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"abstract": "OBJECTIVE\nTo describe the clinical presentation and imaging features of a patient with acute lymphoblastic leukemia that was complicated by optic nerve leukemic infiltration.\n\n\nMETHODS\nA 36-year-old man with history of acute lymphoblastic leukemia on treatment presented with decreased vision and optic nerve leukemic infiltrates.\n\n\nRESULTS\nAt presentation, ocular examination revealed decreased visual acuity at hand movement close to face in his right eye and 20/120 in his left eye. Fundus examination showed a pale optic disk with blurred margins and multiple flame-shaped and dot and blot retinal hemorrhages in his right eye and disk edema with whitish leukemic infiltrates over it with few dot and blot retinal hemorrhages in his left eye. The patient was referred to the treating oncologist, and curative orbital radiotherapy was administered. Vision improved dramatically to 20/40 in the right eye and to 20/20 in the left eye. He again reported with complaints of blurring of vision in the left eye after 1 month. Visual acuity was 20/20, but fundus revealed severe disk edema with whitish leukemic infiltrates. We diagnosed as relapse of leukemic optic nerve infiltration and referred to the treating oncologist for further management.\n\n\nCONCLUSIONS\nIsolated optic nerve relapse of leukemic infiltration is of paramount importance to early diagnosis, as vision can be saved if treatment is initiated promptly.",
"affiliations": "Department of Retina and Vitreous, Retina Foundation, Ahmedabad, India.",
"authors": "Nagpal|Manish P|MP|;Mehrotra|Navneet S|NS|;Mehta|Rajen C|RC|;Shukla|Chaitanya K|CK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "10(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000328:Adult; D006801:Humans; D017254:Leukemic Infiltration; D008297:Male; D009900:Optic Nerve; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012166:Retinal Hemorrhage; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "127-30",
"pmc": null,
"pmid": "26267525",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "LEUKEMIC OPTIC NERVE INFILTRATION IN A PATIENT WITH ACUTE LYMPHOBLASTIC LEUKEMIA.",
"title_normalized": "leukemic optic nerve infiltration in a patient with acute lymphoblastic leukemia"
} | [
{
"companynumb": "IN-JAZZ-2016-IN-007736",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "METHOTREXATE"
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... |
{
"abstract": "Refeeding syndrome is a rare constellation of electrolyte abnormalities after reintroduction of glucose during an adaptive state of starvation and malnutrition, resulting in fluid shifts, end-organ damage, and, potentially, death. We present a case of fetal death in a patient with hyperemesis gravidarum complicated by refeeding syndrome.\n\n\n\nA 32-year-old obese, multigravid patient was admitted at 16 weeks of gestation with hyperemesis gravidarum and laboratory abnormalities concerning for refeeding syndrome after consuming a sugar-rich beverage. She was admitted to the hospital for electrolyte and fluid repletion; however, on hospital day 2, fetal death was diagnosed.\n\n\n\nRefeeding syndrome is a potentially fatal complication of hyperemesis gravidarum. Caution should be taken when reintroducing glucose during prolonged states of malnutrition to prevent the development of refeeding syndrome.",
"affiliations": "Naval Medical Center Portsmouth, Portsmouth, Virginia.",
"authors": "Mayer|Kaitlyn Huegel|KH|;McGill|April L|AL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000003276",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "133(6)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D005260:Female; D005313:Fetal Death; D006801:Humans; D006939:Hyperemesis Gravidarum; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D055677:Refeeding Syndrome",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "1167-1170",
"pmc": null,
"pmid": "31135730",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Second-Trimester Fetal Loss in a Patient With Hyperemesis Gravidarum Complicated by Refeeding Syndrome.",
"title_normalized": "second trimester fetal loss in a patient with hyperemesis gravidarum complicated by refeeding syndrome"
} | [
{
"companynumb": "PHHY2019US197388",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery.\n\n\nMETHODS\nBetween October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0.\n\n\nRESULTS\nTwenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2 months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6%) within a median of 8 days (range, 1-14 days) after SBRT. Nine patients (37.5%) experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1-2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia.\n\n\nCONCLUSIONS\nSBRT is a safe and effective treatment for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Further studies are needed before SBRT can be recommended routinely.",
"affiliations": "Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.;Department of Radiation Oncology, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China.",
"authors": "Zeng|Xian-Liang|XL|;Wang|Huan-Huan|HH|;Meng|Mao-Bin|MB|;Wu|Zhi-Qiang|ZQ|;Song|Yong-Chun|YC|;Zhuang|Hong-Qing|HQ|;Qian|Dong|D|;Li|Feng-Tong|FT|;Zhao|Lu-Jun|LJ|;Yuan|Zhi-Yong|ZY|;Wang|Ping|P|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S102784",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S102784ott-9-3985Original ResearchStereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump Zeng Xian-Liang *Wang Huan-Huan *Meng Mao-Bin Wu Zhi-Qiang Song Yong-Chun Zhuang Hong-Qing Qian Dong Li Feng-Tong Zhao Lu-Jun Yuan Zhi-Yong Wang Ping Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of ChinaCorrespondence: Mao-Bin Meng, Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, People’s Republic of China, Tel +86 22 2334 1405, Fax +86 22 2334 4105, Email doctormm991@hotmail.com* These authors contributed equally to this work\n\n2016 30 6 2016 9 3985 3992 © 2016 Zeng et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background and aim\nThe aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery.\n\nPatients and methods\nBetween October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0.\n\nResults\nTwenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2 months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6%) within a median of 8 days (range, 1–14 days) after SBRT. Nine patients (37.5%) experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1–2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia.\n\nConclusion\nSBRT is a safe and effective treatment for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Further studies are needed before SBRT can be recommended routinely.\n\nKeywords\nstereotactic body radiation therapypancreatic adenocarcinomarecurrent diseaseoverall survival\n==== Body\nIntroduction\nThe prognosis of pancreatic cancer remains poor with a 5-year overall survival (OS) rate <6%.1,2 Surgical resection is the only curative treatment, but unfortunately, only 20% of patients appear to be candidates for surgery at diagnosis.3 Even patients who undergo resection have a poor prognosis with a 5-year survival rate of 7%–25% due to frequent development of local and/or distant metastases.4 The pattern of recurrence for patients with pancreatic cancer after surgery is well known;5,6 however, the most effective therapeutic strategies are not well defined. Some surgeons attempted to re-resect in a small number of patients with recurrent pancreatic carcinoma but achieved a 5-year OS of only ≤5.6%.7,8\n\nThe National Comprehensive Cancer Network recommends chemoradiotherapy for patients with local recurrence if they have not received radiotherapy (RT), and alternative systemic chemotherapy or palliative and best supportive care if they have received prior RT.9 As in the case of local advanced pancreatic cancer, the outcomes of these treatment strategies remain poor due to suboptimal local control (LC) and a poor median OS.10 Therefore, treatment opinion for patients with recurrent pancreatic carcinoma, especially recurrent pancreatic adenocarcinoma, is deemed required.\n\nStereotactic body radiation therapy (SBRT) is a type of external beam RT that delivers radiation more accurately and precisely to the tumor than conventionally fractionated radiation therapy. SBRT can be delivered using either a traditional linear accelerator or a robotic arm (ie, CyberKnife). The purpose of this study is to evaluate the safety and efficacy of SBRT using CyberKnife for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery.\n\nPatients and methods\nStudy design and eligible patients\nWe retrospectively queried our prospectively collected database of patients with recurrent pancreatic cancer. Patients were treated with SBRT using CyberKnife between October 1, 2006 and May 1, 2015. The inclusion criteria were the following: 1) any age; 2) Karnofsky performance score ≥70; 3) recurrent pancreatic adenocarcinoma after surgery, confirmed by biopsy and histology and either computed tomography (CT) or positron emission tomography/CT (PET/CT) images; and (4) written informed consent for the treatment. Exclusion criteria were 1) history of prior RT, 2) contraindication for receiving RT, and 3) uncontrolled comorbidities (metabolic or psychiatric). The study protocol was in accordance with the ethical guidelines of the Declaration of Helsinki and was approved by the independent ethics committees at Tianjin Medical University Cancer Institute and Hospital. In addition, all inclusion patients gave written informed consent.\n\nTreatment schedule\nThe treatment planning and SBRT with CyberKnife was performed as previously described.11,12 The Xsight spine tracking system was used for patients with recurrent disease at the abdominal lymph node, and positional alignment was based on bony spinal skeletal structures. In contrast, it was recommended that gold fiducials were implanted at or near the recurrent stump for the gold fiducials tracking system which used B-ultrasound, endoscopic ultrasound, or CT guidance. Briefly, the patients were immobilized using a vacuum mattress before CT simulation.\n\nA set of planning three-dimensional or four-dimensional CT images were obtained after intravenous radiographic contrast material infusion to highlight recurrent disease. The images included sufficient margins above and below the tumor, which were determined according to pretreatment planning CT and PET/CT images. The gross target volume (GTV) was defined as the volume of recurrent carcinoma, and the planning target volume (PTV) was defined as the GTV plus a margin of 0.3 cm in the x-, y-, and z-axis direction. The PTV was also amended to exclude the relevant anatomic boundaries when the target area was close to the duodenum, small bowel, or stomach in order to avoid damaging critical normal tissue. The normal tissue constraints were adopted from previous studies of advanced pancreatic carcinoma.13–15\n\nFollow-up\nThe patients were observed at 1 month after completion of treatment, then every 3 months for the first year, and every 6 months thereafter until May 1, 2015. Imaging, adverse events, and compliance of all patients were monitored for the follow-up period using our clinical databases.\n\nEnd points\nThe primary end point was the LC rate after SBRT, which was defined as complete response, partial response, or stable disease using the Response Evaluation Criteria in Solid Tumors version 1.1.16 Local failure was defined as evidence of increased tumor size in the treated region. PET/CT scan was employed to differentiate radiation-related changes from local or regional recurrence. LC of recurrent disease was assessed after a minimum of 6 months after SBRT in order to avoid uncertainty associated with early transient radiographic changes within the high-dose region. The secondary end points were the following: 1) OS from diagnosis and SBRT, defined as the time between diagnosis or SBRT and death or last follow-up for censored patients. 2) The time to symptom alleviation or pain reduction: the time to symptom alleviation was defined as the time between SBRT and the date at which symptoms were alleviated or the date of the last follow-up for censored patients, and pain was evaluated from the pain status rated by patients on a visual analog scale (VAS) before and after SBRT (a score of 0 indicated no pain and a score of 10 represented maximum pain). A researcher trained to conduct clinical interviews then contacted the patients to conduct clinical interviews in person via telephone at fixed intervals after their treatment sessions (at 1 day, 1 week, 2 weeks, and 1, 2, 3, and 6 months) or until the patients died or were lost to follow-up. 3) Toxicity was evaluated through Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Acute toxicities and late complications were recorded. All symptoms and complications documented in patient records during and following SBRT were recorded.\n\nStatistical analysis\nLC and OS rates were estimated using Kaplan–Meier analysis. Curves were compared using the stratified log-rank test. A P-value of ≤0.05 was considered to represent statistical significance. Data were analyzed using the statistical software Intercooled Stata version 8.2 for Windows (StataCorp LP, College Station, TX, USA).\n\nResults\nPatients’ characteristics\nBetween January 10, 2011 and June 19, 2014, 24 patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT using CyberKnife (Table 1). Five patients presented with abdominal lymph nodes and synchronous metastasis in the liver or lung. In addition to SBRT for abdominal lymph nodes, patients with synchronous liver metastasis received sequential palliative localized treatment, four patients with synchronous liver and lung metastases received adjuvant chemotherapy, and one patient with synchronous liver metastasis received no treatment.\n\nTreatment characteristics\nThe treatment characteristics and treatment planning parameters for all patients are summarized in Table 2 and Figure 1. A total of 16 patients had negative margins (R0), four patients had microscopically positive margins (R1), and four patients had macroscopically positive margins (R2) after surgery. Eighteen patients had previously received gemcitabine-based chemotherapy, and three patients received other chemotherapy regimes.\n\nThe median PTV was 39.09 mL (range, 7.22–94.81 mL). Patients received a median of five fractions (range, five to eight fractions) with a median dose of 9 Gy per fraction (range, 6–10 Gy), and a total dose of 45 Gy (range, 42–50 Gy). The median biologically equivalent dose (α/β=10, linear-quadratic model used) was 85.50 Gy (range, 71.4–100 Gy). The dose was administered to the median 73% isodose line (range, 63%–79%), which encompassed 95% of the PTV (Table 3).\n\nLC rate and OS\nOut of 24 patients, five (20.8%) had a complete response, eight (33.3%) had a partial response, and nine (37.5%) had no response. The 6-, 12-, and 24-month actuarial LC rates were 95.2%, 83.8%, and 62.1%, respectively (Figure 2).\n\nFor the whole cohort, median follow-up time was 35.8 months (range, 14.2–72.7 months). The median OS from diagnosis and SBRT was 28.9 and 12.2 months, respectively (Figure 3A and B). It is worth noting that the rate of solitary recurrence and synchronous metastases did not differ significantly (P=0.31).\n\nThe time to symptom alleviation\nAlleviation of symptoms was evaluated in 14 patients who reported symptoms (14/24, 58.33%, most commonly abdominal pain and back pain). Relief of symptoms was achieved in eleven patients (11/14, 78.57%), of which eight (8/14, 57.14%) reported complete relief of symptoms and discontinuation of medications. The remaining patients reported partial relief (3/14, 42.86%). Symptom improvement was reported after a median follow-up of 8 days (range, 1–14), and alleviation of symptoms continued throughout the follow-up period in all cases.\n\nPain was evaluated using a VAS score. VAS scores increased slightly from 7.2±2.5 at pre-SBRT to 8.9±1.2 24 hours after SBRT, and decreased from 7.2±2.5 at pre-SBRT to 2.7±1.3 1 week after SBRT. The VAS scores remained low throughout the follow-up period, 1.1±1.2 at 2 weeks, 1.4±1.3 at 1 month, 1.4±1.5 at 2 months, 1.3±0.9 at 3 months, and 1.2±1.4 at 6 months. Mean VAS differed significantly from the pre-SBRT baseline at each post-SBRT time point (all P<0.05).\n\nPatterns of failure\nFive patients (5/24, 20.8%) exhibited relapse within the PTV. Out-of-field progression was detected in 17 patients (17/24, 70.8%) within a median of 10.0 months after SBRT (range, 3.8–28.2 months), and in only two patients (2/24, 8.3%) was progression not observed after SBRT.\n\nToxicities\nAll patients completed SBRT without treatment breaks or dose reductions. As indicated in Table 4, nine patients (37.5%) experienced CTCAE version 4.0 grade 1–2 acute toxicities manifested as diarrhea, nausea, vomiting, abdominal pain, and agranulocytosis. One patient (4.2%) who received gemcitabine-based chemotherapy experienced grade 3 acute toxicity due to thrombocytopenia. These toxicities were generally transient and resolved with conservative management. No acute grade >3 toxicity or late toxicity was observed.\n\nDiscussion\nThe efficacy of treatments for recurrent pancreatic cancer following surgical resection is not well characterized. A majority of patients are not suitable candidates for surgery due to the presence of synchronous metastases, vascular involvement, or poor physical status, and for suitable patients, the rate of positive margin resection remains very high.7,8 To our knowledge, this is the first study to evaluate the safety and efficacy of SBRT for patients with recurrent pancreatic carcinoma at the abdominal lymph node or stump after surgery. Our results demonstrate that SBRT using CyberKnife is a safe and effective treatment for these patients. Further studies will be required to identify which patients benefit most from this treatment modality.\n\nSBRT is an attractive therapeutic option due to its short duration and proven efficacy and safety, which has been reported in many earlier studies on patients with localized advanced pancreatic cancer.13–15,17–22 In the present study, the median OS of patients with recurrent pancreatic carcinoma treated with SBRT was 12.2 months; this is superior to the OS of 7.6–11.8 months of patients with localized advanced pancreatic carcinoma treated using SBRT,17–19 and also superior to the OS of patients with recurrent pancreatic carcinoma who underwent re-resection.7,8 However, the OS did not differ significantly between patients with solitary recurring and synchronous metastases, perhaps due to the small number of samples included, patients’ status, and/or the characteristic of recurrent pancreatic adenocarcinoma.\n\nSBRT achieves promising LC rates in patients with recurrent pancreatic cancer. The 6-, 12-, and 24-month actuarial LC rates were 95.2%, 83.8%, and 62.1%, respectively. However, a total of 22 patients (22/24, 91.67%) exhibited either relapse within the PTV or progression outside of the field. Of these patients, five exhibited relapse within the PTV, and 17 patients exhibited out-of-field progression within a median of 10.0 months of SBRT. Therefore, SBRT should be combined with systemic therapies to reduce recurrence of pancreatic cancer after surgery, and more studies will be required to confirm these findings.\n\nThe treatment of recurrent pancreatic cancer is a continuing challenge because the disease typically causes symptoms that negatively impact patients’ quality of life, such as abdominal and back pain. These symptoms are not typically transient and cannot be resolved with conservative management. However, in this study, the transient increase in pain observed 24 hours after SBRT could be attributed to edema, and the majority of patients in our study achieved complete symptoms relief, typically within 2 weeks of treatment. Our findings concur with published studies suggesting that SBRT can reduce pain and improve quality of life of patients with localized advanced pancreatic cancer.23\n\nThe low-toxicity profile observed in our study is of particular importance in cancer patients, who have received or will receive additional oncologic therapies. In previous trials in which 25 Gy was delivered in one fraction, grade ≥3 toxicities were reported in 5%–18.8% of patients.18,24–26 However, some reports suggested that regimens of SBRT including two to five fractions for localized advanced pancreatic cancer are associated with better LC rates than those using single-fraction SBRT, and a lower incidence of high-grade toxicities.14,15,27 In this study, most patients experienced CTCAE grade 1–2 acute toxic events, and most of these symptoms were transient and resolved with conservative management. No late toxicity was reported, although the relatively short median OS may have underestimated the rate of late toxicities following SBRT.\n\nTo our knowledge, our study is the first to demonstrate the efficacy and safety of SBRT using CyberKnife for patients with recurrent disease at the abdominal lymph node or stump after surgery originating from pancreatic cancer. This study is limited by its retrospective nature, and as our patient group encompassed a range of treatment sites, disease severities, fractionation regimens, and systemic therapies, interpretation of the results is somewhat difficult. However, in light of the paucity of literature on the outcomes of SBRT for these patients, our results further recommend the clinical use of SBRT. Further investigation will be required to identify which patients benefit most from this treatment modality, particularly in combination with other treatment modalities.\n\nAcknowledgments\nThis work was supported by the National Natural Science Foundation of China (No 81472797 and No 81201754) and the National Key Clinical Specialist Construction Programs of China (No N14B04). No benefits in any form have been or will be received from a commercial party directly or indirectly related to the subject of this article. We also thank the anonymous reviewer for his/her very helpful comments, which improved the quality of this paper.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Representative planning CT and isodose distributions with SBRT using CyberKnife in patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery.\n\nNotes: Each patient had SBRT beam angle, cross-sectional, sagittal, and coronal images taken, and red and purple lines indicate GTV and PTV, respectively. (A) A 64-year-old female treated for a solitary recurrent pancreatic adenocarcinoma at the stump. SBRT was performed using six fractions of 42 Gy prescribed to the 72% isodose line. (B) A 55-year-old male treated for a solitary recurrent pancreatic adenocarcinoma at the abdominal lymph node. SBRT was performed using five fractions of 45 Gy to the 75% isodose line.\n\nAbbreviations: CT, computed tomography; SBRT, stereotactic body radiation therapy; GTV, gross tumor volume; PTV, planning target volume.\n\nFigure 2 Actuarial rate of LC from SBRT using CyberKnife for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery.\n\nAbbreviations: LC, local control; SBRT, stereotactic body radiation therapy.\n\nFigure 3 OS from diagnosis and SBRT using CyberKnife for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery.\n\nNotes: (A) OS from diagnosis. (B) OS from SBRT.\n\nAbbreviations: OS, overall survival; SBRT, stereotactic body radiation therapy.\n\nTable 1 Summary of patient characteristics\n\nName\tAge (years)\tSex\tNo of lesions\tLocation of lesion\tPTV volume (mL)\tInterval between surgery and SBRT (months)\tSymptoms\tSynchronous metastases\tTreatment of synchronous metastatic site\t\nMWY\t56\tMale\t1\tAbd LN\t31.65\t8.77\tAbdominal pain\t\t\t\nLYH\t54\tMale\t2\tAbd LN\t71.85\t36.87\tAbdominal pain\tLung\tCT\t\nXDR\t59\tMale\t1\tAbd LN\t24.33\t15.80\tNone\t\t\t\nZJQ\t56\tMale\t1\tAbd LN\t38.20\t4.30\tAbdominal pain\t\t\t\nLJZ\t71\tMale\t1\tAbd LN\t36.55\t25.43\tAbdominal pain\t\t\t\nCGS\t62\tMale\t1\tAbd LN\t90.14\t20.53\tAnorexia and fatigue\t\t\t\nSJF\t68\tFemale\t2\tAbd LN\t7.22\t14.80\tNone\tLiver\tCT\t\nYJ\t38\tFemale\t1\tAbd LN\t32.32\t20.23\tNone\t\t\t\nYSY\t61\tFemale\t1\tAbd LN\t25.48\t6.47\tBack pain\t\t\t\nZL\t27\tMale\t1\tAbd LN\t94.81\t5.13\tAbdominal and back pain\t\t\t\nZLM\t49\tFemale\t2\tAbd LN\t49.48\t11.53\tNone\tLiver\tCT\t\nWGZ\t50\tFemale\t1\tAbd LN\t34.41\t6.23\tAbdominal pain\t\t\t\nGYQ\t65\tFemale\t1\tAbd LN\t75.08\t14.07\tNone\t\t\t\nLZS\t73\tMale\t2\tAbd LN\t41.50\t9.53\tAbdominal and back pain\tLiver\tNone\t\nSCL\t60\tMale\t1\tAbd LN\t41.44\t40.43\tAbdominal pain\t\t\t\nZY\t60\tFemale\t1\tAbd LN\t20.32\t32.33\tNone\t\t\t\nZBJ\t47\tMale\t2\tAbd LN\t47.11\t17.87\tBack pain and jaundice\tLiver\tBiliary stenting\t\nWJX\t59\tMale\t1\tStump\t39.98\t16.63\tNone\t\t\t\nLCR\t56\tFemale\t1\tStump\t34.09\t20.53\tAbdominal pain\t\t\t\nZCF\t64\tFemale\t1\tStump\t33.34\t3.90\tNone\t\t\t\nLXY\t57\tFemale\t1\tStump\t61.74\t1.90\tBack pain\t\t\t\nGWH\t47\tMale\t1\tStump\t30.84\t6.47\tNone\t\t\t\nZQG\t40\tMale\t1\tStump\t90.65\t2.37\tAbdominal pain\t\t\t\nZXL\t59\tMale\t1\tStump\t40.82\t55.03\tNone\t\t\t\nAbbreviations: PTV, planning target volume; SBRT, stereotactic body radiation therapy; Abd LN, abdominal lymph node; CT, chemotherapy.\n\nTable 2 Summary of treatment characteristics\n\nName\tPrescription dose/fractionation\tBED10 (Gy)\tIsodose (%)\tType of surgery\tHistory of CT\tTime of symptoms disappearance and alleviation\tLocation of PD\tLPFS (months)\tOS (months)\tStatus (cause)\t\nMWY\t45/5\t85.50\t75\tR0\tGemcitabine-based\tNo remission\tTreatment site\t18.07\t23.30\tAlive\t\nLYH\t42/6\t71.40\t63\tR0\tGemcitabine-based\t7 days\tLung metastasis\t19.23\t19.23\tAlive\t\nSJF\t50/5\t100.00\t77\tR0\tNo CT\tNA\tLiver metastasis\t18.90\t18.90\tAlive\t\nYJ\t45/5\t85.50\t72\tR1\tNo gemcitabine-based\tNA\tNo\t19.30\t19.30\tAlive\t\nZXL\t45/5\t85.50\t76\tR0\tGemcitabine-based\tNA\tTreatment site and liver metastasis\t12.83\t17.63\tAlive\t\nSCL\t50/5\t100.00\t71\tR0\tNo gemcitabine-based\t9 days\tNo\t22.90\t22.90\tAlive\t\nLCR\t45/5\t85.50\t70\tR0\tGemcitabine-based\t14 days\tAbd LN\t12.03\t12.03\tAlive\t\nYSY\t45/5\t85.50\t76\tR1\tGemcitabine-based\t9 days\tTreatment site\t8.40\t10.53\tDeath (tumor)\t\nZL\t48/6\t86.40\t70\tR0\tGemcitabine-based\t8 days\tAbd LN\t13.83\t13.83\tDeath (tumor)\t\nZQG\t48/8\t76.80\t75\tR2\tGemcitabine-based\t9 days\tLiver metastasis\t7.7\t7.70\tDeath (tumor)\t\nZLM\t45/5\t85.50\t76\tR0\tGemcitabine-based\tNA\tLiver metastasis\t28.17\t28.17\tDeath (tumor)\t\nWGZ\t50/5\t100.00\t70\tR1\tGemcitabine-based\t5 days\tAbd LN\t11.73\t11.73\tDeath (tumor)\t\nGYQ\t48/8\t76.80\t70\tR0\tGemcitabine-based\tNA\tAbd LN\t3.90\t3.90\tDeath (tumor)\t\nLZS\t45/5\t85.50\t70\tR0\tGemcitabine-based\tNo remission\tLiver metastasis\t3.77\t3.77\tDeath (tumor)\t\nWJX\t45/5\t85.50\t66\tR1\tGemcitabine-based\tNA\tLiver metastasis\t12.50\t12.50\tDeath (tumor)\t\nZY\t45/5\t85.50\t75\tR0\tGemcitabine-based\tNA\tStomach metastasis\t6.27\t6.27\tDeath (tumor)\t\nZCF\t42/6\t71.40\t72\tR2\tNo gemcitabine-based\tNA\tTreatment site and Abd LN\t6.8\t12.50\tDeath (tumor)\t\nLXY\t45/6\t78.75\t76\tR0\tNo CT\t8 days\tLiver metastasis\t9.63\t9.63\tDeath (tumor)\t\nZBJ\t45/5\t85.50\t72\tR0\tGemcitabine-based\t7 days\tLiver metastasis\t9.77\t9.77\tDeath (tumor)\t\nXDR\t50/5\t100.00\t75\tR2\tGemcitabine-based\tNA\tLiver metastasis\t12.93\t12.93\tDeath (tumor)\t\nZJQ\t50/5\t100.00\t79\tR0\tGemcitabine-based\tNo remission\tLiver metastasis\t8.47\t8.47\tDeath (tumor)\t\nLJZ\t45/5\t85.50\t74\tR0\tGemcitabine-based\t1 day\tLiver metastasis\t11.20\t11.20\tDeath (tumor)\t\nCGS\t45/5\t85.50\t76\tR0\tNo CT\t5 days\tLiver metastasis\t10.03\t10.03\tDeath (tumor)\t\nGWH\t48/6\t86.40\t72\tR2\tGemcitabine-based\tNA\tTreatment site\t10.80\t12.20\tDeath (tumor)\t\nNote: The R0, R1, and R2 were defined as negative margins, microscopically positive margins, and macroscopically positive margins after surgery, respectively.\n\nAbbreviations: BED, biologically equivalent dose; CT, chemotherapy; PD, progressive disease; LPFS, local progression-free survival; OS, overall survival; Abd LN, abdominal lymph node; NA, not available.\n\nTable 3 Summary of SBRT parameters\n\nParameter\tMedian (range)\t\nPTV (mL)\t39.09 (7.22–94.81)\t\nPrescription dose (Gy)\t45 (42–50)\t\nNumber of fractions\t5 (5–8)\t\nDose per fraction (Gy)\t9 (6–10)\t\nBED10 (Gy)\t85.50 (71.4–100)\t\nPrescription isodose line (%)\t73 (63–79)\t\nAbbreviations: SBRT, stereotactic body radiation therapy; PTV, planning target volume; BED, biologically equivalent dose.\n\nTable 4 Toxicities of pancreatic adenocarcinoma patients with recurrent disease treated with SBRT\n\n\tAny grade, n (%)\tGrade 3, n (%)\tGrade 4, n (%)\tGrade 5, n (%)\t\nAcute toxicities\t\n Diarrhea\t2 (8.3)\t0\t0\t0\t\n Nausea and vomiting\t1 (4.2)\t0\t0\t0\t\n Abdominal pain\t5 (20.8)\t0\t0\t0\t\n Agranulocytosis\t1 (4.2)\t0\t0\t0\t\n Thrombocytopenia\t1 (4.2)\t1 (4.2)\t0\t0\t\nLate toxicities\t\n Intestinal obstruction\t0\t0\t0\t0\t\n Intestinal perforation\t0\t0\t0\t0\t\n Gastric perforation\t0\t0\t0\t0\t\nAbbreviation: SBRT, stereotactic body radiation therapy.\n==== Refs\nReferences\n1 Siegel R Naishadham D Jemal A Cancer statistics, 2013 CA Cancer J Clin 2013 63 1 11 30 23335087 \n2 Thomas RM Truty MJ Nogueras-Gonzalez GM Selective reoperation for locally recurrent or metastatic pancreatic ductal adenocarcinoma following primary pancreatic resection J Gastrointest Surg 2012 16 9 1696 1704 22644446 \n3 Hartwig W Werner J Jäger D Debus J Büchler MW Improvement of surgical results for pancreatic cancer Lancet Oncol 2013 14 11 e476 e485 24079875 \n4 Moningi S Dholakia AS Raman SP The role of stereotactic body radiation therapy for pancreatic cancer: a single-institution experience Ann Surg Oncol 2015 22 7 2352 2358 25564157 \n5 Oettle H Post S Neuhaus P Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial JAMA 2007 297 3 267 277 17227978 \n6 Sperti C Pasquali C Piccoli A Pedrazzoli S Recurrence after resection for ductal adenocarcinoma of the pancreas World J Surg 1997 21 2 195 200 8995078 \n7 Zacharias T Oussoultzoglou E Jaeck D Pessaux P Bachellier P Surgery for recurrence of periampullary malignancies J Gastrointest Surg 2009 13 4 760 767 19050979 \n8 Kleeff J Reiser C Hinz U Surgery for recurrent pancreatic ductal adenocarcinoma Ann Surg 2007 245 4 566 572 17414605 \n9 NCCN clinical practice guidelines in pancreatic adenocarcinoma (Version 1) 2015 Available from: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf Accessed June 21, 2016 \n10 Wilkowski R Thoma M Bruns C Dühmke E Heinemann V Combined chemoradiotherapy for isolated local recurrence after primary resection of pancreatic cancer JOP 2006 7 1 34 40 16407616 \n11 Yuan ZY Meng MB Liu CL Stereotactic body radiation therapy using the CyberKnife system for patients with liver metastases Onco Targets Ther 2014 7 915 923 24959080 \n12 Meng MB Wang HH Zaorsky NG Clinical evaluation stereotactic radiation therapy for recurrent or second primary mediastinal lymph node metastases originating from non-small cell lung cancer Oncotarget 2015 6 17 15690 15703 25881546 \n13 Herman JM Chang DT Goodman KA Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma Cancer 2015 121 17 1128 1137 25538019 \n14 Chuong MD Springett GM Freilich JM Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is efficacy and well tolerated Int J Radiat Oncol Biol Phys 2013 86 3 516 522 23562768 \n15 Mahadevan A Miksad R Goldstein M Induction gemcitabine and stereotactic body radiotherapy for locally advanced nonmetastatic pancreas cancer Int J Radiat Oncol Biol Phys 2011 81 4 e615 e622 21658854 \n16 Eisenhauer EA Therasse P Bogaerts J New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 2 228 247 19097774 \n17 Koong AC Le QT Ho A Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer Int J Radiat Oncol Biol Phys 2004 58 4 1017 1021 15001240 \n18 Koong AC Christofferson E Le QT Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer Int J Radiat Oncol Biol Phys 2005 63 2 320 323 16168826 \n19 Schellenberg D Goodman KA Lee F Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer Int J Radiat Oncol Biol Phys 2008 72 3 678 686 18395362 \n20 Mahadevan A Jain S Goldstein M Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer Int J Radiat Oncol Biol Phys 2010 78 3 735 742 20171803 \n21 Goyal K Einstein D Ibarra RA Stereotactic body radiation therapy for nonresectable tumors of the pancreas J Surg Res 2012 174 2 319 325 21937061 \n22 Wei Q Yu W Rosati LM Herman JM Advances of stereotactic body radiotherapy in pancreatic cancer Chin J Cancer Res 2015 27 4 349 357 26361404 \n23 Polistina F Costantin G Casamassima F Unresectable locally advanced pancreatic cancer: a multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration Ann Surg Oncol 2010 17 8 2092 2101 20224860 \n24 Schellenberg D Kim J Christman-Skieller C Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer Int J Radiat Oncol Biol Phys 2011 81 1 181 188 21549517 \n25 Didolkar MS Coleman CW Brenner MJ Image-guided stereotactic radiosurgery for locally advanced pancreatic adenocarcinoma results of first 85 patients J Gastrointest Surg 2010 14 10 1547 1559 20839073 \n26 Pollom EL Alagappan M von Eyben R Single-versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: outcomes and toxicity Int J Radiat Oncol Biol Phys 2014 90 4 918 925 25585785 \n27 Rwigema JC Parikh SD Heron DE Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas Am J Clin Oncol 2011 34 1 63 69 20308870\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "9()",
"journal": "OncoTargets and therapy",
"keywords": "overall survival; pancreatic adenocarcinoma; recurrent disease; stereotactic body radiation therapy",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "3985-92",
"pmc": null,
"pmid": "27418841",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "25538019;21937061;17227978;17414605;25881546;23562768;20308870;26361404;16168826;25585785;24959080;21549517;19097774;23335087;16407616;25564157;22644446;24079875;21658854;15001240;19050979;20224860;20839073;18395362;20171803;8995078",
"title": "Stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump.",
"title_normalized": "stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump"
} | [
{
"companynumb": "CN-ACCORD-043005",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "There are only a few reports of successful use of mammalian target of rapamycin (mTORI) as primary immunosuppression in pediatric heart transplantation. Compared to calcineurin inhibitors, mTORI have less side effects, especially nephrotoxicity, infections, and malignancies. A retrospective study was conducted at our institution of all 170 heart transplants from 1995 to 2015. Nineteen patients were switched from tacrolimus (n=15) or cyclosporin (n=4) to everolimus (n=4) or sirolimus (n=15) due to nephrotoxicity (n=5), malignancy (n=8), EBV viremia/reactive plasmacytic changes (n=5), and immune hemolytic anemia (n=1). We monitored for rejection, infection, BUN, creatinine, hyperlipidemia, EBV and CMV copies, CBC, cardiac allograft vasculopathy (CAV), and death. Target trough levels of sirolimus and everolimus were 4-10. Four treatment failures included debilitating rash, bone marrow suppression, recurrent rejection, and renal transplantation. There were no deaths. One patient had recurrent rejection episodes, and tacrolimus was reinitiated. One patient with preexisting CAV underwent heart retransplantation. One patient, who was treated for PTLD, transformed to CD30+ Hodgkins disease, and was treated with brentuximab. There were three acute rejection episodes. Median creatinine preswitch was higher 0.82 than postswitch 0.78 (P=.016). Median eGFR was lower preswitch, 75.6, than postswitch, 91.2 (P=.0004). These results indicate that conversion to mTORI as primary immunosuppression may be safely accomplished in some pediatric heart transplant patients.",
"affiliations": "Divisions of Cardiology, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.;Divisions of Cardiology, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.;Divisions of Cardiology, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.;Divisions of Cardiology, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.;Pharmacy, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.;Center for Translational Research, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.",
"authors": "Asante-Korang|Alfred|A|http://orcid.org/0000-0002-3621-2246;Carapellucci|Jennifer|J|;Krasnopero|Diane|D|;Doyle|Abigail|A|;Brown|Brian|B|;Amankwah|Ernest|E|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13054",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "31(10)",
"journal": "Clinical transplantation",
"keywords": "calcineurin inhibitors; conversion; cyclosporin; everolimus; immunosuppression; mTOR inhibitors; sirolimus; tacrolimus",
"medline_ta": "Clin Transplant",
"mesh_terms": "D065095:Calcineurin Inhibitors; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28708333",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Conversion from calcineurin inhibitors to mTOR inhibitors as primary immunosuppressive drugs in pediatric heart transplantation.",
"title_normalized": "conversion from calcineurin inhibitors to mtor inhibitors as primary immunosuppressive drugs in pediatric heart transplantation"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP013270",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
... |
{
"abstract": "Mammalian target of rapamycin inhibitors, such as rapamycin and more recently everolimus, have substituted calcineurin inhibitors in many minimization strategies. Despite their acclaimed renal safety profile, several lines of evidence are emerging on their potential nephrotoxic effect. Predisposing conditions for nephrotoxicity involve a complex interplay between several environmental and genetic factors in the donor-recipient pair. Renal injury may be enhanced by pharmacodynamic interactions when combined with other drugs such as calcineurin inhibitors or nutrients that are predominantly related to an increase in local tissue exposure. These toxic interactions may occur within adequate doses and therapeutic blood levels. This explains the occurrence of nephrotoxicity in some but not all cases. Here, we postulated that activity of a low permeability glycoprotein efflux pump related to low protein expression and/or inhibition enhanced immunosuppressive drug entry in different cells. A rise in intracellular drug concentration increases bioactivity, leading to greater immunosuppression and more immune-related, nonrenal adverse events in the recipient and increased nephrotoxicity in the kidney graft. Under specific isolated or combined environmental and/or genetic conditions in both the recipient and donor affecting the glycoprotein efflux pump and/or the mammalian target of rapamycin pathway, these renal injuries may be aggravated by heightened drug tissue concentrations despite adherence to therapeutic drug and blood levels. Mammalian target of rapamycin inhibitors may induce predominantly a dose-dependent renal epithelial cell injury affecting either the glomerular or the renal tubular epithelial cells, leading to cell death and apoptosis. Epithelial mesenchymal transition mediated interstitial fibrosis and tubular atrophy observed with these drugs may be the result of a cumulative toxic renal tubular injury induced by the direct insult of the drug itself and/or podocytopathy-associated proteinuria. The resulting glomerular tubular damage will ultimately lead to graft failure and loss, if exposure persists.",
"affiliations": "Rafik Hariri University Hospital, Beirut, Lebanon.",
"authors": "Barbari|Antoine|A|;Maawad|Maria|M|;Kfoury Kassouf|Hala|H|;Kamel|Gaby|G|",
"chemical_list": "D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "13(5)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D007674:Kidney Diseases; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D012307:Risk Factors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "377-86",
"pmc": null,
"pmid": "26450460",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Mammalian Target of Rapamycin Inhibitors and Nephrotoxicity: Fact or Fiction.",
"title_normalized": "mammalian target of rapamycin inhibitors and nephrotoxicity fact or fiction"
} | [
{
"companynumb": "PHHY2015LB135104",
"fulfillexpeditecriteria": "1",
"occurcountry": "LB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe NeuroPace RNS System is a method recently approved by the U.S. Food and Drug Administration for closed-loop direct brain stimulation in selected patients with drug-resistant partial seizures. The long-term risks of implant site infection and accompanying bone flap osteomyelitis associated with responsive neurostimulation (RNS) devices have not been fully appreciated.\n\n\nMETHODS\nWe report 3 cases of refractory partial epilepsy that were treated with RNS therapy in conjunction with antiepileptic drugs. Patients underwent invasive epilepsy monitoring and resection of seizure foci. All patients continued to have debilitating partial seizures and underwent implantation of the RNS device, which resulted in various degrees of symptomatic relief. On average, the battery of the implantable pulse generator was replaced every 2 years. All 3 patients developed implant site infection and bone flap osteomyelitis with multiple implantable pulse generator replacements, and the RNS devices were removed. Bone flaps were removed in 2 patients because of significant osteomyelitis and were reconstructed in a delayed fashion with customized cranial implants. No patient had evidence of meningitis or cerebritis. The patients were treated via a multidisciplinary approach, and all patients recovered well with satisfactory wound healing and seizure control.\n\n\nCONCLUSIONS\nImplant site infection and bone flap osteomyelitis are significant adverse events associated with the RNS device. The incidence of infection in this series (10%) is comparable to the incidence reported in the long-term trial. The infection risk is mainly associated with reoperations and increases with multiple implantable pulse generator replacements. The RNS device may benefit from reducing technical risk factors that are associated with postoperative bone and soft tissue infections.",
"affiliations": "Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA. Electronic address: zwei3@jhmi.edu.;Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA; Department of Plastic and Reconstructive Surgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA.;Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland, USA.;Department of Plastic and Reconstructive Surgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA.;Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA. Electronic address: wanders5@jhmi.edu.",
"authors": "Wei|Zhikui|Z|;Gordon|Chad R|CR|;Bergey|Gregory K|GK|;Sacks|Justin M|JM|;Anderson|William S|WS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2015.11.106",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "88()",
"journal": "World neurosurgery",
"keywords": "Implant site infections; Implantable pulse generator; RNS System; Refractory partial epilepsy",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D016025:Bone Transplantation; D046690:Deep Brain Stimulation; D004567:Electrodes, Implanted; D004827:Epilepsy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D010027:Osteotomy; D011859:Radiography; D012886:Skull; D013530:Surgical Wound Infection; D055815:Young Adult",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "687.e1-687.e6",
"pmc": null,
"pmid": "26743382",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Implant Site Infection and Bone Flap Osteomyelitis Associated with the NeuroPace Responsive Neurostimulation System.",
"title_normalized": "implant site infection and bone flap osteomyelitis associated with the neuropace responsive neurostimulation system"
} | [
{
"companynumb": "US-BAYER-2016-096653",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"activesubstancename": "LACOSAMIDE"
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"abstract": "Herewith we are reporting an unusual presentation of testicular tumour. The patient is a 37 years old gentleman diagnosed with Stage III seminoma post orchidectomy on chemotherapy and had spontaneous rupture of retroperitoneal nodal mass and presented with hemoperitoneum and hypovolemic shock. He was successfully salvaged by aggressive resuscitation, emergency laparotomy and resection of ruptured nodal mass and is presently disease free. This article is aimed at highlighting this unusual presentation and complication of advanced testicular tumour and the need for aggressive surgery even in the so called hopeless situations. The need for multidisciplinary care in the cure of advanced testicular care is once again reemphasized.",
"affiliations": "Department of Surgical Oncology, Cancer Institute, Adyar, Chennai, India ; No. 6. First Cross Street, Avadi Road, Karayanchavadi, Poonamallee, Chennai, 600 056 Tamilnadu India.;Division of Urologic Oncology, Department of Surgical Oncology, Cancer Institute, Adyar, Chennai, India.",
"authors": "Chandrasekhar|Senthil Kumar Azhisoor|SK|;Kathiresan|Narayanaswamy|N|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s13193-014-0312-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0975-7651",
"issue": "5(3)",
"journal": "Indian journal of surgical oncology",
"keywords": "Chemotherapy; Hemoperitoneum; Laparotomy; Multidisciplinary care; Retroperitoneal node; Testicular tumour",
"medline_ta": "Indian J Surg Oncol",
"mesh_terms": null,
"nlm_unique_id": "101532448",
"other_id": null,
"pages": "252-4",
"pmc": null,
"pmid": "25419079",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "19942267;8705236",
"title": "Ruptured Retroperitoneal Node Presenting as Hemoperitoneum-An Unusual Presentation of testicular tumour.",
"title_normalized": "ruptured retroperitoneal node presenting as hemoperitoneum an unusual presentation of testicular tumour"
} | [
{
"companynumb": "IN-MYLANLABS-2021M1059706",
"fulfillexpeditecriteria": "1",
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"abstract": "We herein report the case of a male patient with acute myeloid leukemia with fatal outcome attributable to pharmacokinetics of pegfilgrastim.\n\n\nMETHODS\nAn unexplained blast proliferation in a patient with acute myeloid leukemia following cytotoxic induction chemotherapy was investigated in depth. Myeloblast hyperstimulation was likely related to pegfilgrastim, the long half-life of which extended the duration of side-effects, resulting in massive and rapidly fatal leukemia cell proliferation.\n\n\nCONCLUSIONS\nPegfilgrastim can cause unexpected deleterious effects in acute myeloid leukemia. We, thus, recommend administering drugs with a shorter half-life, such as filgrastim or lenograstim, to reduce infection incidence in patients receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia.",
"affiliations": "Pharmacy, University Hospital of Strasbourg, Strasbourg, France celine.duval@chru-strasbourg.fr.;Department of Oncology and Hematology, University Hospital of Strasbourg, Strasbourg, France.;Department of Oncology and Hematology, University Hospital of Strasbourg, Strasbourg, France.;Pharmacy, University Hospital of Strasbourg, Strasbourg, France.;Hematology Laboratory, University Hospital of Strasbourg, Strasbourg, France.;Pharmacy, University Hospital of Strasbourg, Strasbourg, France.;Department of Oncology and Hematology, University Hospital of Strasbourg, Strasbourg, France.",
"authors": "Duval|Celine|C|;Boucher|Stephanie|S|;Moulin|Jean-Charles|JC|;Gourieux|Benedicte|B|;Mauvieux|Laurent|L|;Leveque|Dominique|D|;Herbrecht|Raoul|R|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "34(11)",
"journal": "Anticancer research",
"keywords": "Pegfilgrastim; acute myeloid leukemia; fatal effect",
"medline_ta": "Anticancer Res",
"mesh_terms": "D001752:Blast Crisis; D049109:Cell Proliferation; D017809:Fatal Outcome; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011379:Prognosis; D011994:Recombinant Proteins",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6747-8",
"pmc": null,
"pmid": "25368285",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal stimulation of acute myeloid leukemia blasts by pegfilgrastim.",
"title_normalized": "fatal stimulation of acute myeloid leukemia blasts by pegfilgrastim"
} | [
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"companynumb": "FR-AMGEN-FRASP2012003760",
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"abstract": "BACKGROUND\nTourette syndrome (TS) has been described as peaking in adolescence with subsequent regression. We report patients who were diagnosed with TS during childhood who experienced a latent period (significant reduction in or absence of tics) followed by tic re-emergence in adulthood.\n\n\nMETHODS\nWe performed a retrospective chart review of outpatients over age 21 seen at the Yale neurology clinic between January 2012 and July 2016 who were diagnosed with childhood-onset tics, and who experienced a latent period of greater than 1 year followed by an exacerbation.\n\n\nRESULTS\nSixteen patients were identified. The mean latent period was 16 years. Ten patients (62.5%) identified an exacerbation trigger, most commonly changes in substance use (five patients). Seven patients (43.8%) reported worsening of tics since childhood. Six patients (37.5%) had received pharmacological intervention for tics as children, and 15 patients (93.8%) as adults. Six of 15 patients (40.0%) had an effective response from those pharmacological intervention(s).\n\n\nCONCLUSIONS\nOur study demonstrates that the decline in symptoms as patients age may represent temporary improvement. The latent period lasted years in our patients, different from the more rapid waxing and waning in children. A change in substance use was an important trigger. Requests for pharmacological intervention were not necessarily correlated with worsening tic severity.",
"affiliations": "Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.;Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.;Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA; Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA; Center for Neuroepidemiology and Clinical Neurological Research, Yale School of Medicine, Yale University, New Haven, CT, USA.;Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.",
"authors": "Schaefer|Sara M|SM|;Chow|Christopher A|CA|;Louis|Elan D|ED|;Robakis|Daphne|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.7916/D8FF3Z1Q",
