J. \nEvans \n. 2009 \nQuantitative signal detection using spontaneous ADR reporting . Pharmacoepidemiol. Drug Saf. \n18 :427 –436 .19358225 \n18 \n\nGould , A. L. \n\n2003 \nPractical pharmacovigilance analysis strategies . Pharmacoepidemiol. Drug Saf. \n12 :559 –574 .14558179 \n19 \nFDA's Adverse Event Reporting System . Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ (accessed 30 January 2015).\n20 \n\nEdwards , I. R. \n, and \nJ. K. \nAronson \n. 2000 \nAdverse drug reactions: definition, diagnosis, and management . Lancet \n356 :1255 –1259 .11072960 \n21 \n\nTatonetti , N. P. \n, \nJ. C. \nDenny \n, \nS. N. \nMurphy \n, \nG. H. \nFernald \n, \nG. \nKrishnan \n, \nV. \nCastro \n, et al. 2011 \nDetecting drug interactions from adverse‐event reports: interaction between paroxetine and pravastatin increases blood glucose levels . Clin. Pharmacol. Ther. \n90 :133 –142 .21613990 \n22 \n\nRosen , A. C. \n, \nY. \nBalagula \n, \nD. W. \nRaisch \n, \nV. \nGarg \n, \nB. \nNardone \n, \nN. \nLarsen \n, et al. 2014 \nLife‐threatening dermatologic adverse events in oncology . Anticancer Drugs \n25 :225 –234 .24108082 \n23 \n\nHauben , M. \n, \nL. \nReich \n, and \nS. \nChung \n. 2004 \nPostmarketing surveillance of potentially fatal reactions to oncology drugs: potential utility of two signal‐detection algorithms . Eur. J. Clin. Pharmacol. \n60 :747 –750 .15619136 \n24 \nGuidance for Industry: Good Pharmacovigilance practices and pharmacoepidemiologic Assessment . Available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf (accessed 5 January 2016).\n25 \nDrugBank home page . Available from URL: http://www.drugbank.ca/ (accessed 17 February 2015).\n26 \n\nBrown , E. G. \n\n2002 \nEffects of cording dictionary on signal generation: a consideration of use of MedDRA compared with WHO‐ART . Drug Saf. \n25 :445 –452 .12071782 \n27 \n\nAli , T. B. \n, \nT. R. \nSchleret \n, \nB. M. \nReilly \n, \nW. Y. \nChen \n, and \nR. \nAbagyan \n. 2015 \nAdverse effects of cholinesterase inhibitors in dementia, according to the pharmacovigilance databases of the United States and Canada . PLoS ONE \n10 :e0144337 .26642212 \n28 \nNCCN Guidelines & Clinical Resources: NCCN Chemotherapy Order Templates (NCCN Templates) . Available at https://www.nccn.org/ordertemplates/ (accessed 1 June 2015).\n29 \n\nYeo , W. \n, and \nP. J. \nJohnson \n. 2006 \nDiagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy . Hepatology \n43 :209 –220 .16440366 \n30 \n\nPaul , S. \n, \nA. \nSaxena \n, \nN. \nTerrin \n, \nK. \nViveiros \n, \nE. M. \nBalk \n, and \nJ. B. \nWong \n. 2016 \nHepatitis B virus reactivation and prophylaxis during solid tumor chemotherapy: a systematic review and meta‐analysis . Ann. Intern. Med. \n164 :30 –40 .26595058 \n31 \n\nTanaka , H. \n, \nI. \nSakuma \n, \nS. \nHashimoto \n, \nY. \nTakeda \n, \nS. \nSakai \n, \nT. \nTakagi \n, et al. 2012 \nHepatitis B reactivation in a multiple myeloma patient with resolved hepatitis B infection during bortezomib therapy: case report . J. Clin. Exp. Hematop. \n52 :67 –69 .22706534 \n32 \n\nGoldberg , R. \n, \nE. \nSmith \n, \nS. \nBell \n, \nA. \nThompson \n, and \nP. V. \nDesmond \n. 2013 \nBortezomib monotherapy in patients with multiple myeloma is associated with reactivation of hepatitis B . Intern. Med. J. \n43 :835 –836 .23841765 \n33 \n\nHussain , S. \n, \nR. \nJhaj \n, \nS. \nAhsan \n, \nM. \nAhsan \n, \nR. E. \nBloom \n, and \nS. M. \nJafri \n. 2014 \nBortezomib induced hepatitis B reactivation . Case Rep. Med. \n2014 :964082 .24876846 \n34 \n\nLai , G. M. \n, \nS. L. \nYan \n, \nC. S. \nChang \n, and \nC. Y. \nTsai \n. 2013 \nHepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor . World J. Gastroenterol. \n19 :1318 –1321 .23483799 \n35 \n\nZhu , A. X. \n, \nM. \nKudo \n, \nE. \nAssenat \n, \nS. \nCattan \n, \nY. K. \nKang \n, \nH. Y. \nLim \n, et al. 2014 \nEffect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE‐1 randomized clinical trial . JAMA \n312 :57 –67 .25058218 \n36 \n\nMiyoshi , E. \n, \nJ. \nFujii \n, \nN. \nHayashi \n, \nK. \nUeda \n, \nT. \nTowata \n, \nH. \nFusamoto \n, et al. 1992 \nEnhancement of hepatitis‐B surface‐antigen expression by 5‐azacytidine in a hepatitis‐B‐virus‐transfected cell line . Int. J. Cancer \n52 :137 –140 .1379994 \n37 \n\nArora , A. \n, \nR. K. \nJalali \n, and \nD. \nVohora \n. 2017 \nRelevance of the Weber effect in contemporary pharmacovigilance of oncology drugs . Ther. Clin. Risk Manag. \n13 :1195 –1203 .28979130 \n38 \n\nPerrillo , R. P. \n, \nR. \nGish \n, and \nY. T. \nFalck‐Ytter \n. 2015 \nAmerican Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy . Gastroenterology \n148 :221 –244 .25447852 \n39 \n\nChou , C. K. \n, \nL. H. \nWang \n, \nH. M. \nLin \n, and \nC. W. \nChi \n. 1992 \nGlucocorticoid stimulates hepatitis B viral gene expression in cultured human hepatoma cells . Hepatology \n16 :13 –18 .1319949 \n40 \n\nMa , S. Y. \n, \nG. K. \nLau \n, \nV. C. \nCheng \n, and \nR. \nLiang \n. 2003 \nHepatitis B reactivation in patients positive for hepatitis B surface antigen undergoing autologous hematopoietic cell transplantation . Leuk. Lymphoma \n44 :1281 –1285 .12952220 \n41 \n\nMya , D. H. \n, \nS. T. \nHan \n, \nY. C. \nLinn \n, \nW. Y. \nHwang \n, \nY. T. \nGoh \n, and \nD. C. \nTan \n. 2012 \nRisk of hepatitis B reactivation and the role of novel agents and stem‐cell transplantation in multiple myeloma patients with hepatitis B virus (HBV) infection . Ann. Oncol. \n23 :421 –426 .21551005 \n42 \n\nHauben , M. \n, and \nA. \nBate \n. 2009 \nDecision support methods for the detection of adverse events in post‐marketing data . Drug Discov. Today \n14 :343 –357 .19187799 \n43 \n\nNagashima , T. \n, \nH. \nShirakawa \n, \nT. \nNakagawa \n, and \nS. \nKaneko \n. 2016 \nPrevention of antipsychotic‐induced hyperglycaemia by vitamin D: a data mining prediction followed by experimental exploration of the molecular mechanism . Sci. Rep. \n6 :26375 .27199286 \n44 \n\nXu , L. \n, \nZ. \nTu \n, \nG. \nXu \n, \nY. \nWang \n, \nW. \nPan \n, \nX. \nZhan \n, et al. 2014 \nEpirubicin directly promotes hepatitis B virus (HBV) replication in stable HBV‐expressing cell lines: a novel mechanism of HBV reactivation following anticancer chemotherapy . Mol. Med. Rep. \n9 :1345 –1350 .24566498 \n45 \n\nHsu , C. H. \n, \nH. C. \nHsu \n, \nH. L. \nChen \n, \nM. \nGao \n, \nP. Y. \nYeh \n, \nP. J. \nChen \n, et al. 2004 \nDoxorubicin activates hepatitis B virus (HBV) replication in HBV‐harboring hepatoblastoma cells. A possible novel mechanism of HBV reactivation in HBV carriers receiving systemic chemotherapy . Anticancer Res. \n24 :3035 –3040 .15517913\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "7(6)",
"journal": "Cancer medicine",
"keywords": "Cancer chemotherapy; FDA Adverse Event Reporting System; data mining; hepatitis B virus; signal detection",
"medline_ta": "Cancer Med",
"mesh_terms": "D064420:Drug-Related Side Effects and Adverse Reactions; D006509:Hepatitis B; D006801:Humans; D009369:Neoplasms; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "2269-2279",
"pmc": null,
"pmid": "29663729",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22706534;20516452;24108082;25447852;2230000;23483799;14708680;22711851;25058218;16440366;21613990;19358225;12952220;14558179;1319949;24566498;11828828;27199286;28979130;21788556;22586011;15517913;24876846;26642212;21551005;12071782;22933131;22436845;28219691;20533878;12071774;25962692;11998548;26595058;23841765;1379994;11072960;18802412;15619136;19187799",
"title": "Hepatitis B infection reported with cancer chemotherapy: analyzing the US FDA Adverse Event Reporting System.",
"title_normalized": "hepatitis b infection reported with cancer chemotherapy analyzing the us fda adverse event reporting system"
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"abstract": "In 2016, the World Health Organization adopted dolutegravir (DTG)-based antiretroviral therapy as an alternative first-line treatment of HIV after many clinical trials showed that it was more effective, better tolerated and more protective than efavirenz and boosted protease inhibitors against discontinuation of treatment from adverse drug reactions. However, there was concern that DTG would lead to increased rates of immune reconstitution inflammatory syndrome (IRIS), especially in the setting of late presentation to care. Three cases at the University Teaching Hospital in Lusaka, Zambia highlight this concern, especially in persons living with HIV (PLWH), resulting in tuberculosis (TB) co-infection.",
"affiliations": "Internal Medicine Consultant and Neurology Registrar, Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia.;Infectious Diseases Registrar, Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia.;Neurology Registrar, Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia.;Neurology Registrar, Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia.;Honorary Consultant, University Teaching Hospital, Lusaka, Zambia.",
"authors": "Zimba|Stanley|S|https://orcid.org/0000-0001-6861-6416;Mbewe|Nyuma|N|;Chishimba|Lorraine|L|;Chomba|Mashina|M|;Saylor|Deanna|D|",
"chemical_list": "D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir; C098320:efavirenz",
"country": "England",
"delete": false,
"doi": "10.1177/0049475520953704",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-4755",
"issue": "51(2)",
"journal": "Tropical doctor",
"keywords": "HIV; Tuberculosis; dolutegravir; immune reconstitution inflammatory syndrome",
"medline_ta": "Trop Doct",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D048588:Benzoxazines; D060085:Coinfection; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections; D006575:Heterocyclic Compounds, 3-Ring; D006784:Hospitals, Teaching; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D014376:Tuberculosis; D015024:Zambia",
"nlm_unique_id": "1301706",
"other_id": null,
"pages": "216-218",
"pmc": null,
"pmid": "32903146",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immune reconstitution inflammatory syndrome: a report of TB-IRIS after switching from efavirenz to dolutegravir.",
"title_normalized": "immune reconstitution inflammatory syndrome a report of tb iris after switching from efavirenz to dolutegravir"
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"companynumb": "ZM-MYLANLABS-2021M1031888",
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"activesubstancename": "DOLUTEGRAVIR\\LAMIVUDINE\\TENOFOVIR DISOPROXIL FUMARATE"
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"abstract": "OBJECTIVE\nPreclinical data showed enhancement of breast cancer cell death when G3139 was combined with anthracyclines and taxanes. We evaluated the efficacy and safety of a Bcl-2 antisense oligonucleotide, G3139, in combination with doxorubicin (A) and docetaxel (T) in patients with locally advanced breast cancer (LABC).\n\n\nMETHODS\nFollowing a brief phase I to determine the phase II dose, patients with locally advanced breast cancer received G3139 administered by continuous i.v. infusion for 5 to 7 days with bolus A (50 mg/m2) and T (75 mg/m2) administered on either day 3 or 6 of therapy with G3139. Cycles were repeated every 21 days x 6 in the neoadjuvant setting. Serial plasma samples were obtained for pharmacokinetic analysis. Tissue samples were obtained before and after therapy for pharmacodynamic analysis of Bcl-2 expression.\n\n\nRESULTS\nThirty patients (median age, 49 years; range, 24-71 years) received 160 cycles. During the phase I portion of the trial, the dose of G3139 was escalated from 3 to 7 mg/kg/d (i.v. for 5 days) in combination with AT. During the phase II portion of the trial, several doses and schedules of G3139 were evaluated. There were no pathologic complete responses. Pharmacodynamic studies showed limited Bcl-2 down-regulation in the primary tumors.\n\n\nCONCLUSIONS\nG3139 in combination with doxorubicin and docetaxel is well tolerated. No pathologic complete response was seen and pharmacodynamic studies showed very little down-regulation of Bcl-2 in primary tumors, perhaps related to issues with insufficient drug delivery to the intact tumor.",
"affiliations": "Department of Breast Medical Oncology, Pathology, Surgical Oncology, Radiation Oncology and Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.",
"authors": "Moulder|Stacy L|SL|;Symmans|W Fraser|WF|;Booser|Daniel J|DJ|;Madden|Timothy L|TL|;Lipsanen|Cindy|C|;Yuan|Linda|L|;Brewster|Abenaa M|AM|;Cristofanilli|Massimo|M|;Hunt|Kelly K|KK|;Buchholz|Thomas A|TA|;Zwiebel|James|J|;Valero|Vicente|V|;Hortobagyi|Gabriel N|GN|;Esteva|Francisco J|FJ|",
"chemical_list": "D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; D004317:Doxorubicin; C408162:oblimersen",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-08-1104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "14(23)",
"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; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000077143:Docetaxel; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids; D013873:Thionucleotides",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "7909-16",
"pmc": null,
"pmid": "19047121",
"pubdate": "2008-12-01",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "17214361;10080586;8324744;15277270;12056703;8133533;10784621;16322117;9796962;11751483;7977649;9815973;17513805;10914739;11685732;11895895;11855753;11110054;8673929;16752226;16280040;9815644;15837982;12602766;7640218;16818519;11095261;15020613;8874332;18281659;10655437;15860854;7960234",
"title": "Phase I/II study of G3139 (Bcl-2 antisense oligonucleotide) in combination with doxorubicin and docetaxel in breast cancer.",
"title_normalized": "phase i ii study of g3139 bcl 2 antisense oligonucleotide in combination with doxorubicin and docetaxel in breast cancer"
} | [
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"companynumb": "US-JNJFOC-20130609217",
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"activesubstancename": "DOXORUBICIN"
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... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to compare the efficacy and safety of golimumab (GLM) 50 mg + methotrexate (MTX) combination therapy and GLM 100 mg monotherapy in patients with rheumatoid arthritis (RA).\n\n\nMETHODS\nThe subjects were 115 RA patients (92 females and 23 males; median (range) age, 64 (17-87) years; median (range) disease duration, 8 (0.6-48) years) started on GLM. Eighty-three patients received GLM 50 mg/4 weeks + MTX (C group; median (range) MTX dosage 8 (2-16) mg/week), and 32 patients received GLM 100 mg/4 weeks (M group). Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), matrix metalloproteinase-3, disease activity score (DAS) 28-ESR, DAS28-CRP, simplified disease activity index, and clinical disease activity index were evaluated 4, 12, and 24 weeks after starting GLM.\n\n\nRESULTS\nThere were no significant differences in disease activity, adverse events, and drug continuation rates at 24 weeks between the groups. The DAS28-ESR remission rate was 34% in the C group and 26% in the M group.\n\n\nCONCLUSIONS\nGLM 100 mg monotherapy improved disease activity as well as GLM 50 mg + MTX combination therapy. GLM 100 mg monotherapy appears to have a sufficient therapeutic effect in RA patients who cannot take MTX.",
"affiliations": "a Department of Orthopaedic Surgery , Gunma University Graduate School of Medicine , Maebashi, Gunma , Japan.;a Department of Orthopaedic Surgery , Gunma University Graduate School of Medicine , Maebashi, Gunma , Japan.;b Department of Rheumatology , Isesaki Fukushima Hospital , Isesaki, Gunma , Japan.;c Department of Orthopaedic Surgery , Keiyu Orthopaedic Hospital , Tatebayashi, Gunma , Japan.;d Department of Orthopaedic Surgery , Inoue Hospital , Takasaki, Gunma , Japan.;e Department of Orthopaedic Surgery , Isesaki Fukushima Hospital , Isesaki, Gunma , Japan.;d Department of Orthopaedic Surgery , Inoue Hospital , Takasaki, Gunma , Japan.;f Department of Rheumatology , Gunma Rheumatism Clinic , Takasaki, Gunma , Japan.;a Department of Orthopaedic Surgery , Gunma University Graduate School of Medicine , Maebashi, Gunma , Japan.;e Department of Orthopaedic Surgery , Isesaki Fukushima Hospital , Isesaki, Gunma , Japan.;d Department of Orthopaedic Surgery , Inoue Hospital , Takasaki, Gunma , Japan.;a Department of Orthopaedic Surgery , Gunma University Graduate School of Medicine , Maebashi, Gunma , Japan.",
"authors": "Yonemoto|Yukio|Y|;Okamura|Koichi|K|;Takeuchi|Kimihiko|K|;Ayabe|Keio|K|;Kaneko|Tetsuya|T|;Matsushita|Masatoshi|M|;Tamura|Yasuyuki|Y|;Iso|Takenobu|T|;Okura|Chisa|C|;Otsuka|Keiko|K|;Inoue|Hiroshi|H|;Takagishi|Kenji|K|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D002097:C-Reactive Protein; C529000:golimumab; D019278:Matrix Metalloproteinase 3; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.3109/14397595.2015.1069472",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "26(1)",
"journal": "Modern rheumatology",
"keywords": "Biologics; Golimumab; Monotherapy; Multicenter cohort study; Rheumatoid arthritis",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001799:Blood Sedimentation; D002097:C-Reactive Protein; D015331:Cohort Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3; D008727:Methotrexate; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "24-8",
"pmc": null,
"pmid": "26140464",
"pubdate": "2016",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Comparison of golimumab 100-mg monotherapy to golimumab 50 mg plus methotrexate in patients with rheumatoid arthritis: Results from a multicenter, cohort study.",
"title_normalized": "comparison of golimumab 100 mg monotherapy to golimumab 50 mg plus methotrexate in patients with rheumatoid arthritis results from a multicenter cohort study"
} | [
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"companynumb": "JP-JNJFOC-20160102994",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
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"actiondrug": "1",
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"activesubstancename": "GOLIMUMAB"
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"drugadditional": null,
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{
"abstract": "OBJECTIVE\nTo report parameters and outcomes of phosphorus management in a maintenance hemodialysis patient who experienced atherosclerotic coronary calcification leading to myocardial infarction; to evaluate the role that high calcium intake over 6 years may have played in his coronary artery disease before the dangers of excess calcium intake in phosphorus management were recognized; and to describe an optimized therapeutic approach that provided improved mineral control.\n\n\nMETHODS\nCase study.\n\n\nMETHODS\nA large outpatient in-center hemodialysis treatment unit.\n\n\nMETHODS\nSerum calcium, serum phosphorus, Ca x P product.\n\n\nRESULTS\nThe year before his cardiac event, the patient's mean serum calcium was 9.6 mg/dL, mean serum phosphorus was 5.9 mg/dL, and mean Ca x P product was 57 mg2/dL2. Serum calcium peaked at 10.8 mg/dL shortly before his cardiac event. Treatment phases included high-dose calcium acetate (10 g Ca/day), low-dose calcium acetate (4 g Ca/day), low-dose calcium acetate plus low-dose sevelamer hydrochloride (4 g Ca/day plus 2.4 to 4.8 g sevelamer/day), and low-dose calcium acetate plus higher-dose sevelamer hydrochloride (4 g Ca/day plus 4.0 to 12.0 g sevelamer/day). With calcium acetate and sevelamer doses optimized, serum phosphorus levels and Ca x P products continued decreasing, with mean values of 5.99 mg/dL and 50.7 mg2/dL2, respectively, and serum calcium remained stable at a mean of 8.5 mg/dL. The patient has had no further myocardial infarctions.\n\n\nCONCLUSIONS\nThis case illustrates how our growing understanding of phosphorus management and the addition of a calcium-free binder to our therapeutic armamentarium have improved phosphorus and calcium balance, reducing the risk of cardiovascular calcification.",
"affiliations": "Fresenius Medical Care of Bethlehem, Bethlehem, PA 18017, USA. clp1rd@aol.com",
"authors": "Paret|Cindy Lynch|CL|",
"chemical_list": "D000085:Acetates; D017610:Calcium Compounds; D004852:Epoxy Compounds; D011073:Polyamines; D011095:Polyethylenes; D010758:Phosphorus; D000069603:Sevelamer; D002118:Calcium; C120662:calcium acetate",
"country": "United States",
"delete": false,
"doi": "10.1016/s1051-2276(03)00118-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-2276",
"issue": "13(4)",
"journal": "Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation",
"keywords": null,
"medline_ta": "J Ren Nutr",
"mesh_terms": "D000085:Acetates; D002118:Calcium; D017610:Calcium Compounds; D003324:Coronary Artery Disease; D004852:Epoxy Compounds; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010758:Phosphorus; D011073:Polyamines; D011095:Polyethylenes; D006435:Renal Dialysis; D000069603:Sevelamer",
"nlm_unique_id": "9112938",
"other_id": null,
"pages": "288-94",
"pmc": null,
"pmid": "14566766",
"pubdate": "2003-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Calcium-containing phosphate binder use associated with accelerated atherosclerotic coronary calcification.",
"title_normalized": "calcium containing phosphate binder use associated with accelerated atherosclerotic coronary calcification"
} | [
{
"companynumb": "US-FRESENIUS MEDICAL CARE NORTH AMERICA-1049275",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "2",
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"activesubstancename": "CALCIUM ACETATE"
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"abstract": "Immunotherapy is an expanding area of cancer treatment with significant promise. Despite their efficacy, checkpoint inhibitors are associated with a number of immune-related adverse events; here, we described thrombocytopenia secondary todurvalumab.",
"affiliations": "Department of Internal Medicine University of Virginia Charlottesville VA USA.;Department of Pharmacy University of Virginia Charlottesville VA USA.;Department of Internal Medicine University of Virginia Charlottesville VA USA.",
"authors": "Dougherty|Sean C|SC|https://orcid.org/0000-0001-6076-7084;Lynch|Alia C|AC|;Hall|Richard D|RD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4227",
"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/ccr3.4227\nCCR34227\nCase Report\nCase Reports\nDrug‐induced immune‐mediated thrombocytopenia secondary to durvalumab use\nDOUGHERTY et al.\nDougherty Sean C. MD https://orcid.org/0000-0001-6076-7084\n1\nLynch Alia C. PharmD 2\nHall Richard D. MD, MS 1 RDH3Q@hscmail.mcc.virginia.edu\n\n1 Department of Internal Medicine University of Virginia Charlottesville VA USA\n2 Department of Pharmacy University of Virginia Charlottesville VA USA\n* Correspondence\nRichard D. Hall, Department of Internal Medicine, University of Virginia, 1240 Lee St., Charlottesville, VA, 22903, USA.\nEmail: RDH3Q@hscmail.mcc.virginia.edu\n\n22 6 2021\n6 2021\n9 6 10.1002/ccr3.v9.6 e0422731 3 2021\n19 1 2021\n14 4 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\nImmunotherapy is an expanding area of cancer treatment with significant promise. Despite their efficacy, checkpoint inhibitors are associated with a number of immune‐related adverse events; here, we described thrombocytopenia secondary todurvalumab.\n\nImmunotherapy is an expanding area of cancer treatment with significant promise. Despite their efficacy, checkpoint inhibitors are associated with a number of immune‐related adverse events; here, we described thrombocytopenia secondary todurvalumab.\n\nITP\nmedical oncology\npharmacokinetics\nplatelets—acquired platelet disorders\nthrombocytopenia\nsource-schema-version-number2.0\ncover-dateJune 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:22.06.2021\nDougherty SC , Lynch AC , Hall RD . Drug‐induced immune‐mediated thrombocytopenia secondary to durvalumab use. Clin Case Rep. 2021;9 :e04227. 10.1002/ccr3.4227\n\nWritten informed consent was obtained from the patient prior to manuscript composition\n==== Body\n1 INTRODUCTION\n\nDurvalumab is a human monoclonal antibody targeting the programmed death ligand 1 (PD‐L1) pathway approved for the treatment of non‐small cell lung cancer (NSCLC) and other malignancies. Among other immune‐related adverse events (irAEs), thrombocytopenia has rarely been reported with durvalumab use, though is a potentially life‐threatening complication of treatment.\n\nDurvalumab is a human IgG1 monoclonal antibody approved for the treatment of multiple malignancies, including urothelial carcinoma and non‐small cell lung cancer (NSCLC). 1 , 2 As a checkpoint inhibitor (CPI), durvalumab targets and blocks programmed death ligand 1 (PD‐L1) on tumor cells, resulting in increased T‐cell activation and destruction of cancer cells. 3 , 4 While CPIs are an expanding area of cancer treatment with significant promise, multiple side effects of treatment, or immune‐related adverse events (irAE), have been reported. 5 , 6 , 7 Cytopenias have also been reported with CPI use, and for durvalumab specifically, have been noted to occur in less than 1% of individuals treated. 8\n\nDrug‐Induced thrombocytopenia (DITP) is an immune‐mediated process wherein drugs covalently linked to proteins or other macromolecules induce a humoral immune response, with the antibodies produced binding to and destroying platelets in the presence of the drug. 8 The typical time course for development of such antibodies with resultant thrombocytopenia is 1 to 2 weeks following initiation of a new drug, however, if a patient has previously been exposed, the effects can occur more acutely. 9 Cessation of the offending agent is critical to management of this condition.\n\nIn this clinical report, we detail the presentation, evaluation, and diagnosis of a case of drug‐induced thrombocytopenia secondary to durvalumab use. To our knowledge, this is only the second reported case of this irAE with durvalumab, and represents the first case of steroid‐responsive immune‐mediated thrombocytopenia with this specific CPI.\n\n2 CASE PRESENTATION\n\nA 45 year‐old woman, current smoker without significant medical problems presented to oncology clinic for a follow‐up visit for management of her unresectable, stage IIIB NSCLC. She had been diagnosed with poorly differentiated adenocarcinoma four months prior and was treated with definitive cisplatin and pemetrexed with concurrent radiation therapy (66Gy in 33 fractions). Her platelets were normal throughout concurrent chemotherapy and radiation (CTX + RT). Two weeks after completing CTX + RT, she began durvalumab consolidation therapy every two weeks. She tolerated the first two cycles of durvalumab without evidence of irAEs, though noted increased bruising on her arms following the third cycle. She denied any overt bleeding episodes, epistaxis, hematuria, fever, rash, diarrhea, or dyspnea.\n\nOn physical examination, her temperature was 36.9 degrees Celsius, blood pressure was 127/84 mm Hg, heart rate was 108 beats per minute, and respiratory rate was 18 breaths per minute. She had multiple ecchymoses visible on the arms and abdomen, though no petechial rash or purpura of the lower extremities was seen. She did not have palpable hepatosplenomegaly or lymphadenopathy.\n\nA complete blood count revealed a white blood cell count of 6.73 × 109/L, hemoglobin of 13.7 grams/dL, and platelet count of 24 × 109/L. She did not have a history of thrombocytopenia, and her platelets had previously been within normal limits prior to and during treatment (Figure 1).\n\nFIGURE 1 A, Patient's baseline platelet counts during treatment with chemotherapy and radiation (blue bar), followed by development of severe thrombocytopenia (platelet count of 24 × 10^9/L) with initiation of durvalumab (red bar), and then return of platelet counts to normal limits following initiation of corticosteroids. Initiation and duration of treatment with dexamethasone and prednisone are shown with orange and green bars, respectively. B, Patient's baseline white blood cell and hemoglobin counts during treatment with chemotherapy and radiation (blue bar), initiation of durvalumab (red bar), and following initiation of corticosteroids (orange and green bars). Despite development of severe thrombocytopenia with durvalumab use, our patient did not have evidence of pancytopenia\n\nA peripheral blood smear was reviewed and did not have evidence of platelet clumping, fragmented platelets, or schisctocytes, though large platelets were present. A bone marrow biopsy was not performed in this patient given the high suspicion for DITP secondary to durvalumab.\n\n3 DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS, AND TREATMENT\n\nThe differential diagnosis for isolated thrombocytopenia is broad, and for this patient included immune‐mediated thrombocytopenia, disseminated intravascular coagluation (DIC), hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and pseudothrombocytopenia.\n\nIn regard to immune‐mediated thrombocytopenia, given the previously normal platelet count and temporal relationship of the observed thrombocytopenia and recent initiation of durvalumab, this seemed most likely. Previously published case reports in the literature citing thrombocytopenia secondary to PD‐1/PD‐L1 blockade also supported this diagnosis. 10 , 11 , 12\n\nThe diagnoses of DIC, HUS, TTP, and pseudothrombocytopenia were able to be excluded based on laboratory analysis and examination of the peripheral blood smear. The patient's hemoglobin was at her baseline (~13 g/dL) at the time of presentation, excluding hemolysis and thus HUS. Her creatinine was also at her baseline, further excluding HUS. DIC, TTP, and pseudothrombocytopenia were excluded based on the lack of schistocytes or platelet clumping in the peripheral blood smear and no evidence of overt coagulopathy.\n\n4 OUTCOME AND FOLLOW‐UP\n\nIn the setting of grade IV thrombocytopenia suspected to be due to durvalumab, the patient received dexamethasone, 40 mg by mouth daily for four days. Her platelet count initially corrected to 170 × 109/L (without transfusion) one week after completion of steroids; however, when labs were rechecked the following week, her platelets had decreased to 69 × 109/L. She was then prescribed a prolonged prednisone taper over a four week period, with subsequent normalization of her platelets. Durvalumab was discontinued permanently, and at the time of manuscript composition, the patient remains alive and well. She has not had any overt episodes of bleeding, and her platelet counts remain within normal limits. She has not received further immunotherapy, including durvalumab, and her stage IIIB NSCLC is stable based on repeat imaging without evidence of local or distant metastatic progression.\n\n5 DISCUSSION\n\nDITP is a potentially life‐threatening condition that occurs when drug‐dependent anti‐platelet antibodies are produced against specific macromolecules of a drug and result in platelet destruction. The typical time to presentation of thrombocytopenia following initiation of the offending drug is 1 to 2 weeks, though this may be more acute if the patient has previously been exposed to the drug. The diagnosis is generally made clinically, though assays able to confirm the presence of anti‐platelet antibodies are available. Despite their availability, as with immune thrombocytopenia (ITP), these assays are generally not recommended, as they are labor‐intensive, take a significant amount of time to complete, and are nonspecific, as platelet‐associated IgG levels are elevated in both immune and nonimmune thrombocytopenia. 13 , 14 Management of this condition includes indefinite cessation of the offending drug, platelet transfusions as necessary to control overt bleeding episodes, and corticosteroids for immunomodulation.\n\nDITP secondary to CPI use has previously been reported with ipilimumab, pembrolizumab, and nivolumab. 10 , 11 , 12 , 15 The average time to presentation following initiation of therapy varied greatly, with thrombocytopenia being noted as early as one week following treatment, and up to 16 months later. Patient presentations also varied greatly, with overt hemorrhage, epistaxis, and other bleeding episodes reported in some individuals, whereas other patients were asymptomatic. The mainstay of treatment in these cases included stopping further infusions of the offending agent and initiation of corticosteroids, with methylprednisolone, 1 mg/kg generally being used. Other immunomodulatory drugs, including intravenous immunoglobulins, rituximab, and cyclosporine have also been used. 15\n\nImmune‐mediated thrombocytopenia in the setting of durvalumab use has also been previously reported, however, despite initiation of steroids and platelet transfusions, this case was unfortunately fatal. 16 There were two mechanisms of thrombocytopenia reported in this case: the first was the production of anti‐human platelet antigen auto‐antibodies due to decreased tolerance with durvalumab use, and the second was development of platelet alloimmunization and production of anti‐human leukocyte antigen antibodies in the setting of platelet transfusions received. The authors of this case report hypothesized that it was the latter mechanism, and not durvalumab use, that explained the refractory and deadly nature of the thrombocytopenia.\n\nOur case highlights the need for continued surveillance for irAEs after initiation of treatment, as these can occur months after patients receive immunotherapy. Despite previous presentations of overt bleeding with checkpoint inhibitor‐induced thrombocytopenia, our patient was asymptomatic aside from minor bruising of the bilateral upper extremities and abdomen. She developed thrombocytopenia approximately 6 weeks following initiation of durvalumab and during her third cycle of consolidation therapy. She was treated with dexamethasone, 40 mg by mouth daily for four days, a common ITP treatment regimen, and initially responded to this treatment. However, her platelets quickly declined with steroid discontinuation, and she was started on a four‐week prednisone taper for management of an irAE per American Society of Clinical Oncology guidelines. 17 Her platelets then stabilized within normal limits without further intervention or transfusion, highlighting the importance of treating this as an irAE with a prolonged steroid taper and not as ITP.\n\nAs noted above, durvalumab can result in immune‐mediated thrombocytopenia via production of anti‐platelet antibodies generated in the presence of the drug. Another mechanism by which CPI may cause thrombocytopenia involves the PD‐1:PD‐L1 pathway itself, as it is known that PD‐1 regulates peripheral T‐cell tolerance in multiple ways. 18 , 19 , 20 The first way involves PD‐L1‐dependent development of regulatory T cells (Treg), in turn dampening autoimmune tissue damage through the Treg‐mediated response; the second involves direct suppression of the activation and function of self‐reactive T cells.\n\nIn conclusion, as CPI and immunotherapy use for the management of NSCLC and other malignancies continues to increase, clinicians should remain aware of potential irAE that occur as a result of therapy. Cytopenias, in particular thrombocytopenia, can commonly occur and be potentially fatal if under recognized and under treated.\n\nCONFLICT OF INTEREST\n\nAll authors declare no conflicts of interest.\n\nAUTHOR CONTRIBUTIONS\n\nSD: involved in manuscript writing and designed figure under the mentorship of RH. AL: helped in manuscript writing and assisted in pharmacologic management of the patient. RH: supervised case report formulation, acquired and interpreted clinical data, aided in the diagnosis of disease and the physician of record.\n\nETHICAL APPROVAL\n\nAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. This study did not require IRB approval and was not part of a registered clinical trial.\n\nACKNOWLEDGEMENTS\n\nNone\n\nDATA AVAILABILITY STATEMENT\n\nData sharing is not applicable to this article as no new data were created or analyzed in this study.\n==== Refs\nREFERENCES\n\n1 Antonia SJ , Villegas A , Daniel D , et al. Durvalumab after chemoradiotherapy in stage III non‐small‐cell lung cancer. N Engl J Med. 2017;377 (20 ):1919‐1929. 10.1056/NEJMoa1709937 28885881\n2 Powles T , O'Donnell PH , Massard C , et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open‐label study. JAMA Oncol. 2017;3 (9 ):e172411–10.1001/jamaoncol.2017.2411 28817753\n3 Sharma P , Allison JP . Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161 (2 ):205‐214. 10.1016/j.cell.2015.03.030 25860605\n4 Moya‐Horno I , Viteri S , Karachaliou N , Rosell R . Combination of immunotherapy with targeted therapies in advanced non‐small cell lung cancer (NSCLC). Ther Adv Med Oncol. 2018;10 :1758834017745012. 10.1177/1758834017745012 29383034\n5 Postow MA , Sidlow R , Hellmann MD . Immune‐related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378 (2 ):158‐168. 10.1056/NEJMra1703481 29320654\n6 Ayala FA , Dougherty SC , Swift W , Lapides DA . Overlapping NMDA‐R and GFAP antibody autoimmune encephalitis after Nivolumab therapy. Neurol Clin Prac. 2020;10 :1212. 10.1212/CPJ.0000000000001008\n7 Brahmer JR , Lacchetti C , Thompson JA . management of immune‐related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline summary. J Oncol Pract. 2018;14 (4 ):247‐249. 10.1200/JOP.18.00005 29517954\n8 [8]Durvalumab [Package Insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2017.\n9 Aster RH , Curtis BR , McFarland JG , Bougie DW . Drug‐induced immune thrombocytopenia: pathogenesis, diagnosis, and management. J Thromb Haemost. 2009;7 (6 ):911‐918. 10.1111/j.1538-7836.2009.03360.x 19344362\n10 Aster RH , Bougie DW . Drug‐induced immune thrombocytopenia. N Engl J Med. 2007;357 (6 ):580‐587. 10.1056/NEJMra066469 17687133\n11 Karakas Y , Yuce D , Kilickap S . Immune thrombocytopenia induced by nivolumab in a metastatic non‐small cell lung cancer patient. Oncol Res Treat. 2017;40 (10 ):621‐622. 10.1159/000477968 28950270\n12 Ahmad S , Lewis M , Corrie P , Iddawela M . Ipilimumab‐induced thrombocytopenia in a patient with metastatic melanoma. J Oncol Pharm Pract. 2012;18 (2 ):287‐292. 10.1177/1078155211411001 21807763\n13 Le Roy A , Kempf E , Ackermann F , et al. Two cases of immune thrombocytopenia associated with pembrolizumab. Eur J Cancer. 2016;54 :172‐174. 10.1016/j.ejca.2015.10.073 26687374\n14 Bougie DW , Wilker PR , Aster RH . Patients with quinine‐induced immune thrombocytopenia have both \"drug‐dependent\" and \"drug‐specific\" antibodies. Blood. 2006;108 (3 ):922‐927. 10.1182/blood-2006-01-009803 16861345\n15 Provan D , Arnold DM , Bussel JB , et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3 (22 ):3780‐3817. 10.1182/bloodadvances.2019000812 31770441\n16 Sajjad MZ , George T , Weber JS , Sokol L . Thrombocytopenia associated with ipilimumab therapy of advanced melanoma at a single institution. J Clin Oncol. 2013;31 (15_suppl ):9072‐9072. 10.1200/jco.2013.31.15_suppl.9072\n17 Leroy L , Lafarge X , Blouin L , et al. A fatal allo‐ and immune‐mediated thrombocytopenia with a PD‐L1 inhibitor. Ann Oncol. 2018;29 (2 ):514‐515. 10.1093/annonc/mdx693 29088313\n18 Brahmer JR , Lacchetti C , Schneider BJ , et al. management of immune‐related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36 (17 ):1714‐1768. 10.1200/JCO.2017.77.6385 29442540\n19 Francisco LM , Sage PT , Sharpe AH . The PD‐1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236 :219‐242. 10.1111/j.1600-065X.2010.00923.x 20636820\n20 Francisco LM , Salinas VH , Brown KE , et al. PD‐L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206 (13 ):3015‐3029. 10.1084/jem.20090847 20008522\n21 Keir ME , Liang SC , Guleria I , et al. Tissue expression of PD‐L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203 (4 ):883‐895. 10.1084/jem.20051776 16606670\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(6)",
"journal": "Clinical case reports",
"keywords": "ITP; medical oncology; pharmacokinetics; platelets—acquired platelet disorders; thrombocytopenia",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "e04227",
"pmc": null,
"pmid": "34188921",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "28885881;29517954;16606670;29442540;16861345;29383034;17687133;21807763;25860605;29088313;29320654;20636820;28817753;28950270;20008522;31770441;19344362;26687374",
"title": "Drug-induced immune-mediated thrombocytopenia secondary to durvalumab use.",
"title_normalized": "drug induced immune mediated thrombocytopenia secondary to durvalumab use"
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"abstract": "BACKGROUND\nInspired by the presented case, this paper investigates treatment options for patients under active bisphosphonate therapy, suffering from a traumatic fracture in the absence of MRONJ (patients classified as 'at risk'). We review literature in search of standardized protocols and in combination.\n\n\nMETHODS\nA 75-year-old woman, suffering from osteoporosis for over a decade and being treated with alendronate for about 10 years, stumbled and fell and ended up with a displaced fracture on the right side of her extremely atrophied mandible. Under general anesthesia, using a limited submandibular approach with minimal reflecting of the periosteum, an external fixation device was placed. The patient recovered well from surgery and was discharged after 2 days. Long term follow-up shows good healing with a mouth opening of 46 mm in the absence of any sensory of functional deficits.\n\n\nCONCLUSIONS\nWe conclude from our literature review that there are no clear guidelines regarding fixation of traumatic (non-pathologic) maxillofacial fractures in patients under active antiresorptive therapy. Literature suggests that damaging the periosteum needs to be avoided since this would endanger the already fragile blood supply in the area. This could make an intra-oral approach unfavourable.\n\n\nCONCLUSIONS\nWe prefer an extra-oral approach whenever possible. The choice between the use of supraperiostally placed locking reconstruction plates or external fixation should be based on the overall medical condition of the patient, the regional osseous anatomy and the specific fracture morphology.",
"affiliations": "OMFS Ziekenhuis Oost-Limburg Genk, Belgium. Electronic address: philippe.vancamp@zol.be.;OMFS Ziekenhuis Oost-Limburg Genk, Belgium. Electronic address: bert.gemels@zol.be.;OMFS Ziekenhuis Oost-Limburg Genk, Belgium. Electronic address: guido.heijsters@zol.be.;OMFS Ziekenhuis Oost-Limburg Genk, Belgium. Electronic address: serge.schepers@zol.be.",
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"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(18)30367-510.1016/j.ijscr.2018.08.063ArticleCase report of maxillofacial fracture in a patient under bisphosphonates in the absence of ONJ disease: Guidelines? Van Camp Philippe philippe.vancamp@zol.be⁎Gemels Bert bert.gemels@zol.beHeijsters Guido guido.heijsters@zol.beSchepers Serge serge.schepers@zol.beOMFS Ziekenhuis Oost-Limburg Genk, Belgium⁎ Corresponding author at: Nieuwelaan 52, 2520 Oelegem, Belgium. philippe.vancamp@zol.be10 9 2018 2018 10 9 2018 51 318 322 26 5 2018 20 8 2018 28 8 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Case consisting of traumatic fracture in patient under bisphosphonates.\n\n• No MRONJ, so no pathological fracture.\n\n• No guidelines available for patients ‘at risk’.\n\n• Best treatment avoids periosteal stripping.\n\n• Fixation using external fixation or locking reconstruction plate.\n\n\n\nIntroduction\nInspired by the presented case, this paper investigates treatment options for patients under active bisphosphonate therapy, suffering from a traumatic fracture in the absence of MRONJ (patients classified as ‘at risk’). We review literature in search of standardized protocols and in combination.\n\nPresentation of case\nA 75-year-old woman, suffering from osteoporosis for over a decade and being treated with alendronate for about 10 years, stumbled and fell and ended up with a displaced fracture on the right side of her extremely atrophied mandible. Under general anesthesia, using a limited submandibular approach with minimal reflecting of the periosteum, an external fixation device was placed. The patient recovered well from surgery and was discharged after 2 days. Long term follow-up shows good healing with a mouth opening of 46 mm in the absence of any sensory of functional deficits.\n\nDiscussion\nWe conclude from our literature review that there are no clear guidelines regarding fixation of traumatic (non-pathologic) maxillofacial fractures in patients under active antiresorptive therapy. Literature suggests that damaging the periosteum needs to be avoided since this would endanger the already fragile blood supply in the area. This could make an intra-oral approach unfavourable.\n\nConclusion\nWe prefer an extra-oral approach whenever possible. The choice between the use of supraperiostally placed locking reconstruction plates or external fixation should be based on the overall medical condition of the patient, the regional osseous anatomy and the specific fracture morphology.\n\nKeywords\nBisphosphonateTraumatic maxillofacial fractureGuidelines\n==== Body\n1 Introduction\nAntiresorptive medication is used in pathology affecting the bone in order to prevent pathological fractures, firstly by causing apoptosis of the osteoclast and secondly by decreasing the osteoblast-medicated osteoclastic resorption [[1], [2], [3], [4], [5]]. The combined result is an increase in bone mass anddensity, as well as a modification of the bone architecture resulting in altered mechanical properties. [1,6] Elevated bone turnover, greater blood supply to the jaws and constant strain caused by masticatory function resulting in microdamage accumulation, might explain why the jaws are more susceptible to the effects of these medications.\n\nDiminished or absent osseous and mucosal healing or the oral tissues is a known side effect. This is important in two ways. Firstly, Medication-Related OsteoNecrosis of the Jaws’ (MRONJ) with incidence ranging from 0,8–12% [7], it’s complications and management strategies are well documented and reviewed and will not be discussed in this paper [2,3,7–,1,2,3,4,5,6,7,8,9].Secondly, the decreased osseous healing causes diffult fracture treatment which we will discuss here. Moreover, the elder patient is especially at risk because of the added difficulty of age-related dimished blood flow to the bone and varying degrees of atrophy making fracture treatment very challenging [3,8,10,11]. We specify on traumatic fractures in patients without MRONJ (commonly classified as ‘at risk’)? Although epidemiological data about this specific matter is lacking, the research question is clinically relevant since the amount of patients on antiresorptive medication is growing and so the correct fracture treatment in this population needs to be established. This case report is in line with the SCARE criteria [12].\n\n2 Presentation of case\nA 75-year-old woman, suffering from osteoporosis for over a decade and being treated with alendronate for 10 years, stumbled and fell. She didn’t seek any medical assistance until 2 weeks later. Clinical and radiographical examination revealed extremely atrophic jaws with a displaced mandibular fracture on the right side. (Fig. 1) The image is distorted due to the patient’s inability to stand completely still (as a result of concomitant multiple sclerosis) during the acquisition of the X-ray.Fig. 1 Panoramic X-ray depicting the mandibular fracture on the right side.\n\nFig. 1\n\nUsing a submandibular approach with minimal reflecting of the periosteum, an external fixation device was placed. Fig. 2 shows the post-operative situation. Reduction of the fracture was deliberately done in a non-anatomical position since this would lead to insufficient buttressing of the fragments. Therefore, some overlapping of the bony fragments was intended with the interpositioning of a synthetic bone graft. The patient recovered well and was discharged 2 days later. Check-up shows good, though very slow bone healing. Fixation was removed after 2,5 months (Fig. 3). Long term follow-up after 4 years shows adequate healing of the fracture. (Fig. 4) The patient is functional with a mouth opening of 46 mm in the absence of any sensory deficits. She is free of any remaining complaints. (Fig. 5)Fig. 2 Panoramic X-ray after surgery.\n\nFig. 2Fig. 3 Clinical photograph at time of removal of external fixationg. A: lateral view; B: frontal view; C: lateral view after removal.\n\nFig. 3Fig. 4 Panoramic X-ray after 4 years.\n\nFig. 4Fig. 5 Clinical photograph after 4 years. A: frontal view; B: frontal view with maximal mouth opening; C; lateral view with maximal mouth opening; D: Mouth opening of 46 mm.\n\nFig. 5\n\n3 Discussion\nIn essence, we have an elderly patient under active oral bisphosphonate therapy (classified by AAOMS as ‘at risk’) with a displaced fracture of the mandible. Our research question was: “Are there guidelines for treatment of a traumatic maxillofacial fracture in patients under active antiresorptive treatment but without MRONJ?”\n\nA comprehensive search of the PubMed and Medline database was performed on 07/01/2018 for literature in the last 10 years using MeSH terms ‘jaw fractures’, ‘bone density conservation agents’. To avoid articles discussing pathological fractures and articles concerning BRONJ, we used following MeSH terms as exclusion criteria ‘fractures, spontaneous’ and ‘bisphosphonate-associated osteonecrosis of the jaw’. The initial search rendered 4 articles selected for full text reading [1,[13], [14], [15]]. Because of the limited articles that were found, the exclusion criteria were removed from the search, adding another 2 studies [2,16]. None of these suggest any guidelines concerning the topic.\n\nFurther analysis of literature based the reference lists from the selected articles, reveals some articles suggesting guidelines. In the article from Coletti and Ord [3] a treatment rationale is proposed based on the etiology of the fractures. In their population however, fractures are caused by osteoradionecrosis, osteomyelitis, bisphosphonate-related osteonecrosis, osseous tumors or metastatic bone lesions. This is in contrast to our research question, specifying on patients without any lesions who receive antiresorptive medication on prophylactic basis only. The article by Gerhards et al [17] is not applicable for the same reason.\n\nEllis and Price [9] describe common problems with fractures in atrophic mandibles. They proficiently describe a treatment protocol for these fractures, mostly using an extra-oral approach. However, there were no patients under active bisphosphonate therapy.\n\nWhen looking for treatment options, we are faced with spectrum of possible solutions, each with their benefits but also their disadvantages.1 Conservative approach may be indicated in minimally displaced fractures or in patients with severe medical issues not able to undergo surgery.\n\n2 Intermaxillary fixation (utilizing Erich splints or IMF screws) is a conservative approach, though it is very debilitating for the patients. Also there is no rigid fracture fixation, possibly leading to insufficient fracture healing [6]. Furthermore, IMF in edentulous patients is often challenging.\n\n3 External fixation is a method of fracture stabilization which is used less frequently, but is minimally invasive. This means that it can be used on severely medically impaired patients with relative ease. Although debilitating to the patient, it does not comprise blood flow and can indeed ensure correct fracture healing.\n\n4 Intra-oral open reduction and fixation is the most commonly used method for fractures of the maxillofacial skeleton. It does have several down sides: [7,11]a the exposure of the bone to intra-oral bacteria\n\nb difficulty of fixation due to (severe) atrophy. The correct positioning of bone fragments may become very difficult due to insufficient buttressing. Using multiple mini-plates is difficult because of the reduced bone volume. Therefore, a single thicker plate yielding increased stability will often be needed, impeding functional use of a removable prosthesis [11].\n\nc extensive reflecting of the periosteum comprising blood flow\n\n\n\n5 Extra-oral open reduction and fixation provides better surgical access and allows for less periosteal stripping. Mini-plates or locking reconstruction plates (LRP) can be used. Especially in edentulous jaws, a LRP may be beneficiary as a LRP will better withstand cyclic deformation of the mandibular arch while taking up less space. They can be placed supraperiosteally with minimal compression to the bone as not to disturb blood flow [7,18]. Also, the use of LRP can be successful in rehabilitation function even when no real fracture healing occurs.\n\n\n\nIn healthy patients, the use of bone grafts is said to cause an increase of bone healing through the introduction of osteocompetent cells to the fracture area. However, this results in an increased invasiveness of the procedure [19]. Also, no data is available on this procedure in patients under antiresorptive medication.\n\nFrom the aforementioned important issues, we deduce that adequate fracture healing in this specific situation needs to answer to following key points:1 Strongly consider an extra-oral approach. This approach provides a more sterile operation area and allows for less periosteal stripping.\n\n2 Minimize reflecting of the periosteum as not to impair blood supply.\n\n3 Rigid fixation of the fracture with complete immobilization may be the preferable method, general medical condition of the patient permitting. In (severely) medically impaired patients, an external fixation can be used with good functional outcome.\n\n4 When a LRP is used, supraperiosteal (or even superficial of the platysma) placement may be considered [7,11].\n\n\n\nIn parallel to the guidelines of a drug holiday in case of planned dental surgery [3] discontinuation of the bisphosphonates after the traumatic event may be considered [19,20]. However, one must realize that these molecules have a very long half-life, especially the ones given intravenously. This implies that discontinuation may not have a significant short-term influence on bone healing. The anti-angiogenic effect may recuperate more quickly. The discontinuation is advised, though decision for cessation of the medication should be made in discussion with the treating physician, weighing the pros versus the cons.\n\n3.1 Conclusion\nWe conclude that there are no epidemiological data nor any clear guidelines regarding traumatic (non-pathologic) maxillofacial fractures in patients under active antiresorptive therapy. Hard and soft tissues in these patients have different qualities to those in healthy individuals and will react differently to fracture treatment with delayed and/or incomplete healing. An extra-oral approach should be used whenever possible. The choice between supraperiostally placed locking reconstruction plates or external fixation should be based on the overall medical condition of the patient, the regional osseous anatomy (eg severe atrophy) and the specific fracture morphology. Bisphosphonates should be halted during healing phase, general medical condition permitting.\n\nConflicts of interest\nNone.\n\nSources of funding\nNone.\n\nEthical approval\nThis case report was exempt from ethical approval. The study was written with consent of the patient involved. Patient data were anonymised to protect the privacy of the patient.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case reportand accompanying images. A copy of the written consent is available for review by the\n\nEditor-in-Chief of this journal on request.\n\nAuthor contribution\nVan Camp Philippe: data collection, preparation of paper, review of manuscript.\n\nGemels Bert: preparation of paper, review of manuscript.\n\nHeijsters Guido: review of manuscript.\n\nSchepers Serge: review of manuscript.\n\nRegistration of research studies\nNot applicable, case report.\n\nGuarantor\nVan Camp Philippe.\n\nSchepers Serge.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed\n\nAcknowledgements\nNone\n==== Refs\nReferences\n1 Camacho-Alonso F. Lopez-Jornet P. Vicente-Hernandez A. Short-term effect of zoledronic acid upon fracture resistance of the mandibular condyle and femoral head in an animal model Med. Oral. Patol. Oral Cir. Bucal 18 2013 421 426 \n2 Sehn F. Dias R. Oral bisphosphonate-related mandible fracture J. Craniofac. Surg. 25 2014 709 710 24621737 \n3 Coletti D. Ord R. Treatment rationale for pathological fractures of the mandible: a series of 44 fractures Int. J. Oral Maxillofac. Surg. 37 2008 215 222 18023145 \n4 Grady M. Watson J. Cannada L. Treatment of femoral fracture nonunion after long-term bisphosphonate use Orthopedics 35 6 2012 e991 e995 22691683 \n5 Marx R. Pamidronate(Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic J. Oral Maxillofac. Surg. 61 2003 1115 1118 12966493 \n6 Ruggiero S. Mehrotra B. Rosenberg T. Engroff S. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases J. Oral Maxillofac. Surg. 62 2004 527 534 15122554 \n7 authors No American association of oral and maxillofacial surgeons position paper on bisphosphonate-related osteonecrosis of the jaws J Oral Maxillfac Surg. 65 2007 369 376 \n8 Ruggiero S. Fantasia J. Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 4 2006 433 441 \n9 Ellis E.I. Price C. Treatment protocol for fractures of the atrophic mandible J. Oral Maxillofac. Surg. 66 2008 421 435 18280373 \n10 Bilkay U. Gürler T. Bilkay Ü Görken C. Kececi Y. Argon M. Comparison of fixation methods in treating mandibular fractures: scintigraphic evaluation J. Craniofac. Surg. 8 4 1997 270 273 9482050 \n11 Biglioli F. Pedrazzoli M. Extra-platysma fixation of bisphosphonate-related mandibular fractures: a suggested technical solution Int. J. Oral Maxillofac. Surg. 42 2013 611 614 23490473 \n12 Agha R. Fowler A. Saetta A. Barai I. Rajmohan S. Orgill D. The SCARE statement: consensus-based surgical case report guidelines Int. J. Surg. 2016 \n13 Sener I. Bereket C. Kosker H. Turer A. Kaplan S. The effects of zoledronic acid on mandibular fracture healing in an osteoporotic model: a stereological study J. Craniofac. Surg. 24 2013 1221 1224 23851773 \n14 Yu Y. Lieu S. Miclau T. Colnot C. Site specific effects of zoledronic acid during tibial and mandibular fracture repair PLoS One 2012 7 \n15 Tatli U. Ustün Y. Kürkcü M. Erdogan O. Gürbüz C. Ozgür H. Effects of zoledronic acid on healing of mandibular fractures: an experimental study in rabbits J. Oral Maxillofac. Surg. 69 2011 1726 1735 21256644 \n16 Roldan C. Paniagua L. Complications of new medications West. J. Emerg. Med. 16 2015 154 156 25671027 \n17 Gerhards F. Kuffner H.D. Wagner W. Pathological fractures of the mandible Int. J. Oral Maxillofac. Surg. 27 1998 186 190 9662010 \n18 Marx R. Sawatari Y. Fortin M. Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment J. Oral Maxillofac. Surg. 63 2005 1567 1575 16243172 \n19 Castro-Nunez J. Cunningham L. Van Sickels J. Atrophic mandible fractures: are bone grafts necessary? An update J. Oral Maxillofac. Surg. 75 2017 2391 2398 28732221 \n20 Ruggiero S. Dodson T. Fantasia J. Goodday R. Aghaloo T. Mehrotra B. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw-2014 updat J. Oral Maxillofac. Surg. 72 2014 1938 1956 25234529\n\n",
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"title": "Case report of maxillofacial fracture in a patient under bisphosphonates in the absence of ONJ disease: Guidelines?",
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"abstract": "Chronic uveitis is a common manifestation of pediatric rheumatologic conditions and may result in irreversible blindness and long-term disability. While chronic anterior uveitis is the most commonly encountered ocular manifestation of rheumatic disease, little is known about the clinical presentation, management, and long-term outcome of more complex eye conditions such as pars planitis (PP), panuveitis (PU), and Vogt-Koyanagi-Harada disease (VKH). The present study was undertaken to comprehensively assess the long-term safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and biologics for the treatment of pediatric and adolescent patients with PP, PU, and VKH.\n\n\n\nWe retrospectively reviewed a cohort of 75 children and adolescents with idiopathic PP (n = 50), PU (n = 12), and VKH (n = 14) followed by the Pediatric Rheumatology Core at Children's Hospital Los Angeles and evaluated referral patterns, clinical presentation, treatment response, and long-term clinical outcome.\n\n\n\nPatients were followed for an average of 52 months. Their mean age at disease onset was 10 years. Bilateral eye involvement was seen in 87% of the patients. At first presentation to an ophthalmologist, glaucoma was noted in 21% of patients and vision loss (<20/40) in 87% of patients, while legal blindness (≤20/200 in the better-seeing eye) was diagnosed in 18 of 75 (24%) of patients (PP 22%, PU 36%, and VKH 21%). The average referral time to a pediatric rheumatologist was 13 months (range 1-96 months). Topical steroids were used in all patients, but 98% of patients required additional DMARDs, and 73% required therapy with biologics. After a mean of 52 months, 35% of patients across all disease groups had significant vision loss or were blind, and only 28% were in clinical remission without medications. The worst outcome was observed in children with PU. Regression analysis, young age at onset, delayed referral to a pediatric rheumatologist, and chronic disease were strong predictors for the risk of long-term blindness.\n\n\n\nPP, PU, and VKH involve a high risk of permanent vision loss and should be managed by a skilled rheumatologist as early and as aggressively as possible.",
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"abstract": "Background: Lymphangioleiomyomatosis (LAM) is a rare systemic disease that generally leads to a progressive decline in pulmonary function. Experience, especially from the Asian population, including combined drug therapy before and after lung transplantation (LT) in LAM, is still limited. This study aimed to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China. Methods: A retrospective review of all patients with LAM undergoing LT at the two largest centers in China between 2010 and 2018 was conducted. Pre- and posttransplant data were assessed and analyzed. Results: Overall, 25 patients with LAM underwent bilateral LT. The mean age was 35.0 ± 8.6 years at diagnosis and 36.8 ± 9.3 years at the time of transplant. Before LT, only six patients could complete pulmonary function test; the reachable mean forced expiratory volume in one second (FEV1) before LT was 15.9 ± 6.9%. Twenty-one patients (84%) had a recurrent pneumothorax, four (16.0%) of which required pleurodesis. Eight patients (32%) were treated with sirolimus pretransplant for 3.9 years (1-9 years). The average intra-surgery bleeding volume was 1,280 ± 730 ml in need of a transfusion of 1,316 ± 874 ml due to moderate-to-severe adhesion and pretransplant pleurodesis. The causes of death of four patients (16%) included primary graft dysfunction, bronchial dehiscence with long-term use of sirolimus, and uncontrollable infections. The median follow-up time from LT was 41.1 ± 25.0 months. Conclusions: LT for LAM patients from the Asian population has been reinforced from the data that we presented. Peri-transplantation use of sirolimus and LAM-related complications should be further defined and under constant surveillance.",
"affiliations": "Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.;Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.;Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China.;Department of Lung Transplantation, Center for Lung Transplantation, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.",