"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services 10.7916/D8FF3Z1QBrief ReportsTic Exacerbation in Adults with Tourette Syndrome: A Case Series Tic Exacerbation in AdultsSchaefer Sara M. 1Chow Christopher A. 1Louis Elan D. 123Robakis Daphne 1*1 Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA2 Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA3 Center for Neuroepidemiology and Clinical Neurological Research, Yale School of Medicine, Yale University, New Haven, CT, USABenito-Leon Julian Hospital “12 de Octubre”, Spain*To whom correspondence should be addressed. E-mail: daphne.robakis@yale.edu2017 6 3 2017 7 45013 1 2017 16 2 2017 © 2017 Schaefer et al.2017Schaefer et al.This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nTourette syndrome (TS) has been described as peaking in adolescence with subsequent regression. We report patients who were diagnosed with TS during childhood who experienced a latent period (significant reduction in or absence of tics) followed by tic re-emergence in adulthood.\n\nMethods\nWe performed a retrospective chart review of outpatients over age 21 seen at the Yale neurology clinic between January 2012 and July 2016 who were diagnosed with childhood-onset tics, and who experienced a latent period of greater than 1 year followed by an exacerbation.\n\nResults\nSixteen patients were identified. The mean latent period was 16 years. Ten patients (62.5%) identified an exacerbation trigger, most commonly changes in substance use (five patients). Seven patients (43.8%) reported worsening of tics since childhood. Six patients (37.5%) had received pharmacological intervention for tics as children, and 15 patients (93.8%) as adults. Six of 15 patients (40.0%) had an effective response from those pharmacological intervention(s).\n\nDiscussion\nOur study demonstrates that the decline in symptoms as patients age may represent temporary improvement. The latent period lasted years in our patients, different from the more rapid waxing and waning in children. A change in substance use was an important trigger. Requests for pharmacological intervention were not necessarily correlated with worsening tic severity.\n\nTicsTourette syndrome\n==== Body\nIntroduction\nTourette syndrome (TS) is a life-long disorder but it is characterized by childhood onset, with the most severe symptoms occurring between 8 and 12 years, usually followed by a linear decline in severity.1 It has been shown in a number of follow-up studies of TS patients that by young adulthood one-third to one-half of patients have minimal to no tics.1–4 Many patients follow a less benign course and suffer from impairing tics that persist into adulthood. However, the average age at follow-up evaluation has generally not exceeded the late 20s, and is often even younger.1,5 Pappert et al.6 identified and videotaped 31 adult patients who had been videotaped for tics as children, and found that 90% of them still had tics. However, all of the patients were under 30 years of age. A recent questionnaire-based study investigating the time course of tics included patients up to age 35, but also included children as young as 13, diluting the results of the adult group.7 We therefore have an incomplete understanding of the natural history of tics as patients progress through age categories, and do not know if young adults whose tics improve will experience recurrences or worsening later in life.\n\nThere is some indication from small case series and reports that tics do recur later in adult life in patients who had tics as children. The largest report to date that separately identified such patients is by Chouinard and Ford.8 They described nine patients who presented for tics as adults who retrospectively had mild tics as children but had not sought neurological care until adulthood. Their symptom-free hiatus spanned 25–63 years. Klawans and Barr9 reported four such cases in 1985; the patients had remission from tics before the age of 20 years, then recurrence after 60 years old. Sandyk and Awerbuch10 reported one case of tic recurrence in a woman at the age of 50, after previous resolution in early adulthood. Owing to the scarcity of such reports in the literature, it remains difficult to know whether delayed recurrence of tics is a rare event or simply underreported.\n\nIn this exploratory chart review, we sought to identify adult patients in our movement disorders clinic who experienced tic recurrences after a latency period (period of significant reduction in or absence of tics), and to identify any patterns related to demographics, exacerbation triggers, or tic phenomenology that could inform our understanding of the waxing and waning of tics in adult patients.\n\nMethods\nIn July 2016, one of the authors (D.R.) performed an electronic search of the electronic medical record (EPIC) at Yale to identify 1) outpatients 2) seen at the Yale Medical Group neurology clinic, 3) evaluated between January 2012 and July 2016, 4) diagnosed by a movement disorders neurologist 5) with tics or Tourette Syndrome. Sixty-five patients fulfilled these search criteria. Their medical charts were reviewed and those who had tics of childhood onset, had experienced a latent period of relative tic abatement (defined as the significant reduction in or absence of tics) of greater than one year, and were greater than 21 years of age at the time of the tic exacerbation, were included in the series. The ICD-9 codes for tics of organic origin: 333.3 and Tourette syndrome: 307.23 were used as EPIC search terms. Sixteen patients met all our inclusion criteria. The study was approved by the Yale institutional review board. Demographic and clinical data from the medical record was abstracted by trained staff (C.C.) using a data abstraction form designed for this study.\n\nResults\nOf the 16 patients identified, 12 (75.0%) were male and four (25.0%) were female, with an average age at the time of presentation to our clinic of 47 years old (Table 1). Sixteen (100%) of the patients had a diagnosis of TS. Fifteen of the 16 patients (93.8%) had comorbidities commonly associated with tic disorders (obsessive compulsive disorder [OCD], attention deficit disorder [ADD], autism spectrum disorder [ASD], anxiety, depression), and many patients demonstrated more than one of these comorbidities. Other neurological and psychiatric comorbidities included migraine (one patient), multiple sclerosis (one), cervical dystonia (one), seizures (one), and insomnia (one). Eight of the 16 patients (50.0%) had a first-degree relative with tics, OCD, ADD, ASD, anxiety, or depression. Other neurological and psychiatric disorders in first-degree relatives included schizophrenia (one patient) and bipolar disorder (one patient).\n\n\nTable 1 Group Clinical Characteristics of 16 Adult Patients with a History of Childhood Tics and Subsequent Tic Exacerbation in Adulthood\nCharacteristic\tData\t\nMean age at presentation (years)\t47\t\nMean age at exacerbation (years)\t40\t\nMale gender (N)\t12 (75.0%)\t\nTourette syndrome diagnosis (N)\t16 (100.0%)\t\nPsychiatric comorbidity (N)\t15 (93.4%)\t\n\n\n\nThe mean age at exacerbation was 40 years old. The mean latent period was 16 years (range 3–35 years); two patients did not have specifically recorded latent periods but the notes indicated that it was “years”. Ten out of 16 (62.5%) patients reported one or more identifiable stressor(s) that may have induced the exacerbation, including work-related stress (four), comorbid psychiatric disease (three), illness of a family member (one), marital problems (two), medication cessation or reduction (two), high caffeine intake (two), alcohol cessation (one), smoking cessation (one), and poor sleep (one). Six of fifteen patients (37.5%) were unable to identify a trigger.\n\nThe phenomenology of tics was the same as had been present when the patient was a child in eight patients (50.0%). In four patient charts (25.0%), the phenomenology of the childhood tics was not clearly documented. Three patients (18.8%) had clear documentation of tic evolution, such that a set of tics in childhood changed to more varied tics in adulthood. In one patient (6.3%) with a history of multiple types of vocal and motor tics in childhood, one tic in particular (winking) became more prominent and bothersome in adulthood. Seven patients (43.8%) had clearly reported that their adult tics were worse than those they had experienced as children; these patients reported that their tics were more prominent, loud, violent, frequent, or varied. The remaining nine patients (56.3%) either reported that their tics were of the same severity (four), were better (one), or it was not documented (four). Fourteen patients (87.5%) reported both motor and vocal tics in adulthood, while the remaining two patients (12.5%) had motor tics only, by report.\n\nSix patients (37.5%) sought treatment at the time of their exacerbation because their tics (both motor and vocal) interfered with work, particularly with public speaking and interacting with clients and coworkers. One patient (6.3%) reported social embarrassment related to her tics (winking). For the remaining patients, a clear precipitant for presentation to a medical professional was not documented, other than exacerbation of tics.\n\nTen of sixteen patients (62.5%) had not been treated with any medications for tics as children, while six (37.5%) had been treated with medications during childhood. On presentation to our clinic, eleven patients (68.9%) were on a medication for tics or mood including: clonidine (two), benzodiazepines (three), pimozide (one), selective serotonin–norepinephrine reuptake inhibitors (two), buproprion (one), haloperidol (one), and topiramate (one). Fourteen patients (87.5%) were treated with medication for their tics by their Yale movement disorders physician at the time of their exacerbation. One patient (6.3%) underwent lifestyle modifications, and two patients (12.5%) received botulinum toxin injections (one in addition to medication). The medications prescribed were clonidine (six), benzodiazepines (three), guanfacine (two), levetiracetam (two), topiramate (two), tetrabenazine (one), haloperidol (one), buproprion (one), amantadine (one), and pimozide (one). Medication responses are recorded in Table 2. Excluding patients without follow up and one non-adherent patient, medications were effective in about half of the patients (seven or 46.7%). One medication was discontinued because of side effects. Patients tried an average of 1.25 medications, and only six of 15 patients who received pharmacologic treatment had a documented effective response at some point in their treatment. Five patients were lost to follow-up. With the exclusion of non-compliant cases and those lost to follow-up, clonidine was effective in one out of three cases (33.3%), benzodiazepines in one out of two cases (50.0%), guanfacine in one out of two cases (50.0%), and levetiracetam in zero out of two cases (0.0%). Botulinum toxin was effective in combination with medications in one patient, and there was an unknown outcome in the other patient.\n\n\nTable 2 Individual Demographic and Clinical Information of 16 Adult Patients with a History of Childhood Tics and Subsequent Tic Exacerbation in Adulthood\n\tAge at Presentation (years)\tAge at Exacerbation (years)\tGender\tDiagnosis\tLatent Period (years)\tTrigger for Exacerbation\tComorbidities\tFamily History\tMedications Tried, Effectiveness\t\n1\t23\t21\tM\tTS\t3\tAnxiety, high caffeine intake, cessation of alcohol and tobacco\tAnxiety, ADD\tNone\tClonidine, not effective; clonazepam, effective\t\n2\t25\t23\tM\tTS\t5\tHigh caffeine intake, poor sleep\tOCD\tNone\tNo medications\t\n3\t30\t28\tM\tTS\t8\tWork\tAnxiety, multiple sclerosis\tNone\tClonidine, unknown\t\n4\t31\t31\tM\tTS\t10\tNew job\tOCD, migraine\tMother (OCD, anxiety), father (anxiety), sister (OCD, anxiety)\tClonidine, not effective\t\n5\t32\t29\tM\tTS\t10\tNone\tASD, insomnia\tNone\tBotulinum toxin, unknown\t\n6\t32\t24\tM\tTS\t6\tNew job\tADD\tFather (tics)\tClonidine, unknown\t\n7\t33\t32\tF\tTS\t\tNone\tOCD, seizures\tNone\tClonidine, effective; levetiracetam, side effects\t\n8\t34\t33\tM\tTS\t12\tNone\tOCD, ASD\tBrother (tics)\tAmantadine + botulinum toxin + topiramate, effective\t\n9\t38\t33\tF\tTS\t25\tNone\tOCD\tNone\tClonidine, non-compliant\t\n10\t40\t37\tM\tTS\t19\tNew business, marriage\tAnxiety, depression\tBrother (tTics)\tBuproprion, not effective\t\n11\t47\t41\tF\tTS\t15\tNone\tOCD, depression\tNone\tGuanfacine, not effective; clonazepam + levetiracetam, not effective\t\n12\t56\t48\tM\tTS\t\tNone\tADHD\tNone\tGuanfacine, effective\t\n13\t62\t61\tM\tTS\t20\tDepression with suicidality\tOCD, depression\tSister (TS)\tHaloperidol, effective\t\n14\t63\t62\tM\tTS\t30\tStopped meds; anxiety\tOCD, anxiety\tSister (depression)\tTopiramate, unknown\t\n15\t66\t66\tF\tTS\t30\tDivorce, medication reduction\tNone\tFather (OCD), sister (schizophrenia)\tPimozide, effective; tetrabenazine, not effective\t\n16\t69\t66\tM\tTS\t35\tIll family member\tOCD, depression, anxiety\tFather (anxiety), sister (bipolar)\tClonazepam, unknown\t\nAbbreviations: ADD, Attention Deficit Disorder; ADHD, Attention Deficit Hyperactivity Disorder; ASD, Autism Spectrum Disorder; F, Female; M, Male; OCD, Obsessive Compulsive Disorder; TS, Tourette Syndrome.\n\n\n\n\nDiscussion\nIn this study, we retrospectively identified 16 patients who belong to a little-described subset of TS patients: those who are diagnosed with TS during childhood, then experience a period of relief from or absence of symptoms before tic re-emergence in adulthood. This temporal pattern has not been depicted as part of the natural history of tic disorders, mainly because there are no longitudinal studies of children with tics far into adulthood. Our study, which represents the largest single series to date of adults with tic recurrences, raises the possibility that, for some patients, the steady decline in symptoms many patients experience as they enter their early 20s may represent temporary improvement.\n\nThe major implication of this study relates to the way in which tic patients may be educated about their disorder, and managed into adulthood. Tic patients and their families are often educated about the natural history of their tic disorders using the classic paradigm that the tics will likely become less severe as the patients exit adolescence. It is important for neurologists to be aware that tics may recur or worsen in adulthood even after a significant latent period. The neurological community should therefore 1) consider that there may be more patients than expected who suffer from recurrences in adulthood, and 2) ultimately attempt to identify factors that predict which patients go on to have recurrences.\n\nThe mean age at onset of tic re-emergence in our patients was 40 years, very similar to the mean age of 47 years reported by Chouinard and Ford;8 the latency period was shorter for our patients, averaging 16 years (range 3–35 years) vs. 35 years (range 12–56 years). Notably, Klawans and Barr9 reported four patients, each with an age of exacerbation greater than 60 years, and latency periods exceeding 40 years in all cases. In each of these studies, adults experienced shifts in their symptomatology over periods of years or decades, unlike the more rapid fluctuations over weeks to months that has been observed in children.15\n\nDay-to-day factors that influence variability of tics have been studied in adults and children,16,17 but there is little information in the literature on what factors may affect tic fluctuations over years. Sixty-three percent of our patients reported identifiable triggers linked to their tic exacerbations. These were often common life stressors of adulthood related to work and interpersonal relationships, which are similar to the psychosocial stressors that have been reported to induce tic exacerbations in children, namely school-related and interpersonal/family stressors.18 Initiation, increase, or cessation of substances such as tobacco, alcohol, caffeine, and/or medications were found to temporally correlate with re-emergence of tics in five (31.3%) of our patients. Substance use is less prevalent in children, so it is important for practitioners to ask adult patients about use of neurologically active substances or medications, as these may influence tics. Patients with tic disorders have been shown to have heightened levels of internalizing disorders (e.g., depression, anxiety, OCD), and these have been correlated with more self-reported triggers for tic exacerbations.16,19 Twelve of 16 (75.0%) of our patients had one or more diagnoses of internalizing disorders, which may partially explain why these patients developed exacerbations later in life that warranted medical attention.\n\nStudies have reported variable results regarding tic evolution from childhood to adulthood—that tics in adulthood are milder, more severe, or the same as those found in children.8,12,13 These studies did not compare the same patients over time. Slightly less than half of our patients (43.8%) reported a clear worsening. Nine patients for whom tics were milder, the same, or not documented accepted medical intervention for their tics, even though four of those patients (44.4%) had not received medications for their tics as children. Himle et al.16 found that older children reported more tic-exacerbating consequences for their tics (defined as outcomes that occur after tics, such as being stared at), and proposed that this may be due to an increasingly complex social environment that comes with age. It may be that, in adults, the social environment continues to increase in complexity, and with that, external exacerbating consequences may become more influential, particularly in those patients with internalizing disorders. The influence of social impact on the decision to seek medical attention is supported by the common theme that tics interfered with the ability to function at work, and/or caused embarrassment in social settings in seven (43.8%) of our patients. Future studies should aim to differentiate between objective tic severity and subjective tic impact, particularly as these factors relate to psychiatric comorbidities.\n\nTen different medications and botulinum toxin were used in the 15 patients who received medical therapy for their tics, and they were only effective about half of the time. In some cases, medications were not standard of care, but were used either because they were continued from a previous provider, or because multiple other medications had been tried prior to presentation to our center without success. At the time of the chart review, only six of the 15 patients (40.0%) who were treated pharmacologically were on treatments that were known to be effective for their tics. Past studies have demonstrated that adults may respond more poorly to medications than children, particularly neuroleptics.13 Two of our patients were treated with neuroleptics (pimozide, haloperidol), and both reported effectiveness of the medication. Alpha-2 agonists such as clonidine and guanfacine have been shown in several studies to be efficacious in less than half of patients, although some studies doubt their efficacy for tics at all.23 Alpha-2 agonists were the most commonly prescribed medications for tics in our patients; eight of 16 patients were treated with either clonidine or guanfacine, and of those only two reported that they were efficacious. Control of tics in these patients was challenging and the therapeutic strategies employed were highly variable, a situation unlikely to be unique to our institution.\n\nThe major limitation of our study is that it is a retrospective review of medical records and this resulted in incomplete data in some instances. Given the retrospective nature of the study, medications were not standardized and efficacy was difficult to determine. Patients often do not seek medical attention for tics, which makes a true incidence of tics difficult to assess.24,25 Ideally, the percentage of patients with tic disorders in childhood who experience re-emergence of tics as adults should be elucidated with a prospective study. Second, the sample size of 16 is small. Third, patients were not evaluated in clinic during their latent periods—the latency of tics was purely by patient report—so it is unclear to what extent the patients had a true abatement of symptoms. It has been observed that as many as 30–50% of patients were unaware of tics noted by examiners.6,25 Still, subclinical tics may be of little practical relevance. Likewise, tic severity in adulthood relative to childhood severity was by patient report and therefore may not be entirely reliable.\n\nIn conclusion, the improvement of tics as patients enter adulthood may, in some patients, represent a temporary process rather than a permanent resolution. Neurologists and patients should be aware that tics may recur in adulthood even after a significant latent period. More research is needed to better understand the many facets of this complex neuropsychiatric disorder in the adult population.\n\nFunding: None.\n\nFinancial Disclosures: None.\n\nConflict of Interest: The authors report no conflict of interest.\n\nEthics Statement: This study was reviewed by the authors’ institutional ethics committee and was considered exempted from further review.\n==== Refs\nReferences\n1 Leckman JF Zhang H Vitale A et al Course of tic severity in Tourette syndrome: The first two decades Pediatrics 1998 102 (Pt 1) 14 19 doi: 10.1542/peds.102.1.14 9651407 \n2 Bloch MH Peterson BS Scahill L et al Adulthood outcome of tic and obsessive-compulsive symptom severity in children with Tourette syndrome Arch Pediatr Adolesc Med 2006 160 65 69 doi: 10.1001/archpedi.160.1.65 16389213 \n3 Erenberg G Cruse RP Rothner AD The natural history of Tourette syndrome: A follow-up study Ann Neurol 1987 22 (3) 383 385 doi: 10.1002/ana.410220317 3479043 \n4 Burd L Kerbeshian PJ Barth A et al Long-term follow-up of an epidemiologically defined cohort of patients with Tourette syndrome J Child Neurol 2001 16 431 437 doi: 10.1177/088307380101600609 11417610 \n5 Rizzo R Gulisano M Cali PV et al Long term clinical course of Tourette syndrome Brain Dev 2012 34 667 673 doi: 10.1016/j.braindev.2011.11.006 22178151 \n6 Pappert EJ Goetz CG Louis ED et al Objective assessments of longitudinal outcome in Gilles de la Tourette’s syndrome Neurology 2003 61 936 940 doi: 10.1212/01.WNL.0000086370.10186.7C 14557563 \n7 Shprecher DR Rubenstein LA Gannon K et al Temporal course of the Tourette syndrome clinical triad Tremor Other Hyperkinet Mov 2014 4 doi: 10.7916/D8HD7SV6 \n8 Chouinard S Ford B Adult onset tic disorders J Neurol Neurosurg Psychiatry 2000 68 738 743 doi: 10.1136/jnnp.68.6.738 10811697 \n9 Klawans HL Barr A Recurrence of childhood multiple tic in late adult life Arch Neurol 1985 42 1079 1080 doi: 10.1001/archneur.1985.04060100061023 4051837 \n10 Sandyk R Awerbuch G Recurrence of complex motor and vocal tics in an elderly woman responsive to opiates Int J Neurosci 1989 44 317 320 doi: 10.3109/00207458908986209 2722417 \n11 Bloch MH Leckman JF Clinical course of Tourette syndrome J Psychosom Res 2009 67 497 501 doi: 10.1016/j.jpsychores.2009.09.002 19913654 \n12 Cubo E Chmura T Goetz CG Comparison of tic characteristics between children and adults Mov Disord 2008 23 2407 2411 doi: 10.1002/mds.22117 18855922 \n13 Eapen V Lees AJ Lakke JP et al Adult-onset tic disorders Mov Disord 2002 17 735 740 doi: 10.1002/mds.10180 12210863 \n14 Evans J Seri S Cavanna AE The effects of Gilles de la Tourette syndrome and other chronic tic disorders on quality of life across the lifespan: a systematic review Eur Child Adolesc Psychiatry 2016 25 939 948 doi: 10.1007/s00787-016-0823-8 26880181 \n15 Leckman JF Phenomenology of tics and natural history of tic disorders Brain Dev 2003 25 (Suppl. 1) S24 28 doi: 10.1016/S0387-7604(03)90004-0 14980368 \n16 Himle MB Capriotti MR Hayes LP et al Variables associated with tic exacerbation in children with chronic tic disorders Behav Modif 2014 38 163 183 doi: 10.1177/0145445514531016 24778433 \n17 O’Connor K Brisebois H Brault M et al Behavioral activity associated with onset in chronic tic and habit disorder Behav Res Ther 2003 41 241 249 doi: 10.1016/S0005-7967(02)00051-7 12547383 \n18 Buse J Kirschbaum C Leckman JF et al The modulating role of stress in the onset and course of Tourette’s syndrome: A review Behav Modif 2014 38 184 216 doi: 10.1177/0145445514522056 24516255 \n19 Lin H Katsovich L Ghebremichael M et al Psychosocial stress predicts future symptom severities in children and adolescents with Tourette syndrome and/or obsessive-compulsive disorder J Child Psychol Psychiatry 2007 48 157 166 doi: 10.1111/j.1469-7610.2006.01687.x 17300554 \n20 Knight T Steeves T Day L et al Prevalence of tic disorders: A systematic review and meta-analysis Pediatr Neurol 2012 47 77 90 doi: 10.1016/j.pediatrneurol.2012.05.002 22759682 \n21 Gadow KD Nolan EE Sprafkin J et al Tics and psychiatric comorbidity in children and adolescents Dev Med Child Neurol 2002 44 330 338 doi: 10.1111/j.1469-8749.2002.tb00820.x 12033719 \n22 Centers for Disease Prevention Prevalence of diagnosed Tourette syndrome in persons aged 6-17 years—United States, 2007 MMWR 2009 58 581 585 19498335 \n23 Eddy CM Rickards HE Cavanna AE Treatment strategies for tics in Tourette syndrome Ther Adv Neurol Disord 2011 4 25 45 doi: 10.1177/1756285610390261 21339906 \n24 Robertson MM Gourdie A Familial Tourette’s syndrome in a large British pedigree. Associated psychopathology, severity, and potential for linkage analysis Br J Psychiatry 1990 156 515 521 doi: 10.1192/bjp.156.4.515 2386860 \n25 Kurlan R Behr J Medved L et al Severity of Tourette’s syndrome in one large kindred. Implication for determination of disease prevalence rate Arch Neurol 1987 44 268 269 doi: 10.1001/archneur.1987.00520150024013 3469941\n\n",
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"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "Tics; Tourette syndrome",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
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"title": "Tic Exacerbation in Adults with Tourette Syndrome: A Case Series.",
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"abstract": "BACKGROUND\nAdult hemophagocytic lymphohistiocytosis is a secondary immunopathologic phenomenon, mainly secondary to malignancy, infection, or autoimmune disorders. The performance of diagnostic criteria, studied in the pediatric population, is yet to be validated in the adult population. Some of the criteria include cytopenias and organomegaly that are inherent features to malignant processes, thus making the diagnosis of hemophagocytic lymphohistiocytosis a challenge in patients with cancer.\n\n\nMETHODS\nWe describe the case of a 54-year-old white man with history of metastatic maxillary sinus adenoid cystic carcinoma who had severe liver injury and cytopenias with progressive clinical deterioration. We performed an evaluation, by flow cytometry, of the expression of surface markers in his natural killer cells that revealed remarkable abnormalities. His syndrome eventually fulfilled criteria for hemophagocytic lymphohistiocytosis and he received therapy with steroids with interval clinical improvement. Unfortunately, he refused further cytotoxic treatment and died 2 weeks later.\n\n\nCONCLUSIONS\nThe conventional criteria for the diagnosis of hemophagocytic lymphohistiocytosis are suboptimal for adult patients with cancer resulting in delays in diagnosis and timely initiation of treatment. The diagnostic criteria have to be re-evaluated in patients with cancer; novel, easily available, and accurate diagnostic methods are needed.",
"affiliations": "Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA.;Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Section of Benign Hematology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit Number: 1464, Houston, TX, 77030, USA. cmrojas@mdanderson.org.",
"authors": "Hust|Michael A|MA|;Blechacz|Boris R A|BRA|;Bonilla|Diana L|DL|;Daver|Naval|N|;Rojas-Hernandez|Cristhiam M|CM|",
"chemical_list": "D014408:Biomarkers, Tumor",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 134410.1186/s13256-017-1344-xCase ReportAdult cancer-related hemophagocytic lymphohistiocytosis – a challenging diagnosis: a case report Hust Michael A. Michael.A.Hust@uth.tmc.edu 1Blechacz Boris R. A. BBlechacz@mdanderson.org 2Bonilla Diana L. DLBonilla@mdanderson.org 3Daver Naval NDaver@mdanderson.org 4Rojas-Hernandez Cristhiam M. 713-745-5339cmrojas@mdanderson.org 51 0000 0000 9206 2401grid.267308.8Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX USA 2 0000 0001 2291 4776grid.240145.6Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX USA 3 0000 0001 2291 4776grid.240145.6Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX USA 4 0000 0001 2291 4776grid.240145.6Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA 5 0000 0001 2291 4776grid.240145.6Section of Benign Hematology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit Number: 1464, Houston, TX 77030 USA 27 6 2017 27 6 2017 2017 11 17223 3 2017 3 6 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAdult hemophagocytic lymphohistiocytosis is a secondary immunopathologic phenomenon, mainly secondary to malignancy, infection, or autoimmune disorders.\n\nThe performance of diagnostic criteria, studied in the pediatric population, is yet to be validated in the adult population. Some of the criteria include cytopenias and organomegaly that are inherent features to malignant processes, thus making the diagnosis of hemophagocytic lymphohistiocytosis a challenge in patients with cancer.\n\nCase presentation\nWe describe the case of a 54-year-old white man with history of metastatic maxillary sinus adenoid cystic carcinoma who had severe liver injury and cytopenias with progressive clinical deterioration. We performed an evaluation, by flow cytometry, of the expression of surface markers in his natural killer cells that revealed remarkable abnormalities. His syndrome eventually fulfilled criteria for hemophagocytic lymphohistiocytosis and he received therapy with steroids with interval clinical improvement. Unfortunately, he refused further cytotoxic treatment and died 2 weeks later.\n\nConclusions\nThe conventional criteria for the diagnosis of hemophagocytic lymphohistiocytosis are suboptimal for adult patients with cancer resulting in delays in diagnosis and timely initiation of treatment. The diagnostic criteria have to be re-evaluated in patients with cancer; novel, easily available, and accurate diagnostic methods are needed.\n\nKeywords\nHemophagocytosisCancerDiagnosisAdulthttp://dx.doi.org/10.13039/100007313University of Texas MD Anderson Cancer CenterCA016672Daver Naval issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nHemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunopathologic syndrome with increasing prevalence in adults, necessitating systematic characterization and development of adult-specific criteria. Early recognition and diagnosis is critical with <10% survival without prompt treatment [1]. The HLH-2004 criteria offer a basis for clinical consideration, yet lack validation in the adult population [2]. Criteria such as cytopenias and organomegaly are inherent to malignant processes, especially hematologic or metastatic disease or concomitant chemotherapy.\n\nWe present a case of malignancy-related HLH with clinical manifestations that represented diagnostic ambiguity and difficulty in therapy initiation. We also describe the potential use of the evaluation of surface markers in cytokine-producing natural killer (NK) cells and cytotoxic NK cells by flow cytometry for diagnosis of that entity. Finally, we synthetize a literature review exploring current and developing HLH diagnostic criteria, as well as barriers to therapy, in particular for malignancy-related HLH.\n\nCase presentation\nA 54-year-old white man with a past medical history of right maxillary sinus adenoid cystic carcinoma with metastatic lesions to lung and vertebrae, hypertension, hypothyroidism, and nonalcoholic steatohepatitis presented to our emergency room in June 2016 with mental status changes accompanied by abdominal pain, dyspnea, and fever. He was not on active therapy for his malignancy. He previously received a trial regimen of coenzyme Q10, 12 g every 3 days, from October 2015 to April 2016. His past medical history was remarkable for two prior episodes of ascites and 3 months of progressive liver dysfunction and coagulopathy (Table 1). He had atorvastatin-induced myalgias leading to its discontinuation in April 2016 although his creatine kinase levels were not elevated. He was taking increasing doses of acetaminophen (2 grams daily) prior to admission. His physical examination vital signs were stable with one recorded febrile episode. In general, he appeared ill and lethargic, and was only oriented to person. He exhibited diminished bibasilar breath sounds, ascites with guarding, hypoactive bowel sounds, right lower quadrant tenderness, and hepatosplenomegaly.Table 1 Laboratory and diagnostic data\n\nCharacteristic (reference laboratory value)\tBaseline\tPeak of liver enzyme abnormalities\tAdmission\tSteroid initiation\t1 week post-steroid\t2 weeks post-admission\t\nWhite blood cell (4–11×103/uL)\t5.5\t4.0\t5.0\t8.5\t4.8\t41.0\t\nHemoglobin (14.0–18.0 gm/dL)\t11.0\t9.0\t11.1\t10.8\t9.5\t13.1\t\nPlatelet (140–440 K/uL)\t164\t109\t60\t75\t29\t96\t\nProthrombin time (12.7–15.0 seconds)\t15.7\t20.6\t22.5\t35.7\t24.6\t26.3\t\nInternational normalization ratio (0.90–1.20)\t1.25\t1.80\t2.02\t3.76\t2.22\t2.43\t\nPartial thromboplastin time (24.7–35.9 seconds)\t42.0\t37.7\t31.6\t45.1\t30.1\t32.9\t\nFibrinogen (mg/dL)\t452\t\t166\t141\t173\t155\t\nAlbumin (g/dL)\t2.9\t2.3\t2.3\t2.2\t3.3\t4.0\t\nAspartate aminotransferase (15–46 U/L)\t150\t807\t395\t314\t136\t145\t\nAlanine aminotransferase (7–56 U/L)\t67\t319\t54\t53\t26\t39\t\nAlkaline phosphatase (38–126 U/L)\t123\t139\t432\t350\t182\t187\t\nGamma-glutamyl transferase (8–78 U/L)\t42\t\t\t148\t291\t252\t\nSerum lactate dehydrogenase (U/L)\t2372\t3879\t3449\t\t2769\t3867\t\nFerritin (30–400 ng/mL)\t\t28,942\t\t10,283\t6031\t5863\t\nSerum triglyceride level (≤1500 mg/dL)\t167\t212\t101\t\t\t\t\nNK-cell activity (7–125 LU30)\t\t\t\t\t\t5\t\nCD25 (<1033 pg/mL)\t\t\t\t3910\t\t\t\nIL-1 (<1.0 pg/mL)\t\t\t\t\t\t1.8\t\nIL-6 (<5.0 pg/mL)\t\t\t\t\t\t27\t\nIFN-y (<2.0 pg/mL)\t\t\t\t\t\t<0.4\t\nTumor necrosis factor (1.2–15.3 pg/mL)\t\t\t\t\t\t20.9\t\n\nIFN interferon, IL interleukin, LU lytic unit, NK natural killer\n\n\n\n\nLaboratory data were remarkable for hyperferritinemia, hypofibrinogenemia, anemia, and thrombocytopenia along with elevated transaminases and coagulopathy (Table 1). A peripheral blood smear showed neutrophilia, monocytosis, and reticulocytopenia. No microangiopathic changes were seen. Extensive platelet clumping was noted.\n\nImaging studies revealed small pleural effusions, ascites, and hepatosplenomegaly with no evidence of portal hypertension or splanchnic thrombosis. We were suspicious of HLH in light of laboratory and physical examination findings. Additional differential diagnosis workup – infectious, autoimmune, acetaminophen levels – yielded unremarkable results, including: serology for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), herpes simplex virus (HSV), alpha 1-antitrypsin levels, and antinuclear, anti-mitochondrial, anti-smooth muscle, and transglutaminase antibodies (immunoglobulin A (IgA) and immunoglobulin G (IgG)). ADAMTS 13 activity was >34%. HLH-specific laboratory studies were sent, including soluble CD25 (sCD25), NK cell activity studies, and bone marrow biopsy.\n\nHe continued to deteriorate with multiple organ failure including renal failure, myocardial injury, and respiratory failure requiring intubation. Empiric therapy, considering the evidence of liver injury and the possibility of HLH, with N-acetylcysteine on a 20-hour intravenous protocol and dexamethasone 8 mg intravenously administered three times daily was initiated. HLH chemotherapy was not done during this time as hepatotoxicity risk outweighed benefits and a definite diagnosis was not confirmed.\n\nAs an attempt to expedite the evaluation of possible HLH, we isolated mononuclear cells from peripheral blood and evaluated expression of surface markers in cytokine-producing NK cells and cytotoxic NK cells by flow cytometry. We compared the profile with normal controls. The results, available after 36 hours, were remarkable for an increased expression of CD69 in cytotoxic NK cells, and decreased NKG2A in cytokine-producing NK cells in our case. The expression of CD69 and NKG2A in NK cells was evaluated in four other normal donors and the results were similar to the one acquired in parallel to the HLH sample (Fig. 1). No differences in protein expression of other markers were observed by flow cytometry (data not shown). These findings included similar surface levels of OX40, GITR, 4-1BB, TIM-3, PD-1, CTLA-4, LAG-3, and ICOS in CD8+ CD3+ T cells, as well as effector (CD127+, FoxP3-) and regulatory (CD127-, FoxP3+) CD4+ CD3+ T cells; similar expression of NKp44, NKG2C, NKG2D, 4-1BB, NKp30, and NKp46 in NK cells (CD56+ CD3-); and similar expression of CD28, CD27, ICOS, Eomes, Blimp-1, Bcl-6, T-bet, Ki-67, and cMyc in naïve (CCR7+ CD45RA+), effector (CCR7- CD45RA+), effector memory (CCR7-CD45RA-), and central memory (CCR7+ CD45RA-) CD4+ and CD8+ T cells. The frequency of all the evaluated immune cell populations was also similar, when comparing cells from our patient with those ones from a healthy control.Fig. 1 Natural killer cell flow cytometric analysis of peripheral blood mononuclear cells of patient with hemophagocytic lymphohistiocytosis. Natural killer cell gating was performed on live single CD56+ cells (a). Representation of CD69 and NKG2A surface expression in cytotoxic (CD56+ CD16+) and cytokine-secreting (CD56+ CD16-) natural killer cells (b). Results from the patient with hemophagocytic lymphohistiocytosis and a normal donor are shown. HLH hemophagocytic lymphohistiocytosis, NK natural killer\n\n\n\n\nOur patient’s bone marrow biopsy was performed 10 days after admission and delayed due to severe coagulopathy and demonstrated normocellularity (40 to 50%), megakaryocytic hypoplasia, and clusters of foamy histiocytes with ingested marrow cells. Fifteen days after admission, he fulfilled multiple HLH-2004 diagnostic criteria including hyperferritinemia, fever, splenomegaly, cytopenias, hemophagocytosis on biopsy of bone marrow, elevated CD25, and decreased NK cell activity by standardized studies (Table 1).\n\nHe steadily recovered with the steroid therapy instituted for 12 days and supportive measures. He was weaned off intubation and sedation. However, he refused further interventions for HLH, namely etoposide-based therapy and continuation of steroid treatment; he chose palliative care and died 2 weeks later.\n\nDiscussion\nAdult onset HLH is mainly a secondary phenomenon, arising from four components of pathology: a susceptible host; intrinsic/acquired immune defects; a trigger resulting in immune activation; and immunopathology resulting in host end organ failure [3]. Adult patients with HLH are immunocompromised individuals with malignancy, infection, or autoimmune disorders. Ramos-Casals et al. [4] found that 48% of cases were triggered by neoplasms, especially hematologic malignancies. Furthermore, patients with active malignancy are at greatest risk [4–6]. Differentiation of HLH from other sequelae of hematologic malignancies is based upon degree of inflammation [7]. Allen and McClain hypothesized that the syndrome results from complex interactions of host genetics and extrinsic immune challenges [7]. Studies have shown that immune defects in genes affecting regulation of granule-dependent lymphocyte activity as well as intracellular granule trafficking, mutations in T cell functioning (CD27), and cytokine production, that is, interferon (IFN)-gamma and interleukin (IL)-6, by malignant cells play a key role in HLH evolution [5, 8]. Similar genes and inflammatory responses may become affected during neoplasm therapy, inciting an iatrogenic HLH in adults [9–11]. The HLH-2004 criteria, validated in the pediatric community, are consensus criteria developed to guide inclusion and enrollment to studies [7]. The sensitivity and specificity of these criteria in the adult population have yet to be validated through prospective studies. However, a recent study from the MD Anderson Cancer Center (MDACC) identified an “extended 18-point diagnostic criteria” of clinical and laboratory variables closely associated with a diagnosis of malignancy-associated HLH (M-HLH) in adults. Sensitivity analysis suggested that individuals with an underlying malignancy who met 5/18 criteria could be considered to have a high likelihood of M-HLH [6]. These extended criteria include available parameters at the community level such as serum albumin, serum transaminases, lactate dehydrogenase, and basic coagulation testing that may function as early effective surrogates of M-HLH. These 18 markers are currently being validated in a prospective clinical trial at MDACC (NCT02385110).\n\nHLH consensus definitions implicate specific cell lines responsible for the severe inflammatory propagation, including: CD8+ T lymphocytes overactivation and uncontrolled expansion and NK cell dysfunction. Familial HLH (FHL) studies identified genetic deficiencies in these cell lines [3, 7, 12]. More recently, flow cytometry has been used to screen genetically predisposed patients, measuring intracellular perforin levels in NK cells [13]. To the best of our knowledge, similar flow cytometry studies, as described in our case, have not been conducted in adult patients with secondary HLH. Although well documented in patients with malignancies, NK cell line alterations may ultimately lead to secondary HLH. Various mechanisms of NK cell anti-tumor activity inhibition have been described, including: downregulation of NK-activating receptors, that is, natural cytotoxic receptors (NCRs) and NKG2D; upregulation of inhibitory receptors, that is, killer-cell immunoglobulin-like receptors (KIRs) and NKG2A; and modifications of expression of receptor-specific ligands. Ultimately, this inhibits NK cell-mediated anti-tumor surveillance, and impairs molecular crosstalk between NK cells and other immune cells [14]. Another study noted that excessive CD8+ T cells activation during FHL suppressed the regulatory T cell (Treg) population, allowing for rapid growth of CD8+ T-cell line and unchecked progression of persistent systemic inflammation. This resulted in an overall reduction of IL-2 and reversal in the IL-2 hierarchy of consumption by T cells, with pathologic preferential consumption by inflammatory CD8+ T cells via upregulated CD25, release of sCD25 by CD8+ T cells, reduction in Treg cell IL-2-induced anti-inflammatory properties, and reduction in Treg cell lines; this ultimately resulted in diverting “the normally anti-inflammatory IL-2 feedback loop into a proinflammatory circuit” [13].\n\nAnother major problem is the lack of effective therapy. Hurdles to therapy initiation, similar to our case report, include: (a) delayed recognition of HLH, (b) advanced stage of underlying disease, and (c) concurrent immunocompromised state with a need for further cytotoxic HLH-directed therapy. However, our experience with adult HLH suggests that early suspicion and treatment are of paramount priority as high mortality rate is secondary to the aggressive and rapid HLH process [6]. Emerging non-cytotoxic therapies such as IFN-gamma inhibitor (NI-0501), anti-IL-6 agents (tocilizumab), and JAK-inhibitors (ruxolitinib), either as single agents or in combination with traditional HLH therapies, hold promise for the therapy of M-HLH in adults.\n\nConclusions\nThe current diagnostic criteria of HLH might be suboptimal for adult patients and perhaps result in delays in its diagnosis and timely initiation of treatment. Given the high prevalence of cancer in an ageing population, current diagnostic criteria have to be re-evaluated in adult patients and novel, easily available, and highly specific diagnostic methods must be developed.\n\nFunding\nThis study was supported in part by the MD Anderson Cancer Centre Support Grant (CCSG) CA016672.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nMAH jointly conceived the idea for the manuscript (with CMR, BRB, ND), searched the background literature, wrote the report, and refined the text in accordance with comments from all authors. BRB conceived the idea for the manuscript, contributed to drafting of the manuscript and final approval of the version to be published. DLB collaborated with acquisition and analysis of flow cytometry data, drafting of the manuscript, and final approval of the version to be published. ND conceived the idea for the manuscript, contributed to drafting of the manuscript and final approval of the version to be published. CMR was the lead physician responsible for the clinical care of the case, supplied all clinical details, drafting of the manuscript, and final approval of the version to be published. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nGiven the case report nature of the manuscript and according to institutional Human Subject Research regulations, the need for approval was waived.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Janka GE Familial hemophagocytic lymphohistiocytosis Eur J Pediatr. 1983 140 221 30 10.1007/BF00443367 6354720 \n2. Henter JI Horne A Arico M Egeler RM Filipovich AH Imashuku S Ladisch S McClain K Webb D Winiarski J Janka G HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer. 2007 48 124 31 10.1002/pbc.21039 16937360 \n3. Jordan MB Allen CE Weitzman S Filipovich AH McClain KL How I treat hemophagocytic lymphohistiocytosis Blood. 2011 118 4041 52 10.1182/blood-2011-03-278127 21828139 \n4. Ramos-Casals M Brito-Zeron P Lopez-Guillermo A Khamashta MA Bosch X Adult haemophagocytic syndrome Lancet. 2014 383 1503 16 10.1016/S0140-6736(13)61048-X 24290661 \n5. Lehmberg K Sprekels B Nichols KE Woessmann W Muller I Suttorp M Bernig T Beutel K Bode SF Kentouche K Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents Br J Haematol. 2015 170 539 49 10.1111/bjh.13462 25940575 \n6. Tamamyan GN Kantarjian HM Ning J Jain P Sasaki K McClain KL Allen CE Pierce SA Cortes JE Ravandi F Malignancy-associated hemophagocytic lymphohistiocytosis in adults: Relation to hemophagocytosis, characteristics, and outcomes Cancer. 2016 122 2857 66 10.1002/cncr.30084 27244347 \n7. Allen CE McClain KL Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis Hematology Am Soc Hematol Educ Program. 2015 2015 177 82 26637718 \n8. Zhang K Jordan MB Marsh RA Johnson JA Kissell D Meller J Villanueva J Risma KA Wei Q Klein PS Filipovich AH Hypomorphic mutations in PRF1 , MUNC13-4 , and STXBP2 are associated with adult-onset familial HLH Blood. 2011 118 5794 8 10.1182/blood-2011-07-370148 21881043 \n9. Papadopoulou A Krance RA Allen CE Lee D Rooney CM Brenner MK Leen AM Heslop HE Systemic inflammatory response syndrome after administration of unmodified T lymphocytes Mol Ther. 2014 22 1134 8 10.1038/mt.2014.48 24651135 \n10. Teachey DT Rheingold SR Maude SL Zugmaier G Barrett DM Seif AE Nichols KE Suppa EK Kalos M Berg RA Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy Blood. 2013 121 5154 7 10.1182/blood-2013-02-485623 23678006 \n11. Grupp SA Kalos M Barrett D Aplenc R Porter DL Rheingold SR Teachey DT Chew A Hauck B Wright JF Chimeric antigen receptor-modified T cells for acute lymphoid leukemia N Engl J Med. 2013 368 1509 18 10.1056/NEJMoa1215134 23527958 \n12. Usmani GN Woda BA Newburger PE Advances in understanding the pathogenesis of HLH Br J Haematol. 2013 161 609 22 10.1111/bjh.12293 23577835 \n13. Lehmberg K Ehl S Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis Br J Haematol. 2013 160 275 87 10.1111/bjh.12138 23206255 \n14. Chretien AS Le Roy A Vey N Prebet T Blaise D Fauriat C Olive D Cancer-Induced Alterations of NK-Mediated Target Recognition: Current and Investigational Pharmacological Strategies Aiming at Restoring NK-Mediated Anti-Tumor Activity Front Immunol. 2014 5 122 10.3389/fimmu.2014.00122 24715892\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Adult; Cancer; Diagnosis; Hemophagocytosis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D014408:Biomarkers, Tumor; D003528:Carcinoma, Adenoid Cystic; D017809:Fatal Outcome; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "172",
"pmc": null,
"pmid": "28651636",
"pubdate": "2017-06-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26637718;16937360;6354720;24715892;21881043;23678006;23527958;25940575;23206255;24651135;24290661;21828139;27244347;23577835",
"title": "Adult cancer-related hemophagocytic lymphohistiocytosis - a challenging diagnosis: a case report.",
"title_normalized": "adult cancer related hemophagocytic lymphohistiocytosis a challenging diagnosis a case report"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0092363",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nTo describe a patient with morphine-induced myoclonus treated with a continuous infusion of midazolam and continued morphine dose escalation.\n\n\nMETHODS\nSingle case report.\n\n\nMETHODS\nDelivery, monitoring, and titration of morphine and midazolam in the patient's home by a homecare agency.\n\n\nRESULTS\nThe use of high dosages of morphine (i.e., 500 mg/h) produced myoclonic spasms in this patient, which in turn resulted in increasing pain. To allow for continuation of effective analgesia and to control the myoclonic spasms, an infusion of midazolam was initiated and titrated. The midazolam infusion allowed for continuation of the morphine dosage and also permitted further dosage escalation. As morphine dosages were further escalated, it was also necessary to increase the midazolam infusion to control additional myoclonic spasms.\n\n\nCONCLUSIONS\nUse of a concomitant midazolam infusion with high doses of morphine appears to be safe and is an effective means of controlling morphine-induced myoclonus. If further dosage increase of morphine are necessary in this setting, increases in the midazolam infusion also may be required.",
"affiliations": "College of Pharmacy, University of New Mexico, Albuquerque 87131.",
"authors": "Holdsworth|M T|MT|;Adams|V R|VR|;Chavez|C M|CM|;Vaughan|L J|LJ|;Duncan|M H|MH|",
"chemical_list": "D009020:Morphine; D008874:Midazolam",
"country": "United States",
"delete": false,
"doi": "10.1177/106002809502900105",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "29(1)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000293:Adolescent; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam; D009020:Morphine; D009207:Myoclonus",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "25-9",
"pmc": null,
"pmid": "7711342",
"pubdate": "1995-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Continuous midazolam infusion for the management of morphine-induced myoclonus.",
"title_normalized": "continuous midazolam infusion for the management of morphine induced myoclonus"
} | [
{