"authors": "Zhang|Ji|J|;Liu|Dong|D|;Yue|Bingqing|B|;Ban|Le|L|;Zhou|Min|M|;Wang|Hongmei|H|;Lv|Jian|J|;Wu|Bo|B|;Zhai|Zhenguo|Z|;Xu|Kai-Feng|KF|;Chen|Wenhui|W|;Chen|Jingyu|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.584826",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X Frontiers Media S.A. \n\n10.3389/fmed.2021.584826\nMedicine\nOriginal Research\nA Retrospective Study of Lung Transplantation in Patients With Lymphangioleiomyomatosis: Challenges and Outcomes\nZhang Ji 1† Liu Dong 1† Yue Bingqing 1 Ban Le 1 Zhou Min 1 Wang Hongmei 1 Lv Jian 1 Wu Bo 1 Zhai Zhenguo 23 Xu Kai-Feng 4 Chen Wenhui 5 Chen Jingyu 15* 1Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China\n2Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China\n3National Clinical Research Center for Respiratory Diseases, Peking University Health Science Center, Beijing, China\n4Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China\n5Department of Lung Transplantation, Center for Lung Transplantation, Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China\nEdited by: Marco Confalonieri, University of Trieste, Italy\n\nReviewed by: Michel Gonzalez, Centre Hospitalier Universitaire Vaudois (CHUV), Switzerland; Olga Torre, Santi Paolo e Carlo Hospital, Italy\n\n*Correspondence: Jingyu Chen chenjy@wuxiph.comThis article was submitted to Pulmonary Medicine, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work\n\n\n16 2 2021 \n2021 \n8 58482618 7 2020 12 1 2021 Copyright © 2021 Zhang, Liu, Yue, Ban, Zhou, Wang, Lv, Wu, Zhai, Xu, Chen and Chen.2021Zhang, Liu, Yue, Ban, Zhou, Wang, Lv, Wu, Zhai, Xu, Chen and ChenThis 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: Lymphangioleiomyomatosis (LAM) is a rare systemic disease that generally leads to a progressive decline in pulmonary function. Experience, especially from the Asian population, including combined drug therapy before and after lung transplantation (LT) in LAM, is still limited. This study aimed to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China.\n\nMethods: A retrospective review of all patients with LAM undergoing LT at the two largest centers in China between 2010 and 2018 was conducted. Pre- and posttransplant data were assessed and analyzed.\n\nResults: Overall, 25 patients with LAM underwent bilateral LT. The mean age was 35.0 ± 8.6 years at diagnosis and 36.8 ± 9.3 years at the time of transplant. Before LT, only six patients could complete pulmonary function test; the reachable mean forced expiratory volume in one second (FEV1) before LT was 15.9 ± 6.9%. Twenty-one patients (84%) had a recurrent pneumothorax, four (16.0%) of which required pleurodesis. Eight patients (32%) were treated with sirolimus pretransplant for 3.9 years (1–9 years). The average intra-surgery bleeding volume was 1,280 ± 730 ml in need of a transfusion of 1,316 ± 874 ml due to moderate-to-severe adhesion and pretransplant pleurodesis. The causes of death of four patients (16%) included primary graft dysfunction, bronchial dehiscence with long-term use of sirolimus, and uncontrollable infections. The median follow-up time from LT was 41.1 ± 25.0 months.\n\nConclusions: LT for LAM patients from the Asian population has been reinforced from the data that we presented. Peri-transplantation use of sirolimus and LAM-related complications should be further defined and under constant surveillance.\n\nlymphangioleiomyomatosislung transplantationsirolimusinfectionanastomotic complication\n==== Body\nIntroduction\nLymphangioleiomyomatosis (LAM) is a rare disease characterized by the proliferation of abnormal smooth muscle-like cells (LAM cells), leading to diffuse pulmonary cyst formation, chylous pleural effusions, and the formation of lymphangioleiomyomas (1). LAM occurs sporadically (S-LAM) or as a pulmonary manifestation related to tuberous sclerosis complex (TSC-LAM) carrying mutations in TSC1 or TSC2 genes (2).\n\nIt generally affects women of reproductive age and presents a variable course, including indolent lung cysts, progressive dyspnea on exertion, recurrent pneumothorax, and thoracic lymphadenopathy, ultimately leading to respiratory failure, renal angiomyolipoma, and chylous effusions, as extrapulmonary manifestations. However, 30–40% of women with tuberous sclerosis complex developed pulmonary LAM (3). The inhibitors of the mechanistic target of rapamycin (mTOR) sirolimus have demonstrated treatment benefit in LAM (4–6).\n\nWhen all medical therapies are exhausted, end-stage patients should be considered for lung transplantation (LT) (7), which is a definitive treatment option evidenced by increasing survival benefit and improvement in the quality of life (5, 8–17). The first LT was performed for LAM in 1984 (18). From 1987 to 2002, LAM accounted for only approximately 1% of all causes for LT, according to the data from the United Network for Organ Sharing (19). The survival rate seemed to be comparable with that of patients undergoing LT for other forms of end-stage lung diseases (1, 20). The results from the United States (19), Brazil (21), and France (12) have shown a preference for bilateral lung transplantation (BLT). More patients received BLT compared with single lung transplantation (SLT) between January 1995 and June 2014, according to the registry of the International Society for Heart and Lung Transplantation (ISHLT). However, a report from Japan chose SLT considering donor sharing; more than 80% of lung transplant recipients with LAM underwent SLT during 2000–2016 (22).\n\nMoreover, limited published data are available regarding patients' clinical pretransplant status, types of procedure, posttransplant complications, and LAM-related morbidity in the current era. The primary aim of this study was to summarize the clinical data from patients with pulmonary LAM who underwent LT at centers in China, particularly documenting pretransplant features, posttransplant morbidity, and outcomes.\n\nMethods\nStudy Cohorts and Data Collection\nThe institutional ethics committees of Wuxi People's Hospital and China–Japan Friendship Hospital approved the study, including the present retrospective review, verbal consent procedure, and analysis of data. All patient data were anonymous. Written informed consent was obtained from the patients or their next of kin. The study was conducted in accordance with the 2000 Declaration of Helsinki and the Declaration of Istanbul 2008. None of the transplant donors were from a vulnerable population, and all donors or next of kin provided written informed consent that was freely given.\n\nPatients undergoing LT for end-stage pulmonary LAM from 2010 to 2018 were identified and reviewed. LAM diagnosis was based on the 2010 guidelines of the European Respiratory Society (1). All pretransplant diagnoses of pulmonary LAM were confirmed in the explants. All patients with LAM had undergone a systematic assessment. The first was to assess the ABO type, human leukocyte antigen type, and donor-specific human leukocyte antigen antibodies (DSA) of our patients. The second was to assess the function of target organs, involving lung function test, blood gas analysis, 6-min walk test (6MWT), and chest computed tomography (CT). The third concerned the function of other organs, including liver and kidney functions, coagulation function, bone marrow function, and heart function (electrocardiogram, echocardiography, and coronary CT angiography if necessary). The fourth was the exclusion of cancer, including blood cancer marker level, whole-body CT examination, and positron emission tomography-CT if necessary. The fifth related to whether LAM was associated with other organs, involving CT of the head, chest, and whole abdomen and B-ultrasound of the uterus and its accessories. The last concerned the preoperative infection status and the immunity level of patients. Preoperative discussions were conducted with multidisciplinary experts to determine whether the patient would be included in the waiting list for LT, including LT doctors, respiratory physicians, cardiologists, thoracic surgeons, anesthesiologists, emergency doctors, intensive care unit doctors, rehabilitation doctors, nutritionists, and ethics committee members. The surgical indications of patients with LAM at the center referred to the 2006 guidelines of ISHLT (23).\n\nThe ABO blood groups of the donors and recipients were identical before the surgery. The preoperative chest X-ray or chest CT examination did not find any pulmonary infection or other pulmonary diseases in the donors, with the oxygenation index reaching above 300 mmHg. Pretransplant demographics of recipients, clinical history, diagnostic methods to confirm LAM diagnosis, medical treatments, surgical characteristics, complications, morbidity, mortality, survival rate after LT, and use of sirolimus after transplantation were reviewed in all patients. The patients were followed up every 3 months during the first year after LT, 6 months after 1–3 years, and once annually after 3 years. The review covered the target organ and other organ functions and the immunity level and infection status of patients.\n\nStatistical Analysis\nDescriptive statistics were used to analyze patient characteristics. Normally distributed continuous data were described as mean ± standard deviation. Categorical variables were presented as percentages. Medians and ranges were presented for skewed data. Survival was estimated by Kaplan–Meier analysis. All calculations and comparisons were performed using SPSS version 16 (SPSS Inc., IL, USA) and GraphPad Prism 7 (GraphPad Software Inc., CA, USA). A P-value of <0.05 was considered significant.\n\nResults\nStudy Population and Establishment of Lymphangioleiomyomatosis Diagnosis\nFrom January 2010 to December 2018, 25 female patients with sporadic LAM underwent sequential BLT at the centers. The main clinical characteristics before LT are described in Table 1. The mean ages at diagnosis and while undergoing LT were 35.0 ± 8.6 years and 36.8 ± 9.3 years, respectively.\n\nTable 1 Clinical characteristics of LAM patients (n = 25) at registration for LT.\n\nVariable\tValue\t\nFemale (n,%)\t25 (100)\t\nAge at diagnosis (years)\t35.0 ± 8.6\t\nAge at transplantation (years)\t36.8 ± 9.3\t\nPregnancy history (n, %)\t19 (76)\t\nClinical features\t\t\nPatients with lung involvement alone (n, %)\t15 (60)\t\nPatients with extrapulmonary manifestation (n, %)\t10 (40)\t\nRenal angiomyolipoma (n, %)\t6 (24)\t\nMediastinal lymphadenopathy (n, %)\t2 (8)\t\nRetroperitoneal lymphangioleiomyoma (n, %)\t2 (8)\t\nPelvic lymphangioleiomyoma (n, %)\t5 (20)\t\nPneumothorax (n, %)\t21 (84)\t\nPleurodesis (n, %)\t4 (16)\t\nChylous effusion (n, %)\t3 (12)\t\nChylothorax (n, %)\t3 (12)\t\nAscites (n, %)\t1 (4)\t\nSupplemental oxygen therapy (n, %)\t25 (100)\t\nOxygenation index\t168.1 ± 52.0\t\nUse of sirolimus (n, %)\t8 (32)\t\nUse of sirolimus until lung transplantation (n, %)\t8 (32)\t\nPulmonary function test (n, %)\t6 (24)\t\nFEV1 (%predicted)\t15.9 ± 6.9\t\nFVC (%predicted)\t33.7 ± 19.6\t\n6-min walk test\t5 (20)\t\nDistance (m)\t85.4 ± 46.0\t\nMinimum SpO2 (%)\t81.8 ± 4.3\t\nClinical and Radiologic Findings Before Transplantation\nTwenty-one (84%) recipients had a history of pneumothorax, which was the most common pretransplant symptom, and four patients (16%) had been treated by pleurodesis. Ten patients (40%) presented with extrapulmonary manifestations of LAM (Table 1), involving the kidney, pelvic, mediastinal, and retroperitoneal regions. Three patients (12%) had chylothorax. The most common radiologic features on chest CT were diffuse, cystic lung disease consistent with LAM, further confirmed in the explants of all patients.\n\nAll the patients had severe hypoxia and required continuous oxygen before surgery; seven patients (28%) required mechanical ventilation before transplantation, and one patient (4%) received a tracheotomy. Due to the critical status, six (24%) patients completed the pulmonary function test, which showed FEV1 15.9 ± 6.9% of predicted and FVC 33.7 ± 19.6% of predicted. All patients used supplemental oxygen before transplant with a concentration of 29–53% and an oxygenation index of 168.1 ± 52.0. Five (20%) patients completed 6MWT. The mean distance walked was 85.4 ± 46 m, and the minimum SpO2 at the end of the test was 81.8 ± 4.32%. The last pulmonary function test and 6MWT results before LT are summarized in Table 1.\n\nMedical and Surgical Interventions Before Transplantation\nEight (32%) patients received sirolimus before transplantation, for an average time of 3.9 years (range 1–9 years). One patient repeatedly had a bilateral pneumothorax, atelectasis, intractable chylothorax, abdominal chylous fluid, and a uterine muscle lipoma. She received pleural and peritoneal drainage, followed by right middle lobe wedge resection with lung repair. A uterus lymphatic smooth muscle tumor was resected. Then, she received thoracic duct ligation and bilateral pleurodesis treatment. The postoperative histological examination confirmed lung and uterine LAM. Another four patients (16%) received pleurodesis due to recurrent pneumothorax and/or chylothorax. Moreover, 19 patients (76%) had a history of pregnancy, and 6 patients (24%) had a recent history of pregnancy (within 1 year of pregnancy, including abortion or production).\n\nLung Transplantation and Posttransplantation Outcomes\nNo significant intraoperative complications were reported, although two patients (8%) required intraoperative extracorporeal membrane oxygenation support. The average volume of intraoperative blood loss was 1,280 ±730 ml, and the mean blood transfusion was 1,316 ± 874 ml. One patient (4%) experienced intraoperative blood loss of up to 4,000 ml due to extensive pleural adhesions in the thoracic cavity regarding pretransplant bilateral pleurodesis.\n\nThe complications after the surgery included the disturbance of anastomotic integrity. One patient developed anastomotic stenosis after anastomotic infection in the early stage after LT. The condition of anastomotic stenosis improved after antibiotics and balloon dilatation treatment. However, another patient died due to anastomotic leakage. After the surgery, 45% of the patients developed an infection, and two patients died of tuberculosis infection. One patient died of primary graft dysfunction during the early postoperative period. Bronchiolitis obliterans syndrome was diagnosed in one patient (4%) 48 months after LT. The postoperative details are described in Table 2. Twenty-one (84%) patients received triple-drug maintenance immunosuppressive therapy (tacrolimus, mycophenolate, and prednisone) after transplantation. Four patients (16%) temporarily received tacrolimus and prednisone treatment because of infection in an early stage after the surgery. One patient received sirolimus (maintained serum level 8–10 ng/ml) instead of tacrolimus 3 months after transplantation when anastomosis completely healed, but meanwhile, a retroperitoneal mass was suspected.\n\nTable 2 Intra- and posttransplantation data (n = 25).\n\nVariable\tValue\t\nFollow-up (months)\t41.1 ± 25.0\t\nImmunosuppression\t\t\nTacrolimus + mycophenolate + prednisone (n, %)\t21 (84)\t\nTacrolimus + prednisone (n, %)\t4 (16)\t\nComplications\t\t\nNeoplasm or lymphoproliferative disease (n, %)\t0 (0)\t\nChylothorax (n, %)\t1 (4)\t\nRecurrence of LAM (n, %)\t0 (0)\t\nPulmonary retransplantation (n, %)\t0 (0)\t\nIntraoperative bleeding (n, %)\t1 (4)\t\nAnastomotic complications (n, %)\t2 (8)\t\nAnastomotic leakage (n, %)\t1 (4)\t\nAnastomotic stenosis (n, %)\t1 (4)\t\nBronchiolitis obliterans syndrome (n, %)\t1 (4)\t\nRecurrence of LAM (n, %)\t0 (0)\t\nPrimary graft dysfunction (n, %)\t1 (4)\t\nInfection (n, %)\t12 (48)\t\nTuberculosis infection\t3 (12)\t\nAspergillus\t3 (12)\t\nAcinetobacter baumannii\t4 (16)\t\nOther infection\t2 (8)\t\nCause of death\t\t\nPrimary graft dysfunction (n, %)\t1 (4)\t\nAnastomotic leakage (n, %)\t1 (4)\t\nInfection (n, %)\t2 (8)\t\nThe median follow-up of this group of patients was 41.1 ± 25.0 months. The range of follow-up from LT to either death or closing date was 0.5–84 months. Four deaths (16%) occurred during the study. One patient (4%) died of primary graft dysfunction 30 days after the surgery. Two patients died of uncontrollable infections 2 and 13 months after the surgery. Another patient (4%) died of anastomotic leakage 12 days after the surgery. The patient had been on oral sirolimus for 9 years and until transplantation.\n\nNo LAM recurrence was observed, no patient developed the malignant proliferative disease after the procedure, and no patient underwent pulmonary re-transplantation. The estimated 1- and 2-year posttransplant survival rates were 88 and 84%, respectively (Figure 1).\n\nFigure 1 Kaplan–Meier survival analysis after lung transplantation in 25 patients with LAM.\n\nDiscussion\nThis study demonstrated a favorable outcome for LT in LAM patients similar to that published in a USA report from actuarial Kaplan–Meier survival for LAM was 85% at 1 year, and 76% at 3 years (19). Despite three (12%) early deaths (<3 months after transplantation), the survival rate of the present cohort was more favorable than that of patients with other indications (24) and Japan's data, as well as the 1-year survival of 78–81% in the report of ISHLT registry (25). The estimated survival rates from a Brazilian cohort have been shown to be 90% after 1 year, 90% after 3 years, and 77% after 5 years, which were greater than those observed in previous studies (15–20). The long-term survival was also promising, attributing to the fact that it often involved younger patients without any extrapulmonary organ dysfunction (11).\n\nA newly adopted lung allocation scoring system based on disease severity in the USA since 2005 (26) has categorized LAM with chronic obstructive pulmonary disease and other obstructive diseases, giving a lower priority to patients with idiopathic pulmonary fibrosis when allocating donor lungs. Thus, a longer waiting time for patients with LAM should be optimized. Recently, BLT has been performed with a higher frequency compared with SLT for LAM (13, 15, 27). BLT could achieve a better long-term outcome (28) due to lower incidence of bronchiolitis obliterans syndrome, reducing the rate of complications such as pneumothorax, chylothorax, and recurrence of LAM following LT, together with better pulmonary function tests. Hence, BLT is recommended if donor lungs are available.\n\nRecurrent pneumothorax and chylothorax requiring surgical or chemical pleurodesis are common in patients with LAM. The average lifetime pneumothorax-related burden for patients with LAM is a high in-patient cost (29). The upmost challenge for LT in patients with LAM would be to minimize the risk of severe hemorrhage in patients who had pretransplant pleurodesis for pneumothorax or chylothorax, which is a serious triggering factor for excessive bleeding by dissection of the adhesions. According to the previous reports, the pretransplant rates of pleurodesis and pleurectomy ranged from 18 to 100% and from 21 to 43%, respectively, whereas the rate of intraoperative complications varied from 25 to 71% (11–17) (Table 3). However, in the present cohort with a pleurodesis rate of 16%, the rate of intraoperative complications was only 4%.\n\nTable 3 Summaries of studies on LT for LAM.\n\nStudy\tNo. of LT\tAge at LT (years)\tFEV1%\tFEV1/FVC\tPre-LT complications\tIntra-surgery\tMain Post-LT complications\t30 days of mortality\t1-year survival\t\nBoehler et al. (9)\t34\t40 ± 9\t24 ± 12\t38 ± 12\tPleural effusion 16% \n Pleurodesis 18%\tAdhesions 54% \n Hemorrhage 12%\tBronchial stenosis \n or dehiscence 18%\t15%\t69%\t\nUrban et al. (10)\t13\t-\tFEV1 0.57 ± 0.15 L\t-\tPleurodesis 58% (in total)\t-\t-\t8%\t69%\t\nPechet et al. (11)\t14\t41.8 ± 6.8\t20 ± 8\t-\tPleural effusion 7.1% \n Pleurodesis 00%\tAdhesions 71.4% \n Hemorrhage 50%\tSepsis 21.4% \n Dehiscence 14.3% \n Chylothorax 28.6%\t0%\t100%\t\nKpodonuJ et al. (19)\t79\t41.1 ± 8.3\t-\t-\t-\t-\tFungal infection 2.5%\t5%\t86%\t\nReynaud-Gauber et al. (12)\t45\t41 ± 10\tObstructive 26.4 ± 14.1 \n Combined19.7 ± 7.2\tCombined 47.4 ± 12.3\tPleural effusion 13.3% \n Pleurodesis 48.8%\tAdhesions 46.6% \n Hemorrhage 46.6%\tBronchial stenosis or dehiscence 15.6%\t-\t80%\t\nBenden et al. (13)\t61\t41.3 ± 9.1\t27 ± 14\t-\tPleural effusion 14% \n Pleurodesis 54.1%\tAdhesions 57.4% \n Hemorrhage 33.3%\tRespiratory tract infection 59%\t5%\t79%\t\nMachuca et al. (14)\t10\t43.8 ± 6.7\tMean 32.9\t-\tPleural effusion 0% \n Pleurodesis 100%\tHemorrhage (>1,000 ml) 30%\tInfections 30%\t10%\t90%\t\nNakagirin et al. (16)\t13\t42 ± 4.6\t-\t-\tPleural effusion 30.7% \n Pleurodesis 53.8%\t-\t-\t-\t-\t\nAndo et al. (17)\t57\t39.5 ± 7.3\t32.8 ± 17\t40.2 ± 15.2\tPleural effusion 21% \n Pleurodesis 53.8%\t-\tBronchial stenosis or dehiscence 0%\t\t93.5%\t\nBruno et al. (21)\t11\t43 ± 7\t28 ± 14\t45 ± 16\tPleurodesis 9%\t-\tStenosis 9% \n Pulmonary infections 55%\t\t90%\t\nOishi et al. (22)\t29\t45.3 ± 8.4\t-\t-\tPleural effusion 6.9% \n Pleurodesis 31%\tAdhesions 31% \n Hemorrhage \n (>2,000 ml) 13.8%\tChylothorax 20.7%\t0%\t83.3%\t\nKhawar et al. (30)\t138\t45 (38–52)\t23 (17.0–33.3)\t-\t-\t-\t-\t-\t94%\t\nSalman et al. (31)\t25\t50 ± 9\t22 ± 10\t-\t-\t-\tDialysis (32%)\t0%\t92%\t\nKurosaki et al. (32)\t12\t32 ± 7.3\tFEV1 0.7 ± 0.4\t\tPleurodesis (58%)\t\tChylothorax 50% \n Acute rejection 42%\t0\t100%\t\nPrevious studies showed that almost all patients with LAM died 10 years after the start of symptoms (33, 34). The guideline for LAM recipients from ISHLT suggested that the New York Heart Association functional class III or IV, severe impairment of lung function, and poor exercise tolerance should be considered for LT (23). When determined to perform LT, severe obstruction, compromised gas exchange impairing quality of life, and progressive respiratory failure are among the most important factors for evaluation (35). How to refine the specific timing of LT is very difficult. The poor prognostic factors included decreased FEV1/FVC, decreased total lung capacity, and cystic lesions. In the published reports of cohorts, the age at onset, diagnosis, diffusing capacity for carbon monoxide (DLCO)% predicted, PaO2, and 6MWT at registration were quite similar. However, FEV1% predicted at registration and during the waiting period have been shown to be worthy of special note. In the present cohort, most of the patients in the present study had end-stage respiratory failure and required oxygen or even high-flow oxygen to extend their life before the surgery. Most of them could not complete the pulmonary function test. As few as six patients could complete the necessary ventilatory function test as required but were unable to undergo the diffusion function test, as well as 6MWT. The pretransplant FEV1% was 15.9 ± 6.9% of predicted and obviously lower than that found in most previous reports, ranging from 19 ± 11% to 32.8 ± 17% (11–17). This signified the difficulties related to patient management at the centers to perform BLT. Although pleural intervention is not seen as a contraindication to transplant, it would become a contributor to both intra-surgery and post-surgery morbidities.\n\nIn the present cohort, the waiting time of patients seemed relatively shorter than the Japanese center's interval, partly due to the donation volume and the endurance of the patients (17). The time to choose LT for patients with LAM was also crucial for long-term survival. With the delay in choosing LT, intractable chylothorax or metastatic LAM lesions could be seen. If patients received LT in a later phase, critical status, high cost, and risk of retransplant were implicated. More assessment tools are needed in the future to fully evaluate the timing and benefit of LT in patients with LAM.\n\nInfections are a major complication after LT in LAM. The frequency of respiratory infections ranged from 10 to 59%, with heterogeneous etiology such as cytomegalovirus, Aspergillus sp., and bacterial pathogens (11–16). Two patients died of uncontrollable infections pathologically confirmed as tuberculosis infection. Another surviving patient also had a relapsed tuberculosis infection 6 months after the surgery. This patient recovered well after antituberculosis treatment. Hence, patients with LAM undergoing LT are recommended to receive conventional inhalation isoniazid to prevent tuberculosis infection. Immunosuppression use after LT is also a risk factor.\n\nFor patients with LAM, the use of mTOR inhibitors is a topic with special interest. As a conventional immunosuppressant in organ transplantation (36), sirolimus has been proved in vitro and in preclinical models for stabilizing lung function in LAM and treating extrapulmonary manifestations, such as renal angiomyolipoma, by inhibiting T- and B-lymphocyte activation via the IL-2 signaling pathway (3, 37). mTOR inhibitors are appealing to physicians in decreasing the rate of cytomegalovirus infection (38) and effective for post-surgery chylous pleural and peritoneal effusions (3). A significant concern regarding the use of mTOR inhibitors is that these drugs interfere with wound healing corresponding to the suppression of fibroblast proliferation and angiogenesis, which is related to the increased rate of bronchial anastomotic integrity disorder (39). In the present cohort, one patient died of anastomotic leakage 12 days after the surgery. She had received sirolimus for 9 years before the surgery and did not stop treatment before the surgery. No anastomotic leakage was observed in the other seven patients treated with sirolimus medication for 1–6 years. Whether it is necessary to stop the drug before the surgery and when need to be confirmed by further exploration. Some centers suggest initiating mTOR inhibitors only after confirming complete bronchial anastomotic healing, 3 months (12) after LT or even waiting up to 9 months. A high incidence of airway dehiscence occurred when sirolimus was begun immediately after transplantation (40).\n\nPrevious studies found the predominance of LAM in women of reproductive age. Pregnancy worsened the disease (41), and menopause caused disease remission (42). Patients enrolled in the present cohort seemed to be younger and mainly sporadic LAM dominant compared with clinical analysis findings from the Chinese mainland (43) and the American National Heart, Lung and Blood Institute (2, 35). Exploring whether the younger age of female patients to undergo LT can improve their life expectations, including pregnancy demanding, can be highly challenging.\n\nThis study had certain limitations because of the paucity of available knowledge regarding the pathophysiology and treatment of LAM. Small sample size and its retrospective heterogeneous characteristic were the main factors to be considered as insufficiencies similar to previous reports due to the rarity of LAM and a high requirement of the large-center qualification. The condition of patients was quite serious in the present study, and most patients could not complete the preoperative lung function and 6MWT, resulting in incomplete data. Hence, large-scale clinical research is needed in the future. For the surveillance of the posttransplantation course, convincing evidence of maintenance therapeutic agents and improvements in patients with LAM undergoing transplantation with regard to their posttransplant survival will be the key points to explore in future studies.\n\nConclusions\nThe present study reinforced the role of LT for patients with end-stage LAM. Favorable survival and quality of life were demonstrated. Nevertheless, the occurrence of LAM-related and transplant-related complications should be monitored continuously. Pre- and posttransplantation immunosuppressive approaches confer a special interest in further demystifying LAM via coordination of medical therapy providers and transplant surgeons, thus allowing for the optimization of recipients both while waiting and after the surgery.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by The Institutional Ethics Committees of Wuxi People's Hospital The Institutional Ethics Committees of China-Japan Friendship Hospital. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nJZ and JC take full responsibility for the content of this manuscript, including its data and analysis. DL, BY, LB, MZ, HW, JL, BW, and K-FX made substantial contributions to the conception and design of the study. JZ and WC made substantial contributions to the analysis and interpretation of data. JZ drafted the initial manuscript. All authors read and approved the final 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.\n\nFunding. The National Key Research and Development Program of China No. 2016YFC0901502.\n==== Refs\nReferences\n1. Johnson SR Cordier JF Lazor R Cottin V Costabel U Harari S . Review panel of the ERS LAM task force. European respiratory society guidelines for the diagnosis and management of lymphangioleiomyomatosis\n. Eur Respir J. (2010 ) 35 :14 –26\n. 10.1183/09031936.00076209 20044458 \n2. Maurer JR Ryu J Beck G Moss J Lee JC Finlay G . 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Munich Lung Transplant Group. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression\n. J Heart Lung Transplant. (2004 ) 23 :632 –8\n. 10.1016/S1053-2498(03)00309-7 15135383 \n40. King-Biggs MB Dunitz JM Park SJ Kay Savik S Hertz MI . Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation\n. Transplantation. (2003 ) 75 :1437 –43\n. 10.1097/01.TP.0000064083.02120.2C 12792493 \n41. Brunelli A Catalini G Fianchini A . Pregnancy exacerbating unsuspected mediastinal lymphangioleiomyomatosis and chylothorax\n. Int J Gynaecol Obstet. (1996 ) 52 :289 –90\n. 10.1016/0020-7292(95)02619-3 8775689 \n42. Johnson SR Tattersfield AE . Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment\n. Am J Respir Crit Care Med. (1999 ) 160 :628 –33\n. 10.1164/ajrccm.160.2.9901027 10430739 \n43. Ye L Jin M Bai C . Clinical analysis of patients with pulmonary lymphangioleiomyomatosis (PLAM) in mainland China\n. Respir Med. (2010 ) 104 :1521 –6\n. 10.1016/j.rmed.2010.05.003 20627505\n\n",
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"keywords": "anastomotic complication; infection; lung transplantation; lymphangioleiomyomatosis; sirolimus",
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"title": "A Retrospective Study of Lung Transplantation in Patients With Lymphangioleiomyomatosis: Challenges and Outcomes.",
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"abstract": "BACKGROUND\nWe present two cases with symptoms of progressively worsening cough, dyspnea, decreased exercise tolerance and right-sided back pain in the first case and upper respiratory symptoms characterized by cough and a low grade fever in the second case.\n\n\nMETHODS\nReport of two cases.\n\n\nRESULTS\nThe initial chest X-ray in both the cases showed pleural effusion. Further imaging with computed tomography of the chest confirmed the effusion in both cases. Thoracentesis was done in both of them revealed an exudative effusion that did not reveal any infection or malignancy. Both cases underwent surgical biopsy and the diagnosis of primary pleural epithelioid hemangioendothelioma was made.\n\n\nCONCLUSIONS\nBoth the cases had progressive clinical deterioration despite chemotherapy with Taxol and Bevacizumab in one case and carboplatin, etoposide, and bevacizumab, in the second case. Both developed metastatic disease to lungs and died.",
"affiliations": "Uniformed Services University, National Naval Medical Center, Bethesda, MD, USA. angeline.lazarus@med.navy.mil",
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"abstract": "There are a variety of possible adverse drug reactions that can have differing presentations. Recognizing these presentations and the temporal relationship between drug intake and reaction is essential in preventing severe and potentially fatal results. We present a patient who had a sudden post-injection inflammatory response consistent with Nicolau syndrome after a 6 month course of repeated intramuscular naltrexone injections.",
"affiliations": "University of Connecticut School of Medicine, Farmington, CT. momalik@uchc.edu.",
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"abstract": "An 18-year-old woman with a history of hollow visceral myopathy presented with a small-bowel obstruction. High-dose opioid analgesia was required subsequently during hospital admission. She suffered two episodes of documented fasting hypoglycaemia, despite adjustment of parenteral carbohydrate administration. Investigations for non-insulin-mediated hypoglycaemia revealed a low morning cortisol of 109 nmol/L and an inappropriately low Adrenocorticotropic hormone (ACTH) level of 2.2 pmol/L. A diagnosis of secondary adrenal insufficiency was confirmed on repeat cortisol and ACTH testing. The 250 µg short Synacthen test cortisol response was normal, suggestive of acute rather than chronic ACTH deficiency. This pattern was consistent after further opioid exposure. Adrenal recovery occurred shortly after opioid cessation. Opioid-induced hypoadrenalism is likely an under-recognised clinical entity with potentially serious adverse patient outcomes. There are reported cases involving commonly prescribed opioids including fentanyl and tramadol. However, we believe this is the first reported clinical case of acute transient opioid-induced secondary hypoadrenalism associated with fasting hypoglycaemia.",
"affiliations": "Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia etab2186@uni.sydney.edu.au.;Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.;Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.",
"authors": "Tabet|Eddy J|EJ|;Clarke|Antonia Jean|AJ|;Twigg|Stephen M|SM|",
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"title": "Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia.",
"title_normalized": "opioid induced hypoadrenalism resulting in fasting hypoglycaemia"
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"abstract": "Listeria Monocytogenes, a small facultative anaerobic, gram positive, motile bacillus is a rare, but consequential etiologic agent of food borne illness which inordinately impacts immunocompromised individuals. The organism infects many types of animals and contaminates a multitude of foodstuffs such as milk, chicken, beef and vegetables. This microbe additionally has a distinct proclivity to infect the maternal-fetoplacental unit with resultant adverse perinatal outcomes inclusive of spontaneous abortion, preterm delivery, chorioamnionitis, neonatal meningitis and death. We present a case of Listeriosis complicating pregnancy with a subsequent comprehensive review of the literature.",
"affiliations": "NYC Health+ Hospitals/Lincoln, Department of Ob/Gyn, 234 East 149th Street, Bronx, 10451, NY.;NYC Health+ Hospitals/Lincoln, Department of Ob/Gyn, 234 East 149th Street, Bronx, 10451, NY.;NYC Health+ Hospitals/Lincoln, Department of Ob/Gyn, 234 East 149th Street, Bronx, 10451, NY.;NYC Health+ Hospitals/Lincoln, Department of Ob/Gyn, 234 East 149th Street, Bronx, 10451, NY.;NYC Health+ Hospitals/Lincoln, Department of Ob/Gyn, 234 East 149th Street, Bronx, 10451, NY.;NYC Health+ Hospitals/Lincoln, Department of Ob/Gyn, 234 East 149th Street, Bronx, 10451, NY. Electronic address: keciagaithermd@aol.com.",
"authors": "Serventi|Lisa|L|;Curi|Berenice|B|;Johns|Rochelle|R|;Silva|Jessica|J|;Bainbridge|Ronald|R|;Gaither|Kecia|K|",
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"title": "Pregnancy Complicated by Listeria Monocytogenes: A Case Report and Review of the Literature.",
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"abstract": "To characterize the clinical features, associated disorders, and treatment of necrobiotic xanthogranuloma (NXG), a rare non-Langerhans cell histiocytosis, we conducted a retrospective review of pathologically confirmed NXG at Mayo Clinic Arizona from 1987 to June 2017. Data on clinical findings, laboratory findings, associated disorders, therapy, and response to therapy were extracted. Nineteen patients were identified. Mean age was 54 years (range, 17-84) with equal gender distribution. Median follow-up was 5.5 years (range, 1-18). Most patients had a detectable monoclonal protein (84%), and IgG kappa constituted 58%. The most common cutaneous lesions involved the periorbital region (53%). The majority of patients had extracutaneous manifestations, most commonly affecting the liver (32%) and the sinuses (21%). Hematologic malignancies were diagnosed in 26% of patients and included Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), smoldering myeloma, and multiple myeloma. The most common treatment was chlorambucil with or without systemic corticosteroids. Response was seen in most patients (95%), and most patients received 1-3 lines of therapy (74%). NXG is a reactive histiocytic disorder that commonly involves multiple organ systems and requires a high degree of clinical suspicion for accurate diagnosis. Treatment decisions should be based on coexisting conditions and pattern of disease involvement.",
"affiliations": "Division of Hematology/Oncology, Mayo Clinic, 5777 E. Mayo Boulevard, Phoenix, AZ, 85054, USA. hilal.talal@mayo.edu.;Department of Dermatology, Mayo Clinic, Phoenix, AZ, USA.;Department of Dermatology, Mayo Clinic, Phoenix, AZ, USA.;Division of Hematology/Oncology, Mayo Clinic, 5777 E. Mayo Boulevard, Phoenix, AZ, 85054, USA.",
"authors": "Hilal|Talal|T|http://orcid.org/0000-0001-8249-4128;DiCaudo|David J|DJ|;Connolly|Suzanne M|SM|;Reeder|Craig B|CB|",
"chemical_list": "D015415:Biomarkers",
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"journal": "Annals of hematology",
"keywords": "Histiocytosis; Lymphoma; MGUS; Myeloma; NXG; Necrobiotic xanthogranuloma",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001706:Biopsy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D058252:Necrobiotic Xanthogranuloma; D000072078:Positron Emission Tomography Computed Tomography; D012189:Retrospective Studies; D063189:Symptom Assessment; D055815:Young Adult",
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"title": "Necrobiotic xanthogranuloma: a 30-year single-center experience.",
"title_normalized": "necrobiotic xanthogranuloma a 30 year single center experience"
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"abstract": "Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.\n\n\n\nThe following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.\n\n\n\nThis case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.",
"affiliations": "Deptments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.;Deptments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.;Deptments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.;Deptments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.;Deptments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA. nucifora@jhmi.edu.",
"authors": "Martos|Natalie|N|;Hall|William|W|;Marhefka|Alicia|A|;Sedlak|Thomas W|TW|;Nucifora|Frederick C|FC|",
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"fulltext": "\n==== Front\nBMC Psychiatry\nBMC Psychiatry\nBMC Psychiatry\n1471-244X BioMed Central London \n\n3073\n10.1186/s12888-021-03073-w\nCase Report\nPaliperidone induced neutropenia in first episode psychosis: a case report\nMartos Natalie Hall William Marhefka Alicia Sedlak Thomas W. Nucifora Frederick C. Jrnucifora@jhmi.edu grid.21107.350000 0001 2171 9311Deptments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287 USA \n6 2 2021 \n6 2 2021 \n2021 \n21 7621 8 2020 25 1 2021 © The Author(s) 2021Open 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\nNeutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.\n\nCase presentation\nThe following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.\n\nConclusions\nThis case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.\n\nKeywords\nFirst episode psychosisNeutropeniaPaliperidoneSchizophreniaClozapineissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nNeutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].\n\nIn the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.\n\nCase presentation\nA 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.\n\nSeveral weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.\n\nOn presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.\n\nAdmission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.\n\nGiven lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.\n\nDiscussion and conclusions\nIn our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.\n\nWe also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.\n\nTo date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.\n\nOur case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.\n\nCurrently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.\n\nThis case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.\n\nAbbreviations\nANCAbsolute Neutrophil Count\n\nANAAntinuclear Antibody\n\nHIVHuman Immunodeficiency Virus\n\nFDAFood and Drug Administration\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNatalie Martos and William Hall contributed equally to this work.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nFCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.\n\nFunding\nNo funding sources.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nWritten informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.\n\nConsent for publication\nWritten informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.\n\nCompeting interests\nThe authors have no competing interests to declare.\n==== Refs\nReferences\n1. Atkin K Kendall F Gould D Freeman H Liberman J O'Sullivan D Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland Br J Psychiatry 1996 169 4 483 488 10.1192/bjp.169.4.483 8894200 \n2. Nucifora FC Jr Mihaljevic M Lee BJ Sawa A Clozapine as a model for antipsychotic development Neurotherapeutics. 2017 14 3 750 761 10.1007/s13311-017-0552-9 28653280 \n3. Honigfeld G Arellano F Sethi J Bianchini A Schein J Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry J Clin Psychiatry 1998 59 Suppl. 3 3 7 9541331 \n4. Bautista-Quach MA Liao YM Hsueh CT Pancytopenia associated with clonazepam J Hematol Oncol 2010 3 24 10.1186/1756-8722-3-24 20630089 \n5. Maher KN Tan M Tossell JW Weisinger B Gochman P Miller R Greenstein D Overman GP Rapoport JL Gogtay N Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia J Child Adolesc Psychopharmacol 2013 23 2 110 116 10.1089/cap.2011.0136 23510445 \n6. Lally J Flanagan RJ Severe neutropenia and agranulocytosis. Life Threatening effects of antipsychotic drugs 2016 105 148 \n7. Matsuura H Kimoto S Harada I Naemura S Yamamuro K Kishimoto T Lithium carbonate as a treatment for paliperidone extended-release-induced leukopenia and neutropenia in a patient with schizoaffective disorder; a case report BMC Psychiatry 2016 16 161 10.1186/s12888-016-0874-x 27229149 \n8. Raj V Druitt T Purushothaman S Dunsdon J Risperidone/paliperidone induced neutropenia and lymphopenia Aust N Z J Psychiatry 2013 47 3 291 292 10.1177/0004867412460594 22984110 \n9. Kim JN Lee BC Choi IG Jon DI Jung MH Paliperidone-induced leukopenia and neutropenia: a case report Prog Neuro-Psychopharmacol Biol Psychiatry 2011 35 1 284 285 10.1016/j.pnpbp.2010.09.018 \n10. Manfredi G Solfanelli A Dimitri G Cuomo I Sani G Kotzalidis GD Girardi P Risperidone-induced leukopenia: a case report and brief review of literature Gen Hosp Psychiatry 2013 35 1 102.e3 102.e6 10.1016/j.genhosppsych.2012.03.009 \n11. Kattalai Kailasam V Chima V Nnamdi U Sharma K Shah K Risperidone-induced reversible neutropenia Neuropsychiatr Dis Treat 2017 13 1975 1977 10.2147/NDT.S141472 28794632 \n12. Schulte P Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring Ann Pharmacother 2006 40 4 683 688 10.1345/aph.1G396 16595571 \n13. Ingimarsson O Maccabe JH Haraldsson M Jónsdóttir H Sigurdsson E Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland BMC Psychiatry. 2016 16 1 441 10.1186/s12888-016-1167-0 27955666 \n14. Rettenbacher MA Hofer A Kemmler G Fleischhacker WW Neutropenia induced by second generation antipsychotics: a prospective investigation Pharmacopsychiatry. 2010 43 2 41 44 10.1055/s-0030-1249071 20175050 \n15. Drew L Clozapine and agranulocytosis: re-assessing the risks Australas Psychiatry 2013 21 4 335 337 10.1177/1039856213491990 23804114\n\n",
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"title": "Paliperidone induced neutropenia in first episode psychosis: a case report.",
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"abstract": "Schimke immuno-osseous dysplasia is a rare autosomal recessive disease resulting from biallelic SMARCAL1 mutations. It presents in early childhood and is characterized by short stature, nephropathy, and immunodeficiency. Approximately 50% of those affected have neurological complications including migraines, transient ischemic attacks, and strokes.\n\n\n\nWe present a six-year-old boy with Schimke immuno-osseous dysplasia without evidence of atherosclerosis with recurrent episodes of severe headache, fluctuating hemiparesis, and aphasia.\n\n\n\nMagnetic resonance imaging and angiography were normal during the initial episode; multiple areas of reversible restricted diffusion with decreased perfusion and arterial stenosis were seen with subsequent attacks.\n\n\n\nThis constellation of symptoms and imaging findings is suggestive of reversible cerebral vasoconstriction syndrome, which we propose as a mechanism for the transient ischemic attacks and infarcts seen in some patients with Schimke immuno-osseous dysplasia, as opposed to accelerated atherosclerosis alone. This new insight may provide a basis for novel preventative therapy in this rare disorder.",
"affiliations": "Division of Pediatric Neurology, Department of Pediatrics and Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas; Children's Health System of Texas, Dallas, Texas. Electronic address: Darrah.haffner@utsouthwestern.edu.;Children's Health System of Texas, Dallas, Texas; Department of Radiology, University of Texas Southwestern Medical Center Dallas, Dallas, Texas.;Division of Pediatric Neurology, Department of Pediatrics and Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas; Children's Health System of Texas, Dallas, Texas.",
"authors": "Haffner|Darrah N|DN|;Rollins|Nancy K|NK|;Dowling|Michael M|MM|",
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"abstract": "Amlodipine predominantly affects vascular smooth muscle cells. Amlodipine overdose usually presents with vasodilatory shock, accompanied by reflex tachycardia rather than bradycardia.An 81-year-old woman presented with impaired consciousness 8 h after ingesting 50 5-mg amlodipine tablets with suicidal intent. On admission, her blood pressure was 50/40 mmHg and her heart rate was 45 b.p.m. Serum amlodipine level was extremely high (474.4 ng/mL), causing refractory bradycardia. She remained hypotensive despite fluid resuscitation, and therefore was administered dopamine and norepinephrine. She was also administered glucagon and calcium gluconate, and underwent high-dose insulin euglycemic therapy.\n\n\n\nAlthough her blood pressure improved, bradycardia progressively worsened and isoproterenol infusion was initiated, which resulted in an improvement in her heart rate. The patient discharged on day 14 without any complications.\n\n\n\nIsoproterenol is effective for treating bradycardia after amlodipine overdose.",
"affiliations": "Department of Critical Care Medical Center Sakai City Medical Center Osaka Japan.;Department of Critical Care Medical Center Sakai City Medical Center Osaka Japan.;Department of Critical Care Medical Center Sakai City Medical Center Osaka Japan.;Department of Critical Care Medical Center Sakai City Medical Center Osaka Japan.;Department of Emergency and Critical Care Medicine Saiseikai Shiga Hospital Shiga Japan.;Department of Critical Care Medical Center Sakai City Medical Center Osaka Japan.",
"authors": "Ebihara|Takeshi|T|0000-0003-4101-0419;Morita|Masanori|M|;Kawada|Masahiro|M|;Amano|Koji|K|;Kato|Fumitaka|F|0000-0001-8165-4521;Nakata|Yasuki|Y|",
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"doi": "10.1002/ams2.284",
"fulltext": "\n==== Front\nAcute Med SurgAcute Med Surg10.1002/(ISSN)2052-8817AMS2Acute Medicine & Surgery2052-8817John Wiley and Sons Inc. Hoboken 10.1002/ams2.284AMS2284Case ReportCase ReportsEfficacy of isoproterenol for treating amlodipine overdose resulting in bradycardia T. Ebihara et al.Ebihara Takeshi http://orcid.org/0000-0003-4101-0419ebihara.830@hp-emerg.med.osaka-u.ac.jp \n1\n\n3\nMorita Masanori \n1\nKawada Masahiro \n1\nAmano Koji \n1\nKato Fumitaka http://orcid.org/0000-0001-8165-4521\n2\nNakata Yasuki \n1\n\n1 \nDepartment of Critical Care Medical Center\nSakai City Medical Center\nOsaka\nJapan\n\n2 \nDepartment of Emergency and Critical Care Medicine\nSaiseikai Shiga Hospital\nShiga\nJapan\n3 Present address:\nSakai City Medical Center on April 1, 2017\n* Corresponding: Takeshi Ebihara, MD, Department of Traumatology and Acute Critical Medicine Osaka University Graduate School, 2‐15 Yamadaoka, Suita, Osaka, 565‐0871, Japan. E‐mail: ebihara.830@hp-emerg.med.osaka-u.ac.jp.26 5 2017 7 2017 4 3 10.1002/ams2.2017.4.issue-3353 357 21 10 2016 29 3 2017 © 2017 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Case\nAmlodipine predominantly affects vascular smooth muscle cells. Amlodipine overdose usually presents with vasodilatory shock, accompanied by reflex tachycardia rather than bradycardia.\n\nAn 81‐year‐old woman presented with impaired consciousness 8 h after ingesting 50 5‐mg amlodipine tablets with suicidal intent. On admission, her blood pressure was 50/40 mmHg and her heart rate was 45 b.p.m. Serum amlodipine level was extremely high (474.4 ng/mL), causing refractory bradycardia. She remained hypotensive despite fluid resuscitation, and therefore was administered dopamine and norepinephrine. She was also administered glucagon and calcium gluconate, and underwent high‐dose insulin euglycemic therapy.\n\nOutcome\nAlthough her blood pressure improved, bradycardia progressively worsened and isoproterenol infusion was initiated, which resulted in an improvement in her heart rate. The patient discharged on day 14 without any complications.\n\nConclusion\nIsoproterenol is effective for treating bradycardia after amlodipine overdose.\n\namlodipinebradycardiaisoproterenoloverdose source-schema-version-number2.0component-idams2284cover-dateJuly 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:07.11.2017\nFunding Information\n\n\nNo funding information provided.\n==== Body\nIntroduction\nAmlodipine is a dihydropyridine calcium‐channel blocker (CCB) that predominantly affects vascular smooth muscle cells, and causes marked peripheral vasodilation and hypotension. Amlodipine overdose usually presents with vasodilatory shock, accompanied by reflex tachycardia rather than bradycardia. Here, we report a case of amlodipine overdose with refractory bradycardia effectively treated with isoproterenol infusion.The protocol for this research project was approved by a suitably constituted Ethics Committee of the institution and it conforms to the provisions of the Declaration of Helsinki. The Ethics Committee permitted publication of this clinical case without registration. The patient provided her informed consent for her anonymized data to be used in this report.\n\nCase\nAn 81‐YEAR‐OLD woman with a history of hypertension treated with only amlodipine was admitted to our emergency department with impaired consciousness 8 h after ingesting 50 5‐mg amlodipine tablets with suicidal intent. On admission to the emergency department, blood pressure (BP) of 50/40 mmHg and heart rate (HR) 45 b.p.m. were recorded. Her Glasgow Coma Scale score was 13. The results of routine laboratory tests on admission were as follows: total leukocyte count 10,140/μL, serum creatinine 1.37 mg/dL, blood urea nitrogen 22.2 mg/dL, serum ionized calcium 1.14 mmol/L, and lactate 5.5 mmol/L. A 12‐lead electrocardiogram revealed no abnormalities. Comprehensive toxicological analysis of the urine was negative.\n\nHer medical history revealed only hypertension, treated with amlodipine, without a β‐blocker or angiotensin‐converting enzyme inhibitor. She was not diagnosed with depression before admission. The patient was diagnosed with an amlodipine overdose. She was intubated for airway protection and given fluid boluses. Intravenous vasopressor therapy was initiated (dopamine, 10 μg/kg/min; noradrenaline, 0.2 μg/kg/min). Atropine showed no effect on HR. She was hospitalized in the intensive care unit (ICU). The clinical course of the patient is shown in Figure 1. On admission to the ICU, her BP was 50/35 mmHg with an HR of 40 b.p.m. She remained in a hypotensive state despite high‐dose vasopressor therapy. A calcium gluconate (8.5%) infusion was initiated at a rate of 0.7 mL/kg/h, and her serum ionized calcium level was maintained at up to two times the upper limit of the reference range. On admission to the hospital, hyperglycemia was not shown. In this case, glucagon was given as a 100‐μg/kg bolus followed by further doses at a rate of 100 μg/kg/h. In addition, high‐dose insulin euglycemic therapy (HEIT) was initiated by an insulin infusion at a rate of 15 units/h with 10% dextrose. Despite these interventions, the patient's hemodynamic parameters did not improve. High‐dose insulin euglycemic therapy was subsequently stopped because the patient developed hypoglycemia 13 h after admission to the ICU. As the patient's serum ionized calcium level increased, her BP improved (Fig. 2). The doses of noradrenaline and dopamine were decreased, but bradycardia continued to worsen. After 24 h in the ICU, the serum ionized calcium level peaked at 2.7 mmol/L. Blood pressure fell despite a consistently high serum ionized calcium level. A dobutamine infusion was started and was increased up to 6 μg/kg/min to improve cardiac output with little effect. Despite these interventions, the patient's HR remained at 30–50 b.p.m., therefore, an isoproterenol infusion was started 26 h after ICU admission to improve cardiac output by increasing the HR. Soon after the infusion was started, the patient's HR increased. After 48 h in the ICU, the patient's serum ionized calcium level decreased to 1.5 mmol/L, and her HR and BP remained stable. Isoproterenol was weaned and stopped on ICU day 3. The patient was extubated on the same day, and she was discharged on day 14 without any complications.\n\nFigure 1 Clinical course of an 81‐year‐old woman with amlodipine overdose with hypotension and refractory bradycardia treated with calcium, glucagon, and high‐dose insulin euglycemic therapy (HEIT) with various vasopressor agents and isoproterenol. Isoproterenol is effective for improving bradycardia. BP, blood pressure; HR, heart rate; ICU, intensive care unit.\n\nFigure 2 Relationship between hemodynamic parameters and serum ionized calcium level, potassium level, and glucose level in an 81‐year‐old woman with amlodipine overdose with hypotension and refractory bradycardia. The serum calcium level was up to two times the upper limit of the reference range following continuous calcium infusion. Isoproterenol is effective for improving bradycardia. High‐dose insulin euglycemic therapy (HEIT) was discontinued because the patient developed hypoglycemia 13 h after admission to the intensive care unit (ICU). BP, blood pressure; HR, heart rate.\n\nDiscussion\nCalcium‐channel blockers are among the most widely used treatments for hypertension, angina pectoris, and congestive heart failure. The American Poison Control Centers reported that cardiovascular drugs have the fourth greatest rate of increase of serious outcomes.1 According to the National Poison Data System, CCBs were responsible for at least 17,720 exposures and 52 deaths in 2014 in the USA alone.1 Expert consensus recommendations for the management of CCB poisonings were published and stepwise management was recommended. However, unfortunately, there are no strongly recommended first‐line treatments for refractory patients and the level of evidence was very low.2 Therefore, a multimodal therapeutic approach is often used according to the situation.3, 4, 5\n\n\nCalcium‐channel blockers are categorized into three classes according to differences in chemical structure: phenylalkylamines, benzothiazepines, and dihydropyridines. Due to pharmacological selectivity, dihydropyridine CCBs (e.g. amlodipine, nifedipine) primarily affect the calcium channels in the smooth muscle6 and, in cases of overdose, cause vasodilatory shock with reflex sinus tachycardia.7, 8 Phenylalkylamines such as verapamil and benzothiazepines such as diltiazem cause cardiogenic shock in the case of overdose. Amlodipine overdose with β‐adrenergic blockers or the other classes of CCBs do not present with reflex sinus tachycardia. In fatal cases, cardiac arrest can occur and extracorporeal life support is required to rescue the patient.9\n\n\nIn the present case, refractory bradycardia continued after admission to the hospital. The serum amlodipine level was 474.43 ng/mL at admission and 251.75 ng/mL 24 h later. These levels are extremely high compared to the maximum concentration produced by a single oral dose of amlodipine (5 mg) reported in a study of 16 healthy elderly people10 (3.0 ± 1.1 ng/mL) and the peak serum amlodipine level reported in a study of six elderly Japanese patients given amlodipine (5 mg) daily for 8 days (14.9 ± 2.2 ng/mL) (published only in Japanese)11. A high serum amlodipine level causes loss of pharmacological selectivity. This could explain why the patient in this report experienced bradycardia with severe hypotension rather than reflex sinus tachycardia, as may be expected.\n\nIn the present case, the serum calcium level was up to two times the upper limit of the reference range following continuous calcium infusion. Hypotension improved, but oliguria and lactic acidosis continued. Dobutamine infusion was not enough to improve the patient's hemodynamic condition, thus, isoproterenol infusion was started to improve cardiac output by increasing the HR. The patient's condition began improving once the HR increased, and diuresis and normalization of the serum lactic acid level were also observed (Fig. 3). A FlowTrack (Edwards Lifesciences, Irvine, CA, USA) was used to monitor the hemodynamic parameters, and the cardiac output index increased from 1.7 to 2.4 L/min/m2 after starting the isoproterenol infusion. Isoproterenol is a non‐selective β‐adrenoreceptor to treat bradycardia associated with diltiazem and verapamil overdoses, which cause cardiotoxicity.12 Based on the current report,13 isoproterenol was used at 5–25 μg/min (maximal infusion rate is 60 μg/min). In our case, we started isoproterenol at 12 μg/min and increased up to 30 μg/min. Because bradycardia is not often present in amlodipine overdose cases, there are no reports that used isoproterenol for amlodipine overdose. In our case, isoproterenol prevented the use of a pacemaker or extracorporeal life support. Isoproterenol may be effective for refractory bradycardia caused by extremely high serum amlodipine.\n\nFigure 3 Relationship between hemodynamic parameters and in–out balance and serum lactate level in an 81‐year‐old woman with amlodipine overdose with hypotension and refractory bradycardia. The patient's condition began improving once her heart rate (HR) increased, and diuresis and normalization of the serum lactic acid level were also observed. BP, blood pressure; ICU, intensive care unit.\n\nThe use of calcium to treat CCB poisoning is physiologically reasonable and clinically indicated, but the response to calcium is also inadequate.3, 4, 5 A systematic review4 reported that adverse effects of therapeutic calcium infusion are rare following CCB poisoning. In the present case, the patient's BP improved in proportion to rising serum calcium levels, but her HR decreased. This finding was surprising, as calcium infusion has been reported to improve BP, but no reports to date have documented that calcium has an effect on HR.4 Mild hyperkalemia (K = 6.0 mmol/L) due to acute renal failure was also present. It is unclear whether the progressively worsening bradycardia reported in this case was related to the adverse effects of artificial hypercalcemia due to continuous calcium infusion or hyperkalemia. However, acute hypercalcemia causes bradycardia,14 and artificial hypercalcemia could have contributed to worsening bradycardia.\n\nIn conclusion, isoproterenol infusion is a promising treatment for hypotension with bradycardia caused by amlodipine overdose.\n\nDisclosure\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 \n\nMowry \nJB \n, \nApyker \nDA \n, \nBrooks \nDE \n. ‘2014 annual report of the american association of poison control centers’ national poison data system (NPDS): 32nd annual report . Clin. Toxicol. \n2015 ; 53 : 962 –1147 .\n2 \n\nMaude \nSt \n, \nKurt \nA \n, \nFrank \nLC \n. Experts consensus recommendations for the management of calcium channel blocker poisoning in adults . Crit. Care Med. \n2017 ; 45 : e306 –15 .27749343 \n3 \n\nShepherd \nG \n. Treatment of poisoning caused by beta‐adrenergic and calcium‐channel blockers . Am. J. Health Syst. Pharm. \n2006 ; 63 : 1828 –35 .16990629 \n4 \n\nGraudins \nA \n, \nLee \nHM \n, \nDruda \nD \n. Calcium channel antagonist and beta‐blocker overdose: antidotes and adjunct therapies . Br. J. Clin. Pharmacol. \n2016 ; 81 : 453 –61 .26344579 \n5 \n\nSt‐Onge \nM \n, \nDubé \nPA \n, \nGosselin \nS \n. Treatment for calcium channel blocker poisoning: a systematic review . Clin. Toxicol. \n2014 ; 52 : 926 –44 .\n6 \n\nDeWitt \nCR \n, \nWaksman \nJC \n. Pharmacology, pathophysiology and management of calcium channel blocker and beta‐blocker toxicity . Toxicol. Rev. \n2004 ; 23 : 223 –38 .15898828 \n7 \n\nPatel \nT \n, \nTietze \nD \n, \nMehta \nAN \n. Amlodipine overdose . Proc. (Bayl. Univ. Med. Cent.) \n2013 ; 26 : 410 –1 .24082424 \n8 \n\nUpreti \nV \n, \nRatheesh \nVR \n, \nDhull \nP \n. Shock due to amlodipine overdose . Indian J. Crit. Care Med. \n2013 ; 17 : 375 –7 .24501491 \n9 \n\nMaskell \nKF \n, \nFerguson \nNM \n, \nBain \nJ \n. Survival after cardiac arrest: ECMO rescue therapy after amlodipine and metoprolol overdose . Cardiovasc. Toxicol. \n2017 ; 17 : 223 –5 .26913719 \n10 \n\nElliott \nHL \n, \nMeredith \nPA \n, \nFaulker \nJK \n. A comparison of the disposition of single oral doses of amlodipine in young and elderly subjects . J. Cardiovasc. Pharmacol. \n1988 ; 12 : 64 –6 .\n11 \n\nKuwajima \nI \n, \nSuzuki \nY \n, \nKumamoto \nK \n. Study of pharmacokinetics of amlodiphine in essential hypertension of elderly people . Geriat.Med . 1991 ; 29 : 899 –902 .\n12 \n\nRamoska \nEA \n, \nSpiller \nHA \n, \nWinter \nM \n. A one‐year evaluation of calcium channel blocker overdoses: toxicity and treatment . Ann. Emerg. Med. \n1993 ; 22 : 196 –200 .8427431 \n13 \n\nMichael \nL \n, \nSteven \nCC \n, \nAngela \nP \n. Critical care management of verapamil and diltiazem overdose with a focus on vasopressors: a 25‐year experience at a single center . Ann. Emerg. Med. \n2013 ; 62 : 252 –8 .23642908 \n14 \n\nBadertscher \nE \n, \nWamica \nJW \n, \nEmst \nDS \n. Acute hypercalcemia and severe bradycardia in a patient with breast cancer . CMAJ \n1993 ; 148 : 1506 –8 .8477369\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2052-8817",
"issue": "4(3)",
"journal": "Acute medicine & surgery",
"keywords": "amlodipine; bradycardia; isoproterenol; overdose",
"medline_ta": "Acute Med Surg",
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"other_id": null,
"pages": "353-357",
"pmc": null,
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"title": "Efficacy of isoproterenol for treating amlodipine overdose resulting in bradycardia.",
"title_normalized": "efficacy of isoproterenol for treating amlodipine overdose resulting in bradycardia"
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"abstract": "OBJECTIVE\nMultiple instances of DILI in the same patient with drugs of similar structure or function as well as completely unrelated drugs are not well understood and poorly documented. We have sought evidence of the frequency and characteristics of patients who have experienced two DILI episodes due to different drugs.\n\n\nMETHODS\nAll cases of DILI systematically collected in the Spanish DILI Registry between 1994 and 2009 were retrieved. Data on demographics, clinical, laboratory and pathological findings, and outcome were analyzed.\n\n\nRESULTS\nNine patients (mean age 67 years, four women) out of 742, 1.21%, had evidence of two DILI episodes caused by different drugs. In four cases DILI was associated with structurally related drugs and in an additional two cases the drugs had a common target. In another case, unrelated antibiotics were implicated. In only two cases, the two drugs/herbals were not related in structure or function. All but one patient exhibited hepatocellular damage. The type of damage was consistent in both DILI episodes. Four cases presented as autoimmune hepatitis (AIH) in the second episode.\n\n\nCONCLUSIONS\nMultiple episodes of DILI in association with different drugs occur infrequently. In each individual, the type of injury was similar during the two DILI episodes, regardless of the causative drug. Second episodes of DILI are more likely to be associated with features of AIH. It remains uncertain if this is drug-induced unmasking of true AIH or DILI with autoimmune features. These cases illustrate the dilemma faced by clinicians in distinguishing these possibilities.",
"affiliations": "Servicio de Farmacología Clínica, Grupo de Estudio para las Hepatopatías Asociadas a Medicamentos, Co-ordinating Centre, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Campus Universitario de Teatinos s/n, Málaga, Spain. lucena@uma.es",
"authors": "Lucena|M I|MI|;Kaplowitz|N|N|;Hallal|H|H|;Castiella|A|A|;García-Bengoechea|M|M|;Otazua|P|P|;Berenguer|M|M|;Fernandez|M C|MC|;Planas|R|R|;Andrade|R J|RJ|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000890:Anti-Infective Agents; D000924:Anticholesteremic Agents; D018931:Antineoplastic Agents, Hormonal; D014150:Antipsychotic Agents; D018501:Antirheumatic Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jhep.2010.12.041",
"fulltext": null,
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"issn_linking": "0168-8278",
"issue": "55(4)",
"journal": "Journal of hepatology",
"keywords": null,
"medline_ta": "J Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000889:Anti-Arrhythmia Agents; D000890:Anti-Infective Agents; D000924:Anticholesteremic Agents; D018931:Antineoplastic Agents, Hormonal; D014150:Antipsychotic Agents; D018501:Antirheumatic Agents; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012042:Registries; D013030:Spain",
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"references": null,
"title": "Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.",
"title_normalized": "recurrent drug induced liver injury dili with different drugs in the spanish registry the dilemma of the relationship to autoimmune hepatitis"
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"abstract": "OBJECTIVE\nTo evaluate the pregnancy rate in Japanese women treated with levonorgestrel for emergency contraception.\n\n\nMETHODS\nThis retrospective record-based medical study included 1000 women who visited our clinic for emergency contraceptive treatment with 1.5 mg single-dose oral levonorgestrel, followed by 50 μg hormonal oral contraceptive from May 2011 to December 2017. The outcomes of the emergency contraceptive treatment were recorded at a follow-up visit, and descriptive statistics were obtained.\n\n\nRESULTS\nThe number of women treated with levonorgestrel at the clinic increased from 2011 to 2015, but there was no subsequent increase thereafter. Most women were in their 20s (57.4%), followed by their 30s (19.3%) and teens (18.3%). Of the 1000 women treated with levonorgestrel, 659 were followed up. Among the 659 women with follow-up data, 16 were pregnant (2.4%), of whom 11 underwent abortions, three had miscarriages, and two delivered at term. The timing of unprotected sexual intercourse relative to the estimated ovulation date among the pregnant women ranged from -3 to 23 days. The most commonly used contraceptive method before the emergency contraceptive visit was condoms (89.3%, 887/993). No new safety concerns were identified throughout the study period.\n\n\nCONCLUSIONS\nThe pregnancy rate after levonorgestrel treatment in Japanese women was low, and similar to that reported in previous studies. Information on contraceptive methods and emergency contraception with levonorgestrel needs to be better disseminated among women of childbearing age.",
"affiliations": "Sakurai Obstetrics and Gynecology Clinic, Koriyama, Japan.",
"authors": "Sakurai|Shigeru|S|https://orcid.org/0000-0001-9889-4150",
"chemical_list": "D003271:Contraceptive Agents, Female; D016912:Levonorgestrel",
"country": "Australia",
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"doi": "10.1111/jog.14049",
"fulltext": "\n==== Front\nJ Obstet Gynaecol ResJ. Obstet. Gynaecol. Res10.1111/(ISSN)1447-0756JOGThe Journal of Obstetrics and Gynaecology Research1341-80761447-0756John Wiley & Sons Australia, Ltd Kyoto, Japan 10.1111/jog.14049JOG14049Original ArticleOriginal ArticlesPregnancy rate after emergency contraception with single‐dose oral levonorgestrel in Japanese women Levonorgestrel contraception in JapanS. SakuraiSakurai Shigeru https://orcid.org/0000-0001-9889-4150\n1\nsakurais@dream.com \n1 \nSakurai Obstetrics and Gynecology Clinic\nKoriyama\nJapan\n* Correspondence: Dr Shigeru Sakurai, Sakurai Obstetrics and Gynecology Clinic, 23‐18 Toramaru‐machi, Koriyama, Fukushima 963‐8014, Japan. Email: sakurais@dream.com08 7 2019 9 2019 45 9 10.1111/jog.v45.81892 1898 17 3 2019 12 6 2019 © 2019 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and GynecologyThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nAim\nTo evaluate the pregnancy rate in Japanese women treated with levonorgestrel for emergency contraception.\n\nMethods\nThis retrospective record‐based medical study included 1000 women who visited our clinic for emergency contraceptive treatment with 1.5 mg single‐dose oral levonorgestrel, followed by 50 μg hormonal oral contraceptive from May 2011 to December 2017. The outcomes of the emergency contraceptive treatment were recorded at a follow‐up visit, and descriptive statistics were obtained.\n\nResults\nThe number of women treated with levonorgestrel at the clinic increased from 2011 to 2015, but there was no subsequent increase thereafter. Most women were in their 20s (57.4%), followed by their 30s (19.3%) and teens (18.3%). Of the 1000 women treated with levonorgestrel, 659 were followed up. Among the 659 women with follow‐up data, 16 were pregnant (2.4%), of whom 11 underwent abortions, three had miscarriages, and two delivered at term. The timing of unprotected sexual intercourse relative to the estimated ovulation date among the pregnant women ranged from −3 to 23 days. The most commonly used contraceptive method before the emergency contraceptive visit was condoms (89.3%, 887/993). No new safety concerns were identified throughout the study period.\n\nConclusion\nThe pregnancy rate after levonorgestrel treatment in Japanese women was low, and similar to that reported in previous studies. Information on contraceptive methods and emergency contraception with levonorgestrel needs to be better disseminated among women of childbearing age.\n\nemergency contraceptivehormonal oral contraceptivelevonorgestrelpregnancy ratesex educationASKA Pharmaceutical Co., Ltd source-schema-version-number2.0component-idjog14049cover-dateSeptember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:01.10.2019\n==== Body\nIntroduction\nEmergency oral hormonal contraceptive methods have evolved since the first use of high‐dose estrogen in the 1960s,1 followed by the Yuzpe regimen (medium pill, 100 μg ethinylestradiol combined with 1.0 mg of dl‐norgestrel, twice 12 h apart) in the 1970s2 and levonorgestrel in the 1990s.3, 4 In a large‐scale study, the World Health Organization reported that the levonorgestrel regimen (0.75 mg, repeated 12 h later) was better tolerated, more effective, and caused fewer side effects, such as nausea and vomiting than the Yuzpe regimen (ethinylestradiol 100 μg plus levonorgestrel 0.5 mg, repeated 12 h later).3 Levonorgestrel (two 0.75 mg doses 12 h apart) prescription was approved as an emergency contraceptive method in the United States in 1999 and has been marketed in many countries,5, 6, 7, 8, 9 and the same regimen was subsequently approved as an over‐the‐counter drug in 2006. It was shown in 2002 that a single 1.5 mg oral levonorgestrel dose within 72 h of sexual intercourse could substitute for two 0.75 mg doses 12 h apart,4 and this new regimen was approved as an over‐the‐counter treatment in the United States in 2013.\n\nIn Japan, two 0.75 mg doses of levonorgestrel 12 h apart was first approved in 2011, followed by approval of the 1.5 mg regimen in 2016. The ‘Guidelines on proper use of emergency contraceptive method’ issued by the Japan Society of Obstetrics and Gynecology recommended single‐dose levonorgestrel as the standard for emergency contraception in May 2011.10 Notably, however, the approval of levonorgestrel as an over‐the‐counter drug is still pending in Japan.\n\nBecause levonorgestrel was approved relatively late in Japan compared with other countries, the medication's efficacy and safety in a real clinical setting among Japanese women has only been addressed in a review.11 We have been treating women who visited our clinic for emergency contraceptive treatment, most of whom received 1.5 mg levonorgestrel. We considered that the subsequent pregnancy rate calculated on the basis of these data would provide valuable information on the real‐world efficacy and tolerance of levonorgestrel. The results of this study also emphasize the need to improve the awareness of and access to levonorgestrel as an effective and safe emergency contraceptive method, among physicians, teachers, and women of childbearing age.\n\nMethods\nThis retrospective record‐based medical study aimed to evaluate the pregnancy rate in Japanese women after emergency contraceptive treatment with levonorgestrel. A total of 1030 women visited our clinic for emergency contraceptive treatment from May 30, 2011 to December 25, 2017. The following information was recorded for each patient at their first visit: standard demographic information, smoking status, marital status, partner's age, age at first sexual intercourse, pregnancy/delivery history, reason for requesting emergency contraceptive, source of information about the emergency contraceptive and time from estimated ovulation to unprotected sexual intercourse (UPSI) and from emergency contraceptive treatment to UPSI.\n\nPatients were treated with one of the following contraceptive methods: single treatment with oral 1.5 mg levonorgestrel, Yuzpe regimen or copper intrauterine device (IUD), plus 50 μg hormonal oral contraceptive (OC) starting on the day after the emergency contraceptive treatment, in accordance with the standard treatment protocol issued by Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists.12 Patients were instructed to visit the clinic for a follow‐up after 3–4 weeks. Additional information (contraceptive methods after the emergency contraceptive treatment, side effects, and pregnancy outcome) were recorded at the follow‐up visit.\n\nEach patient was given an identification number, and demographic and outcome information were analyzed as of February 2, 2018. The numbers of women who received levonorgestrel were obtained according to the year of visit and patient's age group. Descriptive statistics were obtained for pregnant, non‐pregnant, and all women. No statistical between‐group analysis was carried out because of the small sample size of the pregnant group.\n\nResults\nAmong 1030 women who visited the clinic from May 2011 to December 2017, 1000 were treated with a single oral 1.5 mg levonorgestrel tablet, 24 with a copper IUD and six with the Yuzpe regimen (Fig. 1). Of the 1000 women who received levonorgestrel, 977 were treated with levonorgestrel within 72 h of UPSI, 20 within 4–6 days, and the interval was unknown in the other three women.\n\nFigure 1 Participants’ disposition. IUD, intrauterine device.\n\nThe number of women treated with levonorgestrel at the clinic increased each year up to 2015, but remained similar thereafter (Fig. 2a). Most women were in their 20s (57.4%, 574/1000 women), followed by their 30s (19.3%, 193/1000) and teens (18.3%, 183/1000) (Fig. 2b). The mean patient age was 25.5 ± 6.8 years (Table 1). Commonly used contraceptive methods before the visit to the clinic were condoms (89.3%, 887/993), withdrawal (4.5%, 45/993), and OC (4.2%, 42/993), but no women used an IUD or other intrauterine system (Table 2).\n\nFigure 2 Numbers of women treated with levonorgestrel according to year (a) and age group (b).\n\nTable 1 Characteristics of participants treated with levonorgestrel according to pregnancy status\n\nCharacteristic\tFollowed‐up (n = 659)\tTotal (n = 1000)\t\nPregnant (n = 16)\tNot pregnant (n = 643)\t\nAge at first clinic visit (years), n\n\t16\t643\t1000\t\n27.1 ± 6.6\t25.6 ± 6.9\t25.5 ± 6.8\t\nAge at first sexual intercourse (years), n\n\t16\t637\t987\t\n18.0 ± 1.7\t18.0 ± 2.8\t17.8 ± 2.7\t\nPaternal age (years), n\n\t16\t584\t883\t\n31.2 ± 7.3\t27.8 ± 8.1\t28.0 ± 8.0\t\nNumber with prior delivery, n\n\t16\t643\t998\t\n0.9 ± 1.2\t0.4 ± 0.8\t0.4 ± 0.9\t\nNumber with prior D&C, n\n\t16\t643\t998\t\n0.4 ± 0.8\t0.3 ± 0.6\t0.3 ± 0.7\t\nSmoking status, n\n\t16\t642\t998\t\nYes, n (%)\t3 (18.8)\t142 (22.1)\t246 (24.6)\t\nNo n (%)\t13 (81.3)\t500 (77.9)\t752 (75.3)\t\nD&C, dilation and curettage.\n\nValues presented as mean ± standard deviation unless otherwise specified.\n\nTable 2 Characteristics of participants treated with levonorgestrel\n\nCharacteristic\tTotal (n = 1000)\t\nUsual contraceptive method, n (%)\t993\t\nCondom\t887 (89.3)\t\nWithdrawal\t45 (4.5)\t\nHormonal oral contraceptives\t42 (4.2)\t\nNone\t17 (1.7)\t\nOther\t2 (0.2)\t\nContraceptive method leading to the clinic visit, n (%)\t995\t\nCondom\t684 (68.7)\t\nNone\t214 (21.5)\t\nWithdrawal\t81 (8.1)\t\nOther\t8 (0.8)\t\nIntrauterine system\t5 (0.5)\t\nReason for clinic visit, n (%)\t992\t\nCondom breakage\t330 (33.3)\t\nCondom slipped off\t282 (28.4)\t\nNo contraceptive used\t186 (18.8)\t\nWithdrawal\t67 (6.8)\t\nOther\t127 (12.8)\t\nSource of information on emergency contraceptives, n (%)\t991\t\nInternet\t474 (47.8)\t\nFriends\t231 (23.3)\t\nPartner\t93 (9.4)\t\nPhysician\t86 (8.7)\t\nSchool education\t58 (5.9)\t\nHospital staff\t26 (2.6)\t\nFamily members\t12 (1.2)\t\nBooks\t9 (0.9)\t\nTV\t2 (0.2)\t\nThe most commonly used contraceptive method leading to the visit to the clinic for emergency contraceptive treatment was condoms (68.7%, 684/995), followed by no contraceptive (21.5%, 214/995) and withdrawal (8.1%, 81/995) and the most common reason for the clinic visit was condom‐related incidences (condom breakage, 33.3%, 330/992; condom slipped off, 28.4%, 282/992). Of the 1000 women, 47.8% (474/991) obtained their information on emergency contraceptives through the internet, 23.3% (231/991) from friends, 9.4% (93/991) from partners, and 8.7% (86/991) from physicians (Table 2).\n\nAs of February 28, 2018, 341 women were lost to follow‐up with unknown pregnancy outcome and 659 women visited the clinic for a follow‐up (65.9%). Among these 659 women, 16 pregnancies were observed (2.4%, 16/659), of whom 11 underwent abortions, three had miscarriages, and two delivered. Fifteen pregnant women were treated with levonorgestrel within 55 h of UPSI. All except one pregnant patient started OC the day after levonorgestrel administration. The time from UPSI to ovulation was between −3 and 23 days in the 16 pregnant women, but no patient had UPSI more than 4 days before her estimated ovulation. Of the two delivered women, one was married and another was single at a time of emergency contraceptive visit, but both were married when they delivered (Table 3). There were no notable differences in characteristics, such as age and smoking status, between pregnant and non‐pregnant women (Table 1).\n\nTable 3 Characteristics of participants who were pregnant after emergency contraception with levonorgestrel\n\nSubject ID\tAge (years)\tPrior pregnancy\tPrior delivery\tContraceptive†\n\tSource of information\tBetween estimated ovulation and UPSI (days)\tInitiation of emergency contraceptive treatment after UPSI (hours)\tContraceptive after the emergency clinic visit\tOutcome\tMarital status\t\n1\t28\t1\t0\tCondom\tPartner\t−3\t34\tOC\tMiscarriage, 5 w\tSingle\t\n2\t22\t0\t0\tCondom\tPartner\t−2\t13\tOC\tMiscarriage, 7 w\tSingle\t\n3\t37\t1\t1\tNone\tInternet\t−2\t34\tOC\tD&C, 6 w\tMarried\t\n4\t40\t2\t2\tCondom\tInternet\t−1\t8\tOC\tD&C, 7 w\tMarried\t\n5\t25\t3\t2\tNone\tFriends\t−1\t13\t–\tD&C, 6 w\tDivorced\t\n6\t35\t3\t3\tCondom\tInternet\t0\t31\tOC\tD&C, 6 w\tMarried\t\n7\t33\t3\t3\tCondom\tInternet\t0\t33\tOC\tD&C, 6 w\tMarried\t\n8\t20\t0\t0\tNone\tPartner\t0\t55\tOC\tD&C, 7 w\tSingle\t\n9\t30\t0\t0\tWithdrawal\tInternet\t0\t93\tOC\tD&C, 7 w\tSingle\t\n10\t24\t1\t1\tWithdrawal\tInternet\t2\t12\tOC\tDelivered\tMarried\t\n11\t20\t0\t0\tCondom\tFriends\t3\t6\tOC\tD&C, 7 w\tSingle\t\n12\t19\t1\t0\tCondom\tPartner\t3\t18\tOC\tD&C, 8 w\tSingle\t\n13\t19\t0\t0\tCondom\tSchool education\t4\t7\tOC\tD&C, 6 w\tSingle\t\n14\t30\t4\t3\tCondom\tInternet\t17\t52\tOC\tD&C, 7 w at another clinic\tMarried\t\n15\t24\t3\t0\tCondom\tPhysician\t18\t14\tOC\tMiscarriage, 6 w\tSingle\t\n16\t28\t0\t0\tCondom\tInternet\t23\t11\tOC\tDelivered\tMarried before delivery\t\nD&C, dilation and curettage; OC, oral contraceptive; UPSI, unprotected sexual intercourse; w, week.\n\n† \nContraceptive that led to the clinic visit for the emergency contraceptive treatment.\n\nDay 0 = estimated ovulation day.\n\n–: data not available.\n\nDiscussion\nOur clinic has been providing emergency contraception with 1.5 mg levonorgestrel since May 2011, when levonorgestrel was approved and became available from ASKA Pharmaceutical Co., Ltd. We analyzed the efficacy of levonorgestrel for preventing pregnancy when 1000 women had been treated, to provide a large enough sample size to produce meaningful results in a real clinical setting. In addition, we considered that the issue was clinically significant given that some women became pregnant and delivered despite treatment with levonorgestrel within 72 h.\n\nThe pregnancy rate in this study was 2.4%, which was consistent with previous reports (0.7–2.6%).4, 13, 14, 15 Similar pregnancy rates were reported in Japanese women in post‐marketing surveillance (0.7%, 4/570 women, unpublished report; ASKA Pharmaceutical Co. Ltd.) and in a phase III study (1.6%, 1/63 women, unpublished report; Sosei Co. Ltd.) with smaller sample sizes. The present and previous results thus suggest that emergency contraception with levonorgestrel is a highly effective method for preventing pregnancy.\n\nThe timing of UPSI relative to the expected ovulation date may affect the success/failure of emergency contraceptive treatment with levonorgestrel. Sexual intercourse within 6 days before ovulation was previously shown to result in a high pregnancy rate.16 Indeed, nine of the 16 pregnant women in the current study had UPSI within 6 days before their expected ovulation day. Because levonorgestrel delays or inhibits ovulation by suppressing luteinizing hormone,17 the relative timing of UPSI, activation of luteinizing hormone, and treatment with levonorgestrel could have affected the pregnancy outcome. However, similar data were not collected for non‐pregnant women in this study, and more data are therefore needed to support this interpretation. Notably, insertion of a copper IUD might have prevented pregnancy in a few women with a past delivery experience who were treated with levonorgestrel more than 10 days after UPSI, given that copper IUDs have been shown to prevent pregnancy even when inserted more than 10 days after UPSI.18, 19\n\n\nTwo of the 16 pregnant women in the current study gave birth; no clinically significant issues with the delivery process or the newborns were reported, suggesting that levonorgestrel failure had no clinical adverse effects on the newborns.\n\nThe Public Health Administration statistics provided by the Ministry of Health, Labour and Welfare in Japan have shown that the number of abortions has been declining in recent years (e.g., 226 878 women in 2009 vs 186 253 in 2013), although the number of abortions carried out each year remains high.20 Approximately 880 women visited our clinic for an abortion during the study period, confirming the high number of abortions. Although the reasons for the abortion visits were not analyzed in this study, lack of knowledge and access to emergency contraceptive methods should be taken into consideration. Promoting sex education to improve awareness of emergency contraception could have prevented women from seeking surgical termination, as well as financial distress over the associated medical costs. Notably, medical expenses associated with abortion, except in rape cases, are not covered by health insurance in Japan.12\n\n\nAccording to the latest survey carried out every 2 years by the Japan Family Planning Association, only 50% of women and 40% of men in 2017 were aware of the available emergency contraceptive methods.21 In Japan, no specific actions leading to pregnancy, or information on contraceptive and emergency contraceptive methods, are included in the compulsory sex education curriculum.22, 23 Indeed, the present results showed that over 70% of women learned about emergency contraceptive methods via the internet or friends, compared with less than 6% at school. The scant school education on pregnancy and contraception suggests that broader platforms are urgently needed to inform people, women in particular, about all available contraceptive options.\n\nThe most commonly used contraceptive method in the current study was condoms (89.3%), with only 4.2% of women using OCs, supporting the fact that Japanese people tend to rely on condoms to avoid unwanted pregnancies. However, as also indicated in this study, over 60% of women who visited the clinic for emergency contraceptive treatment did so as a result of condom‐related incidences, indicating that condoms do not provide a reliable contraceptive method. Better education programs on contraceptive methods, such as OC and emergency contraception, need to be available to the general public, especially women, to allow them to become more proactive and responsible in implementing contraceptive methods.\n\nOf 661 women with available records, no side effects were reported in 638 (96.5%) women and no new safety concerns were identified,4 indicating that emergency contraceptive treatment with a single 1.5 mg dose of levonorgestrel was safe and well tolerated in Japanese women.\n\nThis study was limited by the fact that a proportion of the pregnancies prevented was not assessed. Furthermore, this was a single‐center study, which might have caused bias; however, the sample size was large enough to assess the outcome in current clinical practice. Another limitation is that the efficacy of levonorgestrel was assessed only by the pregnancy rate in this study. Since the clinical efficacy of emergency contraceptive methods in general is often overestimated, patients should be notified that the actual clinical efficacy may be lower than expected, and what options, such as copper IUD, are available.\n\nIn conclusion, the results of this study showed that the pregnancy rate after levonorgestrel treatment in Japanese women in a real clinical setting was low and similar to that reported in previous studies. Information on regular contraceptive methods and emergency contraception with levonorgestrel needs to be better disseminated among women of childbearing age.\n\nDisclosure\nNone declared.\n\nAcknowledgments\nThe author thanks ASCA Corporation for providing medical writing and editorial support, funded by ASKA Pharmaceutical Co., Ltd.\n==== Refs\nReferences\n1 \n\nHaspels \nAA \n. The “morning‐after pill”‐—preliminary report . IPPF Med Bull \n1969 ; 3 : 6 .12275493 \n2 \n\nYuzpe \nAA \n, \nLancee \nWJ \n. Ethinylestradiol and dl‐norgestrel as a postcoital contraceptive . Fertil Steril \n1977 ; 28 : 932 –936 .892044 \n3 \nTask Force on Postovulatory Methods of Fertility Regulation \n. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception . Lancet \n1998 ; 352 : 428 –433 .9708750 \n4 \n\nvon Hertzen \nH \n, \nPiaggio \nG \n, \nDing \nJ \n\net al\nWHO research group on post‐ovulatory methods of fertility regulation. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: A WHO multicentre randomised trial . Lancet \n2002 ; 360 : 1803 –1810 .12480356 \n5 \nWorld Health Organization \n. Selected Practice Recommendations for Contraceptive Use , 2nd edn. Geneva : World Health Organization , 2004 .\n6 \n\nHaeger \nKO \n, \nLamme \nJ \n, \nCleland \nK \n. State of emergency contraception in the U.S., 2018 . Contracept Reprod Med \n2018 ; 3 : 20 –31 .30202545 \n7 \n\nChen \nQJ \n, \nXiang \nWP \n, \nZhang \nDK \n\net al\nEfficacy and safety of a levonorgestrel enteric‐coated tablet as an over‐the‐counter drug for emergency contraception: A phase IV clinical trial . Hum Reprod \n2011 ; 26 : 2316 –2321 .21672924 \n8 \n\nCarvajal \nA \n, \nSáinz \nM \n, \nVelasco \nV \n\net al\nEmergency contraceptive pill safety profile. Comparison of the results of a follow‐up study to those coming from spontaneous reporting . Pharmacoepidemiol Drug Saf \n2015 ; 24 : 93 –97 .25408302 \n9 \n\nGainer \nE \n, \nMéry \nC \n, \nUlmann \nA \n. Levonorgestrel‐only emergency contraception: Real‐world tolerance and efficacy . Contraception \n2001 ; 64 : 17 –21 .11535208 \n10 \nJapan Society of Obstetrics and Gynecology \n. Guidelines on Proper Use of Emergency Contraceptive Method . Tokyo, Japan: Japan Society of Obstetrics and Gynecology, 2011 [Cited 21 Jan 2019]. Available from URL: http://www.jsog.or.jp/news/pdf/guiding-principle.pdf\n\n11 \n\nKitamura \nK \n. Emergency contraception and progestin . Hormone Frontier in Gynecology \n2010 ; 17 : 44 –53 .\n12 \nJapan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists \n. Gynecology Guidelines. Gynecologic Outpatient Edn . Tokyo : Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists , 2017 .\n13 \nUnited Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Post‐Ovulatory Methods of Fertility Regulation \n. Efficacy and side effects of immediate postcoital levonorgestrel used repeatedly for contraception . Contraception \n2000 ; 61 : 303 –308 .10906500 \n14 \n\nArowojolu \nAO \n, \nOkewole \nIA \n, \nAdekunle \nAO \n. Comparative evaluation of the effectiveness and safety of two regimens of levonorgestrel for emergency contraception in Nigerians . Contraception \n2002 ; 66 : 269 –273 .12413624 \n15 \n\nGlasier \nAF \n, \nCameron \nST \n, \nFine \nPM \n\net al\nUlipristal acetate versus levonorgestrel for emergency contraception: A randomised non‐inferiority trial and meta‐analysis . Lancet \n2010 ; 375 : 555 –562 .20116841 \n16 \n\nWilcox \nAJ \n, \nWeinberg \nCR \n, \nBaird \nDD \n. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby . N Engl J Med \n1995 ; 333 : 1517 –1521 .7477165 \n17 \n\nDurand \nM \n, \ndel Carmen Cravioto \nM \n, \nRaymond \nEG \n\net al\nOn the mechanisms of action of short‐term levonorgestrel administration in emergency contraception . Contraception \n2001 ; 64 : 227 –234 .11747872 \n18 \n\nZhou \nL \n, \nXiao \nB \n. Emergency contraception with multiload cu‐375 SL IUD: A multicenter clinical trial . Contraception \n2001 ; 64 : 107 –112 .11704087 \n19 \n\nCheng \nL \n, \nGülmezoglu \nAM \n, \nPiaggio \nG \n, \nEzcurra \nE \n, \nVan Look \nPF \n. Interventions for emergency contraception . Cochrane Database Syst Rev \n2008 ; 16 (2 ): CD001324 .\n20 \nMinistry of Health, Labour, and Welfare \n. Overview of the public health administration . 2014 [Cited 21 Jan 2019]. Available from URL: https://www.mhlw.go.jp/toukei/saikin/hw/eisei_houkoku/13/dl/gaikyo.pdf\n\n21 \nJapan Family Planning Association \n(ed). The Eighth Survey Report on Life and Consciousness of Men and Women . Tokyo : Japan Family Association , 2017 .\n22 \n\nNishioka \nE \n. Historical transition of sexuality education in Japan and outline of reproductive health/rights . Jpn J Hyg \n2018 ; 73 : 178 –184 .\n23 \n\nNishioka \nE \n. Trends in research on adolescent sexuality education, fertility awareness, and the possibility of life planning based on reproductive health education . Jpn J Hyg \n2018 ; 73 : 185 –199 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1341-8076",
"issue": "45(9)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "emergency contraceptive; hormonal oral contraceptive; levonorgestrel; pregnancy rate; sex education",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D044363:Contraception, Postcoital; D003271:Contraceptive Agents, Female; D005260:Female; D006801:Humans; D007564:Japan; D016912:Levonorgestrel; D011247:Pregnancy; D018873:Pregnancy Rate; D055815:Young Adult",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1892-1898",
"pmc": null,
"pmid": "31286635",
"pubdate": "2019-09",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": "18425871;12413624;11704087;7477165;11747872;12275493;25408302;30202545;9708750;892044;20116841;11535208;29848870;10906500;29848871;21672924;12480356",
"title": "Pregnancy rate after emergency contraception with single-dose oral levonorgestrel in Japanese women.",
"title_normalized": "pregnancy rate after emergency contraception with single dose oral levonorgestrel in japanese women"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2019-04698",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
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"drugadditi... |
{
"abstract": "Paclitaxel (PTX) is one of the most important breast cancer treatment drugs. However, severe hypersensitivity reactions such as decreases in blood pressure and impaired breathing occur with high frequency. For the prevention of such hypersensitivity reactions, administration of a premedication composed of three components, diphenhydramine, ranitidine (or famotidine), and dexamethasone, has been advised in package insert information of medicine. Administration of diphenhydramine is difficult in breast cancer patients complicated with closed-angle glaucoma, because diphenhydramine has a weak anticholinergic adverse effect which can induce mydriasis and glaucoma attack. We studied the prevention of severe hypersensitivity reactions and of glaucoma attack in 2 breast cancer patients complicated with closed angle glaucoma at our hospital from April 2007 to March 2008. We switched from diphenhydramine to fexofenadine as the medicine to prevent hypersensitivity reactions. Hypersensitivity reactions were not observed throughout all courses in both patients, and no glaucoma attack was observed.",
"affiliations": "Department of Pharmacy, National Hospital Organization Shikoku Cancer Center, Japan.",
"authors": "Komatsubara|Kazuo|K|;Miyoshi|Kyoko|K|;Kogure|Yuuki|Y|;Matsuhisa|Tetsuaki|T|;Eguchi|Hisae|H|",
"chemical_list": "D018926:Anti-Allergic Agents; D000972:Antineoplastic Agents, Phytogenic; D016593:Terfenadine; C093230:fexofenadine; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "37(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D018926:Anti-Allergic Agents; D000972:Antineoplastic Agents, Phytogenic; D001943:Breast Neoplasms; D004342:Drug Hypersensitivity; D005260:Female; D015812:Glaucoma, Angle-Closure; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D011292:Premedication; D016593:Terfenadine",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "107-10",
"pmc": null,
"pmid": "20087041",
"pubdate": "2010-01",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Administration of premedication with fexofenadine for paclitaxel-induced hypersensitive reactions in breast cancer patients complicated with closed-angle glaucoma.",
"title_normalized": "administration of premedication with fexofenadine for paclitaxel induced hypersensitive reactions in breast cancer patients complicated with closed angle glaucoma"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1029799",
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"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "FEXOFENADINE\\FEXOFENADINE HYDROCHLORIDE"
},
... |
{
"abstract": "An 87-year-old blind man was admitted due to repeatedly disturbed consciousness and fever. Brain CT showed a pituitary tumor with a hematoma and an occlusive lesion of the right internal carotid artery. He experienced consciousness disturbance and left limb weakness with hypotension for a few minutes on the day of admission. We considered pituitary apoplexy caused adrenal failure with hypotension and transient ischemic attack (TIA) induced by a hemodynamic mechanism. An increased dose of hydrocortisone improved the fever and hypotension, and resolved consciousness disturbance. This is a unique example of TIA caused by the occlusive lesion of the internal carotid artery compressed as a result of pituitary apoplexy and a hemodynamic mechanism.",
"affiliations": "Division of Cerebrovascular Medicine and Neurology, National Hospitalization Organization, Kyushu Medical Center.;Division of Cerebrovascular Medicine and Neurology, National Hospitalization Organization, Kyushu Medical Center.;Division of Cerebrovascular Medicine and Neurology, National Hospitalization Organization, Kyushu Medical Center.;Division of Cerebrovascular Medicine and Neurology, National Hospitalization Organization, Kyushu Medical Center.;Division of Cerebrovascular Medicine and Neurology, National Hospitalization Organization, Kyushu Medical Center.;Division of Cerebrovascular Medicine and Neurology, National Hospitalization Organization, Kyushu Medical Center.",
"authors": "Hashimoto|Go|G|;Wada|Shinichi|S|;Yoshino|Fumitaka|F|;Kuwashiro|Takahiro|T|;Yasaka|Masahiro|M|;Okada|Yasushi|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.cn-001372",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": "60(2)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": "adrenal insufficiency; hemodynamic; ischemic stroke; pituitary apoplexy",
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000309:Adrenal Insufficiency; D000369:Aged, 80 and over; D001157:Arterial Occlusive Diseases; D002343:Carotid Artery, Internal; D006439:Hemodynamics; D006801:Humans; D002546:Ischemic Attack, Transient; D008297:Male; D010899:Pituitary Apoplexy",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "146-151",
"pmc": null,
"pmid": "31956196",
"pubdate": "2020-02-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Case report: transient ischemic stroke caused by internal carotid artery occlusion due to compression by pituitary apoplexy and hemodynamic mechanism.",
"title_normalized": "case report transient ischemic stroke caused by internal carotid artery occlusion due to compression by pituitary apoplexy and hemodynamic mechanism"
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"abstract": "Hemolytic anemia (HA) of the newborn should be considered in cases of rapidly developing, severe, or persistent hyperbilirubinemia. Several causes of corpuscular hemolysis have been described, among which red blood cell enzyme defects are of particular concern. We report a rare case of red blood cell enzyme defect in a male infant, who presented during his first months of life with recurrent and isolated neonatal hemolysis. All main causes were ruled out. At 6.5 months of age, the patient presented with gastroenteritis requiring hospitalization; fortuitously, urine organic acid chromatography revealed a large peak of 5-oxoproline. Before the association between HA and 5-oxoprolinuria was noted, glutathione synthetase deficiency was suspected and confirmed by a low glutathione synthetase concentration and a collapse of glutathione synthetase activity in erythrocytes. Moreover, molecular diagnosis revealed 2 mutations in the glutathione synthetase gene: a previously reported missense mutation (c.[656A>G]; p.[Asp219Gly]) and a mutation not yet described in the binding site of the enzyme (c.[902T>C]; p.[Leu301Pro]). However, 15 days later, a control sample revealed no signs of 5-oxoprolinuria and the clinical history discovered administration of acetaminophen in the 48 hours before hospitalization. Thus, in this patient, acetaminophen exposure allowed the diagnosis of a mild form of glutathione synthetase deficiency, characterized by isolated HA. Early diagnosis is important because treatment with bicarbonate, vitamins C and E, and elimination of trigger factors are recommended to improve long-term outcomes. Glutathione synthetase deficiency should be screened for in cases of unexplained newborn HA.",
"affiliations": "Department of Biochemistry and Genetics, University Hospital, Angers, France.;Department of Biochemistry and Genetics, University Hospital, Angers, France.;Department of Biochemistry and Genetics, University Hospital, Angers, France.;Department of Biochemistry and Genetics, University Hospital, Angers, France.;Department of Biochemistry and Genetics, University Hospital, Angers, France.;Department of Biochemistry and Genetics, University Hospital, Angers, France.;Department of Biochemistry and Genetics, University Hospital, Angers, France gisimard@chu-angers.fr.",
"authors": "Signolet|Isabelle|I|;Chenouard|Rachel|R|;Oca|Florine|F|;Barth|Magalie|M|;Reynier|Pascal|P|;Denis|Marie-Christine|MC|;Simard|Gilles|G|",
"chemical_list": "D005981:Glutathione Synthase",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0031-4005",
"issue": "138(3)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000592:Amino Acid Metabolism, Inborn Errors; D000743:Anemia, Hemolytic; D005981:Glutathione Synthase; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D012008:Recurrence",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27581854",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent Isolated Neonatal Hemolytic Anemia: Think About Glutathione Synthetase Deficiency.",
"title_normalized": "recurrent isolated neonatal hemolytic anemia think about glutathione synthetase deficiency"
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"activesubstancename": "ACETAMINOPHEN"
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"abstract": "BACKGROUND\nChlamydia psittaci pneumonia is a zoonotic infectious disease caused by Chlamydia psittaci. Diagnostic tools, including culture, serologic test and PCR-based methods, are available but prone to false negative results.\n\n\nMETHODS\nThis report included five cases of Chlamydia psittaci pneumonia. Symptoms and signs common to all 5 cases included fever, coughing, generalized muscle ache, and most notably, inflammatory infiltration of the lungs upon chest CT and X-ray. Metagenomic next-generation sequencing (mNGS) revealed the presence of Chlamydia psittaci in biopsy lung tissue in 3 cases and bronchoalveolar lavage fluid in the remaining 2 cases. Three patients responded to doxycycline plus moxifloxacin; two patients responded to moxifloxacin alone.\n\n\nCONCLUSIONS\nmNGS could be used to diagnose Chlamydia psittaci pneumonia.",
"affiliations": "Graduate College of Fujian Medical University, Minhou, Fuzhou, 350108, China.;Department of Respiratory and Critical Care Medicine, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025, China.;Pharmacy Department, The 985th Hospital of the Joint Logistic Support Force, PLA, Yingze, Taiyuan, 030001, China.;Graduate College of Fujian Medical University, Minhou, Fuzhou, 350108, China.;Department of Nephrology, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025, China.;Department of Respiratory and Critical Care Medicine, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025, China.;Department of Respiratory and Critical Care Medicine, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025, China.;Department of Respiratory and Critical Care Medicine, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025, China.;Department of Respiratory and Critical Care Medicine, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025, China.;Department of Respiratory and Critical Care Medicine, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025, China.;Department of Respiratory and Critical Care Medicine, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025, China. fjfzfisher@163.com.",
"authors": "Gu|Lei|L|;Liu|Wei|W|;Ru|Meng|M|;Lin|Jing|J|;Yu|Guoqing|G|;Ye|Jia|J|;Zhu|Zheng-An|ZA|;Liu|Yuebin|Y|;Chen|Jian|J|;Lai|Guoxiang|G|;Wen|Wen|W|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s12890-020-1098-x",
"fulltext": "\n==== Front\nBMC Pulm Med\nBMC Pulm Med\nBMC Pulmonary Medicine\n1471-2466 BioMed Central London \n\n1098\n10.1186/s12890-020-1098-x\nCase Report\nThe application of metagenomic next-generation sequencing in diagnosing Chlamydia psittaci pneumonia: a report of five cases\nGu Lei 12 Liu Wei 2 Ru Meng 3 Lin Jing 1 Yu Guoqing 4 Ye Jia 2 Zhu Zheng-an 2 Liu Yuebin 2 Chen Jian 2 Lai Guoxiang 2 Wen Wen fjfzfisher@163.com 2 1 0000 0004 1797 9307grid.256112.3Graduate College of Fujian Medical University, Minhou, Fuzhou, 350108 China \n2 0000 0004 1806 5283grid.415201.3Department of Respiratory and Critical Care Medicine, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025 China \n3 Pharmacy Department, The 985th Hospital of the Joint Logistic Support Force, PLA, Yingze, Taiyuan, 030001 China \n4 Department of Nephrology, Dongfang Hospital of Xiamen University, Fuzhou General Hospital of Fujian Medical University, The 900th Hospital of the Joint Logistic Support Force, PLA, Gulou, Fuzhou, 350025 China \n17 3 2020 \n17 3 2020 \n2020 \n20 656 11 2019 24 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\nChlamydia psittaci pneumonia is a zoonotic infectious disease caused by Chlamydia psittaci. Diagnostic tools, including culture, serologic test and PCR-based methods, are available but prone to false negative results.\n\nCase presentation\nThis report included five cases of Chlamydia psittaci pneumonia. Symptoms and signs common to all 5 cases included fever, coughing, generalized muscle ache, and most notably, inflammatory infiltration of the lungs upon chest CT and X-ray. Metagenomic next-generation sequencing (mNGS) revealed the presence of Chlamydia psittaci in biopsy lung tissue in 3 cases and bronchoalveolar lavage fluid in the remaining 2 cases. Three patients responded to doxycycline plus moxifloxacin; two patients responded to moxifloxacin alone.\n\nConclusions\nmNGS could be used to diagnose Chlamydia psittaci pneumonia.\n\nKeywords\nmNGSChlamydia psittaciCase reportNational Key Clinical Specialty Discipline Construction Program of China (CN)2015ZDZKHXissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nChlamydia psittaci is an obligatory intra-cellular Gram-negative bacterium that typically infects birds, but could occasionally cause psittacosis in humans when contaminated aerosols from infected birds are inhaled. Chlamydia psittaci pneumonia in humans is underestimated due to low awareness of the disease and atypical clinical presentation in majority of the cases [1–3]. The low sensitivity and complex procedure of Chlamydia psittaci culture causes it hardly routinely performed in most diagnostic laboratories. Other laboratory testing included serological assay and polymerase chain reaction (PCR) based methods, but both have questionable sensitivity and specificity [2]. Untargeted metagenomic next-generation sequencing (mNGS) has been increasingly used in the diagnosis of infectious diseases, particularly when conventional diagnostic approaches have limitations [4]. Here we report 5 cases of Chlamydia psittaci pneumonia, in which the diagnosis was established with mNGS. All together, mNGS was conducted in a total of 120 pneumonia cases in the index period. Demographical and basic clinical features of the 5 cases are summarized in Table 1.\nTable 1 Demographical and basic clinical features of the 5 patients\n\nCase #\tSex\tAge (y)\tSample\tUnderlying diseases\tLaboratory test\tmetagenomics sequencing results and specific reads(n)\t\nroutine blood test\tCRP (mg/L)\tPCT (ng/ml)\tESR (mm/h)\t\n1\tFemale\t81\tBALF\thypertension, diabetes, coronary artery diseases\tWBC 7.71*10^9, NE% 69.8, NE 5.38*10^9, LN% 17.5↓, LN 1.35*10^9\t53\t<0.05\t74\tCandida albicans\n(182) Staphylococcus capitis (12)\n\nChlamydia psittaci (6) Human betaherpesvirus 5 (2)\n\n\t\n2\tMale\t45\tBALF\tdiabetes\tWBC 8.22*10^9, NE% 93.1↑, NE 7.65*10^9↑, LN% 4.0↓, LN 0.33*10^9↓\t226\t1.712\t42\tChlamydia psittaci (225) Lautropia mirabilis (28) Leuconostoc lactis (19)\n\nRothia mucilaginosa (19) Rothia dentocariosa (12)\n\nStreptococcus parasanguinis (10) Actinomyces odontolyticus (8)\n\nStreptococcus mitis\n(4)\n\n\t\n3\tFemale\t85\tLung tissue\tnone\tWBC 6.38*10^9, NE% 88.9, NE 5.67*10^9, LN% 8.0↓, LN 0.51*10^9\t184\t1.64\t64\tChlamydia psittaci (48)\nStaphylococcus epidermidis\n(1)\t\n4\tFemale\t66\tLung tissue\tnone\tWBC 5.47*10^9, NE% 69.8, NE 3.82*10^9, LN% 19.4↓, LN 1.06*10^9↓\t124\t0.13\t17\tChlamydia psittaci (205) Corynebacterium striatum (1)\nKlebsiella pneumoniae\n(1)\t\n5\tFemale\t61\tLung tissue\tnone\tWBC 6.88*10^9, NE% 68.4, NE 4.70*10^9, LN% 22.7↓, LN 1.56*10^9↓\t96.7\t<0.05\t37\tChlamydia psittaci (2)\t\nAbbreviations: BALF Bronchoalveolar lavage fluid, CRP C-reactive protein (normal reference range: 0–8 mg/L), ESR Erythrocyte sedimentation rate (normal < 15 mm/h);\n\nLN Lymphocyte, PCT Procalcitonin (normal < 0.05 ng/ml), NE Neutrophil, WBC White blood cell\n\n\n\nCase presentation\nCase #1\nAn 81-year-old woman was transferred to us with fever, productive coughing with white sticky sputum, and generalized muscle ache and malaise for 10 days. On the 5th day after the onset of symptoms, she visited a local hospital. A chest computed tomography (CT) scan showed inflammatory infiltration in the lower lobe of the left lung. She was treated with moxifloxacin (0.4 g, I.V., qd) plus meropenem (1 g, I.V., q12h) for 3 days, but fever continued (highest body temperature 39.4 °C). A repeat CT scan suggested progression of pulmonary infection. Moxifloxacin was replaced with linezolid (600 mg, I.V., q12h), with continuing meropenem treatment. On the second day after linezolid/meropenem, fever subsided. However, other symptoms and signs continued.\n\nBody temperature upon arriving to us was 36.7 °C. Physical examination revealed inspiratory crackles in the lower left lung. CT and chest X-ray showed alveolar consolidation in the left lower lobe (Fig. 1a, b). White blood cell was largely normal: total count 7.71*109/L (reference range: 3.5–9.5*109/L), neutrophil count 5.38*109/L (1.8–6.3*109/L), 69.8% neutrophils (40–75%), 17.5% lymphocytes (20–50%), and lymphocytes 1.35*109/L (1.1–3.2*109/L). C-reactive protein (CRP) was 53 mg/L (0–8 mg/L). Erythrocyte sedimentation rate (ESR) was 74 mm/h (< 15 mm/h). Procalcitonin (PCT) was normal (< 0.05 ng/ml). Past history included hypertension, diabetes and coronary artery disease. Treatment with linezolid continued at 600 mg, I.V., q12h and meropenem was replaced with ertapenem (1 g, I.V., qd). Bronchoalveolar lavage (BAL) was conducted on the second day and BAL fluid (BALF) was sent for testing using mNGS (KindStar Global-Wuhan). On the 6th day of arrival to our hospital, mNGS reported sequence reads of Chlamydia psittaci (Table 1). Linezolid and ertapenem were discontinued. The patient was placed on doxycycline (100 mg, P.O., q12h). Symptoms gradually improved. CT scan and X-ray 21 days later showed radiological improvement (Fig. 1c, d). Upon close investigation, the patient disclosed pneumonia in her pet dog 2 days before her symptoms started (Fig. 1e). Treatment of the dog with ceftriaxone plus metronidazole was apparently not effective; pneumonia was cured with subsequent erythromycin.\nFig. 1 Chest CT and X-ray of case 1: a, b On the day of admission, c, d 21 days after doxycycline treatment, and e Chest X ray of patient’s pet dog\n\n\n\nCase #2\nA 45-year-old man was transferred to us with fever, productive coughing, generalized muscle ache and malaise for 7 days. On the 4th day of the onset, he visited a local hospital. A chest CT scan showed consolidation in the right upper lobe (Fig. 2a). Test results included: WBC count 8.22*109/L, neutrophil count 7.65*109/L, 93.1% neutrophils, 4.0% lymphocytes (count 0.33*109/L), CRP 226 mg/L, ESR 42 mm/h, and PCT 1.712 ng/ml. A de novo diagnosis of diabetes was also established based on repeated testing of fasting blood glucose and hemoglobin A1c. Treatment with ceftazidime (2 g, I.V., q8h) and levofloxacin (500 mg, I.V., qd) was initiated for 3 days, but symptoms did not dissipate.\nFig. 2 Chest CT of case 2: a On the 4th day of the onset, b On the 4th day of arrival to our hospital, c 7 days after treatment with doxycycline plus moxifloxacin, and d 3 weeks later after treatment with doxycycline plus moxifloxacin\n\n\n\nUpon transferring, the body temperatures was 39.5 °C, with crackles in both lungs. The patient received ertapenan (1 g, I.V., qd) and oseltamivir (75 mg, P.O., q12h), and fever subsided in 3 days. One days later, however, he developed high fever again (40 °C), with signs of respiratory failure (PaO2 40 mmHg). On the 4th day of arrival to our hospital, a chest CT scan showed bilateral diffuse infiltration (Fig. 2b).\n\nBAL was conducted at this point. BALF analysis with mNGS (BGI-Shenzhen) revealed Chlamydia psittaci as well as a few other potential pathogens (Table 1). A close inquiry yielded a 20-year history of pigeon-farming. Ertapenan and oseltamivir were discontinued. Doxycycline (100 mg, P.O., q12h) plus moxifloxacin (0.4 g, I.V., qd) was initiated. The symptoms gradually subsided. CT scans 7 days later (Fig. 2c) and 3 weeks later (Fig. 2d) showed progressive infiltrate absorption.\n\nCase #3\nAn 85-year-old previously healthy woman presented with fever, productive coughing, headache, generalized muscle ache and emesis for 2 days. A chest CT scan showed consolidation in the right upper lobe (Fig. 3a, b). Laboratory test showed 6.38*109/L WBC count, 88.9% neutrophils (absolute count: 5.67*109/L), 8.0% lymphocytes (0.51*109/L), 184 mg/L CRP, 64 mm/h ESR, and 1.64 ng/ml PCT.\nFig. 3 Chest CT of case 3: a, b On the day of admission, c, d 9 days after treatment with doxycycline plus moxifloxacin\n\n\n\nSymptoms did not improve 3 days after ertapenem treatment (1 g, I.V., qd). Switching to biapenan (0.6 g, I.V., q12h) and teicoplanin (400 mg, I.V., qd) did not alleviate the symptoms. A percutaneous lung tissue biopsy was conducted; mNGS analysis (IngeniGen-Hangzhou) revealed infection with Chlamydia psittaci (Table 1). Treatment with doxycycline (100 mg, P.O., q12h) and moxifloxacin (0.4 g, I.V., qd) was initiated, and the patient recovered rapidly. A CT scan 9 days later showed partial absorption of the pulmonary infiltrate (Fig. 3c, d). The patient recalled planting a vegetable plot where birds often gathered.\n\nCase #4\nA 66-year-old woman was transferred to us with fever, rigor, dry cough and dizziness for 6 days. At the beginning of the illness, she received levofloxacin and cefotaxime in a local hospital but symptoms persisted. A chest CT scan upon transferring showed consolidation in the right upper lobe (Fig. 4a, b). Laboratory test showed 5.47*109/L WBC count, 69.8% neutrophils (3.82*109/L), 19.4% lymphocytes (1.06*109/L), 124 mg/L CPR, 17 mm/h ESR, and 0.13 ng/ml PCT. Treatment with moxifloxacin (0.4 g, I.V., qd) was initiated, and body temperature returned to normal within 2 days. A percutaneous lung biopsy was conducted; the sample testing with mNGS (IngeniGen-Hangzhou) detected Chlamydia psittaci (Table 1). Later, we learned that she had close contact with a large poultry farm on a daily basis. Moxifloxacin treatment lasted for 10 days. CT scan 8 days after moxifloxacin treatment initiation (Fig. 4c) and 16 days after discontinuation showed gradual infiltrate absorption (Fig. 4d).\nFig. 4 Chest CT of case 4: a, b On the day of admission, c Eight days after treatment with moxifloxacin, and dSixteen days after discontinuation\n\n\n\nCase #5\nA 61-year-old woman presented with fever, rigor, weakness, productive coughing and dizziness for 3 days. A chest CT scan showed patchy infiltration and consolidation of both lungs (Fig. 5a, b, c). Laboratory test showed 6.88*109/L WBC count, 68.4% neutrophils (4.70*109/L), 22.7% lymphocytes (1.56*109/L), 96.7 mg/L CRP, 37 mm/h ESR, and normal PCT. She disclosed close contact with a pet parrot. She was treated with moxifloxacin and her body temperature returned to normal on the next day. Analysis of lung biopsy tissue with mNGS (IngeniGen-Hangzhou) reported Chlamydia psittaci (Table 1). A CT scan 8 days later showed partial absorption of the pulmonary infiltrate (Fig. 5d, e, f).\nFig. 5 Chest CT of case 5: a, b, c On the day of admission, d, e, f Eight days after treatment with moxifloxacin\n\n\n\nDiscussion and conclusions\nChlamydia psittaci can be classified into 10 genotypes, with varying preference for host species [5]. Genotype A and E could infect humans. After entry via contaminated aerosols, Chlamydia psittaci spreads to the reticuloendothelial system. The lungs are the most common sites of Chlamydia psittaci infection. Chlamydia psittaci pneumonia is estimated to account for approximately 1% of community-acquired pneumonia cases [3, 6]. Symptoms mimics that of influenza, and typically include fever, fatigue, headache, myalgia, and coughing [7, 8].\n\nIn 4 out of the 5 cases in this report, patients had contacts with birds (parrot and pigeon) or poultry, suggesting the need to investigate such exposure upon suspected cases. Two out of the 5 patients had diabetes; and the other 3 were otherwise healthy, suggesting that Chlamydia psittaci could infect human subjects regardless of underlying diseases.\n\nChlamydia psittaci infection tends to be overlooked due to relatively low awareness by physicians. Laboratory testing for Chlamydia psittaci includes culture, serological assay, and PCR. Culture is time consuming, and most formidably, requires P3 facility [6]. Serological tests are only appropriate for retrospective diagnosis because sera from the both acute and convalescent phase of the illness are required [9]. PCR-based testing is the most specific and fastest method but only sensitive in the acute phases of the infection [2]. The current case series indicated that mNGS could be used to diagnose Chlamydia psittaci infection. If using a set of universally accepted standards, mNGS could even provide semiquantitative information (based on sequence reads) about the load of Chlamydia psittaci, such information could be critically important in determining whether a specific microbe is the causative pathogen(s) in polymicrobial samples. The limitations of mNGS analysis, for infection with a Chlamydia psittaci or any other agent, include host background sequences. In future studies, targeted sequencing and host depletion methods could be used to minimize the human host background, workflow quality control procedures could be optimized to reduce false positives. It is also likely that Chlamydia psittaci is merely present in the sample and not the culprit of infection. The fact that many other pathogens, including Candida albicans, have been identified in the 5 cases illustrate the complexity and a need to integrate the mNGS results into the overall clinical scenario. Lack of verification with serologic tests and/or culture is a significant limitation in the current study. These findings therefore must be interpreted with caution.\n\nIn the current series, mNGS was conducted only after initial empirical antibiotic treatment failed to control the infection in 4 out of the 5 cases. Considering the feasibility and cost of mNGS, we believed the timing of mNGS is appropriate, and recommend mNGS testing only if patients do not respond to treatments against other more common causes.\n\nThe specific reads for Chlamydia psittaci ranged from 2 to 225 in the 5 cases. Comparison across cases is not possible since the assay was conducted by several different companies. In case #1 and #5, the detected Chlamydia psittaci reads were 6 and 2, respectively. We speculate that the relatively low specific reads of Chlamydia psittaci in Case #1 may reflect the therapeutic effects of moxifloxacin, albeit not adequate. In Case #5, the low specific reads of Chlamydia psittaci may reflect the loss of biological activity of pathogens and degradation of nucleic acid during the process of sample collection and transportation or the treatments that the patient received prior to sample collection.\n\nRecommended treatment for Chlamydia psittaci pneumonia included tetracycline, macrolide and quinolones [10]. Treatment must continue for at least 10–14 days to prevent relapse. In case #1, moxifloxacin was used as an initial treatment for 3 days, but no significant improvement was obtained. In our opinion, the lack of response to moxifloxacin in this case could be due to several reasons, including: 1) possible superinfection by other agents that could be readily controlled by doxycycline; 2) relative insensitivity of the Chlamydia psittaci isolate in this specific case to moxifloxacin. Indeed, recommended first-line treatment of Chlamydia psittaci pneumonia is doxycycline and not quinolones [11].\n\nIn conclusion, the current series suggested that mNGS could be used in diagnosing Chlamydia psittaci infection. This preliminary finding should be examined with diagnostic trial in the future.\n\nAbbreviations\nBALBronchoalveolar lavage\n\nBALFBronchoalveolar lavage fluid\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nESRErythrocyte sedimentation rate\n\nLNLymphocyte\n\nmNGSMetagenomic next-generation sequencing\n\nNENeutrophil\n\nPCRPolymerase chain reaction\n\nPCTProcalcitonin\n\nWBCWhite blood cell\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nLei Gu and Wei Liu contributed equally to this work.\n\nAcknowledgements\nThe authors thank the five patients and their families for agreeing to use their data for research purposes, and specifically, for publication of this report.\n\nAuthors’ contributions\nLG and WL contributed equally to this work. LG, WL, MR, JL and GQY participated in manuscript drafting. JY, ZAZ, YBL and JC collected and analyzed clinical data. WL, GXL, WW participated in data interpretation and manuscript revision. All authors read and approved the final manuscript.\n\nFunding\nThis work was supported by Clinical Key Specialty Construction Project in Fujian Province (No. 2015–593).\n\nAvailability of data and materials\nAll the data supporting our findings is contained within the manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nAll 5 patients provided written consent to use their data for research purposes, and specifically, for publication of this manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. de Gier B Hogerwerf L Dijkstra F van der Hoek W Disease burden of psittacosis in the Netherlands Epidemiol Infect 2018 146 303 305 10.1017/S0950268817003065 29361998 \n2. Nieuwenhuizen AA Dijkstra F Notermans DW van der Hoek W Laboratory methods for case finding in human psittacosis outbreaks: a systematic review BMC Infect Dis 2018 18 442 1 16 29291713 \n3. Hogerwerf L DE Gier B Baan B Van Der Hoek W Chlamydia psittaci (psittacosis) as a cause of community-acquired pneumonia: a systematic review and meta-analysis Epidemiol Infect 2017 145 3096 3105 10.1017/S0950268817002060 28946931 \n4. Gu W Miller S Chiu CY Clinical metagenomic next-generation sequencing for pathogen detection Annu Rev Pathol 2019 14 319 338 10.1146/annurev-pathmechdis-012418-012751 30355154 \n5. Radomski N Einenkel R Muller A Knittler MR Chlamydia-host cell interaction not only from a bird's eye view: some lessons from chlamydia psittaci FEBS Lett 2016 590 3920 3940 10.1002/1873-3468.12295 27397851 \n6. Balsamo G Maxted AM Midla JW Murphy JM Wohrle R Edling TM Compendium of measures to control chlamydia psittaci infection among humans (psittacosis) and pet birds (avian Chlamydiosis), 2017 J Avian Med Surg 2017 31 262 282 10.1647/217-265 28891690 \n7. Branley JM Weston KM England J Dwyer DE Sorrell TC Clinical features of endemic community-acquired psittacosis New Microbes New Infect 2014 2 7 12 10.1002/2052-2975.29 25356332 \n8. Homma T Yamaguchi T Komatsu N Hashimoto S Doki Y Senda K A case of acute psittacosis with severe abdominal pain J Med Microbiol 2011 60 547 549 10.1099/jmm.0.021154-0 21212142 \n9. Tuuminen T Palomaki P Paavonen J The use of serologic tests for the diagnosis of chlamydial infections J Microbiol Methods 2000 42 3 265 279 10.1016/S0167-7012(00)00209-8 11044570 \n10. Cilloniz C Torres A Niederman M van der Eerden M Chalmers J Welte T Community-acquired pneumonia related to intracellular pathogens Intensive Care Med 2016 42 9 1374 1386 10.1007/s00134-016-4394-4 27276986 \n11. Mandell LA Wunderink RG Anzueto A Bartlett JG Campbell GD Dean NC Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults Clin Infect Dis 2007 44 Suppl 2 S27 S72 10.1086/511159 17278083\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2466",
"issue": "20(1)",
"journal": "BMC pulmonary medicine",
"keywords": "Case report; Chlamydia psittaci; mNGS",
"medline_ta": "BMC Pulm Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001992:Bronchoalveolar Lavage Fluid; D002691:Chlamydophila psittaci; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D018410:Pneumonia, Bacterial; D009956:Psittacosis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100968563",
"other_id": null,
"pages": "65",
"pmc": null,
"pmid": "32178660",
"pubdate": "2020-03-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27276986;17278083;29361998;28946931;21212142;11044570;30355154;27397851;30165831;28891690;25356332",
"title": "The application of metagenomic next-generation sequencing in diagnosing Chlamydia psittaci pneumonia: a report of five cases.",
"title_normalized": "the application of metagenomic next generation sequencing in diagnosing chlamydia psittaci pneumonia a report of five cases"
} | [
{
"companynumb": "CN-BAYER-2020-055920",
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"occurcountry": "CN",
"patient": {
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"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
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... |
{
"abstract": "BACKGROUND\nMethylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, mainly the C677T, have been implicated as risk factors for several cancers as the acute lymphoblastic leukemia (ALL). In addition, a potential effect of such variant on the efficacy of methotrexate (MTX) has been reported.\n\n\nOBJECTIVE\nIn this study, we evaluated the impact of the C677T variant of MTHFR on MTX-related toxicity in ALL patients from Tunisia; to provide new insights for a personalized therapy based on the human genotype.\n\n\nMETHODS\nGenotyping was carried out with restriction fragment length polymorphism (RFLP) on blood samples from a total of 35 younger patients; suffering from ALL.\n\n\nRESULTS\nIn the ALL patients, the MTHFR 677CT genotype confers a greater risk of toxicity with 1.3 times as relative risk mainly the hepatic toxicity when compared with MTHFR 677CC.\n\n\nCONCLUSIONS\nOur findings suggest that C677T polymorphism of MTHFR seems to be a good marker for MTX-related toxicity in ALL.",
"affiliations": "1 Faculty of Medicine of Sfax, Laboratory of Histology, University of Sfax, Sfax, Tunisia.;1 Faculty of Medicine of Sfax, Laboratory of Histology, University of Sfax, Sfax, Tunisia.;2 Faculty of Medicine of Sfax, Laboratory of Pharmacology, University of Sfax, Sfax, Tunisia.;3 Faculty of Sciences of Sfax, University of Sfax, Sfax, Tunisia.;4 Department of Haematology, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia.;4 Department of Haematology, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia.;4 Department of Haematology, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia.;1 Faculty of Medicine of Sfax, Laboratory of Histology, University of Sfax, Sfax, Tunisia.",
"authors": "Frikha|Rim|R|https://orcid.org/0000-0003-4415-8785;Rebai|Tarek|T|;Lobna|Ben Mahmoud|BM|;Frikha|Fakher|F|;Mdhaffar|Moez|M|;Frikha|Imen|I|;Elloumi|Moez|M|;Bouayed|Nouha|N|",
"chemical_list": "D042965:Methylenetetrahydrofolate Reductase (NADPH2)",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218818244",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "C677T polymorphism; Methylenetetrahydrofolate reductase; acute lymphoblastic leukemia; methotrexate",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D055815:Young Adult",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1182-1186",
"pmc": null,
"pmid": "30545275",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comprehensive analysis of Methylenetetrahydrofolate reductase C677T in younger acute lymphoblastic leukemia patients: A single-center experience.",