"companynumb": "US-PFIZER INC-2021484041",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "There is no international consensus on front-line optimal chemotherapy regimen for advanced stage follicular lymphoma (FL) patients, or a clear definition of cure for this disease. Aim of this study was to test the degree of effectiveness and the safety of the regimen containing fludarabine, mitoxantrone, and rituximab in a subset of poor prognosis FL patients with particular focus on the long-term disease-free survival. A retrospective study was conducted on 142 intermediate/high-risk FL patients treated in first-line with fludarabine, mitoxantrone, and rituximab regimen. Responses, safety, and survival were evaluated. The prognostic value of positron emission tomography (PET) was also investigated in a 56-patients subset. Overall response rate was 95.5% including 88% of complete responses. With a median follow-up of 48 months, 18% of patients had disease relapse, yielding an estimated 12-year disease-free survival (DFS) of 72%. All cases showed the lymphoma recurrence within 40 months: after this timing the DFS curve presented a plateau. Overall survival was 73% at 12 years. Post-treatment PET positivity remains a highly significant predictor of disease progression. The observed high rate of complete responses following the use of fludarabine, mitoxantrone-based regimen in combination with rituximab seems to be the first step to improve DFS. Our study could be the starting point to consider DFS as a potential alternative endpoint of future clinical trials on FL patients.",
"affiliations": "Institute of Hematology \"L. e A. Seràgnoli,\", University of Bologna, Bologna, Italy.",
"authors": "Zinzani|Pier Luigi|PL|;Pellegrini|Cinzia|C|;Broccoli|Alessandro|A|;Casadei|Beatrice|B|;Argnani|Lisa|L|;Pileri|Stefano|S|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.23540",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "88(11)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D016019:Survival Analysis; D014740:Vidarabine",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "E273-6",
"pmc": null,
"pmid": "23843267",
"pubdate": "2013-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fludarabine-mitoxantrone-rituximab regimen in untreated intermediate/high-risk follicular non-Hodgkin's lymphoma: experience on 142 patients.",
"title_normalized": "fludarabine mitoxantrone rituximab regimen in untreated intermediate high risk follicular non hodgkin s lymphoma experience on 142 patients"
} | [
{
"companynumb": "IT-TEVA-528930ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nThere is an increased rate of sudden cardiac death (SCD) in mental health patients. Some antipsychotic medications are known to prolong the QT interval, thus increasing a patient's risk of SCD via the arrhythmia, torsades de pointes (TdP). Our aim was to evaluate assessment for QT prolongation within a public inpatient mental health facility by auditing electrocardiograph (ECG) use.\n\n\nMETHODS\nWe reviewed records of all mental health inpatient admissions to a public emergency mental health inpatient unit between 1 January 2016 and 11 February 2016. ECG availability was noted and QT interval was manually measured and assessed for risk of TdP using the QT nomogram when present. Demographic information and medication use was collected.\n\n\nRESULTS\nOf 263 mental health inpatient admissions, 50 (19%) presentations had an ECG. A total of four (8%) had a prolonged QT interval. Of the 50 patients with an ECG, 12 (24%) were taking medication known to prolong the QT interval.\n\n\nCONCLUSIONS\nThere was very limited risk assessment for QT prolongation in a public hospital psychiatric inpatient unit, with less than 20% of patients having an ECG performed. Our study supports an association between QT-prolonging drugs and a clinically significant prolonged QT interval; however, a larger study with routine ECG screening is required.",
"affiliations": "Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Newcastle, NSW, and; Discipline of Clinical Pharmacology, University of Newcastle, NSW, and; Faculty of Health and Medicine, University of Newcastle, NSW, Australia.;Hunter New England Mental Health Service, Newcastle, NSW, and; Faculty of Health and Medicine, University of Newcastle, NSW, Australia.;Hunter New England Mental Health Service, Newcastle, NSW, Australia.;Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Newcastle, NSW, Australia.;Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Newcastle, NSW, and; Discipline of Clinical Pharmacology, University of Newcastle, NSW, and; Faculty of Health and Medicine, University of Newcastle, NSW, Australia.;Hunter New England Mental Health Service, Newcastle, NSW, Australia.",
"authors": "Berling|Ingrid|I|;Gupta|Rahul|R|;Bjorksten|Cecilia|C|;Prior|Felicity|F|;Whyte|Ian M|IM|;Berry|Sherman|S|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1177/1039856217726212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1039-8562",
"issue": "26(1)",
"journal": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
"keywords": "ECG; QT; prevalence; psychiatric inpatient; torsades de pointes",
"medline_ta": "Australas Psychiatry",
"mesh_terms": "D014150:Antipsychotic Agents; D004562:Electrocardiography; D006778:Hospitals, Psychiatric; D006801:Humans; D007297:Inpatients; D008133:Long QT Syndrome; D001523:Mental Disorders; D016171:Torsades de Pointes",
"nlm_unique_id": "9613603",
"other_id": null,
"pages": "50-55",
"pmc": null,
"pmid": "28836822",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "A review of ECG and QT interval measurement use in a public psychiatric inpatient setting.",
"title_normalized": "a review of ecg and qt interval measurement use in a public psychiatric inpatient setting"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-208257",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drug... |
{
"abstract": "BACKGROUND\nCYP2D6, a major drug-metabolizing enzyme, is encoded by a highly polymorphic and complex gene locus. We have identified a patient who failed to produce a CYP2D6 genotype with the AmpliChip P450 Test (AmpliChip), whereas his CYP2C19 genotype was readily determined. The aim of this investigation was to fully characterize the patient's CYP2D6 gene locus to resolve the AmpliChip no-call.\n\n\nMETHODS\nThe case, a brother, and son were genotyped with the AmpliChip and subsequently characterized using long-range (XL)-PCR coupled with TaqMan assay technology. Copy number variation was assessed by XL-PCR and quantitative PCR. Selected XL-PCR products were sequenced.\n\n\nRESULTS\nThe AmpliChip also produced a no-call for the son; the brother produced a result. The two alleles of the case were subsequently found to carry additional gene units that likely caused the AmpliChip no-calls. One was characterized as a CYP2D6*68+*4 tandem (CYP2D6*68 is a hybrid gene composed of 2D6 and 2D7), the other as a rare CYP2D6*13+*2 tandem (CYP2D6*13 is a 2D7/2D6 hybrid formerly known as CYP2D6*77). A novel CYP2D6*2 subvariant was identified in the son; the brother also carried the CYP2D6*68+*4 tandem.\n\n\nCONCLUSIONS\nThe implementation of pharmacogenetics-guided drug therapy relies on accurate clinical-grade genotype analysis. Although the AmpliChip is deemed to be a reliable platform, numerous more recently discovered allelic variants and gene arrangements are not detected or trigger no-calls. Although such cases may be rare, the clinical/genetic testing community must be aware of the challenges of CYP2D6 testing on the AmpliChip platform and implications regarding accuracy of test results.",
"affiliations": null,
"authors": "Gaedigk|Andrea|A|;Riffel|Amanda K|AK|;Berrocal|Belén García|BG|;Solaesa|Virginia García|VG|;Dávila|Ignacio|I|;Isidoro-García|María|M|",
"chemical_list": "D019389:Cytochrome P-450 CYP2D6",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1434-6621",
"issue": "52(6)",
"journal": "Clinical chemistry and laboratory medicine",
"keywords": null,
"medline_ta": "Clin Chem Lab Med",
"mesh_terms": "D000368:Aged; D000483:Alleles; D003198:Computer Simulation; D019389:Cytochrome P-450 CYP2D6; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005188:False Negative Reactions; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D008297:Male",
"nlm_unique_id": "9806306",
"other_id": null,
"pages": "799-807",
"pmc": null,
"pmid": "24445243",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Characterization of a complex CYP2D6 genotype that caused an AmpliChip CYP450 Test no-call in the clinical setting.",
"title_normalized": "characterization of a complex cyp2d6 genotype that caused an amplichip cyp450 test no call in the clinical setting"
} | [
{
"companynumb": "PHHY2014US106368",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "Hypokalaemic paralysis covers a heterogeneous group of disorders caused either by an enhanced shift of potassium into the cells or following a significant renal or gastrointestinal loss of potassium. We present the case of a 48-year-old Caucasian man with paralysis of both upper and lower extremities. ECG showed sinus rhythm and characteristic changes of hypokalaemia with depression of the ST segment, prolonged QTc interval of 581ms and U waves seen as a small positive deflection at the T wave in the middle precordial leads. We suspected the cause of hypokalaemia leading to paralysis to be due to administration of high doses of furosemide without oral potassium supplementation coupled with regular use of insulin. Initial therapy included both oral and intravenous potassium replacement and close monitoring of cardiac rhythm and serum potassium levels. Twenty-four hours after admission, the potassium level had normalised and the patient slowly recovered and gained strength. The patient was discharged after 1 week of careful follow-up and did not experience any serious degree of rebound hyperkalaemia. At the time of discharge, all laboratory tests were normal and ECG revealed a normal sinus rhythm and normal QTc intervals.",
"affiliations": "Department of Internal Medicine, Regionshospitalet Randers, Randers, Denmark.;Department of Internal Medicine, Regionshospitalet Randers, Randers, Denmark.;Department of Internal Medicine, Regionshospitalet Randers, Randers, Denmark.",
"authors": "Lybecker|Martin Bell|MB|;Madsen|Henrik Bjørnsgaard|HB|;Bruun|Jens Meldgaard|JM|",
"chemical_list": "D004232:Diuretics; D007328:Insulin; D005665:Furosemide; D011188:Potassium",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220735",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Arrhythmias; Diabetes; Endocrine System; Neuromuscular Disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D001145:Arrhythmias, Cardiac; D004232:Diuretics; D005665:Furosemide; D006801:Humans; D020514:Hypokalemic Periodic Paralysis; D007328:Insulin; D008297:Male; D008875:Middle Aged; D011188:Potassium; D035583:Rare Diseases; D020127:Recovery of Function; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28751432",
"pubdate": "2017-07-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11304665;12401935;15277290;15982543;1735925;19377223;20411077;5032523",
"title": "Severe hypokalaemia as a cause of acute transient quadriparesis.",
"title_normalized": "severe hypokalaemia as a cause of acute transient quadriparesis"
} | [
{
"companynumb": "DK-NOVOPROD-561042",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN ASPART"
},
"drugadditional": "3",
... |
{
"abstract": "Treatment resistant restless legs syndrome (RLS) in the setting of psychiatric comorbidities can be difficult to manage. Our patient is a 69-year-old Caucasian gentleman with bipolar disorder type I, unspecified anxiety disorder, obstructive sleep apnea (OSA), and treatment-refractory RLS. At initial presentation, the patient's prescribed medication regimen included fluoxetine 40 mg daily, gabapentin 800 mg in the morning and 3200 mg at bedtime, pramipexole 0.375 mg daily, lamotrigine 200 mg daily, trazodone 200 mg at bedtime, and temazepam 15 to 30 mg as needed for insomnia and RLS. Over the course of nearly 4 years, treatment interventions for this patient's RLS included: cognitive behavioral therapy for insomnia, discontinuation of exacerbating medications, switching dopamine agonists, use of pregabalin and iron supplement. This report demonstrates a challenging case of RLS in the setting of psychiatric comorbidities, development of augmentation, and polypharmacy.",
"affiliations": "Southwest Minnesota Region, Mankato, MN, USA.;Southwest Minnesota Region, Mankato, MN, USA.;Mayo Clinic, Rochester, MN, USA.;Mayo Clinic, Rochester, MN, USA.",
"authors": "Umbreit|Audrey|A|0000-0003-4930-4497;Sinha|Shirshendu|S|0000-0001-7114-4480;Kolla|Bhanu Prakash|BP|;Mansukhani|Meghna P|MP|0000-0003-2351-5640",
"chemical_list": "D018491:Dopamine Agonists",
"country": "United States",
"delete": false,
"doi": "10.1177/21501327211019590",
"fulltext": "\n==== Front\nJ Prim Care Community Health\nJ Prim Care Community Health\nJPC\nspjpc\nJournal of Primary Care & Community Health\n2150-1319\n2150-1327\nSAGE Publications Sage CA: Los Angeles, CA\n\n34032164\n10.1177/21501327211019590\n10.1177_21501327211019590\nCase Studies\nChallenges in the Treatment of Restless Legs Syndrome: A Case Report\nhttps://orcid.org/0000-0003-4930-4497\nUmbreit Audrey 1\nhttps://orcid.org/0000-0001-7114-4480\nSinha Shirshendu 12\nKolla Bhanu Prakash 2\nhttps://orcid.org/0000-0003-2351-5640\nMansukhani Meghna P. 2\n1 Southwest Minnesota Region, Mankato, MN, USA\n2 Mayo Clinic, Rochester, MN, USA\nShirshendu Sinha, Department of Psychiatry and Psychology, Mayo Clinic Heath System, Southwest Minnesota Region, 101 Martin Luther King Jr. Drive, Mankato, MN 56001, USA. Email: sinha.shirshendu@mayo.edu\n25 5 2021\nJan-Dec 2021\n12 2150132721101959022 3 2021\n3 5 2021\n4 5 2021\n© The Author(s) 2021\n2021\nSAGE Publications Inc unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nTreatment resistant restless legs syndrome (RLS) in the setting of psychiatric comorbidities can be difficult to manage. Our patient is a 69-year-old Caucasian gentleman with bipolar disorder type I, unspecified anxiety disorder, obstructive sleep apnea (OSA), and treatment-refractory RLS. At initial presentation, the patient’s prescribed medication regimen included fluoxetine 40 mg daily, gabapentin 800 mg in the morning and 3200 mg at bedtime, pramipexole 0.375 mg daily, lamotrigine 200 mg daily, trazodone 200 mg at bedtime, and temazepam 15 to 30 mg as needed for insomnia and RLS. Over the course of nearly 4 years, treatment interventions for this patient’s RLS included: cognitive behavioral therapy for insomnia, discontinuation of exacerbating medications, switching dopamine agonists, use of pregabalin and iron supplement. This report demonstrates a challenging case of RLS in the setting of psychiatric comorbidities, development of augmentation, and polypharmacy.\n\nrestless legs\nmood disorder\ncase report\nmedications\npsychiatry\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nRestless legs syndrome (RLS) affects 5% to 15% of the general population and is a sleep-related movement disorder.1 It is characterized by uncomfortable sensations in the legs accompanied by an urge to move that occurs predominantly during inactivity in the evening/night and is relieved by movement.1 Periodic limb movements in sleep (PLMS) are noted on polysomnography in over 80% of patients with RLS compared to 6% in the general population but the diagnosis is based on clinical features.2\n\nThe underlying pathophysiology of RLS is thought to relate to dysfunction of iron and dopamine metabolism in the central nervous system.3 The treatment primarily includes dopamine agonists (DAs) (commonly, pramipexole, and ropinirole) and alpha-2-delta calcium channel ligands (gabapentin and pregabalin).4 The severity of RLS symptoms is variable in an individual patient and over time some patients develop intractable symptoms. Interestingly, long-term treatment with DAs is associated with augmentation, characterized by greater severity and frequency of symptoms compared to baseline, often occurring earlier in the day and/or with spread to the arms.5\n\nRLS is commonly comorbid with psychiatric conditions. Prior studies have indicated a higher lifetime prevalence of psychiatric disorders in subjects with RLS (37%) versus those without RLS (15%).6 Pharmacotherapies for psychiatric disorders such as antipsychotics and antidepressants inhibit dopamine neurotransmission and can lead to new-onset or worsening of RLS.7 The case we present here highlights many of the challenges experienced in the treatment of patients with RLS. It demonstrates the interplay between RLS, mood disorders, and medication-related aberrant behaviors as well as cost barriers to effective treatment.\n\nCase Presentation\n\nInformed consent was obtained from the patient described for use as a case report.\n\nMr. A, a 69-year-old Caucasian gentleman with bipolar disorder type I, unspecified anxiety disorder, obstructive sleep apnea (OSA) on continuous positive airway pressure (CPAP) therapy, and treatment-refractory restless legs syndrome (RLS) was referred for a psychiatric consultation for comprehensive management of bipolar I disorder. He had a history of inpatient psychiatric hospitalizations, with the most recent one for mania triggered by sleep disturbance secondary to worsening RLS. He noted a past history of misusing lorazepam to alleviate his RLS symptoms. The first polysomnogram conducted over 10 years ago showed an apnea-hypopnea index (AHI) of 22 events per hour and a periodic limb movement index (PLMI) of 41 per hour, with a periodic limb movement arousal index (PLMAI) of 1 per hour. The patient’s other medical history was significant for obesity with BMI >40, gastroesophageal reflux disease, benign essential hypertension, irritable bowel disease, low back pain, moderate obstructive sleep apnea on CPAP. He has a 30-pack-year smoking history before he quit. Pertinent the physical examination was significant for crowded oropharynx, Friedman class IV, elevated tongue base, low dripping soft palate. External inspection of ears and nose when normal. Nasal mucosa, sputum, and turbinates are normal. Lips, teeth, and gums were normal. No abnormal lymphadenopathy in neck or supraclavicular region. Focused lower extremity neurological examination showed normal strength and sensory examination without evidence of neuropathy. Romberg test was negative. Pertinent family history was significant for RLS in mother, father and paternal uncle.\n\nAt initial presentation, the patient’s prescribed medication regimen included fluoxetine 40 mg daily, gabapentin 800 mg in the morning, and 3200 mg at bedtime, pramipexole 0.375 mg daily, lamotrigine 200 mg daily, trazodone 200 mg at bedtime, and temazepam 15 to 30 mg as needed for insomnia and RLS. His baseline ferritin level was 174 ng/mL. He did admit to using temazepam at higher than prescribed doses to treat his severe RLS symptoms. Due to his diagnosis of bipolar disorder type I with a recent history of mania, trazodone was tapered and discontinued. Thereafter, temazepam was also gradually discontinued to reduce the risk of misuse. Although the use of a longer half-life benzodiazepine, such as clonazepam, could have been considered for RLS, we opted not to pursue that route due to patient’s history of temazepam misuse and later, concurrent codeine use would have increased risk for central nervous system and respiratory depression. The bedtime dose of gabapentin was reduced to 1600 mg and all of his other medications were left unchanged. Although fluoxetine can also worsen RLS, it was continued at this time because the focus of the psychiatry consultation was management of the bipolar I disorder and not the RLS. Further, patient had noted his mood previously to be stable on fluoxetine 40 mg daily and lamotrigine 200 mg daily. Figure 1 outlines the timeline of medication changes following initial presentation.\n\nFigure 1. Timeline of medication changes.\n\nA month later, he presented with concerns for worsening mood and irritability; fluoxetine was stopped and he underwent a short trial of quetiapine to manage mood lability. This was followed by a trial of olanzapine when the former was noted to be ineffective in attempt to treat what appear to be a mixed episode of bipolar I disorder due to symptoms of irritability, worsening mood and sleep disturbances. Although atypical antipsychotics can worsen RLS, quetiapine and olanzapine were chosen for trial instead of divaloproex to minimize risk for developing severe cutaneous reactions such as Stevens-Johnson Syndrome as patient was already taking lamotrigine.\n\nAt the next follow-up visit, he reported further worsening of symptoms of RLS while misusing quetiapine, olanzapine and gabapentin to self-medicate for sleep disturbance brought on by severe RLS symptoms. Subsequently, the olanzapine was also discontinued due to lack of benefit. His ferritin level at the time was 228 ng/mL. Because the antiepileptics have less risk for causing RLS, but can also be used to treat bipolar disorder, the patient was then started on divalproex 1500 mg at bedtime to stabilize his mood while he was also maintained on lamotrigine, albeit at a lower dose of 150 mg daily at bedtime, to minimize his risk of developing Stevens-Johnson syndrome. He was diagnosed with augmentation of RLS on pramipexole after 12 months of progressively increasing the dose on his own, with continued worsening of symptoms with earlier onset and nighttime breakthrough. It was then recommended that he switch to rotigotine patch to reduce the risk of augmentation due to its long half-life with fewer peaks and troughs in the plasma level. Unfortunately, the patient could not afford the rotigotine patch; he was advised not to increase the dose of pramipexole beyond 0.375 mg nightly and codeine at 30 mg at bedtime was added to his regimen. Due to the risk for respiratory depression with opioids, and given the patient’s suboptimal adherence to CPAP for moderate OSA and history of hypnotic abuse, codeine was chosen because of its lower potency relative to other opioids and better evidence for treatment in refractory RLS compared to several other medications in this category.8\n\nA few months later, pramipexole 0.375 mg at bedtime was transitioned to ropinirole at 0.5 mg before bedtime with a plan for further adjustment as needed to help improve control of RLS symptoms. He remained on gabapentin at a dose of 800 mg in the morning and 1600 mg at bedtime. Ferritin level at the time was 188 ng/mL.\n\nDue to persistent severe RLS symptoms, the patient was referred to a sleep clinic at a tertiary medical center. Polysomnography was conducted and revealed a PLMI of 2.7 per hour and PLMAI of 0.9 per hour. At the time that he was evaluated at the sleep clinic, RLS symptoms were fairly well controlled on gabapentin 800 mg in morning and 1600 mg at bedtime, ropinirole, which had been titrated up to 6 mg daily, and codeine 30 mg at bedtime. He was also taking combination of divalproex and lamotrigine for bipolar I disorder. No medication changes were suggested. Mr. A was diagnosed with insomnia, sleep state misperception type. Cognitive behavioral therapy for insomnia (CBT-I) was recommended and he completed a total of 6 sessions.\n\nSeveral months later, he noted a recurrence of RLS symptoms. He was commenced on carbidopa-levodopa with a plan to taper ropinirole. Although carbidopa-levodopa is commonly associated with augmentation, the plan was to discontinue the ropinirole to help decease augmentation of symptoms and use the carbidopa-levodopa as needed in conjunction with gabapentin. However, the patient took the carbidopa-levodopa twice daily on a scheduled basis. Due to a history of augmentation of RLS on a low dose of ropinirole, pharmacogenomics (PGx) testing was completed. Relevant to his RLS treatment, the patient was a rapid metabolizer for CYP1A2, which could indicate a reduced response to ropinirole, and an intermediate metabolizer for CYPD2D6, which could indicate a reduced response to codeine. Subsequently, codeine was tapered and discontinued. In order to better manage his residual mood symptoms, the dose of lamotrigine was increased from 200 mg per day to a total of 300 mg per day while the dose of divalproex was reduced from 1500 mg at bedtime to 1000 mg at bedtime.\n\nAbout 6 months later, gabapentin was discontinued due to an adverse drug reaction of peripheral edema and the patient noted worsening RLS symptoms in this context. Supplementation with ferrous sulfate was commenced at 325 mg daily, along with pregabalin 150 mg at bedtime, which was later increased to twice daily. Although typically dosed twice a day for RLS, a lower dose of ferrous sulfate was chosen as patient’s ferritin levels had not been less than 75 ng/mL, which is the typical threshold for treating RLS with iron supplementation.9 A change in formulary coverage rendered the pregabalin too expensive for the patient and it was discontinued. The doses of ropinirole and carbidopa-levodopa were gradually titrated upwards for worsening RLS symptoms at various points during the next several months with continued RLS symptoms throughout. Once pregabalin became generic in 2020, the patient was able to restart this medication and taper off the carbidopa-levodopa.\n\nHis most recent regimen included pregabalin 300 mg daily at bedtime, ropinirole 8 mg 3 times a day, and ferrous sulfate 325 mg daily, on which his RLS symptoms remained stable for several months at the date of the last follow-up. For bipolar disorder type I, he was maintained on divalproex 1000 mg at bedtime along with lamotrigine 100 mg in the morning and 200 mg at bedtime.\n\nDiscussion\n\nEarly on, the patient was taking several antidepressants including fluoxetine and trazodone that could worsen RLS and/or exacerbate mania in bipolar disorder type I.7 Other medications known to aggravate RLS include sedating antihistamines, antipsychotics, and dopamine-blocking anti-emetics.10 Caffeine can also worsen RLS symptoms and insomnia.7 Discontinuation of exacerbating medications should always be considered in the treatment plan of RLS, as was done in this case. Furthermore, mood stabilizers such as divalproex and lamotrigine from the antiepileptic category were favored in our patient as they have shown some efficacy in treating RLS and would not worsen symptoms.11\n\nNon-pharmacologic strategies for RLS should also be explored. Our patient did undergo cognitive behavioral therapy for insomnia. Other non-pharmacologic options with evidence to improve RLS include regular exercise and completing mental alerting activities during times of boredom.9 Although not clearly documented, our patient did report attempting these strategies. One non-pharmacologic treatment method that was not explored for this patient was pneumatic compression devices, which have been shown in small trials to reduce the symptoms of RLS.12\n\nAugmentation with dopaminergic therapy occurs when RLS symptom severity increases with increasing doses of medication; this generally develops slowly over time at higher doses of the medication.10 It can be difficult to distinguish augmentation from other causes of worsening RLS symptoms, such as tolerance to the medication, rebound symptoms from end-of-dose effects, iron deficiency, sleep deprivation, and medication-related adverse effects.10 Four screening questions have been developed to help identify augmentation from dopaminergic medications, including: Do symptoms appear earlier than when the drug was first started, Are higher doses of the drug needed or taken earlier in the day to control symptoms, Has the intensity of symptoms worsened since starting the drug, and, Have symptoms spread to other body parts since starting the drug.13 Our patient demonstrated 3 of the 4 of these symptoms. After removing exacerbating medications and treating underlying conditions, it was ruled augmentation to be the causative factor in our patient’s progressive symptoms. Treatment strategies for when augmentation develops have limited supporting evidence and include replacing depleted iron stores, switching to rotigotine, switching to an alpha-2-delta calcium channel ligand such as gabapentin, or using low potency opioids.10 All of these options were explored in our patient, ultimately finding that a combination of an oral iron supplement, dopamine agonist, and alpha-2-delta calcium channel ligand was effective in controlling RLS symptoms. Although the maximum FDA recommended dose for ropinirole for the treatment of RLS is 4 mg per day, in some cases higher doses are required for symptom control; the maximum dose for Parkinson’s Disease is 24 mg per day.\n\nOur case also demonstrates the role of medication cost as a barrier to adequate RLS treatment. Despite noting good results with pregabalin, the patient was unable to continue this medication and was never able to try the rotigotine patch. The retail price of rotigotine patch ranges from $700 to $850 for a 1-month supply whereas ropinirole is available at a fraction of that cost, at $9 to $25 for a 1-month supply.14 A generic formulation of pregabalin has recently become available, so cost may be less of an issue with this medication in the future.\n\nA personalized medicine approach with PGx testing was used for this patient. The results were used to identify potentially ineffective therapy with codeine and led to discontinuation of this medication; there was already a low threshold to stop the medication due to the patient’s history of substance misuse. A prospective application of PGx may have been even more helpful in that the use of codeine use could potentially have been avoided altogether. The practicality of PGx-guided therapy in RLS is limited as only codeine and tramadol currently have clinical guideline annotations available for dosing based on PGx.15\n\nFinally, and importantly, this case also illustrates the need for long-term care in patients with RLS that is patient-centric and encompasses the tenets of good clinical care- consistency of the treatment team, regular follow-up, validation of symptoms, and associated suffering, utilization of the latest evidence on diagnostic and treatment approaches with individualized application, and efforts to contain costs and minimize financial burden on patients.\n\nConclusion\n\nThis report demonstrates a challenging case of RLS in the setting of psychiatric co-morbidities, development of augmentation, and polypharmacy. Multiple treatment strategies may need to be considered simultaneously in these patients that may include pharmacogenomics testing, medication adherence strategies, optimizing medication management, cognitive behavioral therapy for insomnia, and treating underlying conditions. Availability of longitudinal specialty care, psychiatry and pharmacy services offered in conjunction with primary care in a community care setting facilitated safe and effective treatment to optimize the patient’s outcome.\n\nAuthors’ Note: The case report was presented as a poster at American Psychiatric Association (APA) 2019 Annual Meeting in San Francisco, CA, USA, May 18-22, 2019.\n\nDeclaration of Conflicting Interests: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The publication of this article was funded by a research grant from the Mayo Midwest Pharmacy Research Committee.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iDs: Audrey Umbreit https://orcid.org/0000-0003-4930-4497\n\nShirshendu Sinha https://orcid.org/0000-0001-7114-4480\n\nMeghna P. Mansukhani https://orcid.org/0000-0003-2351-5640\n==== Refs\nReferences\n\n1 Yeh P Walters AS Tsuang JW. Restless leg syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment. Sleep Breath. 2012;16 :987-1007.22038683\n2 Stefansson H Rye DB Hicks A , et al . A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007; 357 :639-647.17634447\n3 Miyamoto M Miyamoto T Iwanami M Suzuki K Hirata K. Pathophysiology of restless legs syndrome. Brain Nerve. 2009;61 :523-532.19514512\n4 Winkelmann J Allen RP Högl B , et al . Treatment of restless legs syndrome: evidence-based review and implications for clinical practice (revised 2017). Mov Disord. 2018;33 :1077-1091.29756335\n5 García-Borreguero D Allen RP Kohnen R , et al . Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med. 2007;8 :520–530.17544323\n6 Lee HB Hening WA Allen RP , et al . Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community. J Neuropsychiatry Clin Neurosci. 2008;20 :101-105.18305292\n7 Cuellar NG. The psychopharmacological management of RLS in psychiatric conditions: a review of the literature. J Am Psychiatr Nurses Assoc. 2012;18 :214-225.22529225\n8 Silber MH Becker PM Buchfuhrer MJ , et al . The appropriate use of opioids in the treatment of refractory restless legs syndrome. Mayo Clin Proc. 2018;93 :59-67.29304922\n9 Silber MH Becker PM Earley C Garcia-Borreguero D Ondo WG ; Medical Advisory Board of the Willis-Ekbom Disease Foundation. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc. 2013;88 :977-986.24001490\n10 Wijemanne S Ondo W. Restless legs syndrome: clinical features, diagnosis and a practical approach to management. Pract Neurol. 2017;17 :444-452.29097554\n11 Rinaldi F Galbiati A Marelli S Ferini Strambi L Zucconi M. Treatment options in intractable restless legs syndrome/Willis-Ekbom disease (RLS/WED). Curr Treat Options Neurol. 2016;18 :7.26874840\n12 Lettieri CJ Eliasson AH. Pneumatic compression devices are an effective therapy for restless legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial. Chest. 2009;135 :74-80.19017878\n13 Garcia-Borreguero D Silber MH Winkelman JW , et al . Guidelines for the first-line treatment of restless legs syndrome/Willis-Eckbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21 :1-11.27448465\n14 GoodRx©. 2020. Accessed August 6, 2020. www.GoodRx.com\n15 Whirl-Carrillo M McDonagh EM Hebert JM , et al . Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92 :414-417.22992668\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2150-1319",
"issue": "12()",
"journal": "Journal of primary care & community health",
"keywords": "case report; medications; mood disorder; psychiatry; restless legs",
"medline_ta": "J Prim Care Community Health",
"mesh_terms": "D000368:Aged; D015897:Comorbidity; D018491:Dopamine Agonists; D006801:Humans; D012148:Restless Legs Syndrome; D020181:Sleep Apnea, Obstructive",
"nlm_unique_id": "101518419",
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"pages": "21501327211019590",
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"pmid": "34032164",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22529225;19514512;29097554;17634447;19017878;22992668;24001490;26874840;17544323;29304922;22038683;18305292;27448465;29756335",
"title": "Challenges in the Treatment of Restless Legs Syndrome: A Case Report.",
"title_normalized": "challenges in the treatment of restless legs syndrome a case report"
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"abstract": "Despite worldwide scale-up of human immunodeficiency virus (HIV) care services, relatively few countries have implemented isoniazid preventive therapy (IPT). Among other programmatic concerns, IPT completion tends to be low, especially when not fully integrated into HIV care clinics.\n\n\n\nTo estimate non-completion of 6-month IPT and its predictors among HIV-positive adults aged 16 years.\n\n\n\nA prospective cohort study nested within a cluster-randomised trial of TB prevention was conducted between February 2012 and June 2014. IPT for 6 months was provided with pyridoxine at study clinics. Non-completion was defined as loss to follow-up (LTFU), death, active/presumptive TB or stopping IPT for any other reason. Random-effects logistic regression was used to determine predictors of non-completion.\n\n\n\nOf 1284 HIV-positive adults initiated on IPT, 885/1280 (69.1%) were female; the median CD4 count was 337 cells/μl (IQR 199-511); 320 (24.9%) did not complete IPT. After controlling for antiretroviral treatment status, IPT initiation year, age and sex, non-completion of IPT was associated with World Health Organization stage 3/4 (aOR 1.76, 95%CI 1.22-2.55), CD4 count 100-349 cells/μl (aOR 1.93, 95%CI 1.10-3.38) and any reported side effects (aOR 22.00, 95%CI 9.45-46.71).\n\n\n\nCompletion of IPT was suboptimal. Interventions to further improve retention should target immunosuppressed HIV-positive adults and address side effects.",
"affiliations": "Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi, Department of Infectious Disease Epidemiology, Imperial College London, London.;Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, Department of Public Health and Policy, University of Liverpool, Liverpool.;Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi, Infectious Disease Epidemiology Department, London School of Hygiene & Tropical Medicine (LSHTM), London, UK.;Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.;Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.;Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.;Department of HIV/AIDS, Ministry of Health, Lilongwe, Malawi.;Department of HIV/AIDS, Ministry of Health, Lilongwe, Malawi.;Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi, Clinical Research Department, LSHTM, London, UK.",
"authors": "Thindwa|D|D|;MacPherson|P|P|;Choko|A T|AT|;Khundi|M|M|;Sambakunsi|R|R|;Ngwira|L G|LG|;Kalua|T|T|;Webb|E L|EL|;Corbett|E L|EL|",
"chemical_list": "D044966:Anti-Retroviral Agents; D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "France",
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"doi": "10.5588/ijtld.17.0370",
"fulltext": "\n==== Front\nInt J Tuberc Lung DisInt. J. Tuberc. Lung DisjtldInternational Union Against Tuberculosis and Lung DiseaseThe International Journal of Tuberculosis and Lung Disease1027-37191815-7920International Union Against Tuberculosis and Lung Disease 10.5588/ijtld.17.0370i1027-3719-22-3-273Original ArticlesTuberculosisCompletion of isoniazid preventive therapy among human immunodeficiency virus positive adults in urban Malawi Thindwa D. *†MacPherson P. ‡§Choko A. T. *¶Khundi M. *Sambakunsi R. *Ngwira L. G. *Kalua T. #Webb E. L. ¶Corbett E. L. **** Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi† Department of Infectious Disease Epidemiology, Imperial College London, London‡ Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool§ Department of Public Health and Policy, University of Liverpool, Liverpool¶ Infectious Disease Epidemiology Department, London School of Hygiene & Tropical Medicine (LSHTM), London, UK# Department of HIV/AIDS, Ministry of Health, Lilongwe, Malawi** Clinical Research Department, LSHTM, London, UKCorrespondence to: Deus Thindwa, Department of Infectious Disease Epidemiology, Imperial College London, London W2 IPG, UK. e-mail: deus.thindwa@gmail.com3 2018 22 3 273 279 29 5 2017 2 11 2017 © 2018 Thindwa et al.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.SETTING:\nDespite worldwide scale-up of human immunodeficiency virus (HIV) care services, relatively few countries have implemented isoniazid preventive therapy (IPT). Among other programmatic concerns, IPT completion tends to be low, especially when not fully integrated into HIV care clinics.\n\nOBJECTIVE:\nTo estimate non-completion of 6-month IPT and its predictors among HIV-positive adults aged ⩾16 years.\n\nDESIGN:\nA prospective cohort study nested within a cluster-randomised trial of TB prevention was conducted between February 2012 and June 2014. IPT for 6 months was provided with pyridoxine at study clinics. Non-completion was defined as loss to follow-up (LTFU), death, active/presumptive TB or stopping IPT for any other reason. Random-effects logistic regression was used to determine predictors of non-completion.\n\nRESULTS:\nOf 1284 HIV-positive adults initiated on IPT, 885/1280 (69.1%) were female; the median CD4 count was 337 cells/μl (IQR 199–511); 320 (24.9%) did not complete IPT. After controlling for antiretroviral treatment status, IPT initiation year, age and sex, non-completion of IPT was associated with World Health Organization stage 3/4 (aOR 1.76, 95%CI 1.22–2.55), CD4 count 100–349 cells/μl (aOR 1.93, 95%CI 1.10–3.38) and any reported side effects (aOR 22.00, 95%CI 9.45–46.71).\n\nCONCLUSION:\nCompletion of IPT was suboptimal. Interventions to further improve retention should target immunosuppressed HIV-positive adults and address side effects.\n\nCONTEXTE :\nEn dépit de l'expansion mondiale des services de prise en charge de l'infection par le virus de l'immunodéficience humaine (VIH), assez peu de pays ont mis en œuvre le traitement préventif par isoniazide (IPT) en routine. Parmi d'autres préoccupations programmatiques, l'achèvement de l'IPT tend à être faible, surtout quand il n'est pas totalement intégré dans les centres de traitement du VIH.\n\nOBJECTIF :\nEstimer le niveau de non-achèvement des 6 mois d'IPT et ses facteurs de prédiction parmi des adultes âgés de ⩾16 ans positifs au VIH.\n\nSCHÉMA :\nUne étude prospective de cohorte au sein d'un essai randomisé en grappes de prévention de la tuberculose (TB) a été réalisée entre février 2012 et juin 2014. Un IPT de 6 mois a été fourni avec de la pyridoxine dans les centres de l'étude. Le non achèvement a été défini comme une perte de vue, un décès, une TB active/présumée ou un arrêt de l'IPT pour n'importe quelle autre raison. Une régression logistique à effets aléatoires a été utilisée pour déterminer les facteurs de prédiction de non achèvement.\n\nRÉSULTATS :\nSur 1284 adultes positifs au VIH mis sous IPT, 885/1280 (69,1%) étaient des femmes et le CD4 médian a été de 337 cellules/μl (intervalle interquartile 199–511). Des 1284 adultes positifs au VIH, 320 (24,9%) n'ont pas achevé l'IPT. Après contrôle du statut du traitement antirétroviral, de l'année de mise en route de l'IPT, de l'âge et du sexe, le non achèvement de l'IPT a été associé au stade 3–4 de l'Organisation Mondiale de la Santé (ORa 1,76 ; IC95% 1,22–2,55), le nombre de CD4 100–349 cellules/μl (ORa 1,93 ; IC95% 1,10–3,38) et tout effet secondaire rapporté (ORa 22,00 ; IC95% 9,45–46,71).\n\nCONCLUSION :\nL'achèvement de l'IPT a été sousoptimal. Les interventions visant à améliorer la rétention devraient cibler les adultes immunodéprimés positifs au VIH et aborder le problème des effets secondaires.\n\nMARCO DE REFERENCIA:\nPese a la ampliación mundial de escala de los servicios relacionados con la infección por el virus de la inmunodeficiencia humana (VIH), relativamente pocos países han introducido el tratamiento preventivo con isoniazida (IPT) en la práctica corriente. Entre otras dificultades programáticas, se observa una baja tasa de compleción del IPT, sobre todo cuando no se encuentra plenamente integrado en los consultorios de atención de la infección por el VIH.\n\nOBJETIVO:\nCalcular la tasa de tratamientos incompletos con un esquema de TPI de 6 meses y definir los factores asociados, en adultos a partir de los 16 años de edad, positivos frente al VIH.\n\nMÉTODO:\nSe llevó a cabo un estudio de cohortes prospectivo, anidado en un ensayo clínico aleatorizado por conglomerados sobre la prevención de la tuberculosis (TB), de febrero del 2012 a junio del 2014. El IPT con piridoxina se suministró durante 6 meses en los consultorios del estudio. La falta de compleción del tratamiento se definió como pérdida durante el seguimiento, muerte, TB activa confirmada o su presunción o interrupción del IPT por cualquier otra razón. Con un modelo de regresión logística de efectos aleatorios se determinaron los factores pronósticos de un tratamiento incompleto.\n\nRESULTADOS:\nSe inició el IPT en 1284 adultos positivos frente al VIH; 885 de 1280 eran de sexo femenino (69,1%) y la mediana de la cifra de linfocitos CD4 fue 337 células/μl (amplitud intercuartílica 199–511). No completaron el IPT 320 de los 1284 pacientes (24,9%). Tras ajustar con respecto a la situación frente al tratamiento antirretrovírico, el año de iniciación del IPT, la edad y el sexo, la falta de compleción del tratamiento se asoció con el estado 3 o 4 de la enfermedad según la clasificación de la Organización Mundial de la Salud (OR ajustado [ORa] 1,76; IC95% 1,22–2,55), la cifra de linfocitos CD4 de 100–349 células/μl (ORa 1,93; IC95% 1,10–3,38) y la notificación de algún efecto secundario (ORa 22,00; IC95% 9,45–46,71).\n\nCONCLUSIÓN:\nLa tasa de compleción del IPT fue deficiente. Las intervenciones encaminadas a mejorar la retención en la atención se deben dirigir a los adultos positivos frente al VIH con inmunodepresión y deben abordar los efectos secundarios.\n\ntuberculosisloss to follow-uprisk factorsprospectivesub-Saharan Africa\n==== Body\nTUBERCULOSIS (TB) IS A GLOBAL public health threat, with a quarter of the population estimated to be latently infected worldwide.1 In 2015, the World Health Organization (WHO) estimated that there were 10.4 million incident TB cases and 1.4 million TB deaths globally.2 Approximately 11–13% of incident TB cases are co-infected with the human immunodeficiency virus (HIV).2–4 HIV-associated TB is highest in the WHO African Region, with HIV prevalence in TB patients exceeding 50% in some parts of southern Africa.2,5,6\n\nIsoniazid (INH) preventive therapy (IPT) reduces the overall risk of TB in HIV-infected individuals by 35%, with greater reduction among tuberculin skin test (TST) positive individuals (pooled relative risk of 52%).7 When IPT is combined with antiretroviral treatment (ART), there is a multiplicative protective effect.6,8,9 Since the late 1990s, at least 6 months of IPT has been recommended by the WHO for HIV-positive individuals. Guidelines from 2015 now recommend no less than 36 months for people without symptoms of active TB, irrespective of CD4 count, availability of TST, ART status or pregnancy.10–12 In high TB incidence, resource-constrained settings, absence of current cough, fever, night sweats and weight loss can be used as a screening tool for IPT eligibility.13–16 IPT provision should be supported by regular adherence support and monitoring, and ideally accompanied by pyridoxine to reduce the risk of symptomatic peripheral neuropathy.17\n\nBarriers to the uptake and completion of IPT have been widely reported, and include longer regimens,18,19 lack of health worker training and patient education on treatment guidelines,18,20 distance from the clinic and incompletely integrated HIV-TB care.20,21 In Malawi, the first wide-scale use of IPT by the national HIV programme was not implemented until 2015.15,22 Lack of nationwide implementation was initially driven by concerns from the National TB Programme around the theoretical risk of inducing INH resistance, given the difficulties of excluding active TB disease, and historically low completion rates under stand-alone IPT services.21,23 Experience, however, suggests little impact on drug resistance patterns in practice.15 From the perspective of HIV programmes, ongoing concerns have included the cost and logistics of adding one (INH) or two (plus pyridoxine) drugs to already overstretched HIV care programmes, with the increasing pill burden and side-effect profile potentially having a deleterious impact on ART adherence, and the limited evidence of broader health benefits beyond TB prevention. Understanding the factors associated with non-completion of IPT could therefore help accelerate wider implementation, and inform strategies to improve both the uptake and completion of IPT at the programme level.\n\nThe main aims of the present study were to estimate non-completion of IPT and determine its predictors among HIV-positive adults initiating a 6-month course of IPT delivered in urban Blantyre by a research project before national roll-out.\n\nMATERIALS AND METHODS\nStudy design and participants\nThis was a prospective cohort study nested within the intervention arm of a community cluster randomised trial of TB prevention (HitTB: ISRCTN02004005) conducted between February 2012 and June 2014. In the parent trial, community-based HIV testing and TB active case finding were offered in the 14 urban intervention communities comprising 16 660 adult residents, while 14 control communities received TB active case finding only. The trial profile and HIV testing procedures have previously been described in detail.24,25\n\nIn brief, participants who tested HIV-positive in the community were referred to their nearest primary care clinic for confirmatory HIV testing and counselling (HTC), WHO clinical staging assessment, CD4 count measurement, and linkage to HIV and TB care and prevention services, including IPT, all of which were completed by study nurses. Eligible participants for this cohort study were HIV-positive adults aged ⩾16 years who were resident within intervention neighbourhood clusters in urban Blantyre, Malawi, and who initiated IPT as part of trial interventions. During clinic assessment, participants were assessed for IPT eligibility using a symptom screening tool, with the presence of any of cough, fever, weight loss or night sweats prompting clinical assessment and investigation for active TB. Participants without TB symptoms and weighing ⩾35 kg were offered 300 mg INH and 25 mg pyridoxine once a day for 6 months to minimise the risk of INH peripheral neuropathy. IPT was, however, stopped in patients who developed neuropathy without attempting to distinguish the causative agent.\n\nFollow-up and outcome measurement\nIPT was dispensed separately from ART, such that patients also receiving ART had to visit a second clinic room within the same facility for their repeat IPT prescriptions and final follow-up on months 1, 2, 3, 4, 5 and 6. IPT follow-up visits were harmonised as far as possible with other HIV care clinic appointments, but in some instances a special IPT visit was required. Adherence to IPT was monitored through monthly prescription refill records. During IPT clinic visits, participants were screened for TB symptoms (and investigated if required), and assessed for adverse events. The main emphasis was on early detection of clinical hepatitis and peripheral neuropathy through systematic enquiry for jaundice, nausea or vomiting, or any symptoms of peripheral neuropathy. All toxicities that led to IPT being temporarily or permanently discontinued, and all grade 3 or 4 toxicity effects,26 were recorded in participant-held treatment cards as well as in clinic registers.\n\nParticipants with serious adverse events (SAEs) were referred to Queen Elizabeth Central Hospital, Blantyre, for clinical management. SAEs and other adverse events were documented and reported to the Malawi College of Medicine Research Ethics Committee (COMREC), Blantyre, by the principal investigator (PI). Participants who died were followed up by verbal autopsy through a community liaison system of the parent trial, to ascertain the cause of death. IPT was given on a monthly basis, and participants who did not make all six clinic visits to refill INH due to loss to follow-up (LTFU), death, active/presumptive TB or having stopped treatment for any other reason, were classified as not having completed IPT. Home tracing for participants lost to follow-up was not conducted.\n\nData collection and analysis\nStudy participant IPT registers were used to record baseline demographics, clinical characteristics and monthly outcomes. Data from the IPT registers were extracted using an optical character-recognition system, and imported into the study database. Descriptive statistics were used to characterise study participants, and to estimate the proportion of participants lost from IPT, stratified by clinical and socio-demographic characteristics. Age, sex, baseline WHO stage, CD4 count, ART status, provider of HTC service, reported past anti-tuberculosis treatment, year of IPT initiation and side effects were considered to be potential predictors of non-completion of IPT. All potential predictors were evaluated for inclusion in a multivariate model,27 with age and sex included a priori. The final multilevel logistic regression model adjusted for patient characteristics, and a random-effect term to account for clustering by participant neighbourhood of residence.25 Analysis was carried out using Stata v14.0 (StataCorp, College Station, TX, USA) and R v3.3.1 (R Foundation for Statistical Computing, Vienna, Austria).