"title_normalized": "comprehensive analysis of methylenetetrahydrofolate reductase c677t in younger acute lymphoblastic leukemia patients a single center experience"
} | [
{
"companynumb": "PHHY2019TN210408",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"drugadditional": "3",
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{
"abstract": "Gestational choriocarcinoma is a gestational trophoblastic neoplasia (GTN) originating from trophoblastic cells with abnormal proliferation. Although chemotherapy is effective for treating this cancer, when patients develop chemoresistance, personalized treatment, such as the use of drugs matching their genomes, is required. The present report describes a case of intractable gestational choriocarcinoma identified using a next-generation sequencing (NGS)-based tumor panel. A 51-year-old woman was diagnosed with gestational choriocarcinoma via pathological and short tandem repeat analyses. The patient did not achieve remission despite many regimens of chemotherapy, including high-dose therapy with autologous peripheral blood stem cell transplantation. To identify drugs tailored to this particular choriocarcinoma, NGS was performed on the tumor of the patient, and the tumor genome was compared with that of the patient's blood sample using the NCC Oncopanel System. Consequently, 245 single nucleotide variants (SNVs) with a mean SNV allele frequency of 63.1% were identified. This high frequency was because the genome of the gestational choriocarcinoma contained part of the genome of the partner. Therefore, our experience of the present intractable case of choriocarcinoma suggested that matched normal-tumor pair analysis is not appropriate for treatment decisions in GTN cases. When using an NGS-based tumor panel to assess choriocarcinoma, researchers must consider whether the genomic DNA of the patient and their partner are involved in the GTN.",
"affiliations": "Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Medical Genomics Center, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Medical Genomics Center, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Medical Technique, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Medical Genomics Center, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Medical Genomics Center, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.",
"authors": "Niimi|Kaoru|K|;Yamamoto|Eiko|E|;Morita|Sachi|S|;Morikawa|Maki|M|;Hattori|Hikaru|H|;Hatakeyama|Miki|M|;Morita|Mami|M|;Nishino|Kimihiro|K|;Oda|Yukari|Y|;Watanabe|Eri|E|;Yamamoto|Toshimichi|T|;Kajiyama|Hiroaki|H|;Kikkawa|Fumitaka|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2305",
"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450\n2049-9469\nD.A. Spandidos\n\nMCO-0-0-02305\n10.3892/mco.2021.2305\nArticles\nNext-generation genome sequencing of a matched normal-tumor pair from a patient with intractable gestational choriocarcinoma: A case report\nNiimi Kaoru 1\nYamamoto Eiko 12\nMorita Sachi 3\nMorikawa Maki 3\nHattori Hikaru 4\nHatakeyama Miki 3\nMorita Mami 3\nNishino Kimihiro 1\nOda Yukari 1\nWatanabe Eri 1\nYamamoto Toshimichi 5\nKajiyama Hiroaki 1\nKikkawa Fumitaka 1\n1 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan\n2 Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan\n3 Department of Medical Genomics Center, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan\n4 Department of Medical Technique, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan\n5 Department of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan\nCorrespondence to: Dr Kaoru Niimi, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan kaorun@med.nagoya-u.ac.jp\n7 2021\n23 5 2021\n23 5 2021\n15 1 14306 10 2020\n16 4 2021\nCopyright: © Niimi et al.\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This 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.\nGestational choriocarcinoma is a gestational trophoblastic neoplasia (GTN) originating from trophoblastic cells with abnormal proliferation. Although chemotherapy is effective for treating this cancer, when patients develop chemoresistance, personalized treatment, such as the use of drugs matching their genomes, is required. The present report describes a case of intractable gestational choriocarcinoma identified using a next-generation sequencing (NGS)-based tumor panel. A 51-year-old woman was diagnosed with gestational choriocarcinoma via pathological and short tandem repeat analyses. The patient did not achieve remission despite many regimens of chemotherapy, including high-dose therapy with autologous peripheral blood stem cell transplantation. To identify drugs tailored to this particular choriocarcinoma, NGS was performed on the tumor of the patient, and the tumor genome was compared with that of the patient's blood sample using the NCC Oncopanel System. Consequently, 245 single nucleotide variants (SNVs) with a mean SNV allele frequency of 63.1% were identified. This high frequency was because the genome of the gestational choriocarcinoma contained part of the genome of the partner. Therefore, our experience of the present intractable case of choriocarcinoma suggested that matched normal-tumor pair analysis is not appropriate for treatment decisions in GTN cases. When using an NGS-based tumor panel to assess choriocarcinoma, researchers must consider whether the genomic DNA of the patient and their partner are involved in the GTN.\n\nnext-generation genome sequencing\nchoriocarcinoma\ngestational trophoblastic diseases\nFunding: This work was financially supported by grants-in-aid numbers 17K16845 and 20K09639 (to KN) by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funding bodies had no role in study design or data collection, analysis or interpretation.\n==== Body\nIntroduction\n\nGestational choriocarcinoma is a type of gestational trophoblastic neoplasia (GTN) that originates from trophoblasts and can develop from a normal pregnancy, miscarriage, or molar pregnancy. Its estimated incidence in Japan is 1.9-5.5 cases per 100,000 live births (1). Non-gestational choriocarcinoma shows the same morphological pattern as that of the gestational form but originates mostly from germ cells in the ovary and is rarer and associated with worse outcomes. Short tandem repeat analysis using microsatellite markers is useful for distinguishing gestational choriocarcinoma from non-gestational choriocarcinoma (2).\n\nChemotherapy is effective for treating gestational choriocarcinoma. However, patients with multiple metastases or metastases to sites other than the lungs often do not achieve complete remission (3). When the cancer develops chemoresistance, more tailored therapies are required, such as drugs selected based on the specific cancer genome. The OncoGuide™ NCC Oncopanel System (Sysmex Corporation) (4) is a next-generation sequencing (NGS)-based tumor panel that is covered by health insurance in Japan. This panel facilitates the identification of variants of 114 cancer-related genes through matched normal-tumor pair analysis. Here, we report a case of intractable gestational choriocarcinoma identified using this system.\n\nCase report\n\nA 51-year-old Japanese woman was diagnosed with choriocarcinoma with metastases to the lung, spleen, and lymph nodes. Histopathological examination of the uterine biopsy showed a two-cell pattern of choriocarcinoma, consisting of syncytiotrophoblastic cells and cytotrophoblastic cells. She had experienced six pregnancies, and the last pregnancy ended in spontaneous abortion approximately 4 years prior. The patient was treated with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA/CO) and had suspected drug-induced pneumonia after the third course (Fig. 1). Therefore, she could not continue EMA-CO therapy although it was effective. The regimen was modified, but the new regimen proved ineffective. She was then referred to our institution for further treatment. We performed a drug-induced lymphocyte stimulation test and found that the anticancer drugs etoposide, etoposide, methotrexate, actinomycin, cyclophosphamide, and vincristine did not induce the allergy. Thus, we concluded that her pneumonia was induced by infection and that we could use these anticancer drugs. After obtaining written informed consent from the patient and her partner, we performed short tandem repeat analysis of DNA extracted from the oral mucosal cells of the patient and her partner and from the paraffin-embedded sections of the micro-dissected tumor, as previously described (5). This study was approved by the Ethics Committee of Nagoya University Graduate School of Medicine. Tumor analysis revealed gestational choriocarcinoma of both maternal and paternal origins (Table I). The patient underwent four types of chemotherapy regimens and was then treated with high-dose ifosfamide, carboplatin, and etoposide (ICE), along with autologous peripheral blood stem cell transplantation (2,6,7).\n\nAfter three courses of high-dose ICE, we performed total hysterectomy and bilateral adnexectomy to reduce the total choriocarcinoma volume. The patient was administered two courses of mini-ICE after the operation, but multiple metastases were found in the brain. She was thus treated with whole-brain radiotherapy (20 Gy); etoposide, cisplatin, methotrexate, and actinomycin D (EP-EMA) chemotherapy; and radiotherapy for the bone metastases.\n\nTo identify drugs appropriate for treating the choriocarcinoma in this case, we utilized the NCC Oncopanel System to compare the uterine choriocarcinoma DNA with the patient's germline DNA extracted from peripheral blood. Microdissection was performed to obtain the choriocarcinoma tissue from formaldehyde-fixed and paraffin-embedded tissue sections (10 µm thickness). The samples were prepared and analyzed as previously reported (4). NCC Oncopanel test revealed 245 single-nucleotide variants (SNVs). Compared with the usual allele frequency of SNVs in matched normal-tumor pair analysis of ≤30%, the mean SNV allele frequency of the patient was more than double, at 63.1%. Initially, experimental errors such as sample misidentification were suspected; however, we eventually concluded that part of the gestational choriocarcinoma DNA was derived from the partner of the patient, whereby the SNV burden was increased.\n\nThe tumor DNA contained 19 variants in 13 of the 114 cancer-related genes (Table II). The GNAQ p.T96S and TP53 p.R213P variants were considered to be pathogenic variants; the remaining 17 variants are frequent in the Japanese population. There are no targeted therapies for these two pathogenic variants. After nine courses of EP-EMA, the patient was unable to undergo chemotherapy because of pancytopenia and febrile neutropenia. She was treated for 20 months but ultimately died of choriocarcinoma 7 months after the operation.\n\nDiscussion\n\nThis is the first study using the NCC Oncopanel System test for gestational choriocarcinoma. The test was performed to seek appropriate drugs for the intractable choriocarcinoma, but no drug matched the tumor genome. A hospital-based prospective study using the NCC Oncopanel System test showed that only 13.4% of the patients were eligible for targeted drug therapies based on the sequencing results, and this result is similar to that obtained using another cancer-gene panel (11%) (8). The relatively low likelihood of identifying a targeted therapy should be explained to patients before applying a gene-panel test. Additional genome-matched clinical trials are required to determine the applications that these tests would suit the most.\n\nThe results of the NCC Oncopanel test in our case indicate two limitations to using NGS-based tumor-profiling multiplex gene panels for GTN patients. First, panel tests for tumor and matched non-tumor samples, such as the NCC Oncopanel test, show a high SNV burden in the genomic DNA from GTNs, and such results may be misinterpreted as ‘tumor-derived’ variants. The NCC Oncopanel test is inappropriate for tumors like GTNs containing the DNA of other persons. Tumor-profiling gene-testing using only tumor samples should be used for GTNs. Second, the patient, her partner, and/or their children might be the source of pathogenic variants or secondary genetic findings in the tumor DNA of GTNs. A case of choriocarcinoma in a woman whose partner had a genomic TP53 variant leading to Li-Fraumeni syndrome has been reported, wherein the TP53 variant was detected in her tumor but not in her germline DNA (9). Since there are ethical issues associated with genomic screening in GTN cases, informed consent should be obtained from patients and their partners, and specific ethical guidelines should be laid down for tumor-panel testing of patients with GTN.\n\nIn the present case, two pathogenic variants (GNAQ p.T96S and TP53 p.R213P) were identified in the tumor DNA. The sequence report from the NCC Oncopanel revealed a 12.8% variant allele frequency for GNAQ p.T96S, classifying this allele as a somatic variant. The variant allele frequency of TP53 p.R213P was 61.7%, indicating that this allele might have been a germline variant, but the DNA of the patient's blood did not have it. We realized that this allele might have been a true somatic variant in her tumor or a germline variant in the partner, one of the children of the patient, or the lost pregnancy, because the tumor was a gestational choriocarcinoma. Genetic counseling sessions were conducted with the partner of the patient to discuss our findings for this variant and its association with Li-Fraumeni syndrome. Upon the request of the partner, we checked the existence of TP53 p.R213P variants with only his blood but not her children's blood. We found that he did not have this variant.\n\nWe here report a case of intractable gestational choriocarcinoma resistant to numerous chemotherapies, including high-dose ICE with peripheral stem cell rescue. It is suggested that it is difficult for choriocarcinoma patients to achieve complete remission when the second chemotherapy regimen fails and multiple metastases exist (3). High-dose chemotherapy with stem cell rescue and anti-programmed cell death-1 (PD-1) antibody therapy might be an option for intractable choriocarcinoma (2,7,10). The effectiveness of anti-PD-1 antibody therapy for intractable GTN patients has recently been reported (10). Our patient was not eligible for this treatment because her choriocarcinoma did not show a high microsatellite instability status, which is required for health-insurance coverage in Japan. Clinical trials of anti-PD-1 antibody therapy for intractable GTN are needed, as this therapy has been shown to be effective for patients with GTN with unknown microsatellite instability statuses (11).\n\nIn conclusion, our experience of an intractable choriocarcinoma case screened with the NCC Oncopanel System suggests that matched normal-tumor pair analysis is not appropriate for GTN. When using an NGS-based tumor panel to assess choriocarcinoma, researchers must consider whether the patient's and partner's genomic DNA is involved in the GTN.\n\nAcknowledgements\n\nNot applicable.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\n\nKNii, EY, SM, HH, MMorik, HK and FK designed the study. KNii wrote the final manuscript. SM, HH, MMorik, MH and MMorit analyzed and interpreted the data, and wrote the outline of the manuscript regarding genetic analysis. MMorik, MH and MMorit were responsible for genetic counseling. KNis, YO, EW and TY analyzed and interpreted the data of STR analysis. KNii, KNis, YO, EW, HK and FK were involved in the treatment of patients as attending physicians and provided important advice for decision making. EY, TY, HK and FK critically revised the paper for important intellectual content. KNii and EY confirmed the authenticity of all the raw data. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\n\nWritten informed consent was obtained from the study subjects prior to the collection of all the biological samples according to the regulations set out by the Ethics Committee at Nagoya University.\n\nPatient consent for publication\n\nWritten informed consent was obtained from the partner of the patient for the publication of these data.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nFigure 1 Changes in the serum hCG level of the patient and the treatment progress of choriocarcinoma. EMA/CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine; FA, fluorouracil and actinomycin D; EA, etoposide and actinomycin D; MEA, methotrexate, etoposide, and actinomycin D; TPTE, paclitaxel, cisplatin, and etoposide; biweekly TP, biweekly paclitaxel and cisplatin; ICE, ifosfamide, carboplatin, and etoposide; CPA, cyclophosphamide; EP/EMA, etoposide, cisplatin, methotrexate, and actinomycin D; hCG, human chorionic gonadotropin.\n\nTable I Short tandem repeat analysis of DNA from the tumor, patient and her partner.\n\nMarker\tMaternal\tPaternal\tTumor\t\nD8S1179\t10,14\t13,13\t10,13\t\nD21S11\t30,31\t30,30\t30\t\nD7S820\t11,12\t9,12\t9,12\t\nCFS1PO\t10,11\t10,10\t10\t\nD3S1358\t16,16\t16,17\t16\t\nTH01\t6,6\t6,9\t6\t\nD13S317\t11,12\t11,11\t11,12\t\nD16S539\t11,11\t9,9\t9,11\t\nD2S1338\t17,20\t23\t-\t\nD19S433\t13,13\t13,15.2\t13\t\nvWA\t17,19\t16,16\t16,17,19\t\nTPOX\t8,11\t8,11\t11\t\nD18S51\t14,18\t14,17\t17,18\t\nAmerogenin\tX,X\tX,Y\tX,X\t\nD5S818\t10,12\t9,11\t10,11,12\t\nFGA\t23,26\t23,24\t23,24,26\t\nThe tumor contained maternal and paternal alleles, suggesting that it was gestational.\n\nTable II Genomic findings for the tumor and blood of the patient, obtained using the NCC Oncopanel System Test.\n\nGene name\tMutation allele frequency\tAmino acid change\tdbSNP\tHGVD allele frequency\t\nBARD1\t66.3\tR24S\trs1048108\t0.350\t\nSETD2\t68.0\tM1080I\trs76208147\t0.143\t\nROS1\t64.9\tS2229C\trs619203\t0.145\t\nROS1\t67.9\tK2228Q\trs529156\t0.146\t\nROS1\t68.4\tD2213N\trs529038\t0.151\t\nGNAQ\t12.8\tT96S\trs777679970\tΝot detected\t\nTP53\t61.7\tR213P\trs587778720\tΝot detected\t\nBRCA1\t66.5\tS1613G\trs1799966\t0.331\t\nBRCA1\t62.8\tK1183R\trs16942\t0.329\t\nBRCA1\t63.0\tE1038G\trs16941\t0.329\t\nBRCA1\t70.4\tR871L\trs799917\t0.331\t\nFGFR4\t74.9\tG388R\trs351855\t0.414\t\nNOTCH2\t69.0\tR1260H\trs75423398\t0.070\t\nPRKCI\t73.0\tR327R\trs55683301\t0.061\t\nESR1\t78.5\tP146Q\trs17847065\t0.047\t\nPTCH1\t70.1\tR893H\trs138154222\t0.019\t\nBRCA2\t62.8\tM784V\trs11571653\t0.095\t\nCREBBP\t64.6\tL551I\trs61753381\t0.032\t\nBRCA1\t51.0\tY856H\trs80356892\t0.009\t\nSNP allele frequency of GNAQ and TP53 were not detected in the Japanese database, HGVD. These data demonstrated that GNAQ and TP53 may be pathogenic variants. dbSNP, database of single nucleotide polymorphism; HGVD, human genetic variation database.\n==== Refs\nReferences\n\n1 Albrecht C Chamley L Charnock-Jones DS Collins S Fujiwara H Golos T Grayo S Hannan N Harris L Ichizuka K IFPA meeting 2018 workshop report II: Abnormally invasive placenta; inflammation and infection; preeclampsia; gestational trophoblastic disease and drug delivery Placenta 84 9 13 2019 10.1016/j.placenta.2019.02.006 30773233\n2 Yamamoto E Niimi K Fujikake K Nishida T Murata M Mitsuma A Ando Y Kikkawa F High-dose chemotherapy with autologous peripheral blood stem cell transplantation for choriocarcinoma: A case report and literature review Mol Clin Oncol 5 660 664 2016 10.3892/mco.2016.1011 27900108\n3 Powles T Savage PM Stebbing J Short D Young A Bower M Pappin C Schmid P Seckl MJ A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia Br J Cancer 96 732 737 2007 10.1038/sj.bjc.6603608 17299394\n4 Sunami K Ichikawa H Kubo T Kato M Fujiwara Y Shimomura A Koyama T Kakishima H Kitami M Matsushima H Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: A hospital-based study Cancer Sci 110 1480 1490 2019 10.1111/cas.13969 30742731\n5 Yamamoto E Niimi K Shinjo K Yamamoto T Fukunaga M Kikkawa F Identification of causative pregnancy of gestational trophoblastic neoplasia diagnosed during pregnancy by short tandem repeat analysis Gynecol Oncol Case Rep 9 3 6 2014 10.1016/j.gynor.2014.04.001 24944881\n6 Piamsomboon S Kudelka AP Termrungruanglert W Van Besien K Edwards CL Lifshitz S Schomer DF Champlin R Mante RP Kavanagh JJ Verschraegen CF Remission of refractory gestational trophoblastic disease in the brain with ifosfamide, carboplatin, and etoposide (ICE): First report and review of literature Eur J Gynaecol Oncol 18 453 456 1997 9443008\n7 van Besien K Verschraegen C Mehra R Giralt S Kudelka AP Edwards CL Piamsonboom S Termrungruanglert W Champlin R Kavanagh JJ Complete remission of refractory gestational trophoblastic disease with brain metastases treated with multicycle ifosfamide, carboplatin, and etoposide (ICE) and stem cell rescue Gynecol Oncol 65 366 369 1997 10.1006/gyno.1997.4677 9159354\n8 Zehir A Benayed R Shah RH Syed A Middha S Kim HR Srinivasan P Gao J Chakravarty D Devlin SM Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients Nat Med 23 703 713 2017 10.1038/nm.4333 28481359\n9 Cotter JA Szymanski L Karimov C Boghossian L Margol A Dhall G Tamrazi B Varaprasathan GI Parham DM Judkins AR Biegel JA Transmission of a TP53 germline mutation from unaffected male carrier associated with pediatric glioblastoma in his child and gestational choriocarcinoma in his female partner Cold Spring Harb Mol Case Stud 4 a002576 2018 10.1101/mcs.a002576 29581140\n10 Choi MC Oh J Lee C Effective anti-programmed cell death 1 treatment for chemoresistant gestational trophoblastic neoplasia Eur J Cancer 121 94 97 2019 10.1016/j.ejca.2019.08.024 31569067\n11 Ghorani E Kaur B Fisher RA Short D Joneborg U Carlson JW Akarca A Marafioti T Quezada SA Sarwar N Seckl MJ Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia Lancet 390 2343 2345 2017 10.1016/S0140-6736(17)32894-5 29185430\n\n",
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"journal": "Molecular and clinical oncology",
"keywords": "choriocarcinoma; gestational trophoblastic diseases; next-generation genome sequencing",
"medline_ta": "Mol Clin Oncol",
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"pubdate": "2021-07",
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"title": "Next-generation genome sequencing of a matched normal-tumor pair from a patient with intractable gestational choriocarcinoma: A case report.",
"title_normalized": "next generation genome sequencing of a matched normal tumor pair from a patient with intractable gestational choriocarcinoma a case report"
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"abstract": "The association of Pneumocystis jirovecii pneumonia (PJP) with connective tissue disease (CTD) and mycophenolate mofetil's (MMF) potent activity against PJP have been separately reported. Until now, there have been no papers describing the occurrence of PJP following MMF treatment in CTD patients. The objective of this study was to describe the clinical features, risk factors, outcomes of PJP in patients with CTD and investigates the effects of MMF on the occurrence of PJP in China. In this retrospective cohort study, we performed a chart review, analyzing clinical features, treatment, and outcomes of PJP in patients with CTD in a single hospital. A total of 17 cases met the inclusion criteria of having PJP and a CTD diagnosis: systemic lupus erythematosus; polymyositis; dermatomyositis; rheumatoid arthritis; Wegener's granulomatosis; and microscopic polyangiitis. Sixteen patients were treated with glucocorticoids (GCs) plus immunosuppressive drugs. Only one patient had GCs without immunosuppressive drugs. Ten subjects (62.5 %) received MMF (1-1.5 g/day), and all ten had lymphopenia. The mortality rates of MMF and non-MMF patients were 50 and 14 %, respectively. This study is the first report of PJP following MMF plus GC treatment in patients with CTD. CTD itself may be a risk factor for PJP. When CTD patients receiving MMF therapy have low lymphocyte counts and/or CD4 lymphocyte counts <250/µL, we should be care of occurrence of PJP.",
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"mesh_terms": "D000328:Adult; D000368:Aged; D002681:China; D003240:Connective Tissue Diseases; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D009894:Opportunistic Infections; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
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"title": "Pneumocystis jirovecii pneumonia in mycophenolate mofetil-treated patients with connective tissue disease: analysis of 17 cases.",
"title_normalized": "pneumocystis jirovecii pneumonia in mycophenolate mofetil treated patients with connective tissue disease analysis of 17 cases"
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"abstract": "The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.A 32-year-old man with a history of a mixed germ cell tumor of the testis presented with acute-onset, right-sided weakness and numbness. His previous treatment included orchiectomy, which revealed a 5-cm tumor that was 95% yolk sac tumor and 5% embryonal carcinoma, and retroperitoneal lymph node dissection for clinical stage I disease in January 2010, which revealed no nodal metastases. Starting in June 2010, he was treated with four cycles of etoposide and cisplatin for pulmonary and thoracic lymph node metastases and a rising serum alpha-fetoprotein (AFP) level. He subsequently received four cycles of paclitaxel, ifosfamide, and cisplatin for relapse in the lungs and mediastinal nodes with a rising AFP level starting in January 2011. He reported having a 2-week history of intermittent headaches in December 2011, when he presented with acute-onset, right-sided weakness and numbness. Computed tomographs of the head was obtained and demonstrated a left parietal intracranial hemorrhage without midline shift or hydrocephalus. Brain magnetic resonance imaging (MRI) showed a complex, 4.5-cm mass consistent with a hemorrhagic metastasis. His serum AFP level was elevated at 47 ng/mL. The patient became progressively obtunded and underwent emergency surgical decompression and resection of the tumor. Histopathologic evaluation of the resected tissue showed metastatic germ cell tumor predominantly consisting of a yolk sac element (Fig 1). His AFP level declined rapidly after resection, and computed tomography of the chest, abdomen, and pelvis showed no evidence of metastatic disease. However, 2 weeks later, his AFP level rose again, and repeat MRI of the brain showed a 3-cm mass in the left mesial parietal lobe adjacent to the resection site. He started treatment with filgrastim to facilitate collection of circulating hematopoietic stem cells. Several days later, after apheresis, he received his first of two cycles of high-dose carboplatin 700 mg/m(2) on days -5, -4, and -3 and etoposide 750 mg/m(2) on days -5, -4, and -3. The patient had a complete response to high-dose chemotherapy and no major acute complications. His cancer remains in complete remission 3 years later without additional treatment. His three lines of chemotherapy left him with chronic peripheral neuropathy.",
"affiliations": "Cleveland Clinic Taussig Cancer Institute, Cleveland, OH gilligt@ccf.org.",
"authors": "Gilligan|Timothy|T|",
"chemical_list": "D005047:Etoposide; D016190:Carboplatin",
"country": "United States",
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"issue": "34(4)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
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"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D016190:Carboplatin; D003657:Decision Making; D005047:Etoposide; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D013736:Testicular Neoplasms",
"nlm_unique_id": "8309333",
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"references": null,
"title": "Decision Making in a Data-Poor Environment: Management of Brain Metastases From Testicular and Extragonadal Germ Cell Tumors.",
"title_normalized": "decision making in a data poor environment management of brain metastases from testicular and extragonadal germ cell tumors"
} | [
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"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2016-014205",
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"abstract": "OBJECTIVE\nProphylactic antibiotic use in preterm pre-labor rupture of membranes (PPROM) is associated with a significant reduction in intra-amniotic infection and improved neonatal outcome. However, data is insufficient to determine the optimal antibiotic regimen. Considering the rise in Escherichia coli and Klebsiella pneumonia early-onset sepsis rate and the emergence of ampicillin resistance, our aim is to compare the efficiency of two antibiotic regimens in prolonging pregnancy and reducing infectious morbidity.\n\n\nMETHODS\nThis multicenter randomized unblinded controlled prospective trial compared two antibiotic prophylactic protocols in PPROM: ampicillin + roxithromycin vs. cefuroxime + roxithromycin in 84 women with PPROM, from 12/2015-12/2019.\n\n\nRESULTS\nThe median latency period was significantly longer (p = 0.039) in the cefuroxime + roxithromycin group (4.63 [0.59-50.18] days) than in the ampicillin + roxithromycin group (2.3 [0.15-58.3] days). Neonatal admission to neonatal intensive care unit rate, hospitalization length, neonatal respiratory distress syndrome, neonatal fever, and need for respiratory support or mechanical ventilation, were similar between the groups. K. pneumonia cultures were significantly more frequent in the ampicillin + roxithromycin group. None of the cultures were group B Streptococcus positive.\n\n\nCONCLUSIONS\nTo prolong latency period and reduce gram-negative early-onset sepsis, cefuroxime + roxithromycin is recommended as the first-line protocol in PPROM.\n\n\nBACKGROUND\nClinicalTrials.gov Identifier: NCT02819570.",
"affiliations": "Department of Obstetrics and Gynecology, Galilee Medical Center, Nahariya, Israel; Azrieli Faculty of Medicine, Bar Ilan University, Israel. Electronic address: homesickid@yahoo.com.;Department of Obstetrics and Gynecology, Galilee Medical Center, Nahariya, Israel; Azrieli Faculty of Medicine, Bar Ilan University, Israel.;Department of Pediatrics A, Emek Medical Center, Afula, Israel; Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.;Department of Obstetrics and Gynecology, Galilee Medical Center, Nahariya, Israel; Azrieli Faculty of Medicine, Bar Ilan University, Israel.;Azrieli Faculty of Medicine, Bar Ilan University, Israel; Neonatal Intensive Care Unit, Galilee Medical Center, Nahariya, Israel.;Department of Obstetrics and Gynecology, Bnai-Zion Medical Center, Israel; Technion - Israel Institute of Technology, Israel.;Department of Obstetrics and Gynecology, Bnai-Zion Medical Center, Israel; Technion - Israel Institute of Technology, Israel.;Azrieli Faculty of Medicine, Bar Ilan University, Israel; Department of Obstetrics and Gynecology, Ziv Medical Center, Safed, Israel.;Azrieli Faculty of Medicine, Bar Ilan University, Israel; Department of Obstetrics and Gynecology, Ziv Medical Center, Safed, Israel.;Azrieli Faculty of Medicine, Bar Ilan University, Israel; Clinical Microbiology Laboratory, Galilee Medical Center, Nahariya, Israel.;Department of Obstetrics and Gynecology, Galilee Medical Center, Nahariya, Israel; Azrieli Faculty of Medicine, Bar Ilan University, Israel.",
"authors": "Wolf|Maya Frank|MF|;Sgayer|Inshirah|I|;Miron|Dan|D|;Krencel|Amir|A|;Sheffer|Vered Fleisher|VF|;Idriss|Suraya Saied|SS|;Sammour|Rami N|RN|;Peleg|David|D|;Shachar|Inbar Ben|IB|;Rechnitzer|Hagai|H|;Bornstein|Jacob|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000667:Ampicillin",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2020.05.005",
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"issn_linking": "1201-9712",
"issue": "96()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Early-onset sepsis; Latency period; Pathogens distribution; Pre-labor rupture of membranes; Prophylactic antibiotic treatment",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000667:Ampicillin; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D007710:Klebsiella Infections; D011247:Pregnancy; D011446:Prospective Studies; D018805:Sepsis",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "254-259",
"pmc": null,
"pmid": "32407901",
"pubdate": "2020-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "A novel extended prophylactic antibiotic regimen in preterm pre-labor rupture of membranes: A randomized trial.",
"title_normalized": "a novel extended prophylactic antibiotic regimen in preterm pre labor rupture of membranes a randomized trial"
} | [
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"companynumb": "IL-ALKEM LABORATORIES LIMITED-IL-ALKEM-2020-02336",
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"activesubstancename": "CEFUROXIME AXETIL"
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"abstract": "We report a case of adhesions in the epidural space caused by more than 200 times epidural blocks that were observed with epiduroscopy. A 41-year-old man had repeatedly undergone lumbar epidural blocks to treat pain in his leg, resulting in decreased efficacy of the epidural block. We described endoscopic findings that these adhesions were mostly consisted of adhesions formed from the soft connective tissue.",
"affiliations": "Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.;Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan.",
"authors": "Shimada|Nobuhiro|N|0000-0001-8599-5040;Igarashi|Takashi|T|;Murai|Kunihiko|K|;Hara|Tetsuhito|T|;Kuramochi|Tomoko|T|;Takeuchi|Mamoru|M|",
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"country": "Germany",
"delete": false,
"doi": "10.1186/s40981-017-0128-z",
"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJA Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 2945710112810.1186/s40981-017-0128-zCase ReportAdhesions in the epidural space caused by frequent epidural blocks http://orcid.org/0000-0001-8599-5040Shimada Nobuhiro 81-28-558-7383knobdoors203@jichi.ac.jp Igarashi Takashi igat@jichi.ac.jp Murai Kunihiko murai.mane@jichi.ac.jp Hara Tetsuhito r1147th@jichi.ac.jp Kuramochi Tomoko tomokokuramochi0803@gmail.com Takeuchi Mamoru matake@jichi.ac.jp 0000000123090000grid.410804.9Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498 Japan 11 10 2017 11 10 2017 12 2017 3 573 8 2017 5 10 2017 © The Author(s) 2017\nOpen 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.We report a case of adhesions in the epidural space caused by more than 200 times epidural blocks that were observed with epiduroscopy. A 41-year-old man had repeatedly undergone lumbar epidural blocks to treat pain in his leg, resulting in decreased efficacy of the epidural block. We described endoscopic findings that these adhesions were mostly consisted of adhesions formed from the soft connective tissue.\n\nKeywords\nEpidural blockAdhesions in the epidural spaceEpiduroscopyissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nRepeated long-term single or continuous epidural blocks are considered to cause adhesions in the epidural space, resulting in decreased effects of the epidural block. Few reports have detailed epidural space anatomical findings and treatment for such cases [1]. We report our observations of the epidural space in a patient who underwent frequent epidural blocks.\n\nCase presentation\nA 41-year-old man with no significant medical history presented with a chief complaint of pain in his left leg. The top of his left foot had been run over by a car tire. No fractures or joint injuries were noted in the toes. He was diagnosed with complex regional pain syndrome (CRPS).\n\nHe underwent twice-weekly lumbar epidural blocks at his local hospital and a month-long continuous epidural block each winter, which allowed him to return to work. The needle used for a single epidural block was 20 gauge, and the catheter used for the continuous epidural block was 20 gauge. The degree of pain in his left leg according to the numerical rating scale (NRS) was 8 during activities of daily living and 3 after a lumbar epidural block was performed.\n\nFive years after the initiation of epidural blocks, greater resistance was felt while injecting the medication into the epidural space, and it was difficult to insert the catheter. The degree of pain in the leg after the epidural block became NRS 6, indicating that effects of the epidural block were insufficient. The degree of pain in the leg during activities of daily living was not exacerbated, remaining at NRS 8. Adhesions in the epidural space caused by frequent epidural blocks were suspected, and the patient was referred to our department.\n\nThe patient had undergone epidural blocks many times at his local hospital. These comprised single epidural blocks with 10 ml 0.375–0.75% ropivacaine at the L4/5 and L5/S1 levels performed over 200 times as well as continuous epidural blocks using 0.2% ropivacaine for approximately 1 month performed multiple times. During examination, the patient exhibited spontaneous pain from the left leg to the foot accompanied by allodynia. Muscular atrophy and edema were also noted at the same site. Manual muscle testing results ranged from 2 to 3 in the tibialis anterior muscle, triceps surae muscle, gastrocnemius muscle, long extensor muscle of the thumb, and flexor hallucis longus muscle. There was no decreased perception and no other abnormal neurological findings. In the area from the left leg to the foot, plain X-rays revealed mild bone atrophy and magnetic resonance imaging (MRI) revealed mild bone and muscle atrophy. No abnormalities were noted in the lumbar spine on plain X-rays, and MRI did not reveal any abnormal findings in the intervertebral discs, vertebrae, spine, or nerve roots. T1-weighted fat-suppressed images showed uneven contrast effects of gadolinium throughout the back of the epidural space from L4 to S1 (Fig. 1). Epidurography performed from the sacral hiatus revealed blockage in the L5/S1 vertebral area. Lower limb thermography revealed decreased temperature throughout the entire left leg. We diagnosed the pain in his left foot as CRPS because it applied to continuing pain which was disproportionate to any inciting event, hyperesthesia, allodynia, temperature asymmetry, motor dysfunction, and trophic changes among the diagnostic criteria for CRPS by International Association for the Study of Pain, 2005 [2]. However, the attenuated effects of the epidural block were determined to be due to adhesions in the epidural space rather than CRPS exacerbation.Fig. 1 MRI. Transverse section of the L4 vertebral area. a Unenhanced fat-suppressed T1-weighted image. b Gd-contrast enhanced fat-suppressed T1-weighted image. Arrow indicates contrast effects observed in the back of the epidural space\n\n\n\n\nRegarding further treatment, the patient was advised that, although it might be possible to regain the effect of the epidural block by performing adhesiotomy in the epidural space, this was not a radical cure for CRPS of the left leg, and it would be difficult to achieve good-quality continuous epidural blocks over long periods if adhesions in the epidural space recurred following adhesiotomy. Therefore, he was advised to undergo spinal cord stimulation rather than long-term epidural blocks as a means of treating the pain in his leg. However, the patient requested to undergo adhesiotomy in the epidural space.\n\nTherefore, epiduroscopy was performed. We used video-guided catheter and 0.9 mm fiberopticscope (Kobamed system, Japan Medicalnext Co., Ltd., Osaka, Japan). Contrast enhancement of the area from the sacral hiatus to the epidural space performed before epiduroscopy revealed blockage of the L5/S1 vertebral area, with no contrast of the epidural space any further toward the cranial side of this area (Fig. 2a). Endoscopic findings revealed adhesions in the epidural space in the L4 to S1 vertebral area. The adhesions were mainly formed from the soft connective tissue, and little hard scar tissue was observed. The adhesions were distributed throughout the L4 to S1 vertebral area, with many adhesions observed on the left side of the L4 and L5 vertebral area. There were few areas of hyperemia, reddening, or blood vessel proliferation (Fig. 3a). Adhesiotomy was carefully performed using the catheter tip while injecting the physiological saline solution. We were able to easily detach the adhesions, and contrast effects were achieved in the epidural space (Fig. 2b). In the epidural space toward the cranial side from the L3 vertebral area, dura mater and fatty tissue could be clearly observed and appeared to be normal (Fig. 3b). The operation time was 58 min, and the physiological saline solution used for adhesiotomy was 250 ml.Fig. 2 Epidurography. a Before epiduroscopy, there was blockage of the L5/S1 vertebral area (arrow), with no contrast of the epidural space any further toward the cranial side of this area. b After epiduroscopy, contrast effects were achieved the cranial side of the epidural space from the L5 vertebral area\n\n\nFig. 3 Endoscopic findings in the epidural space. a There were adhesions in the L5 vertebral area. Due to the connective tissue, we could not get the clear view. There were increases in the fibrous tissue in the part of the connective tissue (A). These adhesions were mostly formed from the soft connective tissue. b In the L3 vertebral area, dura mater (B) and fatty tissue (C) could be clearly observed and appeared to be normal\n\n\n\n\nAfter epiduroscopy, although the degree of pain in his leg after an outpatient epidural block had recovered to NRS 4, the effects of once-weekly epidural blocks were only sufficient for 1 month. At this point, the patient realized that the treatment of the pain in his leg with epidural blocks would be difficult and requested to undergo spinal cord stimulation.\n\nFor spinal cord stimulation, an 8-pole electrode (Octrode™, Medtronic, Inc., Minneapolis, MN, USA) was percutaneously placed into the epidural space so that the tip was in the Th9 vertebral area and a nerve stimulator (Eon Mini™, Medtronic, Inc) was placed in the right hypogastric region. Thereafter, the degree of pain in his leg during activities of daily living decreased to NRS 5.\n\nDiscussion\nIn our patient, the effects of repeated epidural blocks gradually decreased. MRI, epidurography, and epiduroscopy indicated adhesions at epidural block puncture sites. Furthermore, no spinal disorders were observed on imaging. Therefore, our patient appeared to have adhesions caused by repeated epidural blocks.\n\nMRI and epidurography are generally used to diagnose adhesions in the epidural space. When adhesions are present in the epidural space, MRI shows enhanced contrast effects in the connective tissue in the epidural space and disappearance of epidural fat [3, 4]. Although MRI is noninvasive and can be used for extensive observation of adhesions, its diagnostic precision is low. Epidurography shows blockages at the adhesion sites. It can be used for extensive observation of adhesions and offers high diagnostic precision. However, the diagnosis of adhesions located further toward the epidural space on the cranial side from the blockage requires another puncture site. Although MRI and epidurography are sufficient for the diagnosis of epidural adhesion, it may be possible to obtain findings of epidural space by epiduroscopy which are difficult to obtain by other radiological tests.\n\nEpidural blocks result in connective tissue growth in the epidural space due to microbleeding caused by the punctures, local inflammation caused by high concentration of local anesthetics, and healing process of the inflammation [5]. In our patient, it appeared that multiple epidural blocks and continuous epidural catheter insertion have contributed to this connective tissue growth. Most of the adhesions in our patient resulted from connective tissue growth, and there were few areas with strong adhesions, scarring, hyperemia, or reddening. In contrast, standard endoscopic findings of lumbar degenerative diseases such as lumbar disc herniation, lumbar spinal canal stenosis, and failed back surgery syndrome have been reported [6, 7]. In case of lumbar disc herniation, inflammatory findings such as hyperemia and reddening are common and adhesions are often mild. In case of lumbar spinal canal stenosis, inflammatory findings and connective tissue growth are observed due to the degree of stenosis, and adhesions are often strong. In cases of failed back surgery syndrome, the connective tissue in the epidural space is known to form scars and exhibit strong adhesions around the nerves. Comparing our endoscopic findings to previous reports, the connective tissue that developed in our patient because of epidural blocks was milder than any of other lumbar degenerative diseases.\n\nNormally, lumbar and sciatic nerve pain due to lumbar herniated disc, lumbar canal stenosis, and failed back syndrome are indications for epiduroscopy [7]. We performed adhesiotomy in the epidural space in our patient to enable him to undergo subsequent epidural blocks as treatment. Although adhesions in the epidural space could be detached with epiduroscopy, adhesions recurred because of repeated epidural blocks following adhesiotomy. Therefore, it appears that performing adhesiotomy and subsequent epidural blocks cannot be recommended for such cases of iatrogenic adhesions of epidural space even when the patient asks to perform.\n\nConclusions\nWe described the epiduroscopy findings in the epidural space in which adhesions had formed because of frequent epidural blocks. Adhesions in the epidural space were noted at the epidural block puncture sites. Most adhesions involved the growth of the soft connective tissue, and little hard scar tissue was observed.\n\nAbbreviations\nCRPSComplex regional pain syndrome\n\nMRIMagnetic resonance imaging\n\nNRSNumerical rating scale\n\nAuthors’ contributions\nNS, KM, TH, and TK made a clinical diagnosis and decision. NS drafted the manuscript. TI supervised the clinical diagnosis and decision. TI and MT supervised the manuscript drafting. All authors read and approved the final manuscript.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\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. Igarashi T Hirabayashi Y Shimizu R Mitsuhata H Saitoh K Fukuda H Inflammatory changes after extradural anaesthesia may affect the spread of local anaethetic within the extradural space Br J Anaesth 1996 77 347 351 10.1093/bja/77.3.347 8949808 \n2. Harden RN Bruehl S Stanton-Hicks M Wilson PR Propsed new diagnostic criteria for complex regional pain syndrome Pain Med 2007 8 326 331 10.1111/j.1526-4637.2006.00169.x 17610454 \n3. Babar S Saifuddin A MRI of the post-discectomy lumbar spine Clin Radiol 2002 57 969 981 10.1053/crad.2002.1071 12409106 \n4. Wilkinson LS Elson E Saifuddin A Ransford AO Defining the use of gadolinium enhanced MRI in the assessment of the postoperative lumbar spine Clin Radiol 1997 52 530 534 10.1016/S0009-9260(97)80330-3 9240706 \n5. Sasauchi K, Sunada K, Nakamura T. Long term evaluation of continuous epidural anesthesia in an improved canine model. Anesth Pain Med. 2016; doi:10.5812/aapm.35458.\n6. Igarashi T Hirabayashi Y Seo N Saitoh K Fukuda H Suzuki H Lysis of adhesions and epidural injection of steroid/local anaesthetic during epiduroscopy potentially alleviate low back and leg pain in elderly patients with lumbar spinal stenosis Br J Anaesth 2004 93 181 187 10.1093/bja/aeh201 15194631 \n7. Igarashi T Saberski LR Waldman SD Spinal canal endoscopy Pain Management 2011 2 Philadelphia Elsevier Science 162 174\n\n",
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"keywords": "Adhesions in the epidural space; Epidural block; Epiduroscopy",
"medline_ta": "JA Clin Rep",
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"nlm_unique_id": "101682121",
"other_id": null,
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"pmid": "29457101",
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"references": "15194631;17610454;8949808;9240706;12409106;27843772",
"title": "Adhesions in the epidural space caused by frequent epidural blocks.",
"title_normalized": "adhesions in the epidural space caused by frequent epidural blocks"
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"abstract": "Mouth ulcers are a cutaneous complication that can often affect kidney transplant patients, mostly due to the effect of immunosuppressive treatment. Even so, before asserting that said complication is indeed secondary to drugs, it is very important to establish a differential diagnosis with other mouth ulcer causes, such as systemic diseases or viral infections, which are also common in these patients.",
"affiliations": "Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. Electronic address: adriplanapla@gmail.com.;Department of Nephrology, Hospital Universitari, Germans Trias i Pujol, Badalona, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.;Department of Nephrology, Hospital Universitari, Germans Trias i Pujol, Badalona, Barcelona, Spain.",
"authors": "Plana-Pla|Adrià|A|;Solé|Laura Cañas|LC|;Garcia|Aram Boada|AB|;Valdemoros|Ricardo Lauzurica|RL|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.nefro.2018.05.005",
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"issn_linking": "2013-2514",
"issue": "39(1)",
"journal": "Nefrologia",
"keywords": "Citomegalovirus; Cytomegalovirus; Kidney transplant; Micofenolato mofetilo; Mouth ulcers; Mycophenolate mofetil; Trasplante renal; Úlceras orales",
"medline_ta": "Nefrologia (Engl Ed)",
"mesh_terms": "D000368:Aged; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007668:Kidney; D008297:Male; D009173:Mycophenolic Acid; D019226:Oral Ulcer; D066027:Transplant Recipients",
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"references": null,
"title": "Mycophenolate mofetil-induced mouth ulcers in a kidney transplant patient: Case report and literature review.",
"title_normalized": "mycophenolate mofetil induced mouth ulcers in a kidney transplant patient case report and literature review"
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"abstract": "We describe the case history of a 9-year-old boy who developed Stevens-Johnson syndrome (SJS) following concomitant use of valproic acid and lamotrigine. He presented with rash and fever several weeks after introduction of lamotrigine, having been on valproic acid for seizure disorder. SJS happens to be one of the rare adverse reactions of antiepilepsy drugs (AED). Management is mainly supportive with care escalation when necessary because of the significant morbidity.",
"affiliations": "Department of Paediatrics, Cork University Hospital, Wilton, Cork.;Department of Paediatrics, Cork University Hospital, Wilton, Cork.;Department of Paediatrics, Cork University Hospital, Wilton, Cork.;Department of Paediatrics, Cork University Hospital, Wilton, Cork.",
"authors": "Maduemem|K|K|;Vatca|A|A|;O'Neill|T|T|;Buckley|D|D|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid; D000077213:Lamotrigine",
"country": "Ireland",
"delete": false,
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"issn_linking": "0332-3102",
"issue": "110(6)",
"journal": "Irish medical journal",
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"medline_ta": "Ir Med J",
"mesh_terms": "D000927:Anticonvulsants; D002648:Child; D004359:Drug Therapy, Combination; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D013262:Stevens-Johnson Syndrome; D014635:Valproic Acid",
"nlm_unique_id": "0430275",
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"pmc": null,
"pmid": "28952676",
"pubdate": "2017-06-09",
"publication_types": "D002363:Case Reports",
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"title": "Stevens - Johnson Syndrome Induced by Combination of Lamotrigine and Valproic Acid in a 9-Year-Old Boy.",
"title_normalized": "stevens johnson syndrome induced by combination of lamotrigine and valproic acid in a 9 year old boy"
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"companynumb": "IE-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-147446",
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{
"abstract": "The study aimed to compare the efficacy of methotrexate (MTX) cervical injections + actinomycin-D (ACT-D)(MACT) and 5-fluorouracil (5-Fu) + actinomycin-D (5-Fu plus ACT-D) chemotherapy regimens for low-risk gestational trophoblastic neoplasia (LR-GTN). Clinical data from 66 LR-GTN patients, admitted to the Beijing Obstetrics and Gynecology Hospital from January 2010 to April 2012, were analysed retrospectively. In total, 32 patients were treated with a MACT therapeutic regimen and the remaining 34 with a 5Fu + ACT-D therapeutic regimen. Complete remission rates (CR), duration of treatment, hospital stay and toxicity effects were compared. There was no statistical difference in CR for the MACT (90.63%) or the 5-Fu plus ACT-D (100%) therapeutic regimens (p = 0.0676) or in the duration of treatment [MACT (3.50) or 5-Fu plus ACT-D (3.71; p = 0.2021)]. Moreover, the hospital stay in the 5-Fu plus ACT-D group (32.88 days) was significantly longer than for the MACT group (22.09 days; p ＜ 0.001). Furthermore, the degree of myelosuppression, nausea and vomiting, diarrhoea, stomatitis and alopecia was more severe in the 5Fu + ACT-D group (p ＜ 0.01). However, there was no statistical difference in the severity of liver function damage between the two groups. A shorter hospital stay, lower hospitalization cost and slightly more toxic effects were observed in LR-GTN patients treated with the MACT therapeutic regimen. We suggest that the MACT regimen should be used as first-line chemotherapy for LR-GTN.",
"affiliations": "a Department of Oncology , Beijing Obstetrics and Gynecology Hospital, Capital Medical University , Beijing , China.;a Department of Oncology , Beijing Obstetrics and Gynecology Hospital, Capital Medical University , Beijing , China.;a Department of Oncology , Beijing Obstetrics and Gynecology Hospital, Capital Medical University , Beijing , China.;a Department of Oncology , Beijing Obstetrics and Gynecology Hospital, Capital Medical University , Beijing , China.;a Department of Oncology , Beijing Obstetrics and Gynecology Hospital, Capital Medical University , Beijing , China.;a Department of Oncology , Beijing Obstetrics and Gynecology Hospital, Capital Medical University , Beijing , China.;a Department of Oncology , Beijing Obstetrics and Gynecology Hospital, Capital Medical University , Beijing , China.;a Department of Oncology , Beijing Obstetrics and Gynecology Hospital, Capital Medical University , Beijing , China.",
"authors": "Wang|Yu|Y|;Miao|Jin-Wei|JW|;Wang|Tong|T|;Wang|Yan|Y|;Wu|Yu-Mei|YM|;Kong|Wei-Min|WM|;Su|Li|L|;Duan|Wei|W|",
"chemical_list": "D003609:Dactinomycin; D005472:Fluorouracil; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1080/1120009X.2015.1136778",
"fulltext": null,
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"issn_linking": "1120-009X",
"issue": "28(2)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Drug therapy; Gestational trophoblastic disease; Treatment outcome",
"medline_ta": "J Chemother",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003609:Dactinomycin; D005260:Female; D005472:Fluorouracil; D031901:Gestational Trophoblastic Disease; D006801:Humans; D008727:Methotrexate; D008875:Middle Aged; D011247:Pregnancy; D012189:Retrospective Studies; D012306:Risk; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "135-9",
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"pmid": "27105436",
"pubdate": "2016-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparison of MACT and 5Fu+ACT-D chemotherapy regimens in the treatment of low-risk gestational trophoblastic neoplasia.",
"title_normalized": "comparison of mact and 5fu act d chemotherapy regimens in the treatment of low risk gestational trophoblastic neoplasia"
} | [
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"companynumb": "CN-MYLANLABS-2016M1037459",
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"abstract": "A 66-year-old man was diagnosed with advanced esophagogastric junction cancer and referred to our institution (Department of Gastroenterological Surgery, Chiba Cancer Center) for treatment. Computed tomography imaging confirmed the presence of a tumor, extending from the lower thoracic esophageal to the esophagogastric junction, with swelling of the upper mediastinal lymph nodes. Based on the criteria of the International Union against Cancer Committee (UICC, 8th Edition), the staging was confirmed as follows: 101R, 107 and 106 pre. Based on these findings, a clinical diagnosis of EGJ cancer was made, with a UICC 8th classification of cT3N1M0 c-stage-III. Preoperative chemotherapy was performed, with tumor shrinkage obtained after three courses of chemotherapy (using S-1 plus oxaliplatin). Subsequently, esophagectomy with three-field lymph node dissection and gastric tube reconstruction, via the intrathoracic route, was performed. On postoperative day 2, the patient developed an idiopathic pneumothorax, with brown-green drainage from the chest tube. A repeat thoracotomy was performed, confirming the presence of brown-green pleural fluid and necrosis of esophageal tissue. The area of necrosis was situated 4 cm on the oral side of the anastomosis, with greater necrosis of the right than left side. There was no evidence of necrosis of the gastric tube. The necrotic residual esophagus was excised and reconstructed, as an external fistula on the left side of the neck. On day 38, after the second surgery, reconstruction of the esophageal conduit and gastric tube, via the jejunum, was performed. At 7 months after discharge, the patient was symptom free, with no evidence of cancer recurrence.",
"affiliations": "Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.;Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.;Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.;Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.;Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.;Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.;Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.;Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.;Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.",
"authors": "Tabe|Shunsuke|S|;Hoshino|Isamu|I|;Takiguchi|Nobuhiro|N|;Ikeda|Atsushi|A|;Soda|Hiroaki|H|;Tonooka|Toru|T|;Gunji|Hisashi|H|;Nabeya|Yoshihiro|Y|;Otsuka|Masayuki|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2020.1997",
"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450 2049-9469 D.A. Spandidos \n\n10.3892/mco.2020.1997\nMCO-0-0-1997\nArticles\nResidual esophageal necrosis after radical esophagectomy for esophagogastric cancer: A case report\nTabe Shunsuke 12 Hoshino Isamu 1 Takiguchi Nobuhiro 1 Ikeda Atsushi 1 Soda Hiroaki 1 Tonooka Toru 1 Gunji Hisashi 1 Nabeya Yoshihiro 1 Otsuka Masayuki 12 1 Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan\n2 Department of General Surgery, Chiba University Graduate School of Medicine, Chiba 260.8677, Japan\nCorrespondence to: Dr Isamu Hoshino, Department of Gastroenterological Surgery, Chiba Cancer Center, 666-2 Nitonacho, Chuo-ku, Chiba 260-8717, Japan ihoshino@chiba-cc.jpAbbreviations: EGJ, esophagogastric junction; UICC, International Union against Cancer Committee; PET-CT, positron-emission tomography computed tomography; CT, computed tomography; NAC, neoadjuvant chemotherapy; POD, postoperative day\n\n\n4 2020 \n18 2 2020 \n18 2 2020 \n12 4 321 324\n01 10 2019 31 1 2020 Copyright: © Tabe et al.2020This 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 66-year-old man was diagnosed with advanced esophagogastric junction cancer and referred to our institution (Department of Gastroenterological Surgery, Chiba Cancer Center) for treatment. Computed tomography imaging confirmed the presence of a tumor, extending from the lower thoracic esophageal to the esophagogastric junction, with swelling of the upper mediastinal lymph nodes. Based on the criteria of the International Union against Cancer Committee (UICC, 8th Edition), the staging was confirmed as follows: 101R, 107 and 106 pre. Based on these findings, a clinical diagnosis of EGJ cancer was made, with a UICC 8th classification of cT3N1M0 c-stage-III. Preoperative chemotherapy was performed, with tumor shrinkage obtained after three courses of chemotherapy (using S-1 plus oxaliplatin). Subsequently, esophagectomy with three-field lymph node dissection and gastric tube reconstruction, via the intrathoracic route, was performed. On postoperative day 2, the patient developed an idiopathic pneumothorax, with brown-green drainage from the chest tube. A repeat thoracotomy was performed, confirming the presence of brown-green pleural fluid and necrosis of esophageal tissue. The area of necrosis was situated 4 cm on the oral side of the anastomosis, with greater necrosis of the right than left side. There was no evidence of necrosis of the gastric tube. The necrotic residual esophagus was excised and reconstructed, as an external fistula on the left side of the neck. On day 38, after the second surgery, reconstruction of the esophageal conduit and gastric tube, via the jejunum, was performed. At 7 months after discharge, the patient was symptom free, with no evidence of cancer recurrence.\n\nresidual esophageal necrosisesophagectomyesophagogastric cancer\n==== Body\nIntroduction\nIn recent years, the frequency of esophagogastric junction cancer (EGJ) has been rapidly increasing in Europe and the United States. According to Comprehensive registry of esophageal cancer in japan 2010, the incidence of EGJ cancer is also increasing (1). The EGJ cancers are classified by Rudiger Siewert et al (2) and different types require different treatment strategies, therefore there is no established consensus on the optimal treatment.\n\nIn Europe neoadjuvant-chemoradiotherapy (neo-CRT) is the standard treatment for EGJ cancer based on the CROSS trial (3), but it is concerned that the effect of CRT is lower in adenocarcinoma than in squamous cell carcinoma.\n\nRadical esophagectomy is considered as the standard treatment for patients with esophagogastric junction (EGJ) cancer with extensive invasion of the esophagus and/or suspected metastasis to the mediastinal area. With recent advances in surgical technique and perioperative management, the rate of perioperative mortality for radical esophagectomy has been reported to be <5% (4). The latest study which based on the Japanese national clinical database reported that the overall 30-day mortality rate for open esophagectomy was 0.9%, and total surgery related mortality rate was 2.4% (5). Furthermore, it is suggested that minimally invasive esophagectomy (MIE) may be performed and may contribute to reduction of complications. However, complications during anastomosis which causes mediastinitis and empyema thoracis can led to septic shock may be severe and, thus, caution is required. Specifically, necrosis of the esophageal anastmosis reconstruction conduit after esophagectomy is a complication that carries a risk of mortality of up to 90% (6). The reconstructed conduit necrosis is rare and is only reported in <2% of primary resections with reconstruction (6). Herein, we describe the case of a patient with necrosis in the residual esophagus, rather than in the reconstructed conduit. We include our treatment and the clinical outcome.\n\nCase report\nA 66-year-old man presented to Asai Hospital (Chiba, Japan) with epigastric discomfort and symptoms of gastrointestinal obstruction. Gastrointestinal endoscopy revealed a tumor at the EGJ, which was confirmed as an adenocarcinoma on biopsy. Contrast-enhanced computed tomography (CT) was performed at our institution, which revealed a tumor extending from the lower thoracic esophagus to the EGJ, with associated swelling of the upper mediastinal lymph nodes. Based on the criteria of the International Union against Cancer Committee (UICC, 8th Edition), the clinical staging was as follows: 101R, 107, and 106 pre. There was little suspicion of lymph node metastasis owing to the small amount of accumulation observed on positron-emission tomography (PET) CT (PET-CT) imaging (Fig. 1A and B). Laboratory tests revealed abnormal values of creatinine level (1.14 mg/dl; reference range 0.65-1.07), with all other levels being within normal range. Tumor marker levels were as follows: Carcinoembryonic antigen, 4.7 ng/dl (upper reference limit, 5.0 ng/dl); carbohydrate antigen 19-9, 6.9 IU/ml (upper reference limit, 37.0 IU/ml); and cancer antigen 125, 14.5 IU/ml (upper reference limit, 35.0 IU/ml). Based on these findings, we made a clinical diagnosis of EGJ cancer, with a UICC 8th classification of cT3N1M0 c-stage-Ⅲ.\n\nIn accordance with this diagnosis, preoperative S-1 neoadjuvant chemotherapy (NAC) was implemented (oral fluoropyrimidine, containing tegafur, gimeracil, and oteracil potassium) in combination with oxaliplatin. After 3 courses of NAC, the size of the tumor was reduced, but without a clinical change in lymphadenopathy, with still little accumulation of PET-CT scans (Fig. 2). Based on these findings, we proceeded with esophagectomy, with three-field lymph node dissection and gastric tube reconstruction, via an intrathoracic route. Surgery was performed 4 weeks after the chemotherapy.\n\nWe first proceeded with cervical surgery. The right reflex nerve was identified during right cervical lymph node dissection (101R), with observation of an enlarged lymph node. Accordingly, we proceeded with bilateral dissection of the lymph nodes dissection, but with no observable evidence of lymphadenopathy on the left side. The abdominal component of the surgery was performed as per usual methods, with the stomach used to reconstruct the esophageal conduit. Following upper, middle and lower mediastinal lymphadenectomy, we proceeded with reconstruction of the gastric tube, with dissection of the right bronchial artery and azygos vein. The surgical time was 318 min, with a volume of blood loss of 210 ml.\n\nAn idiopathic pneumothorax developed on postoperative day (POD) 2, with a brown-green drainage from the chest tube. The pneumothorax was confirmed on CT imaging, but with no evidence of abnormality around the anastomosis. As the pneumothorax did not improve with conservative treatment, with persistent green drainage in the thoracic tube, we proceeded with surgical management of the pneumothorax and observation of the anastomosis (Fig. 3). On repeat thoracotomy, the continued presence of brown-green pleural fluid was confirmed, and necrosis of the esophagus was observed, after release of the belaq attached to the anastomosis. The area of necrosis was localized 4 cm on the oral side of the anastomosis, with necrotic damage being more prominent on the right than left side, but with no signs of necrosis in the gastric tube (Fig. 4).\n\nWe proceeded with excision of the residual necrotic esophagus, followed with reconstruction of an external fistula on left side of neck. The residual gastric tube was positioned under the skin, through an antethoracic route. The pneumothorax was detected in the S1 area and closed using staples.\n\nPost-surgery, the patient did not develop further complications and was discharged on POD 17 after the second surgery. On POD 38 (after the second surgery), we proceeded with reconstruction to connect the residual esophagus and gastric tube, through the jejunum. Pathological findings of the resected specimen confirmed residual adenocarcinoma at the esophagogastric junction, with the following tumor components identified: Tub1 >tub2 and >por2. The resected margin was negative. The final pathological diagnosis was ypT1aN0(0/66)M0, ypStageIA (UICC 8th). Owing to the impairment in the local circulation, necrotizing tissue was observed in the entire layer of the residual esophagus, but not in the layer of the conduit (Fig. 5A and B). At 7 months post-discharge, the patient was alive, with no evidence of cancer recurrence.\n\nDiscussion\nIt is very rare for residual esophageal necrosis to occur after esophagectomy. Although conduit necrosis after esophagectomy has previously been reported, we identified only one report regarding necrosis of the esophagus (7). Blood flow to the conduit after esophagectomy is primarily dependent on the mucosal capillary network (8). The nature of this capillary network, however, has not been clearly determined. Takemura et al (7) argued that the capillary network developed in the submucosal layer would sustain the residual esophagus, despite inclusion of the main artery along with lymph node dissection.\n\nThe following factors can contribute to necrosis of the esophageal conduit (6,9): Diabetes, hypertension, and peripheral vascular disease. However, smoking, preoperative chemotherapy, and bodyweight were not identified as contributing factors to conduit necrosis (9). The mortality rate associated with necrosis of the esophageal conduit can be as high as 90% (6). We note that the patient in the case study reported by Takemura et al (7), had a history of myocardial infarction and vascular disease-factors that were not present in our case. The factors that cause necrosis remain unknown in this patient.\n\nAcute ischemic necrosis of the esophagus is possible, as occurs in bowel disease, although the etiology of this acute necrosis is different in the esophagus and bowel. Necrosis of the esophagus (also known as black esophagus) is very rare, with a prevalence of 0.2% in autopsy data (10). The etiology of black esophagus is associated with risk factors for atherosclerosis (such as hypertension, diabetes, and ageing) or diabetic ketoacidosis, as well as multiple organ dysfunction and sepsis (11). However, none of these factors were identified in our case. As such, it is likely that performance of the surgical anastomosis itself was the cause of esophageal necrosis in our case.\n\nThe enlarged right lymph node (101R) was strongly adherent to the wall of the esophagus. Therefore, the possibility of direct invasion of the cancer into the esophageal wall could not be ruled out. During dissection, the muscle layer of the esophagus was excised. Once the 101 lymph nodes were dissected, the cervical esophagus was excised from the surrounding area and released, which differed from traditional cervical dissection and esophagectomy. We do note that this caused a disruption of the local blood flow to the right side of the esophageal wall. Takemura et al (7) reported that the length of the residual esophagus might be one of the causes of necrosis, but the length of residual esophagus in our case was normal. Although it remains unclear what caused necrosis of the residual esophagus in our case, it is possible that the wide anastomosis, which extended into the cervical area, might be an important factor to consider.\n\nResidual esophageal necrosis after esophagectomy is very rare and the possible causative factors remain to be fully clarified. Based on our experience, extensive dissection of the cervical esophagus area might be a contributing factor, due to a deterioration of the local blood flow.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors' contributions\nST and IH designed the study and wrote the initial draft of the manuscript. IH, NT, AI, HS, TT, HG, YN and MO contributed to design and assisted in the preparation of the manuscript. All other authors have contributed to data collection and interpretation, and critically reviewed the manuscript. All authors approved the final version of the manuscript, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nEthics approval and consent to participate\nThis study was approved by the Institutional Ethics Review Board of the Chiba Cancer Center (H29-262) (Chiba, Japan).\n\nPatient consent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. Images before chemotherapy. (Aa) Computed tomography revealed a tumor extending from the lower thoracic esophagus to the esophagogastric junction. (Ab) Swelling of the upper mediastinal lymph nodes. (B) As there was little evidence of accumulation in the lymph nodes, the likelihood of lymph node metastasis was deemed to be low.\n\nFigure 2. After 3 courses of NAC, there was little accumulation in the lymph nodes. NAC, neoadjuvant chemotherapy.\n\nFigure 3. Images after the radical esophagectomy. (A) Computed tomography revealed a pneumothorax in right side. (B) There was no observable abnormality around the anastomosis.\n\nFigure 4. Necrosis of the esophagus, situated 4 cm of the oral side of the anastomosis. Greater damage was observed on the right compared with the left esophagus, with no evidence of necrosis of the gastric tube.\n\nFigure 5. Pathological findings. (Aa) Resected specimen of the adenocarcinoma at the esophagogastric junction. (Ab) Resected specimen after second operation. Necrosis of residual esophagus was observed in right side. (B) Necrotizing tissue was observed through the entire layer of the residual esophagus (black arrow), with no evidence of necrosis in layers of the reconstructed conduit.\n==== Refs\nReferences\n1 Tachimori Y Ozawa S Numasaki H Ishihara R Matubara H Muro K Oyama T Toh Y Udagawa H Uno T Comprehensive registry of esophageal cancer in Japan 2010 Esophagus 14 189 214 2017 10.1007/s10388-017-0578-4 28725168 \n2 Rudiger Siewert J Feith M Werner M Stein HJ Adenocarinoma of the esophagogastric junction: Results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients Ann Surg 232 353 3361 2000 10.1097/00000658-200009000-00007 10973385 \n3 van Hagen P Hulshof MC van Lanschot JJ Steyerberg EW van Berge Henegouwen MI Wijnhoven BP Richel DJ Nieuwenhuijzen GA Hospers GA Bonenkamp JJ Preoperative chemoradiotherapy for esophageal or junctional cancer N Engl J Med 366 2074 2084 2012 10.1056/NEJMoa1112088 22646630 \n4 Lerut T Coosemans W Decker G De Leyn P Nafteux P Van Raemdonck D Anastomotic complications after esophagectomy Dig Surg 19 92 98 2002 10.1159/000052018 11978992 \n5 Yoshida N Yamamoto H Baba H Miyata H Watanabe M Toh Y Matubara H Kakeji Y Seto Y Can minimally invasive esophagectomy replace open esophagectomy for esophageal cancer? Latest analysis of 24,233 esophagectomies from the Japanese national clinical database. Ann Surg, 2019 [Epub ahead of print] \n6 Dickinson KJ Blackmon SH Management of conduit necrosis following esophagectomy Thorac Surg 25 461 470 2015 10.1016/j.thorsurg.2015.07.008 26515946 \n7 Takemura M Fujiwara Y Moriura K Hori T A case of residual esophageal necrosis after lower esophagectomy for early esophageal cancer J Jap College Surgeons (Nihon Gekakei Rengo Gakkaishi) 36 612 616 2011 10.4030/jjcs.36.612 \n8 Liebermann-Meffert DM Meier R Siewert JR Vascular anatomy of the gastric tube used for esophageal reconstruction Ann Thorac Surg 54 1110 1115 1992 10.1016/0003-4975(92)90077-h 1449294 \n9 Urschel JD Esophagogastrostomy anastomotic leaks complicating esophagectomy: A review Am J Surg 169 634 640 1995 10.1016/s0002-9610(99)80238-4 7771633 \n10 Gurvits GE Black esophagus: Acute esophageal necrosis syndrome World J Gastroenterol 16 3219 3225 2010 10.3748/wjg.v16.i26.3219 20614476 \n11 Gurvitis GE Shapsis A Lau N Gualtieri N Robilotti JG Acute esophageal necrosis: A rare syndrome J Gastroenterol 42 29 38 2007 10.1007/s00535-006-1974-z 17322991\n\n",
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"issue": "12(4)",
"journal": "Molecular and clinical oncology",
"keywords": "esophagectomy; esophagogastric cancer; residual esophageal necrosis",
"medline_ta": "Mol Clin Oncol",
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"nlm_unique_id": "101613422",
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"title": "Residual esophageal necrosis after radical esophagectomy for esophagogastric cancer: A case report.",
"title_normalized": "residual esophageal necrosis after radical esophagectomy for esophagogastric cancer a case report"
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{
"abstract": "BACKGROUND\nRecurrent hyperparathyroidism is difficult to manage due to the difficulty in finding the missing adenoma. Herein we present a case of recurrent hyperparathyroidism from ectopic adenomas which basic investigations failed to locate but were finally localized by a 4DCT following selective venous sampling (SVS) of parathyroid hormone (PTH).\n\n\nMETHODS\nA young female presented with recurrent hyperparathyroidism. She had severe primary hyperparathyroidism and temporary normocalcemia after first parathyroidectomy. Her hypercalcemia recurred and required second operation. However, the second operation was unsuccessful due to the pre-operation ultrasound, computed tomography (CT) neck, and sestamibi failed to identify the culprit parathyroid adenoma. After the second operation, positron emission tomography (PET), CT neck and sestamibi failed to identify the tumor but a sequence of SVS PTH and four-dimensional computed tomography (4DCT) successfully identified several ectopic adenomas.\n\n\nCONCLUSIONS\nEctopic parathyroid tissue is the most common cause of recurrent hyperparathyroidism but precisely locating these ectopic glands is often challenging. Despite modern modalities such as PET scans, the success rate is not impressive. SVS PTH is a good method to regionalize the ectopic source of PTH. With the more specified area, fine-tuning imaging with a 4DCT can identify the specific location of the ectopic parathyroid tissue.\n\n\nCONCLUSIONS\nA sequence of SVS PTH followed by 4DCT could identify the exact location of ectopic parathyroid adenomas in a patient when conventional non-invasive imaging studies failed.",
"affiliations": "Endocrinology and Metabolism Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Thailand.;Endocrinology and Metabolism Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Thailand. Electronic address: rattanaleelawattana@gmail.com.",
"authors": "Suntornlohanakul|Onnicha|O|;Leelawattana|Rattana|R|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2020.04.021",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30213-3\n10.1016/j.ijscr.2020.04.021\nArticle\nA case report of successful identification of ectopic parathyroid adenomas with a sequence of selective parathyroid venous sampling and 4D-computed tomography in a patient with recurrent hyperparathyroidism\nSuntornlohanakul Onnicha Leelawattana Rattana rattanaleelawattana@gmail.com⁎ Endocrinology and Metabolism Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Thailand\n⁎ Corresponding author at: Endocrinology and Metabolism Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, 15 Karnjanavanich Road, Hat Yai, Songkhla, 90110, Thailand. rattanaleelawattana@gmail.com\n07 5 2020 \n2020 \n07 5 2020 \n71 183 186\n7 2 2020 24 3 2020 9 4 2020 © 2020 The Author(s)2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Ectopic parathyroid adenoma is a common cause of recurrent hyperparathyroidism.\n\n• Identification of the ectopic parathyroid adenoma is the key to successful treatment.\n\n• A sequence of PTH venous sampling followed by 4DCT found ectopic parathyroid adenomas when other investigations failed.\n\n\n\nIntroduction\nRecurrent hyperparathyroidism is difficult to manage due to the difficulty in finding the missing adenoma. Herein we present a case of recurrent hyperparathyroidism from ectopic adenomas which basic investigations failed to locate but were finally localized by a 4DCT following selective venous sampling (SVS) of parathyroid hormone (PTH).\n\nPresentation of case\nA young female presented with recurrent hyperparathyroidism. She had severe primary hyperparathyroidism and temporary normocalcemia after first parathyroidectomy. Her hypercalcemia recurred and required second operation. However, the second operation was unsuccessful due to the pre-operation ultrasound, computed tomography (CT) neck, and sestamibi failed to identify the culprit parathyroid adenoma. After the second operation, positron emission tomography (PET), CT neck and sestamibi failed to identify the tumor but a sequence of SVS PTH and four-dimensional computed tomography (4DCT) successfully identified several ectopic adenomas.\n\nDiscussion\nEctopic parathyroid tissue is the most common cause of recurrent hyperparathyroidism but precisely locating these ectopic glands is often challenging. Despite modern modalities such as PET scans, the success rate is not impressive. SVS PTH is a good method to regionalize the ectopic source of PTH. With the more specified area, fine-tuning imaging with a 4DCT can identify the specific location of the ectopic parathyroid tissue.\n\nConclusion\nA sequence of SVS PTH followed by 4DCT could identify the exact location of ectopic parathyroid adenomas in a patient when conventional non-invasive imaging studies failed.\n\nKeywords\nCase reportRecurrent primary hyperparathyroidismEctopic parathyroid gland4D-computed tomographySelective parathyroid venous sampling\n==== Body\n1 Introduction\nParathyroidectomy is the standard treatment for primary hyperparathyroidism with a good success rate [1]. If hypercalcemia presents within 6 months after the operation, persistent hyperparathyroidism is diagnosed, while recurrent hyperparathyroidism is defined as hypercalcemia which recurs after 6 months post-parathyroidectomy with some period of normocalcemia [2]. These 2 conditions occur in only 2.5–5% of cases [3]. The major risks of recurrent or persistent hyperparathyroidism are multiple gland disease and ectopic parathyroid gland [2,3].\n\nHerein, we present a case of recurrent hyperparathyroidism who failed two parathyroidectomies including a total thyroidectomy and thymectomy in our university hospital, but normal non-invasive imaging failed to locate the ectopic and supranumerical glands, which were finally located by a sequence of selective venous sampling (SVS) of parathyroid hormone (PTH) and four-dimensional computed tomography (4DCT).\n\nThis case is reported in accordance with the surgical case report (SCARE) guidelines [4].\n\n2 Case presentation\nA young female presented with a fragility fracture. She had unremarkable family and other medical history. Her serum calcium and PTH levels were 15.2 mg/dl and 1304 pg/mL, respectively, and she was diagnosed as primary hyperparathyroidism, which fulfilled the indications of parathyroidectomy. An ultrasound revealed a left parathyroid nodule and 99mTC-sestamibi revealed 2 functioning parathyroid nodules, one below the left lobe and the other behind the right lobe of the thyroid gland. A parathyroidectomy was done, removing 2 glands with an isthmectomy and left thyroid lobectomy. Intraoperatively, the main findings were left inferior and right superior parathyroid adenomas. The PTH levels dropped from 1212 at the beginning of the operation to 169.9 at 10 min and 15.84 pg/mL at 24 h post-removal. She also developed hungry bone syndrome after the operation. A histopathological study confirmed a left parathyroid adenoma and right parathyroid gland.\n\nDuring follow up, her hungry bone syndrome gradually improved, requiring no calcium and vitamin D and the serum calcium rose to 11.7 mg/dl with high serum PTH level of 147 pg/mL at 18 months after the surgery, indicating recurrent hyperparathyroidism. At that time, an ultrasound and 99mTC-sestamibi did not reveal any abnormalities. A CT of the chest including neck showed 2 suspicious nodules in the left thyroid bed, and a second parathyroidectomy was performed. Intraoperatively, there were possible left and right parathyroid glands which were removed together with the remaining thyroid gland and the thymus. However, the PTH levels did not decline after the operation. Histopathology revealed only a left parathyroid gland without other parathyroid tissues identified. The patient remained hypercalcemic (Fig. 1). An SVS PTH was performed, which indicated that the lesion was in the area of the left brachiocephalic vein (Fig. 2). After biochemical localization, anatomical localization methods (CT chest including neck, 99mTC-sestamibi and positron emission tomography (PET) scan) all failed to identify the precise location of the lesions. She was lost to follow up.Fig. 1 Serum calcium (mg/dl) and PTH levels (pg/mL) during the course of her illness.\n\nFig. 1Fig. 2 Nonenhanced phase (A), arterial phase (B) and delayed phase (C) axial images of the ectopic parathyroid adenoma (arrow). Results of PTH levels (pg/mL) from selective parathyroid venous sampling in each vein (D).\n\nFig. 2\n\nOne year after the second operation, she experienced a hypercalcemic crisis which resisted bisphosphonate and cinacalcet and finally required hemodialysis. A third operation was necessary, and a 4DCT of the neck was performed which revealed 2 parathyroid tissue lesions, one at the left lower neck near the left strap muscle just superomedial to the left internal jugular-brachiocephalic vein, and the other superomedial to the first (Fig. 2). This imaging study guided the surgeon to explore the left jugular area and the intraoperative findings revealed one nodule in the left carotid sheath near the ipsilateral strap muscle, and a second nodule inferomedially to the first and a nearby lymph node. All masses were removed and ten minutes later her PTH had dropped from a pre-operative level of 1904 to 234.3 pg/mL. Her serum calcium levels decreased significantly and she developed hungry bone syndrome (Fig. 1). The histopathology reported that all masses including the tissue suspected to be a lymph node were parathyroid hyperplasias.\n\n3 Discussion\nRecurrent hyperparathyroidism is rare and has no specific guideline for management but there is a suggestion to apply the recommendations for primary hyperparathyroidism as if for a naïve patient with higher thresholds due to the difficulties of re-operation [2]. Our patient originally presented with a fragility fracture with marked hypercalcemia and had surgery. Although the first surgery was successful and she developed hungry bone syndrome, her hypercalcemia recurred. This case demonstrates that hungry bone syndrome occurring after an operation does not reliably predict the long term remission of primary hyperparathyroidism.\n\nPatients with recurrent hyperparathyroidism usually have an underlying cause or causes such as multigland pathology, ectopic parathyroid gland or residual hyperfunctioning parathyroid tissues such as parathyromatosis or parathyroid carcinoma [2,3]. Multigland pathology and ectopic parathyroid gland are the two most common causes of recurrent hyperparathyroidism, therefore pre-operative localization is necessary. The method of localization can be invasive or non-invasive. Most physicians use a stepwise approach from non-invasive to invasive tests. The non-invasive tests are ultrasound, 99mTC-sestamibi, sestamibi-SPECT with CT, CT (preferably 4DCT) and PET with CT. Among conventional imaging studies, 99mTC-sestamibi and ultrasound are the main modalities. The 99mTC-sestamibi provides the best sensitivity (65–67%) compared with CT [5]. The 4DCT and PET with CT are emerging modalities which provide higher sensitivity than ultrasound or 99mTC-sestamibi. Although a 4DCT which shows an avid enhancement of parathyroid tissue in the arterial phase followed by a rapid washout has a sensitivity of 79.3% in detecting parathyroid lesions [6], there are some limitations to the test such as an increased number of contrast-enhanced phases, and it is only suitable for a small region of interest due to the rapid wash-out of the contrast, typically only 70–90 seconds after contrast injection [7]. In studies including patients with multigland disease, the sensitivities of the 4DCT for detecting multigland disease were only 32% [8] and 58% [6] and the sensitivities of 99mTC-sestamibi were 0 [8] and 31% [6], while that of ultrasound was 13.6% [8]. These studies show that non-invasive tests have limitations in their usefulness in localization of hard-to-find lesions.\n\nInvasive testing is required when non-invasive tests give negative or discordant results. The invasive tests are selective arteriography and SVS PTH. SVS PTH is a procedure that measures the PTH in each cervical vein and compares the values between each area. The procedure has been reported to have 75–94.7% sensitivity in detecting the specific area of ectopic parathyroid tissue in recurrent or persistent hyperparathyroidism [9]. However, SVS PTH requires clinical expertise and can be confounded by distortions and variations in the venous drainage. In our case, the SVS PTH guided the surgeon only to the left brachiocephalic area, including the mediastinum and along the carotid artery, which is much too large an area to attempt to find small lesions. With additional information from a 4DCT, we were able to precisely pin point the lesions as being in the left jugular area, which allowed the surgeon to successfully identify the ectopic parathyroid lesions. The combination of 4DCT followed by SVS PTH was studied in a series of recurrent hyperparathyroidism cases and found a sensitivity of 95% compared with 50% in 4DCT alone [10]. Most earlier studies began with non-invasive tests followed by SVS PTH, thus data on the use of SVS PTH followed by 4DCT are limited. Our case describes the approach of using SVS PTH followed by 4DCT in identifying ectopic supranumerical parathyroid glands. When the 4DCT is used in a small area identified by SVS PTH, the rate of successfully localizing ectopic parathyroid tissue should increase. Given our patient’s condition of having supranumerical parathyroid disease and the aggressiveness of disease activity, she will require lifelong monitoring.\n\n4 Conclusion\nRecurrent hyperparathyroidism is difficult to treat. Precise pre-operative localization is required to detect ectopic parathyroid lesions. We report a patient whose conventional non-invasive imaging studies failed to identify the precise location of the lesions, but the sequence of SVS PTH followed by 4DCT accurately identified the ectopic and supranumerical glands.\n\nDeclaration of Competing Interest\nNone relates to this report.\n\nFunding\nNone.\n\nEthical approval\nThis case report is approved by the Ethics committee of the Faculty of Medicine, Prince of Songkla University.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nOnnicha Suntornlohanakul: Conceptualization, Writing - Original draft preparation, Writing - Review & Editing.\n\nRatttana leelawattana: Conceptualization, Writing- Review & Editing.\n\nRegistration of research studies\nNot related.\n\nGuarantor\nRattana Leelawattana.\n\nProvenance and peer review\nEditorially reviewed, not externally peer-reviewed.\n==== Refs\nReferences\n1 Bilezikian J.P. Primary hyperparathyroidism J. Clin. Endocrinol. Metab. 103 2018 3993 4004 10.1210/jc.2018-01225 30060226 \n2 Udelsman R. Approach to the patient with persistent or recurrent primary hyperparathyroidism J. Clin. Endocrinol. Metab. 96 2011 2950 2958 10.1210/jc.2011-1010 21976743 \n3 Guerin C. Paladino N.C. Lowery A. Castinetti F. Taieb D. Sebag F. Persistent and recurrent hyperparathyroidism Updates Surg. 69 2017 161 169 10.1007/s13304-017-0447-7 28434176 \n4 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A.J. Orgill D.P. SCARE Group The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 10.1016/j.ijsu.2018.10.028 30342279 \n5 Parikh A.M. Suliburk J.W. Morón F.E. Imaging localization and surgical approach I.N. the management of ectopic parathyroid adenomas Endocr. Pract. 24 2018 589 598 10.4158/EP-2018-0003 29949431 \n6 Yeh R. Tay Y.-K.D. Tabacco G. Dercle L. Kuo J.H. Bandeira L. McManus C. Leung D.K. Lee J.A. Bilezikian J.P. Diagnostic performance of 4D CT and sestamibi SPECT/CT in localizing parathyroid adenomas in primary hyperparathyroidism Radiology 291 2019 469 476 10.1148/radiol.2019182122 30835187 \n7 Hoang J.K. Sung W. Bahl M. Phillips C.D. How to perform parathyroid 4D CT: tips and traps for technique and interpretation Radiology 270 2014 15 24 10.1148/radiol.13122661 24354373 \n8 Kukar M. Platz T.A. Schaffner T.J. Elmarzouky R. Groman A. Kumar S. Abdelhalim A. Cance W.G. The use of modified four-dimensional computed tomography in patients with primary hyperparathyroidism: an argument for the abandonment of routine sestamibi Single-Positron Emission Computed Tomography (SPECT) Ann. Surg. Oncol. 22 2015 139 145 10.1245/s10434-014-3940-y 25074663 \n9 Yamada T. Ikuno M. Shinjo Y. Hiroishi A. Matsushita S. Morimoto T. Kumano R. Yagihashi K. Katabami T. Selective venous sampling for primary hyperparathyroidism: how to perform an examination and interpret the results with reference to thyroid vein anatomy Jpn. J. Radiol. 35 2017 409 416 10.1007/s11604-017-0658-3 28639211 \n10 Ginsburg M. Christoforidis G.A. Zivin S.P. Obara P. Wroblewski K. Angelos P. Grogan R.H. Kaplan E.L. Adenoma localization for recurrent or persistent primary hyperparathyroidism using dynamic four-dimensional CT and venous sampling J. Vasc. Interv. Radiol. 26 2015 79 86 10.1016/j.jvir.2014.09.019 25454737\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2210-2612",
"issue": "71()",
"journal": "International journal of surgery case reports",
"keywords": "4D-computed tomography; Case report; Ectopic parathyroid gland; Recurrent primary hyperparathyroidism; Selective parathyroid venous sampling",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "183-186",
"pmc": null,
"pmid": "32464540",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "24354373;30060226;30342279;29949431;25454737;28434176;30835187;21976743;28639211;25074663",
"title": "A case report of successful identification of ectopic parathyroid adenomas with a sequence of selective parathyroid venous sampling and 4D-computed tomography in a patient with recurrent hyperparathyroidism.",
"title_normalized": "a case report of successful identification of ectopic parathyroid adenomas with a sequence of selective parathyroid venous sampling and 4d computed tomography in a patient with recurrent hyperparathyroidism"
} | [
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"companynumb": "TH-AMGEN-THASP2020096753",
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"actiondrug": "5",
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"activesubstancename": "CINACALCET HYDROCHLORIDE"
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{
"abstract": "Human granulocytic anaplasmosis (HGA), caused by Anaplasma phagocytophilum, is an emerging tick-borne disease. It is spread by the black-legged deer tick Ixodes scapularis that serves as the vector for six human pathogens. HGA is still rarely reported in solid organ transplant recipients. In solid organ transplant recipients, orchitis has been reported secondary to chickenpox, tuberculosis and infections due to Listeria monocytogenes and Nocardia asteroides. Orchitis as a presenting feature of HGA infection has only been reported in animals. We present a unique case of a renal transplant recipient with HGA that presented as orchitis. We also compare the clinical presentation and laboratory findings of our patient with other cases of HGA in transplant recipients. To the best of our knowledge, our patient is one of the first cases of A phagocytophilum mono-infection causing a classical presentation of orchitis in a transplant patient.",
"affiliations": "Department of Internal Medicine, New York Medical College at Westchester Medical Center, Valhalla, New York.;Department of Internal Medicine, New York Medical College at Westchester Medical Center, Valhalla, New York.;Department of Internal Medicine, New York Medical College at Westchester Medical Center, Valhalla, New York.;Department of Microbiology, Virology & Molecular Diagnostics, New York Medical College at Westchester Medical Center, Valhalla, New York.;Department of Transplant Infectious Diseases, New York Medical College at Westchester Medical Center, Valhalla, New York.;Department of Transplant Infectious Diseases, New York Medical College at Westchester Medical Center, Valhalla, New York.;Department of Transplant Infectious Diseases, New York Medical College at Westchester Medical Center, Valhalla, New York.",
"authors": "Khatri|Akshay|A|https://orcid.org/0000-0001-5821-048X;Lloji|Amanda|A|;Doobay|Richard|R|;Wang|Guiqing|G|;Knoll|Bettina|B|;Dhand|Abhay|A|https://orcid.org/0000-0003-3527-1938;Nog|Rajat|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13129",
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"issn_linking": "1398-2273",
"issue": "21(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nAnaplasma phagocytophilum\n; HGA; human granulocytic anaplasmosis; orchitis; renal transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D041081:Anaplasma phagocytophilum; D000712:Anaplasmosis; D000818:Animals; D000900:Anti-Bacterial Agents; D004318:Doxycycline; D006801:Humans; D018884:Ixodes; D016030:Kidney Transplantation; D008297:Male; D009920:Orchitis; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13129",
"pmc": null,
"pmid": "31215144",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Anaplasma phagocytophilum presenting with orchitis in a renal transplant recipient.",
"title_normalized": "anaplasma phagocytophilum presenting with orchitis in a renal transplant recipient"
} | [
{
"companynumb": "US-TEVA-2019-US-1115565",
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"activesubstancename": "LEVOTHYROXINE"
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"abstract": "OBJECTIVE\nNail change after chemotherapy is relatively unfamiliar with gynecological oncologist. It often occurs after docetaxel treatment. For gynecological tract cancers, paclitaxel might be most frequently used but nail change after paclitaxel treatment is seldom reported before.\n\n\nMETHODS\nTwo patients treated with the postoperative dose-dense weekly schedule of paclitaxel 80 mg/m2 plus cisplatin 20 mg/m2 every three weeks were complicated with nail problems during the treatment. They included onycholysis, subungual hemorrhage, proximal white subungual collections of pus obscuring the lunula (onychophosis), dystrophy, Beau's lines, pigmentation, and melanonychia. Topical use of anti-fugal cream and oral antibiotics stopped the nail disease progression and both patients had completed their chemotherapy without interruption.\n\n\nCONCLUSIONS\nClinicians should be aware of paclitaxel-induced nail toxicities. Adequate information, detailed preventive intervention, and early use of prophylactic and/or therapeutic agents to minimize the occurrence of severe morbidity, such as cellulitis and subsequent sepsis is important for women who need the continuous dose-dense paclitaxel chemotherapy.",
"affiliations": "Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan.;Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. Electronic address: phwang@vghtpe.gov.tw.",
"authors": "Yang|Szu-Ting|ST|;Cheng|Min|M|;Lee|Na-Rong|NR|;Chang|Wen-Hsun|WH|;Lee|Yi-Le|YL|;Wang|Peng-Hui|PH|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.tjog.2019.07.023",
"fulltext": null,
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"issn_linking": "1028-4559",
"issue": "58(5)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "Dermatological problems; Dose-dense chemotherapy; Nail; Paclitaxel",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000972:Antineoplastic Agents, Phytogenic; D002277:Carcinoma; D005260:Female; D006801:Humans; D008875:Middle Aged; D009260:Nail Diseases; D010051:Ovarian Neoplasms; D017239:Paclitaxel",
"nlm_unique_id": "101213819",
"other_id": null,
"pages": "709-711",
"pmc": null,
"pmid": "31542098",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paclitaxel-related nail toxicity.",
"title_normalized": "paclitaxel related nail toxicity"
} | [
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"occurcountry": "TW",
"patient": {
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CISPLATIN"
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"drugadditional": null,
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{
"abstract": "OBJECTIVE\nConventional acidic nonsteroidal anti-inflammatory drugs frequently cause small bowel inflammation. Diagnosis is largely based on assay of surrogate markers of inflammation in stool, such as fecal calprotectin. However, stool markers are not widely available and the precise nature of this inflammation is uncertain. We used wireless capsule enteroscopy to quantitate and assess the nature of the small bowel damage caused by nonsteroidal anti-inflammatory drugs when taken on a short-term basis.\n\n\nMETHODS\nForty healthy volunteers underwent a baseline capsule enteroscopy and fecal calprotectin test. After taking diclofenac slow-release 75 mg twice a day (with omeprazole 20 mg twice a day for gastroprotection) for a total of 14 days, both investigations were repeated.\n\n\nRESULTS\nAfter drug treatment, 30 subjects (75%) had increased repeat fecal calprotectin concentrations above the upper limit of normal. Capsule enteroscopy showed new pathology in 27 subjects (68%). The commonest lesions were mucosal breaks, seen in 16 (40%), which were seen to be bleeding in 2 (5%); reddened folds in 14 (35%); petechiae or red spots in 13 (33%); denuded mucosa in 8 (20%); and blood in the lumen without a visualized source in 3 (8%). Fifteen of the 27 subjects had more than one lesion concurrently.\n\n\nCONCLUSIONS\nThis study provides both biochemical and direct evidence of macroscopic injury to the small intestine in 68%-75% of volunteers resulting from 2 weeks' ingestion of slow-release diclofenac.",
"affiliations": "Department of Medicine, Guy's, King's, St Thomas' Medical School, London, England. lpmaiden@doctors.net.uk",
"authors": "Maiden|Laurence|L|;Thjodleifsson|Bjarni|B|;Theodors|Asgeir|A|;Gonzalez|Juan|J|;Bjarnason|Ingvar|I|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D003692:Delayed-Action Preparations; D039841:Leukocyte L1 Antigen Complex; D004008:Diclofenac; D009853:Omeprazole",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2005.03.020",
"fulltext": null,
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"issn_linking": "0016-5085",
"issue": "128(5)",
"journal": "Gastroenterology",
"keywords": null,
"medline_ta": "Gastroenterology",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D003692:Delayed-Action Preparations; D004008:Diclofenac; D020776:Endoscopes, Gastrointestinal; D005243:Feces; D005260:Female; D006801:Humans; D007410:Intestinal Diseases; D007413:Intestinal Mucosa; D007421:Intestine, Small; D039841:Leukocyte L1 Antigen Complex; D008297:Male; D008875:Middle Aged; D009853:Omeprazole",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "1172-8",
"pmc": null,
"pmid": "15887101",
"pubdate": "2005-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy.",
"title_normalized": "a quantitative analysis of nsaid induced small bowel pathology by capsule enteroscopy"
} | [
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"companynumb": "PHBS2009GB00985",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "We observed fluoroquinolone treatment failures in 2 men with Mycoplasma genitalium-positive non-gonococcal urethritis in Japan. A fluoroquinolone regimen of sitafloxacin 100 mg twice daily for 7 days failed to eradicate M. genitalium. In both cases, M. genitalium had fluoroquinolone resistance-associated amino acid changes both in GyrA and ParC and a macrolide resistance-associated mutation in the 23S rRNA gene. The emergence of such multi-drug resistant strains can threaten antimicrobial chemotherapy for M. genitalium infections in Japan, because we will lose the first- (azithromycin) and second-line (sitafloxacin) antimicrobial agents to treat M. genitalium infections. We prescribed an extended minocycline regimen of minocycline 100 mg twice daily for 14 days for our patients, and the regimen was successful in eradicating the M. genitalium. The extended minocycline regimen might be an option that we can try when treating multi-drug resistant M. genitalium infections in clinical practice.",
"affiliations": "Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan. Electronic address: deguchit@gifu-u.ac.jp.;iClinic, 5-9-6 Naga-machi, Taihaku-ku, Sendai 982-0011, Japan.;Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.;Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1194, Japan.",
"authors": "Deguchi|Takashi|T|;Ito|Shin|S|;Yasuda|Mitsuru|M|;Kondo|Hiromi|H|;Yamada|Yoshiteru|Y|;Nakane|Keita|K|;Mizutani|Kosuke|K|;Tsuchiya|Tomohiro|T|;Yokoi|Shigeaki|S|;Nakano|Masahiro|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C076246:sitafloxacin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D008911:Minocycline",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2017.03.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "23(9)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Fluoroquinolone; GyrA; Mycoplasma genitalium; ParC; Sitafloxacin",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents; D027081:DNA Gyrase; D004252:DNA Mutational Analysis; D027101:DNA Topoisomerase IV; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D009175:Mycoplasma Infections; D045704:Mycoplasma genitalium; D012189:Retrospective Studies; D014526:Urethritis",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "648-650",
"pmc": null,
"pmid": "28462860",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Emergence of Mycoplasma genitalium with clinically significant fluoroquinolone resistance conferred by amino acid changes both in GyrA and ParC in Japan.",
"title_normalized": "emergence of mycoplasma genitalium with clinically significant fluoroquinolone resistance conferred by amino acid changes both in gyra and parc in japan"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1061969",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": ... |
{
"abstract": "Acute Intermittent Porphyria (AIP) is a rare inherited autosomal dominant disorder of heme biosynthesis. Porphyria-associated kidney disease occurs in more than 50% of the patients with AIP, and end stage renal disease (ESRD) can be a devastating complication for AIP patients. The outcomes of AIP patients after kidney transplantation are poorly known.\n\n\n\nWe examined the outcomes of 11 individuals with AIP, identified as kidney transplant recipients in the French Porphyria Center Registry.\n\n\n\nAIP had been diagnosed on average 19 years before the diagnosis of ESRD except for one patient in whom the diagnosis of AIP had been made 5 years after the initiation of dialysis. Median follow-up after transplantation was 9 years. A patient died 2 months after transplantation from a cardiac arrest and a patient who received a donation after cardiac death experienced a primary non-function. No rejection episode and no noticeable adverse event occurred after transplantation. Serum creatinine was on average 117 μmol/l, and proteinuria <0.5 g/l in all patients at last follow up. All usually prescribed drugs after transplantation are authorized except for trimethoprim/sulfamethoxazole. Critically, acute porphyria attacks almost disappeared after kidney transplantation, and skin lesions resolved in all patients.\n\n\n\nKidney transplantation is the treatment of choice for AIP patients with ESRD and dramatically reduces the disease activity.",
"affiliations": "Nephrology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris University, France.;French Porphyria Center, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes and Research Center on Inflammation, INSERM U1149, Paris University, France.;Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France.;Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot University Hospital, Lyon, France.;Nephrology and Transplantation Department, University Hospital, Strasbourg, France.;Nephrology and Transplantation Department, University Hospital, Strasbourg, France.;Nephrology, Dialysis and Transplantation Department, CHU Nancy, Nancy, France.;Nephrology, Dialysis and Transplantation Department, Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, CIC-P 1414 (Centre d'investigation clinique), F-35000 Rennes, France.;Nephrology, Dialysis, Transplantation Department, CHU Cote de Nacre, Caen University, Caen, France.;Nephrology, Dialysis and Transplantation Department, CHU Besançon, Besançon, France.;Nephrology, Dialysis and Renal Transplantation Department, Hospital Foch, Suresnes, France.;French Porphyria Center, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes and Research Center on Inflammation, INSERM U1149, Paris University, France.;Nephrology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris University, France.;French Porphyria Center, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes and Research Center on Inflammation, INSERM U1149, Paris University, France.;French Porphyria Center, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes and Research Center on Inflammation, INSERM U1149, Paris University, France.;French Porphyria Center, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes and Research Center on Inflammation, INSERM U1149, Paris University, France.;Nephrology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris University, France; Clinical Chemistry Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris University, Paris, France. Electronic address: nicolas.pallet@aphp.fr.",
"authors": "Lazareth|Helene|H|;Talbi|Neila|N|;Kamar|Nassim|N|;Levi|Charlène|C|;Moulin|Bruno|B|;Caillard|Sophie|S|;Frimat|Luc|L|;Chemouny|Jonathan|J|;Chatelet|Valérie|V|;Vachey|Clément|C|;Snanoudj|Renaud|R|;Lefebvre|Thibaud|T|;Karras|Alexandre|A|;Gouya|Laurent|L|;Schmitt|Caroline|C|;Puy|Hervé|H|;Pallet|Nicolas|N|",
"chemical_list": "D006418:Heme",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ymgme.2020.08.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1096-7192",
"issue": "131(1-2)",
"journal": "Molecular genetics and metabolism",
"keywords": "Acute Intermittent Porphyria; Aminolevulinic acid; Chronic kidney disease; End-stage renal disease; Kidney transplantation; Porphobilinogen; Porphyria cutanea tarda; Porphyrin precursors",
"medline_ta": "Mol Genet Metab",
"mesh_terms": "D000328:Adult; D005260:Female; D006418:Heme; D006801:Humans; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D017118:Porphyria, Acute Intermittent; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9805456",
"other_id": null,
"pages": "259-266",
"pmc": null,
"pmid": "32893121",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Kidney transplantation improves the clinical outcomes of Acute Intermittent Porphyria.",
"title_normalized": "kidney transplantation improves the clinical outcomes of acute intermittent porphyria"
} | [
{
"companynumb": "FR-AMGEN-FRASP2021010493",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the incidence of renal symptoms associated with amoxicillin, a retrospective review of exposures to amoxicillin in children younger than 6 years as reported to the National Poison Data System was done.\n\n\nMETHODS\nAll ingestions of amoxicillin without coingestants in humans younger than 6 years reported to the National Poison Data System from 2004 through 2008 were analyzed. Data included age, sex, management site, outcome, symptoms, amount ingested, certainty of amount, chronicity, weight, and therapy. The study was approved by the institutional review board. Descriptive statistics were used to characterize the data.\n\n\nRESULTS\nA total of 14,717 cases were identified. Related renal symptoms occurred in 5 patients (0.03%). In 1687 patients (9.6%), the total amount (in milligrams) was documented, and the median amount ingested was 1000 mg. In patients with a known amount (in milligrams) along with the child's weight (n = 1356), the median amount was 82.6 mg/kg. In this group, 213 ingested greater than 250 mg/kg (range, 251.4-1531.1 mg/kg; median, 366.5 mg/kg). Treatment sites for this group included the following: treated in the home, 129 (60.6%); treated and released from an health care facility, 63 (29.6%); treated while admitted, 2 (0.9%); refused a referral, 7 (3.3%); lost to follow-up, 9 (4.2%); and managed at other sites, 3 (1.4%). Within this group, 94 patients (44.1%) were followed up to a definitive outcome: 77 (81.9%) had no effect, 15 (16.0%) had minor symptoms, and 2 (2.1%) had moderate symptoms.\n\n\nCONCLUSIONS\nAlthough renal toxicity may occur with amoxicillin ingestions, it is rare and does not seem to be dose related.",
"affiliations": "Pittsburgh Poison Center, University of Pittsburgh Medical Center, PA 15213, USA. mrvosr@upmc.edu",
"authors": "Mrvos|Rita|R|;Pummer|Tara L|TL|;Krenzelok|Edward P|EP|",
"chemical_list": "D000658:Amoxicillin",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0b013e31828e9e78",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "29(5)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000658:Amoxicillin; D001835:Body Weight; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006417:Hematuria; D006701:Home Nursing; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007674:Kidney Diseases; D008297:Male; D009395:Nephritis, Interstitial; D011039:Poison Control Centers; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "641-3",
"pmc": null,
"pmid": "23603656",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Amoxicillin renal toxicity: how often does it occur?",
"title_normalized": "amoxicillin renal toxicity how often does it occur"
} | [
{
"companynumb": "US-RANBAXY-2013US-70568",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": null,
... |
{
"abstract": "Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare immune-related adverse event associated with immunotherapy using immune checkpoint inhibitors for malignant tumors. A 68-year-old man had previously undergone a complete gastrectomy with regional lymph-node dissection for remnant gastric cancer, with a final diagnosis of T4aN2M1, Stage IV. Because he developed lymph-node metastases during postoperative chemotherapy using S-1 plus oxaliplatin, he was treated with ramucirumab plus nab-paclitaxel. Eight months after the operation, the patient developed multiple liver metastases and was treated with nivolumab (3 mg/kg, every 2 weeks). After four cycles of nivolumab treatment, the cortisol level decreased, and the patient reported general fatigue and appetite loss. Pituitary stimulation testing using a combination of corticotropin-releasing hormone, luteinizing hormone-releasing hormone, and thyrotropin-releasing hormone revealed markedly low ACTH and cortisol responses. Magnetic resonance imaging revealed no enlargement of the pituitary gland or thickening of the stalk. After steroid replacement therapy using hydrocortisone, the patient's symptoms of general fatigue improved. After discharge, nivolumab and steroid replacement were continued. During the subsequent 6 months, the clinical course of the patient was mostly uneventful. Abdominal computed tomography revealed a marked shrinkage of liver and lymph-node metastases, which indicated a partial response with a 95.0% decrease in target lesions compared with baseline. To the best of our knowledge, this is the first case reported in the English literature of a patient who developed isolated ACTH deficiency during nivolumab treatment for a metastatic advanced gastric cancer.",
"affiliations": "Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan. tsutomun@kochi-u.ac.jp.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.;Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.",
"authors": "Namikawa|Tsutomu|T|http://orcid.org/0000-0001-8971-404X;Shimizu|Shigeto|S|;Yokota|Keiichro|K|;Tanioka|Nobuhisa|N|;Fukudome|Ian|I|;Munekage|Masaya|M|;Uemura|Sunao|S|;Maeda|Hiromichi|H|;Kitagawa|Hiroyuki|H|;Hanazaki|Kazuhiro|K|",
"chemical_list": "D000077594:Nivolumab; D000324:Adrenocorticotropic Hormone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01384-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(4)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Adrenocorticotropic hormone; Gastric cancer; Immune checkpoint inhibitor; Nivolumab",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000309:Adrenal Insufficiency; D000324:Adrenocorticotropic Hormone; D000368:Aged; D006801:Humans; D008297:Male; D000077594:Nivolumab; D013274:Stomach Neoplasms",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "988-993",
"pmc": null,
"pmid": "33715100",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28871578;29915446;30740300;30680212",
"title": "Isolated adrenocorticotropic hormone deficiency induced by nivolumab treatment for advanced gastric cancer.",
"title_normalized": "isolated adrenocorticotropic hormone deficiency induced by nivolumab treatment for advanced gastric cancer"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-312618",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"dru... |
{
"abstract": "Rivaroxaban is a direct oral anticoagulant (DOAC) used for prophylaxis and treatment of many prothrombotic states. The anticoagulation effects of rivaroxaban are produced by selectively binding and inhibiting factor Xa, causing delayed thrombin generation. Additionally, the delay in thrombin generation produces an indirect, dose dependent antiplatelet effect via reduction in tissue factor platelet aggregation. As with any anticoagulant, rivaroxaban use increases a patient's risk for major and minor hemorrhagic events. With mortality rates reported as high as 25% for those who experience an intracranial hemorrhage (ICH), immediate mitigation of hematoma and hemorrhage volume expansion is imperative. Management strategies include utilizing prothrombin complex concentrates (PCC) and factor Xa inhibitor specific antidotes, such as coagulation factor Xa recombinant, inactivated-zhzo. Routine monitoring or management of DOAC induced antiplatelet effects is ill-defined and not a part of routine standard of care. We report the first case, to our knowledge, of rivaroxaban's indirect antiplatelet effects identified by platelet function assays and managed with four-factor PCC and desmopressin in a patient experiencing an ICH. Further exploration is needed to determine the true clinical impact attributed to rivaroxaban's antiplatelet effects.",
"affiliations": "Emergency Medicine Clinical Pharmacy Specialist, Department of Pharmacy, Wesley Medical Center, Wichita, KS, United States of America. Electronic address: brian.gilbert@wesleymc.com.;PGY-2 Critical Care Pharmacy Resident, Department of Pharmacy, Wesley Medical Center, Wichita, KS, United States of America. Electronic address: Caitlynn.tabaka@wesleymc.com.",
"authors": "Gilbert|Brian W|BW|;Tabaka|Caitlynn A|CA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2021.06.072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": null,
"journal": "The American journal of emergency medicine",
"keywords": "Antiplatelet; Coagulopathy; Factor Xa inhibitor; Intracranial hemorrhage",
"medline_ta": "Am J Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "8309942",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34244010",
"pubdate": "2021-07-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Indirect antiplatelet effects of rivaroxaban in a patient with intracranial hemorrhage: An underappreciated coagulopathy of factor Xa inhibitors?",
"title_normalized": "indirect antiplatelet effects of rivaroxaban in a patient with intracranial hemorrhage an underappreciated coagulopathy of factor xa inhibitors"
} | [
{
"companynumb": "US-JNJFOC-20210744741",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "3",
... |
{
"abstract": "Uterine leiomyosarcoma (UL) is a rare malignant tumor that develops from the uterine smooth muscle tissue. Due to the low frequency and lack of sufficient data from clinical trials there is currently no effective treatment that is routinely accepted for UL. Here we report a case of a 65-years-old female patient with metastatic UL, who progressed on ifosfamide and doxorubicin therapy and developed severe hypertensive crisis after administration of second line pazopanib, which lead to treatment termination. Rapid progression of the tumor stressed the need for the alternative treatment options. We performed RNA sequencing and whole exome sequencing profiling of the patient's biopsy and applied Oncobox bioinformatic algorithm to prioritize targeted therapeutics. No clinically relevant mutations associated with drug efficiencies were found, but the Oncobox transcriptome analysis predicted regorafenib as the most effective targeted treatment option. Regorafenib administration resulted in a complete metabolic response which lasted for 10 months. In addition, RNA sequencing analysis revealed a novel cancer fusion transcript of YWHAE gene with fusion partner JAZF1. Several chimeric transcripts for YWHAE and JAZF1 genes were previously found in uterine neoplasms and some of them were associated with tumor prognosis. However, their combination was detected in this study for the first time. Taken together, these findings evidence that RNA sequencing may complement analysis of clinically relevant mutations and enhance management of oncological patients by suggesting putative treatment options.",
"affiliations": "Medical Holding SM-Clinic, Moscow, Russia.;The Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.;World-Class Research Center \"Digital Biodesign and Personalized Healthcare\", Sechenov First Moscow State Medical University, Moscow, Russia.;The Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.;The Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.;The Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.;Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia.;Laboratory of Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.;World-Class Research Center \"Digital Biodesign and Personalized Healthcare\", Sechenov First Moscow State Medical University, Moscow, Russia.;The Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.",