\n\nEthics consideration\nThe parent study protocol was approved by the COMREC, Blantyre, and the London School of Hygiene & Tropical Medicine, London, UK. Participants provided written (or witnessed thumbprint) informed consent for HIV testing interventions, and verbal consent to initiate IPT as part of routine clinical care.\n\nRESULTS\nCharacteristics of study participants\nOf the 16 660 adult residents of the 14 intervention clusters, 14 004 (84.1%) underwent study HIV testing and 1725 (12.3%) were confirmed to be HIV-positive. Of the 1557/1725 (90.3%) HIV-positive participants screened for IPT eligibility, 1301 (83.6%) met the IPT eligibility criteria. Non-screening of 168 individuals was due to unavailability. Non-eligibility of those screened was due to presumptive TB (212/256, 82.8%), active TB (14/256, 5.5%), epilepsy (11/256, 4.3%), high alcohol intake (10/256, 3.9%), previous reaction to IPT (6/256, 2.3%) and known liver disease (3/256, 1.2%). A further 17 participants declined IPT, resulting in an IPT initiation rate of 1284/1301 (98.7%) among eligible participants (Figure).\n\nFigure Flow of study participants enrolled for IPT. * Not adjusted for migration. † Confirmatory HTC using finger-prick parallel rapid diagnostic testing by study nurse following patient home-based HIV self-testing. HIV = human immunodeficiency virus; IPT = isoniazid preventive therapy; HTC = HIV testing and counselling; TB = tuberculosis.\n\nThe mean age of the participants was 35.1 years (standard deviation ±10.2, interquartile range [IQR] 28–40; n = 1276); the median CD4 count was 337 cells/μl (IQR 199–511; n = 1114). Most participants were female (885/1280, 69.1%), 25 (2.8%) of whom were pregnant. One hundred and eleven participants (8.9%) had previously been treated for TB: 8/111 (7.2%) in the past 2 years and 103/111 (92.8%) over 2 years previously (Table 1).\n\nTable 1 Demographic and clinical characteristics of HIV-positive participants who started IPT\n\nInitiation and completion of IPT\nOf the 1284 IPT initiators, 320 (24.9%, 95% confidence interval [CI] 22.6–27.4) did not complete 6 months of therapy. Non-completion of IPT was due to LTFU (243/320, 75.9%), death (10/320, 3.1%), development of active/presumptive TB (4/320, 1.3%) and approved decision to discontinue IPT (63/320, 19.7%) (Table 2). Of the 63 participants whose IPT was discontinued, 50 (79.4%) were due to side effects, including peripheral neuropathy (12.0%), nausea/vomiting (12.0%), skin rash (46.0%) and other possible adverse reactions (30.0%). The reason for discontinuing IPT was not recorded for 13 participants.\n\nTable 2 Retention rates (cumulative percentage) and outcomes of patients enrolled on IPT in Blantyre, Malawi\n\nApproximately half of this large cohort study comprised HIV-positive participants who were started on cotrimoxazole as well as a first-line ART regimen (stavudine/lamivudine/nevirapine [d4T/3TC/NVP]), which is known to have side effects that overlap with those of INH, notably peripheral neuropathy, hepatitis and nausea. IPT was generally safe and well tolerated, with only 60 (4.6%) participants reporting side effects. Eight patients developed peripheral neuropathy, all of whom had also recently been initiated on d4T-containing ART regimens. Other side effects, including skin rash, were frequent and non-severe. Grade 2 nausea and vomiting were the least observed IPT side effects. There was no case of severe hepatitis. Verbal autopsy of 10 participants who died during treatment did not suggest any relationship to IPT.\n\nComparing the years of IPT implementation, a sharp decrease in the proportion of participants failing to complete IPT occurred in those initiating treatment from 2012 (222/603, 36.8%) to 2013 (84/576, 14.6%) and 2014 (14/105, 13.3%). Overall, LTFU was the most common reason for non-completion of IPT in all years (Table 2).\n\nRisk factors for non-completion of IPT\nIn univariate analysis, WHO stage 3/4, CD4 count <100 cells/μl, CD4 count 100–349 cells/μl, history of anti-tuberculosis treatment and having side effects were independently associated with non-completion of IPT; participants with WHO stage 3/4 had just over 3-fold increased odds of not completing IPT compared with those in WHO stage 1/2 (odds ratio [OR] 3.13, 95%CI 2.35–4.16). Participants with CD4 count <100 cells/μl or 100–349 cells/μl were more likely not to complete IPT than those with CD4 count ⩾350 cells/μl (OR 2.21, 95%CI 1.36–3.58 and OR 1.48, 95%CI 1.11–1.98, respectively). Furthermore, participants who had been treated for TB over 2 years previously were more likely not to complete IPT than those without a history of anti-tuberculosis treatment (OR 1.56, 95%CI 1.01–2.42). There was a 23-fold greater risk of non-completion of IPT among participants who experienced side effects than among those without side effects (OR 23.3, 95%CI 10.90–49.69) (Table 3).\n\nTable 3 Non-completion of IPT at month 6 (using univariate and multivariate random effect models)\n*\n\n\nIn multivariate analysis, the following variables remained significantly associated with non-completion of IPT: WHO stage 3/4 (adjusted OR [aOR] 1.76, 95%CI 1.22–2.55, P=0.004), CD4 count 100–349 cells/μl (aOR 1.93, 95%CI 1.10–3.38, P=0.024) and reporting side effects (aOR 22.00, 95%CI 9.45–46.71, P < 0.001) (Table 3).\n\nDISCUSSION\nA quarter of the adults diagnosed as HIV-positive did not complete IPT in this prospective cohort study, which recruited participants from urban communities of Blantyre. Independent risk factors for non-completion of IPT included being in WHO stage 3 or 4, having a CD4 count of <350 cells/μl and having side effects due to INH. Most non-completion (75.9% of 320 non-completers) was due to LTFU for unknown reasons.\n\nThe highest risk period for LTFU was immediately after confirmatory HIV testing, but before assessment for IPT eligibility (168/1725, 9.7%). The period immediately following diagnosis is known to be a high-risk period for loss to health services for other conditions, such as TB, as well as for HIV testing in routine clinics. National HIV programmes should focus on supporting newly diagnosed patients to remain in care, and they should streamline and integrate IPT eligibility assessments as far as possible. The completion rate of 75.1% reported in the present study is much higher than estimates from several other studies,18,28,29 but lower than in two studies nested within the DarDar trial in Tanzania21,23 and a study in Zimbabwe.4 This finding suggests that setting-specific factors, including the configuration of joint HIV-TB services, have an important influence on completion of IPT, underscoring the importance of studies such as this one. While those aged <30 years and females have been shown to be less likely to complete IPT in previous studies in Africa,23,29 we did not find these characteristics to be associated with non-completion of IPT in the present study, which provided IPT separately from other routine HIV care, but at the primary care level.\n\nOur data show evidence of programmatic learning and the importance of an accompanying ART regimen, with substantially lower discontinuation rates in 2014 than in 2012. This is likely due to the combination of growing prescriber confidence from familiarity with IPT and a programme switch to a better tolerated first-line ART regimen (tenofovir/lamivudine/efavirenz, TDF/3TC/EFV) from February 2014. It should be noted that the previous d4T-containing first-line ART regimen (d4T/3TC/NVP) was the most likely cause of peripheral neuropathy in patients started on both ART and IPT (as pyridoxine was provided to minimise INH-related peripheral neuropathy). However, to simplify subsequent ART management, we elected to manage these events pragmatically by discontinuing IPT and referring patients for alternative first-line ART.\n\nLimitations of the present study included use of self-reported adherence and pill counts, which are less sensitive measures of adherence than, for example, urine drug tests or electronic Medication Event Monitoring System devices. Our completion rates could therefore have been overestimated. Other characteristics, such as marital status, education levels, employment status, religion and ethnicity, play roles in treatment adherence, as reported by other studies,28,29 and were not captured in the present study.\n\nThe main strength of our study was that potential predictors of non-completion of IPT were determined before ascertaining the outcome, thereby minimising information bias. Unrecognised deaths have comprised a substantial fraction of LTFU in other studies, and could explain the higher rates of non-completion among immunosuppressed individuals reported here. However, we think this is unlikely, as the parent study had systematic reporting of all deaths in the community with follow-up verbal autopsy. An alternative explanation could be that participants with lower CD4 counts may have been more likely to migrate out of this urban slum setting if unable to work due to ill health.\n\nThe main policy implications of our findings are to underscore the increased risk of loss to TB prevention services in the period immediately following HIV diagnosis. Our data also highlight the importance of early diagnosis of HIV and prompt ART and IPT initiation,30 as the more severely immunosuppressed HIV-positive adults were at greater risk of failing to complete IPT. A number of interventions, including automated mobile phone short message services (SMS), smart-phone applications and home visits by lay counsellors, could be considered to provide extra support to help retain high-risk individuals in their first months of HIV care.31 IPT guidelines would benefit from detailing the health messages and information needed by individuals initiating IPT to specifically address the potential side effects for patients starting both ART and IPT.\n\nIn summary, completion of 6 months of IPT among HIV-positive adults from poor urban communities in Malawi was suboptimal, but better than observed in several other primary care clinic settings. IPTwas well tolerated, especially in the year after the national switch away from a d4T-containing first-line ART regimen. Interventions to further improve retention should target the period immediately after HIV diagnosis, with support for the more immunosuppressed patients, as well as providing treatment literacy on the benefits of IPT and known side effects. Programmes offering IPT through clinics that are not fully integrated into other pre-ART and ART services should also focus on supporting patients to complete their first and second months of IPT initiation, as most patients drop out at these stages.\n\nThe authors thank the HitTB study staff and study participants for their support for and participation in the HitTB study, respectively.\n\nThe HitTB study was funded by a Wellcome Trust Senior Research Fellowship in Clinical Science (Wellcome, London, UK) to ELC (grant number: WT091769). DT carried out this study as part of a Commonwealth MSc Scholarship.\n\nConflicts of interest: none declared.\n==== Refs\nReferences\n1 \nHouben R M G J ,\nDodd P J. \nThe global burden of latent tuberculosis infection: a re-estimation using mathematical modelling .\nPLOS Med \n2016 ;\n13 :\ne1002152 .\n27780211 \n2 \nWorld Health Organization .\n \nGlobal tuberculosis report, 2016 .\nWHO/HTM/TB/2016.13 \nGeneva, Switzerland :\nWHO ,\n2016 \nhttp://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1 Accessed November 2017 .\n\n3 \nAl-Darraji H A A ,\nKamarulzaman A ,\nAltice F L. \nIsoniazid preventive therapy in correctional facilities: a systematic review [Review] .\nInt J Tuberc Lung Dis \n2012 ;\n16 :\n871 –\n879 .\n22410101 \n4 \nTakarinda K C ,\nChoto R C ,\nHarries A D ,\nMutasa-Apollo T ,\nChakanyuka-Musanhu C. \nRoutine implementation of isoniazid preventive therapy in HIV-infected patients in seven pilot sites in Zimbabwe .\nPublic Health Action \n2017 ;\n7 :\n55 –\n60 .\n28775944 \n5 \nCorbett E L ,\nMarston B ,\nChurchyard G J ,\nDe Cock K M. \nTuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment .\nLancet \n2006 ;\n367 :\n926 –\n937 .\n16546541 \n6 \nLawn S D ,\nWood R ,\nCock K M D ,\nKranzer K ,\nLewis J J ,\nChurchyard G J. \nAntiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in settings with limited health-care resources .\nLancet Infect Dis \n2010 ;\n10 :\n489 –\n498 .\n20610331 \n7 \nAyele H T ,\nMourik M S ,\nDebray T P ,\nBonten M J. \nIsoniazid prophylactic therapy for the prevention of tuberculosis in HIV infected adults: a systematic review and meta-analysis of randomized trials .\nPLOS ONE \n2015 ;\n10 :\ne0142290 .\n26551023 \n8 \nSamandari T ,\nAgizew T B ,\nNyirenda S ,\n \n6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial .\nLancet \n2011 ;\n377 :\n1588 –\n1598 .\n21492926 \n9 \nDurovni B ,\nSaraceni V ,\nMoulton L H ,\n \nEffect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial .\nLancet Infect Dis \n2013 ;\n13 :\n852 –\n858 .\n23954450 \n10 \nKufa T ,\nChihota V N ,\nCharalambous S ,\nChurchyard G J. \nIsoniazid preventive therapy use among patients on antiretroviral therapy: a missed opportunity [Short communication] .\nInt J Tuberc Lung Dis \n2014 ;\n18 :\n312 –\n314 .\n24670568 \n11 \nRangaka M X ,\nWilkinson R J ,\nBoulle A ,\n \nIsoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial .\nLancet \n2014 ;\n384 :\n682 –\n690 .\n24835842 \n12 \nWorld Health Organization .\n \nRecommendation on 36 months isoniazid preventive therapy to adults and adolescents living with HIV in resource-constrained and high TB and HIV-prevalence settings: 2015 update .\nWHO/HTM/TB/2015.15 and WHO/HIV/2015.13 \nGeneva, Switzerland :\nWHO ,\n2015 \nhttp://www.who.int/tb/publications/2015_ipt_update/en/ Accessed November 2017 .\n\n13 \nGetahun H ,\nKittikraisak W ,\nHeilig C M ,\n \nDevelopment of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies .\nPLOS Med \n2011 ;\n8 :\ne1000391 .\n21267059 \n14 \nPerson A K ,\nSterling T R. \nTreatment of latent tuberculosis infection in HIV: shorter or longer? \nCurr HIV/AIDS Rep \n2012 ;\n9 :\n259 –\n266 .\n22581360 \n15 \nWorld Health Organization .\n \nGuidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings .\nGeneva, Switzerland :\nWHO ,\n2011 \nhttp://www.who.int/tb/challenges/hiv/ICF_IPTguidelines/en/ Accessed November 2017 .\n\n16 \nLewis J J ,\nFielding K L ,\nGrant A D ,\n \nEligibility for isoniazid preventive therapy in South African gold mines .\nPLOS ONE \n2013 ;\n8 :\ne81376 .\n24244741 \n17 \nGrant A D ,\nMngadi K T ,\nHalsema C L van ,\nLuttig M M ,\nFielding K L ,\nChurchyard G J. \nAdverse events with isoniazid preventive therapy: experience from a large trial .\nAIDS \n2010 ;\n24 \nSuppl 5 :\nS29 –\nS36 .\n21079425 \n18 \nFiske C T ,\nYan F ,\nHirsch-Moverman Y ,\nSterling TR ,\nReichler M R. \nRisk factors for treatment default in close contacts with latent tuberculosis infection .\nInt J Tuberc Lung Dis \n2014 ;\n18 :\n421 –\n427 .\n24670696 \n19 \nMartinson N A ,\nBarnes G L ,\nMoulton L H ,\n \nNew regimens to prevent tuberculosis in adults with HIV infection .\nN Engl J Med \n2011 ;\n365 :\n11 –\n20 .\n21732833 \n20 \nMindachew M ,\nDeribew A ,\nMemiah P ,\nBiadgilign S. \nPerceived barriers to the implementation of isoniazid preventive therapy for people living with HIV in resource constrained settings: a qualitative study .\nPan Afr Med J \n2014 ;\n17 :\n26 \nhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048699/ Accessed November 2017 .\n24932337 \n21 \nKabali C ,\nvon Reyn C F ,\nBrooks D R ,\n \nCompletion of isoniazid preventive therapy and survival in HIV-infected, TST-positive adults in Tanzania .\nInt J Tuberc Lung Dis \n2011 ;\n15 :\n1515 –\n1522 .\n22008766 \n22 \nMinistry of Health, Malawi .\n \nClinical management of HIV in children and adults .\nLilongwe, Malawi :\nMOH ,\n2011 \nhttp://apps.who.int/medicinedocs/documents/s18802en/s18802en.pdf Accessed December 2017 .\n\n23 \nMunseri P J ,\nTalbot E A ,\nMtei L ,\nFordham von Reyn C. \nCompletion of isoniazid preventive therapy among HIV-infected patients in Tanzania .\nInt J Tuberc Lung Dis \n2008 ;\n12 :\n1037 –\n1041 .\n18713501 \n24 \nChoko A T ,\nMacPherson P ,\nWebb E L ,\n \nUptake, accuracy, safety, and linkage into care over two years of promoting annual self-testing for HIV in Blantyre, Malawi: a community-based prospective study .\nPLOS Med \n2015 ;\n12 :\ne1001873 .\n26348035 \n25 \nMacPherson P ,\nLalloo D G ,\nWebb E L ,\n \nEffect of optional home initiation of HIV care following HIV self-testing on antiretroviral therapy initiation among adults in Malawi: a randomized clinical trial .\nJAMA \n2014 ;\n312 :\n372 –\n379 .\n25038356 \n26 \nDenholm J T ,\nMcBryde E S ,\nEisen D P ,\nPenington J S ,\nChen C ,\nStreet A C. \nAdverse effects of isoniazid preventative therapy for latent tuberculosis infection: a prospective cohort study .\nDrug Healthc Patient Saf \n2014 ;\n6 :\n145 –\n149 .\n25364275 \n27 \nGreenland S. \nModeling and variable selection in epidemiologic analysis .\nAm J Public Health \n1989 ;\n79 :\n340 –\n349 .\n2916724 \n28 \nParsyan A E ,\nSaukkonen J ,\nBarry M A ,\nSharnprapai S ,\nHorsburgh C R. Jr \nPredictors of failure to complete treatment for latent tuberculosis infection .\nJ Infect \n2007 ;\n54 :\n262 –\n266 .\n16772095 \n29 \nNamuwenge P M ,\nMukonzo J K ,\nKiwanuka N ,\n \nLoss to follow up from isoniazid preventive therapy among adults attending HIV voluntary counseling and testing sites in Uganda .\nTrans R Soc Trop Med Hyg \n2012 ;\n106 :\n84 –\n89 .\n22154974 \n30 \nTEMPRANO ANRS 12136 Study Group ;\nDanel C ,\nMoh R ,\nGabillard D ,\n \nA trial of early antiretrovirals and isoniazid preventive therapy in Africa .\nN Engl J Med \n2015 ;\n373 :\n808 –\n822 .\n26193126 \n31 \nGuy R ,\nHocking J ,\nWand H ,\nStott S ,\nAli H ,\nKaldor J. \nHow effective are short message service reminders at increasing clinic attendance? A meta-analysis and systematic review .\nHealth Serv Res \n2012 ;\n47 :\n614 –\n632 .\n22091980\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1027-3719",
"issue": "22(3)",
"journal": "The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease",
"keywords": null,
"medline_ta": "Int J Tuberc Lung Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D044966:Anti-Retroviral Agents; D000995:Antitubercular Agents; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections; D006679:HIV Seropositivity; D006801:Humans; D007538:Isoniazid; D016015:Logistic Models; D008295:Malawi; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D015999:Multivariate Analysis; D011446:Prospective Studies; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "9706389",
"other_id": null,
"pages": "273-279",
"pmc": null,
"pmid": "29471904",
"pubdate": "2018-03-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "22154974;26193126;24932337;25038356;16772095;24244741;22008766;22581360;21732833;2916724;21492926;22091980;28775944;26551023;24670696;25364275;16546541;21079425;22410101;27780211;26348035;18713501;20610331;24835842;24670568;23954450;21267059",
"title": "Completion of isoniazid preventive therapy among human immunodeficiency virus positive adults in urban Malawi.",
"title_normalized": "completion of isoniazid preventive therapy among human immunodeficiency virus positive adults in urban malawi"
} | [
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"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2018-01152",
"fulfillexpeditecriteria": "2",
"occurcountry": "MW",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ISONIAZID"
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"drugad... |
{
"abstract": "No treatment is currently approved for cytomegalovirus infection in pregnancy. Valacyclovir has been studied in symptomatic cytomegalovirus infected fetuses and seems to reduce the risk of serious sequelae.\n\n\n\nWe used off-label valacyclovir on pregnant women with primary cytomegalovirus infection to reduce the risk of fetal infection.\n\n\n\nWe treated 12 pregnant women with 8 g/day valacyclovir after diagnosis of cytomegalovirus infection until amniocentesis. We continued treatment until delivery in case of fetal infection. We periodically performed serology and virology tests on the women from referral until delivery and monitored them for adverse effects while on treatment. All women underwent late amniocentesis. We followed up infants for 5-28 months.\n\n\n\nAt the time of amniocentesis, we observed a transmission rate of 17 %, and at birth we observed a transmission rate of 42 %. Two women with negative amniocentesis and infected newborns had viremia reactivation after valacyclovir discontinuation. We observed no symptomatic infections at birth and one isolated sensory-neural hearing loss at follow-up.\n\n\n\nThis is the first series of antiviral treatment in women with a diagnosis of cytomegalovirus infection before amniocentesis. Valacyclovir may control cytomegalovirus infection while it is administered and reduce transmission at amniocentesis. Late transmission after treatment discontinuation is a risk. We advocate the need for a controlled trial of valacyclovir therapy starting from diagnosis of maternal infection until delivery, regardless of prenatal diagnosis of infection.",
"affiliations": "Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze della salute della donna e del bambino e di sanità pubblica, Rome, Italy; Telefono Rosso - Teratology Information Service, Centro Studi per la Tutela della Salute della Madre e del Concepito, Università Cattolica del Sacro Cuore, Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze della salute della donna e del bambino e di sanità pubblica, Rome, Italy; Telefono Rosso - Teratology Information Service, Centro Studi per la Tutela della Salute della Madre e del Concepito, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address: drmassimoapicella@gmail.com.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze della salute della donna e del bambino e di sanità pubblica, Rome, Italy; Telefono Rosso - Teratology Information Service, Centro Studi per la Tutela della Salute della Madre e del Concepito, Università Cattolica del Sacro Cuore, Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze della salute della donna e del bambino e di sanità pubblica, Rome, Italy; Telefono Rosso - Teratology Information Service, Centro Studi per la Tutela della Salute della Madre e del Concepito, Università Cattolica del Sacro Cuore, Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze della salute della donna e del bambino e di sanità pubblica, Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze di laboratorio e infettivologiche, Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze della salute della donna e del bambino e di sanità pubblica, Rome, Italy; Telefono Rosso - Teratology Information Service, Centro Studi per la Tutela della Salute della Madre e del Concepito, Università Cattolica del Sacro Cuore, Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze della salute della donna e del bambino e di sanità pubblica, Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze di laboratorio e infettivologiche, Rome, Italy.;Fondazione Policlinico Universitario A. Gemelli IRCCS, dipartimento scienze della salute della donna e del bambino e di sanità pubblica, Rome, Italy; Telefono Rosso - Teratology Information Service, Centro Studi per la Tutela della Salute della Madre e del Concepito, Università Cattolica del Sacro Cuore, Rome, Italy.",
"authors": "De Santis|Marco|M|;Apicella|Massimo|M|;De Luca|Carmen|C|;D'Oria|Luisa|L|;Valentini|Piero|P|;Sanguinetti|Maurizio|M|;Lanzone|Antonio|A|;Scambia|Giovanni|G|;Santangelo|Rosaria|R|;Masini|Lucia|L|",
"chemical_list": "D000914:Antibodies, Viral; D000998:Antiviral Agents; D000077483:Valacyclovir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcv.2020.104351",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "127()",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Amniocentesis; Congenital infection; Cytomegalovirus; Fetal therapy; Pregnancy; Valacyclovir",
"medline_ta": "J Clin Virol",
"mesh_terms": "D000914:Antibodies, Viral; D000998:Antiviral Agents; D002675:Child, Preschool; D003586:Cytomegalovirus Infections; D005260:Female; D005865:Gestational Age; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011295:Prenatal Care; D000077483:Valacyclovir",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "104351",
"pmc": null,
"pmid": "32325395",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Valacyclovir in primary maternal CMV infection for prevention of vertical transmission: A case-series.",
"title_normalized": "valacyclovir in primary maternal cmv infection for prevention of vertical transmission a case series"
} | [
{
"companynumb": "NVSC2020IT138301",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThe choice of empiric antibiotics for the treatment of gram-negative bacilli (GNB) bloodstream infections (BSIs) in patients presenting with a β-lactam (BL) allergy is often a difficult decision given that these agents are first-line treatment in many guidelines.\n\n\nOBJECTIVE\nWe sought to compare rates of clinical failure between patients with a history of BL allergy who received either a BL or a non-β-lactam (NBL).\n\n\nMETHODS\nAdult patients with a past medical history of BL allergy and receipt of antibiotics for treatment of a GNB BSI were included from 3 academic medical centers. Treatment groups were classified as BL or NBL groups based on the empiric antibiotics received. Clinical failure was assessed 72 to 96 hours after initiation of empiric antibiotics. Hypersensitivity reactions during receipt of antibiotic therapy for the index BSI were recorded.\n\n\nRESULTS\nA total of 552 patients were included for analysis: 433 patients in the BL group and 119 patients in the NBL group. Clinical failure was higher in the NBL group compared with the BL group (38.7% vs 27.4%, P = .030). The most common cause of clinical failure was a temperature of greater than 38.0°C 72 to 96 hours after receipt of empiric antibiotics (NBL group: 22.7% vs BL group: 13.9%, P = .016). Hypersensitivity occurred in 16 (2.9%) of 552 patients. Thirteen (2.5%) of 552 patients experiencing hypersensitivity reactions were exposed to a BL during treatment for GNB BSI.\n\n\nCONCLUSIONS\nAmong patients with a BL allergy, use of BL antibiotics is associated with a lower rate of clinical failure. The low rate of hypersensitivity provides further evidence about the risk of cross-reactivity between BL classes. These results support the practice of using a BL from an alternative class for patients in need of gram-negative antibiotic coverage.",
"affiliations": "Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colo. Electronic address: Meghan.Jeffres@ucdenver.edu.;Department of Pharmacy, Mayo Clinic Hospital-Rochester, Rochester, Minn.;Department of Pharmacy, Barnes-Jewish Hospital, St Louis, Mo.;Department of Pharmacy, Mayo Clinic Hospital-Rochester, Rochester, Minn.",
"authors": "Jeffres|Meghan N|MN|;Narayanan|Prasanna P|PP|;Shuster|Jerrica E|JE|;Schramm|Garrett E|GE|",
"chemical_list": "D000900:Anti-Bacterial Agents; D047090:beta-Lactams",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaci.2015.10.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-6749",
"issue": "137(4)",
"journal": "The Journal of allergy and clinical immunology",
"keywords": "bloodstream infection; empiric antibiotic; gram-negative; penicillin allergy; β-Lactam allergy",
"medline_ta": "J Allergy Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D004342:Drug Hypersensitivity; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D007902:Length of Stay; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012720:Severity of Illness Index; D017211:Treatment Failure; D055815:Young Adult; D047090:beta-Lactams",
"nlm_unique_id": "1275002",
"other_id": null,
"pages": "1148-1153",
"pmc": null,
"pmid": "26688516",
"pubdate": "2016-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Consequences of avoiding β-lactams in patients with β-lactam allergies.",
"title_normalized": "consequences of avoiding lactams in patients with lactam allergies"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP015055",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nPhenotypic drug susceptibility testing (DST) for Mycobacterium tuberculosis takes several weeks to complete and second-line DST is often poorly reproducible, potentially leading to compromised clinical decisions. Following a fatal case of XDR TB, we investigated the potential benefit of using whole-genome sequencing to generate an in silico drug susceptibility profile.\n\n\nMETHODS\nThe clinical course of the patient was reviewed, assessing the times at which phenotypic DST data became available and changes made to the therapeutic regimen. Whole-genome sequencing was performed on the earliest available isolate and variants associated with drug resistance were identified.\n\n\nRESULTS\nThe final DST report, including second-line drugs, was issued 10 weeks after patient presentation and 8 weeks after initial growth of M. tuberculosis. In the interim, the patient may have received a compromised regimen that had the potential to select for further drug resistance. The in silico susceptibility profile, extrapolated from evolving evidence in the literature, provided comparable or superior data to the DST results for second-line drugs and could be generated in a much shorter timeframe.\n\n\nCONCLUSIONS\nWe propose routine whole-genome sequencing of all MDR M. tuberculosis isolates in adequately resourced settings. This will improve individual patient care, monitor for transmission events and advance our understanding of resistance-associated mutations.",
"affiliations": "Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, Australia Children's Hospital at Westmead, Sydney, Australia alexander.outhred@health.nsw.gov.au.;NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, Australia Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Sydney, Australia.;NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, Australia Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Sydney, Australia.;Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia.;Department of Respiratory and Sleep Medicine, Liverpool Hospital, Sydney, Australia.;Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia Children's Hospital at Westmead, Sydney, Australia.;Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, Australia Centre for Infectious Diseases and Microbiology-Public Health, Westmead Hospital, Sydney, Australia.",
"authors": "Outhred|Alexander C|AC|;Jelfs|Peter|P|;Suliman|Basel|B|;Hill-Cawthorne|Grant A|GA|;Crawford|Archibald B H|AB|;Marais|Ben J|BJ|;Sintchenko|Vitali|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jac/dku508",
"fulltext": "\n==== Front\nJ Antimicrob ChemotherJ. Antimicrob. ChemotherjacjacJournal of Antimicrobial Chemotherapy0305-74531460-2091Oxford University Press 10.1093/jac/dku508dku508Original ResearchAdded value of whole-genome sequencing for management of highly drug-resistant TB Outhred Alexander C. 123*Jelfs Peter 24Suliman Basel 24Hill-Cawthorne Grant A. 1Crawford Archibald B. H. 5Marais Ben J. 13Sintchenko Vitali 1241 Sydney Medical School and the Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, Australia2 NSW Mycobacterium Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research—Pathology West, Sydney, Australia3 Children's Hospital at Westmead, Sydney, Australia4 Centre for Infectious Diseases and Microbiology—Public Health, Westmead Hospital, Sydney, Australia5 Department of Respiratory and Sleep Medicine, Liverpool Hospital, Sydney, Australia* Corresponding author. Tel: +61-2-9845-0000; Fax: +61-2-9845-3291; E-mail: alexander.outhred@health.nsw.gov.au4 2015 09 12 2014 09 12 2014 70 4 1198 1202 13 10 2014 7 11 2014 17 11 2014 18 11 2014 © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comObjectives\nPhenotypic drug susceptibility testing (DST) for Mycobacterium tuberculosis takes several weeks to complete and second-line DST is often poorly reproducible, potentially leading to compromised clinical decisions. Following a fatal case of XDR TB, we investigated the potential benefit of using whole-genome sequencing to generate an in silico drug susceptibility profile.\n\nMethods\nThe clinical course of the patient was reviewed, assessing the times at which phenotypic DST data became available and changes made to the therapeutic regimen. Whole-genome sequencing was performed on the earliest available isolate and variants associated with drug resistance were identified.\n\nResults\nThe final DST report, including second-line drugs, was issued 10 weeks after patient presentation and 8 weeks after initial growth of M. tuberculosis. In the interim, the patient may have received a compromised regimen that had the potential to select for further drug resistance. The in silico susceptibility profile, extrapolated from evolving evidence in the literature, provided comparable or superior data to the DST results for second-line drugs and could be generated in a much shorter timeframe.\n\nConclusions\nWe propose routine whole-genome sequencing of all MDR M. tuberculosis isolates in adequately resourced settings. This will improve individual patient care, monitor for transmission events and advance our understanding of resistance-associated mutations.\n\nextensively drug resistantmultidrug resistantXDRMDR\n==== Body\nIntroduction\nThe global TB epidemic is increasingly being driven by the emergence and spread of drug-resistant strains.1 The WHO estimates that nearly half a million (450 000; range: 300 000–600 000) people developed MDR TB (resistant to isoniazid and rifampicin) in 2012, of whom <20% received appropriate treatment.2 The diagnosis and treatment of MDR TB present major challenges. Dependence on traditional drug susceptibility testing (DST) incurs significant delays in diagnosis, which force clinicians to initiate empirical treatment that may be suboptimal, leading to the multiplication of drug resistance and adverse patient outcomes.\n\nInitiating treatment with an optimal regimen is especially important in patients with XDR TB (MDR with additional resistance to fluoroquinolones and at least one second-line injectable drug), since therapeutic options remain limited. Approximately 10% of MDR cases are thought to be XDR2 and its global rise is driven by treatment that is poorly aligned with local resistance patterns,3 as well as by efficient transmission of some XDR strains.4 Given the poor treatment outcomes of XDR TB patients,5 every effort should be made to reduce delays in case detection and characterization of susceptibility profiles.\n\nConventional phenotypic DST requires a minimum of 2 weeks: one for initial detection of microbial growth and another to assess critical concentrations of first-line anti-TB drugs.6 In reality, full characterization of an XDR strain may take months, since expanded DST is usually performed sequentially and often some tests need to be repeated. In addition, drug resistance breakpoints for most second-line drugs are poorly standardized. Genotypic tests such as the commercial GeneXpert MTB/RIF® and GenoType MTBDRplus® (Hain Lifescience) assays offer rapid assessment of drug resistance mutations against key first-line anti-TB drugs, with testing of second-line agents using the GenoType MTBDRsl® (Hain Lifescience) assay if required. However, culture-based DST remains the reference standard, given the limited number of mutations evaluated by current genotypic tests and our incomplete understanding of the mechanisms of resistance.\n\nWhole-genome sequencing has offered novel insight into the evolution and spread of Mycobacterium tuberculosis, but its application in routine patient care has been limited by the perceived lack of clinical relevance, high cost, complexity of interpretation and slow turn-around times. Recent technological advances have made routine whole-genome sequencing of select M. tuberculosis strains in reference laboratories in a clinically relevant timeframe technically and economically feasible. We present a case of XDR TB diagnosed in New South Wales, Australia, and illustrate the potential clinical value of routine whole-genome sequencing of highly resistant M. tuberculosis strains.\n\nPatient and methods\nA man in his thirties presented to hospital with cough, night sweats and weight loss for more than 3 months. He was of East African ancestry and had spent much of his adult life as a refugee in the Horn of Africa. He first received treatment for TB in Ethiopia in early adolescence; the basis for the diagnosis was uncertain and he discontinued treatment after 3 months due to war. A decade later in Djibouti, he was treated for sputum smear-positive TB. He received 6 months of standard first-line therapy, comprising isoniazid, rifampicin, pyrazinamide and ethambutol during the 2 month intensive phase, with isoniazid/rifampicin during the 4 month continuation phase. He was documented to be sputum smear negative after completion and declared cured.\n\nThree years later he was diagnosed with a third episode of TB. His third treatment course (also received in Djibouti) comprised 2 months of isoniazid/rifampicin/pyrazinamide/ethambutol and streptomycin, followed by 1 month of isoniazid/rifampicin/pyrazinamide/ethambutol and a further 5 months of isoniazid/rifampicin/ethambutol. He was reported to be culture negative at the end of treatment. He subsequently received approval to settle in Australia, on condition that he commit to regular TB screening. He had stable chest radiograph findings and culture-negative sputum for 2 years after migration (Figure 1a), but was subsequently lost to follow-up until his symptomatic presentation, 5 years after migration.\nFigure 1. (a) Chest radiograph when asymptomatic; 3 years before presentation. (b) Chest radiograph with symptomatic presentation.\n\n\n\nPhysical examination on presentation revealed cachexia (38 kg) and finger clubbing. The chest radiograph showed bilateral cavities with extensive fibrocalcific changes (Figure 1b). Sputum microscopy was 3+ for acid-fast bacilli and M. tuberculosis was confirmed on culture. HIV serology was negative. Given his long disease-free interval and poor clinical condition, the patient was commenced immediately on regular first-line therapy with daily isoniazid/rifampicin/pyrazinamide/ethambutol, pending the outcome of genotypic and phenotypic DST. GeneXpert MTB/RIF® testing was not performed, but GenoType MTBDRplus® (Hain Lifescience) assay results suggested MDR TB. When this information became available at week 3, amikacin and moxifloxacin were added to his regimen.\n\nFive weeks after presentation, phenotypic DST results showed resistance to isoniazid (MIC >0.4 mg/L), rifampicin and pyrazinamide, with ethambutol susceptibility. Additional results suggested resistance to streptomycin, amikacin, capreomycin, ciprofloxacin and ethionamide, fulfilling the WHO definition of XDR TB. All medications were temporarily ceased until more complete second-line susceptibilities became available. The expanded DST report, issued 10 weeks after initial diagnosis, listed susceptibility to para-aminosalicylic acid, cycloserine and clofazimine. He was restarted on moxifloxacin, high-dose ethambutol (25 mg/kg) and pyrazinamide with the addition of para-aminosalicylic acid, cycloserine, clofazimine and amoxicillin/clavulanate. On this regimen his clinical situation improved, with no further fevers, reduction in cough, 17 kg of weight gain and some radiological improvement. Unfortunately the patient developed major depression and cycloserine had to be discontinued; it was replaced by trimethoprim/sulfamethoxazole and clarithromycin. Susceptibility testing on an isolate collected 9 months after presentation reported intermediate-level resistance to moxifloxacin (MIC between 1.0 and 2.0 mg/L) and susceptibility to linezolid.\n\nThe patient remained in hospital in strict isolation in a negative-pressure room for 2 years, since his sputum remained culture positive for M. tuberculosis despite smear conversion. Given his stable clinical condition, suitable accommodation was ultimately found where the infectious risk could be minimized and directly observed therapy provided 7 days a week. However, within 4 months of discharge he was readmitted to hospital with extensive ascites, he was culture positive for M. tuberculosis and he died following a major pulmonary haemorrhage.\n\nWhole-genome sequencing\nAfter the patient's death, an early M. tuberculosis isolate was submitted for whole-genome sequencing using the Illumina HiSeq 2000 platform, producing 100 base paired-end reads with >500-fold average depth of coverage after mapping onto the M. tuberculosis H37Rv reference genome (NCBI GenBank NC_000962).\n\nSeveral genetic variants in different genes associated with drug resistance in M. tuberculosis were identified by whole-genome sequencing, providing a plausible genetic basis for the observed phenotypic resistance to isoniazid, rifampicin and pyrazinamide, as well as all fluoroquinolones and injectables (capreomycin and aminoglycosides).7–11 These are shown in Table 1. Although this patient's strain was initially reported to be susceptible to ethambutol using phenotypic methods, the sequenced isolate possessed multiple mutations associated with ethambutol resistance.\nTable 1. Genetic variantsa identified with potential to contribute to drug resistance\n\nDrug\tGene\tH37Rv identifier\tVariant\tLikelihood of resistanceb\tClinical relevance\t\nIsoniazid7,11\tkatG\tRv1908c\tS315T\thigh\tno value in treatment\t\nfabD\tRv2243\tS275N\thigh\t\niniA\tRv0342\tH481Q\tlow\t\nRv1592c\tRv1592c\tI322V\tlow\t\nproA\tRv2427c\tV140L\tlow\t\nRifampicin7,11\trpoB\tRv0667\tS450Wc\thigh\tno value in treatment\t\nPyrazinamide7,11\tpncA\tRv2043c\tD158EAGd\thigh\tno value in treatment\t\n\t\tT160M\thigh\t\n\t\tT167A\tlow\t\nEthambutol7,11\tembC\tRv3793\tT270I\tpossible\tno value in treatment\t\n\t\tN394D\tpossible\t\nembA\tRv3794\tV206M\tpossible\t\n\t\tP913S\tpossible\t\nembB\tRv3795\tD328G\tpossible\t\n\t\tE378A\tpossible\t\n\t\tG406S\thigh\t\nrmlD\tRv3266c\tS257P\tpossible\t\nembR\tRv1267c\tD107N\tpossible\t\n\t\tC110Y\tpossible\t\niniA\tRv0342\tH481Q\tpossible\t\nFluoroquinolones7–9,11\tgyrA\tRv0006\tE21Q\tlow\tlimited value, should not be counted as an ‘active drug’\t\n\t\tA90Ve\thigh\t\n\t\tD94Ye\thigh\t\n\t\tA384V\tvery low\t\n\t\tG668D\tvery low26\t\ngyrB\tRv0005\tM330I\tvery low\t\n\t\tE540D\tlow27\t\nAminoglycosides, streptomycin and capreomycin7,10\trrs\tRvnr01\tA1401G\thigh\tno value in treatment\t\nrpsL\tRv0682\tK43R\thigh\t\ngidB\tRv3919c\tS100F\tpossible\t\nEthionamide7\tethA\tRv3854c\tC403W\tpossible\tlimited value, should not be counted as an ‘active drug’\t\naCompared with H37Rv as the reference strain.\n\nbHigh—strong evidence for a causal association with a drug-resistant phenotype; low—conflicting evidence or evidence suggesting a weak association with a drug-resistant phenotype; possible—theoretical possibility of causal association with a drug-resistant phenotype, but insufficient evidence.\n\ncS531W with Escherichia coli numbering.\n\ndFrameshift mutation.\n\neHeteroresistance—mutations detected in 63% (A90V) and 16% (D94Y) of reads.\n\n\n\nDiscussion\nIn retrospect, this patient's treatment might have been optimized to provide him with the best possible chance of cure if whole-genome sequencing data had been available at the time. More importantly, in future the growing body of knowledge on molecular markers of drug resistance and the availability of new antimycobacterial agents should provide better guidance and more treatment options to clinicians. In our case, the sequenced isolate had genetic evidence of resistance to ethambutol, pyrazinamide and moxifloxacin, which were components of both his expanded first-line regimen and his initial XDR regimen. When XDR TB treatment was ultimately commenced, the only drugs in the regimen with likely activity were para-aminosalicylic acid and cycloserine, with possible contributions from clofazimine and amoxicillin/clavulanate.\n\nThe regimen was suboptimal due to delayed DST results and inadequate laboratory guidance on likely ethambutol resistance. The difficulties of establishing ethambutol breakpoints and performing reliable phenotypic DST have been documented before.12 In addition, DST results arrived in stages over many weeks, hampering rational treatment decision-making. This is of particular importance in TB, where three to four active drugs are required to prevent amplification of drug resistance, and the addition of a single drug to a failing regimen is irresponsible. The therapeutic regimen was compromised when cycloserine had to be ceased and was replaced with trimethoprim/sulfamethoxazole, which act on the same metabolic pathway as para-aminosalicylic acid, and clarithromycin, which has little activity against M. tuberculosis.13,14 With the availability of genomic information, the objective of including at least four active drugs15 might have been achieved if the addition of a carbapenem16 or linezolid17 was considered early in the treatment course. Linezolid was not included in the regimen because of its significant side effect profile, minimal efficacy data and the belief that four active agents were available (ethambutol, PAS, cycloserine and clofazimine). The patient did show clinical improvement on this regimen. Neither delamanid18 nor bedaquiline19 was available and there was little evidence at that time to suggest that carbapenems were sufficiently effective to warrant inclusion.\n\nThis case study emphasizes the heavy clinical reliance on phenotypic DST, which is too slow and insufficiently validated for drugs other than isoniazid, rifampicin, quinolones and the injectables to guide individual patient management. Our patient's treatment failed despite the anticipation of MDR TB and the prompt addition of two extra drugs (moxifloxacin and amikacin) to his regimen following preliminary genetic testing for MDR. Given the urgency to optimize treatment before additional drug resistance develops, every effort should be made to optimize the regimen from the very beginning.\n\nWe propose that all isolates found to be likely MDR on initial genetic testing (GeneXpert MTB/RIF® or GenoType MTBDRplus®) should undergo expedited whole-genome sequencing. A realistic turn-around time for whole-genome sequencing is 1–2 weeks from nucleic acid extraction and costs of US$70–250 per isolate pale in comparison with patient management costs. The estimated total cost of this patient's care was equivalent to US$1 million, with average XDR TB treatment costs in developed countries estimated at US$483 000.20 The price and turn-around time of whole-genome sequencing is rapidly decreasing with ongoing technological advances. Routine whole-genome sequencing would also facilitate detailed transmission analysis, to guide targeted public health interventions and monitor infection control practices.21–25 Phenotypic testing would still be required to validate findings, comply with international recommendations and assist the elucidation of unknown resistance mechanisms, but this may change in future with growing confidence in the genetic markers of resistance. An additional safety advantage of whole-genome sequencing for laboratory personnel can be obtained if there are fewer manipulations of live cultures.\n\nRoutine whole-genome sequencing of all MDR M. tuberculosis isolates will assist patient management and guide public health responses, but is currently feasible only in well-resourced settings. It is important to drive innovation and refine the clinical application of this new technology, since widespread use is anticipated in the near future and TB patients globally stand to benefit.\n\nFunding\nThis study was supported by internal funding.\n\nTransparency declarations\nNone to declare.\n==== Refs\nReferences\n1 Abubakar I Zignol M Falzon D Drug-resistant tuberculosis: time for visionary political leadership Lancet Infect Dis 2013 13 529 39 23531391 \n2 World Health Organization Global Tuberculosis Report 2013 2013 Geneva, Geneva WHO \n3 Chihota VN Müller B Mlambo CK Population structure of multi- and extensively drug-resistant Mycobacterium tuberculosis strains in South Africa J Clin Microbiol 2012 50 995 1002 22170931 \n4 Klopper M Warren RM Hayes C Emergence and spread of extensively and totally drug-resistant tuberculosis, South Africa Emerg Infect Dis 2013 19 449 55 23622714 \n5 Pietersen E Ignatius E Streicher EM Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study Lancet 2014 383 1230 9 24439237 \n6 Goloubeva V Lecocq M Lassowsky P Evaluation of Mycobacteria Growth Indicator Tube for direct and indirect drug susceptibility testing of Mycobacterium tuberculosis from respiratory specimens in a Siberian prison hospital J Clin Microbiol 2001 39 1501 5 11283077 \n7 Sandgren A Strong M Muthukrishnan P Tuberculosis drug resistance mutation database PLoS Med 2009 6 e1000002 \n8 Malik S Willby M Sikes D New insights into fluoroquinolone resistance in Mycobacterium tuberculosis : functional genetic analysis of gyrA and gyrB mutations PLoS One 2012 7 e39754 22761889 \n9 Maruri F Sterling TR Kaiga AW A systematic review of gyrase mutations associated with fluoroquinolone-resistant Mycobacterium tuberculosis and a proposed gyrase numbering system J Antimicrob Chemother 2012 67 819 31 22279180 \n10 Georghiou SB Magana M Garfein RS Evaluation of genetic mutations associated with Mycobacterium tuberculosis resistance to amikacin, kanamycin and capreomycin: a systematic review PLoS One 2012 7 e33275 22479378 \n11 Nebenzahl-Guimaraes H Jacobson KR Systematic review of allelic exchange experiments aimed at identifying mutations that confer drug resistance in Mycobacterium tuberculosis J Antimicrob Chemother 2014 69 331 42 24055765 \n12 Schön T Juréen P Giske CG Evaluation of wild-type MIC distributions as a tool for determination of clinical breakpoints for Mycobacterium tuberculosis J Antimicrob Chemother 2009 64 786 93 19633001 \n13 Köser CU Summers DK Archer JAC Role of the dihydrofolate reductase DfrA (Rv2763c) in trimethoprim-sulfamethoxazole (co-trimoxazole) resistance in Mycobacterium tuberculosis Antimicrob Agents Chemother 2010 54 4951 2 20947864 \n14 Fivian-Hughes AS Houghton J Davis EO Mycobacterium tuberculosis thymidylate synthase gene thyX is essential and potentially bifunctional, while thyA deletion confers resistance to p -aminosalicylic acid Microbiology 2012 158 308 18 22034487 \n15 Caminero JA Sotgiu G Zumla A Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis Lancet Infect Dis 2010 10 621 9 20797644 \n16 Lorenzo SD Alffenaar JW Sotgiu G Efficacy and safety of meropenem–clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB Eur Respir J 2013 41 1386 92 22997218 \n17 Sotgiu G Centis R D'Ambrosio L Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis Eur Respir J 2012 40 1430 42 22496332 \n18 Skripconoka V Danilovits M Pehme L Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis Eur Respir J 2013 41 1393 400 23018916 \n19 Diacon AH Donald PR Pym A Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance Antimicrob Agents Chemother 2012 56 3271 6 22391540 \n20 LoBue P Sizemore C Castro KG Plan to combat extensively drug-resistant tuberculosis: recommendations of the Federal Tuberculosis Task Force Morb Mortal Wkly Rep 2009 58 1 43 \n21 Schürch AC Kremer K Kiers A The tempo and mode of molecular evolution of Mycobacterium tuberculosis at patient-to-patient scale Infect Genet Evol 2010 10 108 14 19835997 \n22 Gardy JL Johnston JC Ho Sui SJ Whole-genome sequencing and social-network analysis of a tuberculosis outbreak New Engl J Med 2011 364 730 9 21345102 \n23 Roetzer A Diel R Kohl TA Whole genome sequencing versus traditional genotyping for investigation of a Mycobacterium tuberculosis outbreak: a longitudinal molecular epidemiological study PLoS Med 2013 10 e1001387 23424287 \n24 Walker TM Ip CL Harrell RH Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study Lancet Infect Dis 2013 13 137 46 23158499 \n25 Pérez-Lago L Comas I Navarro Y Whole genome sequencing analysis of intrapatient microevolution in Mycobacterium tuberculosis : potential impact on the inference of tuberculosis transmission J Infect Dis 2014 209 98 108 23945373 \n26 Lau RWT Ho P-L Kao RYT Molecular characterization of fluoroquinolone resistance in Mycobacterium tuberculosis : functional analysis of gyrA mutation at position 74 Antimicrob Agents Chemother 2011 55 608 14 20956608 \n27 Kim H Nakajima C Yokoyama K Impact of the E540V amino acid substitution in GyrB of Mycobacterium tuberculosis on quinolone resistance Antimicrob Agents Chemother 2011 55 3661 7 21646485\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0305-7453",