"authors": "Seryakov|Alexander|A|;Magomedova|Zaynab|Z|;Suntsova|Maria|M|;Prokofieva|Anastasia|A|;Rabushko|Elizaveta|E|;Glusker|Alexander|A|;Makovskaia|Lyudmila|L|;Zolotovskaia|Marianna|M|;Buzdin|Anton|A|;Sorokin|Maxim|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.666001",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.666001\nOncology\nCase Report\nRNA Sequencing for Personalized Treatment of Metastatic Leiomyosarcoma: Case Report\nSeryakov Alexander 1\nMagomedova Zaynab 2\n\nSuntsova Maria 3\nProkofieva Anastasia 2\nRabushko Elizaveta 2\nGlusker Alexander 2\nMakovskaia Lyudmila 4\n\nZolotovskaia Marianna 5\nBuzdin Anton 3 5 6 7 *\n\nSorokin Maxim 2 5 7\n\n1Medical Holding SM-Clinic, Moscow, Russia\n2The Laboratory of Clinical and Genomic Bioinformatics, I.M. Sechenov First Moscow State Medical University, Moscow, Russia\n3World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia\n4Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia\n5Laboratory of Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia\n6Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia\n7OmicsWay Corp, Walnut, CA, United States\nEdited by: Ihab Younis, Carnegie Mellon University in Qatar, Qatar\n\nReviewed by: Chenkai Ma, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Australia; Albert Grinshpun, Hadassah-Hebrew University Medical Center, Israel; Mujeeb Zafar Banday, Government Medical College (GMC), India\n\n*Correspondence: Anton Buzdin, buzdin@oncobox.com\nThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology\n\n30 8 2021\n2021\n11 66600115 3 2021\n11 8 2021\nCopyright © 2021 Seryakov, Magomedova, Suntsova, Prokofieva, Rabushko, Glusker, Makovskaia, Zolotovskaia, Buzdin and Sorokin\n2021\nSeryakov, Magomedova, Suntsova, Prokofieva, Rabushko, Glusker, Makovskaia, Zolotovskaia, Buzdin and Sorokin\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nUterine leiomyosarcoma (UL) is a rare malignant tumor that develops from the uterine smooth muscle tissue. Due to the low frequency and lack of sufficient data from clinical trials there is currently no effective treatment that is routinely accepted for UL. Here we report a case of a 65-years-old female patient with metastatic UL, who progressed on ifosfamide and doxorubicin therapy and developed severe hypertensive crisis after administration of second line pazopanib, which lead to treatment termination. Rapid progression of the tumor stressed the need for the alternative treatment options. We performed RNA sequencing and whole exome sequencing profiling of the patient’s biopsy and applied Oncobox bioinformatic algorithm to prioritize targeted therapeutics. No clinically relevant mutations associated with drug efficiencies were found, but the Oncobox transcriptome analysis predicted regorafenib as the most effective targeted treatment option. Regorafenib administration resulted in a complete metabolic response which lasted for 10 months. In addition, RNA sequencing analysis revealed a novel cancer fusion transcript of YWHAE gene with fusion partner JAZF1. Several chimeric transcripts for YWHAE and JAZF1 genes were previously found in uterine neoplasms and some of them were associated with tumor prognosis. However, their combination was detected in this study for the first time. Taken together, these findings evidence that RNA sequencing may complement analysis of clinically relevant mutations and enhance management of oncological patients by suggesting putative treatment options.\n\nuterine leiomyosarcoma\nregorafenib\nRNA sequencing\ncancer gene fusion\npersonalized therapy\noncobox\nwhole-exome sequencing\ntargeted therapeutics\nRussian Science Foundation10.13039/501100006769I.M. Sechenov First Moscow State Medical University10.13039/501100013833\n==== Body\npmcBackground\n\nUterine leiomyosarcoma (UL) is the most common type of uterine sarcomas which accounts for about 1-2% of uterine malignancies (1, 2). This tumor has a higher rate of metastasis without prior lymph node involvement compared to adenocarcinomas (2). Most patients experience vaginal bleeding, as well as in cases of patients with adenocarcinomas. Other patients may experience local discomfort from uterine enlargement. The average age of UL diagnosis is about 50 years (3). But in the early stages, the disease course is usually asymptomatic and is often mistakenly diagnosed as uterine leiomyoma (3).\n\nApproximately 0.5% of patients undergoing a hysterectomy for a suspected benign leiomyoma then demonstrate UL, and it is problematic to distinguish between the two tumors before surgery (2). Moreover, since laparoscopic extraction, including morcellation, there is a risk of spreading latent UL to the entire abdominal cavity (2).\n\nLeiomyosarcomas are thought to occur independently of leiomyoma (4). These tumors are characterized by abundant mitoses, prominent cellular atypia, and necrosis. The coincidence of two of the three signs indicates a risk of metastasis of more than 10% (4). When leiomyoma and UL cannot be differentiated, the term STUMP (smooth tumors of undefined malignant potential) is used for diagnosis (5). The lungs are the most frequent site of metastasis. Thus, the initial assessment should include a chest CT scan (6).\n\nDue to the lack of data from randomized trials, management tactics vary. The initial treatment is surgical intervention by hysterectomy. Lymph node involvement is rare, and usually lymph node dissection is not required (7). The use of radiation therapy showed no difference in either overall survival or progression-free survival, and did not lead to an improvement in local control (the rate of local relapses in the radiation therapy group was 20% compared to 24% in the case of surgical treatment in a randomized phase III EORTC study) (8).\n\nFor UL, there is no effective chemotherapy scheme today. The best results were shown for the following regimens: (i) gemcitabine and docetaxel combination in advanced setting. Frequency of the objective response to this regimen was 36% (9); (ii) paclitaxel, with partial or complete response rate of ~8% of the cases (10); (iii) doxorubicin monotherapy with 15% response rate (11); (iv) doxorubicin and ifosfamide treatment results in moderate response rates of 10%-30% (12). Trabectedin and pazopanib may be further used as the second line treatment of UL. Trabectedin treatment results in 1-year survival rate of 61% (13). In turn, administration of pazopanib allows to achieve long-term stabilization or partial regression of the tumor and allows to increase the median survival rate to 17.5 months (14).\n\nThus, to date there is no effective standard treatment for UL, and personalized approach may be needed for better patient management. Such an approach may be based on high-throughput gene expression profiling, because no clinically actionable mutations were described for UL in the literature. Gene expression profiling using RNA sequencing and further bioinformatic analysis may, in turn, provide insights on the pathological processes altered in a specific tumor (15). The only genetic test utilizing both DNA analysis for mutation profiling and RNA analysis for gene expression profiling is Oncobox (16). Oncobox uses advanced pathway analysis of gene expression data to build personalized rating of targeted drugs (17). Here we describe a case of successful application of the Oncobox testing to select treatment for metastatic UL.\n\nCase Presentation\n\nIn February 2019, a 65-year-old woman underwent uterine extirpation from the upper third of the vagina for uterine fibroids, which had been diagnosed for 18 years. Histological examination of the material indicated UL (Figure 1A), G1, pT1b, size 12 cm, with invasion of the entire thickness of the uterine myometrium wall and endometrial invasion. IHC examination revealed spindle-shaped cells with mild nuclear polymorphism and an abundance of mitoses (Figure1A). Lymphovascular invasion was detected (Figure 1A), resection margin and appendages were without a tumor. A histological examination of the omentum was also performed, and no signs of tumor growth were found.\n\nFigure 1 (A) Hematoxylin and eosin (H&E) staining shows uterine leiomyosarcoma (left) with lymphovascular invasion (right). (B) CT (left) and PET-CT (right) scans of the pelvis. Lesion in the area of the removed right ovary in March 2019, December 2019 and March 2020. (C) PET-CT scans of the abdomen. Nodes along the anterior abdominal wall in March 2019, December 2019 and March 2020, sagittal plane.\n\nIn March 2019, PET-CT revealed lesions in the lungs (size 7 mm and 11 mm, Figure S1), in the area of the removed right ovary (3 cm, Figure 1B) and along the anterior abdominal wall (up to 1 cm2, Figure 1C). First-line polychemotherapy (PCT) with ifosfamide (2500 mg/m2/day on days 1 to 4) and doxorubicin (25 mg/m2 intravenously, on days 1 to 3) started, and the patient received two out of four prescribed therapy courses. The patient developed fibril neutropenia and grade 2 thrombocytopenia; therefore, the dose was reduced for the next course to 1875 mg/m2/day intravenously, on days 1 to 4 for ifosfamide and to 18.7 mg/m2 intravenously, on days 1 to 3 for doxorubicin. According to MRI data from June 2019 (Figure S2), the disease progressed: a pathological lesion with dimensions - transverse 2.4 cm, vertical 3.0 cm, craniocaudal 7.5 cm, unevenly accumulating a contrast agent was observed on the right, with the spread to the area of the iliac vessels.\n\nSince the disease progressed after the PCT, the patient received monotherapy with targeted tyrosine kinase inhibitor pazopanib (800 mg daily) as the second line in June. However, the treatment was terminated after the second dose (second day of the treatment) due to the development of a severe hypertensive crisis. MRI in September 2019 revealed lesions in the right iliac region - secondary altered lymph nodes, with signs of invasion in the right ureter (Figure S3).\n\nAs the patient rapidly progressed on standard treatment, an attempt was made to find an alternative treatment option. To identify third-line therapy, Oncobox molecular diagnostic test was performed for the patient tumor biopsy specimen obtained during the operation in February 2019 containing 95% tumor cells. Oncobox test used included whole-exome sequencing (WES) and RNA sequencing (RNAseq) of tumor biosample. WES data are used to identify diagnostic mutations and to calculate tumor mutation burden, whereas RNAseq information helps identifying molecular drug targets that are differentially expressed in the tumor, and also differentially regulated molecular pathways compared to the healthy tissues (16, 18). Annotated Oncobox pathway database was recently published (19). The healthy control tissues were sequenced previously by Oncobox (20) using the same equipment and protocols. Based on the drug target and molecular pathway information, Oncobox algorithm returns personalized rating of targeted therapeutics (17). To this end, balanced efficiency score (BES) of each targeted cancer drug is calculated that is based on the extent of up/downregulation of drug target genes and drug target pathways (15). The latter complements mutation data and helps identifying possible treatment options even when no clinically actionable mutations can be found. This approach was found effective for advanced solid tumors in several clinical screens (21–24) and trials (25, 26), and used for off-label drug prescriptions in the progressive tumors (27–31).\n\nIn the present case, whole exome sequencing (WES) and RNA sequencing (RNAseq) profiling of tumor sample was performed followed by bioinformatic analysis (17). The tumor sample showed no signs of microsatellite instability according to (32). WES identified 583 non-synonymous mutations in protein-coding genes, and an overall tumor mutation burden value (calculated also including synonymous mutations according to (33) was 9.8 per megabase which couldn’t support using immune checkpoint inhibitors according to (34). No clinically actionable mutations were identified in genes ATRX, BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, thus platinum compounds and PARP inhibitors would potentially be ineffective (35, 36). There were no activating mutations in the BRAF, EGFR, and PIK3CA genes and no amplification was found for ERBB2 (HER2), thus corresponding inhibitors could not be prescribed.\n\nHowever, RNAseq analysis detected a previously unknown in-frame cancer fusion transcript of genes YWHAE and JAZF1, directly supported by nine sequencing reads (Figure 2). The fifth exon of YWHAE was fused with the fourth exon of JAZF1. JAZF1 is frequently amplified and overexpressed in many cancers (37). The relative exon coverage of JAZF1 by RNAseq reads downstream to the fusion site was higher than upstream, thus confirming abnormal activation of this gene (Figure 2B). Other fusions separately involving either YWHAE or JAZF1 were previously reported for uterine sarcomas (38), some of them (YWHAE with fusion partners NUTM2A and NUTM2B) were associated with poor prognosis (39). However, YWHAE-JAZF1 combination, to our knowledge, was identified here for the first time, and it could not drive a decision on the patient management.\n\nFigure 2 Schematic representation of YWHAE-JAZF1 fusion transcript identified. (A) gene structures upstream and downstream of fusion site. (B) JAZF1 gene exon coverage by normalized RNA sequencing reads.\n\nGene Ontology (GO) analysis of the top-100 up-regulated genes in the patient’s biosample according to RNAseq data revealed terms associated with extracellular matrix organization, mesenchyme development and organ development (Figure S4). GO-analysis of the 100 most down-regulated genes revealed terms associated with muscle system process, actin−mediated cell contraction, and sarcomere organization. Fold changes for all 36596 genes analyzed can be found in Table S1.\n\nWe then used RNAseq data to analyze molecular pathways with altered cancer-to-healthy tissue activation profiles using Oncobox algorithm (21, 40, 41). We found that the most strongly upregulated pathways dealt with (i) FOXA1 transcription factor network, (ii) downregulation of MTA3 in breast cancer, (iii) basal cell carcinoma network, (iv) elastic fiber formation, (v) cell migration branch of VEGFR signaling in lymphatic endothelium pathway, (vi) keratan sulfate degradation, (vii) endothelial cell regulation branch of cAMP pathway, (viii) L1CAM interactions, (ix) CXCR4 signaling, and (x) tumor cell invasion branch of Syndecan 1 signaling pathway (Figure 3A, top). The main downregulated pathways dealt with (i) type 2 diabetes network, (ii) muscle contraction, (iii-iv) cardiomyopathy network, (v and viii) PPAR signaling, (vi) noradrenaline and adrenaline degradation, (vii and x) acyl chain remodeling, and (ix) antibody-mediated complement activation (Figure 3A, bottom).\n\nFigure 3 (A) Top-10 up-regulated (green color, top) and top-10 down-regulated (red color, bottom) molecular pathways in the patient’s tumor. Line width for each pathway is proportional to the pathway activation level (PAL), scale for PAL values is presented on the right; (B) Gene expression level of Regorafenib targets. Targets included in the “KEGG Pathways in cancer” pathway are highlighted in red.\n\nApplying Oncobox algorithm to RNAseq data, we also built personalized rating of 159 cancer drugs with 164 molecular targets (17). According to the Oncobox report, the patient’s tumor was predicted to be sensitive to the following top-10 targeted drugs (in a decreasing efficiency order): (i) regorafenib, (ii) lenvatinib, (iii) nintedanib, (iv) dovitinib, (v) tivozanib, (vi) dasatinib, (vii) sunitinib, (viii) sorafenib, (ix) pazopanib, and (x) midostaurin (Table S1).\n\nBased on the results of this molecular profiling, the institutional tumor board approved administration of regorafenib, a targeted tyrosine kinase inhibitor with multiple specificities (Figure 3B). The patient received regorafenib as monotherapy (80 mg daily) from September till December 2019, and PET-CT investigation from 21.12.2019 revealed a complete metabolic regression of the tumor (Figures 1 and S1). Regorafenib administration was then continued till February 2020 in the same regimen. Thus, the patient received 5 courses of regorafenib in total. Complete metabolic response of the patient’s tumor was confirmed in March 2020 (Figures 1B, C), but then the treatment was terminated due to poor tolerability of the drug: the patient developed gastrointestinal toxicity, stomatitis, cheilitis, and arterial hypertension. The tumor progressed in July 2020: pathological lesions accumulating contrast agents were found in the lungs, omentum and peritoneum (Figures S5 and S6). Regorafenib treatment was resumed, and the tumor partially regressed in September 2020. However, same regorafenib side effects occurred, and it was decided to make a second attempt of pazopanib treatment. The patient received pazopanib from September till December 2020, but the disease progressed, and the patient had moderate anemia of chronic diseases. It was decided to administer regorafenib and partial response was documented in April 2021. As for August 2021 the patient is alive, receives regorafenib therapy and has mild anemia of chronic diseases.\n\nDiscussion\n\nRegorafenib inhibits multiple tyrosine kinases involved in tumor angiogenesis (VEGFR1-3, TIE2), oncogenic transformation (KIT, RET, RAF1, BRAF), and shaping tumor microenvironment (PDGFR, FGFR) (42). KIT is a proto-oncogene encoding receptor tyrosine kinase. When bound to its ligands, it phosphorylates and activates the PI3K/AKT signaling axis. Previously strong diffused expression of KIT was observed in ~75% of leiomyosarcomas (43), and in 53% of uterine leiomyosarcomas (44). Genes PDGFRA and PDGFRB encode the platelet-derived growth factor receptors that play a significant role in cell growth and differentiation. Previously expression changes of PDGFRA and PDGFRB in UL have not been sufficiently investigated with the exception of a single study showing that their expression was increased in ~60% of UL (45). FGFR1 encodes one of the fibroblast growth factor receptors. Binding FGFR1 to its ligand also leads to the activation of PI3K/AKT axis. This gene upregulation was previously observed in several UL cell lines, and its targeted inhibition resulted in strong suppression of cell proliferation and survival (46). In turn, the PI3K/AKT axis makes a significant contribution to the development of leiomyosarcomas, and this pathway inhibition leads to suppression of growth and activation of apoptosis on both in vitro and in vivo UL models (47).\n\nRNAseq analysis revealed twelve upregulated versus only six downregulated regorafenib target genes in the patient’s tumor (Figure 3B). Moreover, multiple signaling pathways containing regorafenib targets were upregulated in the tumor according to Oncobox analysis (Table S1), For example, all regorafenib targets included in “KEGG Pathways in cancer” network show increased expression levels (Figure 4). The PDGFRA-B, FGFR1-2, and KIT gene products activate the PI3K-AKT axis (Figure 4, circled), which, in turn, was also activated. Thus, increased expression levels of multiple targeted gene products along with the upregulated targeted signaling pathways may indicate on the tumor sensitivity to regorafenib.\n\nFigure 4 “KEGG Pathways in cancer” signaling pathway shown as an interacting network. This pathway was hyperactivated in the patient’s tumor tissue. Green arrows indicate activation, red arrows–inhibition. Transcript nodes are shown in ovals. The color depth of transcript nodes reflects the extent of node activation (logarithms of the case-to-normal (CNR) expression rate for each node, in which “normal” is a geometric average between expression levels in normal tissue samples). Molecular targets of regorafenib are indicated by black arrows. Visualization was implemented using Oncobox software. The PI3Ks-AKT signaling axis is marked in blue ellipse.\n\nCurrently regorafenib is approved for treatment of metastatic colorectal cancer (48), advanced gastrointestinal stromal tumors (49), and advanced hepatocellular carcinoma (50), but not approved for sarcomas including UL (51). We found only one published report where regorafenib was used in UL (52). A group of 56 patients with leiomyosarcomas, where 22 patients had UL, showed significantly longer progression-free survival if treated with regorafenib compared to the placebo cohort (52). In addition to leiomyosarcoma, regorafenib improved PFS in synovial sarcoma, but not in liposarcoma (52). When patients from multiple cohorts with non-adipocytic sarcomas were pooled together, median PFS was 4.0 months in the regorafenib arm and 1.0 month in the placebo arm (HR 0.36, P-value <.0001). Median PFS in leiomyosarcoma group was 3.7 months, while our patient did not progress for 10 months.\n\nIn this study we also found a new YWHAE-JAZF1 cancer fusion transcript that most probably results in enhanced activity of JAZF1 moiety. The latter gene controls lipid metabolism by suppressing lipogenesis and increasing lipolysis, and regulates expression of PPARA and PPARD (53, 54). Interestingly, two out of ten the most strongly suppressed molecular pathways in the patient’s tumor were different versions of PPAR signaling pathway which can be a functional consequence of a fusion oncogene activity (Figure 3A, bottom). Currently, no meaningful conclusion can be made on possible association of the detected fusion on regorafenib response. Future clinical studies are required to elaborate on that.\n\nNowadays there are several medical first-generation second opinion platforms that use genetic profiling data like CARIS Molecular Intelligence and Foundation ONE (55–58). Their clinical utility is limited to the analysis of a modest number of clinically actionable mutations and immunohistochemical profiling of a small panel of approved cancer biomarkers. The enclosed targeted panels contain only up to 2% of the total number of protein-coding genes, thus making most part of the cancer exome invisible. Those platforms also don’t use high throughput gene expression data to prioritize therapeutic options in cases when several drugs could be potentially effective. In the present case, the mutation analysis was not informative, whereas it was the Oncobox transcriptomic/molecular pathway profiling that allowed to identify an effective treatment.\n\nEffectiveness of this method was previously published in several case reports (27–30), retrospective (23, 24) and prospective (26, 59) clinical investigations. In this communication, we describe the use of regorafenib, which was selected based on Oncobox analysis of RNAseq data for the treatment of UL with lung metastases after unsuccessful chemotherapy. Regorafenib treatment resulted in a prolonged complete metabolic response and poor yet acceptable toxicity. This case suggests that personalized approach utilizing both mutation and gene expression profiling may be helpful for guiding treatment selection in advanced UL. However, this suggestion is based on an individual case, which is the main limitation of the current study. Larger prospective clinical studies are needed to investigate clinical utility and validity of such an approach. The strength of the current study is the first to our knowledge integrative (WES and RNAseq) prospective analysis of the UL biopsy, which enabled to choose the effective personalized treatment.\n\nMaterials and Methods\n\nThe patient provided written informed consent for the analysis of her cancer tissue biosample and for presentation of relevant clinical and molecular data in this paper - for disclosure of sex, histological tumor type, diagnosis, relevant instrumental images, and molecular data including RNA sequencing data and whole-exome sequencing data. The study was conducted in accordance with the Declaration of Helsinki ethical principles. The consent procedure and the design of the study were approved by the local ethical committee of the Medical Holding SM-clinic.\n\nThe tumor tissue sample used for gene expression analysis was stored in the form of formalin-fixed paraffin-embedded (FFPE) tissue block at the room temperature. For nucleic acid extraction, we used sections of FFPE block with tumor cell content 95%.\n\nRNA was isolated from FFPE slices and sequenced according to our previous protocols (20, 60). DNA was extracted and used for whole-exome sequencing as described (30). For normalization of gene expression to calculate CNR and pathway activation levels, we used RNA sequencing profiles from ANTE collection for normal tissues (20) of healthy donors killed in road accidents, that was built using the same equipment and protocols.\n\nGene expression, molecular pathway activation and mutation analyses were performed as described previously (16, 17, 29, 30). For molecular pathway analysis we used previously published database of 3044 molecular pathways involving 9022 human genes (61), but included only pathways with 10 or more genes (n = 1682).\n\nWe did Gene Ontology search using GeneOntology tool (http://geneontology.org/) and q-value setting < 0.1 for 20595 genes included in GO terms and verified results using GOrilla software (http://cbl-gorilla.cs.technion.ac.il/) for 19098 HGNC protein coding genes, and using enrichGO clusterProfiler software (org.Hs.eg.db) with ENTREZID as the gene names.\n\nFusion transcripts were initially screened using STAR-Fusion software. Preliminary files containing fusion candidates were generated and the corresponding RNA sequencing reads were extracted. The output data were manually inspected using UCSC BLAT and UCSC Browser (https://genome.ucsc.edu/) to interrogate fusion candidates according to the following criteria: (i) does the read cover exon junction of two different transcripts, (ii) if the junction point exactly matches exon termini of known genes with canonic splice sites, (iii) if both transcripts are in the same orientation.\n\nData Availability Statement\n\nThe datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA700818.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by local ethical committee of the Medical Holding SM-clinic. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nAS and AP were involved in patient management and study design. MSu performed molecular analyses. LM analyzed PET-CT data and prepared figures. AG analyzed clinical information. ER, MSo, and AB identified RNA sequencing reads for fusion transcript and characterized it. MZ, AB, and MSo did bioinformatic analysis of RNA sequencing and WES data. AS, ZM, MSo, and AB wrote the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThe study was supported by the Russian Science Fund grant 20-75-10071.\n\nConflict of Interest\n\nMSo and AB were employed by OmicsWay Corp.\n\nThe remaining 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\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nWe acknowledge the Amazon and Microsoft Azure grants for cloud-based computations, and Omicsway Corp. for providing access to Oncobox software.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.666001/full#supplementary-material\n\nSupplementary Figure 1 CT (left) and PET-CT (right) chest scans of the chest. (A) A node in S6 of the left lung in March 2019, December 2019 and March 2020; (B) A node in S8 of the right lung in March 2019, December 2019 and March 2020.\n\nClick here for additional data file.\n\nSupplementary Figure 2 A pathological lesion on the right, with the spread to the area of the iliac vessels (indicated with green arrow), June 2019.\n\nClick here for additional data file.\n\nSupplementary Figure 3 Lesions in the right iliac region - secondary altered lymph nodes, with signs of invasion in the right ureter, September 2019.\n\nClick here for additional data file.\n\nSupplementary Figure 4 GO visualization of top-30 significant “biological process” terms by R package enrichplot (http://bioconductor.org/packages/release/bioc/html/enrichplot.html). All terms passed Benjamini-Hochberg adjusted p-value threshold of 0.05.\n\nClick here for additional data file.\n\nSupplementary Figure 5 CT (left) and PET-CT (right) chest scans of the chest in July 2020. (A) A node in S6 of the left lung; (B) A node in S8 of the right lung.\n\nClick here for additional data file.\n\nSupplementary Figure 6 CT (left) and PET-CT (right) scans of the pelvis in July 2020. (A) Lesion in the area of the removed right ovary. (B) CT and PET-CT scans of the abdomen, axial plane.\n\nClick here for additional data file.\n\nSupplementary Table 1 Gene fold changes, Pathway Activation Levels and Balanced Efficiency Scores calculated by the Oncobox method.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Abeler VM Røyne O Thoresen S Danielsen HE Nesland JM Kristensen GB . Uterine Sarcomas in Norway. A Histopathological and Prognostic Survey of a Total Population From 1970 to 2000 Including 419 Patients. Histopathology (2009) 54 :355–64. 10.1111/j.1365-2559.2009.03231.x\n2 Ricci S Stone RL Fader AN . Uterine Leiomyosarcoma: Epidemiology, Contemporary Treatment Strategies and the Impact of Uterine Morcellation. 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New York, NY: Springer US (2020). p. 189–206. 10.1007/978-1-0716-0138-9_15\n17 Tkachev V Sorokin M Garazha A Borisov N Buzdin A . “Oncobox Method for Scoring Efficiencies of Anticancer Drugs Based on Gene Expression Data BT - Nucleic Acid Detection and Structural Investigations: Methods and Protocols,”. In: Astakhova K Bukhari SA , editors. Methods Mol Biol. New York, NY: Springer US (2020). p. 235–55. 10.1007/978-1-0716-0138-9_17\n18 Buzdin A Tkachev V Zolotovskaia M Garazha A Moshkovskii S Borisov N . “Using Proteomic and Transcriptomic Data to Assess Activation of Intracellular Molecular Pathways,”. In: Advances in Protein Chemistry and Structural Biology. Cambridge, Massachusetts, US: Academic Press Inc (2021). p. 1–53. 10.1016/bs.apcsb.2021.02.005\n19 Sorokin M Borisov N Kuzmin D Gudkov A Zolotovskaia M Garazha A . Algorithmic Annotation of Functional Roles for Components of 3,044 Human Molecular Pathways. Front Genet (2021) 12 :617059. 10.3389/fgene.2021.617059 33633781\n20 Suntsova M Gaifullin N Allina D Reshetun A Li X Mendeleeva L . Atlas of RNA Sequencing Profiles for Normal Human Tissues. Sci Data (2019) 6 :36. 10.1038/s41597-019-0043-4 31015567\n21 Buzdin A Sorokin M Garazha A Sekacheva M Kim E Zhukov N . Molecular Pathway Activation – New Type of Biomarkers for Tumor Morphology and Personalized Selection of Target Drugs. Semin Cancer Biol (2018) 53 :110–24. 10.1016/j.semcancer.2018.06.003\n22 Kim EL Sorokin M Kantelhardt SR Kalasauskas D Sprang B Fauss J . Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma. Cancers (Basel) (2020) 12 :520. 10.3390/cancers12020520\n23 Sorokin M Poddubskaya E Baranova M Glusker A Kogoniya L Markarova E . RNA Sequencing Profiles and Diagnostic Signatures Linked With Response to Ramucirumab in Gastric Cancer. Cold Spring Harb Mol Case Stud (2020) 6 :a004945. 10.1101/mcs.a004945 32060041\n24 Poddubkaya E Sorokin M Baranova M Lantsov D Glusker A Kogoniya L . P-351 RNA Sequencing for Personalized Therapy Prescription in Colon Cancer. Ann Oncol (2020) 31 :S204. 10.1016/j.annonc.2020.04.433\n25 Sorokin M Ignatev K Barbara V Vladimirova U Muraveva A Suntsova M . Molecular Pathway Activation Markers Are Associated With Efficacy of Trastuzumab Therapy in Metastatic HER2-Positive Breast Cancer Better Than Individual Gene Expression Levels. Biochem (2020) 85 :758–72. 10.1134/S0006297920070044\n26 Poddubskaya E Sorokin M Garazha A Glusker A Moisseev A Sekacheva M . Clinical Use of RNA Sequencing and Oncobox Analytics to Predict Personalized Targeted Therapeutic Efficacy. J Clin Oncol (2020) 38 :e13676–6. 10.1200/JCO.2020.38.15_suppl.e13676\n27 Poddubskaya EV Baranova MP Allina DO Sekacheva MI Makovskaia LA Kamashev DE . Personalized Prescription of Imatinib in Recurrent Granulosa Cell Tumor of the Ovary: Case Report. Cold Spring Harb Mol Case Stud (2019) 5 :a003434. 10.1101/mcs.a003434 30655270\n28 Poddubskaya EV Baranova MP Allina DO Smirnov PY Albert EA Kirilchev AP . Personalized Prescription of Tyrosine Kinase Inhibitors in Unresectable Metastatic Cholangiocarcinoma. Exp Hematol Oncol (2018) 7 :21. 10.1186/s40164-018-0113-x 30202637\n29 Poddubskaya E Bondarenko A Boroda A Zotova E Glusker A Sletina S . Transcriptomics-Guided Personalized Prescription of Targeted Therapeutics for Metastatic ALK-Positive Lung Cancer Case Following Recurrence on ALK Inhibitors. Front Oncol (2019) 9 :1026. 10.3389/fonc.2019.01026 31681574\n30 Moisseev A Albert E Lubarsky D Schroeder D Clark J . Transcriptomic and Genomic Testing to Guide Individualized Treatment in Chemoresistant Gastric Cancer Case. Biomedicines (2020) 8 :67. 10.3390/biomedicines8030067\n31 Samii A Sorokin M Kar S Makovskaia L Garazha A Hartmann C . Case of Multifocal Glioblastoma With Four Fusion Transcripts of ALK , FGFR2 , NTRK2 , and NTRK3 Genes Stresses the Need for Tumor Tissue Multisampling for Transcriptomic Analysis. Mol Case Stud (2021) 7 :a006100. 10.1101/mcs.a006100\n32 Danaher P Warren S Ong S Elliott N Cesano A Ferree S . A Gene Expression Assay for Simultaneous Measurement of Microsatellite Instability and Anti-Tumor Immune Activity. J Immunother Cancer (2019) 7 :15. 10.1186/s40425-018-0472-1 30665466\n33 Chalmers ZR Connelly CF Fabrizio D Gay L Ali SM Ennis R . Analysis of 100,000 Human Cancer Genomes Reveals the Landscape of Tumor Mutational Burden. Genome Med (2017) 9 :34. 10.1186/s13073-017-0424-2 28420421\n34 Marabelle A Fakih M Lopez J Shah M Shapira-Frommer R Nakagawa K . Association of Tumour Mutational Burden With Outcomes in Patients With Advanced Solid Tumours Treated With Pembrolizumab: Prospective Biomarker Analysis of the Multicohort, Open-Label, Phase 2 KEYNOTE-158 Study. Lancet Oncol (2020) 21 :1353–65. 10.1016/S1470-2045(20)30445-9\n35 de Bono J Mateo J Fizazi K Saad F Shore N Sandhu S . Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med (2020) 382 :2091–102. 10.1056/nejmoa1911440\n36 Pennington K Walsh T Harrell M Lee M Pennil C Rendi M . Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas. Clin Cancer Res (2014) 20 :764–75. 10.1158/1078-0432.CCR-13-2287\n37 COSMIC Database. . Available at: https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=JAZF1.\n38 Potter JW Jones KB Barrott JJ . Sarcoma–The Standard-Bearer in Cancer Discovery. Crit Rev Oncol Hematol (2018) 126 :1–5. 10.1016/j.critrevonc.2018.03.007 29759550\n39 Hodge JC Bedroske PP Pearce KE Sukov WR . Molecular Cytogenetic Analysis of JAZF1, PHF1, and YWHAE in Endometrial Stromal Tumors Discovery of Genetic Complexity by Fluorescence in Situ Hybridization. J Mol Diagnostics (2016) 18 :516–26. 10.1016/j.jmoldx.2016.02.001\n40 Zolotovskaia MA Tkachev VS Seryakov AP Kuzmin DV Kamashev DE Sorokin MI . Mutation Enrichment and Transcriptomic Activation Signatures of 419 Molecular Pathways in Cancer. Cancers (Basel) (2020) 12 :271. 10.3390/cancers12020271\n41 Zolotovskaia M Sorokin M Garazha A Borisov N Buzdin A . “Molecular Pathway Analysis of Mutation Data for Biomarkers Discovery and Scoring of Target Cancer Drugs BT - Nucleic Acid Detection and Structural Investigations: Methods and Protocols,”. In: Astakhova K Bukhari SA , editors. Methods Mol Biol. New York, NY: Springer US (2020). p. 207–34. 10.1007/978-1-0716-0138-9_16\n42 Ettrich TJ Seufferlein T . “Regorafenib”. In: Recent Results in Cancer Research. New York LLC: Springer (2018). p. 45–56. 10.1007/978-3-319-91442-8_3\n43 Wang L Felix JC Lee JL Tan PY Tourgeman DE O’Meara AT . The Proto-Oncogene C-Kit Is Expressed in Leiomyosarcomas of the Uterus. Gynecol Oncol (2003) 90 :402–6. 10.1016/S0090-8258(03)00274-9\n44 Raspollini MR Amunni G Villanucci A Pinzani P Simi L Paglierani M . C-Kit Expression in Patients With Uterine Leiomyosarcomas: A Potential Alternative Therapeutic Treatment. Clin Cancer Res (2004) 10 :3500–3. 10.1158/1078-0432.CCR-03-0363\n45 Anderson SE Nonaka D Chuai S Olshen AB Chi D Sabbatini P . P53, Epidermal Growth Factor, and Platelet-Derived Growth Factor in Uterine Leiomyosarcoma and Leiomyomas. Int J Gynecol Cancer (2006) 16 :849–53. 10.1111/j.1525-1438.2006.00542.x\n46 Chen H Shen J Choy E Hornicek FJ Duan Z . Targeting Protein Kinases to Reverse Multidrug Resistance in Sarcoma. Cancer Treat Rev (2016) 43 :8–18. 10.1016/j.ctrv.2015.11.011 26827688\n47 Fourneaux B Chaire V Lucchesi C Karanian M Pineau R Laroche-Clary A . Dual Inhibition of the PI3K/AKT/mTOR Pathway Suppresses the Growth of Leiomyosarcomas But Leads to ERK Activation Through mTORC2: Biological and Clinical Implications. Oncotarget (2017) 8 :7878–90. 10.18632/oncotarget.13987\n48 Loupakis F Antonuzzo L Bachet JB Kuan FC Macarulla T Pietrantonio F . Practical Considerations in the Use of Regorafenib in Metastatic Colorectal Cancer. Ther Adv Med Oncol (2020) 12 :1758835920956862. 10.1177/1758835920956862 33193826\n49 Kelly CM Gutierrez Sainz L Chi P . The Management of Metastatic GIST: Current Standard and Investigational Therapeutics. J Hematol Oncol (2021) 14 :2. 10.1186/s13045-020-01026-6 33402214\n50 Llovet JM Kelley RK Villanueva A Singal AG Pikarsky E Roayaie S . Hepatocellular Carcinoma. Nat Rev Dis Prim (2021) 7 :6. 10.1038/s41572-020-00240-3 33479224\n51 Juhasz-Böss I Gabriel L Bohle RM Horn LC Solomayer EF Breitbach GP . Uterine Leiomyosarcoma. Oncol Res Treat (2018) 41 :680–6. 10.1159/000494299\n52 Mir O Brodowicz T Italiano A Wallet J Blay JY Bertucci F . Safety and Efficacy of Regorafenib in Patients With Advanced Soft Tissue Sarcoma (REGOSARC): A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial. Lancet Oncol (2016) 17 :1732–42. 10.1016/S1470-2045(16)30507-1\n53 Nakajima T Fujino S Nakanishi G Kim YS Jetten AM . TIP27: A Novel Repressor of the Nuclear Orphan Receptor Tak1/Tr4. Nucleic Acids Res (2004) 32 :4194–204. 10.1093/nar/gkh741\n54 Ming GF Li X Yin JY Ai YH Xu DM Ma XH . JAZF1 Regulates Visfatin Expression in Adipocytes via PPARα and PPARβ/δ Signaling. Metabolism (2014) 63 :1012–21. 10.1016/j.metabol.2014.05.006\n55 Popovtzer A Sarfaty M Limon D Marshack G Perlow E Dvir A . Metastatic Salivary Gland Tumors: A Single-Center Study Demonstrating the Feasibility and Potential Clinical Benefit of Molecular-Profiling-Guided Therapy. BioMed Res Int (2015) 2015 :614845. 10.1155/2015/614845 26448941\n56 Vigneswaran J Tan Y-HC Murgu SD Won BM Patton KA Villaflor VM . Comprehensive Genetic Testing Identifies Targetable Genomic Alterations in Most Patients With Non-Small Cell Lung Cancer, Specifically Adenocarcinoma, Single Institute Investigation. Oncotarget (2016) 7 :18876–86. 10.18632/oncotarget.7739\n57 Green DE Jayakrishnan TT Hwang M Pappas SG Gamblin TC Turaga KK . Immunohistochemistry - Microarray Analysis of Patients With Peritoneal Metastases of Appendiceal or Colorectal Origin. Front Surg (2014) 1 :50. 10.3389/fsurg.2014.00050 25593974\n58 Russell K Shunyakov L Dicke KA Maney T Voss A . A Practical Approach to Aid Physician Interpretation of Clinically Actionable Predictive Biomarker Results in a Multi-Platform Tumor Profiling Service. Front Pharmacol (2014) 5 :76. 10.3389/fphar.2014.00076 24782778\n59 Poddubskaya E Buzdin A Garazha A Sorokin M Glusker A Aleshin A . Oncobox, Gene Expression-Based Second Opinion System for Predicting Response to Treatment in Advanced Solid Tumors. J Clin Oncol (2019) 37 :e13143–3. 10.1200/JCO.2019.37.15_suppl.e13143\n60 Sorokin M Ignatev K Poddubskaya E Vladimirova U Gaifullin N Lantsov D . RNA Sequencing in Comparison to Immunohistochemistry for Measuring Cancer Biomarkers in Breast Cancer and Lung Cancer Specimens. Biomedicines (2020) 8 :114. 10.3390/BIOMEDICINES8050114\n61 Buzdin AA Sorokin M Borisov NM Kuzmin D Gudkov A Zolotovskaia MA . Algorithmic Annotation of Functional Roles for Components of 3044 Human Molecular Pathways. Front Genet (2021) 12 :617059. 10.3389/FGENE.2021.617059 33633781\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "RNA sequencing; cancer gene fusion; oncobox; personalized therapy; regorafenib; targeted therapeutics; uterine leiomyosarcoma; whole-exome sequencing",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "666001",
"pmc": null,
"pmid": "34527573",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "8179071;32919526;33040720;31979117;28002802;12893208;34341009;33479224;15161707;26827688;31667773;32259228;29759550;19236512;24782778;34340765;15459493;32397474;24930994;27012429;18378136;28651804;30665466;26934441;27154512;30202637;18534250;24240112;28209496;32210001;28420421;16681772;27751846;30069758;30321869;30655270;31681574;32102350;33402214;33193826;15302918;33633781;31667774;29935311;12694653;32060041;26448941;29576383;29458779;25593974;31412295;31015567;32343890",
"title": "RNA Sequencing for Personalized Treatment of Metastatic Leiomyosarcoma: Case Report.",
"title_normalized": "rna sequencing for personalized treatment of metastatic leiomyosarcoma case report"
} | [
{
"companynumb": "RU-BAYER-2021A218853",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "REGORAFENIB"
},
"drugadditional": "1",
"... |
{
"abstract": "BACKGROUND\nThe endonasal endoscope has become widely integrated into the operative practice of skull-base surgeons. Although it is not the current standard of practice for the drainage of intracranial abscesses, transnasal neuroendoscopy has the potential for benefit over both stereotaxy and open craniotomy because it is minimally invasive and provides a visual confirmation of debridement. We present two recent cases in which patients with intradural abscesses adjacent to the anterior skull base were successfully drained and irrigated using an endoscopic approach.\n\n\nMETHODS\nTwo patients with post-traumatic intradural brain abscess underwent transnasal neuroendoscopic drainage in a 1-year period. In both cases, the abscesses were drained and irrigated without complication under direct visualization. The patients' outcomes were felt to be positive given their initial insults.\n\n\nCONCLUSIONS\nTransnasal endoscopic drainage of brain abscesses appears to be safe and has particular advantages in specific cases over the current operative standard, which are likely to prove beneficial for patients and cement it as a feasible alternative to stereotactic aspiration and craniotomy.",
"affiliations": "School of Medicine, Vanderbilt University, Nashville, Tennessee, United States.;Otolaryngology/Head and Neck Surgery, Walter Reed Army Medical Center, Washington, DC, United States.;Otolaryngology/Head and Neck Surgery, Vanderbilt University, Nashville, Tennessee, United States.",
"authors": "Sacks|Daniel|D|;Kim|Esther|E|;Russell|Paul|P|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0032-1330955",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2193-6315",
"issue": "74 Suppl 1()",
"journal": "Journal of neurological surgery. Part A, Central European neurosurgery",
"keywords": null,
"medline_ta": "J Neurol Surg A Cent Eur Neurosurg",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001922:Brain Abscess; D002277:Carcinoma; D003392:Cranial Sinuses; D003399:Craniotomy; D019723:Endoscopes; D004724:Endoscopy; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009296:Nasal Cavity; D019635:Neurosurgical Procedures; D009669:Nose Neoplasms; D011183:Postoperative Complications; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014948:Wounds, Gunshot; D055815:Young Adult",
"nlm_unique_id": "101580767",
"other_id": null,
"pages": "e54-7",
"pmc": null,
"pmid": "23315668",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The role of the endonasal endoscope in the operative management of brain abscess: a case report.",
"title_normalized": "the role of the endonasal endoscope in the operative management of brain abscess a case report"
} | [
{
"companynumb": "PHHY2015US042346",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 35-year-old female renal transplant recipient was referred to the metabolic bone clinic because of a 15 cm loss of height. She was noted to have thoracic kyphosis and vertebral X-ray confirmed a wedge fracture of the eighth thoracic vertebra. She was managed accordingly but on subsequent follow-up mentioned in passing that her gynaecologist had been unable to obtain a cervical smear for routine screening. This led to further questioning, and the patient reported intermittent urinary stress incontinence, feelings of vaginal fullness and severe dyspareunia. It became apparent that these symptoms had been ongoing for 4 years, but the patient had not brought them to the attention of a healthcare practitioner due to feelings of embarrassment and her religious beliefs. These complaints prompted radiological investigation, which revealed extensive bony pelvic deformity, thought to be an extreme manifestation of chronic kidney disease mineral and bone disorder.",
"affiliations": "Department of Endocrinology, University of Birmingham, Birmingham, UK.;Department of Endocrinology, University of Birmingham, Birmingham, UK.;Radiology, University Hospital of Birmingham, Birmingham, Westmidlands.;Department of Endocrinology, University Hospital of Birmingham, Birmingham, UK.",
"authors": "Moffat|Alexander Henry|AH|;Chauhan|Priyesh|P|;Choudhary|Surabhi|S|;Geberhiwot|Tarekegn|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220729",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "calcium and bone; chronic renal failure; metabolic disorders; renal transplantation; urinary and genital tract disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D007738:Kyphosis; D013902:Radiography, Thoracic; D051436:Renal Insufficiency, Chronic; D016103:Spinal Fractures; D013904:Thoracic Vertebrae",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28942400",
"pubdate": "2017-09-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17251386;22807503;23727169;26785065",
"title": "Extreme bony pelvic deformity in a renal transplant patient.",
"title_normalized": "extreme bony pelvic deformity in a renal transplant patient"
} | [
{
"companynumb": "GB-CONCORDIA PHARMACEUTICALS INC.-E2B_00008838",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CINACALCET HYDROCHLORIDE"
},
... |
{
"abstract": "Management of acute, major or life threatening bleeding in the presence of direct acting oral anticoagulants (DOAC) is unclear. In the absence of a specific antidote, or in situations where there is a need for adjunctive therapy, the ideal prothrombin complex concentrate and dose is unclear. The goal of our study was to evaluate the outcomes of our reduced dosing strategy with FEIBA in patients experiencing a DOAC-related bleeding event.\n\n\n\nRetrospective analysis of patients treated with FEIBA for a DOAC-related bleeding event.\n\n\n\nAcademic medical center PATIENTS: Consecutive patients between May 2011 and April 2017 receiving FEIBA for a DOAC-related bleed INTERVENTIONS: None MEASUREMENTS & MAIN RESULTS: Of the 64 patients included in this analysis, 38 patients received low dose FEIBA (mean 10.0 ± 3.6 units/kg) and 26 received moderate dose (mean 24.3 ± 2.1 units/kg) FEIBA; an additional dose was requested in 6 patients. Six dabigatran patients received idarucizumab. 30 day event rates included 5 thromboembolic events (8%) and 9 (14%) patients expired. Follow-up CT-imaging for ICH, endoscopy/colonoscopy, or interventional radiology exams did not reveal any clinically concerning active bleeding or hematoma expansion except in 2 ICH patients with slight expansion between imaging sessions.\n\n\n\nLow (<20 units/kg) to moderate (20-30 units/kg) doses of FEIBA, with the option for a repeat dose, may be an effective management strategy for obtaining hemostasis in DOAC-related major bleeding events.",
"affiliations": "Department of Pharmacy, University of California Davis Medical Center, 2315 Stockton Blvd, Sacramento, CA 95817, United States of America. Electronic address: wedager@ucdavis.edu.;Department of Pharmacy, University of California Davis Medical Center, 2315 Stockton Blvd, Sacramento, CA 95817, United States of America.;Department of Emergency Medicine, University of California Davis Medical Center, 2315 Stockton Blvd, Sacramento, CA 95817, United States of America.",
"authors": "Dager|W E|WE|;Roberts|A J|AJ|;Nishijima|D K|DK|",
"chemical_list": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; D003029:Coagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D000069552:Rivaroxaban; C065655:anti-inhibitor coagulant complex; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2018.11.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "173()",
"journal": "Thrombosis research",
"keywords": "Anticoagulation; Apixaban; Dabigatran; FEIBA; Reversal; Rivaroxaban",
"medline_ta": "Thromb Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001779:Blood Coagulation Factors; D003029:Coagulants; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles; D011728:Pyridones; D012189:Retrospective Studies; D000069552:Rivaroxaban; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "71-76",
"pmc": null,
"pmid": "30476716",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants.",
"title_normalized": "effect of low and moderate dose feiba to reverse major bleeding in patients on direct oral anticoagulants"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-040546",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDARUCIZUMAB"
},
... |
{
"abstract": "SLC13A5/NaCT is a sodium-coupled citrate transporter expressed in the plasma membrane of the liver, testis, and brain. In these tissues, SLC13A5 has important functions in the synthesis of fatty acids, cholesterol, and neurotransmitters. In recent years, patients homozygous for recessive mutations in SLC13A5, known as SLC13A5 deficiency [early infantile epileptic encephalopathy-25 (EIEE-25)], exhibit severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting tooth development. Although the pathogenesis of SLC13A5 deficiency remains not clearly understood, cytoplasmic citrate deficits, decreased energy status in neurons, and citrate-zinc chelation are hypothesized to explain the neurological deficits. However, no study has examined the possibility of specific pharmacological drugs and/or lifestyle changes synergizing with heterozygosity of SLC13A5 deficiency to increase the risk of EIEE-25 clinical phenotype. Here, we report on a heterozygous SLC13A5-deficient patient who demonstrated evidence of pharmaco-synergistic heterozygosity upon administration of metformin, valproic acid, and starvation. The report illustrates the importance of careful consideration of the potential adverse effects of specific pharmacological treatments in patients with heterozygosity for disease-causing recessive mutations in SLC13A5.",
"affiliations": "Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas.;Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas.;Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.",
"authors": "Kopel|Jonathan|J|;Grooms|Amy|A|;Ganapathy|Vadivel|V|;Clothier|Jeffrey|J|",
"chemical_list": "D000927:Anticonvulsants; D002951:Citrates; D029382:Dicarboxylic Acid Transporters; D029721:Drosophila Proteins; C417606:Indy protein, Drosophila; D007773:Lactates; D011619:Psychotropic Drugs; D011773:Pyruvates; C470492:SLC13A5 protein, human; D027981:Symporters; D014635:Valproic Acid; D000641:Ammonia; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1097/YPG.0000000000000269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0955-8829",
"issue": "31(1)",
"journal": "Psychiatric genetics",
"keywords": null,
"medline_ta": "Psychiatr Genet",
"mesh_terms": "D000328:Adult; D019943:Amino Acid Substitution; D000641:Ammonia; D000818:Animals; D000927:Anticonvulsants; D001321:Autistic Disorder; D001714:Bipolar Disorder; D002951:Citrates; D029382:Dicarboxylic Acid Transporters; D029721:Drosophila Proteins; D004827:Epilepsy; D005260:Female; D005508:Food Deprivation; D006579:Heterozygote; D006801:Humans; D007773:Lactates; D008136:Longevity; D008687:Metformin; D051379:Mice; D020125:Mutation, Missense; D017354:Point Mutation; D011618:Psychotic Disorders; D011619:Psychotropic Drugs; D011773:Pyruvates; D012008:Recurrence; D013036:Spasms, Infantile; D027981:Symporters; D014071:Tooth Abnormalities; D014635:Valproic Acid",
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"title": "Metformin, valproic acid, and starvation induce seizures in a patient with partial SLC13A5 deficiency: a case of pharmaco-synergistic heterozygosity.",
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"abstract": "OBJECTIVE\nTo describe a relatively rare hypersentivity reaction with pulmonary manifestations in a pediatric patient.\n\n\nMETHODS\nElectronic medical records.\n\n\nMETHODS\nPatient treatment in the pediatric critical care unit.\n\n\nMETHODS\nElectronic medical records.\n\n\nCONCLUSIONS\nEosinophilic pneumonias are rare in the pediatric population. Peripheral eosinophilia is not necessary to make the diagnosis. Bronchoalveolar lavage is the diagnostic study of choice. Lung biopsies are rarely needed to make the diagnosis. The treatment of choice is steroids. If steroids fail to improve the patient's condition, consider IVIG, and cyclosporine A.",
"affiliations": "Pediatric Critical Care Medicine, University of Texas Southwestern Medical Center at Dallas, USA. Electronic address: Christopher.Jenks@UTSouthwestern.edu.;Pulmonology and Critical Care Medicine, Department of Anesthesia/Critical Care, Houston Methodist, USA.;Pediatric Critical Care Medicine, University of Texas Southwestern Medical Center at Dallas, USA.",
"authors": "Jenks|Christopher L|CL|;Uysal|Askin|A|;Papacostas|Michael F|MF|",
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"keywords": "Drug hypersensitivity; Eosinophilic pneumonia; Pediatric intensive care; Pneumomediastinum; Pulmonary embolism",
"medline_ta": "Heart Lung",
"mesh_terms": "D018893:Bronchoalveolar Lavage; D002648:Child; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D015278:Intensive Care Units, Pediatric; D011657:Pulmonary Eosinophilia",
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"title": "Drug hypersensitivity causing organizing eosinophilic pneumonia in a pediatric patient.",
"title_normalized": "drug hypersensitivity causing organizing eosinophilic pneumonia in a pediatric patient"
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"abstract": "An adult male underwent a bowel transplant for tufting enteropathy, receiving alemtuzumab, tacrolimus, and steroids as immunosuppressants. Five years later, he developed an autoimmune hemolytic anemia (AIHA), anti-IgG positive, with reduced reticulocyte count, leukopenia, and thrombocytopenia with antiplatelet antibodies. After an unsuccessful initial treatment with high dose steroids, reduction in tacrolimus dose, and intravenous immunoglobulin (IVIG), a bone marrow biopsy revealed absence of erythroid maturation with precursor hyperplasia. The patient was switched to sirolimus and received four doses of rituximab plus two courses of plasmapheresis, which decreased his transfusion requirements. After a febrile episode one month later, the AIHA relapsed with corresponding decreases in platelet and leukocyte count: cyclosporine A (CsA) was started with a second course of rituximab and IVIG without response, even though repeat bone marrow biopsy did not reveal morphology correlated to an acquired pure red cell aplasia (APRCA). Considering the similarity in his clinical and laboratory findings to APRCA, alemtuzumab was added (three doses over a week) with CsA followed by steroids. The patient was eventually discharged transfusion-independent, with increasing hemoglobin (Hb) levels and normal platelet and leukocyte count. One year later he is still disease-free with functioning graft.",
"affiliations": "Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Institute of Hematology \"L. e A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Institute of Hematology \"L. e A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Immunohematology Service and Blood Bank, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Center for Chronic Intestinal Failure, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.;Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy.",
"authors": "Lauro|A|A|;Stanzani|M|M|;Finelli|C|C|;Zanfi|C|C|;Morelli|M C|MC|;Pasqualini|E|E|;Dazzi|A|A|;Ravaioli|M|M|;Di Simone|M|M|;Giudice|V|V|;Pironi|L|L|;Pinna|A D|AD|",
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"fulltext": "\n==== Front\nCase Rep TransplantCase Rep TransplantCRITCase Reports in Transplantation2090-69432090-6951Hindawi Publishing Corporation 10.1155/2014/262953Case ReportAlemtuzumab Plus Cyclosporine Treatment of the Autoimmune Hemolytic Anemia in an Adult Bowel Transplant Lauro A. \n1\n*Stanzani M. \n2\nFinelli C. \n2\nZanfi C. \n1\nMorelli M. C. \n1\nPasqualini E. \n1\nDazzi A. \n1\nRavaioli M. \n1\nDi Simone M. \n1\nGiudice V. \n3\nPironi L. \n4\nPinna A. D. \n1\n1Liver and Multiorgan Transplant Unit, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy2Institute of Hematology “L. e A. Seràgnoli”, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy3Immunohematology Service and Blood Bank, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy4Center for Chronic Intestinal Failure, Sant'Orsola-Malpighi University Hospital, 40138 Bologna, Italy*A. Lauro: augustola@yahoo.comAcademic Editor: Yasuhiko Sugawara\n\n2014 11 8 2014 2014 26295312 5 2014 29 7 2014 Copyright © 2014 A. Lauro et al.2014This 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.An adult male underwent a bowel transplant for tufting enteropathy, receiving alemtuzumab, tacrolimus, and steroids as immunosuppressants. Five years later, he developed an autoimmune hemolytic anemia (AIHA), anti-IgG positive, with reduced reticulocyte count, leukopenia, and thrombocytopenia with antiplatelet antibodies. After an unsuccessful initial treatment with high dose steroids, reduction in tacrolimus dose, and intravenous immunoglobulin (IVIG), a bone marrow biopsy revealed absence of erythroid maturation with precursor hyperplasia. The patient was switched to sirolimus and received four doses of rituximab plus two courses of plasmapheresis, which decreased his transfusion requirements. After a febrile episode one month later, the AIHA relapsed with corresponding decreases in platelet and leukocyte count: cyclosporine A (CsA) was started with a second course of rituximab and IVIG without response, even though repeat bone marrow biopsy did not reveal morphology correlated to an acquired pure red cell aplasia (APRCA). Considering the similarity in his clinical and laboratory findings to APRCA, alemtuzumab was added (three doses over a week) with CsA followed by steroids. The patient was eventually discharged transfusion-independent, with increasing hemoglobin (Hb) levels and normal platelet and leukocyte count. One year later he is still disease-free with functioning graft.\n==== Body\n1. Introduction\nAutoimmune cytopenias are a rare but severe complication after hematopoietic stem cell and solid organ transplantation and have been described after pediatric intestinal transplantation [1, 2]. Transplant-associated hemolytic anemia is most commonly reported in nonidentical ABO bone marrow transplants, due to ABO antibodies that cause hemolysis within days to weeks or, when mediated by autoantibodies, months to years after the transplant (autoimmune hemolytic anemia (AIHA)) [3–5]. Most cases of AIHA in solid organ transplant recipients have been reported in the first year after transplant: Botija and coworkers described an AIHA incidence of 12% after pediatric intestinal transplants, most frequently associated with cold agglutinins followed by warm and mixed types [1]. Although tacrolimus has dramatically improved the outcomes of bowel transplantation, persistent T-cell inhibition may favor polyclonal B proliferation and production of autoantibodies [6]. Additional evidence suggests that tacrolimus impairs thymus function, possibly interfering with the process of negative T-cell selection, especially in children. Alternatively, Lacaille et al. did not report signs of dysimmunity in children treated with cyclosporine A (CsA) probably because the drug has a weaker interference on the immune pathways [7]. Only few patients with posttransplant AIHA respond to steroid-based immunosuppression: more frequently, patients require high dose intravenous immunoglobulin (IVIG), rituximab, plasmapheresis, splenectomy (patient's own spleen or transplanted spleen), alemtuzumab, or chemotherapy with cyclophosphamide and vincristine [8]. Herein, we report the case of a young adult, who received a small bowel transplant for tufting enteropathy [9], that developed late-onset AIHA associated to pancytopenia. His anemia, which was IgG positive and associated with reduced reticulocyte count, leukopenia, and thrombocytopenia with intrabone marrow hemolysis, was resistant to three lines of immunosuppressive therapy. He was eventually treated successfully using a therapeutic approach similar to that required for an acquired pure red cell aplasia [10], a syndrome characterized by severe normochromic, normocytic anaemia associated with reticulocytopenia and absence of erythroblasts in the bone marrow.\n\n2. Case Report\nA 24-year-old male, blood group O positive, was transplanted on May 2007 for tufting enteropathy with an isolated bowel graft from a O negative female donor, preserving his spleen during the transplant. His preconditioning regimen consisted of two doses of alemtuzumab (0.3 mg/kg) followed by tacrolimus (daily through level 10 ng/mL) and low dose steroids (5 mg prednisone). His posttransplant medical course was complicated by one episode of enteritis, requiring hospital admission on March 2010 and medical management. In November 2012 he developed mild fatigue and jaundice with laboratory evidence of hemolysis. At admission blood tests showed severe normocytic anemia (Hb 6.2 g/dL) with reticulocyte count significantly reduced to 0.4%, thrombocytopenia (16.000/109 L), and 3.000 leukocytes/109 L (neutrophil 90%). The unconjugated (indirect) bilirubin was 2.29 mg/dL, while the other parameters of hemolysis were normal (haptoglobin and lactate dehydrogenase (LDH)). Workup for gastrointestinal bleeding, viral infections (absence of specific anti-parvovirus IgM and IgG antibodies and negative parvovirus B19 PCR in the peripheral blood), or posttransplant lymphoproliferative diseases was negative. He was found to be anti-IgG strongly positive in Direct Antiglobulin Test (DAT) for anti-IgG with antiplatelet antibodies, consistent with a clinical pattern of the Evans syndrome (ES). He required an average of 8–10 red blood cell (RBC) concentrate transfusions per week, maintaining Hb level between 5.3 and 7.9 g/dL. Initially he was treated with high dose steroids (1 gr IV followed by tapering) in combination with high dose IVIG (0.5 mg/kg/day for 6 consecutive days), with reduction in his tacrolimus dose. Granulocyte-colony stimulating factor (G-CSF) was added when leukocyte count was less than 1.500/109 L. Unfortunately, the anemia, leukopenia, and thrombocytopenia were unresponsive to treatment and a bone marrow biopsy revealed absence of erythroid maturation with hyperplasia of the precursors, several megakaryocytes, and granulocytopoiesis with prevalence of immature cells. Considering the resistance to previous treatment, tacrolimus was switched to sirolimus (plus steroids) and a second-line treatment was started with rituximab 375 mg/m2 IV per week for 4 consecutive weeks, with the addition of levofloxacin and posaconazole as antibacterial and antifungal prophylaxis. Moreover, he was treated with two courses of plasmapheresis with the intention to clear the autoantibodies. The patient's clinical and laboratory parameters improved on the new regimen, with decreased transfusion requirements (median of 3 transfusions per week to maintain Hb level between 6.5 and 8.7 g/dL) and normalizing platelet count. His leukocyte count was also maintained over 1.500/109 L with a decrease of G-CSF need. Hemolysis tests showed a slight improvement: the indirect bilirubin decreased to 0.9 mg/dL while DAT became negative, but LDH was constantly >280 U/L; haptoglobin was depleted (<5 mg/dL) and reticulocyte count was still very low (0.2%). The bone marrow cytology and histology was unchanged. Twenty days after rituximab administration, the patient developed a febrile episode with negative blood culture, decreasing Hb (ranging from 4.5 to 6.9 g/dL), leukocytes, and platelets. Hemolysis parameters were stable with constant, negative DAT. A repeated bone marrow cytology and histology showed hyperplastic erythropoiesis with absence of erythroid maturation. Although the bone marrow biopsy never showed a typical pattern correlated to an acquired pure red cell aplasia (APRCA), namely, absence of erythroid lineage and normal appearance of granulocytic precursors and megakaryocytes, his clinical and laboratory features appeared to be consistent with the disease. Sirolimus was changed to CsA and high dose IVIG, followed by rituximab 375 mg/m2 IV per week for two consecutive weeks. His anemia and transfusion needs improved modestly on the new regimen but exhibited parameters of persistent hemolysis with indirect bilirubin >1.0 mg/dL, LDH 320 mg/U, and depleted haptoglobin. The DAT was still negative and reticulocyte count showed a constant increase until 3.1%. Eighteen days after the second rituximab cycle and continuous administration of CsA and steroids, the patient developed CMV (Cytomegalovirus) reactivation detected by PCR and successfully treated with valganciclovir 900 mg daily. Unfortunately, the leukocytes, platelets, and Hb decreased again, increasing the transfusion need with laboratory evidence of hemolysis. Considering the patient's high transfusion requirement, iron-chelation therapy with deferasirox was added. Eventually, in March 2013 a course of alemtuzumab was administered with the following scheme: 3 mg on day 1, 10 mg on day 2, and 30 mg on day 3 followed by a new steroid recycle (1 mg/kg/day IV for 5 consecutive days plus a rapid tapering). The immunosuppressive treatment used in this clinical case is summarized in Table 1. One month after the last course of alemtuzumab and steroids, the patient was discharged transfusion- and G-CSF-independent (Hb constantly > 7.7 g/dL, reticulocytes 5.8%, leukocytes > 3.000/109 L, and platelets > 100.000/109 L), but with persistent laboratory evidence of hemolysis (indirect bilirubin 2.0 mg/dL, LDH 315 mg/U, and haptoglobin < 5 mg/dL). Due to the intensive immunosuppression, the patient was continued on antimould and antiviral prophylaxis with posaconazole and valganciclovir, together with iron-chelating therapy which was switched to deferoxamine (1 gr for 5 days per week subcutaneously) because of kidney intolerance to deferasirox. His maintenance immunosuppression consisted of cyclosporine and low dose steroids. In April 2014, one year after the treatment with alemtuzumab, the recipient has no signs or symptoms related to infection or neoplastic disease and has normal leukocyte and platelet count; he is transfusion-independent (Hb level constantly > 11 g/dL) without evidence of AIHA. His graft is functioning without episodes of rejection or enteritis. The clinical management during hospital admission is summarized in Figure 1.\n\n3. Discussion and Conclusions\nMultiple therapeutic modalities have been proposed to treat AIHA after solid organ transplant and pediatric patients with refractory AIHA may respond to a switch from CNI-immunosuppressant like tacrolimus to an mTOR-inhibitor [11]. An alternative approach could be the use of alemtuzumab, acting against the pan-lymphocyte antigen CD52 and resulting in adepletion of the T- and B-cell compartment. While B lineages recover rapidly after alemtuzumab administration, T-cells CD8+ and, overall, CD4+ show persistent and profound depletion lasting for months. Willis and colleagues reported that subsequent maintenance with low dose CsA may be required to prevent relapse, especially in nontransplanted populations [12, 13]. In our case, five years after the bowel transplant, an adult patient presented a severe and resistant AIHA due to warm IgG antibodies, associated with thrombocytopenia and leucopenia. His persistent severe anemia responded only to fourth-line immunosuppressive treatment represented by a combination of low dose CsA and alemtuzumab. A splenectomy was not necessary because the autoimmune disorder was also an extravascular disease located inside the bone marrow. Rituximab is considered to be an effective therapy for warm AIHA [2, 7, 8, 11], but relapses such as in our case are possible. We speculated that his anemia was due to not only the AIHA (which responded to rituximab with the disappearance of the IgG autoantibodies in the blood), but also the absence of erythroid maturation in the bone marrow, probably due to a cell-mediated mechanism. Indeed our patient did not benefit from the switch from tacrolimus to sirolimus. Therefore, we managed the patient as if he had APRCA, even if the bone marrow findings were atypical for this anemia, and he required intensive anti-T-cell immunosuppression (CsA plus alemtuzumab) [12]. Our hypothesis is supported by the fact that the bone marrow examination showed not only an impairment of the erythropoiesis, but also a severe reduction of the more mature granulocyte precursors and a clear increase of the megakaryocytes, consistent with impaired myeloid maturation sustained by a cell-mediated mechanism. We cannot rule out an additional benefit of iron-chelation therapy, which has been reported to improve in some cases the bone marrow erythroid function and maturation. The first response was seen one month after alemtuzumab (also 3 months after CsA), and the patient reached a complete remission after three more months. In conclusion, the presence of autoimmune anemias after intestinal transplantation is calling for a deep haematological workup in order to focus the multimodality therapy required to treat the disease. Our case responded to a differentiated multistep immunosuppressive strategy but a further follow-up will be necessary in order to evaluate its effects on long-term outcome.\n\nAcknowledgment\nAll paper authors are acknowledged for their contribution.\n\nAbbreviations\nAIHA:Autoimmune hemolytic anemia\n\nIVIG:High dose intravenous immunoglobulin\n\nCsA:Cyclosporine A\n\nAPRCA:Acquired pure red cell aplasia\n\nHb:Hemoglobin\n\nDAT:Direct Coombs Test\n\nRBC:Red blood cell\n\nG-CSF:Granulocyte-colony stimulating factor.\n\nDisclosure\nThis paper was not prepared or funded by contributions from a commercial organization, thus with no educational grants.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nAuthors' Contribution\nA. Lauro, M. Stanzani, and C. Finelli took part in the research design, performance of research, and writing of the paper and C. Zanfi, M. C. Morelli, E. Pasqualini, A. Dazzi, M. Ravaioli, M. Di Simone, V. Giudice, L. Pironi, and A. D. Pinna participated in the research design and performance of research.\n\nFigure 1 Correlation between therapy and outcome during hospital admission.\n\nTable 1 Immunosuppressive therapies and response.\n\n \tResponse to therapy\t\n \tTransfusion need\tIndirect bilirubin\t\nDAT\t\nFrom November 20, 2012, to November 26, 2012\tNo\tNo\tNo\t\nHD PDN + HD Ig\t\n\n\n\t\nFrom November 28, 2012, to January 15, 2013\tYes\tYes\tYes\t\nRituximab (4) + PA (2) + sirolimus\t\n\n\n\t\nFrom January 16, 2013, to March 06, 2013\tNo\tNo\tYes\t\nRituximab (2) + HD Ig + CsA\t\n\n\n\t\nFrom March 07, 2013, to April 10, 2014\tYes\tYes\tYes\t\nAlemtuzumab (3) + HD PDN + CsA\t\nHD PDN = high dose prednisolone; HD Ig = high dose immunoglobulin; PA = plasmapheresis; CsA = cyclosporine A; DAT = Direct Coombs Test.\n==== Refs\n1 Botija G Ybarra M Ramos E Autoimmune cytopaenia after paediatric intestinal transplantation: a case series Transplant International 2010 23 10 1033 1037 2-s2.0-77956327539 20444240 \n2 Czubkowski P Williams M Bagia S Kelly D Gupte G Immune-mediated hemolytic anemia in children after liver and small bowel transplantation Liver Transplantation 2011 17 8 921 924 2-s2.0-79960826583 21472974 \n3 Petz LD Hemolysis associated with transplantation Transfusion 1998 38 3 224 228 2-s2.0-0032017953 9563400 \n4 Gehrs BC Friedberg RC Autoimmune hemolytic anemia American Journal of Hematology 2002 69 4 258 271 2-s2.0-0036210260 11921020 \n5 Sokol RJ Stamps R Booker DJ Posttransplant immune-mediated hemolysis Transfusion 2002 42 2 198 204 2-s2.0-0036482547 11896335 \n6 Chen FE Owen I Savage D Late onset haemolysis and red cell autoimmunisation after allogeneic bone marrow transplant Bone Marrow Transplantation 1997 19 5 491 495 2-s2.0-0031048360 9052917 \n7 Lacaille F Moes N Hugot J Cezard J Goulet O Ruemmele FM Severe dysimmune cytopenia in children treated with tacrolimus after organ transplantation American Journal of Transplantation 2006 6 5 1072 1076 2-s2.0-33745227368 16611346 \n8 Li M Goldfinger D Yuan S Autoimmune hemolytic anemia in pediatric liver or combined liver and small bowel transplant patients: a case series and review of the literature Transfusion 2012 52 1 48 54 2-s2.0-84855357278 21790626 \n9 Reifen RM Cutz E Griffiths A Ngan BY Sherman PM Tufting enteropathy: a newly recognized clinicopathological entity associated with refractory diarrhea in infants Journal of Pediatric Gastroenterology and Nutrition 1994 18 3 379 385 2-s2.0-0028258461 8057225 \n10 Sawada K Fujishima N Hirokawa M Acquired pure red cell aplasia: updated review of treatment British Journal of Haematology 2008 142 4 505 514 2-s2.0-47649129731 18510682 \n11 Acquazzino MA Fischer RT Langnas A Coulter DW Refractory autoimmune hemolytic anemia after intestinal transplant responding to conversion from a calcineurin to mTOR inhibitor Pediatric Transplantation 2013 17 5 466 471 2-s2.0-84879888547 23730873 \n12 Willis F Marsh JCW Bevan DH The effect of treatment with Campath-1H in patients with autoimmune cytopenias British Journal of Haematology 2001 114 4 891 898 2-s2.0-0034786378 11564082 \n13 Calne R Friend P Moffatt S Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients The Lancet 1998 351 9117 1701 1702 2-s2.0-0032490341\n\n",
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"title": "Alemtuzumab plus cyclosporine treatment of the autoimmune hemolytic anemia in an adult bowel transplant.",
"title_normalized": "alemtuzumab plus cyclosporine treatment of the autoimmune hemolytic anemia in an adult bowel transplant"
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"abstract": "When trastuzumab + capecitabine and cisplatin chemotherapy could not be conducted continuously because of severe adverse reactions to cisplatin, trastuzumab + capecitabine could be an alternative systemic chemotherapy options for metastatic or recurrent gastric cancer patients.",
"affiliations": "Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.;Department of Surgical Oncology Kanazawa Medical University Hospital Uchinada, Kahoku Japan.",
"authors": "Nakamura|Naohiko|N|https://orcid.org/0000-0002-5542-0163;Kinami|Shinichi|S|https://orcid.org/0000-0001-9867-3120;Fujii|Yoritaka|Y|https://orcid.org/0000-0002-1001-8963;Miura|Seiko|S|https://orcid.org/0000-0002-4545-2671;Fujita|Jun|J|https://orcid.org/0000-0002-2529-2666;Kaida|Daisuke|D|https://orcid.org/0000-0002-6724-5358;Tomita|Yasuto|Y|https://orcid.org/0000-0001-8019-7058;Miyata|Takashi|T|https://orcid.org/0000-0002-0348-2637;Fujita|Hideto|H|https://orcid.org/0000-0002-6702-8011;Ueda|Nobuhiko|N|https://orcid.org/0000-0002-7862-3967;Kosaka|Takeo|T|https://orcid.org/0000-0002-8213-8155",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2056CCR32056Case ReportCase ReportsA remarkable clinical response in advanced gastric cancer treated with trastuzumab plus capecitabine combination chemotherapy: A report of two cases NAKAMURA et al.Nakamura Naohiko https://orcid.org/0000-0002-5542-0163n1982422@kuhp.kyoto-u.ac.jp \n1\nKinami Shinichi https://orcid.org/0000-0001-9867-3120\n1\nFujii Yoritaka https://orcid.org/0000-0002-1001-8963\n1\nMiura Seiko https://orcid.org/0000-0002-4545-2671\n1\nFujita Jun https://orcid.org/0000-0002-2529-2666\n1\nKaida Daisuke https://orcid.org/0000-0002-6724-5358\n1\nTomita Yasuto https://orcid.org/0000-0001-8019-7058\n1\nMiyata Takashi https://orcid.org/0000-0002-0348-2637\n1\nFujita Hideto https://orcid.org/0000-0002-6702-8011\n1\nUeda Nobuhiko https://orcid.org/0000-0002-7862-3967\n1\nKosaka Takeo https://orcid.org/0000-0002-8213-8155\n1\n\n1 \nDepartment of Surgical Oncology\nKanazawa Medical University Hospital\nUchinada, Kahoku\nJapan\n* Correspondence\n\nNaohiko Nakamura, Department of Surgical Oncology, Kanazawa Medical University Hospital, Uchinada, Kahoku, Ishikawa, Japan.\n\nEmail: n1982422@kuhp.kyoto-u.ac.jp\n26 2 2019 4 2019 7 4 10.1002/ccr3.2019.7.issue-4714 718 18 10 2018 26 1 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nWhen trastuzumab + capecitabine and cisplatin chemotherapy could not be conducted continuously because of severe adverse reactions to cisplatin, trastuzumab + capecitabine could be an alternative systemic chemotherapy options for metastatic or recurrent gastric cancer patients.\n\ncapecitabinegastric cancertrastuzumab source-schema-version-number2.0component-idccr32056cover-dateApril 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:08.04.2019\n\n\nNakamura \nN \n, \nKinami \nS \n, \nFujii \nY \n, et al. A remarkable clinical response in advanced gastric cancer treated with trastuzumab plus capecitabine combination chemotherapy: A report of two cases . Clin Case Rep . 2019 ;7 :714 –718 . 10.1002/ccr3.2056\n==== Body\n1 BACKGROUND\nGastric cancer (GC) is the second leading cause of cancer‐related mortality and the fourth most commonly diagnosed malignant disease.1 Systemic chemotherapy is the standard treatment for recurrent or metastatic GC.2 Over the last decade, several new agents which show promising activity against GC have been identified.3 A randomized phase III trial examining the use of Trastuzumab (T‐mab) for Gastric Cancer (ToGA) was conducted as the first study demonstrating the efficacy of a target‐specific agent in advanced or metastatic GC that was positive for human epidermal growth factor receptor 2 (HER2) expression.4 Following the promising results of the ToGA trial, T‐mab combined with capecitabine and cisplatin (XP) is now a reference treatment for the first‐line treatment of HER2‐positive GC. However, the high dosage and long‐term administration of cisplatin can create severe systemic toxicity, including gastrointestinal problems, myelosuppression, and renal toxicity.5 As a result of systemic toxicity, continuation of a cisplatin combinatory regimen can sometimes be difficult for elderly patients or patients with several comorbidities.\n\nWe here presented two cases of metastatic or recurrent GC that showed a remarkable clinical response and resulted in an improved prognosis using long‐term T‐mab plus capecitabine combination chemotherapy without administration of cisplatin.\n\n2 CASE PRESENTATIONS\n2.1 Case 1\n2.1.1 Clinical data\nA 71‐year‐old male (height 157 cm, body weight 40.0 kg and performance status 1) who presented with anorexia and abnormal liver function following a blood examination was diagnosed with a type II advanced GC in the lesser curvature of the antrum after an upper gastrointestinal endoscopy (Figure 1). At the same time, an enhanced computed tomography scan (eCT) revealed multiple liver metastases and enlarged lymph nodes along the branch of superior mesenteric artery region (Figure 2A). Biopsy results from the gastric tumor yielded a diagnosis of a moderately differentiated adenocarcinoma (Figure 3A) and 3 + HER2 status by immunohistochemistry (IHC) (Figure 3B). The clinical diagnosis was L‐Less type 2 T3 N3 M1 H1 stage IVb (according to the 15th edition of Japanese classification of gastric cancer6).\n\nFigure 1 Upper gastrointestinal endoscopy findings. A, Type II advanced GC was identified in the lesser curvature of the antrum at the initial visit. B, Following trastuzumab plus capecitabine therapy, the primary tumor region showed remarkable regression\n\nFigure 2 Enhanced computed tomography scan findings in the case 1. A, Multiple liver metastases in the both lobes and enlarged lymph nodes along the branch of superior mesenteric artery region (arrow) were identified before chemotherapy. B, Remarkable response of liver metastases and lymph node metastases were maintained using trastuzumab plus capecitabine therapy\n\nFigure 3 Histopathological findings in cases 1 and 2. Histological features of gastric tumor with hematoxylin and eosin staining (×10), and immunohistochemistry for human epidermal growth factor receptor 2 in tumor lesions (×20): case 1 (A, B) and case 2 (C, D), respectively\n\n2.1.2 Treatment\nFor this patient, we chose to treat with T‐mab and XP chemotherapy; T‐mab was given by intravenous infusion at a dose of 8 mg/kg on day 1 of the cycle. Cisplatin 80 mg/m2 was given on day 1 by intravenous infusion. Capecitabine 1000 mg/m2 was given twice a day, orally, for 14 days followed by a 1‐week rest. Two weeks following the first treatment, impairment of renal function and anorexia were observed as adverse reaction to cisplatin; the estimated creatinine clearance was reduced to under 30 mL/min, and the severity of anorexia was categorized in grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Therefore, we terminated the administration of cisplatin and converted the regimen of systemic chemotherapy to T‐mab plus capecitabine combination therapy (T‐mab + capecitabine). After the start of T‐mab + capecitabine therapy, serum CEA was decreased rapidly and the multiple liver metastases, metastatic lymph nodes (Figure 2B), and primary tumor region showed a remarkable regression at the eighth course of T‐mab + capecitabine as a partial response due to RECIST ver. 1.17 (Figure 1B).\n\n2.1.3 Outcome\nThe patient has survived for 40 months without progression of either liver metastases or primary tumor due to continuation of T‐mab + capecitabine chemotherapy.\n\n2.2 Case 2\n2.2.1 Clinical Data\nA 76‐year‐old male (height 164 cm, body weight 53.0 kg, and performance status 1) was referred to our hospital with a diagnosis of advanced GC. Upper gastrointestinal endoscopy indicated type III advanced GC in the lesser curvature of gastric body, and biopsy revealed a diagnosis of a papillary adenocarcinoma. Since lymph node metastasis that were closely located to the lesser curvature were suspected but distant metastasis of GC were not detected in preoperative imaging examinations, we performed an open total gastrectomy with lymph node dissection up to D2. The pathological stage was diagnosed as ML‐Less type 2 T4a N3 M0 stage IIIC6 and moderately differentiated adenocarcinoma with 3+ HER2 status in IHC results from the resected specimen (Figure 3C,D). Although adjuvant chemotherapy using oral intake of S‐1 was performed, lymph node recurrences at the para‐aortic region developed in an eCT at 4 months after surgery (Figure 4A).\n\nFigure 4 Enhanced computed tomography scan findings in case 2. A, Lymph node recurrences at the para‐aortic region were identified 4 months after surgery (arrow). B, Para‐aortic lymph node recurrences showed remarkable regression after trastuzumab plus capecitabine therapy\n\n2.2.2 Treatment\nTo treat the recurrences, we started systemic chemotherapy with T‐mab plus paclitaxel as a protocol for a prospective clinical trial (JFMC 45‐1102); nevertheless, lymph nodes at the para‐aortic region had gradually enlarged. As a second‐line treatment, T‐mab with XP chemotherapy (same as the protocol in case 1) was conducted from 9 months following surgery. However, the patient showed grade 3 anorexia and fatigue in spite of the step‐by‐step dose reduction of both cisplatin and capecitabine. Thus, we applied the regiment of T‐mab + capecitabine combination therapy. Following five courses of T‐mab + capecitabine, the para‐aortic lymph node recurrences showed remarkable regression in the eCT (Figure 4B). It was estimated to be a complete response.7\n\n\n2.2.3 Outcome\nNo adverse events and the progression of lymph node recurrences were not observed by T‐mab + capecitabine chemotherapy. However, a lung tumor was detected by eCT at 6 years after the surgery despite of continuation of T‐mab + capecitabine (Figure 5). For the lung tumor, a right lung lobectomy was performed. The postoperative histopathological examination revealed that the lung tumor was a metastasis of GC, and HER2 status was 3+ in IHC. The patient has survived for 6 years and 9 months after surgery without progression or any recurrences.\n\nFigure 5 Chest computed tomography scan findings. A lung tumor was detected in the upper lobe of right lung 6 years after the surgery (arrow)\n\n3 DISCUSSION\nT‐mab has been integrated into the current standard chemotherapy for HER2‐overexpressing GC. The incidence of HER2 overexpression in gastric cancer is approaching 15%‐25%.4, 8 Although HER2 may be correlated to a poor prognosis, HER2 positivity is no longer considered a poor prognostic factor.9 In the ToGA study, T‐mab was found to improve the median OS when combined with XP or cisplatin/5‐FU (13.5 months) in comparison with XP or CF alone (11.1 months).4 Based on these results, cisplatin is recommended in combination with T‐mab as first‐line treatment for HER2‐positive GC. However, it is still unclear whether omitting administration of cisplatin in T‐mab‐based chemotherapy could a provide disadvantage for long‐term survival of HER2‐positive GC patients. We report here that continuation of T‐mab + capecitabine therapy achieved a remarkable clinical response and long‐term survival in metastatic or recurrent GC patients.\n\nThe ToGA study indicated that the overall tumor response rate was 47% and the complete response rate was 5%. In addition, the median progression‐free survival time was reported to be 6.7 months.4 In the present report, patients treated with T‐mab + capecitabine showed a remarkable clinical response for not only the primary cancerous region but also for liver or lymph node metastases. Of note, the long‐term uninterrupted administration of T‐mab + capecitabine without any adverse events could suppress the progression of metastasis and contribute to the long‐term survival of the patient. A previous report discussed a case of advanced GC with multiple liver metastases who reached more than 1 year of progression‐free survival using T‐mab + capecitabine chemotherapy.10 However, it has been not reported that continuation of T‐mab + capecitabine could sustain the disease control for a period of more than 3 years. Our cases may imply that an extremely small portion of HER2‐positive GC patients could show a better response for T‐mab‐based chemotherapy without cisplatin.\n\nCisplatin is one of the first‐line chemotherapy agents for treating advanced GC. Although many clinical trials have been conducted to uncover the best combinatory regimen of cisplatin with other chemotherapy agents such as docetaxel and fluorouracil, high dosage and long‐term administration of cisplatin sometimes causes severe adverse reactions.11 In the ToGA study, the proportion of patients who had anorexia, fatigue, and renal impairment as adverse events of T‐mab with XP chemotherapy was 46, 35, and 16%, respectively. As a result, the dose of cisplatin or capecitabine was reduced in nearly half of all patients following two courses of T‐mab with XP chemotherapy.4 In particular, dose reduction of cisplatin is recommended when creatinine clearance level is decreased under 40 mL/min. On the other hand, anorexia or fatigue caused by repeated utilization of chemotherapy agents could cause a deterioration in the patient's general condition and decrease the patient's quality of life. In our cases, renal impairment, anorexia, and fatigue were overcome by stopping the administration of cisplatin and patients were able to continue to undergo T‐mab + capecitabine chemotherapy for a long‐term period. Furthermore, in our second case, surgical resection could be performed safely for the lung metastasis after long‐term T‐mab + capecitabine chemotherapy. Therefore, it may be very important for multidisciplinary treatments for GC, including conversion surgery, to prevent a deterioration of patient's general condition caused by chemotherapy agent toxicity.\n\nAs potential limitations to current cases, it is unclear what the significance of continuation of T‐mab + capecitabine chemotherapy for control of disease progression following the response had been observed. A continuation of chemotherapy without adverse events, in some cases combining conversion surgery, seems to be necessary to aid long‐term survival at GC patients. However, it is difficult to make judgments on whether to change the chemotherapy regimen or attempt conversion surgery for regression regions when a remarkable clinical response is achieved. Further studies are needed to evaluate the benefit of T‐mab + capecitabine therapy as a multidisciplinary treatment option for recurrent or metastatic HER2‐positive GC.\n\nIn conclusion, we experienced two cases of metastatic or recurrent GC that showed a remarkable clinical response and obtained a better prognosis using long‐term T‐mab + capecitabine combination chemotherapy. When T‐mab + XP chemotherapy could not be conducted continuously because of severe adverse reactions to cisplatin, T‐mab + capecitabine could be an alternative systemic chemotherapy options for GC patients.\n\nCONFLICT OF INTEREST\nThe authors declare that they have no competing interests.\n\nAUTHOR CONTRIBUTION\nSK and TK: involved in conceptualization. NN, YF, SM, JF, DK, YT, TM, HF, and NU: involved in data curation. NN and SK: involved in investigation. NN, SK, YF, SM, JF, DK, YT, TM, HF, and NU: performed the treatment. NN: drafted the manuscript. SK and TK: involved in revision. All authors have read and approved the final manuscript.\n==== Refs\nREFERENCES\n1 \n\nJemal \nA \n, \nCenter \nMM \n, \nDeSantis \nC \n, \nWard \nEM \n. Global patterns of cancer incidence and mortality rates and trends . Cancer Epidemiol Biomarkers Prev . 2010 ;19 :1893 ‐1907 .20647400 \n2 \nJapanese Gastric Cancer Association \n. Japanese Gastric cancer treatment guidelines 2014 (ver.4) . Gastric Cancer . 2016 ;20 :714 ‐19 .\n3 \n\nSaka \nM \n, \nMorita \nS \n, \nFukagawa \nT \n, \nKatai \nH \n. Present and future status of gastric cancer surgery . Jpn J Clin Oncol . 2011 ;41 :307 ‐313 .21242182 \n4 \n\nBang \nYJ \n, \nVan Cutsem \nE \n, \nFeyereislova \nA \n, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2‐positive advanced gastric or gastro‐oesophageal junction cancer (ToGA): a phase 3, open‐label, randomised controlled trial . Lancet . 2010 ;376 :687 ‐697 .20728210 \n5 \n\nTakashima \nA \n, \nYamada \nY \n, \nNakajima \nTE \n, \nKato \nK \n, \nHamaguchi \nT \n, \nShimada \nY \n. Standard first‐line chemotherapy for metastatic gastric cancer in Japan has met the global standard: evidence from recent phase III trials . Gastrointest Cancer Res . 2009 ;3 :239 ‐244 .21151427 \n6 \nJapanese Gastric Cancer Association \n. Japanese classification of gastric carcinoma. 15th edn \nTokyo : Kanehara ; 2017 .\n7 \n\nTherasse \nP \n, \nArbuck \nSG \n, \nEisenhauer \nEA \n, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada . J Natl Cancer Inst . 2000 ;92 :205 ‐216 .10655437 \n8 \n\nGravalos \nC \n, \nJimeno \nA \n. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target . Ann Oncol . 2008 ;19 :1523 ‐1529 .18441328 \n9 \n\nShah \nMA \n, \nJanjigian \nYY \n, \nPauligk \nC \n, et al. Prognostic significance of human epidermal growth factor‐2 (HER2) in advanced gastric cancer: A U.S. and European international collaborative analysis . J Clin Oncol . 2011 ;29 (15 Suppl ):4014 .21911717 \n10 \n\nOneda \nY \n, \nTamura \nS \n, \nMurakami \nK \n, et al. A case of advanced gastric cancer with multiple liver metastases successfully treated with capecitabine, cisplatin, and trastumab . Jpn J Cancer Chemotherapy . 2016 ;43 :2202 ‐2204 .\n11 \n\nFuji \nM \n, \nKochi \nM \n, \nTakayama \nT \n. Recent advances in chemotherapy for advanced gastric cancer in Japan . Surg Today . 2010 ;40 :295 ‐300 .20339982\n\n",
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"title": "A remarkable clinical response in advanced gastric cancer treated with trastuzumab plus capecitabine combination chemotherapy: A report of two cases.",
"title_normalized": "a remarkable clinical response in advanced gastric cancer treated with trastuzumab plus capecitabine combination chemotherapy a report of two cases"
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"abstract": "Kidney transplant recipients who develop coronavirus disease 2019 (COVID-19) are at increased risk of life-threatening illness, which often requires reducing immunosuppression despite the potential risk of causing an allograft rejection. Herein, we describe the clinical presentation and course of a kidney transplant recipient who acquired COVID-19 and was hospitalized with severe symptoms and hypoxemia. Upon admission, the patient was found to have elevated de novo donor-specific antibodies (DSA) yielding a positive cytotoxicity crossmatch and concurrent elevated plasma donor-derived cell-free DNA (dd-cfDNA) level, indicating a possible ongoing rejection despite improvement in his serum creatinine. Because of persistent positive COVID-19 tests and stable serum creatinine, a kidney allograft biopsy was initially deferred and his dd-cfDNA and DSA were monitored closely postdischarge. Three months later, because of persistent elevated dd-cfDNA and positive DSA, a kidney allograft biopsy was performed, which showed chronic active antibody-mediated rejection. Accordingly, the patient was treated with intravenous immunoglobulin and his maintenance immunosuppressive regimen was increased.",
"affiliations": "Johns Hopkins University School of Medicine, Division of Nephrology, Baltimore, Maryland. Electronic address: m_abuzainah@hotmail.co.uk.;Johns Hopkins University School of Medicine, Division of Nephrology, Baltimore, Maryland.;Johns Hopkins University School of Medicine, Department of Pathology, Baltimore, Maryland.;Johns Hopkins University School of Medicine, Division of Nephrology, Baltimore, Maryland.",
"authors": "Abuzeineh|Mohammad|M|;Tariq|Anam|A|;Rosenberg|Avi|A|;Brennan|Daniel C|DC|",
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"title": "Chronic Active Antibody-Mediated Rejection Following COVID-19 Infection in a Kidney Transplant Recipient: A Case Report.",
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"abstract": "Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction and an increased risk of melanoma. For patients with metastatic melanoma, immunotherapy with checkpoint blocking antibodies is a standard of care. In patients with concomitant CLL and metastatic melanoma, it is not known whether CLL might influence the antimelanoma efficacy or immune-related toxicities of immune checkpoint blockade. Fifteen patients with locally advanced or metastatic melanoma and a concomitant diagnosis of CLL who received pembrolizumab or ipilimumab with or without nivolumab for the treatment of their melanoma at Memorial Sloan Kettering Cancer Center between January 1, 2010, and January 1, 2017, were retrospectively identified. Clinical characteristics including absolute lymphocyte counts during therapy were recorded along with a response to treatment (objective radiographic response, progression-free survival, and adverse events) for each patient. Of 9 response-evaluable patients treated with ipilimumab, 3 (33%) had a partial response, 1 (11%) had stable disease, and 5 (56%) developed progressive disease. Objective tumor responses were also observed with single-agent therapy pembrolizumab and with combination therapy of nivolumab and ipilimumab. Grade 3 or 4 toxicity was observed in 6 of 15 patients (40%), including diarrhea, transaminitis, rash, and hemolytic anemia. Although our retrospective assessment was limited, there was no evidence that CLL responded to the checkpoint blockade. This case series demonstrates that ipilimumab, pembrolizumab, and combined ipilimumab and nivolumab therapies show clinical activity in patients with melanoma and concomitant CLL, at rates consistent with those previously reported. This population may warrant closer surveillance for hematologic immune-related toxicities such as autoimmune hemolytic anemia.",
"affiliations": "Melanoma and Immunotherapeutics Service, Department of Medicine.;Rogel Cancer Center, University of Michigan, Ann Arbor, MI.;Melanoma and Immunotherapeutics Service, Department of Medicine.;Melanoma and Immunotherapeutics Service, Department of Medicine.;Melanoma and Immunotherapeutics Service, Department of Medicine.;Melanoma and Immunotherapeutics Service, Department of Medicine.;Melanoma and Immunotherapeutics Service, Department of Medicine.;Melanoma and Immunotherapeutics Service, Department of Medicine.;Leukemia Service, Department of Medicine.;Melanoma and Immunotherapeutics Service, Department of Medicine.",
"authors": "Smithy|James W|JW|;Pianko|Matthew J|MJ|;Maher|Colleen|C|;Postow|Michael A|MA|;Shoushtari|Alexander N|AN|;Momtaz|Parisa|P|;Chapman|Paul B|PB|;Wolchok|Jedd D|JD|;Park|Jae H|JH|;Callahan|Margaret K|MK|",
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"title": "Checkpoint Blockade in Melanoma Patients With Underlying Chronic Lymphocytic Leukemia.",
"title_normalized": "checkpoint blockade in melanoma patients with underlying chronic lymphocytic leukemia"
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"abstract": "Linagliptin is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that is approved for the treatment of type 2 diabetes mellitus. About 5% of linagliptin is eliminated by the kidneys and no dose adjustment is recommended in kidney impairment. We report a first case of linagliptin-associated acute kidney injury (AKI) in a patient with preexisting chronic kidney disease (CKD). We hypothesize that AKI was due to renal hypoperfusion from linagliptin-induced natriuresis and intravascular volume contraction in the setting of concomitant lisinopril use, which is known to impair autoregulation and potentiate hypotension-induced AKI. It may be prudent to exert caution and closely monitor kidney function when initiating linagliptin in combination with ACE-inhibitors in CKD patients.",
"affiliations": "Kidney Specialists of Southern Nevada, Las Vegas, NV 89106, USA.;Nephrology Section, Stratton VA Medical Center, Albany, NY 12208, USA.;Endocrinology Section, Stratton VA Medical Center, Albany, NY 12208, USA.",
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"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi Publishing Corporation 10.1155/2016/5695641Case ReportAcute Kidney Injury Associated with Linagliptin Nandikanti Deepak K. \n1\n\n*\nGosmanova Elvira O. \n2\nGosmanov Aidar R. \n3\n1Kidney Specialists of Southern Nevada, Las Vegas, NV 89106, USA2Nephrology Section, Stratton VA Medical Center, Albany, NY 12208, USA3Endocrinology Section, Stratton VA Medical Center, Albany, NY 12208, USA*Deepak K. Nandikanti: doc.deeps@gmail.comAcademic Editor: John Broom\n\n2016 14 2 2016 2016 569564111 7 2015 21 1 2016 Copyright © 2016 Deepak K. Nandikanti et al.2016This 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.Linagliptin is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that is approved for the treatment of type 2 diabetes mellitus. About 5% of linagliptin is eliminated by the kidneys and no dose adjustment is recommended in kidney impairment. We report a first case of linagliptin-associated acute kidney injury (AKI) in a patient with preexisting chronic kidney disease (CKD). We hypothesize that AKI was due to renal hypoperfusion from linagliptin-induced natriuresis and intravascular volume contraction in the setting of concomitant lisinopril use, which is known to impair autoregulation and potentiate hypotension-induced AKI. It may be prudent to exert caution and closely monitor kidney function when initiating linagliptin in combination with ACE-inhibitors in CKD patients.\n==== Body\n1. Introduction\nLinagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved for the treatment of type 2 diabetes in 2011. A single daily dose of linagliptin is well tolerated [1]. In contrast with other DPP-4 inhibitors, kidney excretion has minimal contribution for linagliptin elimination (~5%) and no dose adjustment is recommended in patients with kidney impairment [2]. Linagliptin has been used in patients with chronic kidney disease (CKD) [3]; however, the safety of linagliptin in combination with renin-angiotensin system (RAS) blockers in CKD patients is unknown. Here, we report a case of linagliptin-associated acute kidney injury (AKI) in a patient with preexisting CKD.\n\n2. Case Description\nA 54-year-old African-American male with hypertension treated with multiple medications, including lisinopril 80 mg daily, amlodipine 10 mg daily, hydralazine 50 mg trice daily, and clonidine 0.2 mg twice daily; type 2 diabetes controlled with glimepiride 1 mg daily; and stage 4 CKD due to diabetic kidney disease was evaluated in nephrology office during routine follow-up visit. Blood pressure was 156/70 mmHg, which was similar to home measurements. The remaining physical examination was unremarkable. Kidney function was stable with serum creatinine (SCr) of 4.3 mg/dL (estimated glomerular filtration rate (eGFR) of 18 mL/min/1.73 m2) and blood urea nitrogen of 64 mg/dL. Potassium level was elevated at 6.4 mmol/L. Hyperkalemia was attributed to several glasses of orange juice that patient was ingesting daily in the last week for the prevention and treatment of recurrent episodes of hypoglycemia. Blood glucose was 70 mg/dL and hemoglobin A1c was 5.5%; therefore, glimepiride was discontinued and linagliptin 5 mg once daily was initiated to reduce the incidence of hypoglycemia. Due to elevated potassium, electrolyte measurement was reassessed one week following linagliptin initiation. At that time, SCr and BUN increased to 7.0 mg/dL and 101 mg/dL, respectively, and hyperkalemia persisted. The patient was admitted to the hospital for evaluation of AKI. On admission, he denied recurrent hypoglycemia, vomiting or diarrhea, or any new medications with the exception of linagliptin. The patient lived with his mother who administered his medications. She denied any changes in compliance and conformed that the patient was in his usual health when he was contacted about elevated SCr. During physical examination blood pressure was 120/57 mmHg with no orthostatic changes. The patient's weight was 2.5 kg lower as compared with his weight in nephrology clinic 1 week ago. Skin turgor was slightly reduced and no signs of peripheral edema were observed. Urinalysis was bland. Fractional excretion of sodium was 3.4%. Linagliptin was discontinued, as the onset of AKI on CKD coincided with linagliptin initiation. Because patient's weight and blood pressure were significantly lower than the usual for him with no signs of infection, the presence of volume depletion was suspected and lisinopril was discontinued. After administration of 2 L of normal saline over 24 hours and oral kayexalate, SCr and potassium levels improved to 5.7 mg/dL and 5.1 mmol/L, respectively. Blood pressure increased to 142/76 mmHg. The patient refused any further interventions and was discharged home. While continuing to hold lisinopril and linagliptin, SCr improved to 3.4 mg/dL in 10 days and remained stable for the next 2 months. Due to chronic proteinuria, a low dose of lisinopril at 10 mg daily was restarted. SCr was unchanged at 3.5 mg/dL 4 weeks following lisinopril initiation (Figure 1). Patient did not require any hypoglycemic medications and was following a diabetic diet.\n\n3. Discussion\nThis report describes patient characteristics and course of AKI after the initiation of linagliptin. The efficacy and safety of linagliptin has been investigated in the recent 52-week study involving diabetic patients with estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m2 [3]. Overall, the incidence of AKI in linagliptin-treated patients was 7.4% and it was similar to the control group. The investigators believed that AKI events were not related to linagliptin; however, no additional details regarding AKI cases were provided. Moreover, it is unknown if linagliptin-treated patients were concomitantly receiving RAS-blockers. In rats, the DDP-4 inhibition downregulates Na+/H+ exchanger in the proximal renal tubule, which, in turn, leads to natriuresis, diuresis, and attenuation of blood pressure [4, 5]. In the present case, we also observed mild reduction in blood pressure at the time of AKI. While the normal kidney response during hypotension is to preserve sodium, we found an increased fractional urinary excretion of sodium and weight reduction that may be consistent with diuretic effect of linagliptin. In the present case, we hypothesize that AKI occurred from renal hypoperfusion caused by linagliptin-induced natriuresis and intravascular volume contraction in the setting of concomitant lisinopril administration. ACE-inhibitors are known to impair autoregulation and potentiate hypotension-induced AKI [6]. It may be prudent to exert caution when linagliptin is initiated in combination with ACE-inhibitors in patients with limited kidney reserve. Of note, a case of transient AKI associated with linagliptin use was reported in a patient with normal renal function who was also on ACE-inhibitor [7]. Therefore, we recommend to closely monitoring kidney function and blood pressure after linagliptin initiation in diabetic patients with advanced CKD also treated with ACE-inhibitors.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Time-course of changes in serum creatinine and serum potassium in relationship with linagliptin use.\n==== Refs\n1 Owens D. R. Swallow R. Dugi K. A. Woerle H. J. Efficacy and safety of linagliptin in persons with Type2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study Diabetic Medicine 2011 28 11 1352 1361 10.1111/j.1464-5491.2011.03387.x 2-s2.0-80053072352 21781152 \n2 Tradjenta® (Linaglitpin). Prescribing Information 2012 Boehringer Ingelheim Pharmaceuticals \n3 McGill J. B. Sloan L. Newman J. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study Diabetes Care 2013 36 2 237 244 10.2337/dc12-0706 2-s2.0-84873864348 23033241 \n4 Girardi A. C. C. Fukuda L. E. Rossoni L. V. Malnic G. Rebouças N. A. Dipeptidyl peptidase IV inhibition downregulates Na+ -H+ exchanger NHE3 in rat renal proximal tubule American Journal of Physiology—Renal Physiology 2008 294 2 F414 F422 10.1152/ajprenal.00174.2007 2-s2.0-38849093208 18077600 \n5 Pacheco B. P. Crajoinas R. O. Couto G. K. Dipeptidyl peptidase IV inhibition attenuates blood pressure rising in young spontaneously hypertensive rats Journal of Hypertension 2011 29 3 520 528 10.1097/hjh.0b013e328341939d 2-s2.0-79951677095 21150640 \n6 Schoolwerth A. C. Sica D. A. Ballermann B. J. Wilcox C. S. Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association Circulation 2001 104 16 1985 1991 10.1161/hc4101.096153 2-s2.0-0035899896 11602506 \n7 Kutoh K. Potential linagliptin-induced renal impairment Journal of Medical Cases 2012 3 361 364 10.4021/jmc807w\n\n",
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"title": "Acute Kidney Injury Associated with Linagliptin.",
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"abstract": "BACKGROUND\nIntrahepatic artery pseudoaneurysms are mostly iatrogenic and result from hepatobiliary interventions. The incidence of intrahepatic artery pseudoaneurysms within liver tumors without prior intervention is extremely rare. We presented herein the first report of a case of an intratumoral pseudoaneurysm within a liver metastasis of gastric cancer without any prior intervention during chemotherapy.\n\n\nMETHODS\nA 59-year-old male patient underwent a distal gastrectomy and D2 lymph node dissection for gastric cancer. He was treated in the emergency room for right abdominal pain following the 4th cycle of nivolumab administration as second-line chemotherapy after adjuvant chemotherapy with S-1 and first-line chemotherapy for a liver metastasis of gastric cancer with ramucirumab plus paclitaxel. CT showed a 72-mm metastatic liver tumor containing a 9-mm pseudoaneurysm and fluid collection around the hepatic edge. Intrahepatic artery pseudoaneurysm within the metastatic liver tumor was diagnosed, with the surrounding fluid indicating potential, active bleeding. An emergency angiography confirmed the presence of a pseudoaneurysm in the intrahepatic artery, which was embolized using microcoils. The contributory causes of the intratumoral pseudoaneurysm were assumed to be the following: (1) tumor necrosis leading to encasement, erosion of the vessel wall, and subsequent arterial wall weakening; and (2) inhibition of vascular endothelial growth by ramucirumab resulting in a vessel wall breach and pseudoaneurysm formation.\n\n\nCONCLUSIONS\nIt is necessary to recognize that pseudoaneurysms can arise within a metastatic liver tumor during chemotherapy.",
"affiliations": "Department of Surgery, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.;Department of Surgery, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan. ishibashi_y@live.jp.;Department of Surgery, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.;Department of Surgery, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057, Japan.;Department of Surgery, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.;Department of Radiology, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.;Department of Surgery, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.;Department of Surgery, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.",
"authors": "Ohara|Hiroki|H|;Ishibashi|Yuji|Y|http://orcid.org/0000-0001-8637-1387;Yoshimura|Shuntaro|S|;Yamazaki|Ryoto|R|;Hatao|Fumihiko|F|;Koshiishi|Takeshi|T|;Morita|Yasuhiro|Y|;Imamura|Kazuhiro|K|",
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"fulltext": "\n==== Front\nSurg Case RepSurg Case RepSurgical Case Reports2198-7793Springer Berlin Heidelberg Berlin/Heidelberg 80610.1186/s40792-020-00806-zCase ReportIntratumoral pseudoaneurysm within a liver metastasis of gastric cancer: a case report Ohara Hiroki 1http://orcid.org/0000-0001-8637-1387Ishibashi Yuji ishibashi_y@live.jp 1Yoshimura Shuntaro 1Yamazaki Ryoto 2Hatao Fumihiko 1Koshiishi Takeshi 3Morita Yasuhiro 1Imamura Kazuhiro 11 grid.417089.30000 0004 0378 2239Department of Surgery, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524 Japan 2 grid.417102.1Department of Surgery, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya-ku, Tokyo, 156-0057 Japan 3 grid.417089.30000 0004 0378 2239Department of Radiology, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524 Japan 18 2 2020 18 2 2020 12 2020 6 3923 12 2019 12 2 2020 © The Author(s) 2020Open 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.Background\nIntrahepatic artery pseudoaneurysms are mostly iatrogenic and result from hepatobiliary interventions. The incidence of intrahepatic artery pseudoaneurysms within liver tumors without prior intervention is extremely rare. We presented herein the first report of a case of an intratumoral pseudoaneurysm within a liver metastasis of gastric cancer without any prior intervention during chemotherapy.\n\nCase presentation\nA 59-year-old male patient underwent a distal gastrectomy and D2 lymph node dissection for gastric cancer. He was treated in the emergency room for right abdominal pain following the 4th cycle of nivolumab administration as second-line chemotherapy after adjuvant chemotherapy with S-1 and first-line chemotherapy for a liver metastasis of gastric cancer with ramucirumab plus paclitaxel. CT showed a 72-mm metastatic liver tumor containing a 9-mm pseudoaneurysm and fluid collection around the hepatic edge. Intrahepatic artery pseudoaneurysm within the metastatic liver tumor was diagnosed, with the surrounding fluid indicating potential, active bleeding. An emergency angiography confirmed the presence of a pseudoaneurysm in the intrahepatic artery, which was embolized using microcoils. The contributory causes of the intratumoral pseudoaneurysm were assumed to be the following: (1) tumor necrosis leading to encasement, erosion of the vessel wall, and subsequent arterial wall weakening; and (2) inhibition of vascular endothelial growth by ramucirumab resulting in a vessel wall breach and pseudoaneurysm formation.\n\nConclusion\nIt is necessary to recognize that pseudoaneurysms can arise within a metastatic liver tumor during chemotherapy.\n\nKeywords\nPseudoaneurysmHepatic arteryGastric cancerMetastatic liver tumorissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nPseudoaneurysms result from the partial to complete disruption of the vascular wall and lead to hemorrhaging contained by the adventitia of the vessel wall or the perivascular soft tissues [1]. Intrahepatic artery pseudoaneurysms are rare and mostly iatrogenic, resulting from hepatobiliary interventions. The incidence of pseudoaneurysms within a liver tumor without prior intervention is extremely rare. We presented herein the first report of a case of intratumoral pseudoaneurysm (ITPA) within a liver metastasis of gastric cancer during chemotherapy without any prior intervention.\n\nCase report\nA 59-year-old male patient underwent a distal gastrectomy and D2 lymph node dissection for gastric cancer. The final pathological stage was T4aN3aM0 Stage IIIC according to the Japanese Gastric Cancer Association Classification, 14th Edition [2]. Postoperative adjuvant chemotherapy with S-1 (100 mg/day p.o., twice daily for 28 consecutive days) was administered for 1 year in accordance with treatment guidelines. One and a half years after surgery, computed tomography (CT) revealed a liver metastasis in hepatic segment VI. The recurrence was detected within 6 months after adjuvant chemotherapy with S-1, and combination therapy with ramucirumab (RAM: 8 mg/kg on days 1 and 15) and paclitaxel (PTX: 80 mg/m2 on days 1, 8, and 15) was administered as first-line chemotherapy, with the regimen repeated at 28-day intervals. After eight cycles with RAM plus PTX, follow-up CT revealed a new liver metastasis in segments VI and VIII. Nivolumab (3 mg/kg, biweekly) was administered as second-line treatment. Five days after the 4th cycle of nivolumab injections, the patient visited our emergency room due to right abdominal pain. Guarding and rebound tenderness were denied. On initial physical examination, the blood pressure was 100/64 mmHg and the heart rate was 109 beats per min. Serum biochemistry showed a white blood cell count of 8.1 × 103/μL, red blood cell count of 478 × 104/μL, and hemoglobin 14.2 g/dL. CT showed a 72 × 68 mm metastatic liver tumor in segment VI. The tumor rim was enhanced, but the center was not, and thus considered to consist of necrotic tissue. The tumor contained a 9-mm pseudoaneurysm, and fluid collection was visible around hepatic edge (Fig. 1). An intrahepatic artery pseudoaneurysm within the metastatic liver tumor was diagnosed, with the surrounding fluid indicating potential, active bleeding. An emergency angiography confirmed the presence of a pseudoaneurysm stemming from a branch of the hepatic artery in segment VI (Fig. 2). The pseudoaneurysm was cannulated and successfully embolized using microcoils. After embolization, there were no clinical signs, and the patient was discharged 9 days after the angiography without any recurrence of bleeding. Follow-up CT 1 month after the angiography detected enlarged liver and bone metastasis. In accordance with the wishes of the patient and his family, palliative care was begun. The patient remains alive with palliative care 5 months after the angiography.\nFig. 1 a, b CT revealed a 72 × 68 mm metastatic liver tumor in segment VI containing a 9-mm pseudoaneurysm (black arrow) and fluid collection around the hepatic edge (white arrow)\n\nFig. 2 a, b Emergency angiography showed a pseudoaneurysm stemming from a branch of the hepatic artery in segment VI. c The pseudoaneurysm was cannulated and successfully embolized using microcoils (white arrow)\n\n\n\nDiscussion\nIn this rare case, ITPA within a liver metastasis of gastric cancer following chemotherapy without any prior hepatobiliary intervention was ruptured and treated using arterial embolization.\n\nVisceral artery aneurysms are rare. Aneurysms of the hepatic artery, celiac axis, and branches, and splenic artery have a prevalence of 39%, 39%, and 18%, respectively [3]. Of cases of hepatic artery aneurysm, 77% are confined to the segment proximal to the liver, 20% have combined intra- and extraparenchymal involvement, and 3% are localized exclusively within the liver [4]. The present case was a pseudoaneurysm arising exclusively from the intrahepatic artery (branch of the segment VI hepatic artery).\n\nThe causes of visceral artery pseudoaneurysms are trauma, infection, inflammatory diseases, and complications of abdominal surgery, hepatobiliary interventions, and endoscopic explorations [5]. On the other hand, the incidence of pseudoaneurysms caused by malignant tumors is low although pseudoaneurysms caused by hepatocellular carcinomas (HCC), malignant lymphomas, desmoids, neurofibromatosis, giant cell tumors, leukemia, and so on have been reported [6–13].\n\nAn ITPA arising from the intrahepatic artery within a liver tumor is rare. While some cases of ITPA in the liver have been reported, almost all these tumors were hepatocellular carcinomas (HCC) [6–8, 14, 15]. ITPA within a liver metastasis of gastric cancer is extremely rare (Table 1). Liu et al. reported such a case caused by vascular injury after radiofrequency ablation (RFA) [16].\nTable 1 Clinical characteristics of patients with ITPA within a liver metastasis of gastric cancer\n\nAuthor\tGender\tAge\tSymptom\tPrior intervention\tTumor size (mm)\tSite\tITPA size (mm)\tTreatment\tOutcome\t\nLiu [16]\tM\t77\tHematemesis\tRFA\t45\tSegment III\tNot described\tEmbolization\tAlive\t\nOur case\tM\t59\tAbdominal pain\tnone\t72\tSegment VI\t9\tEmbolization\tAlive\t\nITPA intratumoral pseudoaneurysm, RFA radiofrequency ablation\n\n\n\nIntrahepatic artery pseudoaneurysms are iatrogenic, resulting from hepatobiliary intervention [17]. Even in ITPA, hepatobiliary interventions like transcatheter arterial chemoembolization and RFA resulting in vascular catastrophe are the most common causes [14–16, 18]. Yoshikawa et al. reported a case of ITPA within an HCC after carbon ion radiotherapy and described the cause as being angiogenesis, fragmentation of the vascular mesothelial elastic fibers, and edema of the subcutaneous blood vessels due to radiation [8]. However, few researchers have reported pseudoaneurysms arising de novo from within a HCC without any prior intervention [6, 7]. Among these, Haider et al. reported a case series (including 25 cases) and an annual incidence of 0.24% for the condition. The development of pseudoaneurysms is thought to be related to tumor angiogenesis [7].\n\nIn the present case, the patient had no hypertension, cardiovascular history, inflammatory disease, or recent trauma, and the metastatic liver tumor had not been treated by any hepatobiliary or other surgical procedure or radiation. Anatomical abnormalities, such as vascular malformation and tumor angiogenesis, were not observed on either the CT or angiogram. The cause of the ITPA in the present case was unclear, but the tumor necrosis found on CT likely led to encasement, erosion of the vessel wall, and subsequent arterial wall weakening leading to the development of the pseudoaneurysm as the tumor progressed. The chemotherapeutic drugs administered to the patient may have contributed to the conditions favoring its development. Two cases of pseudoaneurysm developing after FOLFIRI (irinotecan, leucovorin, 5-fluorouracil: 5-FU) combined with bevacizmab and FOLFOX (oxaliplatin, leucovorin, 5-FU) have been reported [19, 20]. Two other cases involved acute enlargement of an abdominal aortic aneurysm following chemotherapy with gemcitabine, cisplatin, docetaxel, and 5-FU [21, 22]. Some chemotherapy drugs have vascular toxicity and induce cell apoptosis leading to loss of integrity of the vascular wall [19–23]. In the present case, the ITPA was diagnosed during nivolumab administration as second-line chemotherapy following S-1 as adjuvant chemotherapy and RAM plus PTX as first-line chemotherapy. A previous study reported that 5-FU, its oral pro-drug, and PTX primarily alter the molecular signaling pathways controlling vascular smooth muscle cell tone, thereby inducing vasoconstriction, but did not explain the relationship of these drugs to pseudoaneurysm formation [23]. RAM is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) receptor-2, preventing its activation. Bleeding is a major adverse event reported in some clinical trials caused by angiogenesis inhibitors disrupting the tumor vasculature by inhibiting VEGF signaling, leading to thrombosis or bleeding [24, 25]. RAM may inhibit endothelial growth, thus resulting in a vessel wall breach and pseudoaneurysm formation. However, due to the absence of reports of similar cases, it is unclear whether any correlation exists between RAM and ITPA formation. However, such a correlation cannot be entirely ruled out, and it is possible that RAM is responsible for the bleeding caused by an ITPA rupture.\n\nThe prevalence of hepatic artery pseudoaneurysm ruptures can be as high as 90% [26]. As patients with visceral artery aneurysm rupture frequently present with hemorrhagic shock, prompt resuscitation with blood products and hemorrhage control are critical [27]. There are several effective approaches for treating hepatic artery pseudoaneurysms, including open surgery, which has a 21% mortality rate, as well as endovascular methods, which have a low complication and mortality rate [28]. Recent interventions using arterial embolization or stent grafts have been proposed as alternatives to surgical repair and offer real advantages in terms of survival [3].\n\nConclusion\nWe reported a case of intratumoral pseudoaneurysm within a liver metastasis of gastric cancer detected during chemotherapy. It is necessary to recognize that pseudoaneurysms can arise within a metastatic liver tumor during chemotherapy.\n\nAbbreviations\nCTComputed tomography\n\nFOLFIRIIrinotecan, leucovorin, 5-fluorouracil\n\nFOLFOXOxaliplatin, leucovorin, 5-FU\n\nHCCHepatocellular carcinoma\n\nITPAIntratumoral pseudoaneurysm\n\nPTXPaclitaxel\n\nRAMRamucirumab\n\nRFARadiofrequency ablation\n\nVEGFVascular endothelial growth factor\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone\n\nAuthors’ contributions\nKI performed the surgery. TK performed the endovascular procedure. HO and YI carried out the data acquisition and drafted the manuscript. SY, RY, FH, KI, and YM revised the article. The author(s) read and approved the final manuscript.\n\nFunding\nNone\n\nAvailability of data and materials\nThe data are not available for public access due to patient privacy concerns but are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe present study was conducted in accordance with the ethical standards of our institution.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Núñez DB Torres-León M Múnera F Vascular injuries of the neck and thoracic inlet: helical CT–angiographic correlation RadioGraphics. 2004 24 1087 1098 10.1148/rg.244035035 15256630 \n2. Sano T Kodera Y Japanese gastric cancer treatment guidelines 2010 (ver. 3) Gastric Cancer. 2011 14 113 123 10.1007/s10120-011-0040-6 21573742 \n3. Tulsyan N Kashyap VS Greenberg RK Sarac TP Clair DG Pierce G The endovascular management of visceral artery aneurysms and pseudoaneurysms J Vasc Surg. 2007 45 276 283 10.1016/j.jvs.2006.10.049 17264002 \n4. Berceli SA Hepatic and splenic artery aneurysms Semin Vasc Surg. 2005 18 196 201 10.1053/j.semvascsurg.2005.09.005 16360576 \n5. Boufi M Belmir H Hartung O Ramis O Beyer L Alimi YS Emergency stent graft implantation for ruptured visceral artery pseudoaneurysm J Vasc Surg. 2011 53 1625 1631 10.1016/j.jvs.2011.02.003 21530142 \n6. Chingkoe CM Chang SD Legiehn GM Weiss A Hepatic artery pseudoaneurysms arising from within a hepatocellular carcinoma Br J Radiol. 2010 83 252 254 10.1259/bjr/55365425 19723769 \n7. Haider Z Idris M Sajjad Z Humayun S Kashif N Ali S Intratumoral pseudoaneurysms in hepatocellular carcinoma: do they occur de novo without any prior intervention? A tertiary care center experience of 6 years Acta radiol. 2015 56 1027 1033 10.1177/0284185114549569 25267920 \n8. Yoshikawa S Asano T Watanabe M Ishii T Ohtake H Fujiwara J Rupture of hepatic pseudoaneurysm formed nine years after carbon ion radiotherapy for hepatocellular carcinoma Intern Med. 2019 58 2639 2643 10.2169/internalmedicine.2682-19 31178501 \n9. Hiraoka T Komiya T Tsuneyoshi H Shimamoto T Thoracic pseudoaneurysm caused by malignant lymphoma Ann Thorac Surg. 2018 105 e19 e20 10.1016/j.athoracsur.2017.08.008 29233355 \n10. Blanes Ortí PC Bernal LR Requejo García L Hernández MM Abdominal aortic rupture secondary to lymphoma recurrence Ann Vasc Surg 2019 58 381.e5 381.e9 10.1016/j.avsg.2018.10.050 \n11. Smith BL Munschauer CE Diamond N Rivera F Ruptured internal carotid aneurysm resulting from neurofibromatosis: treatment with intraluminal stent graft J Vasc Surg. 2000 32 824 828 10.1067/mva.2000.107769 11013049 \n12. Fraile NMP Toloi D Kurimori CO Matutino ARB Codima A Camargo VP Case report successful intravascular correction of intratumoral pseudoaneurysm by erosion of the aorta in a patient with thoracic giant cell tumor of bone responding to denosumab Case Rep Oncol Med. 2015 2015 626741 26600960 \n13. Kim MD Kim H Kang SW Jeong BG Nontraumatic hepatic artery pseudoaneurysm associated with acute leukemia: a possible complication of pyogenic liver abscess Abdom Imaging. 2002 27 458 460 10.1007/s00261-001-0078-8 12066246 \n14. Tamai F Furuse J Maru Y Yoshino M Intrahepatic pseudoaneurysm: a complication following radio-frequency ablation therapy for hepatocellular carcinoma Eur J Radiol. 2002 44 40 43 10.1016/S0720-048X(01)00436-3 12350410 \n15. Chuang CH Chen CY Tsai HM Hepatic infarction and hepatic artery pseudoaneurysm with peritoneal bleeding after radiofrequency ablation for hepatoma Clin Gastroenterol Hepatol. 2005 3 A23 10.1016/S1542-3565(05)00159-X 16271331 \n16. Liu CA Chiu NC Chiou YY Massive hematemesis after radiofrequency ablation of metastatic liver tumor with successful hemostasis achieved through transarterial embolization Clin Imaging. 2018 51 192 195 10.1016/j.clinimag.2018.03.007 29859483 \n17. Priyadarshi RN Kumar R Anand U Case report: spontaneous resolution of intracavitary hepatic artery pseudoaneurysm caused by amebic liver abscess following percutaneous drainage Am J Trop Med Hyg. 2019 101 157 159 10.4269/ajtmh.19-0103 31162010 \n18. Evangelos T Vassiliki P Dimitrios K Theodoros P Hepatic artery aneurysm complicating intra-arterial chemotherapy for hepatocellular carcinoma Hepatogastroenterology. 2003 50 830 831 12828096 \n19. Cosic L Theivendren M Spanger M Weinberg L Popliteal pseudoaneurysm after FOLFOX chemotherapy for metastatic colorectal cancer Int J Surg Case Rep. 2019 63 1 4 10.1016/j.ijscr.2019.08.028 31494411 \n20. Li C, Tsai H, Huang C, Yeh Y, Tsai T, Wang J. Iatrogenic pseudoaneurysm after bevacizumab therapy in patients with metastatic colorectal cancer: two case reports. Mol Clin Oncol. 2018:499–503.\n21. Zanow J Leistner Y Ludewig S Rauchfuss F Settmacher U Unusual course of an abdominal aortic aneurysm in a patient treated with chemotherapy for gastric cancer J Vasc Surg. 2012 55 841 843 10.1016/j.jvs.2011.09.005 22209605 \n22. Palm SJ Russwurm GP Chang D Rozenblit AM Ohki T Veith FJ Acute enlargement and subsequent rupture of an abdominal aortic aneurysm in a patient receiving chemotherapy for pancreatic carcinoma J Vasc Surg. 2000 32 197 200 10.1067/mva.2000.105665 10876224 \n23. Herrmann J Yang EH Iliescu CA Cilingiroglu M Charitakis K Hakeem A Vascular toxicities of cancer therapies: the old and the new - an evolving avenue Circulation. 2016 133 1272 1289 10.1161/CIRCULATIONAHA.115.018347 27022039 \n24. Xiao B Wang W Zhang D Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials Onco Targets Ther. 2018 11 5059 5074 10.2147/OTT.S166151 30174444 \n25. Arnold D Fuchs CS Tabernero J Ohtsu A Zhu AX Garon EB Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab Ann Oncol. 2017 28 2932 2942 10.1093/annonc/mdx514 28950290 \n26. O’Driscoll D Olliff SP Olliff JF Hepatic artery aneurysm Br J Radiol. 1999 72 1018 1025 10.1259/bjr.72.862.10673957 10673957 \n27. Reiter DA Fischman AM Shy BD Hepatic artery pseudoaneurysm rupture: a case report and review of the literature J Emerg Med. Elsevier Ltd 2013 44 100 103 10.1016/j.jemermed.2011.08.021 \n28. Bashiri K Roushan N Hamidian SM Hepatic artery pseudoaneurysm; simple or difficult to diagnose? Arch Iran Med. 2016 19 521 522 27362248\n\n",
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"keywords": "Gastric cancer; Hepatic artery; Metastatic liver tumor; Pseudoaneurysm",
"medline_ta": "Surg Case Rep",
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"title": "Intratumoral pseudoaneurysm within a liver metastasis of gastric cancer: a case report.",
"title_normalized": "intratumoral pseudoaneurysm within a liver metastasis of gastric cancer a case report"
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"abstract": "We herein report a case of migratory aortitis after the administration of granulocyte-colony-stimulating factor (G-CSF) to a 65-year-old woman with a history of pancreatic cancer. She was being administered pegfilgrastim and developed aortitis around the aortic arch. Although it resolved within two weeks, she again developed aortitis around the descending aorta, presenting as migratory aortitis, after pegfilgrastim was resumed. We further experienced three additional cases of G-CSF-induced aortitis that also showed spontaneous resolution, suggesting no or short-term use of immunosuppression. Aortitis due to G-CSF can present as migratory aortitis, since aortitis can quickly resolve and inflammation can recur at a different location.",
"affiliations": "Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Japan.;Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Japan.;Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Japan.;Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Japan.;Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Japan.;Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Japan.",
"authors": "Shirai|Tsuyoshi|T|;Komatsu|Hiroka|H|;Sato|Hiroko|H|;Fujii|Hiroshi|H|;Ishii|Tomonori|T|;Harigae|Hideo|H|",