"issue": "70(4)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": "MDR; XDR; extensively drug resistant; multidrug resistant",
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D024901:Drug Resistance, Multiple, Bacterial; D054908:Extensively Drug-Resistant Tuberculosis; D016680:Genome, Bacterial; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "1198-202",
"pmc": null,
"pmid": "25492392",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D023362:Evaluation Study; D016428:Journal Article",
"references": "20947864;20797644;21345102;21646485;22034487;22170931;22279180;22479378;22391540;22761889;22496332;23158499;23424287;23622714;23531391;22997218;23018916;23945373;24055765;24439237;11283077;19214162;19209951;19633001;19835997;20956608",
"title": "Added value of whole-genome sequencing for management of highly drug-resistant TB.",
"title_normalized": "added value of whole genome sequencing for management of highly drug resistant tb"
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"companynumb": "AU-BAYER-2015-184906",
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"abstract": "BACKGROUND\nEarly T-cell precursor acute lymphoblastic leukaemia was recently recognised as a distinct leukaemia and reported as associated with poor outcomes. We aimed to assess the outcome of early T-cell precursor acute lymphoblastic leukaemia in patients from the Italian Association of Pediatric Hematology Oncology (AIEOP) centres treated with AIEOP-Berlin-Frankfurt-Münster (AIEOP-BFM) protocols.\n\n\nMETHODS\nIn this retrospective analysis, we included all children aged from 1 to less than 18 years with early T-cell precursor acute lymphoblastic leukaemia immunophenotype diagnosed between Jan 1, 2008, and Oct 31, 2014, from AIEOP centres. Early T-cell precursors were defined as being CD1a and CD8 negative, CD5 weak positive or negative, and positive for at least one of the following antigens: CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. Treatment was based on AIEOP-BFM acute lymphoblastic leukaemia 2000 (NCT00613457) or AIEOP-BFM acute lymphoblastic leukaemia 2009 protocols (European Clinical Trials Database 2007-004270-43). The main differences in treatment and stratification of T-cell acute lymphoblastic leukaemia between the two protocols were that in the 2009 protocol only, pegylated L-asparaginase was substituted for Escherichia coli L-asparaginase, patients with prednisone poor response received an additional dose of cyclophosphamide at day 10 of phase IA, and high minimal residual disease at day 15 assessed by flow cytometry was used as a high-risk criterion. Outcomes were assessed in terms of event-free survival, disease-free survival, and overall survival.\n\n\nRESULTS\nEarly T-cell precursor acute lymphoblastic leukaemia was diagnosed in 49 patients. Compared with overall T-cell acute lymphoblastic leukaemia, it was associated with absence of molecular markers for PCR detection of minimal residual disease in 25 (56%) of 45 patients; prednisone poor response in 27 (55%) of 49 patients; high minimal residual disease at day 15 after starting therapy in 25 (64%) of 39 patients (bone marrow blasts ≥ 10%, by flow cytometry); no complete remission after phase IA in 7 (15%) of 46 patients (bone marrow blasts ≥ 5%, morphologically); and high PCR minimal residual disease (≥ 5 × 10(-4)) at day 33 after starting therapy in 17 (85%) of 20 patients with markers available. Overall, 38 (78%) of 49 patients are in continuous complete remission, including 13 of 18 after haemopoietic stem cell transplantation, with three deaths in induction, five deaths after haemopoietic stem cell transplantation, and three relapses. Severe adverse events in the 2009 study were reported in 10 (30%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 24 (15%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia and life-threatening events in induction phase IA occurred in 4 (12%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 7 (4%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia. No difference was seen in the subsequent consolidation phase IB of protocol I.\n\n\nCONCLUSIONS\nEarly T-cell precursor acute lymphoblastic leukaemia is characterised by poor early response to conventional induction treatment. Consolidation phase IB, based on cyclophosphamide, 6-mercaptopurine, and ara-C at conventional (non-high) doses is effective in reducing minimal residual disease. Although the number of patients and observational time are limited, patients with early T-cell precursor acute lymphoblastic leukaemia treated with current BFM stratification and treatment strategy have a favourable outcome compared with earlier reports. The role of innovative therapies and haemopoietic stem cell therapy in early T-cell precursor acute lymphoblastic leukaemia needs to be assessed.\n\n\nBACKGROUND\nNone.",
"affiliations": "Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy. Electronic address: v.conter@hsgerardo.org.;Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Milan, Italy.;Department of Woman and Child Health, Hemato-Oncology Division, University of Padova, Azienda Ospedale Padova, Padova, Italy.;Department of Pediatric Hemato-Oncology, Santobono-Pausilipon Children's Hospital, Napoli, Italy.;Department of Pediatric Hemato-Oncology, IRCCS Ospedale Bambino Gesù, Roma, Italy; University of Pavia, Pavia, Italy.;Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.;Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.;Department of Woman and Child Health, Hemato-Oncology Division, University of Padova, Azienda Ospedale Padova, Padova, Italy.;Department of Pediatric Hemato-Oncology, Regina Margherita Children's Hospital, Torino, Italy.;Department of Pediatric Hemato-Oncology, Azienda Policlinico-OVE, Catania, Italy.;Department of Pediatric Hemato-Oncology, University of Bari, Bari, Italy.;Department of Pediatric Hemato-Oncology, ARNAS Ospedali Civico, G Di Cristina, Palermo, Italy.;Department of Pediatric Hemato-Oncology, University of Bologna, Bologna, Italy.;Department of Cellular Biotechnologies and Hematology, University La Sapienza, Roma, Italy.;Department of Pediatric Hemato-Oncology, IRCCS I G Gaslini, Genova, Italy.;Department of Pediatric Hemato-Oncology, University of Napoli, Napoli, Italy.;Department of Pediatric Hemato-Oncology, Ancona, Italy.;Department of Pediatric Hemato-Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.;Department of Pediatric Hemato-Oncology, Modena, Italy.;Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy; Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Milan, Italy.;Centro Ricerca M Tettamanti, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.;Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.;Department of Woman and Child Health, Hemato-Oncology Division, University of Padova, Azienda Ospedale Padova, Padova, Italy.",
"authors": "Conter|Valentino|V|;Valsecchi|Maria Grazia|MG|;Buldini|Barbara|B|;Parasole|Rosanna|R|;Locatelli|Franco|F|;Colombini|Antonella|A|;Rizzari|Carmelo|C|;Putti|Maria Caterina|MC|;Barisone|Elena|E|;Lo Nigro|Luca|L|;Santoro|Nicola|N|;Ziino|Ottavio|O|;Pession|Andrea|A|;Testi|Anna Maria|AM|;Micalizzi|Concetta|C|;Casale|Fiorina|F|;Pierani|Paolo|P|;Cesaro|Simone|S|;Cellini|Monica|M|;Silvestri|Daniela|D|;Cazzaniga|Giovanni|G|;Biondi|Andrea|A|;Basso|Giuseppe|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3026",
"issue": "3(2)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007558:Italy; D008297:Male; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e80-6",
"pmc": null,
"pmid": "26853647",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis.",
"title_normalized": "early t cell precursor acute lymphoblastic leukaemia in children treated in aieop centres with aieop bfm protocols a retrospective analysis"
} | [
{
"companynumb": "IT-JAZZ-2016-IT-003925",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
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"drugadditional": "3",
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{
"abstract": "The anticoagulant edoxaban is used clinically at doses of 30-60 mg/day; however, we experienced a patient who had taken an overdose of edoxaban of 750 mg. We investigated the pharmacokinetics of edoxaban in this patient by using liquid chromatography-tandem spectrometry to estimate the follow-up period in emergency clinical practice with this medicine.\nThe patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban in a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient's edoxaban plasma concentrations during ambulance transport (8 h after oral administration) were ~ 4900 ng/ml, and the concentration gradually decreased to ~ 10 ng/mL and to detectable but unmeasurable levels of ~ 1.0 ng/mL at 60 h and 100 h, respectively. The linear range of the relationship between the dose and plasma concentration was assumed to have been exceeded during the first 8 h; however, the measured elimination rate of edoxaban was similar to that visualized curves predicted by a simplified physiologically based pharmacokinetic model previously established.\nSimplified physiologically based pharmacokinetic models for creating visualized curves have proven to be useful not only during drug discovery or chemical risk assessment but also in cases of medical poisoning. We used a physiologically based pharmacokinetic model previously established for edoxaban to predict the pharmacokinetics in the current case. It is hoped that the results of this study, which encompass drug monitoring data in the patient and visualized pharmacokinetic prediction, will serve as an index when setting the treatment and follow-up period in cases of drug overdose for medicines such as edoxaban in emergency clinical practice.",
"affiliations": "Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543 Japan.;Kyoto Medical Center, Fushimi-ku, Kyoto, 612-8555 Japan.;Kyoto Medical Center, Fushimi-ku, Kyoto, 612-8555 Japan.;Kyoto Medical Center, Fushimi-ku, Kyoto, 612-8555 Japan.;Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543 Japan.;Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543 Japan.",
"authors": "Adachi|Koichiro|K|;Tuchiya|Jumpei|J|;Beppu|Satoru|S|;Nishiyama|Kei|K|;Shimizu|Makiko|M|;Yamazaki|Hiroshi|H|0000-0002-1068-4261",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40780-020-00176-6",
"fulltext": "\n==== Front\nJ Pharm Health Care Sci\nJ Pharm Health Care Sci\nJournal of Pharmaceutical Health Care and Sciences\n2055-0294 BioMed Central London \n\n176\n10.1186/s40780-020-00176-6\nCase Report\nPharmacokinetics of anticoagulant edoxaban in overdose in a Japanese patient transported to hospital\nAdachi Koichiro d1801@g.shoyaku.ac.jp 12 Tuchiya Jumpei 2 Beppu Satoru 2 Nishiyama Kei 2 Shimizu Makiko 1 http://orcid.org/0000-0002-1068-4261Yamazaki Hiroshi hyamazak@ac.shoyaku.ac.jp 1 1 grid.412579.c0000 0001 2180 2836Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543 Japan \n2 grid.410835.bKyoto Medical Center, Fushimi-ku, Kyoto, 612-8555 Japan \n11 9 2020 \n11 9 2020 \n2020 \n6 209 5 2020 4 9 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\nThe anticoagulant edoxaban is used clinically at doses of 30–60 mg/day; however, we experienced a patient who had taken an overdose of edoxaban of 750 mg. We investigated the pharmacokinetics of edoxaban in this patient by using liquid chromatography–tandem spectrometry to estimate the follow-up period in emergency clinical practice with this medicine.\n\nCase presentation\nThe patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban in a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient’s edoxaban plasma concentrations during ambulance transport (8 h after oral administration) were ~ 4900 ng/ml, and the concentration gradually decreased to ~ 10 ng/mL and to detectable but unmeasurable levels of ~ 1.0 ng/mL at 60 h and 100 h, respectively. The linear range of the relationship between the dose and plasma concentration was assumed to have been exceeded during the first 8 h; however, the measured elimination rate of edoxaban was similar to that visualized curves predicted by a simplified physiologically based pharmacokinetic model previously established.\n\nConclusion\nSimplified physiologically based pharmacokinetic models for creating visualized curves have proven to be useful not only during drug discovery or chemical risk assessment but also in cases of medical poisoning. We used a physiologically based pharmacokinetic model previously established for edoxaban to predict the pharmacokinetics in the current case. It is hoped that the results of this study, which encompass drug monitoring data in the patient and visualized pharmacokinetic prediction, will serve as an index when setting the treatment and follow-up period in cases of drug overdose for medicines such as edoxaban in emergency clinical practice.\n\nKeywords\nAnticoagulantsPharmacokinetic modelingOverdoseissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDirect oral anticoagulants have gained increasing popularity for the treatment of venous thromboembolism because of their wide therapeutic ranges and predictable pharmacological effects [1, 2]. After aspirin discontinuation, platelet reactivity increased to a great extent with a low-dose of anticoagulant edoxaban [3]. However, a recent study reported that hospitalizations as a result of bleeding events associated with treatment with direct oral anticoagulants (apixaban, dabigatran, and rivaroxaban) have been increasing [4]. Despite initially not being recommended, the monitoring of plasma concentrations of anticoagulants should now be recognized as essential in emergency situations and in special populations. However, only limited information is available on the pharmacokinetics of direct oral anticoagulants.\n\nTherapeutic drug monitoring is accepted to be the clinical practice of measuring specific and drugs (such as antibiotics) in blood samples from patients at designated intervals to maintain a range of constant drug concentrations. For creating these visualized plasma concentration curves for limited antibiotics, some computer system has been freely supported by the drug manufacturers or commercially provided by software houses. However, many medicines in critical care area have not been fully supported by simple and easy handling software system for visualizing plasma concentration curves in clinical hospital pharmacies [5, 6].\n\nIn general, drug monitoring of steady-state plasma concentrations of individual patients in a clinical setting could be predictable by complex and detailed physiologically based pharmacokinetic (PBPK) models consisting of multiple compartments [7]. However, such PBPK models are impractical for widespread daily use in clinical hospital pharmacies to support the care of a verity of patients. Against this background, we proposed simple PBPK models for drugs for practical use by paramedical staff [8]. A prototype PBPK simulator [9] for creating the visualized plasma concentration curves for important medicines by easy input was provided by our group and has been currently updated and modified. Simple pharmacokinetic models and simulation systems would be expected for the drug monitoring results even in emergency rooms.\n\nCase presentation\nHere we describe the case of a woman who intentionally took an overdose of edoxaban (usual clinical dose in the range 30–60 mg/day). The patient’s plasma concentrations during ambulance transport (~ 4900 ng/ml) after an oral overdose of 750 mg of edoxaban gradually decreased to ~ 370 ng/mL at 28 h after administration. The linear range for doses and plasma concentrations was assumed to have been exceeded during the first 8 h because of saturated elimination. However, the predicted plasma concentration curve showed a linear relationship. We report herein the drug monitoring data and the results of pharmacokinetic modeling, which indicate that such prediction is a suitable tool for application in an emergency. The ethics committee of Kyoto Medical Center approved this study.\n\nThe patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban as a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient was then administered vitamin K (20 mg) as primary treatment. To assess the effects of treatment, plasma samples were collected from the patient at seven time points (8, 28, 36, 52, 60, 76, and 100 h after oral administration) and were frozen. The patient gave written informed consent to take part in this study and for publication. Concentrations of edoxaban in the plasma samples were analyzed using liquid chromatography–tandem mass spectrometry assays according to previously described methods [10]. Under the present conditions, edoxaban in plasma was measurable (≥ 2.0 ng/mL) or detectable (≥ 0.20 ng/mL) and each time point.\n\nA simplified PBPK model consisting of gut, liver, and central compartments was previously set up for patients receiving normal clinical oral doses of edoxaban [10]. This model was employed in the current study without making changes to the input parameters, such as the physiological hepatic blood flow rate (96.6 L/h), the hepatic volume (1.5 L), the urinary volume (1.5 L/day), and the body weight (70 kg). Calculated parameters for the PBPK model for absorption rate constant, fraction absorbed × intestinal availability, volume of systemic circulation, hepatic intrinsic clearance, hepatic clearance, and renal clearance were 1.33 1/h, 0.700, 127 L, 30.3 L/h, 40.2 L/h, and 10.0 L/h, respectively, as described previously [10]. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [10]. The mean hepatic clearance in the previous PBPK model was approximately 2-fold to a total clearance of 21.8 L/h for edoxaban (shown in the package insert of edoxaban in Japan). The predicted human virtual output Cmax and AUC0–24 values extrapolated from the previous PBPK model were consistent with those taken from reported means in subjects, supporting the relatively good fitting results (within roughly a two-fold range of predictions) as described previously [10].\n\nThe clinical laboratory results for the patient who had taken a single oral dose of 750 mg of edoxaban are shown in Table 1. Prolonged activated partial thromboplastin times and prothrombin times, as markers for blood coagulation disorder, were observed from the beginning of hospitalization to 13 h after the oral dose; no bleeding occurred during this time. These parameter values had decreased to the normal levels at 28 h, and these normal levels were maintained up to 60 h after oral doses. Other laboratory test results for hemoglobin, hematocrit, and platelet count were essentially stable during the 60-h observation period. It was assumed that apparent normal renal function of the subject and possible little interactions with concomitant drugs shown in Table 1 would not cause any saturation of edoxaban clearance.\nTable 1 Clinical laboratory results in a patient who had taken a single oral overdose of 750 mg of edoxaban\n\n\tTime after administration (h) of oral dose\t\n8\t13\t28\t36\t52\t60\t\nActivated partial thromboplastin time (s)\t59.4\t43.0\t30.9\t26.2\t26.1\t25.9\t\nProthrombin time (s)\t54.8\t33.7\t14.9\t13.4\t11.5\t11.5\t\nInternational normalized ratio\t4.34\t2.69\t1.21\t1.09\t0.94\t0.94\t\nHemoglobin (g/dL)\t12.8\t\t12.1\t\t11.9\t12.1\t\nHematocrit (%)\t36.2\t\t35.2\t\t36.4\t33.4\t\nPlatelet count (per μL)\t197,000\t\t168,000\t\t187,000\t170,000\t\nSerum creatinine (mg/dL)\t0.76\t0.82\t0.93\t0.82\t0.83\t0.73\t\nCreatinine clearance (mL/min)\t89\t82\t73\t82\t81\t93\t\nConcomitant drugs for this subject were fluvoxamine, lorazepam, valproic acid, promethazine, quazepam, levomepromazine, sertraline, quetiapine, esomeprazole, and polycarbophil calcium, which might not substantially affect the edoxaban pharmacokinetics\n\n\n\nDiscussion and conclusions\nThe measured plasma concentrations of edoxaban after the single oral overdose are shown in Fig. 1. The plasma concentration of edoxaban at 8 h after administration was 4920 ng/mL, and the concentrations gradually decreased to 368 ng/mL, 154 ng/mL, and 31 ng/mL at 28, 36, and 52 h after administration. The plasma concentration was still at a measurable level of around 7 ng/mL even 60 and 76 h after administration. Edoxaban in plasma was detectable (~ 1.8 ng/mL), but was judged to be unmeasurable (i.e., below the measurable level of 2.0 ng/mL), 100 h after administration.\nFig. 1 Measured (circles) and estimated (lines) plasma concentrations of edoxaban in a patient who took an excessive single oral dose of 750 mg. The plasma concentration curve after virtual administration of 750 mg of edoxaban (solid line) is shown with the 95% confidence interval (broken lines) based on the hepatic intrinsic clearance values of 100 virtual subjects created using random numbers, as described previously [10]. The open circle at 100 h indicates that edoxaban was detectable, but below the measurable limit, using the present liquid chromatography–tandem mass spectrometry system\n\n\n\nPredicted virtual plasma concentration curves (with 95% CIs based on the variation in hepatic intrinsic clearance values) are plotted along with the measured plasma concentrations of edoxaban versus time after the overdose administration (Fig. 1). The observed concentrations in the patient who took an overdose of 750 mg edoxaban were higher than the 95% CI of the predicted plasma concentration curves. The measured AUC0–100 was calculated to be 75.9 μg・h/L, which was 3-fold to the predicted AUC0–100 (24.6 μg・h/L) in the linear model. However, the disappearance rate of edoxaban, even for such a large overdose, generally matched the slope predicted by the PBPK model. It was assumed that the linear range was exceeded at least up to 8 h after oral administration, presumably because of metabolic saturation during the process. A lesson from this overdosed case was that later phase of edoxaban would be within the linear range, but initial phase might be out of range of linearity probably because of saturated elimination caused by the overdose. Visualized pharmacokinetic prediction curves by simple simulators will serve as an index when setting the treatment and follow-up period in the future cases of drug overdose for medicines such as edoxaban in emergency clinical practice. These observations could help in understanding the predictive pharmacokinetics of edoxaban, in setting the follow-up, and in determining whether to administer gastric lavage and/or blood products in the patients.\n\nUser-friendly bioanalytical techniques are still required to predict plasma concentrations of edoxaban in routine clinical practice and in phase IV clinical trials ongoing worldwide. At present, no drug that selectively neutralizes the anticoagulant effects of edoxaban has been marketed in Japan. According to patient interview forms, edoxaban is difficult to remove by hemodialysis. Therefore, the administration of concentrated red blood cells or fresh frozen plasma transfusion are considered as symptomatic treatments in patients whose plasma concentrations of oral thrombin or factor Xa inhibitors have become dangerously high [11]. In the current patient, blood coagulation disorder was observed; however, the patient was followed up for 100 h, because of the possibility of asymptomatic effects. Because the pharmacokinetics of edoxaban overdose were unknown, a clear follow-up period has not been set for emergency clinical practice.\n\nIn the present study, by using drug monitoring data and the results of pharmacokinetic prediction, we revealed the pharmacokinetics of edoxaban in a patient who took an overdose. It was evident that the PBPK model constructed as part of a previous study based on normal clinical oral doses of edoxaban [10] without any making changes with visualized blood concentration curves of drugs could be applied successfully in the clinical setting. Application of the PBPK model simulators may help in understanding the pharmacokinetics of edoxaban, in setting the follow-up period, and in determining whether to administer blood products and/or gastric lavage. Furthermore, this type of PBPK model simulator may be applicable for patients who have taken overdoses of other drugs.\n\nThe simplified PBPK model applied here is useful not only in the drug discovery or chemical risk assessment field but also in the management of poisoning. The simplified model simulator has the advantage that it can be handled by clinicians who are not experts in pharmacokinetics. Especially, in hospitals without systems for measuring blood levels of drugs routinely, the simplified PBPK model simulator should be of use. It is hoped that the results of this study with drug monitoring data and pharmacokinetic prediction will serve as an index when setting the treatment period in cases of overdoses of drugs such as edoxaban.\n\nAbbreviations\nCIsConfidence intervals\n\nPBPKPhysiologically based pharmacokinetic\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThe authors greatly thank Ayane Nakano and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.\n\nAuthors’ contributions\nKA, ST, SB, and KN monitored the patients and carried out acquisition of the patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. ST, SB, and KN analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was approved by the Ethics Committee of Kyoto Medical Center.\n\nConsent for publication\nInformed consent was obtained from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Lu G Conley PB Leeds JM Karbarz MJ Levy GG Mathur VS A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers Blood Adv 2020 4 728 739 10.1182/bloodadvances.2019000885 32092140 \n2. Parasrampuria DA Truitt KE Pharmacokinetics and pharmacodynamics of edoxaban, a non-vitamin K antagonist oral anticoagulant that inhibits clotting factor Xa Clin Pharmacokinet 2016 55 641 655 10.1007/s40262-015-0342-7 26620048 \n3. Franchi F Rollini F Garcia E Rivas Rios J Rivas A Agarwal M Effects of edoxaban on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and Clopidogrel: results of the EDOX-APT study Thromb Haemost 2020 120 83 93 10.1055/s-0039-1695772 31470444 \n4. Marco Garbayo JL Koninckx Canada M Perez Castello I Faus Soler MT Perea RM Hospital admissions for bleeding events associated with treatment with apixaban, dabigatran and rivaroxaban Eur J Hosp Pharm 2019 26 106 112 31157109 \n5. Aoyama T Hirata K Yamamoto Y Yokota H Hayashi H Aoyama Y Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis J Clin Pharm Ther 2016 41 392 398 10.1111/jcpt.12395 27178380 \n6. Aoyama T Hirata K Hirata R Yamazaki H Yamamoto Y Hayashi H Population pharmacokinetics of fluconazole after administration of fosfluconazole and fluconazole in critically ill patients J Clin Pharm Ther 2012 37 356 363 10.1111/j.1365-2710.2011.01297.x 21883330 \n7. Jamei M Marciniak S Feng K Barnett A Tucker G Rostami-Hodjegan A The Simcyp population-based ADME simulator Expert Opin Drug Metab Toxicol 2009 5 211 223 10.1517/17425250802691074 19199378 \n8. Kamiya Y Otsuka S Miura T Takaku H Yamada R Nakazato M Plasma and hepatic concentrations of chemicals after virtual oral administrations extrapolated using rat plasma data and simple physiologically based pharmacokinetic models Chem Res Toxicol 2019 32 211 218 10.1021/acs.chemrestox.8b00307 30511563 \n9. Takano R Yamazaki H Appication of human physiologically based pharmacokinetic models for chemical risk accessment (in Japanese) CICSJ Bulletin 2012 46 \n10. Yamazaki-Nishioka M Kogiku M Noda M Endo S Takekawa M Kishi H Pharmacokinetics of anticoagulants apixaban, dabigatran, edoxaban and rivaroxaban in elderly Japanese patients with atrial fibrillation treated in one general hospital Xenobiotica. 2019 49 1001 1006 10.1080/00498254.2018.1524188 30216091 \n11. Kaatz S Kouides PA Garcia DA Spyropolous AC Crowther M Douketis JD Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors Am J Hematol 2012 87 Suppl 1 S141 S145 10.1002/ajh.23202 22473649\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2055-0294",
"issue": "6()",
"journal": "Journal of pharmaceutical health care and sciences",
"keywords": "Anticoagulants; Overdose; Pharmacokinetic modeling",
"medline_ta": "J Pharm Health Care Sci",
"mesh_terms": null,
"nlm_unique_id": "101672177",
"other_id": null,
"pages": "20",
"pmc": null,
"pmid": "32944263",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "32092140;21883330;19199378;30216091;27178380;30511563;31157109;22473649;26620048;31470444",
"title": "Pharmacokinetics of anticoagulant edoxaban in overdose in a Japanese patient transported to hospital.",
"title_normalized": "pharmacokinetics of anticoagulant edoxaban in overdose in a japanese patient transported to hospital"
} | [
{
"companynumb": "JP-DSJP-DSJ-2020-110016",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMetronidazole, a widely used antibacterial and antiprotozoal drug, is often the drug of choice in amoebic liver abscess. The drug, otherwise safe, can cause serious central nervous disturbances in rare circumstances.\n\n\nMETHODS\nHere, we report a case of cerebellar dysfunction in the form of slurring of speech and episodes of falls, in an elderly male following a three-week course of metronidazole therapy.\n\n\nCONCLUSIONS\nThe patient manifested classic radiologic features of metronidazole neurotoxicity. Marked improvement in clinical symptoms was seen following drug discontinuation.",
"affiliations": "Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.;Department of Radiodiagnosis & Imaging, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.;Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.;Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.;Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.",
"authors": "Kaur|Upinder|U|;Kumar|Ishan|I|;Singh|Anup|A|;Kumar|Mukesh|M|;Chakrabarti|Sankha Shubhra|SS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008795:Metronidazole",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886314666190206154735",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "14(2)",
"journal": "Current drug safety",
"keywords": "CSF; Nitro imidazole; amoebiasis; neurotoxicity; pharmacogenetics; pharmacovigilance.",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002526:Cerebellar Diseases; D006801:Humans; D008101:Liver Abscess, Amebic; D008297:Male; D008795:Metronidazole",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "163-166",
"pmc": null,
"pmid": "30727914",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cerebellar Dysfunction in an Elderly Male After a Brief Course of Metronidazole.",
"title_normalized": "cerebellar dysfunction in an elderly male after a brief course of metronidazole"
} | [
{
"companynumb": "IN-INSUD PHARMA-1912IN00187",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ONDANSETRON"
},
"drugadditional": null,
... |
{
"abstract": "The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.",
"affiliations": "Department of Bone Marrow Transplantation and Oncohematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice branch, Gliwice, Poland.;Department of Bone Marrow Transplantation and Oncohematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice branch, Gliwice, Poland.;Department of Hematology and Bone Marrow Transplantation, Pomeranian Hospitals, Gdynia, Poland.;Oncologic Hospital, Tomaszów Mazowiecki, Poland.;Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.;Department of Lymphoid Malignancies, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw branch, Warsaw, Poland.;Department of Hematology, Independent Public Health Care Ministry of the Interior of Warmia and Mazury Oncology Center, Olsztyn, Poland.;Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland.;Department of Bone Marrow Transplantation and Oncohematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice branch, Gliwice, Poland.;Department of Bone Marrow Transplantation and Oncohematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice branch, Gliwice, Poland.;Department of Bone Marrow Transplantation and Oncohematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice branch, Gliwice, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland.;Department of Hematology, Jagiellonian University, Krakow, Poland.;Internal Medicine and Oncology Clinic, Silesian Medical University, Katowice, Poland.;Department of Hematology, Military Institute of Medicine, Warsaw, Poland.;Department of Hematology, Ludwik Rydygier Hospital, Krakow, Poland.;Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland.;Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland.;Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland. jzaucha@gumed.edu.pl.",
"authors": "Swoboda|Ryszard|R|;Giebel|Sebastian|S|;Knopińska-Posłuszny|Wanda|W|;Chmielowska|Ewa|E|;Drozd-Sokołowska|Joanna|J|;Paszkiewicz-Kozik|Ewa|E|;Kulikowski|Waldemar|W|;Taszner|Michał|M|;Mendrek|Włodzimierz|W|;Najda|Jacek|J|;Czerw|Tomasz|T|;Olszewska-Szopa|Magdalena|M|;Czyż|Anna|A|;Giza|Agnieszka|A|;Spychałowicz|Wojciech|W|;Subocz|Edyta|E|;Szwedyk|Paweł|P|;Krzywon|Aleksandra|A|;Wilk|Agata|A|;Zaucha|Jan Maciej|JM|http://orcid.org/0000-0002-0986-8936",
"chemical_list": "D003841:Deoxycytidine; D003907:Dexamethasone; D000069461:Bendamustine Hydrochloride; C056507:gemcitabine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-021-04448-5",
"fulltext": "\n==== Front\nAnn Hematol\nAnn Hematol\nAnnals of Hematology\n0939-5555\n1432-0584\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33625572\n4448\n10.1007/s00277-021-04448-5\nOriginal Article\nHigh efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma\nSwoboda Ryszard 1\nGiebel Sebastian 1\nKnopińska-Posłuszny Wanda 2\nChmielowska Ewa 34\nDrozd-Sokołowska Joanna 5\nPaszkiewicz-Kozik Ewa 6\nKulikowski Waldemar 7\nTaszner Michał 8\nMendrek Włodzimierz 1\nNajda Jacek 1\nCzerw Tomasz 1\nOlszewska-Szopa Magdalena 9\nCzyż Anna 9\nGiza Agnieszka 10\nSpychałowicz Wojciech 11\nSubocz Edyta 12\nSzwedyk Paweł 13\nKrzywon Aleksandra 14\nWilk Agata 14\nhttp://orcid.org/0000-0002-0986-8936\nZaucha Jan Maciej jzaucha@gumed.edu.pl\n\n8\n1 grid.418165.f 0000 0004 0540 2543 Department of Bone Marrow Transplantation and Oncohematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice branch, Gliwice, Poland\n2 Department of Hematology and Bone Marrow Transplantation, Pomeranian Hospitals, Gdynia, Poland\n3 Oncologic Hospital, Tomaszów Mazowiecki, Poland\n4 Department of Oncology, Oncology Centre, Bydgoszcz, Poland\n5 grid.13339.3b 0000000113287408 Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland\n6 Department of Lymphoid Malignancies, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw branch, Warsaw, Poland\n7 Department of Hematology, Independent Public Health Care Ministry of the Interior of Warmia and Mazury Oncology Center, Olsztyn, Poland\n8 grid.11451.30 0000 0001 0531 3426 Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland\n9 grid.4495.c 0000 0001 1090 049X Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland\n10 grid.5522.0 0000 0001 2162 9631 Department of Hematology, Jagiellonian University, Krakow, Poland\n11 grid.411728.9 0000 0001 2198 0923 Internal Medicine and Oncology Clinic, Silesian Medical University, Katowice, Poland\n12 grid.415641.3 0000 0004 0620 0839 Department of Hematology, Military Institute of Medicine, Warsaw, Poland\n13 Department of Hematology, Ludwik Rydygier Hospital, Krakow, Poland\n14 Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland\n24 2 2021\n24 2 2021\n2021\n100 7 17551767\n30 5 2020\n2 2 2021\n© The Author(s) 2021, corrected publication 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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 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/.\nThe optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19–82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1–4. Median number of BGD cycles was 4 (2–7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)—partial response, 7 (7.6%)—stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.\n\nKeywords\n\nHodgkin lymphoma\nChemotherapy\nTreatment\nSalvage\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nHodgkin lymphoma (HL), accounting for approximately 10% of all lymphomas, is one of the most curable malignancies. However, up to 30% of patients do not respond to the first-line therapy or relapse after initial response [1]. For patients with relapsed or refractory disease, salvage chemotherapy followed by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (autoHCT) is still the treatment of choice [2, 3]. The long-term cure can be obtained in up to 80% of patients provided a complete metabolic remission (CMR) is achieved before transplant [4]. Consequently, the optimal salvage regimen should be highly effective but also should have a high mobilization rate. However, the standard for salvage chemotherapy before autoHCT is still not established. The most commonly used are platinum-based ICE (ifosfamide, carboplatin, etoposide); DHAP (dexamethasone, cytarabine, cisplatin); ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin); and gemcitabine-based GDP (gemcitabine, dexamethasone, cisplatin), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), IGEV (ifosfamide, gemcitabine, vinorelbine), and GCD (gemcitabine, carboplatin, dexamethasone) combination chemotherapy with response rates ranging between 54 and 88% and mobilization rate of 86–100% [5–10]. Due to rather low rate of complete responses (CRs) achieved with the most frequently used salvage regimens, there is the persisting need to develop new salvage regimens especially in the second-line treatment. Recently, bendamustine both in monotherapy and in combination with other drugs was shown to induce high response rates with an acceptable toxicity profile in third or more line in patients with relapsed/refractory (R/R) HL [11–13]. Experience with bendamustine in the second line is very limited. Santoro et al. modified their original IGEV protocol substituting ifosfamide with bendamustine achieving a very high efficacy as a second-line therapy in patients with R/R HL [9, 14]. The Polish Lymphoma Research Group (PLRG) proposed replacement of vinorelbine with dexamethasone (bendamustine, gemcitabine, dexamethasone; BGD regimen) and is carrying out a prospective, multicenter study in patients with progressive disease during or after ABVD treatment [15] based on the very good preliminary results obtained with BGD in heavily pretreated R/R HL patients [16]. Here we report long-term outcome of these patients enrolled to the multicenter retrospective PLRG study aiming at evaluating the efficacy and toxicity of BGD in a real-life setting.\n\nMethods\n\nStudy design\n\nWe retrospectively reviewed the data of all patients aged ≥ 18 years with R/R HL who were treated with BGD regimen between April 2012 and December 2018 in 15 centers allied within the PLRG. Primary refractory HL was defined as no CMR achieved after the first line or if progression occurred within 3 months after completion of the first-line chemotherapy. In patients with relapsed HL, the disease reappeared later after achieving CMR. Patients’ records were reviewed to obtain patient characteristics at diagnosis and the start of BGD treatment, including clinical stage according to the Lugano system, presence of B symptoms, extranodal site involvement, and bulky disease.\n\nTreatment and response criteria\n\nThe dosage and administration schedule of BGD is shown in Table 1. The interim imaging assessment was performed after second or third cycle of BGD in 86 patients (93.5%). Patients could continue BGD treatment up to 4 cycles or longer at the discretion of a treating physician. The metabolic response to BGD treatment at the end of the therapy was assessed according to the Lugano treatment response criteria using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) [17]. The 18F-FDG uptake less than in the liver was defined as CMR. The higher 18F-FDG uptake, but decreased from baseline, was defined as partial metabolic response (PMR). In case of no significant change in 18F-FDG uptake from baseline or new FDG-avid foci, stable or progressive disease (SD or PD) were diagnosed, respectively. The overall response rate (ORR) was defined as the sum of CMR and PMR. Table 1 BGD regimen repeated every 4 weeks\n\nDrug\tDose\tRoute of administrationa\tDay of administration\t\nBendamustine\t90 mg/m2\ti.v. 60 min\t1 and 2\t\nGemcitabine\t800 mg/m2\ti.v. 30 min\t1 and 4\t\nDexamethasone\t40 mg\ti.v. or p.o.\t1, 2, 3, and 4\t\nai.v., intravenous; p.o., per os\n\nStudy end-points and statistical analysis\n\nPrimary end-point was the percentage of CMR and ORR whereas progression-free survival (PFS) and overall survival (OS) as well as adverse events (AEs) were secondary end-points. PFS was defined as the time from start of BGD treatment to the date of documented disease progression, death from any cause, or start of new anticancer therapy. The patients at the time of autoHCT or allogeneic hematopoietic stem cell transplantation (alloHCT) were censored for PFS since transplants were not considered a new anticancer therapy. OS was defined as the time from the first BGD administration to death for any reason. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [18]. PFS and OS were estimated using the Kaplan-Meier method. Ninety-five percent confidence intervals (CIs) for the survival curves were calculated for chosen times. The log-rank test was performed to compare survival curves between groups. Two-sided P values ≤ 0.05 were considered statistically significant. The statistics were performed descriptively. Statistical analysis was performed using Statistica software (version 13.1, Tulsa, OK, USA) and R statistical software package version 4.0.1. (R Foundation for Statistical Computing, http://www.r-project.org).\n\nResults\n\nPatients’ characteristics\n\nThe median age of 92 analyzed patients was 34.5 (range from 19 to 82 years) years with 9 patients at the age or above 60 years. More than 60% of patients were in advanced stages of HL at the time of diagnosis (III and IV according to the Lugano classification). Median number of prior chemotherapy lines was 2 (range from 1 to 6 lines). Thirty-four patients (37%) had previously been treated with only one line of chemotherapy. ABVD was the first-line therapy in 80.4% cases. Forty-four patients (47.8%) were primary refractory to the first-line chemotherapy. Almost 35% of patients had received radiotherapy prior to BGD treatment. Twenty-one patients (22.8%) underwent autoHCT, and three patients (3.3%) underwent alloHCT prior to BGD treatment. The median number of BGD cycles was 4 (range from 2 to 7 cycles). Demographic and clinical data are shown in Table 2. Table 2 Demographics and clinical characteristics of 92 subjects\n\nCharacteristic\tNo.\t%\t\nAge, years\t\n- Median (range)\t34.5 (19–82)\t\t\n- ≥ 60 years\t9\t9.7\t\nSex\t\n- Male\t44\t47.8\t\n- Female\t48\t52.2\t\nLugano classification at diagnosis/before BGDa\t\n- I\t0/3\t0/3.3\t\n- II\t33/38\t35.9/41.3\t\n- III\t25/9\t27.2/9.8\t\n- IV\t34/42\t37/45.7\t\nB-symptoms at diagnosis/before BGDa\t67/27\t72.9/29.3\t\nExtranodal site involvement at diagnosis/before BGDa\t32/39\t34.8/42.4\t\nBulky disease at diagnosis/before BGDa\t32/10\t34.8/10.9\t\nFirst-line treatment\t\nABVDb\t74\t80.4\t\nBEACOPPc\t13\t14.1\t\nOtherd\t5\t5.4\t\nNo. of previous treatment lines\t\n- 1.\t34\t37\t\n- 2.\t26\t28.3\t\n- 3.\t16\t17.4\t\n- 4.\t9\t9.8\t\n- 5.\t3\t3.3\t\n- 6.\t4\t4.3\t\nPrimary refractory to 1st-line treatment\t44\t47.8\t\nPatents with late (> 12 months) relapse\t20\t21.7\t\nNo. of BGDa courses\t\n- Median (range)\t4 (2–7)\t\t\nRadiotherapy prior to BGDa\t32\t34.8\t\nPrior autoHCTe\t21\t22.8\t\nPrior alloHCTf\t3\t3.3\t\naBGD, bendamustine, gemcitabine, dexamethasone\n\nbABVD, adriamycin, bleomycin, vinblastine, dacarbazine\n\ncBEACOPP, bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine\n\ndOther: PVAG, prednisone, vincristine, adriamycin, gemcitabine; OEPA/COPDAC, vincristine, etoposide, prednisone, doxorubicin/ cyclophosphamide, vincristine, prednisone, dacarbazine\n\neautoHCT, autologous hematopoietic cell transplantation\n\nfalloHCT, allogeneic hematopoietic cell transplantation\n\nEfficacy of BGD\n\nOut of 86 patients who were assessed by interim PET/CT after 2 or 3 cycles of BGD, 67 (77.9%) patients achieved overall response, including 33 (38.4%) CMRs. At the end of BGD therapy, ORR and CMR rate increased to 80.4% and 55.4%, respectively. Eleven patients (12%) experienced disease progression, and seven patients (7.6%) had stable disease. Among 34 patients who achieved PMR in the interim imaging test, 14 (41.2%) patients achieved CMR at the end of BGD treatment. In the subgroup of patients treated with BGD only as a second line of chemotherapy (n = 34), ORR was 79.4% while CMR rate was 64.7%. Out of 44 patients being refractory to the first line of chemotherapy, 30 (68.2%) patients achieved overall response and 34.1% achieved CMR. Among the whole study population, five patients were refractory to BEACOPP given as the first line of chemotherapy. All these patients achieved response and two of them (40%) achieved CMR after BGD. The autoHCT was successfully performed after BGD therapy in 42 (45.7%) patients. Furthermore, 16 (17.4%) patients underwent alloHCT after BGD therapy (Table 3). Among 21 patients treated with autoHCT before BGD therapy, 18 (85.7%) achieved response, 11 (52.4%) CMR, and 9 (42.9%) patients proceeded to alloHCT. PFS and OS are shown as Kaplan-Meier curves in Figs. 1 and 2. With a median follow-up of 18 months (range from 3 to 51 months), the median PFS for the overall population was 21 months while the median OS was not reached. PFS and OS rates at 2 years were 44.5% (95%CI: 33.7–58.8) and 75% (95%CI: 64.8–86.7), respectively. There were no differences between patients with relapsed or primary refractory HL in terms of PFS and OS (Figs. 3 and 4, P > 0.05). Similarly, no statistical differences in PFS and OS were noted between patients in whom BGD was used after first line or subsequent line of chemotherapy (Figs. 5 and 6, P > 0.05). Of note, most of the patients (80%) who responded to BGD maintain their response for at least 6 months (Fig. 1). In a subgroup of 9 patients ≥ 60 years old, 5 (55.6%) patients achieved CMR, 2 (22.2%)—PMR (ORR 77.8%), and 2 patients progressed during BGD treatment. PFS at 18 months was 62.2% (95%CI: 35.5–100) and OS at 23 months was 87.5% (95%CI: 67.3–100) (Figs. 7 and 8). Table 3 Response to BGD therapy\n\n\tNo.\t% (95%CI)\t\nInterim (after 2–3 courses)\tn = 86\t\t\n- PMDa\t6\t7 (1.6–12.4)\t\n- SMDb\t13\t15.1 (7.5–22.7)\t\n- PMRc\t34\t39.5 (29.2–49.9)\t\n- CMRd\t33\t38.4 (28.1–48.6)\t\n- ORRe\t67\t77.9 (69.1–86.7)\t\nEnd of BGDf therapy\tn = 92\t\t\n- PMDa\t11\t12 (5.3–18.6)\t\n- SMDb\t7\t7.6 (2.2–13.0)\t\n- PMRc\t23\t25 (16.2–33.8)\t\n- CMRd\t51\t55.4 (45.3–65.6)\t\n- ORRe\t74\t80.4 (2.3–88.5)\t\nAutoHCTg after BGD therapy\t\n- Yes\t42\t45.7\t\n- No\t50\t54.3\t\nAlloHCTh after BGD therapy\t\n- Yes\t16\t17.4\t\n- No\t76\t82.6\t\naPMD, progressive metabolic disease\n\nbSMD, stable metabolic disease\n\ncPMR, partial metabolic response\n\ndCMR, complete metabolic response\n\neORR, overall response rate\n\nfBGD, bendamustine, gemcitabine, dexamethasone\n\ngautoHCT, autologous hematopoietic cell transplantation\n\nhalloHCT, allogeneic hematopoietic cell transplantation\n\nFig. 1 Progression-free survival (PFS) for the entire population\n\nFig. 2 Overall survival (OS) for the entire population\n\nFig. 3 Progression-free survival (PFS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)\n\nFig. 4 Overall survival (OS) for the subjects with relapsed or primary refractory Hodgkin lymphoma (HL)\n\nFig. 5 Progression-free survival (PFS) for patients treated with BGD as second or subsequent line of chemotherapy\n\nFig. 6 Overall survival (OS) for patients treated with BGD as second or subsequent line of chemotherapy\n\nFig. 7 Progression-free survival (PFS) for the subgroup of elderly patients (≥ 60 years)\n\nFig. 8 Overall survival (OS) for the subgroup of elderly patients (≥ 60 years)\n\nToxicity of BGD\n\nThe treatment-related AEs, mainly grade 1 or 2, were observed in 64 (69.6%) patients. Among grade ≥ 3 hematological toxicities, anemia was reported in 15.2% cases, thrombocytopenia in 20.7%, and neutropenia in 22.8% individuals. Severe non-hematological toxicities included infections (10.9%), alanine and/or aspartate aminotransferase (ALT or AST) increase (2.2%), and skin rush (1.1%). We recorded one death from unknown reasons during BGD therapy. All AEs reported during BGD therapy are shown in Table 4. In the subgroup of elderly patients (≥ 60 years), anemia and thrombocytopenia of grade 3 or 4 occurred in 2 (22.2%) patients, while neutropenia was found in 1 (11.1%) patient. Moreover, 2 (22.2%) patients experienced grade ≥ 3 infection, and 1 (11.1%) grade 3 skin rash in this subgroup. Table 4 Toxicity of BGD therapy\n\nToxicity\tGrade 1–2\nNo. (%)\tGrade 3–4\nNo. (%)\t\nHematological:\t\n- Anemia\t37 (40.2)\t14 (15.2)\t\n- Thrombocytopenia\t25 (27.2)\t19 (20.7)\t\n- Neutropenia\t19 (20.7)\t21 (22.8)\t\nNon-hematological:\t\n- Infection\t20 (21.7)\t10 (10.9)\t\n- ALT/ASTa increase\t0\t2 (2.2)\t\n- Skin rush\t7 (7.6)\t1 (1.1)\t\n- Fatigue\t4 (4.3)\t0\t\n- Diarrhea\t1 (1.1)\t0\t\n- Thrombotic events\t2 (2.2)\t0\t\n- Guillain-Barré syndrome\t1 (1.1)\t0\t\n- Autoimmune thyroiditis\t1 (1.1)\t0\t\nDeath from unknown reasons\t1 (1.1)\t\naAlanine/aspartate aminotransferase\n\nDiscussion\n\nDespite the significant progress in the management of patients with HL, relapsed and refractory disease constitutes a big challenge. According to the current treatment standards, high-dose chemotherapy followed by autoHCT has to be regarded as treatment of choice in the first relapse or primary progressive disease. However, even in the era of new agents such as brentuximab vedotin (BV) or immune checkpoint inhibitors, there are no accepted standards for salvage treatment before autoHCT. In the PLRG allied centers BGD was used since 2012 when the first cases of successful outcome of heavily pretreated patients were reported [16]. We had started to use BGD since both bendamustine and gemcitabine were effective in monotherapy as well as in combination with other agents.