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"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32188815\n10.2169/internalmedicine.4331-19\nCase Report\nMigratory Aortitis Associated with Granulocyte-colony-stimulating Factor\nShirai Tsuyoshi 1 Komatsu Hiroka 1 Sato Hiroko 1 Fujii Hiroshi 1 Ishii Tomonori 1 Harigae Hideo 1 \n1 Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Japan\nCorrespondence to Dr. Tsuyoshi Shirai, tsuyoshirajp@med.tohoku.ac.jp\n\n\n19 3 2020 \n15 6 2020 \n59 12 1559 1563\n13 12 2019 30 1 2020 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/).We herein report a case of migratory aortitis after the administration of granulocyte-colony-stimulating factor (G-CSF) to a 65-year-old woman with a history of pancreatic cancer. She was being administered pegfilgrastim and developed aortitis around the aortic arch. Although it resolved within two weeks, she again developed aortitis around the descending aorta, presenting as migratory aortitis, after pegfilgrastim was resumed. We further experienced three additional cases of G-CSF-induced aortitis that also showed spontaneous resolution, suggesting no or short-term use of immunosuppression. Aortitis due to G-CSF can present as migratory aortitis, since aortitis can quickly resolve and inflammation can recur at a different location. \n\naortitischemotherapygranulocyte-colony-stimulating factormigratory aortitis\n==== Body\nIntroduction\nAortitis is a disease that causes inflammation in the vascular walls of the aorta and its main branches with various inflammatory symptoms, such as a fever and pain (1). As aortitis progresses, it leads to serious pathological conditions, such as aortic aneurysms and dissection, and becomes life threatening. Therefore, the early detection and immediate treatment are important.\n\nThe most common causes of aortitis are the primary vasculitides that include large vessel vasculitis (LVV) [Takayasu arteritis (TAK) and giant cell arteritis (GCA)], Behçet's disease, and Cogan's disease (2). In addition, infection and drugs have also been reported to cause aortitis (3, 4). These etiologies are sometimes difficult to distinguish, and the detailed mechanisms that cause inflammation in the vascular wall are unknown.\n\nRecently, the development of aortitis following the use of granulocyte-colony-stimulating factor (G-CSF) has been recognized (5). We experienced four cases of aortitis associated with the use of G-CSF.\n\nWe herein report a case of migratory aortitis, an unusual manifestation of aortitis, associated with the administration of G-CSF.\n\nCase Report\nA 65-year-old woman was referred to our rheumatology department for the evaluation of a fever accompanied by thickening of the aortic arch. Two years earlier, she had suffered from pancreatic cancer and undergone distal pancreatectomy. Since then, the patient had been treated with titanium silicate (TS-1). Two months prior to admission, a liver metastasis had been diagnosed in her left lateral hepatic lobe. A central venous (CV) port had been inserted 27 days prior to admission, and FOLFIRINOX (fluorouracil, levofolinate calcium, irinotecan hydrochloride hydrate, and oxaliplatin) therapy had been initiated 15 days prior to admission. To prevent myelosuppression, pegfilgrastim (a long-acting G-CSF) had been administered 12 days prior to admission.\n\nShe experienced a fever (37°C) 4 days prior to admission to the general surgery department. Laboratory findings showed elevated inflammatory markers, such as C-reactive protein (11.8 mg/dL), so she was admitted to our hospital. Computed tomography (CT) revealed soft-tissue thickening around the aortic arch without aortic dissection (Fig. 1). It was suspected that she was suffering from LVV, so she was referred to our department.\n\nFigure 1. Thoracic aorta imaged by computed tomography. Findings at the time of referral and at months 3, 4, and 6 after referral are shown. White arrows indicate affected regions.\n\nOn referral, she had chest pain that corresponded to the position of the aortic arch. A physical examination revealed the following findings: blood pressure, 120/71 mmHg (without any difference between the upper limbs); pulse, 98 beats/min; body temperature, 39.1°C; and 98% oxygen saturation on room air. A cardiovascular examination revealed normal findings without bruits. Her lungs were clear during auscultation, and an abdominal examination was completely unremarkable with no skin lesions noted. Laboratory tests revealed an elevated erythrocyte sedimentation rate (94 mm/h) and C-reactive protein (CRP) level (7.45 mg/dL, Fig. 2). The other findings were macrocytic anemia and hypoalbuminemia. Although her rheumatoid factor was slightly elevated (20.8 IU/mL), tests for other autoantibodies were negative. The tumor marker CA19-9 was high (92.0 U/mL). Blood cultures and tests for syphilis and Chlamydia were negative.\n\nFigure 2. Clinical course. CRP: C-reactive protein, G-CSF: granulocyte-colony stimulating factor\n\nContrast-enhanced CT showed soft-tissue thickening with weak enhancement around the wall of the aortic arch (Fig. 1). Large-vessel magnetic resonance imaging (MRI) also confirmed wall enhancement of the affected lesion. These results indicated the presence of aortitis. Since the aortitis had occurred following the insertion of the CV port and chemotherapy, the differential diagnosis included infection, drug-induced inflammation, and primary LVV. Because the infectious etiology had not been ruled out, she was initially treated with minocycline. One week after the initiation of minocycline, marked improvement of the fever and inflammation were observed, and the patient's CRP levels had normalized. She was discharged on day 10, and CT showed improvement of the wall thickening (Fig. 1).\n\nShe received additional FOLFIRINOX treatments with pegfilgrastim, and occasionally manifested a fever and elevated CRP levels, both of which spontaneously resolved. Chemotherapy with pegfilgrastim was then restarted. Four months later, when she received her 7th cycle of FOLFIRINOX therapy, she again complained of a high fever (39°C), and her CRP levels were elevated at 13.68 mg/dL (Fig. 2). Using contrast-enhanced CT, soft-tissue thickening was found around the descending aorta without involvement of the aortic arch (Fig. 1). She was again referred to our department for an evaluation of aortitis. The affected artery lesions were migratory, which was an unusual manifestation of primary LVV. This, along with her medical history of spontaneous resolution of CRP levels during chemotherapy, which excluded an infectious etiology, prompted us to consider drug-induced aortitis.\n\nAmong the medications she had received, the complication of aortitis was documented only after the administration of pegfilgrastim. As continuing chemotherapy without pegfilgrastim was considered to pose a significant risk, partial hepatectomy was performed. Disappearance of the aortitis in the descending aorta was confirmed on follow-up CT (Fig. 1), and aortitis has not recurred in over one year.\n\nWe further experienced an additional three cases of aortitis associated with chemotherapy, with pegfilgrastim commonly used in all three (Table). In cases #20 and #21 in particular, aortitis developed when pegfilgrastim was administered for leukopenia, even though these patients had received the same chemotherapy regimen. This confirmed that a relationship thus exists between G-CSF and aortitis. In these three cases, the use of pegfilgrastim was discontinued, and aortitis has not recurred.\n\nTable. The Clinical Characteristics of Patients with G-CSF-induced Aortitis.\n\nCase\tCountry\tAge (years)\tSex\tUnderlying disease\tG-CSF\tTime to onset aortitis\tCancer treatment\tAortitis\tTreatment\tOutcome following discontinuation\tRef\t\n1\tFrance\t55\tFemale\tNone\tFilgrastim\t6 days\tn/a\tAbdominal\tSteroid\tResolved in 6 months\t(7)\t\n2\tGermany\tUnknown\tMale\tB cell lymphoma\tPegfilgrastim\t15 days\tNot reported\tNot reported\tNot reported\tResolved\t(8)\t\n3\tJapan\t49\tFemale\tUterine cancer\tFilgrastim\t6 days\tNot reported\tNot reported\tNSAID\tResolved in 1 months\t(8)\t\n4\tUS\t54\tMale\tLung cancer\tFilgrastim\t13 days\tCarboplatin\tAbdominal\tSteroid\tResolved\t(5)\t\n5\tIsrael\t52\tMale\tn/a\tFilgrastim\t6 months\tn/a\tAbdominal\tSteroid\tResolved\t(9)\t\n6\tJapan\t72\tFemale\tUterine cancer,\tPegfilgrastim\t13 days\tNot reported\tNot reported\tNone\tResolved in 1.5 months\t(8)\t\n7\tJapan\t76\tFemale\tBreast cancer\tPegfilgrastim\t7 days\tNot reported\tNot reported\tNone\tResolved in 11 days\t(8)\t\n8\tJapan\t77\tFemale\tOvarian cancer\tFilgrastim\t7 days\tNot reported\tNot reported\tNone\tResolved in 1 month\t(8)\t\n9\tJapan\t47\tFemale\tOvarian cancer\tLenograstim\t8 days\tNot reported\tNot reported\tSteroid\tResolved in 3 months\t(8)\t\n10\tJapan\t61\tFemale\tBreast cancer\tPegfilgrastim\t7 days\tNot reported\tNot reported\tNone\tResolved in 26 days\t(8)\t\n11\tJapan\t62\tFemale\tB cell lymphoma\tPegfilgrastim\t12 days\tNot reported\tNot reported\tSteroid\tResolved\t(8)\t\n12\tJapan\t65\tFemale\tBreast cancer\tPegfilgrastim\t9 days\tNot reported\tNot reported\tSteroid\tResolved in 1 month\t(8)\t\n13\tJapan\t66\tMale\tProstate cancer\tPegfilgrastim\t8 days\tNot reported\tNot reported\tNone\tResolved in 1 month\t(8)\t\n14\tJapan\t67\tFemale\tLung cancer\tPegfilgrastim\t8 days\tNot reported\tThoracic\tSteroid\tResolved with dissection at day 36\t(11)\t\n15\tJapan\t69\tFemale\tEsophageal cancer\tPegfilgrastim\t11 days\tNot reported\tNot reported\tNone\tResolved in 11 days\t(8)\t\n16\tSweden\t70\tFemale\tBreast cancer\tFilgrastim\t9 days\tDocetaxel, Trastuzumab, Pertuzumab\tThoracic\tSteroid\tResolved in 15 days\t(10)\t\n17\tSweden\t60\tFemale\tBreast cancer\tFilgrastim\t11 days\tDocetaxel\tThoracic\tSteroid\tResolved in 10 days\t(10)\t\n18\tJapan\t65\tFemale\tLiver metastasis of pancreatic cancer\tPegfilgrastim\t8 days\tFOLFILINOX\tThoracic\tNone\tResolved in 10 days\tPresent case\t\n19\tJapan\t74\tFemale\tTongue cancer\tPegfilgrastim\t8 days\tCDDP, 5-FU, DOC, Dexamethasone\tThoracic\tNone\tResolved in 10 days\tOther case in our department\t\n20\tJapan\t47\tFemale\tUterine cancer\tPegfilgrastim\t10 days\tCarboplatin, Paclitaxel\tThoracic\tNone\tResolved in 14 days\tOther case in our department\t\n21\tJapan\t43\tFemale\tUterine cancer\tPegfilgrastim\t7 days\tCarboplatin, Paclitaxel\tThoracic\tNone\tResolved in 21 days\tOther case in our department\t\nHL: hyperlipidemia, MI: myocardial infarction, US: United States, FOLFILINOX: fluorouracil, levofolinate calcium, irinotecan hydrochloride hydrate, and oxaliplatin, CDDP: cisplatin, 5-FU: 5-fluorouracil, DOC: docetaxel hydrate, G-CSF: granulocyte-colony-stimulating factor\n\nDiscussion\nIn the present report, we described a case of migratory aortitis caused by the administration of G-CSF. Although the occurrence of aortitis following the use of G-CSF has been recognized increasingly frequently, the natural course of aortitis caused by G-CSF has not been well documented, as corticosteroids were used in previously reported cases. We further experienced three additional cases, which also showed spontaneous improvement. Although it was difficult to exclude the effects of anti-cancer drugs on the development of aortitis completely, the use of pegfilgrastim was common among these cases, indicating the critical role of G-CSF for the development of aortitis. The present cases provided the following evidence in G-CSF-induced aortitis: a spontaneous resolution was expected; aortitis did not occur every time following G-CSF administration; and the site of inflammation was migratory.\n\nTo gather data related to G-CSF-induced aortitis, we searched the PubMed database using the term “G-CSF and aortitis” (6). Seventeen case reports were found between 2004 and 2019 (5, 7-11). In addition to the previous reports, a total of 21 cases were summarized, including the present case and other cases from our department (Table). The median age was 65 years old, and 17 of the 21 cases occurred in women. The most common underlying cancers were uterine and breast (4 cases, each). In all cases, aortitis developed in a short period of time (within 15 days) after the administration of G-CSF. It is notable that many reports are from Japan, and pegfilgrastim was used in most of those cases. Although we were not able to identify the site of inflammation in some cases, the site of aortitis was located at the abdominal aorta in three cases and at the thoracic aorta in seven cases. Only 9 of the 21 cases were treated with steroids. Nevertheless, all cases improved without developing chronic aortitis, such as TAK (12). Since steroids were used in most of the cases reported, this is the first detailed report describing the natural course of aortitis induced by repeated G-CSF use. As in the present case, aortitis due to G-CSF use can be expected to improve when the effect of G-CSF disappears. This means that immunosuppressive therapy is not required in most cases. However, it should also be noted that intense acute inflammation can rarely cause fatal side effects, such as asymptomatic aortic dissection, as previously reported (11). Parodis et al. reviewed the contribution of corticosteroids and concluded that moderate-to-high doses of corticosteroids should be started immediately following the diagnosis (10). Since vascular inflammation can improve spontaneously, as shown in the present case, it is difficult to conclude that immunosuppressants should be initiated for the treatment of LVV. However, the short-term use of immunosuppressants may be an option, considering the risk of developing aortic dissection. Although we did not treat any cases with immunosuppressants, aortitis resolved spontaneously without complication.\n\nIn the present case, the continuation of chemotherapy took precedence, and the patient did not experience aortitis following four cycles of chemotherapy. However, the elevation of inflammatory markers was eventually observed in three of eight cycles of chemotherapy. This clinical course indicated that this adverse event was not merely due to an allergic reaction to the G-CSF. In the present case, CT showed an improvement in wall thickening around the aortic arch three months after referral. Interestingly, at the last event, a new lesion appeared in the descending aorta, which had been intact at the first event, providing an unusual finding of migratory aortitis. Anti-cancer drugs are thought to cause chemical inflammation due to vascular disorders, but G-CSF is thought to cause inflammation due to an autoimmune mechanism induced by neutrophils. The occurrence of Sweet syndrome and leukocytoclastic vasculitis due to G-CSF has also been reported (13). Importantly, the incidence of aortitis was higher with pegfilgrastim, a long-acting form, than with filgrastim (Table). Although TAK and GCA are diseases affecting the aorta, vascular Behcet's disease, in which neutrophils play critical roles, also manifests aortitis. The serum G-CSF levels are reported to be elevated in the active phase of Behçet's disease (14). Since G-CSF increases the number of neutrophils, it is reasonable to consider that the administration of G-CSF triggered a pathomechanism similar to that involved in vascular Behçet's disease.\n\nHowever, one of the most important findings of this report was that most of the patients with aortitis induced by G-CSF were Japanese women. These features are actually characteristic of TAK, in which neutrophil-associated diseases, such as pyoderma gangrenosum, have also been documented (15, 16). Therefore, the mechanisms underlying the aortitis induced by G-CSF use might also contribute to the initiation of TAK. The association of specific human leukocyte antigen (HLA) with TAK has been recognized (17). Although we did not perform HLA-typing of our patients, checking the HLA status might be useful for clarifying the mechanisms involved in G-CSF-induced aortitis. Umeda et al. reported a patient with GCA that developed after the administration of G-CSF (18). Because the patient was treated with prednisolone, it was difficult to distinguish G-CSF-induced arteritis from GCA in that case. However, their patient possessed HLA alleles, a condition that is reportedly frequent in GCA, suggesting an association of G-CSF with the initiation of LVV.\n\nIn conclusion, G-CSF-induced aortitis can show spontaneous resolution and thus does not necessarily require continuous immunosuppression. However, in rare cases, aortic dissection has been reported, which may support the use of short-term immunosuppression therapy. It should also be noted that repeated G-CSF use causes aortitis to recur in different locations, presenting as migratory aortitis.\n\n\nWritten informed consent for publication of this case report was obtained from the patient.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\nThis work was supported by JSPS KAKENHI Grant Numbers 16H06642 and 18K16136 for TS and research grants from the Kanae Foundation and Nanbyo Medical Foundation for TS.\n\n\nTsuyoshi Shirai and Hiroka Komatsu contributed equally to this work.\n\nAcknowledgement\nThe authors thank the staff of the Department of Hematology & Rheumatology, Tohoku University for their helpful discussions.\n==== Refs\n1. \nBossone E , Pluchinotta FR , Andreas M , et al \nAortitis\n. Vascul Pharmacol \n80 : 1 -10\n, 2016 .26721213 \n2. \nJennette JC , Falk RJ , Bacon PA , et al \n2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides\n. Arthritis Rheum \n65 : 1 -11\n, 2013 .23045170 \n3. \nKeser G , Aksu K \nDiagnosis and differential diagnosis of large-vessel vasculitides\n. Rheumatol Int \n39 : 169 -185\n, 2019 .30221327 \n4. \nMutoh T , Ishii T , Shirai T , et al \nRefractory Takayasu arteritis successfully treated with rituximab: case-based review\n. Rheumatol Int \n39 : 1989 -1994\n, 2019 .31388749 \n5. \nAdiga GU , Elkadi D , Malik SK , Fitzpatrick JD , Madajewicz S \nAbdominal aortitis after use of granulocyte colony-stimulating factor\n. Clin Drug Invest \n29 : 821 -825\n, 2009 .\n6. \nGasparyan AY , Ayvazyan L , Blackmore H , Kitas GD \nWriting a narrative biomedical review: considerations for authors, peer reviewers, and editors\n. Rheumatol Int \n31 : 1409 -1417\n, 2011 .21800117 \n7. \nDarie C , Boutalba S , Fichter P , et al \nAortitis after G-CSF injections\n. Rev Med Interne \n25 : 225 -229\n, 2004 (in French, Abstract in English).14990294 \n8. \nLardieri A , McCulley L , Jones SC , Woronow D \nGranulocyte colony-stimulating factors and aortitis: a rare adverse event\n. Am J Hematol \n93 : E333 -E336\n, 2018 .30016548 \n9. \nMiller EB , Grosu R , Landau Z \nIsolated abdominal aortitis following administration of granulocyte colony stimulating factor (G-CSF)\n. Clin Rheumatol \n35 : 1655 -1657\n, 2016 .27094941 \n10. \nParodis I , Dani L , Notarnicola A , et al \nG-CSF-induced aortitis: Two cases and review of the literature\n. Autoimmun Rev \n18 : 615 -620\n, 2019 .30959218 \n11. \nSato Y , Kaji S , Ueda H , Tomii K \nThoracic aortitis and aortic dissection following pegfilgrastim administration\n. Eur J Cardio-Thorac \n52 : 993 -994\n, 2017 .\n12. \nMutoh T , Shirai T , Fujii H , Ishii T , Harigae H \nInsufficient use of corticosteroids without immunosuppressants results in higher relapse in Takayasu arteritis\n. J Rheumatol \n47 : 255 -263\n, 2020 .31092708 \n13. \nSpiekermann K , Roesler J , Emmendoerffer A , Elsner J , Welte K \nFunctional features of neutrophils induced by G-CSF and GM-CSF treatment: differential effects and clinical implications\n. Leukemia \n11 : 466 -478\n, 1997 .9096685 \n14. \nKawakami T , Ohashi S , Kawa Y , et al \nElevated serum granulocyte colony-stimulating factor levels in patients with active phase of sweet syndrome and patients with active Behçet disease - implication in neutrophil apoptosis dysfunction\n. Arch Dermatol \n140 : 570 -574\n, 2004 .15148101 \n15. \nShirai T , Hanaoka R , Goto Y , et al \nTakayasu arteritis coexisting with sclerosing osteomyelitis\n. Intern Med \n57 : 1929 -1934\n, 2018 .29434141 \n16. \nUjiie H , Sawamura D , Yokota K , Nishie W , Shichinohe R , Shimizu H \nPyoderma gangrenosum associated with Takayasu's arteritis\n. Clin Exp Dermatol \n29 : 357 -359\n, 2004 .15245528 \n17. \nRenauer P , Sawalha AH \nThe genetics of Takayasu arteritis\n. Presse Med \n46 : e179 -e187\n, 2017 .28756073 \n18. \nUmeda M , Ikenaga J , Koga T , et al \nGiant cell arteritis which developed after the administration of granulocyte-colony stimulating factor for cyclic neutropenia\n. Intern Med \n55 : 2291 -2294\n, 2016 .27523011\n\n",
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"keywords": "aortitis; chemotherapy; granulocyte-colony-stimulating factor; migratory aortitis",
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"pubdate": "2020-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14990294;31388749;28549110;28756073;29434141;15148101;31092708;30959218;19888788;26721213;23045170;30221327;27523011;15245528;30016548;21800117;27094941;9096685",
"title": "Migratory Aortitis Associated with Granulocyte-colony-stimulating Factor.",
"title_normalized": "migratory aortitis associated with granulocyte colony stimulating factor"
} | [
{
"companynumb": "NVSC2020JP205837",
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"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOLEUCOVORIN CALCIUM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThis case report highlights serious cardiovascular adverse effects with a conventional dose of trazodone as a result of its potential interaction with omeprazole.\n\n\nMETHODS\nA 54-year-old man who was a former smoker, with dyslipidemia, coronary artery disease, and anxiety disorder developed lightheadedness and syncope the morning of admission. He was taking trazodone 50 mg daily, omeprazole 20 mg daily, and simvastatin 20 mg at bedtime. He doubled the dose of trazodone 50 mg on the night prior to presentation to calm his anxiety. An electrocardiogram revealed sinus rhythm at 60 beats per minute and second-degree Mobitz type 1 atrioventricular (AV) block with 5:4 AV conduction. Results of basic metabolic panel, thyroid-stimulating hormone, and chest radiograph were normal. A transthoracic echocardiogram revealed aortic valve sclerosis. We tested for Lyme disease given his history of hunting in the woods 8 months prior to presentation, but the titer was negative. Trazodone and omeprazole were discontinued. By the 3rd day of medication discontinuation, all symptoms had resolved and the frequency of second-degree AV Mobitz type 1 AV block had decreased to once per hour.\n\n\nCONCLUSIONS\nDue diligence and meticulous attention to detail needs to be exercised to uncover drug interactions as potential causes of lethal and nonlethal patient symptomatology, as in this case of syncope caused by concomitant use of trazodone and a widely prescribed medication, omeprazole.",
"affiliations": "Department of Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, Jamaica, NY, USA.;Department of Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, Jamaica, NY, USA.;Department of Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, Jamaica, NY, USA.;Department of Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, Jamaica, NY, USA.",
"authors": "Akinseye|Oluwaseun A|OA|;Alfishawy|Mostafa|M|;Radparvar|Farshid|F|;Bakshi|Sanjiv|S|",
"chemical_list": "D014151:Anti-Anxiety Agents; D054328:Proton Pump Inhibitors; D009853:Omeprazole; D014196:Trazodone",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.893427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "16()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D014151:Anti-Anxiety Agents; D001007:Anxiety; D054537:Atrioventricular Block; D003937:Diagnosis, Differential; D004347:Drug Interactions; D004562:Electrocardiography; D006801:Humans; D008297:Male; D008875:Middle Aged; D009853:Omeprazole; D054328:Proton Pump Inhibitors; D013575:Syncope; D014196:Trazodone",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "319-21",
"pmc": null,
"pmid": "26017199",
"pubdate": "2015-05-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "7018873;6859324;19384678;7506393;9616194;11603256;19017591;18693067;6496797;23192413;23620487;16960982",
"title": "Trazodone and omeprazole interaction causing frequent second-degree Mobitz type 1 atrioventricular (AV) block (Wenckebach phenomenon) and syncope: a case report and literature review.",
"title_normalized": "trazodone and omeprazole interaction causing frequent second degree mobitz type 1 atrioventricular av block wenckebach phenomenon and syncope a case report and literature review"
} | [
{
"companynumb": "US-TEVA-578903USA",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAZODONE HYDROCHLORIDE"
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"drugadditional": null,
... |
{
"abstract": "Thromboembolic events such as deep vein thrombosis and pulmonary embolism are well-known complications that can occur after prothrombin complex concentrate therapy. However, acute myocardial infarction is a very rare but potentially life-threatening complication that was exclusively described in patients with bleeding disorders who received chronic and recurrent concentrate infusions. We report the case of a 70 year-old male patient with cholangiocarcinoma who was admitted to our hospital with worsening fatigue and weakness. His stay was complicated by uncontrolled bleeding secondary to rivaroxaban use and advanced liver disease. By the end of the prothrombin complex concentrate infusion used to reverse his coagulopathy, patient developed ST-segment elevation myocardial infarction with cardiogenic shock and passed away. This is the first reported case of acute myocardial infarction that occurs in a patient without hemophilia and after the first prothrombin complex concentrate infusion.",
"affiliations": "Department of Internal Medicine at Staten Island University Hospital, Northwell Health.;Department of Internal Medicine at Staten Island University Hospital, Northwell Health.;Department of Cardiovascular Medicine at Staten Island University Hospital, Northwell Health.;Department of Cardiovascular Medicine at Staten Island University Hospital, Northwell Health.;Department of Cardiovascular Medicine at Staten Island University Hospital, Northwell Health.",
"authors": "Tabet|Rabih|R|;Shammaa|Youssef|Y|;Karam|Boutros|B|;Yacoub|Harout|H|;Lafferty|James|J|",
"chemical_list": "D001779:Blood Coagulation Factors; C025667:prothrombin complex concentrates; D000069552:Rivaroxaban",
"country": "Japan",
"delete": false,
"doi": "10.5582/ddt.2018.01012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1881-7831",
"issue": "12(2)",
"journal": "Drug discoveries & therapeutics",
"keywords": "Prothrombin complex concentrate; ST-segment elevation myocardial infarction; liver disease; thromboembolic adverse event",
"medline_ta": "Drug Discov Ther",
"mesh_terms": "D000368:Aged; D001650:Bile Duct Neoplasms; D001779:Blood Coagulation Factors; D018281:Cholangiocarcinoma; D017809:Fatal Outcome; D006470:Hemorrhage; D006801:Humans; D008297:Male; D000069552:Rivaroxaban; D000072657:ST Elevation Myocardial Infarction; D012770:Shock, Cardiogenic",
"nlm_unique_id": "101493809",
"other_id": null,
"pages": "104-107",
"pmc": null,
"pmid": "29681563",
"pubdate": "2018-05-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prothrombin complex concentrate and fatal thrombotic adverse events: A complication to keep in mind.",
"title_normalized": "prothrombin complex concentrate and fatal thrombotic adverse events a complication to keep in mind"
} | [
{
"companynumb": "US-IGSA-SR10006253",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "The risk of developing pericarditis secondary to Methicillin-Resistant Staphylococcus aureus (MRSA) infection in the absence of preceding surgical procedure is extremely low. We present a case report of a 36-year-old woman who developed disseminated MRSA infection leading to purulent pericarditis.",
"affiliations": "Department of Infectious diseases, Louisiana State University Health Sciences Center, Shreveport, USA pmada@lsuhsc.edu.;Department of Infectious diseases, Louisiana State University Health Sciences Center, Shreveport, USA.;Department of Infectious diseases, Louisiana State University Health Sciences Center, Shreveport, USA.;Department of Infectious diseases, Louisiana State University Health Sciences Center, Shreveport, USA.",
"authors": "Mada|Pradeep Kumar|PK|;Cady|Beth|B|;De Silva|Anajana|A|;Alam|Mohammad|M|",
"chemical_list": "D002511:Cephalosporins; C490727:T 91825; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218463",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Cardiovascular system; Drugs and medicines; Infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D002511:Cephalosporins; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus; D010493:Pericarditis; D011239:Prednisolone; D013203:Staphylococcal Infections; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28360036",
"pubdate": "2017-03-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11294701;12622586;15725041;15972563;17940231;26461998",
"title": "Disseminated MRSA infection with purulent pericarditis.",
"title_normalized": "disseminated mrsa infection with purulent pericarditis"
} | [
{
"companynumb": "US-APOTEX-2017AP012635",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
"drugadditional": "1",
... |
{
"abstract": "Influenza virus infection may present with fever, chills, headache, myalgia, malaise, and respiratory symptoms, with a few cases developing into pneumonia, respiratory failure, and other organ damage. Very few cases of atraumatic splenic rupture associated with influenza infection have been reported. Atraumatic splenic rupture, while rare, is associated with high mortality. Here, we report the first case of atraumatic splenic rupture associated with influenza infection in the English literature and review the prior reported literature. The patient was diagnosed with influenza A (H1N1) pneumonia and subsequently developed hemorrhagic shock requiring emergency laparotomy and removal of the ruptured spleen.",
"affiliations": "Department of Medicine, MedStar Good Samaritan Hospital, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland Saint Joseph Medical Center, Towson, Maryland, USA.;Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.",
"authors": "Deol|Dilraj|D|;Wu|Huimin|H|;Lasso-Pirot|Anayansi|A|;Robinett|Kathryn S|KS|;Diaz-Abad|Montserrat|M|https://orcid.org/0000-0001-8877-7313",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6516064",
"fulltext": "\n==== Front\nCase Rep Med\nCase Rep Med\nCRIM\nCase Reports in Medicine\n1687-9627\n1687-9635\nHindawi\n\n10.1155/2021/6516064\nCase Report\nAtraumatic Splenic Rupture Associated with Influenza A (H1N1) Pneumonia: Case Report and Review of the Literature\nDeol Dilraj 1\nWu Huimin 2\nLasso-Pirot Anayansi 3\nRobinett Kathryn S 4\nhttps://orcid.org/0000-0001-8877-7313\nDiaz-Abad Montserrat mdiaz@som.umaryland.edu\n4\n1Department of Medicine, MedStar Good Samaritan Hospital, Baltimore, Maryland, USA\n2Department of Medicine, University of Maryland Saint Joseph Medical Center, Towson, Maryland, USA\n3Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA\n4Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA\nAcademic Editor: Timothy J. Craig\n\n2021\n3 8 2021\n2021 65160648 4 2021\n29 7 2021\nCopyright © 2021 Dilraj Deol 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.\nInfluenza virus infection may present with fever, chills, headache, myalgia, malaise, and respiratory symptoms, with a few cases developing into pneumonia, respiratory failure, and other organ damage. Very few cases of atraumatic splenic rupture associated with influenza infection have been reported. Atraumatic splenic rupture, while rare, is associated with high mortality. Here, we report the first case of atraumatic splenic rupture associated with influenza infection in the English literature and review the prior reported literature. The patient was diagnosed with influenza A (H1N1) pneumonia and subsequently developed hemorrhagic shock requiring emergency laparotomy and removal of the ruptured spleen.\n==== Body\n1. Introduction\n\nInfluenza viruses are divided into three types, influenza A, B, and C viruses. Influenza A viruses cause epidemic influenza and sporadic pandemics, and they are further classified into subtypes on the basis of the antigenic properties of two surface glycopeptides, hemagglutinin (H) and neuraminidase (N). There are 18 different H subtypes and 11 different N subtypes (H1 to H18 and N1 to N11). Influenza A (H1N1), which caused a world pandemic in 2009, is one of the common influenza viruses and is now included in each year's influenza vaccine [1].\n\nInfluenza infection may present with fever, chills, headache, myalgia, malaise, and anorexia, accompanied by respiratory symptoms, including nonproductive cough, nasal discharge, and sore throat [1]. Some patients may develop pneumonia, respiratory failure, and other organ damage [2].\n\nVery few cases [3–7] of atraumatic splenic rupture associated with influenza infection have been reported in the literature. Atraumatic splenic rupture, is rare and, if missed, can be associated with high mortality [8]. We report the first case in the English literature of atraumatic splenic rupture associated with influenza infection and review the prior reported literature.\n\n2. Case Presentation\n\nA 50-year-old man with past medical history of hypothyroidism and cigarette smoking had been on vacation in Florida, USA, with his family for 3 weeks. The day of his return flight in July, he developed a sore throat and body aches followed by fever and a productive cough. He went to urgent care, was diagnosed with acute bronchitis, and was treated as outpatient with azithromycin and prednisone for 5 days without improvement. On the eighth day of symptoms, he developed confusion and was brought to the emergency department (ED) for further evaluation.\n\nIn the ED, the patient had mild shortness of breath but denied nausea, vomiting, or abdominal pain. On physical exam, he had temperature 38.3°C, heart rate 120 beats/min, respiratory rate 25 breaths/min, and SpO2 90% on room air, with coarse breath sounds bilaterally on lung exam; he was started on oxygen 2 L/min via nasal cannula. A chest X-ray showed bibasilar lung infiltrates. Testing revealed white blood cell count 9.0 k/uL (4.0–10.0 k/uL), hemoglobin (Hb) 15.8 g/dL (13.0–18.0 g/dL), platelets 249 k/uL (150–400 k/uL), international normalized ratio 1.4 (≤3.5), protime 15.1 seconds (10.0–12.0 seconds), partial thromboplastin time 37.4 seconds (25.0–35.0 seconds), blood urea nitrogen 28 mg/dL (9–20 mg/dL), creatinine 1.46 mg/dL (0.66–1.25 mg/dL), total protein 7.5 g/dL (6.3–8.2 g/dL), albumin 3.9 g/dL (3.5–5.0 g/dL), total bilirubin 1.4 mg/dL (0.2–1.3 mg/dL), alkaline phosphatase 195 U/L (38–126 U/L), alanine aminotransferase 160 U/L (21–72 U/L), and aspartate aminotransferase 243 U/L (17–59 U/L). Urine Legionella antigen and Streptococcus pneumoniae antigen tests were negative. An ultrasound of the abdomen showed a contracted gallbladder with probable calculi and normal pancreas and spleen. He was diagnosed with community acquired pneumonia, started on intravenous ceftriaxone and azithromycin, and admitted to the medical floor. He was also started on heparin 5000 U subcutaneously every 8 hours for thromboembolism prophylaxis.\n\nThe patient's shortness of breath deteriorated overnight. Chest X-ray showed worsening lung infiltrates, predominantly in the left lung. He had increased work of breathing and worsening hypoxemia requiring oxygen via high flow nasal cannula and transfer to the intensive care unit. More information was obtained from the family: his wife and father also had developed a cough and no one in the family including the patient had ever received influenza vaccination. A polymerase chain reaction (PCR) respiratory viral panel on a nasopharyngeal swab sample was positive for influenza A (H1N1) virus, and therapy was started with oseltamivir.\n\nThe patient's respiratory status continued to worsen. He developed hypotension and severe abdominal pain on the third day of hospitalization. Serum amylase was 157 U/L (30–110 U/L) and lipase 1454 U/L (23–300 U/L). Hb decreased from 15.8 to 7.4 g/dL. Coagulation parameters were normal. Arterial blood gases revealed pH 7.5 (7.35–7.45), PaCO2 21 mm Hg (35–45 mm Hg), and PaO2 52 mm Hg (80–100 mm Hg) on high flow nasal cannula FiO2 70% at 50 L/min and the patient was subsequently intubated. Computed tomography (CT) of the chest and abdomen revealed lung consolidation of the left upper lobe and infiltrates in both lower lobes and right middle lobe, with no evidence of pulmonary embolism (Figure 1). The lateral margin of the spleen was indistinct and with low density areas, concerning for splenic injury or rupture (Figure 2). The patient denied any prior abdominal trauma.\n\nDue to these findings along with suspected ongoing hemorrhage with decreasing Hb values since admission, the patient underwent an embolization of the splenic artery by interventional radiology. Despite this procedure, Hb values continued to decrease, remaining at 7.7 g/dL despite transfusion with 3 units of packed red blood cells. The patient underwent emergency laparotomy with splenectomy to control the hemorrhage. During the surgery, there was extensive hemoperitoneum and the spleen capsular surface was found to be hemorrhagic with a large laceration in the mid portion (Figure 3). Pathologic examination revealed a spleen with weight 521 g and size 15 cm × 10 cm × 6 cm. The capsular surface was deep red due to hemorrhage with an irregular 10 cm laceration in the mid portion nearly bisecting the specimen with an intact hilar margin. There was a slightly puckered area located 5.5 cm from the point of laceration with an underlying somewhat stellate area of apparent fibrous tissue with vascular proliferation consistent with a hemangioma measuring 1.5 cm in greatest dimension. The splenic parenchyma was red brown. There was a large hematoma with a focal rim of tan white fibrous tissue. There was no evidence of malignancy.\n\nA bronchoscopy with bronchoalveolar lavage was performed in the operating room after the splenectomy, and the culture was positive for influenza A (H1N1) virus only. Infectious mononucleosis and malaria work up were negative. The patient was continued on oseltamivir for treatment of influenza pneumonia and acute hypoxemic respiratory failure, was extubated successfully after 14 days of mechanical ventilatory support, and was discharged home in good condition after 40 days of hospitalization.\n\n3. Discussion\n\nWe present the case of a patient with severe influenza A (H1N1) pneumonia and respiratory failure, who experienced atraumatic splenic rupture requiring emergency splenectomy to control hemorrhagic shock. While associated with other viral infections, atraumatic splenic rupture has been very rarely reported in association with influenza infection, and to our knowledge, never in the English literature as the only associated condition.\n\nIn addition to its common symptoms, some patients with influenza A (H1N1) virus infection develop severe disease, complicated with pneumonia, acute respiratory distress syndrome, respiratory failure, and other organ damage such as myositis, rhabdomyolysis, renal failure, myocarditis, pericarditis, encephalopathy, and liver function abnormalities [2]. In addition to pneumonia and respiratory failure, our patient experienced acute renal failure and transaminitis, as well as an atraumatic splenic rupture with hemorrhagic shock, requiring multiple transfusions and emergency splenectomy after a failed splenic artery embolization. Splenic rupture can be life-threatening and requires a high index of clinical suspicion and emergent intervention to prevent death. Since the spleen plays a key role in combating infection, a conservative, interventional, or spleen-preserving surgical approach should be attempted first. However, total splenectomy should be performed for patients with severe rupture, hemodynamic instability, or continued and recurrent bleeding [9].\n\nAtraumatic splenic rupture is rare. Common causes include infection, neoplasms, and vasculitis [8, 10]. One large systematic review reported 613 cases of splenic rupture without risk factors or previously diagnosed diseases [8]. Malaria, mononucleosis, cytomegalovirus infection, and typhoid fever were common infectious causes. Only 3 cases were associated with pneumonia, 2 of them caused by Legionella infection. Influenza infection was not reported in that study. Another systematic review reported 845 patients with atraumatic splenic rupture [10]; of those, 137 patients had an infectious cause, but none had influenza infection.\n\nThe precise pathologic mechanisms implicated in atraumatic splenic rupture have not been conclusively determined and probably vary from case to case. Mechanisms that have been proposed in different cases include (1) increased intra-abdominal pressure (related to coughing, sneezing, emesis, defecation, and pregnancy) leading to accumulated trauma on the splenic capsule; (2) an increase in intrasplenic tension due to cellular hyperplasia and vascular engorgement; and (3) reticular endothelial hyperplasia resulting in thrombosis and infarction, leading to hemorrhage and rupture of the splenic capsule. In addition, coagulopathy, thrombocytopenia, and platelet dysfunction may prolong hemorrhage that would otherwise be self-limited [11, 12].\n\nIt is possible that an exaggerated immune response to influenza infection may play a role in this rare complication. The influenza A (H1N1) virus has been isolated on organ samples of the lung, brain, kidney, and spleen on animal experiments, [13] and it has also been reported that the spleen plays a particularly active role in the innate immune response to influenza A (H1N1) [14]. The precise mechanisms involved in this case are unclear, but there was a productive cough present which could have contributed to the rupture and the patient was also receiving a prophylactic dose of heparin. While a very small hemangioma was noted on histologic examination, there was no evidence of bleeding in its location.\n\nSo far, there have been at least 5 other cases reported of atraumatic splenic rupture associated with influenza infection, none in the English literature. The first case was in Russia (former Soviet Union) in 1963 [3]. A 43 y/o woman with severe influenza reported mild pain in the left upper abdomen. She was treated as an outpatient and recovered completely. One month after the symptoms started, she developed severe abdominal pain in the same area and fever 38°C. Four days later, she was admitted to the hospital with severe diffuse abdominal pain, nausea, vomiting, lightheadedness, fever 38.5°C, and unmeasurable blood pressure. On exam, she was very pale, the abdomen was distended and tender, and a fluid shift was present. She was treated for hemorrhagic shock and underwent emergency laparotomy with splenectomy. Surgical findings were an enlarged ruptured spleen and 1.5 L of blood and clots in the abdominal cavity. On pathology, the spleen was congested with blood, with lymphoid hyperplasia and necrotic tissue around the rupture. The patient recovered.\n\nThe second case occurred in Poland in 1964 [4]. A 22-year-old male had influenza and related symptoms for 10 days. One day after admission, he developed severe pain in the left epigastric and lumbar regions and anemia that did not respond to transfusion. On the sixth day, the pain increased, and the patient underwent a laparotomy with splenectomy. An enlarged, necrosed spleen was noted with blood clots surrounding it and 1 L of blood in the peritoneal cavity. He recovered.\n\nA third case was reported in Ukraine (former Soviet Union) in 1969 [5]. A 60-year-old woman was admitted with influenza pneumonia confirmed by antibody titers. She had severe headache, fever 38.1°C, cough, and rhinorrhea. Over the next four days, all symptoms resolved, but she then developed acute, severe pain in the epigastric area, nausea, and vomiting. Blood pressure was 80/40 mm Hg, with severe tachycardia and Hb 5.2 g/dL. The patient underwent emergency laparotomy for worsening shock. During the surgery, 2 L of blood and clots were found in the abdominal cavity along with a ruptured spleen requiring splenectomy. On pathology of the spleen, there was significant sclerosis of the red pulp and of the stroma surrounding the follicles. Almost all vessels were significantly narrowed with thickened walls; parts of the vessel walls had necrotic changes and there was cellular debris in some follicles. The patient was discharged home 2 months later. Of note, the article references one additional case of splenic rupture with influenza authored by PM Geyler in 1963; full reference was not provided, and the report was not able to be located despite a comprehensive search.\n\nA fourth case was published in Hungary in 1979 [6]. A 57-year-old man with influenza had experienced 7 days of fever and limb pain at home and was already improving. He then developed weakness and dizziness and was admitted to the hospital. He had abdominal pain, Hb 9.9 g/dL, tachycardia, and hypotension. He underwent laparotomy where a large amount of clotted blood was found in the abdominal cavity. The spleen had a transverse rupture of 1.5 cm on its anterior surface, which did not penetrate the entire thickness and a splenectomy was done. On gross examination, the spleen weighed 160 g and demonstrated a 3 cm disruption laterally in the lower third extending 5–6 mm into the parenchyma. On microscopy, the follicular pattern was preserved with prominent germinal centers. Areas of parenchymal hemorrhage were also noted. The histological picture was thought to be similar to changes seen in sepsis, which suggested to the authors the possibility of a viral infection as the cause.\n\nA fifth case was published in Spain in 2011 [7]. A 36-year-old man had fever 39.5°C, vomiting, diarrhea, and epigastric pain for 5 days and was admitted. On exam, he had blood pressure 95/55 mm Hg and heart rate 100 beats/min. One day later, the patient had intense abdominal pain and lost consciousness when standing. His Hb was 8.9 g/dL and an abdominal CT showed lung alveolar infiltrate in the bases and a splenic rupture with active hemorrhage and hemoperitoneum. A laparotomy with splenectomy was done. On pathology, the spleen was of normal size with the external surface showing some hemorrhagic areas with adherent clots that covered less than 5% of the external surface. A histologic diagnosis of capsular rupture with hemorrhagic foci over a normal spleen was made. After the urgent surgery, the patient recovered and was later diagnosed with influenza A (H1N1) pneumonia with a positive PCR test.\n\nThe above mentioned 5 cases, except for the last one, were reported more than 40 years ago. Reports were brief, with limited information provided including figures and diagnostic methods and with outdated terminology. They do, however, have all in common a diagnosis of splenic rupture without a history of prior trauma and an associated diagnosis of influenza, with the influenza-related symptoms preceding the abdominal signs and symptoms, anemia, and hemorrhagic shock associated with the splenic rupture.\n\nBesides the abovementioned cases, there is one reported case in the English literature of atraumatic splenic rupture associated with influenza A (H1N1) infection. However, this case also had coinfection with Legionella pneumonia [15], which has also been associated with splenic rupture [8], so it cannot be ruled out that the splenic rupture could be due to Legionella infection instead of the influenza infection, or due to coinfection. The patient was a 42-year-old man who was hospitalized with fever of 39°C, progressive dyspnea, and nonproductive cough. On admission, he had anemia with Hb of 5 g/dL and tested positive both for influenza A (H1N1) virus by PCR test on a throat swab and for Legionella by urinary antigen test and PCR in peripheral blood. Total body CT showed extensive bilateral interstitial pneumonia and signs of incipient splenic rupture. He underwent laparotomy with splenectomy. Histological examination showed diffuse splenic intravascular coagulation. The patient achieved full clinical recovery.\n\nIn conclusion, we present a very rare case of atraumatic splenic rupture associated with influenza A (H1N1) infection, which required emergency laparotomy with splenectomy to control hemorrhage after a failed splenic artery embolization. To our knowledge, this is the first case reported in the English literature of this complication associated with influenza infection, and only one of a handful reported previously worldwide. Clinicians should be aware of this very rare but potentially fatal complication of influenza infection, in particular in patients who develop abdominal signs and symptoms, unexplained anemia, and hemodynamic instability.\n\nAcknowledgments\n\nThe authors wish to thank Yelena Gerashchenko, MD, PA-C, Euriko Torrazza Perez, MD, and Susan E. Harman, MSLS, for help with literature search and translations.\n\nData Availability\n\nNo data were used to support this study.\n\nConflicts of Interest\n\nThe authors declare that there are no conflicts of interest.\n\nFigure 1 Computed tomography scan (CT) of the chest showing infiltrates in both lower lung lobes.\n\nFigure 2 Initial computed tomography scan (CT) of the abdomen showing perihepatic and perisplenic fluid, and the lateral margin of the spleen indistinct with low density areas, concerning for splenic injury or rupture.\n\nFigure 3 Appearance of the spleen after splenectomy. The capsular surface was hemorrhagic with an irregular 10 cm laceration in the mid portion nearly bisecting the spleen with an intact hilum.\n==== Refs\n1 Paules C. Subbarao K. Influenza The Lancet 2017 390 10095 697 708 10.1016/S0140-6736(17)30129-0 2-s2.0-85019701331\n2 Pham T. Combes A. Rozé H. Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome American Journal of Respiratory and Critical Care Medicine 2013 187 3 276 285 10.1164/rccm.201205-0815OC 2-s2.0-84873334263 23155145\n3 IuS F. Berezin I. M. On spontaneous splenic ruptures Khirurgiia (Mosk) 1963 39 81 84\n4 Wojtowicz M. Rupture of the spleen as a complication of influenza Polski Przeglad Chirurgiczny 1964 36 1111 1113 14250248\n5 Barchuk V. F. Zagorodniaia I. S. Bzenko V. F. Spontaneous rupture of spleen in patients with gripp Vrachebnoe Delo 1969 5 127 128 5368861\n6 Vizer G. Weiland O. Spontaneous splenic rupture in influenza Orvosi Hetilap 1979 120 19 1139 1140 450447\n7 Domínguez Pérez A. D. Iribarren Marín M. A. González Martín R. Martínez Moya M. Rotura espontánea del bazo en paciente con neumonía por virus H1N1 Medicina Clínica 2011 136 6 267 268 10.1016/j.medcli.2010.01.007 2-s2.0-79952312133 20537359\n8 Aubrey-Bassler F. K. Sowers N. 613 cases of splenic rupture without risk factors or previously diagnosed disease: a systematic review BMC Emergency Medicine 2012 12 1 p. 11 10.1186/1471-227X-12-11 2-s2.0-84864922125\n9 Dumic I. Patel J. Hart M. Niendorf E. R. Martin S. Ramanan P. Splenic rupture as the first manifestation of babesia microti infection: report of a case and review of literature American Journal of Case Reports 2018 19 335 341 10.12659/ajcr.908453 2-s2.0-85044728406\n10 Renzulli P. Hostettler A. Schoepfer A. M. Gloor B. Candinas D. Systematic review of atraumatic splenic rupture British Journal of Surgery 2009 96 10 1114 1121 10.1002/bjs.6737 2-s2.0-70350120709\n11 Gedik E. Girgin S. Aldemir M. Keles C. Tuncer M. C. Aktas A. Non-traumatic splenic rupture: report of seven cases and review of the literature World Journal of Gastroenterology 2008 14 43 6711 6716 10.3748/wjg.14.6711 2-s2.0-63449125760 19034976\n12 Guy S. De Clercq S. Splenic rupture in community acquired pneumonia: a case report International Journal of Surgery Case Reports 2016 29 85 87 10.1016/j.ijscr.2016.10.054 2-s2.0-84994372741 27833056\n13 Prokopyeva E. A. Romanovskaya A. A. Sharshov K. A. Zaykovskaya A. V. Alekseev A. Y. Shestopalov A. M. Pathogenicity assessment of wild-type and mouse-adapted influenza A(H1N1) pdm09 viruses in comparison with highly pathogenic influenza A(H5N1) virus Histology and Histopathology 2017 32 10 1057 1063 10.14670/HH-11-866 2-s2.0-85021837040 28083862\n14 Helin A. S. Wille M. Atterby C. Järhult J. D. Waldenström J. Chapman J. R. A rapid and transient innate immune response to avian influenza infection in mallards Molecular Immunology 2018 95 64 72 10.1016/j.molimm.2018.01.012 2-s2.0-85041644274 29407578\n15 Citton R. Del Borgo C. Belvisi V. Mastroianni C. M. Pandemic influenza H1N1, legionellosis, splenic rupture, and vascular thrombosis: a dangerous cocktail Journal of Postgraduate Medicine 2012 58 3 228 229 10.4103/0022-3859.101652 2-s2.0-84867283352 23023365\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2021()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "6516064",
"pmc": null,
"pmid": "34394356",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "14135678;23023365;19034976;20537359;22889306;14250248;450447;23155145;28302313;29567936;19787754;28083862;27833056;29407578;5368861",
"title": "Atraumatic Splenic Rupture Associated with Influenza A (H1N1) Pneumonia: Case Report and Review of the Literature.",
"title_normalized": "atraumatic splenic rupture associated with influenza a h1n1 pneumonia case report and review of the literature"
} | [
{
"companynumb": "US-SLATE RUN PHARMACEUTICALS-21US000722",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"drugadditiona... |
{
"abstract": "Eccrine poroma (EP) is a benign tumor of the eccrine duct. Multiple EPs are defined as eccrine poromatosis (EPS), an uncommon phenomenon. To date there are only eight reported cases of EPS. This review exemplifies the epidemiology, pathogenesis, differential diagnosis, and histology of EP, while reviewing the eight cases of EPS. Six of the eight cases of EPS had a history of immunosuppression from either radiation or chemotherapy. This paper will also emphasize the importance of excision to avoid possible malignancy. Here we present a 73-year-old gentleman with EPS who was also treated with radiation and chemotherapy prior to the onset of the lesions.",
"affiliations": "Western University - Pacific Hospital, Long Beach, CA, USA.",
"authors": "Deckelbaum|Scott|S|;Touloei|Khasha|K|;Shitabata|Paul K|PK|;Sire|David J|DJ|;Horowitz|David|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-4632.2012.05831.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "53(5)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000368:Aged; D005534:Foot Diseases; D006801:Humans; D008297:Male; D057091:Poroma; D013544:Sweat Gland Neoplasms",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "543-8",
"pmc": null,
"pmid": "23968240",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Eccrine poromatosis: case report and review of the literature.",
"title_normalized": "eccrine poromatosis case report and review of the literature"
} | [
{
"companynumb": "US-PFIZER INC-2020131611",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nTo report palinopsia as a possible side effect of topiramate.\n\n\nMETHODS\nCase series and review of the literature.\n\n\nRESULTS\nNine patients in our series, and 4 previously reported patients, who developed palinopsia while on topiramate, are reviewed. All patients were women, and comorbidities included migraine, idiopathic intracranial hypertension, and bulimia nervosa. Palinopsia resolved in 8 patients after stopping or decreasing the dose of topiramate. The lowest dose of topiramate causing palinopsia was 25 mg twice a day. More than half of our patients reported exacerbation of visual disturbance in early morning or late evening.\n\n\nCONCLUSIONS\nTopiramate-induced palinopsia may be underdiagnosed because physicians do not inquire about such visual symptoms.",
"affiliations": "Department of Ophthalmology and Visual Sciences (SHY, RLL), Yale School of Medicine, New Haven, Connecticut; Departments of Neurology, and Ophthalmology and Visual Sciences (PL), Vanderbilt University School of Medicine, Nashville, Tennessee; and Department of Ophthalmology (MS), University of Texas Health Science Center, San Antonio, Texas.",
"authors": "Yun|Samuel H|SH|;Lavin|Patrick J|PJ|;Schatz|Martha P|MP|;Lesser|Robert L|RL|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-8022",
"issue": "35(2)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D005260:Female; D005632:Fructose; D006801:Humans; D007088:Illusions; D008297:Male; D008875:Middle Aged; D012678:Sensation Disorders; D000077236:Topiramate; D014796:Visual Perception",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "148-51",
"pmc": null,
"pmid": "25634739",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Topiramate-induced palinopsia: a case series and review of the literature.",
"title_normalized": "topiramate induced palinopsia a case series and review of the literature"
} | [
{
"companynumb": "US-APOTEX-2015AP015604",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
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"drugadditional": null,
... |
{
"abstract": "We herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.",
"affiliations": "Department of Cardiology, Toyama Prefectural Central Hospital, Japan.;Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Japan.;Department of Cardiology, Toyama Prefectural Central Hospital, Japan.;Department of Pediatrics, Toyama Prefectural Central Hospital, Japan.;Department of Cardiology, Toyama Prefectural Central Hospital, Japan.;Department of Cardiology, Toyama Prefectural Central Hospital, Japan.;Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Japan.;Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Japan.",
"authors": "Chikata|Akio|A|;Kato|Takeshi|T|;Usuda|Kazuo|K|;Fujita|Shuhei|S|;Otowa|Kan-Ichi|KI|;Maruyama|Michiro|M|;Hayashi|Kenshi|K|;Takamura|Masayuki|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.6627-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33518578\n10.2169/internalmedicine.6627-20\nCase Report\nTorsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation\nChikata Akio 12\nKato Takeshi 2\nUsuda Kazuo 1\nFujita Shuhei 3\nOtowa Kan-Ichi 1\nMaruyama Michiro 1\nHayashi Kenshi 2\nTakamura Masayuki 2\n1 Department of Cardiology, Toyama Prefectural Central Hospital, Japan\n2 Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Japan\n3 Department of Pediatrics, Toyama Prefectural Central Hospital, Japan\nCorrespondence to Dr. Akio Chikata, akio.chikata@gmail.com\n\n1 2 2021\n1 7 2021\n60 13 20892092\n9 11 2020\n10 12 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The 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/).\nWe herein report a 60-year-old woman with long-standing persistent atrial fibrillation (AF) who developed QT prolongation and torsade de pointes (TdP) after pulmonary vein isolation (PVI). When electrical cardioversion was performed three months before PVI, prominent QT prolongation was not observed. QT prolongation emerged after PVI and was sustained until AF recurrence on the third day after ablation, and TdP disappeared along with AF recurrence. PVI affects the ganglionated plexi around the atrium, leading to modification of the intrinsic cardiac autonomic system. This case indicates that PVI has the potential risk of inducing lethal ventricular arrhythmias due to QT prolongation.\n\ntorsade de pointes\nQT prolongation\npulmonary vein isolation\n==== Body\nIntroduction\n\nCatheter ablation is a highly effective therapeutic strategy for atrial fibrillation (AF) (1,2). Pulmonary vein isolation (PVI) is a cornerstone of AF ablation. The ablation line of PVI transects the sites where the major atrial ganglionated plexi (GP) exists. GP ablation carries a risk of increasing atrial and ventricular vulnerability to arrhythmias, and GP ablation induced QT prolongation after myocardial infarction in a canine model (3,4,5). QT prolongation and lethal ventricular arrhythmias related to PVI and antiarrhythmic drugs have also been reported (6).\n\nWe herein report a patient who developed QT prolongation and torsade de pointes (TdP) after PVI for persistent AF without an antiarrhythmic drug.\n\nCase Report\n\nA 60-year-old woman with long-standing persistent AF was referred to our hospital for catheter ablation. She had no structural heart disease or inherited arrhythmias. Her prescribed medication included bisoprolol fumarate 1.25 mg daily; edoxaban tosilate hydrate 30 mg daily; olmesartan medoxomil 20 mg daily; sodium valproate 200 mg twice daily; and ifenprodil tartrate 20 mg three times a day. Bisoprolol fumarate was discontinued two days before the ablation procedure. We performed electrical cardioversion three months before the ablation procedure, and prominent QT prolongation was not observed early after cardioversion. Intravenous injection of 150 mg thiopental sodium was performed before electrical cardioversion (Fig. 1A).\n\nFigure 1. (A) A 12-lead electrocardiogram acquired soon after electrical cardioversion 3 months before pulmonary vein isolation. The HR was 54 bpm. The raw QT interval was 487 ms, and the Fridericia formula [QTc=QT/ (RR 1/3)]-corrected QTc was 470 ms. (B) A 12-lead electrocardiogram showing atrial fibrillation before catheter ablation. The raw QT was 427 ms, and the Fridericia-corrected QTc was 449 ms. The raw QT was measured using the tangent method as an average of six or more beats.\n\nRecurrence of AF occurred, and a 12-lead electrocardiogram (ECG) showed no QT prolongation before ablation (Fig. 1B). Wide antral ipsilateral PVI using radiofrequency (RF) ablation was performed under the guidance of three-dimensional (3D) ultrasound geometries and 3D merged computed tomography (CT) using the CARTO 3 system (Biosense Webster, Diamond Bar, USA). RF ablation was performed under deep sedation with noninvasive positive pressure ventilation support. Deep sedation was initiated with 6 μg/kg/h dexmedetomidine for 10 min and fentanyl citrate 0.1 mg. Subsequently, it was maintained with 0.6 μg/kg/h dexmedetomidine. The total dexmedetomidine dose was 150 μg. First-pass isolation was achieved in both PVs, and electrical cardioversion was performed to restore sinus rhythm.\n\nWe performed right PVI first to avoid the vagal reflex, followed by left PVI (Fig. 2). Intravenous injection of 50 mg thiopental sodium was performed before electrical cardioversion. The bidirectional block was confirmed, and a dissociated potential was observed in both PVs. No complications were observed during the procedure, and the patient returned to the general ward in sinus rhythm. The total procedure time was 104 minutes.\n\nFigure 2. Three-dimensional computed tomography merged voltage map after pulmonary vein isolation. Each tag shows an ablation point.\n\nSeventeen hours after the procedure, TdP suddenly occurred and spontaneously terminated. A 12-lead ECG revealed prominent QT prolongation. Laboratory data showed a slightly low serum magnesium (Mg) level of 1.6 mg/dL. Creatine phosphokinase levels were within the normal limits (85 IU/L). T wave inversions were found in I, aVL, and V2, but there were no obvious local wall motion abnormalities on bedside echocardiography. QT prolongation persisted, and TdP was not suppressed despite normalization of the serum Mg level using intravenous administration of Mg sulfate hydrate (Fig. 3). TdP appeared occasionally but resolved spontaneously and did not progress to ventricular fibrillation. TdP disappeared together with AF recurrence three days after ablation. QT prolongation and negative T waves were also improved (Fig. 4).\n\nFigure 3. QT prolongation was observed two days after pulmonary vein isolation. The HR was 71 bpm. The raw QT was 540 ms, and the Fridericia-corrected QTc was 549 ms. T wave inversions were found in I, aVL, and V2. Torsade de pointes (TdP) occurred despite the normalization of serum Mg levels. TdP disappeared with the recurrence of atrial fibrillation.\n\nFigure 4. A 12-lead electrocardiogram was acquired on the third day after the procedure, showing atrial fibrillation. The raw QT was 362 ms, and the Fridericia-corrected QTc was 440 ms. QT prolongation and negative T waves were improved.\n\nA genetic test using the TruSight Cardio sequencing panel (Illumina, San Diego, USA) detected no known gene mutations related to long QT syndrome. On the sixth day after the procedure, coronary angiography showed no obstruction or stenosis, and left ventriculography reveled no local wall motion abnormalities. She did not take any antiarrhythmic drugs before or after ablation.\n\nDiscussion\n\nThe QT interval is affected by various factors, including the heart rate, electrolyte disorders, autonomic nervous system, and anesthesia. In this case, the QT interval was prolonged after PVI, and the prolongation was sustained despite the normalization of electrolyte disorders. Exaggerated QT prolongation after cardioversion has been reported (7); however, in the present case, QT prolongation was not observed when electrical cardioversion was performed three months before the ablation. Her prescribed medications did not change after the ablation procedures. These observations suggest the involvement of the PVI procedure in QT prolongation.\n\nThe ablation line of PVI for AF transects the sites where the major atrial GP exists; therefore, PVI inadvertently modifies the intrinsic cardiac autonomic nervous system, which is a determinant of the QT interval (8). In animal models, GP ablation is associated with a prolonged QT interval and increased atrial/ventricular vulnerability to arrhythmias (3,4). QT prolongation has also been observed after PVI, especially in the acute phase, in humans (9). Although TdP associated with QT prolongation after PVI with antiarrhythmic drugs has been reported (6), no antiarrhythmic drugs were used in the present case. Approximately 30% of acquired long QT syndrome cases have a known clinical long QT syndrome gene mutation (10), but no relevant genetic background was detected in this case; nevertheless, discontinuation of the beta-blocker two days before the procedure may have been involved in QT prolongation after the ablation procedure.\n\nThis case indicates the potential risk of lethal arrhythmia induced by QT prolongation due to PVI, even in patients without a known genetic background of long QT syndrome or antiarrhythmic drug prescription.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Packer DL , Mark DB , Robb RA , et al ; CABANA Investigators. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 321 : 1261-1274, 2019.30874766\n2. Marrouche NF , Brachmann J , Andresen D , et al ; CASTLE-AF Investigators. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 378 : 417-427, 2018.29385358\n3. He B , Lu Z , He W , et al . Effects of ganglionated plexi ablation on ventricular electrophysiological properties in normal hearts and after acute myocardial ischemia. Int J Cardiol 168 : 86-93, 2013.23041007\n4. Mao J , Yin X , Zhang Y , et al . Ablation of epicardial ganglionated plexi increases atrial vulnerability to arrhythmias in dogs. Circ Arrhythm Electrophysiol 7 : 711-7, 2014.24860179\n5. Wu B , Xu S , Dai R , Hong M , Wu H , Lin R . Epicardial ganglionated plexi ablation increases the inducibility of ventricular tachyarrhythmias in a canine postmyocardial infarction model. J Cardiovasc Electrophysiol 30 : 741-746, 2019.30957344\n6. Park YM , Cha MS , Kang WC , et al . Torsades de pointes associated with QT prolongation after catheter ablation of paroxysmal atrial fibrillation. Indian Pacing Electrophysiol J 17 : 146-149, 2017.29192591\n7. Choy AM , Darbar D , Dell'Orto S , et al . Exaggerated QT prolongation after cardioversion of atrial fibrillation. J Am Coll Cardiol 34 : 396-401, 1999.10440151\n8. Diedrich A , Jordan J , Shannon JR , et al . Modulation of QT interval during autonomic nervous system blockade in humans. Circulation 106 : 2238-2243, 2002.12390954\n9. Chikata A , Kato T , Usuda K , et al . Prolongation of QT interval after pulmonary vein isolation for paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 31 : 2371-2379, 2020.32558029\n10. Itoh H , Crotti L , Aiba T , et al . The genetics underlying acquired long QT syndrome: impact for genetic screening. Eur Heart J 37 : 1456-1464, 2016.26715165\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(13)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "QT prolongation; pulmonary vein isolation; torsade de pointes",
"medline_ta": "Intern Med",
"mesh_terms": "D001281:Atrial Fibrillation; D005260:Female; D006325:Heart Atria; D006801:Humans; D008133:Long QT Syndrome; D008875:Middle Aged; D011667:Pulmonary Veins; D016171:Torsades de Pointes",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2089-2092",
"pmc": null,
"pmid": "33518578",
"pubdate": "2021-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32558029;29192591;12390954;23041007;10440151;30957344;29385358;30874766;24860179;26715165",
"title": "Torsade de Pointes Due to QT Prolongation after Pulmonary Vein Isolation for Persistent Atrial Fibrillation.",
"title_normalized": "torsade de pointes due to qt prolongation after pulmonary vein isolation for persistent atrial fibrillation"
} | [
{
"companynumb": "JP-DSJP-DSJ-2021-123645",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
"drugadditional": "3",
... |
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