\n\nGemcitabine, a cytidine analog, was assessed in several studies. Kuruvilla et al. showed satisfactory (62%) response rate to GDP (gemcitabine, dexamethasone, and cisplatin) as a second-line therapy in patients with R/R HL [19]. Gemcitabine and vinerolbine combination showed ORR of 72% and 35% of CR [20]. In similar population, four-agent combination of gemcitabine with ifosfamide, vinorelbine, and prednisolone (IGEV) or double-agent schema of vinorelbine and pegylated liposomal doxorubicin (GVD) resulted in ORR of 81.3% and 70%, respectively [8, 9]. Bendamustine, another component of BGD, is a molecule containing the purine analog and the alkylating group. It was assessed in a phase II trial in heavily pretreated patients with HL (including those with relapse after auto- or alloHCT) at the dose of 120 mg/m2 and resulted in the intent-to-treat ORR of 53%, with CRs of 33% [11].\n\nThe combination of bendamustine with gemcitabine and vinorelbine (BeGEV) was first assessed in a multicenter phase II study by Santoro et al. [14]. The authors have demonstrated high efficacy of BeGEV as a second-line treatment in autoHCT-eligible patients (ORR 83%, CR 75%). In our retrospective analysis, ORR of BGD was similar to BeGEV although patient characteristics with regard to age and number of prior treatment regimens differ [14]. Moreover, almost one-fourth of patients in our study had been treated using autoHCT. This also most likely explains slightly higher rate of hematological toxicities at grade 3 or 4 in comparison to BeGEV. In contrast, severe non-hematological AEs occurred at similar incidence rates. We did not observe increased pulmonary toxicity which was reported by Cohen et al. in his cohort of patients. This might be due to the use of high dose of steroids (dexamethasone) in our regimen [21]. However, in spite of high efficacy of BGD in relation to ORR and CMR rate, estimated PFS in our study seems to be rather short (21 months). Most likely, this is a consequence of the large group of heavily pretreated patients (up to 6 previous line of therapy) including those after auto- and alloHCT and the subgroup of elderly patients in this cohort.\n\nDHAP and ICE are among of the most commonly used salvage chemotherapy regimens in HL. Similar efficacy of these regimens as the second-line treatment was shown resulting in ORR of 88% for both, while CRs of 21% for DHAP and of 26.2% for ICE [5, 6]. Despite more heavily pretreated patients in our study, we report comparable ORR (80.4%) and much higher CMR rate (55.4%). Moreover, the difference in relation to CR rate increases in sub-analysis restricted to patients treated with BGD as the second line of chemotherapy (64.7%). The optimal number of BGD cycles is four, since about 40% of patients improved their response at the end of treatment compared to the interim assessment.\n\nMost patients (80.4%) in this study were treated with ABVD as the first line of chemotherapy. Out of 13 patients being initially treated with BEACOPP, 5 (38.5%) patients were refractory to this regimen and all these patients achieved ORR after BGD therapy with CMR rate of 40%. In view of the fact that there are not many effective treatment options to overcome the BEACOPP refractoriness, this finding seems very interesting and encouraging for further studies.\n\nIn recent years, there have been many new agents evaluated for patients with R/R HL such as BV and immune checkpoint inhibitors. Brentuximab vedotin—an anti-CD30 antibody conjugated to antimicrotubule agent, monomethyl auristatin E—showed ORR of 75% and CR rate of 34% in heavily pretreated patients with HL after autoHCT [22]. Furthermore, BV showed similar efficacy as a second-line therapy in R/R HL (ORR 68%, CR 35%), and 89% of the subjects were able to proceed to autoHCT [23]. Addition of bendamustine to BV seems to increase its efficacy [12, 13]. However, in comparison to BGD regimen, BV does not appear to be superior both in monotherapy and in combination with bendamustine. Immune checkpoint inhibitors, mainly antibodies against programmed cell death protein 1 (PD-1) such as nivolumab or pembrolizumab, showed high efficacy as a salvage therapy for patients with R/R HL [24–27]. Ansell et al. reported ORR 87% in the heavily pretreated HL patients although CR rate was relatively low (17%) compared to BGD [24]. The authors reported similar incidence of AEs of any grade (78% vs. 69.6%) but relatively fewer cases of grade ≥ 3 AEs (22% vs. 38%) during nivolumab therapy when compared to BGD therapy [24].\n\nThe high efficacy of BGD in patients after failure of autoHCT is worth noting. This is a very challenging group, in which effective chemotherapy followed by alloHCT is the only option to achieve long-lasting remission. In this population checkpoint inhibitors, nivolumab and pembrolizumab resulted in high ORR rate (69% and 73%, respectively). However, once again, CR rates (16% and 14%, respectively) appear lower compared to BGD in our study (55.4%) and there are still some concerns about the increased incidence of immune complications after alloHCT in patients treated with immune checkpoint inhibitors before transplant [25, 26, 28, 29].\n\nAnother interesting finding of this study refers to elderly HL patients. We showed that in the patients at or above the age of 60 years BGD regimen has a similar efficacy (ORR 77.8%, CMR 55.6%) than in younger patients. Moreover, BGD-related toxicity seems to be acceptable in this subgroup.\n\nRelatively small number of subjects included in the analysis as well as its retrospective nature and the lack of metabolic assessment in all patients are the major limitations of this study. Another important limitation of our study is a long accrual time. However, during this period, most of our patients were treated uniformly since novel therapies were not available due to reimbursement hurdles. Addition limitation may pose a large number of accruing centers. However, most of PLRG allied centers are reference centers with good-quality data management which somehow mitigate this flaw. However, our data clearly indicate that BGD which has a high rate of obtaining ORR and a relatively good time in response maintaining (5–6 months in 80% of patients) and an acceptable toxicity profile seems to provide a very good option for R/R HL patients even after BEACOPP first-line chemotherapy. In several patients, it opened a window to perform either autologous or allogeneic transplantation. Despite the fact that in recent years new treatment options, including BV and checkpoint inhibitors, showed promising results in treatment of patients with R/R HL, neither of them as yet is formally approved in the second-line treatment for HL. In addition, although pharmaco-economy was not a subject of this study, we speculate that BGD treatment may be a relatively cheap option. Therefore, we conclude that the BGD should be considered a viable option for patients with R/R HL and may serve as a bridge for individuals being candidates for auto- or alloHCT.\n\nAuthor contributions\n\nWKP, JMZ, and SG designed the study; all authors except for JMZ, AK, and AW enrolled patients; SG, RS, AK, and AW performed the bioinformatics and statistical analysis; RS and JMZ wrote the paper. All authors read and revised the manuscript critically.\n\nData availability\n\nNot applicable\n\nCode availability\n\nNot applicable\n\nDeclarations\n\nEthics approval\n\nAccording to Polish regulations, this was a retrospective study and it does not require approval of the bioethical committee. The study was approved by the board of The Polish Lymphoma Research Group.\n\nConsent to participate\n\nNot applicable\n\nConsent for publication\n\nNot applicable\n\nConflict of interest\n\nThe authors declare no conflict of interest.\n\nThe original version of this article was revised: This article was originally published with an incorrect affiliation. It should be 9 ( Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland).\n\nWojciech Spychałowicz passed away during the writing of this article.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nChange history\n\n3/24/2021\n\nA Correction to this paper has been published: 10.1007/s00277-021-04503-1\n==== Refs\nReferences\n\n1. 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Chen R Palmer JM Martin P Tsai N Kim Y Chen BT Popplewell L Siddiqi T Thomas SH Mott M Sahebi F Armenian S Leonard J Nademanee A Forman SJ Results of a multicenter phase II trial of brentuximab vedotin as second-line therapy before autologous transplantation in relapsed/refractory Hodgkin Lymphoma Biol Blood Marrow Transplant 2015 21 2136 2140 10.1016/j.bbmt.2015.07.018 26211987\n24. Ansell SM Lesokhin AM Borrello I Halwani A Scott EC Gutierrez M Schuster SJ Millenson MM Cattry D Freeman GJ Rodig SJ Chapuy B Ligon AH Zhu L Grosso JF Kim SY Timmerman JM Shipp MA Armand P PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma N Engl J Med 2015 372 311 319 10.1056/NEJMoa1411087 25482239\n25. Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman JM, Collins GP, Ramchandren R, Cohen JB, De Boer JP, Kuruvilla J, Savage KJ, Trneny M, Shipp MA, Kato K, Sumbul A, Farsaci B, Ansell SM (2018) Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial. J Clin Oncol 36:1428-1439\n26. Armand P Shipp MA Ribrag V Michot JM Zinzani PL Kuruvilla J Snyder ES Ricart AD Balakumaran A Rose S Moskowitz CH Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure J Clin Oncol 2016 34 3733 3739 10.1200/JCO.2016.67.3467 27354476\n27. Chen R Zinzani PL Fanale MA Armand P Johnson NA Brice P Radford J Ribrag V Molin D Vassilakopoulos TP Tomita A von Tresckow B Shipp MA Zhang Y Ricart AD Balakumaran A Moskowitz CH KEYNOTE-087 Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma J Clin Oncol 2017 35 2125 2132 10.1200/JCO.2016.72.1316 28441111\n28. Merryman RW Kim HT Zinzani PL Carlo-Stella C Ansell SM Perales MA Avigdor A Halwani AS Houot R Marchand T Dhedin N Lescaut W Thiebaut-Bertrand A François S Stamatoullas-Bastard A Rohrlich PS Labussière Wallet H Castagna L Santoro A Bachanova V Bresler SC Srivastava A Kim H Pesek E Chammas M Reynolds C Ho VT Antin JH Ritz J Soiffer RJ Armand P Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma Blood 2017 129 1380 1388 10.1182/blood-2016-09-738385 28073785\n29. Oshima Y Tanimoto T Yuji K Tojo A Association between GvHD and nivolumab in the FDA adverse event reporting system Bone Marrow Transplant 2017 52 1463 1464 10.1038/bmt.2017.158 28759026\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0939-5555",
"issue": "100(7)",
"journal": "Annals of hematology",
"keywords": "Chemotherapy; Hodgkin lymphoma; Salvage; Treatment",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064591:Allografts; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D003907:Dexamethasone; D004341:Drug Evaluation; D005260:Female; D006402:Hematologic Diseases; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D007239:Infections; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000077982:Progression-Free Survival; D018714:Radiotherapy, Adjuvant; D012008:Recurrence; D012189:Retrospective Studies; D016879:Salvage Therapy; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1755-1767",
"pmc": null,
"pmid": "33625572",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "12086759;8096958;22184409;11157476;12377653;25802695;23248254;29703778;29276022;27382096;21072518;28759026",
"title": "High efficacy of BGD (bendamustine, gemcitabine, and dexamethasone) in relapsed/refractory Hodgkin Lymphoma.",
"title_normalized": "high efficacy of bgd bendamustine gemcitabine and dexamethasone in relapsed refractory hodgkin lymphoma"
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"abstract": "A 12-year-old female patient with biliary atresia underwent living donor liver transplantation (LDLT). Twelve months after the LDLT, she developed acute hepatitis (alanine aminotransferase 584 IU/L) and was diagnosed with disseminated varicella-zoster virus (VZV) infection with high level of serum VZV-DNA (1.5 × 10(5) copies/mL) and generalized vesicular rash. She had received the VZV vaccination when she was 5-years-old and had not been exposed to chicken pox before the LDLT, and her serum was positive for VZV immunoglobulin G at the time of the LDLT. Although she underwent treatment with intravenous acyclovir, intravenous immunoglobulin, and withdrawal of immunosuppressants, her symptoms worsened and were accompanied by disseminated intravascular coagulation, pneumonia, and encephalitis. These complications required treatment in the intensive care unit for 16 days. Five weeks later, her clinical findings improved, although her VZV-DNA levels remained high (8.5 × 10(3)copies/mL). Oral acyclovir was added for 2 weeks, and she was eventually discharged from our hospital on day 86 after admission; she has not experienced a recurrence. In conclusion, although disseminated VZV infection with multiple organ failure after pediatric LDLT is a life-threatening disease, it can be cured via an early diagnosis and intensive treatment.",
"affiliations": "Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. yn708@jichi.ac.jp.;Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. yuki371@jichi.ac.jp.;Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. r0906no@jichi.ac.jp.;Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. wakiya@jichi.ac.jp.;Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. ihara@jichi.ac.jp.;Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. turahashi@jichi.ac.jp.;Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. koimizu@jichi.ac.jp.",
"authors": "Yamada|Naoya|N|;Sanada|Yukihiro|Y|;Okada|Noriki|N|;Wakiya|Taiichi|T|;Ihara|Yoshiyuki|Y|;Urahashi|Taizen|T|;Mizuta|Koichi|K|",
"chemical_list": "D000914:Antibodies, Viral; D004279:DNA, Viral; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D000212:Acyclovir",
"country": "England",
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"doi": "10.1186/s12985-015-0311-7",
"fulltext": "\n==== Front\nVirol JVirol. JVirology Journal1743-422XBioMed Central London 2608164431110.1186/s12985-015-0311-7Case ReportSuccessful rescue of disseminated varicella infection with multiple organ failure in a pediatric living donor liver transplant recipient: a case report and literature review Yamada Naoya yn708@jichi.ac.jp Sanada Yukihiro yuki371@jichi.ac.jp Okada Noriki r0906no@jichi.ac.jp Wakiya Taiichi wakiya@jichi.ac.jp Ihara Yoshiyuki ihara@jichi.ac.jp Urahashi Taizen turahashi@jichi.ac.jp Mizuta Koichi koimizu@jichi.ac.jp Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498 Japan 17 6 2015 17 6 2015 2015 12 912 1 2015 15 5 2015 © Yamada et al. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.A 12-year-old female patient with biliary atresia underwent living donor liver transplantation (LDLT). Twelve months after the LDLT, she developed acute hepatitis (alanine aminotransferase 584 IU/L) and was diagnosed with disseminated varicella-zoster virus (VZV) infection with high level of serum VZV-DNA (1.5 × 105 copies/mL) and generalized vesicular rash. She had received the VZV vaccination when she was 5-years-old and had not been exposed to chicken pox before the LDLT, and her serum was positive for VZV immunoglobulin G at the time of the LDLT. Although she underwent treatment with intravenous acyclovir, intravenous immunoglobulin, and withdrawal of immunosuppressants, her symptoms worsened and were accompanied by disseminated intravascular coagulation, pneumonia, and encephalitis. These complications required treatment in the intensive care unit for 16 days. Five weeks later, her clinical findings improved, although her VZV-DNA levels remained high (8.5 × 103copies/mL). Oral acyclovir was added for 2 weeks, and she was eventually discharged from our hospital on day 86 after admission; she has not experienced a recurrence. In conclusion, although disseminated VZV infection with multiple organ failure after pediatric LDLT is a life-threatening disease, it can be cured via an early diagnosis and intensive treatment.\n\nKeywords\nDisseminated varicella-zoster infectionLiving donor liver transplantationMultiple organ failureVZV-DNA PCRissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nVaricella-zoster virus (VZV) is a DNA virus that belongs to the family of herpes viruses, and is the cause of both chicken pox (as a primary infection) and herpes zoster, which is a reactivation infection that is typically observed in adults. Chicken pox is generally a mild disease, VZV infection is known to be more severe in adolescent patients, and although disseminated VZV infection is a rare disease, it is potentially life-threating in patients with immunosuppression after organ transplantation [1–4]. We had previously reported VZV infections after pediatric living donor liver transplantation (LDLT), which was the largest analysis of VZV infections after pediatric LDLT [5–9]. Based on our findings, we concluded that we could prevent the infection from developing into serious illness via our pre-and post-transplant strategies. However, we recently experienced a case of severe disseminated VZV infection with multiple organ failure (MOF) after pediatric LDLT, and successfully rescued the patient. Therefore we report this case of disseminated VZV infection with MOF after pediatric LDLT, and re-consider the pre-and post-transplant strategies for preventing and treating VZV infection.\n\nCase presentation\nA 12-year-old female patient with biliary atresia underwent LDLT using a left lobe graft from her ABO-compatible father. She had received the VZV vaccination when she was 5-years-old and she had not been exposed to chicken pox before the LDLT. Her serum was positive for VZV immunoglobulin G (IgG) (×160; Artus VZV-PCR kit, Qiagen, USA) at the time of the LDLT. The recipients’ cytomegalovirus (CMV) status was seronegative (IgG-negative and IgM-negative) before the LDLT, although the donor’s CMV status was seropositive (IgG-positive [×1,500] and IgM-negative). Her immunosuppression regimen after LDLT consisted of tacrolimus (FK), methylprednisolone (MP), and mycophenolate mofetil (MMF). She did not receive prophylactic therapy for CMV infection, and was evaluated each month for CMV antigenemia (C7-HRP) [10].\n\nTwelve months after the LDLT, she developed a fever and back pain with generalized vesicular rash and was admitted to our hospital 5 days later (Fig. 1). She had not been exposed to any person with chicken pox, she had not been receiving varicella-zoster immune globulin, and she was negative for VZV-IgG antibodies at the hospitalization. We subsequently diagnosed her as having a VZV infection, based on her clinical findings and the PCR results for VZV-DNA (1.6 × 105 copies/mL). As we could not investigate the strain type of the VZV, we were unable to determine whether her infection was primary infection or secondary dissemination. In addition, she exhibited signs of severe hepatic damage (alanine aminotransferase: 584 IU/L) and disseminated intravascular coagulation (DIC) (Table 1). We considered performing a liver biopsy, although we chose not to perform the biopsy, given her bleeding tendency. Based on the findings, we diagnosed her with disseminated VZV infection that was accompanied by acute hepatitis and DIC, and started intensive treatment.Fig. 1 The patient’s skin rash with blisters, which were already partially covered with scabs\n\nTable 1 Laboratory data from admission reveals severe hepatic damaged and disseminated intravascular coagulation\n\nWBC\t3,400\t/mm3\n\tT-bil\t3.14\tmg/dl\t\nRBC\t456×104\n\t/mm3\n\tD-Bil\t1.54\tmg/dl\t\nHb\t14.3\tg/dl\tBUN\t16\tmg/ dl\t\nHt\t41.4\t%\tCre\t0.42\tmg/dl\t\nPlt\t3.8 ×104\n\t/mm3\n\tCRP\t0.67\tmg/mi\t\nT-P\t6.5\tg/d\tPT-%\t44.2\t%\t\nAlb\t3.5\tg/cl\tAPTT\t34.6\tsec\t\nCPK\t36\tIU/L\tPT-INR\t1.50\t\t\nAST\t956\tIU/L\tFib\t168\tmg/dl\t\nALT\t584\tIU/L\tFDP\t38.4\tμ/ml\t\nALP\t779\tIU/L\tD-dimer\t36.3\tμ/ml\t\nLDH\t1581\tIU/L\tEBV-DNA\t12x102\n\tcopies/1O6WBC\t\nr-GTP\t583\tIUL\tCMV-antigen\t(−)\t\t\n\nWBC white blood cell, RCB red blood cell, Hb hemoglobin, Ht hematocrit, Plt platelet count, T-P total protain, Alb serum albumin, CPK cretine phosphokinase, AST aspartate transaminase, ALT alanine amino transaminase, ALP alkaline phosphatase, LDH lactate dehydrogenese, r-GTP γ-glutamyltranspeptidase, T-bil total-bilirubin, D-Bil direct bilirubin, BUN blood urea nitrogen, Cre cretinine, CRP c-creative protain, PT prothrombin time, APTT activated partial trhomboplastin time, PT-INR prothrombin time-international normalized ratio, Fib fibrinogen, FDP fibrin degradetion product, EBV Epstein-Barr virus, CMV cytomegalovirus\n\nEBV-DNA 12x102 copies/1O6WBC ⇒ EBV-DNA 12x102 copies/106 WBC\n\n\n\nAlthough she underwent treatment with intravenous acyclovir (30 mg/kg/day), intravenous immunoglobulin (125 mg/kg/day), and withdrawal of all immunosuppressants (FK, MP, and MMF), her symptoms worsened, and she developed pneumonia that required artificial respiratory management for 11 days (Fig. 2). Based on the clinical course, we assumed that this was VZV pneumonia, although we could not perform a bronchoalveolar lavage to confirm this hypothesis. On day 4 after admission, she exhibited neutropenia (<1000/mm3), due to bone marrow suppression. On day 12, she experienced a generalized tonic-clonic seizure. Although brain magnetic resonance imaging did not reveal any abnormal findings, we suspected encephalitis due to disseminated VZV infection and considered performing a lumbar puncture, although we chose not to perform the puncture, based on her unresolved bleeding tendency. Therefore, she remained in the intensive care unit for 16 days, and as her symptoms gradually improved, we resumed the oral immunosuppressants (FK and MP) after 12 days of cessation. In addition, on day 16, we changed the intravenous acyclovir to intravenous ganciclovir (12.5 mg/kg/day), because she had developed a CMV infection (CMV antigen: 2/50,000 white blood cells). After 14 days of intravenous ganciclovir, we changed the treatment to oral valganciclovir after we had confirmed the absence of CMV antigen. At 5 weeks after these treatments were started, all of her skin rash was covered with scabs, her organ symptoms had disappeared, and her clinical findings appeared to be completely improved, although her VZV-DNA levels remained high (8.5 × 103 copies/mL). We continued the oral acyclovir treatment for another 2 weeks, and she was discharged on day 86 after the admission; she has not experienced a recurrence. She was well at 6 months after discharge, and follow-up PCR testing did not reveal any VZV-DNA.Fig. 2 The patient’s clinical course. The patient exhibited severe hepatitis (alanine aminotransferase: 951 IU/mL), which gradually improved. PCR testing for varicella-zoster virus (VZV) DNA revealed decreasing values after treatment with intravenous acyclovir in the first two weeks. However, the VZV-DNA remained high and tended to be elevated after five weeks of antiviral therapy. Therefore we added prophylactic oral acyclovir for two weeks after her clinical symptoms had improved. She was eventually discharged on day 86 after her admission, and has not experienced a recurrence\n\n\n\nDiscussion\nVZV infection is a frequent complication of solid organ transplantation, although most cases are mild and can be treated in the outpatient clinic with oral acyclovir. However, because of their immunocompromised status, some patients develop a severe illness that is known as disseminated VZV infection with visceral involvement, which includes pneumonitis, hepatitis, meningoencephalitis, glomerulonephritis or hemorrhagic complications, and may result in MOF. Fehr et al. have reported that the mortality rate for disseminated VZV infection after renal transplantation is as high as 34 % [1]. Rommelaere et al. have also recently reported that the mortality rate of disseminated VZV infection after renal transplantation appears to have decreased since 1995, although no improvements have been observed over the last 10 years [11]. We have summarized the recently reported cases of disseminated VZV infection that led to MOF in Table 2 [12–23]. Immunocompromised patients, including solid organ or bone marrow transplant recipients, have the potential to experience a disseminated VZV infection with MOF, and it is noteworthy that the mortality rate is high once VZV infection leads to MOF. Early diagnosis and treatment are critical to rescuing these patients, and liver transplantation should be considered in cases with fulminant hepatic failure.Table 2 Recently reported cases of varicella-zoster infection that ledto multiple organfailure\n\n\tAuthor\tAge Sex\tPatient background\tTypes of organ symptoms\tMain Treatment\tPrognosis\t\nSolid organ transplantation associated\tAlvite-Canos [12]\t43 M\tHeart transplanatation\tHepatitis, Encephalopathy\tIVIG, Acyclovir Liver Transplantation,\tAlive\t\n\tverleden [13]\t30 M\tLung transplantation\t(hepatic, polmunary, renal insufficiency\tAcyclovir\tDead\t\n\tOur patient\t13 F\tLDLT\tHepatitis, DIC, Pneumonia Encephalopathy\tAcyclovir, IVIG withdrew the immunosuppressants\tAlive\t\n\tSpring field C [4]\t25 M\tCrohn disease\tpulmonary\tAcyclovir\tDead\t\n\tHagiya [14]\t75 F\tAcute pancreatitis\tPneumonia, Hepatitis\tAcyclovir, topical vidarabine\tDead\t\n\tHirose [15]\t13 F\tSLE ALL\tHepatitis. DIC. cardiac muscle, Pneumonia. Encephalopathy\tAcyclovir, IVIG, Plasma exclian2e\tDead\t\n\tKim [16]\t8 M\tALL\tARDS, Hepatitis DIC, encephilopathy\tAcyclovir, IVIG\tAlive\t\n\tLu [17]\t14 M\tALL\thepatitis, DIC, Myocarditis\tAcyclovir, WIG\tAlive\t\nNon-Solid organ transplantation associated\tMaggi [18]\t49 M\tHealthy\tHepatitis\thepatectomy\tDead\t\n\tBabv-Defaux [19]\t28 M\tHealthy\tHepatitis. Pneumonia, Rhabdomyolysis DIC Encephalopathy\tAcyclovir\tAlive\t\n\tPlesek [20]\t26 F\tspinal demyelination syndrome\tHepatitis, DIC\tAcyclovir\tDead\t\n\tSaitoh [21]\t47 M\tMultiple myeloma\tHepatitis, DIC, encephalopathy\tTransfusion\tDead\t\n\tWiegering [22]\t4 M\tHealthy\tPuhnonary, Hepatitis, DIC\tAcyclovir\tDead\t\n\tRoque-Afons [23]\t63 F\tAsthma and sinusitis\tFuluminant hepatic failure, DIC\tAcyclovir, IVIG Liver transplantation,\tAlive\t\n\nM male, F female, SLE Systemic Lupus Erythematosus, ALL A cute Lympocytic Leukemia, LDLT Living donor liver transplantation, DIC disseminated intravascular coagulation, IVIG intravenous immunoglobulin\n\n\n\nWe have previously reported our strategies for preventing VZV infection after pediatric LDLT, which was the largest study regarding VZV infection after pediatric LDLT [8]. Interestingly, Yamada et al. have also reported a case of severe disseminated VZV infection that occurred in an immunocompromised host, although that patient exhibited positive immunity [24]. However, we still believe that preoperative vaccination and positive immunity after the transplant are the critical considerations for managing patients after LDLT. We have performed 266 LDLTs between May 2001 and March 2015, including 36 (14.3 %) cases in which the patients were between 10-20-years-old at the LDLT; their VZV-IgG values at the LDLT are shown in Fig. 3. Among these cases we found that three patients (including this present case) exhibited relatively low VZV-IgG values and another one patient did not have VZV-IgG at the LDLT. Therefore, we currently believe that an additional vaccination may be added for similar patients before their LDLT, although it is difficult to select an appropriate VZV-IgG cut-off value for the additional vaccination. Besides, we are considering about performing re-vaccination for patients who don’t have positive immunity at 2 years after their LDLT.Fig. 3 VZV-IgG values at LDLT in 36 patients received LDLTs at 10–20 years old in our institute. The values are shown as ln VZV-IgG titers. Three patients, including the patient in the present case, exhibited relatively low antibody titers. There existed one patient who didn’t have VZV-IgG and not be shown in the figure\n\n\n\nIn the present case, the patient had received an episode of steroid pulse therapy treatment and was receiving three immunosuppressants (FK, MP, and MMF). Although it is unknown whether the present case was primary infection or re-activation of the vaccine strain, it is possible that re-activation of the vaccine strain might have led to severe disseminated VZV infection [25–27]. Patients who are receiving a potent immunosuppressant regimen have a higher risk of latent infection or vaccine re-activation, and may develop severe illness if VZV infection occurs, regardless of whether it is primary infection or re-activation. Therefore, an early diagnosis and treatment are essential to rescue patients with disseminated VZV infection and MOF. In addition, when VZV infection is suspected in solid organ transplant recipients, it is critical to consider their vaccination history, anti-VZV titers, and presence of VZV-DNA via PCR, as this information can help facilitate an early and accurate diagnosis. If a diagnosis of disseminated VZV infection is made, appropriate early treatment is dictated by the patients’condition, and may include hospitalization, intravenous acyclovir, intravenous immunoglobulin, and the withdrawal of immunosuppressants.\n\nThe primary treatment for disseminated VZV infection with MOF should address the organ failure and involve antiviral therapy, including intravenous acyclovir. In general, the antiviral therapy should be continued until all skin rashes are covered with scabs, and the organ symptoms have disappeared. Interestingly, Kronenberg et al. have reported four cases of disseminated VZV infection after solid organ transplantation in which the VZV-DNA levels were monitored via PCR [28]. Among those cases, one patient exhibited an increase in VZV-DNA that was accompanied by recurrent gastritis. In our case, we monitored the VZV-DNA levels via PCR, and they remained high (8.5 × 103copies/mL), even after all skin rashes and organ symptoms had completely resolved. Therefore, we added prophylactic oral acyclovir and continued monitoring until a decrease in the patient’s VZV-DNA was observed without any symptoms. This course appears to have been effective, as the patient has not experienced a recurrence. Similarly, monitoring for Epstein Barr virus DNA via PCR is and established method for prophylaxis and management of those infections, which are also common after liver transplantation [29, 30]. However, VZV-DNA monitoring via PCR is not an established method, although it appears to have the potential to be an effective biomarker for early diagnosis of VZV infection. In addition, this monitoring can evaluate the efficacy of treatment in cases of organ transplant recipients with severe disseminated VZV infection, especially in patients who have clinical symptoms of MOF.\n\nIn conclusion, although disseminated VZV infection with MOF after pediatric LDLT is a life-threatening disease, it can be cured via an early diagnosis and intensive treatment. In these cases, PCR monitoring of VZV-DNA is helpful to quickly reach an accurate diagnosis and evaluate the efficacy of the subsequent treatment.\n\nConsent\nWritten informed consent was obtained from the patient and her parents for publication of this case report and the accompanying images. A copy of the written consent is available for review by the Editor-in-Chief.\n\nEthics\nThis study was approved by Ethics Committee of Jichi Medical University (rA15-042).\n\nAbbreviations\nVZVVaricella zoster virus\n\nLDLTLiving donor liver transplantation\n\nMOFMultiple organ failure\n\nFKTacrolimus\n\nMPMethylprednisolone\n\nMMFMycophenolate mofetil\n\nCMVCytomegalovirus\n\nDICDisseminated intravascular coagulation\n\nPCRPolymerase chain reaction\n\nIgGImmunoglobulin G\n\nCompeting interests\n\nThe authors have no competing to disclose, as described by the Virology Journal guidelines.\n\nAuthors’ contributions\n\nNY drafted the manuscript. YS, NO, TW, YI, TU, and KM researched the literature, coordinated the management of the case, discussed the scientific issues regarding the patient’s management, and helped to draft the manuscript. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Fehr T Bossart W Wahl C Binswanger U Disseminated varicella infection in adult renal allograft recipients: four cases and a review of literature Transplantation 2002 73 608 11 10.1097/00007890-200202270-00023 11889440 \n2. Ishikawa N Tanabe K Shinmura H Tokumoto T Toma H Primary varicella virus in adult renal transplant recipients Case Reports Transplant Proc 2000 32 1952 3 10.1016/S0041-1345(00)01508-6 \n3. Infectious Disease Surveillance Center Chickenpox 1982–2004 Infectious Agents Surveillance Report 2004 25 318 20 \n4. Springfield C Sauerbrei A Filusch A Konstandin M Hartschuh W Sauer P Fatal varicella in an immunocompromised adult associated with a European genotype E2 variant of varicella zoster virus J Clin Virol 2009 44 70 3 10.1016/j.jcv.2008.10.004 19056312 \n5. Gourishankar S McDermid JC Jhangri GS Preiksaitis JK Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era Am J Transplant 2004 4 108 15 10.1046/j.1600-6143.2003.00287.x 14678041 \n6. Herrero JI Quiroga J Sangro B Pardo F Rotellar F Alvarez-Cienfuegos J Herpes zoster after liver transplantation: incidence, risk factors, and complications Liver Transpl 2004 10 1140 3 10.1002/lt.20219 15350004 \n7. Levistky J Kalil AC Meza JL Hurst GE Freifield A Chicken pox after pediatric liver transplantation Liver Transpl 2005 11 1563 6 10.1002/lt.20527 16315312 \n8. Mizuta K Urahashi T Ihara Y Sanada Y Wakiya T Yamada N Varicella zoster virus disease after pediatric liver transplantation: is it serious? Transplant Proc 2012 44 780 3 10.1016/j.transproceed.2012.01.009 22483494 \n9. Pacini-Edelstein SJ Mehra M Ament ME Vargas JH Martin MG McDiarmid SV Varicella in pediatric liver transplant recipients: a retrospective analysis of treatment and outcome J Pediatr Gastroenterol Nutr 2003 37 183 6 10.1097/00005176-200308000-00018 12883306 \n10. Kawano Y Mizuta K Sanada Y Urahashi T Ihara Y Okada N Risk factors of cytomegalovirus infection after pediatric liver transplantation Transplant Proc 2014 46 3543 7 10.1016/j.transproceed.2014.09.150 25498086 \n11. Rommelaere M Marechal C Yombi JC Goffin E Kanaan N Disseminated varicella zoster virus infection in adult renal transplant recipients: outcome and risk factors Transplant Proc 2012 44 2814 7 10.1016/j.transproceed.2012.09.090 23146530 \n12. Alvite-Canosa M Paniagua-Martín MJ Quintela-Fandiño J Ostero A Crespo-Leiro MG Fulminant hepatic failure due to varicella zoster in a heart transplant patient: successful liver transplant J Heart Lung Transplant 2009 28 1215 6 10.1016/j.healun.2009.06.017 19782606 \n13. Verleden GM Vos R Van Raemdonck DE Laleman W Vanaudenaerde BM Acute liver failure due to Varicella zoster virus infection after lung transplantation: a case report Transplant Proc 2012 44 1457 9 10.1016/j.transproceed.2011.12.077 22664036 \n14. Hagiya H Kimura M Miyamoto T Otsuka F Systemic varicella-zoster virus infection in two critically ill patients in an intensive care unit Virol J 2013 10 225 10.1186/1743-422X-10-225 23829348 \n15. Hirose I Yamaguchi H Inaguma D Ono K Shimada S Kawada J Fatal varicella infection in a girl with systemic lupus erythematosus after oral acyclovir prophylaxis Eur J Pediatr 2006 165 280 1 10.1007/s00431-005-0066-z 16411087 \n16. Kim JH Kwon DK Bae EY Han SB Lee JW Chung NG Use of intravenous immunoglobulin in a disseminated varicella infection in an immunocompromised child Korean J Pediatr 2014 57 370 3 10.3345/kjp.2014.57.8.370 25210525 \n17. Lu YC Fan HC Wang CC Cheng SN Concomitant use of acyclovir and intravenous immunoglobulin rescues an immunocompromised child with disseminated varicella caused multiple organ failure J Pediatr Hematol Oncol 2011 33 e350 1 10.1097/MPH.0b013e3181ec0efb 21127434 \n18. Beby-Defaux A Brabant S Chatellier D Bourgoin A Robert R Ruckes T Disseminated varicella with multiorgan failure in an immunocompetent adult J Med Virol 2009 81 747 9 10.1002/jmv.21447 19235868 \n19. Maggi U Russo R Conte G Chiumello D Lunghi G Maggioni M Fulminant multiorgan failure due to varicella zoster virus and HHV6 in an immunocompetent adult patient, and anhepatia Transplant Proc 2011 43 1184 6 10.1016/j.transproceed.2011.01.142 21620083 \n20. Plisek S Pliskova L Bostik VJ Fulminant hepatitis and death associated with disseminated varicella in an immunocompromised adult from the Czech Republic caused by a wild-type clade 4 varicella-zoster virus strain J Clin Virol 2011 50 72 5 10.1016/j.jcv.2010.09.014 21056000 \n21. Saitoh H Takahashi N Nanjo H Kawabata Y Hirokawa M Sawada K Varicella-zoster virus-associated fulminant hepatitis following allogeneic hematopoietic stem cell transplantation for multiple myeloma Intern Med 2013 15 1727 30 10.2169/internalmedicine.52.0118 23903507 \n22. Wiegering V Schick J Beer M Weissbrich B Gattenlöhner S Girschick HJ Varicella-zoster virus infections in immunocompromised patients - a single centre 6-years analysis BMC Pediatr 2011 11 31 10.1186/1471-2431-11-31 21569228 \n23. Roque-Afonso AM Bralet MP Ichai P Desbois D Vaghefi P Castaing D Chickenpox-associated fulminant hepatitis that led to liver transplantation in a 63-year-old woman Liver Transpl 2008 14 1309 12 10.1002/lt.21514 18756459 \n24. Yamada M Kamberos N Grose C Breakthrough varicella in a cancer patient with persistent varicella antibody after varicella vaccination J Pediatr 2013 163 1511 10.1016/j.jpeds.2013.06.043 23932212 \n25. Han JY Hanson DC Way SS Herpes zoster and meningitis due to reactivation of varicella vaccine virus in an immunocompetent child Pediatr Infect Dis J 2011 20 266 10.1097/INF.0b013e3181f63cf9 20844461 \n26. Iyer S Mittal MK Hodinka RL Herpes zoster and meningitis resulting from reactivation of varicella vaccine virus in an immunocompetent child Ann Emerg Med 2009 53 792 10.1016/j.annemergmed.2008.10.023 19028409 \n27. Levin MJ DeBiasi RL Botstik V Schmid DS Herpes zoster with skin lesions and meningitis caused by 2 different genotypes of the Oka varicella-zoster virus vaccine J Infect Dis 2008 198 1444 10.1086/592452 18826373 \n28. Kronenberg A Bossart W Wuthrich RP Cao C Lautenschlager S Wiegand ND Retrospective analysis of varicella zoster virus (VZV) copy DNA numbers in plasma of immunocompetent patients with herpes zoster, of immunocompromised patients with disseminated VZV disease, and of asymptomatic solid organ transplant recipients Transpl Infect Dis 2005 7 116 21 10.1111/j.1399-3062.2005.00106.x 16390399 \n29. Loginov R Aalto S Piiparinen H Halme L Arola J Hedman K Monitoring of EBV-DNAemia by quantitative real-time PCR after adult liver transplantation J Clin Virol 2006 37 104 8 10.1016/j.jcv.2006.06.012 16931140 \n30. Shigeta T Imadome K Sakamoto S Fukuda A Kakiuchi T Matsuno N Epstein-Barr virus infection after pediatric living-related liver transplantation—management and risk factors Transplant Proc 2010 42 4178 80 10.1016/j.transproceed.2010.09.134 21168657\n\n",
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"journal": "Virology journal",
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"medline_ta": "Virol J",
"mesh_terms": "D000212:Acyclovir; D000914:Antibodies, Viral; D002644:Chickenpox; D002648:Child; D004279:DNA, Viral; D005076:Exanthema; D005260:Female; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D016031:Liver Transplantation; D019520:Living Donors; D009102:Multiple Organ Failure; D066027:Transplant Recipients; D016896:Treatment Outcome; D019562:Viral Load",
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"pages": "91",
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"pubdate": "2015-06-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "19782606;23932212;15350004;11120016;14678041;22483494;23829348;19056312;12883306;21569228;16931140;16315312;20844461;23146530;23903507;16411087;21127434;18826373;22664036;16390399;21056000;18756459;19028409;21168657;19235868;25498086;11889440;21620083;25210525",
"title": "Successful rescue of disseminated varicella infection with multiple organ failure in a pediatric living donor liver transplant recipient: a case report and literature review.",
"title_normalized": "successful rescue of disseminated varicella infection with multiple organ failure in a pediatric living donor liver transplant recipient a case report and literature review"
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"abstract": "We aimed to describe medication use in pregnancies that resulted in births and abortions, as well as use after a pregnancy-related visit to characterize the receipt of medication after knowledge of pregnancy. Abortions included both spontaneous and induced abortions. Rates of medication use among women with a pregnancy outcome (2001-2013) were described using the Manitoba Population Research Data Repository at the Manitoba Centre for Health Policy. Use was determined as ≥ 1 prescription filled during pregnancies that resulted in births (livebirth/stillbirth) and abortions. Rates were calculated at any time during pregnancy and after a pregnancy-related visit. Rates were additionally characterized by risk in pregnancy using Briggs classification (2017). Of 174,848 birth pregnancies, overall 64.9% filled ≥ 1 prescription during pregnancy (a significant increase from 62.3% to 68.8% from 2001-2013, p<0.0001); 55.4% filled ≥ 1 prescription after a pregnancy-related visit. Of 71,967 abortions, 44.7% filled ≥ 1 prescription (a significant increase from 42.6% to 46.8% from 2001-2013, p<0.0001). Only 3.7% of birth pregnancies had at least one prescription for a contraindicated medication (according to Briggs classification), whereas 10.8% of abortions filled a prescription for a contraindicated medication. The most common drugs used in pregnancy were amoxicillin, doxylamine, codeine combinations, nitrofurantoin, cephalexin, salbutamol and ranitidine. Fewer women filled prescriptions for undesirable medications according to Briggs classification during pregnancy after a pregnancy-related visit.",
"affiliations": "College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.;Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.;Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.;College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.;Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.;College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.;Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.",
"authors": "Leong|Christine|C|0000-0003-0033-6877;Chateau|Dan|D|;Dahl|Matthew|M|;Falk|Jamie|J|;Katz|Alan|A|;Bugden|Shawn|S|;Raymond|Colette|C|",
"chemical_list": "D055553:Prescription Drugs",
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"doi": "10.1371/journal.pone.0211319",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0211319PONE-D-18-06381Research ArticleMedicine and Health SciencesWomen's HealthMaternal HealthPregnancyMedicine and Health SciencesWomen's HealthObstetrics and GynecologyPregnancyMedicine and Health SciencesWomen's HealthObstetrics and GynecologyTermination of PregnancyMedicine and Health SciencesWomen's HealthObstetrics and GynecologyMedicine and Health SciencesPharmacologyDrugsPeople and placesGeographical locationsNorth AmericaCanadaManitobaMedicine and Health SciencesWomen's HealthMaternal HealthBirthMedicine and Health SciencesWomen's HealthObstetrics and GynecologyBirthMedicine and Health SciencesPharmacologyDrugsAnalgesicsOpioidsCodeineMedicine and Health SciencesPain ManagementAnalgesicsOpioidsCodeineMedicine and Health SciencesPharmacologyDrugsOpioidsCodeineMedicine and Health SciencesWomen's HealthMaternal HealthPregnancyPregnancy ComplicationsMiscarriageMedicine and Health SciencesWomen's HealthObstetrics and GynecologyPregnancyPregnancy ComplicationsMiscarriagePrescription medication use during pregnancies that resulted in births and abortions (2001-2013): A retrospective population-based study in a Canadian population Medication use in pregnancyhttp://orcid.org/0000-0003-0033-6877Leong Christine ConceptualizationMethodologyVisualizationWriting – original draftWriting – review & editing1*Chateau Dan ConceptualizationFunding acquisitionMethodologyProject administrationValidationVisualizationWriting – original draftWriting – review & editing2Dahl Matthew ConceptualizationData curationFormal analysisMethodologyVisualizationWriting – original draftWriting – review & editing2Falk Jamie ConceptualizationMethodologyWriting – original draftWriting – review & editing1Katz Alan ConceptualizationMethodologyResourcesSupervisionWriting – original draftWriting – review & editing2Bugden Shawn MethodologyWriting – original draftWriting – review & editing1Raymond Colette ConceptualizationInvestigationMethodologyProject administrationSupervisionVisualizationWriting – original draftWriting – review & editing21 \nCollege of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada2 \nManitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, CanadaMintzes Barbara Editorthe University of Sydney, AUSTRALIACompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: christine.leong@umanitoba.ca6 3 2019 2019 14 3 e021131927 2 2018 12 1 2019 © 2019 Leong et al2019Leong 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 credited.We aimed to describe medication use in pregnancies that resulted in births and abortions, as well as use after a pregnancy-related visit to characterize the receipt of medication after knowledge of pregnancy. Abortions included both spontaneous and induced abortions. Rates of medication use among women with a pregnancy outcome (2001–2013) were described using the Manitoba Population Research Data Repository at the Manitoba Centre for Health Policy. Use was determined as ≥ 1 prescription filled during pregnancies that resulted in births (livebirth/stillbirth) and abortions. Rates were calculated at any time during pregnancy and after a pregnancy-related visit. Rates were additionally characterized by risk in pregnancy using Briggs classification (2017). Of 174,848 birth pregnancies, overall 64.9% filled ≥ 1 prescription during pregnancy (a significant increase from 62.3% to 68.8% from 2001–2013, p<0.0001); 55.4% filled ≥ 1 prescription after a pregnancy-related visit. Of 71,967 abortions, 44.7% filled ≥ 1 prescription (a significant increase from 42.6% to 46.8% from 2001–2013, p<0.0001). Only 3.7% of birth pregnancies had at least one prescription for a contraindicated medication (according to Briggs classification), whereas 10.8% of abortions filled a prescription for a contraindicated medication. The most common drugs used in pregnancy were amoxicillin, doxylamine, codeine combinations, nitrofurantoin, cephalexin, salbutamol and ranitidine. Fewer women filled prescriptions for undesirable medications according to Briggs classification during pregnancy after a pregnancy-related visit.\n\nFunding for this study was provided by the Canadian Network for Observational Drug Effects Studies (CNODES), a collaborating centre of the Drug Safety and Effectiveness Network funded by the Canadian Institutes of Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityData used in this article was derived from administrative health and social data as a secondary use. The data was provided under specific data sharing agreements only for approved use at MCHP. The original source data is not owned by the researchers or Manitoba Centre for Health Policy (MCHP) and as such cannot be provided to a public repository. Where necessary, source data specific to this article or project may be reviewed at MCHP with the consent of the original data providers, along with the required privacy and ethical review bodies. Researchers may request access to the MCHP data from Charles Burchill (Charles_Burchill@cpe.umanitoba.ca). Statistical and anonymous aggregate data associated with this paper, along with metadata describing the original source, has been submitted to MSpace, DOI http://hdl.handle.net/1993/33753. The authors have no special access or privileges for the data that other interested qualified researchers would not have.Data Availability\nData used in this article was derived from administrative health and social data as a secondary use. The data was provided under specific data sharing agreements only for approved use at MCHP. The original source data is not owned by the researchers or Manitoba Centre for Health Policy (MCHP) and as such cannot be provided to a public repository. Where necessary, source data specific to this article or project may be reviewed at MCHP with the consent of the original data providers, along with the required privacy and ethical review bodies. Researchers may request access to the MCHP data from Charles Burchill (Charles_Burchill@cpe.umanitoba.ca). Statistical and anonymous aggregate data associated with this paper, along with metadata describing the original source, has been submitted to MSpace, DOI http://hdl.handle.net/1993/33753. The authors have no special access or privileges for the data that other interested qualified researchers would not have.\n==== Body\nIntroduction\nDrug prescribing in pregnancy remains a complex and controversial issue for pregnant women and clinicians [1–3]. As the availability and use of medications change over time, understanding the real world use of prescription medications during pregnancy is imperative to assessing exposure and risk at a population level [3].\n\nWhile several studies have evaluated prescription drug use in large populations [1–9], wide variation in drug use estimates during pregnancy exists [3] and limited data describes North American prescribing patterns [1,3–5]. Many of these studies only use gestational age estimates [1,6] and few population-based studies have assessed prescription drug use during pregnancy [4,5,7]. Studies that describe medication use after a pregnancy-related healthcare visit to approximate intentional use during pregnancy [6,8] or pattern of drug use in aborted pregnancies [9] are also limited.\n\nThe risk assessment of medications used in pregnancy has traditionally been guided by the United States (US) Food and Drug Administration (FDA) classification system, which up until June 30, 2015 classified the potential risk of drug exposure to the developing fetus into five categories (A, B, C, D, and X) based on the type of available data. These risk categories continue to evolve [10]; however, this system can be misleading because there is a lack of safety data in humans for the majority of medications. As a result, many medications are categorized as FDA Category C where use in pregnancy is determined by weighing the potential benefit against the potential risk, which could impact clinical practice and research. It should be noted that after June 30, 2015, the U.S. FDA developed a new labeling system to provide general information on risk during pregnancy, clinical considerations, and level of evidence to support the risk statements [11,12]. However, this will only be applied to medications approved from 2001 onwards 11,12]. The Briggs’ Drugs in Pregnancy and Lactation (2017) [13] textbook of medication use in pregnancy is an alternative evidence-based classification system that is used in clinical practice and by several studies [6]. This reference has 17 pregnancy recommendation categories of risk based on the type of available data and trimester of exposure, which can help provide further clinical context into decision-making (S2 Table).\n\nTo date, there are no large Canadian database studies that assess the use of medications in pregnancy after a pregnancy-related visit to a health professional, or for pregnancies that resulted in abortion. Furthermore, no studies to date have described the use of medications in pregnancy using the Briggs’ risk criteria. We examined the use of medications before, during, and after pregnancy, as well as after a pregnancy-related health care visit in Manitoba, Canada. This study also described the population risk of drug exposure using the Briggs’ criteria for risk in pregnancy.\n\nMethods\nData sources\nThis retrospective cohort study used the Manitoba Population Research Data Repository of administrative health data housed at the Manitoba Centre for Health Policy, which includes de-identified linked data for over 95% of the 1.2 million individuals living in Manitoba. These data include administrative information for the universal healthcare system for nearly all Manitobans, are linkable at the person-level using an encrypted identifier, and have been validated and used in health services research [14,15]. The Manitoba Health Insurance Registry provided demographic information for the population. Prescription drug data was obtained from the Drug Program Information Network (DPIN), which captures the drug name and quantity of medication dispensed from community pharmacies in Manitoba for all Manitobans regardless of drug insurance coverage. Receipt of medication is captured within DPIN regardless of whether the prescriber phones in the prescription or if the prescription is handed in person or faxed to the pharmacy. Physician claims data and hospital discharge abstract data were used to identify diagnoses and pregnancy outcomes by International Classification of Disease (ICD) diagnosis codes. Hospital records also provided information on the gravidity, parity, and gestational age for each birth. Socioeconomic status was determined by the neighborhood income quintile available through Statistics Canada census public use files. Dissemination Area level average household income values from the public-use Census files are used to construct the quintiles.\n\nStudy population\nAll women with a pregnancy outcome identified through hospital discharge records and medical claims data [16] and continuous healthcare coverage from 365 days preconception to 90 days post-partum between the calendar years 2001 and 2013 were included. Pregnancy outcomes were identified through hospital discharge records and medical claims data included: (1) livebirth, stillbirth, or intrauterine death (ICD9CM V27, 656.4, ICD10 Z37, O36.4); and (2) spontaneous and induced abortion ICD9CM 632, 634–637, ICD10 O03-O05, ICD9-CM procedure codes 6901, 6951, 7491, 750, ICD-10 procedure code 5.CA 88–90). Women with molar or ectopic pregnancies were excluded. Due to uncertainty around delivery date, women with a hospital length of stay for more than seven days and no newborn data to assign a birthdate (and therefore, gestational age) were excluded [4]. A pregnancy-related visit to a health professional included prenatal care visits and diagnostic codes related to the pregnancy, labor, and/or delivery (with Manitoba tariff code 8400 or 8401 or diagnosis code of ICD-9-CM 640–648, 650–659, 660–669, V22, V23) [16]. Gestational age was available through hospital discharge data (maternal and newborn records) for 98.6% of livebirths/stillbirths, the remainder of which were excluded in the analysis. For abortions, gestational age from hospital discharge or medical claims data was used if available, if not, the earliest date of any pregnancy-related visit to a health care professional [16] (with Manitoba tariff code 8400 or 8401 or diagnosis code of ICD-9-CM 640–648, 650–659, 660–669, V22, V23) was used as the best estimate of the date of conception. If neither were available, the date of conception was assumed to be eight weeks prior to abortion procedure data, based on the definition used in previous research [9,17]. For abortions, pregnancy end date was based on the admission record for the first occurrence of an abortion procedure or medical claim. Readmissions with an abortion event within 28 days of the first abortion event were excluded [9]. Pregnancies resulting in multiples were included as a single pregnancy and women with multiple pregnancies were included as multiple pregnancy observations. Date of conception was determined by subtracting the gestational age (in weeks) from the date of maternal hospital admission [4]. First trimester was determined as date of conception plus 91 days, second trimester plus 92–182 days and third trimester was plus 183 days through date of pregnancy outcome.\n\nMedication exposure\nUse of medication was defined as at least one filled prescription identified from the DPIN [4,5,9]. Medication use during pregnancy was calculated separately for pre-pregnancy (defined as use during the 365 days pre-conception), each trimester of pregnancy, the entire pregnancy period (defined as use between date of conception and pregnancy outcome), and three months after the pregnancy outcome. A medication dispensation after a pregnancy-related visit to a health professional [prenatal care visit (Manitoba tariff code 8400 or 8401) or diagnosis code of ICD-9-CM 640–648, 650–659, 660–669, V22, V23) defined intentional medication use in pregnancy. The World Health Organization Anatomical Therapeutic Chemical (ATC) drug classification system was used to categorize medications by drug class [18]. Medications were also classified according to Briggs’ Drugs in Pregnancy and Lactation (S2 Table) [13]. For prescriptions with combinations products, exposure was placed in the highest risk category. For oral solid doses that were combination drug products where the systemic medication was available for more than one separate products, this was assessed as multiple products. Exposure during pregnancy was based on the date that the prescription was filled at an outpatient pharmacy. Over-the-counter medications, even if provided by prescription, as well as vitamins and minerals were excluded. For medications classified as contraindicated or as associated with risk according to Briggs et al, the rates of pregnancies with exposure to these medications was characterized excluding female reproductive hormones (contraceptives, medications to stimulate ovulation, estrogens, progesterones and other fertility drugs) [6]. Medications were also classified as undesirable according to Briggs categories 10 to 17 (S2 Table), which indicate that human data exist that suggest risk in pregnancy or contraindicated in pregnancy.\n\nStatistical analysis\nDescriptive statistics with 95% confidence intervals (CIs) on prevalence of use of medications during pregnancy is presented. All data management, programming, and analyses were performed using SAS statistical analysis software, version 9.4 (SAS Institute Inc., 2011). Chi-squared tests were used to test for time trends. Where applicable, poisson regression models were used to compare the percent of weighted pregnancies over the study period since not all women completed all trimesters. The weighted value was calculated by summing over all pregnancies, the actual number of days each woman contributed during a time period and that by the possible number of days in that time period (e.g. 91 days for each trimester).\n\nEthics\nThis study was approved by the University of Manitoba Human Research Ethics Board.\n\nResults\nThere were a total of 174,848 (70.8%) birth pregnancies between 2001 and 2013, of which, 173,680 (99.3%) resulted in a livebirth and 1,168 (0.7%) resulted in a stillbirth. The mean gestational age for birth pregnancies was 38.93 weeks (SD 2.24 weeks). There were 71,969 (29.2%) abortions that were identified, in which a gestational age was available from health records (i.e., hospital, physician claims, and pregnancy-related visits) for 15,766 (21.9%). The gestational age was estimated to be eight weeks for the remaining pregnancies that resulted in abortion 56,201 (78.1%). The mean gestational age for abortions was 8.56 weeks (SD 2.21 weeks), which includes the eight-week imputed estimate. Table 1 describes the characteristics of the study population. A higher proportion of women under 25 years and over 40 years of age had a pregnancy resulting in an abortion compared to women with a pregnancy resulting in birth (43.0% vs. 30.2% and 4.6% vs. 2.2%, respectively). A higher proportion of women with a pregnancy resulting in an abortion resided in the lowest income quintile neighborhood compared to the proportion of women with a pregnancy resulting in a livebirth (29.4% vs. 26.3%).\n\n10.1371/journal.pone.0211319.t001Table 1 Characteristics of the population.\n\tOverall\n(N = 246,817)\tBirth\n(N = 174,848)\tAbortion (N = 71,969)\t\nMaternal Age at Delivery (N,%)\t \t \t \t\n < 25 Years\t83824 (33.96)\t52862 (30.23)\t30962 (43.02)\t\n 25–29 Years\t68678 (27.83)\t51850 (29.65)\t16828 (23.38)\t\n 30–39 Years\t87124 (35.30)\t66279 (37.91)\t20845 (28.96)\t\n 40+ Years\t7191 (2.91)\t3857 (2.21)\t3334 (4.63)\t\nMaternal Age at Delivery (years) (Mean, SD)\t27.52 (6.24)\t27.84 (5.90)\t26.76 (6.96)\t\nGestational Age (N,%)\t \t \t \t\n <20 Weeks\t71632 (29.02)\t51 (0.03)\t71581 (99.46)*\t\n 20–36 Weeks\t13859 (5.62)\t13456 (7.70)\t388 (0.54)*\t\n 37+ Weeks\t161326 (65.36)\t161341 (92.27)\t0 (0.00)\t\nGestational Age (weeks) (Mean, SD)\t30.08 (13.98)\t38.93 (2.24)\t8.56 (2.21)*\t\nNumber of Past Pregnancies (including current one) (N,%)\t \t \t-\t\n Missing\t72169 (29.24)\t201 (0.11)\t71968 (100)\t\n 1 Pregnancy\t51236 (20.76)\t51236 (29.30)\tN/A\t\n 2 Pregnancies\t49925 (20.23)\t49925 (28.55)\tN/A\t\n 3 Pregnancies\t31192 (12.64)\t31192 (17.84)\tN/A\t\n 4 Pregnancies\t17755 (7.19)\t17755 (10.15)\tN/A\t\n 5 Pregnancies\t10025 (4.06)\t10025 (5.73)\tN/A\t\n 6+ Pregnancies\t14515 (5.90)\t14515 (8.34)\tN/A\t\nNumber of Past Pregnancies (including current one) (Mean, SD) (Missing Excluded)\t2.71 (1.91)\t2.71 (1.91)\tN/A\t\nNumber of Past Deliveries (N,%)\t \t \t-\t\n Missing\t72149 (29.23)\t184 (0.11)\t71965 (99.99)\t\n 0 Deliveries\t65814 (26.67)\t65811 (37.64)\ts**\t\n 1 Delivery\t55963 (22.67)\t55963 (32.01)\tN/A\t\n 2 Deliveries\t27468 (11.13)\t27468 (15.71)\tN/A\t\n 3 Deliveries\t12318 (4.99)\t12318 (7.04)\tN/A\t\n 4 Deliveries\t6086 (2.47)\t6085 (3.48)\tN/A\t\n 5 Deliveries\t3327 (1.35)\t3327 (1.90)\tN/A\t\n 6+ Deliveries\t3692 (1.50)\t3710 (2.13)\tN/A\t\nNumber of Past Deliveries (Mean, SD) (Missing Excluded)\t1.24 (1.76)\t1.24 (1.76)\tN/A\t\nDays Difference between Conception Date and First Pregnancy-related Physician Visit (Median, IQR)\t67 (48–90)\t72 (52–93)\t39 (24–51)\t\nIncome Quintile at Delivery (N,%)\t \t \t \t\n Income Quintile 1 (lowest)\t67152 (27.21)\t45968 (26.29)\t21184 (29.43)\t\n Income Quintile 2\t51407 (20.83)\t35802 (20.48)\t15605 (21.68)\t\n Income Quintile 3\t45345 (18.37)\t32377 (18.52)\t12968 (18.02)\t\n Income Quintile 4\t44001 (17.83)\t32237 (18.44)\t11764 (16.35)\t\n Income Quintile 5 (highest)\t37947 (15.37)\t27825 (15.91)\t10122 (14.06)\t\n Income Quintile Not Found\t965 (0.39)\t639 (0.37)\t326 (0.45)\t\n* Gestational age was available for 15,766 (21.9%) and missing in 56,201 (78.1%) of pregnancies resulting in abortion. Gestational age was assumed to be eight weeks for abortions where gestational age information was missing.\n\n**s represents <6 people to comply with privacy policy\n\nS1 Table lists the rates of prescriptions by the World Health Organization Anatomical Therapeutic Chemical Level 1 during pregnancy overall and after a pregnancy-related visit. The most frequently filled medication classes during pregnancy were antinfectives for systemic use (41.3% of all pregnancies) and respiratory medications (28.0% of all pregnancies).\n\nOverall, 64.9% of pregnancies that resulted in a birth received at least one prescription medication over the entire study period (Fig 1). This proportion dropped to 55.4% (p<0.0001) when the prescription was filled after a pregnancy-related visit to a health professional. In contrast, 47.7% of pregnancies that ended in abortion had a prescription filled. There was no difference between the proportion of pregnancies that resulted in abortions and births that received at least one prescription in the first trimester (44.1% and 44.2%, respectively, p = 0.771). For both births and abortions, the proportion of pregnancies involving at least one prescription medication increased slightly from 2001 to 2013 (from 62.3% to 68.8% (p < 0.0001) and 42.6% to 46.8% (p<0.0001), respectively; Fig 2A and Fig 2B).\n\n10.1371/journal.pone.0211319.g001Fig 1 Pregnancies involving the receipt of at least one prescription medication, by time period and pregnancy outcome (2001–2013).\n*births, N = 174,848; abortions, N = 71,969.\n\n10.1371/journal.pone.0211319.g002Fig 2 (a) Births (livebirth/stillbirth) and (b) Abortions involving the receipt of at least one prescription medication during pregnancy, by time period and year.\n\nWhen medication exposure during pregnancy was examined by drug risk category, the most commonly used medications during pregnancy included those in the “Compatible” category (42.6% and 18.2% of births and abortions, respectively), followed by “Human data suggest risk in 1st and 3rd trimester” (24.4% and 10.5% of births and abortions, respectively) (Fig 3). In pregnancies that resulted in a live birth, more women were exposed to a medication before the first pregnancy-related visit than in the remaining pregnancy period after this first visit (p<0.0001). A greater proportion of pregnancies that ended in abortions were exposed to medications that are categorized as contraindicated (3.7% and 10.8% of births and abortions, respectively, p<0.0001). Fig 4A and Fig 4B compare the proportion of pregnancies involving at least one medication by risk category in 2001 and 2013 for births and abortions, respectively. An increase in the use of medications considered “Compatible” (Briggs category 1 in S2 Table), “Probably Compatible” (Briggs category 2, “No (limited) Human Data–Probably Compatible”) or low risk during pregnancy (Briggs category 4, “Human Data Suggest Low Risk”; and Briggs category 5, “No (limited) Human Data–Animal Data Suggest Low Risk”) was observed among births from 2001 to 2013 from 37.4% to 48.7% (p<0.0001) and 8.3% to 14.4% (p<0.0001), respectively (Fig 4A). However, a slight decrease in the use of medications categorized as “Human Data Suggest Risk in 1st and 3rd Trimesters” was observed for this population from 26.2% in 2001 to 24.0% in 2013 (p = 0.001). For pregnancies that resulted in abortion, the use of medications in this category also slightly decreased from 11.0% to 10.5% (p = 0.263) over the same time period (Fig 4B). Interestingly, the use of “Contraindicated” medications increased from 8.7% in 2001 to 15% in 2013 (p<0.0001) among the pregnancies that resulted in abortion, and increased only from 3.4% to 3.8% (p = 0.515) during the same time period among pregnancies that did not result in abortion.\n\n10.1371/journal.pone.0211319.g003Fig 3 Pregnancies involving the receipt of at least one prescription medication, by pregnancy outcome and risk during pregnancy (2001–2013).\n10.1371/journal.pone.0211319.g004Fig 4 (a) Births (livebirth/stillbirth) and (b) Abortions involving the receipt of at least one prescription medication, by year and risk during pregnancy.\n\nThe most common drugs used in pregnancy were amoxicillin, doxylamine, codeine combinations, nitrofurantoin, cephalexin, salbutamol and ranitidine (Table 2). A greater proportion of pregnancies that ended in abortion received a prescription for codeine, metronidazole, lorazepam, naproxen and citalopram than birth pregnancies.\n\n10.1371/journal.pone.0211319.t002Table 2 Most common drugs and their risk category filled among pregnant women who received at least one prescription.\nDrug\tBriggs Category\tPregnancies resulting in birth (n = 174,848)\tPregnancies resulting in abortion (N = 71,969)\t\n\t\tPregnancies with ≥ 1 prescription (N)\t% (95% CI)\tPregnancies with ≥ 1 Rx after pregnancy-related visit (N)\t% (95% CI)\tPregnancies with ≥1 prescription (N)\t% (95% CI)\tPregnancies with ≥ 1 Rx after pregnancy-related visit (N)\t% (95% CI)\t\nAmoxicillin\tHuman Data Suggest Risk in 1st and 3rd Trimesters\t37,811\t21.62 (21.41–21.84)\t30,842\t17.64 (17.44–17.84)\t4,159\t5.78 (5.6–5.95)\t961\t1.34 (1.25–1.42)\t\nDoxylamine\tCompatible\t33,804\t19.33 (19.13–19.54)\t26,799\t15.33 (15.14–15.51)\t4,210\t5.85 (5.67–6.03)\t1,651\t2.29 (2.18–2.4)\t\nCodeine, combinations\tHuman and animal data suggest risk\t12,461\t7.13 (7–7.25)\t8,018\t4.59 (4.49–4.69)\t5,429\t7.54 (7.34–7.74)\t1,577\t2.19 (2.08–2.3)\t\nNitrofurantoin\tHuman Data Suggest Risk in 3rd Trimester\t12,372\t7.08 (6.95–7.2)\t10,374\t5.93 (5.82–6.05)\t1,158\t1.61 (1.52–1.7)\t362\t0.5 (0.45–0.55)\t\nCefalexin\tCompatible\t11,353\t6.49 (6.37–6.61)\t9,259\t5.3 (5.19–5.4)\t1,388\t1.93 (1.83–2.03)\t470\t0.65 (0.59–0.71)\t\nSalbutamol\tCompatible\t8,185\t4.68 (4.58–4.78)\t6,581\t3.76 (3.67–3.85)\t1,620\t2.25 (2.14–2.36)\t240\t0.33 (0.29–0.38)\t\nRanitidine\tCompatible\t6,415\t3.67 (3.58–3.76)\t5,559\t3.18 (3.1–3.26)\t562\t0.78 (0.72–0.85)\t94\t0.13 (0.1–0.16)\t\nMetronidazole\tHuman Data Suggest Low Risk\t5,472\t3.13 (3.05–3.21)\t4,470\t2.56 (2.48–2.63)\t3,376\t4.69 (4.53–4.85)\t685\t0.95 (0.88–1.02)\t\nAzithromycin\tCompatible\t5,370\t3.07 (2.99–3.15)\t3,739\t2.14 (2.07–2.21)\t1,192\t1.66 (1.56–1.75)\t187\t0.26 (0.22–0.3)\t\nHydrocortisone topical\tHuman (and animal) Data Suggest Risk\t4,972\t2.84 (2.76–2.92)\t4,048\t2.32 (2.24–2.39)\t640\t0.61 (0.55–0.67)\t81\t0.11 (0.09–0.14)\t\nBetamethasone topical\tCompatible—Maternal Benefit >> Embryo-Fetal Risk\t4,794\t2.74 (2.66–2.82)\t3,472\t1.99 (1.92–2.05)\t437\t0.89 (0.82–0.96)\t92\t0.13 (0.1–0.15)\t\nLevothyroxine\tCompatible\t4,691\t2.68 (2.61–2.76)\t4,536\t2.59 (2.52–2.67)\t946\t1.31 (1.23–1.4)\t220\t0.31 (0.27–0.35)\t\nErythromycin\tCompatible\t4,498\t2.57 (2.5–2.65)\t3,238\t1.85 (1.79–1.92)\t553\t0.77 (0.7–0.83)\t94\t0.13 (0.1–0.16)\t\nTMP/SMX\tHuman (and animal) Data Suggest Risk\t3,898\t2.23 (2.16–2.3)\t2,194\t1.25 (1.2–1.31)\t951\t1.32 (1.24–1.41)\t117\t0.16 (0.13–0.19)\t\nPhenoxymethylpenicillin\tCompatible\t3,732\t2.13 (2.07–2.2)\t2,232\t1.28 (1.22–1.33)\t636\t0.88 (0.82–0.95)\t83\t0.12 (0.09–0.14)\t\nLabetalol\tHuman Data Suggest Low Risk\t3,248\t1.86 (1.79–1.92)\t3,213\t1.84 (1.77–1.9)\t143\t0.2 (0.17–0.23)\t74\t0.1 (0.08–0.13)\t\nAcyclovir topical\tCompatible\t3,005\t1.72 (1.66–1.78)\t2,581\t1.48 (1.42–1.53)\t234\t0.33 (0.28–0.37)\t44\t0.06 (0.04–0.08)\t\nHydrocortisone rectal\tHuman (and animal) Data Suggest Risk\t2,966\t1.7 (1.64–1.76)\t2,737\t1.57 (1.51–1.62)\t133\t0.18 (0.15–0.22)\t39\t0.05 (0.04–0.07)\t\nProgesterone\tNot Briggs listed\t2,877\t1.65 (1.59–1.71)\t1,781\t1.02 (0.97–1.07)\t646\t0.9 (0.83–0.97)\t286\t0.4 (0.35–0.44)\t\nClindamycin\tCompatible\t2,616\t1.5 (1.44–1.55)\t1,913\t1.09 (1.05–1.14)\t481\t0.67 (0.61–0.73)\t237\t0.17 (0.14–0.2)\t\nFluticasone inhaled\tCompatible\t2,505\t1.43 (1.38–1.49)\t1,988\t1.14 (1.09–1.19)\t430\t0.6 (0.54–0.65)\t70\t0.1 (0.07–0.12)\t\nLorazepam\tHuman Data Suggest Risk in 1st and 3rd Trimesters\t2,440\t1.4 (1.34–1.45)\t1,409\t0.81 (0.76–0.85)\t1,124\t1.56 (1.47–1.65)\t237\t0.33 (0.29–0.37)\t\nInsulin (human)\tCompatible\t2,337\t1.34 (1.28–1.39)\t2,275\t1.3 (1.25–1.35)\t270\t0.38 (0.33–0.42)\t158\t0.22 (0.19–0.25)\t\nMometasone inhaled\tNo (limited) Human Data—Probably Compatible\t2,281\t1.3 (1.25–1.36)\t1,709\t0.98 (0.93–1.02)\t288\t0.4 (0.35–0.45)\t33\t0.05 (0.03–0.06)\t\nNaproxen\tHuman Data Suggest Risk in 1st and 3rd Trimesters\t2,132\t1.22 (1.17–1.27)\t548\t0.31 (0.3–0.3)\t1,745\t2.42 (2.31–2.54)\t616\t0.86 (0.79–0.92)\t\nCloxacillin\tCompatible\t2,083\t1.19 (1.14–1.24)\t1,356\t0.8 (0.7–0.8)\t312\t0.4 (0.4–0.5)\t45\t0.06 (0.04–0.08)\t\nCitalopram\tHuman Data Suggest Risk in 3rd Trimester\t2,011\t1.15 (1.1–1.2)\t1,183\t0.7 (0.6–0.7)\t1,015\t1.4 (1.3–1.5)\t146\t0.2 (0.17–0.24)\t\nFusidic acid topical\tNot Briggs listed\t1,750\t1 (0.95–1.05)\t1,130\t0.7 (0.6–0.7)\t292\t0.4 (0.4–0.5)\t41\t0.06 (0.04–0.07)\t\nTMP/SMX = trimethoprim/sulfamethoxazole\n\nAgain, a higher proportion of pregnancies that resulted in abortion had received a prescription for a contraindicated medication compared to pregnancies that resulted in birth regardless if the prescription was filled at any time or only after a pregnancy-related visit (p<0.0001) (Fig 5). However, a greater proportion of birth pregnancies filled a prescription for an undesirable medication after conception (31.1%), and this proportion dropped to 23.7% after a pregnancy-related visit (p<0.0001). Among birth pregnancies, there was a slight drop in the use of undesirable medications during pregnancy from 32.8% in 2001 to 31.1% in 2013 (p = 0.003) (Fig 6A). In contrast, there was an increase in the receipt of an undesirable medication among pregnancies that ended in abortion from 18.7% in 2001 to 24.4% in 2013 (p<0.0001) (Fig 6B). The most common medications used that are considered undesirable in pregnancy according to Briggs pregnancy recommendation categories 10 to 1711 (excluding female reproductive hormones) included amoxicillin and codeine combinations (S3 Table).\n\n10.1371/journal.pone.0211319.g005Fig 5 Pregnancies involving the receipt of at least one prescription for an undesirable medication during pregnancy, by risk category.\n*Excludes oral contraceptives, estrogens, progestogens, ovulation stimulants and leuprolide. CI–contraindicated.\n\n10.1371/journal.pone.0211319.g006Fig 6 (a) Births (livebirth/stillbirth) and (b) Abortions involving dispensation of at least one prescription for an undesirable medication, by year and risk during pregnancy. Excludes oral contraceptives, estrogens, progestogens, ovulation stimulants and leuprolide; CI = contraindicated.\n\nDiscussion\nWe found an increase in the proportion of pregnancies involving at least one medication from 2001 to 2013, with a higher proportion of pregnancies resulting in abortion exposed to a medication considered “Contraindicated” compared to pregnancies resulting in birth. We also observed a drop in the receipt of undesirable medication among birth pregnancies after a pregnancy-related health visit, which may indicate a decrease in the intentional use of medication in pregnancy.\n\nThe increase in the use of prescription medications over time that was observed in this study is similar to previously reported trends in pregnant women [5,19–23]. This could reflect a shift in the perceived risk of exposure for certain drugs to the fetus relative to the importance of maternal treatment and the availability of newer drugs into the market over time. While a higher proportion of pregnancies resulting in abortion were exposed to a contraindicated medication than birth pregnancies, it is uncertain as to whether the abortion was a result of the medication exposure or if the medication use was based on the knowledge that the pregnancy would be aborted. Furthermore, it is not possible to determine based on this data if the aborted pregnancy was intentional or spontaneous. If the abortion was spontaneous following medication exposure, this might be a reflection of the safety of the medication during pregnancy. However, if the abortion was intentional, there could have been less attention to the safety of medication use during an unwanted pregnancy. Interestingly, there appears to be a drop in medications being filled among pregnant women after a pregnancy-related visit. This could be due to the perceived risk of harm to the fetus or treatment no longer being needed.\n\nWe found nearly 65% of women with a pregnancy that resulted in birth took at least one prescription medication in pregnancy and 55% of women received a prescription after a pregnancy-related visit. Furthermore, 3.7% of births and 10.8% of abortions were exposed to a medication categorized as “Contraindicated” according to Briggs. The rate of drug use in pregnancy ranged from 27% to 93% for exposure to at least one prescription (excluding vitamins and minerals) and 0.9% to 4.5% for contraindicated medications in previous studies [3]. In a recent prospective study of 9,546 nulliparous women by Haas, et al., 73% of women took at least one medication during pregnancy and 55% took a medication in the first trimester. Similar to previous large population-based [1–9] and survey-based studies [24–28], antiinfectives for systemic use was among the most common class of medications used during pregnancy in the present study. Haas et al. found gastrointestinal agents, antibiotics, and analgesics were the most common medication classes taken in pregnancy. The slight differences in rates of medication use between our study and the study by Haas, et al. is likely attributed to the inclusion of over-the-counter medications and the prospective interview-based design to capture all medication use in the study by Haas, et al. [28] However, both the present study and the study by Haas et al. highlight the potential exposure to medications during an important period in fetal development in the first trimester, particularly when the receipt of medication was unintentional or prior to knowledge of pregnancy.\n\nNot surprisingly, amoxicillin and doxylamine were the two most common medications filled during pregnancy, which was also reported by Smolina et al. [5]. Amoxicillin and codeine were the two most common undesirable medications filled during pregnancy. Of note, the risk category for amoxicillin changed from “Compatible” to “Risk in first and third trimester”, which contributed to the increase in the number of women included in the “drugs not recommended in pregnancy” group. This change was based on a 2012 observational study that observed a low but increased risk of cleft lip with/without cleft palate for infants exposed to amoxicillin in the first trimester (adjusted odds ratio (OR) 2.0 (95% CI 1.0–4.1)) and third gestational month (OR 4.3 (95% CI 1.4–13)) between 1994 and 2008 [29]. The risk of cleft palate alone was OR 1.0 (95% CI 0.4–2.3) and OR 7.1 (95% CI 1.4–36) for the two exposure periods, respectively. Of note, the observation period in the current study (2001–2013) is reflective of a time when amoxicillin was not considered to be of risk.\n\nThe strengths of our study include the ability to study a large population of all residents in Manitoba with a comprehensive database not restricted to income, age, or drug insurance coverage. We also were able to identify the rates of drug use after a pregnancy-related visit to capture those who filled the prescription knowing that they were pregnant. We also reported on pregnancies that resulted in abortion in addition to pregnancies that resulted in livebirth or stillbirth, which is a limitation in previous studies5. Moreover, we examined medication use by Briggs category, which may provide more clinical insight into risk by pregnancy timing than the FDA categories. The successive FDA categories do not necessarily mean increasing severity of risk.\n\nThere were limitations of our study that warrant discussion. The use of administrative data for this study only captured those who used medical services during pregnancy, and only included hospital births. However, only 0.8% of deliveries in Manitoba have been reported to occur at home with a midwife [16]. The majority of abortions in Manitoba occur in hospitals (61.2%) [17], and mifepristone was not yet available in Canada at the time of the study, although it is possible that some abortions captured in physician billing claims only were not captured. However, this study is unique in capturing medication use during abortions in a Canadian population. Like most pharmacoepidemiology studies using administrative data, drug dispensions may not always reflect drug consumption and we only reported on drugs filled in an outpatient community pharmacy. Furthermore, the DPIN does not consistently capture over-the-counter medications and therefore was excluded in the current analysis, even if there were prescriptions for over the counter medications used in pregnancy. Although many women take over the counter medications in pregnancy, without an ability to quantify use though prescription filling, we felt that it was more accurate to exclude these medications. Pregnancy-related visits were used as an indicator that the patient had knowledge of the pregnancy. However, because home pregnancy tests are not captured through administrative claims data, these visits may not reflect the very first knowledge of pregnancy or the start of pregnancy. It is also important to note that the average time at risk of a medication use after a pregnancy-related visit was shorter for abortions. Of note, since conception usually occurs approximately two weeks after the last menstrual period, our estimation of conception may actually be an approximation of the last menstrual period rather than true conception of pregnancy. Medication taking behavior prior to an abortion, perception of risk, and many other factors are likely important to consider in a holistic approach to medication use during aborted pregnancies, this information is not captured in administrative health claims data. We did not conduct analyses based on spontaneous or induced abortions, although medication-taking behavior in these two situations are likely different. There were more estimated gestational ages for abortions and potential for misclassification, however, we attempted a conservative window of exposure to medications during these pregnancies to avoid misclassification of a mother taking a medication but not being pregnant yet. We were also not able to capture medications received in hospital, however, antenatal hospitalization in Manitoba (without delivery) in 2008/09 was 11 per 100 [16], and any discharge prescriptions would be captured through DPIN. Our findings may only be generalizable to jurisdictions with a similar drug coverage program in which eligible prescriptions are covered for Manitoba residents by the province after an income-based deductible is reached per year. Finally, future work could investigate whether certain medication classes or medications contributed to the overall trend in medication use during pregnancy.\n\nConclusion\nThere was an increase in the proportion of pregnancies involving at least one medication from 2001 to 2013. Few women fill prescriptions for medications undesirable during pregnancy after a pregnancy-related visit. Contraindicated medications in pregnancy were dispensed to a higher proportion of pregnancies resulting in abortion compared to pregnancies resulting in a birth. We observed a drop in the receipt of medication among birth pregnancies after a pregnancy-related health visit. When describing intentional use of medication during pregnancy, it is important to consider prescriptions filled after the first pregnancy-related visit.\n\nSupporting information\nS1 Table Pregnancies during which at least 1 prescription filled, by World Health Organization Anatomical Therapeutic Chemical Level 1 (ATC1) classification and study period.\nWeighted total pregnancies = 191,222.06 (N, weighted %, 95% CI)\n\n(DOCX)\n\nClick here for additional data file.\n\n S2 Table Briggs categories.\n*Medications under this category were considered undesirable during pregnancy\n\n(DOCX)\n\nClick here for additional data file.\n\n S3 Table Pregnancies involving the receipt of at least one prescription for undesirable medication during pregnancy.\nExcludes oral contraceptives, estrogens, progestogens, ovulation stimulants and leuprolide, *Prescription filled in first trimester **Prescription filled in third trimester, S = Suppressed (value is <6)\n\n(DOCX)\n\nClick here for additional data file.\n\n The authors acknowledge the Manitoba Centre for Health Policy for use of data contained in the Population Health Research Data Repository under project # 2013–035 (HIPC# 2013/2014-35). The results and conclusions are those of the authors and no official endorsement by the Manitoba Centre for Health Policy, Manitoba Health, Seniors and Active Living, or other data providers is intended or should be inferred. Data used in this study are from the Population Health Research Data Repository housed at the Manitoba Centre for Health Policy, University of Manitoba and were derived from data provided by Manitoba Health, Seniors and Active Living.\n==== Refs\nReferences\n1 Palmsten K , Hernández-Díaz S , Chambers CD , Mogun H , Lai S , Gilmer TP , Huybrechts KF . The Most Commonly Dispensed Prescription Medications Among Pregnant Women Enrolled in the U.S. Medicaid Program . Obstet Gynecol . 2015 \n9 ;126 (3 ):465 –73 . 10.1097/AOG.0000000000000982 \n26244530 \n2 Gagne JJ , Maio V , Berghella V , Louis DZ , Gonnella JS . Prescription drug use during pregnancy: a population-based study in Regione Emilia-Romagna, Italy . Eur J Clin Pharmacol . 2008 \n11 ;64 (11 ):1125 –32 . 10.1007/s00228-008-0546-y \n18685836 \n3 Daw JR , Hanley GE , Greyson DL , Morgan SG . Prescription drug use during pregnancy in developed countries: a systematic review . Pharmacoepidemiol Drug Saf . 2011 \n9 ;20 (9 ):895 –902 . 10.1002/pds.2184 \n21774029 \n4 Daw JR , Mintzes B , Law MR , Hanley GE , Morgan SG . Prescription drug use in pregnancy: a retrospective, population-based study in British Columbia, Canada (2001–2006) . Clin Ther . 2012 \n1 ;34 (1 ):239 –249.e2 . 10.1016/j.clinthera.2011.11.025 \n22169049 \n5 Smolina K , Hanley GE , Mintzes B , Oberlander TF , Morgan S .Trends and Determinants of Prescription Drug Use during Pregnancy and Postpartum in British Columbia, 2002–2011: A Population-Based Cohort Study . PLoS One . 2015 \n5 \n26 ;10 (5 ):e0128312 \n10.1371/journal.pone.0128312 \n26011706 \n6 Andrade SE , Gurwitz JH , Davis RL , Chan KA , Finkelstein JA , Fortman K , McPhillips H , Raebel MA , Roblin D , Smith DH , Yood MU , Morse AN , Platt R . Prescription drug use in pregnancy . Am J Obstet Gynecol . 2004 \n8 ;191 (2 ):398 –407 . 10.1016/j.ajog.2004.04.025 \n15343213 \n7 Zomerdijk IM , Ruiter R , Houweling LM , Herings RM , Sturkenboom MC , Straus SM , Stricker BH . Isotretinoin exposure during pregnancy: a population-based study in The Netherlands . BMJ Open . 2014 \n11 \n12 ;4 (11 ):e005602 \n10.1136/bmjopen-2014-005602 \n25392022 \n8 Margulis AV , Palmsten K , Andrade SE , Charlton RA , Hardy JR , Cooper WO , Hernández-Díaz S . Beginning and duration of pregnancy in automated health care databases: review of estimation methods and validation results . Pharmacoepidemiol Drug Saf . 2015 \n4 ;24 (4 ):335 –42 . 10.1002/pds.3743 \n25627986 \n9 Colvin L , Slack-Smith L , Stanley FJ , Bower C . Pharmacovigilance in pregnancy using population-based linked datasets . Pharmacoepidemiol Drug Saf . 2009 \n3 ;18 (3 ):211 –25 . 10.1002/pds.1705 \n19173342 \n10 Law R , Bozzo P , Koren G , Einarson A . FDA pregnancy risk categories and the CPS: Do they help or are they a hindrance? \nCanadian Family Physician \n2010 ;56 :239 –241 . 20228306 \n11 Food Drug Administration HHS . Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling . Final rule . Fed Regist 2014 ;79 :72063 –103 .\n12 Fantasia HC , Harris AL . Changes to Pregnancy and Lactation Risk Labeling for Prescription Drugs . Nurs Womens Health \n2015 ;19 :266 –70 . 10.1111/1751-486X.12209 \n26058910 \n13 Briggs Gerald G. ; Freeman Roger K. ; Towers Craig V. ; Forinash Alicia B (2017 ). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk , 11th edition \nLippincott Williams & Wilkins (LWW) .\n14 Roos LL , Roos NP , Cageorge SM , Nicol JP . How good are the data: Reliability of one health care data bank . Med Care \n1982 , 20 : 266 –276 \n7078285 \n15 Roos LL , Nicol JP : A research registry: uses, development, and accuracy . J Clin Epidemiol \n1999 ;52 (1 ):39 –47 \n9973072 \n16 Heaman M , Kingston D , Helewa M , Brownell M , Derksen S , Bogdanovic B , McGowan K , Bailly A . Perinatal Services and Outcomes in Manitoba . Winnipeg, MB : Manitoba Centre for Health Policy , 20 \n17 Canadian Institute for Health Information. Induced Abortions. Available: https://www.cihi.ca/en/ta_10_alldatatables20120417_en.pdf. Accessed December 19, 2017.\n18 WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2017. Available: https://www.whocc.no/atc_ddd_index/. Accessed December 19, 2017.\n19 Stephansson O , Granath F , Svensson T , Haglund B , Ekbom A , Kieler H . Drug use during pregnancy in Sweden–assessed by the Prescribed Drug Register and the Medical Birth Register . Clin Epidemiol . 2011 ; 3 :43 –50 . d 10.2147/CLEP.S16305 \n21386973 \n20 Mitchell AA , Gilboa SM , Werler MM , Kelley KE , Louik C , Hernández-Díaz S . Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008 . Am J Obstet Gynecol . 2011 ; 205 (1 ):51.e1 –e8 .21514558 \n21 Bjorn AM , Norgaard M , Hundborg HH , Nohr EA , Ehrenstein V . Use of prescribed drugs among primiparous women: an 11-year population-based study in Denmark . Clin Epidemiol . 2011 ; 3 :149 –56 . Epub 2011/05/25. 10.2147/CLEP.S17747 \n21607016 \n22 Engeland A , Bramness JG , Daltveit AK , Rønning M , Skurtveit S , Furu K . Prescription drug use among fathers and mothers before and during pregnancy. A population‐based cohort study of 106 000 pregnancies in Norway 2004–2006 . Br J Clin Pharmacol . 2008 ; 65 (5 ):653 –60 . 10.1111/j.1365-2125.2008.03102.x \n18294334 \n23 Bérard A , Sheehy O . The Quebec pregnancy cohort–prevalence of medication use during gestation and pregnancy outcomes . PLoS One . 2014 ; 9 (4 ):e93870 \n10.1371/journal.pone.0093870 \n24705674 \n24 Haas DM , Marsh DJ , Dang DT , Parker CB , Wing DA , Simhan HN , et al\nPrescription and other medication use in pregnancy . Obstetrics & Gynecology \n2018 ;131 (5 ):789 –798 .29630018 \n25 Lee E , Maneno MK , Smith L , Weiss SR , Zuckerman IH , Wutoh AK , et al\nNational patterns of medication use during pregnancy . Pharmacoepidemiol Drug Saf \n2006 ;15 :537 –45 . 10.1002/pds.1241 \n16700083 \n26 Glover DD , Amonkar M , Rybeck BF , Tracy TS . Prescription, over-the-counter, and herbal medicine use in a rural, obstetric population . Am J Obstet Gynecol \n2003 ;188 :1039 –45 . 12712107 \n27 Lacroix I , Damase-Michel C , Lapeyre-Mestre M , Montastruc JL . Prescription of drugs during pregnancy in France . Lancet \n2000 ;356 :1735 –6 . 11095263 \n28 Thorpe PG , Gilboa SM , Hernandez-Diaz S , Lind J , Cragan JD , Briggs G , et al\nMedications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk . Pharmacoepidemiol Drug Saf \n2013 ;22 :1013 –8 . 10.1002/pds.3495 \n23893932 \n29 Lin KJ , Mitchell AA , Yau W-P , Louik C , Hernandez-Diaz S . Maternal exposure to amoxicillin and the risk of oral clefts . Epidemiology \n2012 ;23 :699 –705 . 10.1097/EDE.0b013e318258cb05 \n22766750\n\n",
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"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D002170:Canada; D005260:Female; D006801:Humans; D008350:Manitoba; D036801:Parturition; D011247:Pregnancy; D011256:Pregnancy Outcome; D055553:Prescription Drugs; D055656:Prescriptions; D012189:Retrospective Studies",
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"title": "Prescription medication use during pregnancies that resulted in births and abortions (2001-2013): A retrospective population-based study in a Canadian population.",
"title_normalized": "prescription medication use during pregnancies that resulted in births and abortions 2001 2013 a retrospective population based study in a canadian population"
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"abstract": "We report a 34-years-old woman who presented with bilateral incongruous inferior visual field defects after the commencement of topiramate for management of migraine. Investigations did not reveal any underlying angle closure glaucoma, reported in current literature to be associated commonly with topiramate associated visual field defects. The changes in the peripheral visual fields gradually improved over several months after the medication was withdrawn. There were only minor changes persistent on the left side on a background of pre-existing myopia and keratoconus. Visual field deficits secondary to topiramate are more commonly attributed to angle closure glaucoma due to ciliochoroidal effusion syndrome. In such instance, the visual field defects are associated with considerable pain due to raised intra-ocular pressure. There have also been reports of visual scotomas due to retinal damage and maculopathy in patients taking topiramate. It is worthwhile to obtain a baseline perimetry in patients being considered for topiramate therapy in order to gauge any changes in their peripheral field of vision during the treatment. Changes in visual fields during the course of medication use and after cessation can be easily compared especially if there are other possible confounders such as refractive errors or a history of migraine.",
"affiliations": "Neurology Department, Canberra Hospital, Yamba Dr, Garran, ACT 2605, Australia. Electronic address: sameenhaque@hotmail.com.;Neurology Department, Nepean Hospital, Derby St, Kingswood, NSW 2747, Australia.;Midwest Ophthalmology, Orange, NSW 2800, Australia.",
"authors": "Haque|Sameen|S|;Shaffi|Mohamed|M|;Tang|Kong C|KC|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose",
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"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Maculopathy; Side effects; Topiramate; Visual field defects; Visual loss",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D005260:Female; D005632:Fructose; D006801:Humans; D008881:Migraine Disorders; D000077236:Topiramate; D014786:Vision Disorders; D014794:Visual Fields",
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"title": "Topiramate associated non-glaucomatous visual field defects.",
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"abstract": "Heart transplantation is an effective therapy for patients with end-stage heart failure. In some cases, Takotsubo syndrome (TTS) was seen in the donor heart. We report a case of TTS in a 40-year-old woman with a history of epileptic seizures who underwent heart transplantation from a donor with TTS. The donor was brain-dead due to severe hypoxic encephalopathy during cardiac arrest with TTS. Fifteen months after heart transplantation, she was readmitted for epileptic seizures. Electrocardiogram showed T-wave inversion, and transthoracic echocardiography showed apical ballooning. Coronary angiography was normal, and endomyocardial biopsy was negative for rejection. Iodine-123 metaiodobenzylguanidine imaging demonstrated a low heart-to-mediastinum ratio and high washout rate. Eighteen days after admission, recovery of left ventricular dysfunction was confirmed, and she was diagnosed with TTS triggered by epileptic seizures. It is important to recognize the risk of recurrent TTS in heart transplantation patients from a donor with TTS.",
"affiliations": "Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.",
"authors": "Tsuji|Masaki|M|;Amiya|Eisuke|E|https://orcid.org/0000-0003-2810-8040;Bujo|Chie|C|;Maki|Hisataka|H|;Ishida|Junichi|J|;Hatano|Masaru|M|;Ono|Minoru|M|;Komuro|Issei|I|",
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"doi": "10.1002/ehf2.12970",
"fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822 John Wiley and Sons Inc. Hoboken \n\n32964639\n10.1002/ehf2.12970\nEHF212970\nESCHF-20-00428\nCase Report\nCase Reports\nTakotsubo syndrome in the same heart before and after heart transplantation\nTTS before and after heart transplantationM. Tsuji et al.Tsuji Masaki \n1\n Amiya Eisuke https://orcid.org/0000-0003-2810-8040\n1\n\n2\namiyae-tky@umin.ac.jp Bujo Chie \n1\n Maki Hisataka \n1\n Ishida Junichi \n1\n Hatano Masaru \n1\n\n2\n Ono Minoru \n3\n Komuro Issei \n1\n \n1 \nDepartment of Cardiovascular Medicine, Graduate School of Medicine\nThe University of Tokyo\nTokyo\nJapan\n\n\n2 \nDepartment of Therapeutic Strategy for Heart Failure\nThe University of Tokyo\nTokyo\nJapan\n\n\n3 \nDepartment of Cardiac Surgery, Graduate School of Medicine\nThe University of Tokyo\nTokyo\nJapan\n\n* \nCorrespondence to: Eisuke Amiya, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Therapeutic Strategy for Heart Failure, The University of Tokyo, Tokyo, Japan. Tel: +81‐3‐3815‐5411; Fax: +81‐3‐5800‐9142. Email: amiyae-tky@umin.ac.jp\n\n10 9 2020 \n12 2020 \n7 6 10.1002/ehf2.v7.64311 4314\n17 5 2020 04 7 2020 06 8 2020 © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of CardiologyThis 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\nHeart transplantation is an effective therapy for patients with end‐stage heart failure. In some cases, Takotsubo syndrome (TTS) was seen in the donor heart. We report a case of TTS in a 40‐year‐old woman with a history of epileptic seizures who underwent heart transplantation from a donor with TTS. The donor was brain‐dead due to severe hypoxic encephalopathy during cardiac arrest with TTS. Fifteen months after heart transplantation, she was readmitted for epileptic seizures. Electrocardiogram showed T‐wave inversion, and transthoracic echocardiography showed apical ballooning. Coronary angiography was normal, and endomyocardial biopsy was negative for rejection. Iodine‐123 metaiodobenzylguanidine imaging demonstrated a low heart‐to‐mediastinum ratio and high washout rate. Eighteen days after admission, recovery of left ventricular dysfunction was confirmed, and she was diagnosed with TTS triggered by epileptic seizures. It is important to recognize the risk of recurrent TTS in heart transplantation patients from a donor with TTS.\n\nHeart transplantationTakotsubo syndromeRecurrence source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:22.12.2020\n\n\nTsuji , M. \n, \nAmiya , E. \n, \nBujo , C. \n, \nMaki , H. \n, \nIshida , J. \n, \nHatano , M. \n, \nOno , M. \n, and \nKomuro , I. \n (2020 ) Takotsubo syndrome in the same heart before and after heart transplantation\n. ESC Heart Failure , 7 : 4311 –4314\n. 10.1002/ehf2.12970 .\n==== Body\nIntroduction\nTakotsubo syndrome (TTS) is an acute transient heart failure syndrome with left ventricular (LV) dysfunction and serious complications. Several pathophysiologic mechanisms have been proposed, such as the contributions of the autonomic sympathetic nervous system, circulating catecholamine, or endothelial dysfunction; however, the exact pathophysiology remains unknown. Here, we report a rare case of TTS after heart transplantation from a donor who suffered brain death with TTS. This is the first report of recurrent TTS beyond heart transplantation, which may lead to the elucidation of the mechanistic insight of TTS.\n\nCase report\nA 40‐year‐old woman with end‐stage hypertrophic cardiomyopathy underwent heart transplantation following LV assist device support. She also had several events of epileptic seizures due to a previous cerebrovascular disease.\n\nThe donor, who was in her sixties, was brain‐dead due to severe hypoxic encephalopathy during cardiac arrest. After resuscitation, electrocardiogram (ECG) revealed ST‐segment elevation in leads II, III, and aVF (Figure\n\n1\nA\n). Cardiac catheterization showed hyperkinesis of the LV base and akinesia of the apex without coronary artery stenosis (Figure\n\n2\nA–D\n). Transthoracic echocardiography (TTE) demonstrated apical ballooning on the initial assessment, which improved during donor management with intra‐aortic balloon pumping support. Intra‐aortic balloon pumping was successfully weaned 2 days before procurement. Before the procurement (7 days after cardiac arrest), LV dysfunction normalized, leading to the diagnosis of TTS. Cardiac arrest was considered to be due to TTS, and the haemodynamic derangement was considered to be temporary, which suggested the validity of the donor candidate for heart transplantation.\n\nFigure 1 Electrocardiogram of the donor after resuscitation in the first takotsubo syndrome (TTS) event (A). Electrocardiogram of the recipient on the day of admission (B), at 4 AM on the next day of admission (C), and at 6 PM on the next day of admission (D) in the second TTS event.\n\nFigure 2 Coronary angiography of the donor after resuscitation showed no significant stenosis in the left coronary artery (A) or right coronary artery (B) in the first takotsubo syndrome (TTS) event. Left ventriculography in the first TTS event showed hyperkinesis of the left ventricular base and akinesia of the apex: at end‐diastole (C) and end‐systole (D).\n\nThe recipient received the marginal donor heart because of haemodynamic instability due to aortic insufficiency under LV assist device support and underwent orthotopic heart transplantation using the modified bicaval technique. Within 6 months after heart transplantation, there was no overt problem in the transplanted heart. However, she was admitted three times for epileptic seizures, and her epilepsy was controlled with antiepileptic drugs (i.e. levetiracetam and zonisamide).\n\nNine months after the last episode of epileptic seizure, she was readmitted for epileptic seizure recurrence. On admission, her heart rate was 135 beats/min, and her blood pressure was 140/100 mmHg. Endotracheal intubation was performed to maintain the airway. ECG revealed sinus tachycardia with right bundle branch block (Figure\n\n1\nB\n).\n\nOn the next day, ECG revealed T‐wave inversion in leads I, aVL, V5, and V6 (Figure\n\n1\nC,D\n). High‐sensitivity troponin I was 1872.1 pg/mL (normal, <26.2 pg/mL), and brain natriuretic peptide was 1005.7 pg/mL (normal, <18.4 pg/mL). TTE demonstrated apical ballooning (Figure\n\n3\nA,B\n). We calculated the InterTAK diagnostic score value of 59 points and suspected TTS rather than acute coronary syndrome.\n1\n\n\n\nFigure 3 Two‐dimensional transthoracic echocardiography in the second takotsubo syndrome (TTS) event at admission demonstrated apical ballooning (red arrowheads) at end‐diastole (A) and end‐systole (B). Coronary angiography showed no significant stenosis in the left (C) and right (D) coronary arteries in the second TTS event. Two‐dimensional transthoracic echocardiography in the second TTS event on Day 18 demonstrated recovery of left ventricular dysfunction at end‐diastole (E) and end‐systole (F). A bull's‐eye map of iodine‐123 metaiodobenzylguanidine imaging after the second TTS event demonstrated uptake reduction in the inferior–posterior, lateral, and apex regions in the early (G) and delayed (H) phases.\n\nDobutamine was administered at a rate of 2.8 μg/kg/min, and intravenous furosemide was used for heart failure treatment. Successful extubation was achieved on Day 2. Repeated TTE showed a gradual improvement in LV contraction, and dobutamine administration was discontinued on Day 4.\n\nCoronary angiography showed no significant stenosis (Figure\n\n3\nC,D\n). Right ventricular endomyocardial biopsy showed partial fibrosis, sparse lymphocyte infiltration, and hemosiderin deposition, which were considered as artefacts due to injury evoked by previous biopsies. There were no findings suggesting acute cellular or antibody‐mediated rejection. On Day 18, TTE revealed recovery of LV dysfunction (Figure\n\n3\nE,F\n), confirming the diagnosis of TTS triggered by epileptic seizures. On Day 49, iodine‐123 metaiodobenzylguanidine (MIBG) imaging demonstrated uptake reduction in the inferior–posterior, lateral, and apex regions (Figure\n\n3\nG,H\n). The heart‐to‐mediastinum ratios in the early and delayed phases were 1.55 and 1.25, respectively. The total washout rate was 39.0%, and in the apical region, it was >40%. The patient was discharged on Day 63 with stable condition.\n\nDiscussion\nTakotsubo syndrome is an acute cardiac condition triggered by emotional and physical stress characterized by reversible LV dysfunction.\n2\n, \n3\n International diagnostic criteria help to improve the identification and stratification of TTS.\n4\n Cerebrovascular disease and epilepsy are the most frequent central nervous system diseases triggering TTS.\n5\n\n\n\nThis case had two novel points: first, TTS developed in a transplanted heart, and second, TTS recurred after heart transplantation.\n\nA transplanted heart is completely denervated at the time of the transplant operation. Transplanted heart, not all the heart, gradually reinnervated. Sympathetic reinnervation extends from the base to the apex of the anterior and septal walls.\n6\n The lateral and inferior walls appear to be involved later.\n6\n MIBG findings in this case revealed partial reinnervation of the sympathetic nerve, which corresponded to previous reports.\n7\n According to the impact on the development of TTS, the reinnervation of the sympathetic nerve may be necessary in developing TTS\n8\n and could possibly explain the rationale for the absence of TTS events in previous epileptic seizures after heart transplantation. In the case of TTS, neuronally transmitted norepinephrine was a prerequisite, along with an increased concentration of circulating catecholamine. The reduced MIBG uptake in the inferior–posterior and lateral regions may be due to incomplete sympathetic reinnervation, and the susceptibility to TTS after heart transplantation may be significantly affected by the pattern of sympathetic reinnervation, which may change over time after heart transplantation. However, the absence of MIBG uptake was also affected by myocardial injury from the TTS event.\n\nThe TTS recurrence rate is reported to be 1.8% per patient year.\n3\n Neurologic and psychiatric disorders were independent predictors of recurrence, and triggering factors and ballooning patterns could change during recurrence.\n9\n Indeed, the first TTS event in this case seemed to be the primary one, whereas the second event was secondary to epileptic seizures. ECG abnormalities also differed between the first and second TTS events: ST‐segment elevation in the first and right bundle branch block with T‐wave inversion in the second. Although ECG was modified after heart transplantation, it was not clear why the ECG abnormalities were different despite similar wall motion abnormalities of ballooning.\n\nNotably, the trait of TTS susceptibility was unexpectedly inherited from the donor by the recipient through the transplanted myocardium. The contributing factors for the occurrence of TTS in this case were considered: the donor's myocardium, recipient's sympathetic nervous system, and recipient‐derived trigger.\n\nTo the best of our knowledge, this is the first report on recurrent TTS after heart transplantation from a donor with TTS. It is important to recognize that epileptic seizures are a predisposing factor for recurrent TTS and should be controlled well.\n\nConflict of interest\nNone declared.\n==== Refs\nReferences\n1 \n\nGhadri \nJR \n, \nWittstein \nIS \n, \nPrasad \nA \n, \nSharkey \nS \n, \nDote \nK \n, \nAkashi \nYJ \n, \nCammann \nVL \n, \nCrea \nF \n, \nGaliuto \nL \n, \nDesmet \nW \n, \nYoshida \nT \n, \nManfredini \nR \n, \nEitel \nI \n, \nKosuge \nM \n, \nNef \nHM \n, \nDeshmukh \nA \n, \nLerman \nA \n, \nBossone \nE \n, \nCitro \nR \n, \nUeyama \nT \n, \nCorrado \nD \n, \nKurisu \nS \n, \nRuschitzka \nF \n, \nWinchester \nD \n, \nLyon \nAR \n, \nOmerovic \nE \n, \nBax \nJJ \n, \nMeimoun \nP \n, \nTarantini \nG \n, \nRihal \nC \n, \nHassan \nSY \n, \nMigliore \nF \n, \nHorowitz \nJD \n, \nShimokawa \nH \n, \nLuscher \nTF \n, \nTemplin \nC \n. International expert consensus document on takotsubo syndrome (part II): diagnostic workup, outcome, and management\n. Eur Heart J \n2018 ; 39 : 2047 –2062\n.29850820 \n2 \n\nSato \nH \n, \nTaiteishi \nH \n, \nUchida \nT \n. Takotsubo‐type cardiomyopathy due to multivessel spasm In Kodama K. , Haze K. , Hon M. , eds. Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure . Tokyo, Japan : Kagakuhyouronsha ; 1990 p 56 –64\n.\n3 \n\nTemplin \nC \n, \nGhadri \nJR \n, \nDiekmann \nJ \n, \nNapp \nLC \n, \nBataiosu \nDR \n, \nJaguszewski \nM \n, \nCammann \nVL \n, \nSarcon \nA \n, \nGeyer \nV \n, \nNeumann \nCA \n, \nSeifert \nB \n, \nHellermann \nJ \n, \nSchwyzer \nM \n, \nEisenhardt \nK \n, \nJenewein \nJ \n, \nFranke \nJ \n, \nKatus \nHA \n, \nBurgdorf \nC \n, \nSchunkert \nH \n, \nMoeller \nC \n, \nThiele \nH \n, \nBauersachs \nJ \n, \nTschöpe \nC \n, \nSchultheiss \nHP \n, \nLaney \nCA \n, \nRajan \nL \n, \nMichels \nG \n, \nPfister \nR \n, \nUkena \nC \n, \nBöhm \nM \n, \nErbel \nR \n, \nCuneo \nA \n, \nKuck \nKH \n, \nJacobshagen \nC \n, \nHasenfuss \nG \n, \nKarakas \nM \n, \nKoenig \nW \n, \nRottbauer \nW \n, \nSaid \nSM \n, \nBraun‐Dullaeus \nRC \n, \nCuculi \nF \n, \nBanning \nA \n, \nFischer \nTA \n, \nVasankari \nT \n, \nAiraksinen \nKE \n, \nFijalkowski \nM \n, \nRynkiewicz \nA \n, \nPawlak \nM \n, \nOpolski \nG \n, \nDworakowski \nR \n, \nMacCarthy \nP \n, \nKaiser \nC \n, \nOsswald \nS \n, \nGaliuto \nL \n, \nCrea \nF \n, \nDichtl \nW \n, \nFranz \nWM \n, \nEmpen \nK \n, \nFelix \nSB \n, \nDelmas \nC \n, \nLairez \nO \n, \nErne \nP \n, \nBax \nJJ \n, \nFord \nI \n, \nRuschitzka \nF \n, \nPrasad \nA \n, \nLüscher \nTF \n. Clinical features and outcomes of takotsubo (stress) cardiomyopathy\n. N Engl J Med \n2015 ; 373 : 929 –938\n.26332547 \n4 \n\nGhadri \nJR \n, \nWittstein \nIS \n, \nPrasad \nA \n, \nSharkey \nS \n, \nDote \nK \n, \nAkashi \nYJ \n, \nCammann \nVL \n, \nCrea \nF \n, \nGaliuto \nL \n, \nDesmet \nW \n, \nYoshida \nT \n, \nManfredini \nR \n, \nEitel \nI \n, \nKosuge \nM \n, \nNef \nHM \n, \nDeshmukh \nA \n, \nLerman \nA \n, \nBossone \nE \n, \nCitro \nR \n, \nUeyama \nT \n, \nCorrado \nD \n, \nKurisu \nS \n, \nRuschitzka \nF \n, \nWinchester \nD \n, \nLyon \nAR \n, \nOmerovic \nE \n, \nBax \nJJ \n, \nMeimoun \nP \n, \nTarantini \nG \n, \nRihal \nC \n, \nHassan \nSY \n, \nMigliore \nF \n, \nHorowitz \nJD \n, \nShimokawa \nH \n, \nLüscher \nTF \n, \nTemplin \nC \n. International expert consensus document on takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology\n. Eur Heart J \n2018 ; 39 : 2032 –2046\n.29850871 \n5 \n\nFinsterer \nJ \n, \nWahbi \nK \n. CNS disease triggering takotsubo stress cardiomyopathy\n. Int J Cardiol \n2014 ; 177 : 322 –329\n.25213573 \n6 \n\nBengel \nFM \n, \nUeberfuhr \nP \n, \nZiegler \nSI \n, \nNekolla \nS \n, \nReichart \nB \n, \nSchwaiger \nM \n. Serial assessment of sympathetic reinnervation after orthotopic heart transplantation. A longitudinal study using PET and C‐11 hydroxyephedrine\n. Circulation \n1999 ; 99 : 1866 –1871\n.10199884 \n7 \n\nBuendia‐Fuentes \nF \n, \nAlmenar \nL \n, \nRuiz \nC \n, \nVercher \nJL \n, \nSanchez‐Lazaro \nI \n, \nMartinez‐Dolz \nL \n, \nNavarro \nJ \n, \nBello \nP \n, \nSalvador \nA \n. Sympathetic reinnervation 1 year after heart transplantation, assessed using iodine‐123 metaiodobenzylguanidine imaging\n. Transplant Proc \n2011 ; 43 : 2247 –2248\n.21839246 \n8 \n\nChinali \nM \n, \nFormigari \nR \n, \nGrutter \nG \n. Takotsubo cardiomyopathy in a young adult with transplanted heart: what happened to denervation?\n\nESC Heart Fail \n2018 ; 5 : 197 –200\n.29330935 \n9 \n\nKato \nK \n, \nDi Vece \nD \n, \nCammann \nVL \n, \nMicek \nJ \n, \nSzawan \nKA \n, \nBacchi \nB \n, \nLuscher \nTF \n, \nRuschitzka \nF \n, \nGhadri \nJR \n, \nTemplin \nC \n. Takotsubo recurrence: morphological types and triggers and identification of risk factors\n. J Am Coll Cardiol \n2019 ; 73 : 982 –984\n.30819368\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2055-5822",
"issue": null,
"journal": "ESC heart failure",
"keywords": "Heart transplantation; Recurrence; Takotsubo syndrome",
"medline_ta": "ESC Heart Fail",
"mesh_terms": null,
"nlm_unique_id": "101669191",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32964639",
"pubdate": "2020-09-10",
"publication_types": "D002363:Case Reports",
"references": "29850871;29850820;32964639;25213573;30819368;29330935;10199884;26332547;21839246",
"title": "Takotsubo syndrome in the same heart before and after heart transplantation.",
"title_normalized": "takotsubo syndrome in the same heart before and after heart transplantation"
} | [
{
"companynumb": "JP-UCBSA-2021003260",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZONISAMIDE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Hepatitis C virus (HCV) infection in patients undergoing haemodialysis is prevalent and aggressive. The treatment of chronic hepatitis C has been revolutionised by the advent of direct-acting antivirals (DAAs). However, the safety, efficacy, and tolerance of DAAs in the treatment of acute HCV infection in patients with end-stage renal disease who are on haemodialysis are unknown.\n\n\n\nTo evaluate the safety and efficacy of sofosbuvir plus daclatasvir in this specific, difficult-to-treat population.\n\n\n\nWe conducted a prospective and observational study of end-stage renal disease patients who were undergoing haemodialysis and were acutely infected with HCV. Patients received a half dose of sofosbuvir (200 mg) and a full dose of daclatasvir (60 mg) daily. The primary endpoint was the proportion of patients with sustained virological responses (SVRs); the other primary outcomes were safety and tolerability.\n\n\n\nThirty-three patients were enrolled in the study. The median HCV RNA viral load at baseline was 6.8 log10 IU/mL. Twenty-four patients were infected with HCV genotype 2a, seven patients with 1b, and two patients with 2a+1b. All patients achieved a SVR at 12 weeks after the end of treatment. The treatment was well tolerated, and there were no drug-related serious adverse events.\n\n\n\nA half dose of sofosbuvir (200 mg once daily) plus a full dose of daclatasvir (60 mg once daily) were suitable for the treatment of acute HCV-infected patients who were undergoing end-stage renal disease and were on haemodialysis.",
"affiliations": "Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Department of Haemodialysis, Zhen'An County Hospital, Zhen'An, China.;Xi'an Health School, Xi'an City, China.;Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.;Institution of Hepatology, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.",
"authors": "He|Y L|YL|0000-0001-9444-3678;Yang|S J|SJ|;Hu|C H|CH|0000-0001-7292-6222;Dong|J|J|;Gao|H|H|;Yan|T T|TT|;Liu|J F|JF|0000-0003-2790-1303;Yang|Y|Y|0000-0002-7033-6330;Ren|D F|DF|;Zhu|L|L|;Zhao|Y R|YR|;Chen|T Y|TY|",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.1111/apt.14429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "47(4)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D002219:Carbamates; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006526:Hepatitis C; D006801:Humans; D007093:Imidazoles; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011759:Pyrrolidines; D006435:Renal Dialysis; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014633:Valine; D055815:Young Adult",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "526-532",
"pmc": null,
"pmid": "29250808",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and efficacy of sofosbuvir-based treatment of acute hepatitis C in end-stage renal disease patients undergoing haemodialysis.",
"title_normalized": "safety and efficacy of sofosbuvir based treatment of acute hepatitis c in end stage renal disease patients undergoing haemodialysis"
} | [
{
"companynumb": "CN-GILEAD-2018-0313942",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DACLATASVIR"
},
"drugadditional": null,
... |
{
"abstract": "In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC).\n\n\n\nTo determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC.\n\n\n\nDouble-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018).\n\n\n\nmFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent.\n\n\n\nThe primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level.\n\n\n\nAmong 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]).\n\n\n\nAmong patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial.\n\n\n\nClinicalTrials.gov Identifier: NCT01516216.",
"affiliations": "Dana-Farber Cancer Institute, Boston, Massachusetts.;Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Beth Israel Deaconess Medical Center, Boston, Massachusetts.;Beth Israel Deaconess Medical Center, Boston, Massachusetts.;Massachusetts General Hospital, Boston.;St Luke's Mountain States Tumor Institute, Boise, Idaho.;Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber at Milford Regional Medical Center, Milford, Massachusetts.;New Hampshire Oncology Hematology, Hookset.;Dana-Farber at South Shore Hospital, South Weymouth, Massachusetts.;New England Cancer Specialists, Scarborough, Maine.;Newton-Wellesley Hospital, Newton, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Massachusetts General Hospital, Boston.;Medical University of South Carolina, Charleston.;Dana-Farber Cancer Institute, Boston, Massachusetts.;Yale Cancer Center, New Haven, Connecticut.",
"authors": "Ng|Kimmie|K|;Nimeiri|Halla S|HS|;McCleary|Nadine J|NJ|;Abrams|Thomas A|TA|;Yurgelun|Matthew B|MB|;Cleary|James M|JM|;Rubinson|Douglas A|DA|;Schrag|Deborah|D|;Miksad|Rebecca|R|;Bullock|Andrea J|AJ|;Allen|Jill|J|;Zuckerman|Dan|D|;Chan|Emily|E|;Chan|Jennifer A|JA|;Wolpin|Brian M|BM|;Constantine|Michael|M|;Weckstein|Douglas J|DJ|;Faggen|Meredith A|MA|;Thomas|Christian A|CA|;Kournioti|Chryssanthi|C|;Yuan|Chen|C|;Ganser|Christine|C|;Wilkinson|Brittney|B|;Mackintosh|Christopher|C|;Zheng|Hui|H|;Hollis|Bruce W|BW|;Meyerhardt|Jeffrey A|JA|;Fuchs|Charles S|CS|",
"chemical_list": "D014815:Vitamins; D014807:Vitamin D; D002762:Cholecalciferol; C104450:25-hydroxyvitamin D",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.2019.2402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-7484",
"issue": "321(14)",
"journal": "JAMA",
"keywords": null,
"medline_ta": "JAMA",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002762:Cholecalciferol; D015179:Colorectal Neoplasms; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D000077982:Progression-Free Survival; D016016:Proportional Hazards Models; D014807:Vitamin D; D014815:Vitamins",
"nlm_unique_id": "7501160",
"other_id": null,
"pages": "1370-1379",
"pmc": null,
"pmid": "30964527",
"pubdate": "2019-04-09",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "10328225;10786699;10812003;10966885;11089522;11121228;11158062;11830528;11927275;12081833;15037631;15208365;17397543;17962355;1847660;18565885;19621386;20594355;20945439;21422438;21876081;22503810;22647055;24705652;25002714;25934710;29872317;3024816;30415629;8033137;9330287;9651351",
"title": "Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial.",
"title_normalized": "effect of high dose vs standard dose vitamin d3 supplementation on progression free survival among patients with advanced or metastatic colorectal cancer the sunshine randomized clinical trial"
} | [
{
"companynumb": "US-PFIZER INC-2019163943",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Recently, everolimus (Evl) has been introduced in the management of hormone receptor-positive metastatic breast cancer, in combination with aromatase inhibitors. Evl-induced acute kidney injury has hitherto been described in other malignancies, especially renal cell cancer, but only once before in a patient with breast cancer. We describe two cases of Evl-associated nephrotoxicity in patients with breast cancer, one of whom underwent a renal biopsy showing acute tubular necrosis. Both our patients improved after withdrawal of the offending agent and have normal renal functions on follow-up.",
"affiliations": "Department of Nephrology, Dr. RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.;Department of Nephrology, Dr. RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.;Department of Pathology, Dr. RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.;Department of Radiation Oncology, Dr. RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.;Department of Radiation Oncology, Dr. RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.",
"authors": "Chandra|A|A|;Rao|N S|NS|;Malhotra|K P|KP|;Rastogi|M|M|;Khurana|R|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_304_16",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-27-40610.4103/ijn.IJN_304_16Case ReportEverolimus-associated Acute Kidney Injury in Patients with Metastatic Breast Cancer Chandra A. Rao N. S. Malhotra K. P. 1Rastogi M. 2Khurana R. 2Department of Nephrology, Dr. RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, India1 Department of Pathology, Dr. RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, India2 Department of Radiation Oncology, Dr. RML Institute of Medical Sciences, Lucknow, Uttar Pradesh, IndiaAddress for correspondence: Dr. N. S. Rao, Department of Nephrology, Dr. RML Institute of Medical Sciences, Vibhuti Khand, Lucknow - 226 001, Uttar Pradesh, India. E-mail: snamratarao@yahoo.co.inSep-Oct 2017 27 5 406 409 Copyright: © 2017 Indian Journal of Nephrology2017This 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.Recently, everolimus (Evl) has been introduced in the management of hormone receptor-positive metastatic breast cancer, in combination with aromatase inhibitors. Evl-induced acute kidney injury has hitherto been described in other malignancies, especially renal cell cancer, but only once before in a patient with breast cancer. We describe two cases of Evl-associated nephrotoxicity in patients with breast cancer, one of whom underwent a renal biopsy showing acute tubular necrosis. Both our patients improved after withdrawal of the offending agent and have normal renal functions on follow-up.\n\nKeywords\nAcute kidney injuryacute tubular necrosiscancereverolimusnephrotoxicity\n==== Body\nIntroduction\nMammalian target of rapamycin (mTOR) inhibitors is a recent addition to the treatment of hormone receptor-positive advanced breast cancer, following the pivotal BOLERO-2 trial and subsequent Food and Drug Agency (FDA) approval.[1] These agents are known to ameliorate resistance to endocrine therapies, by suppressing intracellular signaling through the PI3K-Akt-mTOR pathway. Everolimus (Evl) at a dose of 10 mg is given in combination with aromatase inhibitors, either steroidal (exemestane) or nonsteroidal (letrozole, anastrozole). Evl has been reported to cause acute kidney injury (AKI), especially so, in patients with underlying chronic kidney disease (CKD), such as patients with renal cell carcinoma (RCC) after tumor resection.[2] Renal biopsy in some cases has revealed acute tubular necrosis (ATN), with variable recovery of renal function.[3] Evl nephrotoxicity, however, is extremely rare in non-RCC cancers and has been reported only once before[4] in breast cancer. Here, we present two cases of Evl-induced AKI in patients with advanced breast cancer.\n\nCase Reports\nCase 1\nA 54-year-old normotensive nondiabetic postmenopausal woman, with previous history of hysterectomy, was diagnosed with infiltrating ductolobular carcinoma of the right breast in 2011. She underwent surgery with modified radical mastectomy and right axillary clearance; postoperative histopathology showed pT2N3M0, hormone receptor-positive, and human epidermal growth factor receptor 2/neu (HER2/neu) positive. She received 6 cycles of adjuvant chemotherapy with TAC (docetaxel, adriamycin, and cyclophosphamide) from December 2011 to April 2012. After completion of chemotherapy, external beam radiotherapy (EBRT) was given, with a dose of 50 Gy/25# to the right chest wall and subclavian fossa till June 2012, followed by hormonal treatment with tablet anastrozole 1 mg daily. She remained asymptomatic till February 2014, when she presented with a backache. Magnetic resonance imaging of the whole spine revealed multiple bony metastases, and positron emission tomography-computed tomography (CT) showed lung and liver metastases as well. Then, she was treated with palliative EBRT and second-line chemotherapy with paclitaxel and carboplatin was given till May 2014, but the disease was progressive, with increased pulmonary metastases. Third-line chemotherapy with two cycles of gemcitabine, carboplatin, and zoledronic acid was given till July 2014. Evl at a dose of 10 mg/day, along with exemestane 25 mg/day and zoledronate 4 mg/month was started in August 2014, as the patient developed pleural effusion and mediastinal lymphadenopathy while on previous chemotherapy.\n\nAt baseline, on October 1, 2015, her serum creatinine (SCr) was 0.87 mg/dl, and estimated glomerular filtration rate (eGFR) (by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) was 76 ml/min/1.73 m2. On October 7, she visited the OPD with the complaints of vomiting, malaise, and decreased urine output for 5 days. She had a blood pressure of 100/60 mmHg, pulse rate of 92/min, and the rest of her physical examination was unremarkable. Laboratory results showed a rise in SCr to 5.4 mg/dl. Her hemoglobin was 9.1 g/dl, total lymphocyte count was 8.7 × 103/μl, and platelet counts were 230 × 103/μl. Evl was stopped, and she was hospitalized. Intravenous fluids were started because of signs of dehydration and AKI. Echocardiography showed normal cardiac function. In the following days, despite rehydration with 1.5 L/day of intravenous sodium chloride, her renal functions continued to worsen. SCr levels peaked at 7.2 mg/dl and she became oliguric with urine output falling to 250 ml/day. A renal ultrasound excluded postrenal causes of acute renal failure and showed normal sized kidneys. Urine and blood cultures remained sterile. Urine microscopy showed 100 mg/dl of proteinuria, rare granular casts, and no dysmorphic erythrocytes with few leukocytes. Because of uremic symptoms, she was started on hemodialysis. By October 18 (day 11 of renal failure), her renal functions started to improve with her SCr falling to 1.49 mg/dl by October 21 and returned to baseline by October 30. No rechallenge of Evl was attempted. She is presently on fulvestrant 500 mg with stable renal function.\n\nCase 2\nA 56-year-old woman was diagnosed as stage T4bN0M0 estrogen receptor (ER)-positive infiltrating ductal carcinoma of the left breast in August 2014. Besides, she had well-controlled Type 2 diabetes mellitus and hypertension for last 4 years as comorbidities, for which she was on glimepiride 2 mg, metformin 500 mg, amlodipine 5 mg, and aspirin 75 mg/day. On CT evaluation, she was found to have metastases in bilateral lungs and liver. She received six consecutive 3-weekly cycles of docetaxel 100 mg, epirubicin 80 mg with 4 mg monthly dose of zoledronic acid. After achieving a partial response to therapy, she was shifted to anastrozole 1 mg dose to which Evl 10 mg OD was added in June 2015, and zoledronate was continued.\n\nAt baseline, 1 week after starting Evl, on June 30, 2015, her SCr was 0.98 mg/dl, and eGFR was 64 ml/min/1.73 m2. Two days later, on July 2, SCr rose to 1.9 mg/dl, on routine investigations, while the patient remained asymptomatic. Evl was stopped on the same day. After 1 week, she reported to the hospital with breathlessness, lethargy, and anorexia. On laboratory evaluation, her SCr had risen to 3.95 mg/dl, and she was hospitalized. However, in the next few days, her renal function continued to deteriorate and SCr peaked at 8.85 mg/dl. With uremic symptoms and worsening metabolic acidosis, she was started on hemodialysis. A renal ultrasound excluded obstructive uropathy and showed normal-sized kidneys. A chest X-ray showed bilateral minimal pleural effusions, but no infiltrates suspicious for infection were observed. Urine and blood cultures remained sterile. Urine microscopy showed 2+ proteinuria, 8–10 granular casts and 1–2 dysmorphic erythrocytes, and few leukocytes per high-power field. A 24-h urine collection showed 0.91 g protein excretion/day. Her urine output dropped to 300–400 ml/day, and she remained dialysis dependent. With no recovery of renal functions after almost a month, a renal biopsy was performed. It was reported as ATN [Figure 1]. From August 19, her S. Cr levels slowly started improving, and she became dialysis-independent. Her S. Cr dropped to 1.86 mg/dl by November 4, 2015, and touched a nadir of 1.26 mg/dl on January 9, 2016. No rechallenge of Evl was attempted.\n\nFigure 1 Section from renal biopsy shows unremarkable glomeruli and dilated tubules with detached epithelial cells in tubular lumina (arrow). (H and E, ×100); Inset shows detached necrotic luminal epithelial cells and flattened tubular lining epithelium (arrow). (H and E, ×400)\n\nThe trend of renal function in both patients in relation to Evl exposure is shown in Figure 2.\n\nFigure 2 Trend of serum creatinine in the index patients. X-axis - days from everolimus exposure, Y-axis - serum creatinine in mg/dl. Pre-Evl-time before Evl exposure\n\nDiscussion\nmTOR inhibitors have come a long way in clinical therapeutics. Rapamycin was discovered from Streptomyces hygroscopicus and was initially noted for its antifungal activity.[5] Over the years, mTOR inhibitors have earned a place in the immunosuppression armamentarium in solid organ transplants. While both sirolimus and Evl are known to be associated with posttransplant proteinuria, AKI is quite uncommon. Nevertheless, mTOR inhibitors can cause prolongation of delayed graft function, purportedly, through increased tubular cell apoptosis and defective regeneration of tubular epithelium. This finding has limited the de novo use of mTOR inhibitors in the immediate posttransplant period, but these agents are often used to substitute calcineurin inhibitors in the late posttransplant period, in patients with chronic allograft nephropathy, for their role in preventing tubulointerstitial fibrosis.[6]\n\nIn the recent years, mTOR inhibitors have been found to have antitumor effects. mTOR inhibitors have been found to prolong progression-free survival in renal cell cancer and hormone receptor-positive breast cancer, and Evl has been approved by FDA to be used in combination with other agents.[5] Similar observations in kidney transplant recipients, have spurred the use of mTOR inhibitors in patients with posttransplant malignancies, including lymphoproliferative disorders, skin, and visceral malignancies. The dosing strategy of Evl, however, is different in patients on cancer chemotherapy, where a fixed dose of 10 mg/day is used, compared to the much lower starting dose of 0.5–0.75 mg twice a day in transplant recipients (along with trough concentration monitoring).\n\nNephrotoxicity of mTOR inhibitors has been described very rarely, outside of transplant literature. The mechanism of mTOR inhibitor-associated nephrotoxicity is thought to involve impaired recovery of injured tubular epithelial cells (in delayed graft function and ATN), endothelial cells (thrombotic microangiopathies and glomerulonephritis), and mesangial cells (glomerulonephritis). The impaired cellular regeneration and proapoptotic effect of sirolimus and Evl, is secondary to inhibition of the FKBP12-rapamycin associated protein kinase or mTOR, which is crucial in G1 to S cell-cycle transition. In addition to proteinuric effect, mTOR inhibitors exacerbate proteinuria-mediated tubular toxicity.[7] In 2014, Ha et al. published an observational study, in which they noted 14.2% incidence of AKI with Evl administration, almost exclusively in patients with RCC.[2] They observed that deterioration of renal function was associated with underlying CKD (multivariate analysis showed 0.7-fold decreased risk of AKI with 10 ml/m2/min rise in eGFR). Recently, Evl has been approved for use in hormone receptor-positive HER2/neu negative advanced breast cancer with secondary hormone resistance, following encouraging results from the BOLERO-2 trial. However, unlike in RCC, only one case of Evl-related nephrotoxicity has been published so far. Donders et al. described a patient of ER-positive metastatic breast cancer on exemestane and Evl, who developed dialysis-requiring renal failure after 4 weeks of therapy, accompanied by persistent diarrhea, and documented hypotension.[4] Another possible confounding factor in their patient was the concomitant use of simvastatin, which could have led to reciprocal increase in drug levels of both Evl and simvastatin. While the first patient had history of vomiting, which could have led to dehydration, the second patient had no clear inciting factors leading to AKI. It is possible that the eGFR by CKD-EPI equation was an overestimation of renal function, thereby placing these patients at risk of AKI. However, both the index patients were concomitantly receiving an aromatase inhibitor (exemestane in the first case and anastrozole in the second case) and zoledronic acid. Both exemestane and anastrozole are not eliminated by the kidney, and no dose modifications are prescribed in renal failure. While renal failure has not been reported with exemestane, it has rarely been reported with anastrozole, having been associated with glomerular injury in two published case reports, so far (one case of sclerosing glomerulonephritis, and another case of crescentic glomerulonephritis).[89] Zoledronate, on the other hand, has been commonly associated with AKI, histologically ATN.[10] Risk factors for zoledronate nephrotoxicity include older age, chronic kidney disease at baseline, previous bisphosphonate use, higher doses, shorter infusion time, and increased dosing frequency. While it is unlikely that the index patient had anastrozole-induced nephrotoxicity (no clinical and laboratory evidence of glomerular involvement as well as in the renal biopsy), contribution of zoledronate to the renal failure cannot be totally ruled out. It can be argued that both the patients had received zoledronate for many months before the onset of renal failure (3 months in the first case and 11 months in the second case), and that the rise in S. Cr correlated temporally with the administration of Evl. One purported mechanism of Evl nephrotoxicity in our patients is that zoledronate had probably caused subclinical renal tubular injury, which was exacerbated by Evl administration, as mTORi may have delayed repair and regeneration of tubular cells, leading to ATN. Similar to our patients, two of the four cancer patients with mTOR inhibitor nephrotoxicity described in the biopsy case series by Izzedine et al. were on concomitant zoledronate therapy though none of their patients had breast cancer.[3] Similar to Izzedine et al., the biopsy in our patient also showed ATN, and to the best of our knowledge, this is the first reported biopsy of Evl toxicity in a patient with advanced breast cancer.\n\nConclusion\nEvl, an mTOR inhibitor with antitumor activity in breast cancer can cause AKI, histologically characterized by ATN. Renal failure usually responds to stoppage of drug and supportive management. Nephrologists and oncologists must be aware of this potential complication and must be cautious while using Evl, especially in combination with zoledronate. In additon, consideration must be given to testing efficacy of lower doses of Evl for antitumor activity and drug concentration monitoring to avoid nephrotoxicity.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Baselga J Campone M Piccart M Burris HA 3rd Rugo HS Sahmoud T Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer N Engl J Med 2012 366 520 9 22149876 \n2 Ha SH Park JH Jang HR Huh W Lim HY Kim YG Increased risk of everolimus-associated acute kidney injury in cancer patients with impaired kidney function BMC Cancer 2014 14 906 25466872 \n3 Izzedine H Escudier B Rouvier P Gueutin V Varga A Bahleda R Acute tubular necrosis associated with mTOR inhibitor therapy: A real entity biopsy-proven Ann Oncol 2013 24 2421 5 23798615 \n4 Donders F Kuypers D Wolter P Neven P Everolimus in acute kidney injury in a patient with breast cancer: A case report J Med Case Rep 2014 8 386 25420955 \n5 Seto B Rapamycin and mTOR: A serendipitous discovery and implications for breast cancer Clin Transl Med 2012 1 29 23369283 \n6 Pascual J Everolimus in clinical practice – Renal transplantation Nephrol Dial Transplant 2006 21 Suppl 3 iii18 23 16815852 \n7 Marti HP Frey FJ Nephrotoxicity of rapamycin: An emerging problem in clinical medicine Nephrol Dial Transplant 2005 20 13 5 15632347 \n8 Kalender ME Sevinc A Camci C Turk HM Karakok M Akgul B Anastrozole-associated sclerosing glomerulonephritis in a patient with breast cancer Oncology 2007 73 415 8 18515982 \n9 Yoshimoto S Nakatani K Maruyama N Fujiki K Nakano T Ueshima K A case of crescentic glomerulonephritis developed under oral anastrozole treatment Gan To Kagaku Ryoho 2013 40 267 70 23411970 \n10 Perazella MA Markowitz GS Bisphosphonate nephrotoxicity Kidney Int 2008 74 1385 93 18685574\n\n",
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"abstract": "A 74-year-old man with diabetes mellitus since 64 years of age had been treated with glimepiride, metformin and alogliptin; however, his glycemic control remained poor, i.e., a casual blood glucose level of 318 mg/dl, HbA1c level of 10.6% and glycated albumin level of 24.9%. Although his blood glucose level improved with intensive insulin therapy, he exhibited dementia with an MMSE score of 9/30 and was unable to continue insulin injections by himself, thus rejecting his family's help. The extended-release form of the GLP-1 agonist exenatide (Bydureon(®)) was recently introduced in Japan. This new anti-diabetic agent enables the administration of once-weekly type 2 diabetes treatment that delivers a continuous dose of exenatide in a single weekly injection. We employed weekly exenatide therapy in combination with oral hypoglycemic agents in this case. The patient visited our outpatient clinic for injections every week, showing a remarkable improvement in his HbA1c level, from 10.7% to 7.1% in five months. Subcutaneous induration was the only side effect of weekly exenatide injection. Weekly exenatide therapy can be easily managed by other caregivers and is expected to be a useful treatment approach in elderly diabetic patients with dementia.",
"affiliations": "Department of Endocrinology and Metabolism, Kanto Central Hospital.",
"authors": "Maruyama|Satoko|S|;Tsurutani|Yuya|Y|;Kondo|Mai|M|;Sagawa|Naoko|N|;Sata|Akira|A|;Miyao|Mariko|M|;Mizuno|Yuzo|Y|",
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"title": "A case of an elderly diabetic patient with dementia effectively treated with weekly exenatide.",
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"abstract": "BACKGROUND\nPlasmablastic lymphoma is an aggressive variant of diffuse large B cell lymphoma, mostly found in the oral cavity and associated with human immunodeficiency virus. There are no clear guidelines for its treatment. Therapies more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone are not associated with a prolonged survival. Lymphomas of the breast are rare, in one series representing 0.14% of all female breast malignancies, with diffuse large B cell lymphoma comprising up to 55% of all cases. Only one case of plasmablastic lymphoma involving the breast has been reported in the literature.\n\n\nMETHODS\nA 30 year old Pakistani woman, presented with a small nodule in the floor of the mouth. An excisional biopsy revealed CD20, CD3, and CD117 negative and CD138, CD79a, CD56, MUM1/IFR4 and CD30 positive lesion with Ki-67 of 60% with cells which were plasmablastic in appearance. The morphological and immunohistochemistry features were consistent with plasmablastic lymphoma. The staging scans did not reveal any lymphadenopathy and the bone marrow biopsy and human immunodeficiency virus test were both negative. After treatment with four courses of CHOP and later radiation to the floor of the mouth, her disease was in complete remission. Two months later, she presented with velvety red lesions in both breasts and its trucut biopsy was consistent with plasmablastic lymphoma. Her CT scans revealed multiple nodules involving both breasts with no lymphadenopathy. The bone marrow was now positive for disease. Her disease continued to progress despite second and third line chemotherapy with DHAP (dexamethasone, cisplatin and cytarabine) and ICE (ifosfamide, carboplatin and etoposide) respectively. Her last CT scans revealed progressive disease with new lung lesions. The patient decided to opt for best supportive care.\n\n\nCONCLUSIONS\nTo our knowledge this is the second report of plasmablastic lymphoma involving the breast. The patient who was human immunodeficiency virus negative and immune competent had progressive disease despite three lines of chemotherapies with an overall survival (to date) of 15 months.",
"affiliations": "Department of Oncology, The Aga Khan University Hospital, Stadium Road, PO BOX: 3500, Karachi, 74800, Pakistan. zarka.samoon@aku.edu.;Department of Pathology, The Aga Khan University Hospital, Stadium Road, PO BOX: 3500, Karachi, 74800, Pakistan. romana.idrees@aku.edu.;Department of Oncology, The Aga Khan University Hospital, Stadium Road, PO BOX: 3500, Karachi, 74800, Pakistan. nehal.masood@aku.edu.;Department of Oncology, The Aga Khan University Hospital, Stadium Road, PO BOX: 3500, Karachi, 74800, Pakistan. tayyaba.ansari@aku.edu.",
"authors": "Samoon|Zarka|Z|;Idrees|Romana|R|;Masood|Nehal|N|;Ansari|Tayyaba Zehra|TZ|",
"chemical_list": "D051925:CD79 Antigens; D053668:Syndecan-1",
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"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 25933603113210.1186/s13104-015-1132-xCase ReportPlasmablastic lymphoma of the oral cavity with breast recurrence: a case report Samoon Zarka zarka.samoon@aku.edu Idrees Romana romana.idrees@aku.edu Masood Nehal nehal.masood@aku.edu Ansari Tayyaba Zehra tayyaba.ansari@aku.edu Department of Oncology, The Aga Khan University Hospital, Stadium Road, PO BOX: 3500, Karachi, 74800 Pakistan Department of Pathology, The Aga Khan University Hospital, Stadium Road, PO BOX: 3500, Karachi, 74800 Pakistan 2 5 2015 2 5 2015 2015 8 1806 4 2014 22 4 2015 © Samoon et al.; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPlasmablastic lymphoma is an aggressive variant of diffuse large B cell lymphoma, mostly found in the oral cavity and associated with human immunodeficiency virus. There are no clear guidelines for its treatment. Therapies more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone are not associated with a prolonged survival. Lymphomas of the breast are rare, in one series representing 0.14% of all female breast malignancies, with diffuse large B cell lymphoma comprising up to 55% of all cases. Only one case of plasmablastic lymphoma involving the breast has been reported in the literature.\n\nCase presentation\nA 30 year old Pakistani woman, presented with a small nodule in the floor of the mouth. An excisional biopsy revealed CD20, CD3, and CD117 negative and CD138, CD79a, CD56, MUM1/IFR4 and CD30 positive lesion with Ki-67 of 60% with cells which were plasmablastic in appearance. The morphological and immunohistochemistry features were consistent with plasmablastic lymphoma. The staging scans did not reveal any lymphadenopathy and the bone marrow biopsy and human immunodeficiency virus test were both negative. After treatment with four courses of CHOP and later radiation to the floor of the mouth, her disease was in complete remission. Two months later, she presented with velvety red lesions in both breasts and its trucut biopsy was consistent with plasmablastic lymphoma. Her CT scans revealed multiple nodules involving both breasts with no lymphadenopathy. The bone marrow was now positive for disease. Her disease continued to progress despite second and third line chemotherapy with DHAP (dexamethasone, cisplatin and cytarabine) and ICE (ifosfamide, carboplatin and etoposide) respectively. Her last CT scans revealed progressive disease with new lung lesions. The patient decided to opt for best supportive care.\n\nConclusion\nTo our knowledge this is the second report of plasmablastic lymphoma involving the breast. The patient who was human immunodeficiency virus negative and immune competent had progressive disease despite three lines of chemotherapies with an overall survival (to date) of 15 months.\n\nKeywords\nPlasmablastic lymphomaBreastTreatmentissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPlasmablastic lymphoma (PBL) is a rare variant of Diffuse large B cell lymphoma, mostly found in the oral cavity [1] and associated with human immunodeficiency virus (HIV). Other rare sites of its occurrence include oropharynx, nasopharynx, stomach, skin, lungs, sacrococcygeal, pericardial, anorectal, nasal, paranasal or submandibular regions [2]. Lymphoma of the breast is a rare entity; representing 0.14% of all female breast malignancies [3]. However, amongst the breast lymphomas, the most common type is diffuse large B cell lymphoma involving up to 55% of all cases. This subtype usually occurs in women of older age, with slight predominance of right side [3]. Other rare types of lymphomas to involve the breast are Burkitt’s lymphoma, Extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) type, follicular lymphoma, and very rarely, T-cell lymphomas. Lymphomas involving the breast are very rare, yet very aggressive. Hence they need to be treated with combination chemotherapy with or without local irradiation. In case of progression or relapse, the response to salvage therapy is poor [3].\n\nHerein, we present a case of a 30 year old HIV-negative immunocompetent woman, who presented with a nodule in the floor of the mouth. A histopathological diagnosis of PBL was made and she was treated with chemotherapy followed by local radiation. She later presented with disease relapse in the breast. To our knowledge this is the second report of PBL involving the breast [4].\n\nCase presentation\nA 30 year old Pakistani woman, presented with few weeks history of dysphagia. Clinically she was well preserved and examination revealed small firm 1 cm nodule on the floor of the mouth. The excisional biopsy thus performed revealed neoplastic cells, which were arranged in diffuse sheets and were plasmablastic in appearance with vesicular nuclei, and centrally located prominent nucleolus, with abundant basophilic cytoplasm (Figure 1). On immunohistochemistry these plasmacytoid cells were negative for conventional B cell marker CD20 while pan T CD 3 was also negative. These cells showed strong positivity for CD138, CD79a, CD56, and MUM1/IFR4 with Ki-67 of approximately 60% (Figures 2, 3 and 4). The morphological and immunohistochemistry features were consistent with PBL. The rest of her systemic examination was unremarkable. The CT scan of head, neck, chest, abdomen and pelvis with contrast did not reveal any lymphadenopathy and the bone marrow biopsy was negative for disease. Patient was tested to be negative for HIV. She did not have any other condition which could compromise her immunity. Her last pregnancy was about eight years back. She was treated with standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy. She had no evidence of disease at the time of initiation of chemotherapy and remained in remission after 4 courses of CHOP; hence, treatment was consolidated with local radiation. Two months later, she presented with self-discovered lumps in both breasts. It was not associated with pain or nipple discharge. Examination revealed diffuse erythema of the skin of both breasts with peau-d-orange and velvety red lesions. The rest of her systemic examination was unremarkable. She did not have any high risk features for breast cancer such as history of oral contraceptive usage, personal or family history of breast cancer. A trucut biopsy of the breast lesions was consistent with the prior diagnosis of plasmablastic lymphoma (Figure 5). Her CT scans of head, neck, chest, abdomen and pelvis with contrast revealed multiple rounded soft tissue density nodules involving both breasts with no lymphadenopathy. The bone marrow was now positive for disease and was weakly positive for CD56. She received four courses of DHAP (dexamethasone, cisplatin and cytarabine). She had good clinical and radiological response to chemotherapy initially however by the end of four courses, her breast lesions recurred. She was then switched to third line chemotherapy with ICE (ifosfamide, cyclophosphamide and etoposide). Her breast lesions initially regressed but grew before next cycle of chemotherapy in 2 weeks’ time. Her CT scans of head, neck, chest, abdomen and pelvis with contrast revealed progressive disease with increase in the number of breast lesions with new development of pleural effusion and multiple lung nodules bilaterally. Further treatment options were discussed but considering futility of treatment only best supportive care was pursued and she went back to her native town.Figure 1 H&E (hematoxylin and eosin) image shows large sheets of mostly large plasmacytoid appearing mononuclear cells.\n\nFigure 2 CD79a, immunohistochemical stain demonstrates plasmacytic differentiation.\n\nFigure 3 CD138, immunohistochemical stain demonstrates plasmacytic differentiation.\n\nFigure 4 MUM1/IRF4 shows positivity in neoplastic cells.\n\nFigure 5 Breast biopsy shows involvement by plasmablastic lymphoma.\n\n\n\nDiscussion\nPlasmablastic lymphoma is usually associated with HIV infection, where it accounts for 2.6% of all HIV related Non-Hodgkin’s lymphomas [5]. However it may be present in patients who are HIV negative but otherwise immunocompromised, such as patients who have undergone solid organ transplantation or bone marrow transplantation or those with autoimmune disease [2]. It was in 1997 when Delecluse and colleagues reported the first series of sixteen patients with diffuse large B cell lymphoma of oral cavity with unique immunohistochemical features [6]. Based on their morphologic and immunohistologic features these tumors were named plasmablastic lymphoma [6]. PBL is said to be derived from post germinal-center activated B cells, which are terminally differentiated, believed to be in evolution from immunoblast to plasma cell [7]. PBL reveal little to no expression of leukocyte common antigen (CD45) or the B-cell markers CD20 and CD79a. However, there is almost unanimous expression of plasma cell markers VS38c, CD38, multiple myeloma oncogene-1 (MUM1/IRF4), and CD138 (syndecan-1) [8].\n\nPlasmablastic lymphoma has a very aggressive clinical course with a median overall survival of about fifteen months [8]. There are no clear guidelines for its treatment. Therapies more intensive than CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) are not associated with a prolonged survival [9]. There are several features associated with better survival, which include the clinical stage, use of antiretroviral therapy (in HIV patients) and achievement of complete response to chemotherapy [9]. Autologous stem cell transplantation has been tried in such patients however the follow up data has been too short to conclude it being effective [10]. Bortezomib, a proteasome inhibitor may be a new therapeutic option for plasmablastic lymphoma, which has resulted in dramatic responses, however, the response has not been sustained [11].\n\nConclusion\nIn conclusion we report a case of plasmablastic lymphoma of the breast which initially presented with a hard palate lesion. Our case was unique in presentation that there was no evidence of disease after excisional biopsy of hard palate and at recurrence breast was the only site. Later however she also developed bilateral lung nodules and pleural effusion. To our knowledge this is the second reported case of PBL involving the breast [4] and the first case report of how PBL of the breast was treated.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCHOPCyclophosphamide, Doxorubicin, Vincristine and Prednisolone\n\nDHAPDexamethasone, cisplatin and cytarabine\n\nHIVHuman immunodeficiency virus\n\nICEIfosfamide, carboplatin and etoposide\n\nPBLPlasmablastic lymphoma\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nZS did the literature search and drafted the manuscript. TZA conceived the case report and helped in drafting the manuscript. RI provided the histopathological images in addition to providing guidance for the drafting of the manuscript. NM helped in reviewing the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe would like to thank Dr. Yasmin Abdul Rashid who provided important intellectual input during the drafting phase of the manuscript.\n\nThe authors did not receive any research support for this manuscript and do not have any financial disclosures to make.\n==== Refs\nReferences\n1. Choi SY Cho YA Hong SD Lee JI Hong SP Yoon HJ Plasmablastic lymphoma of the oral cavity in a human immunodeficiency virus-negative patient: a case report with literature review Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2014 117 2 e115 20 10.1016/j.oooo.2013.04.017 \n2. Scheper MA Nikitakis NG Fernandes R Gocke CD Ord RA Sauk JJ Oral plasmablastic lymphoma in an HIV-negative patient: a case report and review of the literature Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005 100 2 198 206 10.1016/j.tripleo.2004.11.050 16037778 \n3. Kuper-Hommel MJ Snijder S Janssen-Heijnen ML Vrints LW Kluin-Nelemans JC Coebergh JW Treatment and survival of 38 female breast lymphomas: a population-based study with clinical and pathological reviews Ann Hematol 2003 82 7 397 404 10.1007/s00277-003-0664-7 12764549 \n4. Wang J Hernandez OJ Sen F Plasmablastic lymphoma involving breast: a case diagnosed by fine-needle aspiration and core needle biopsy Diagn Cytopathol 2008 36 4 257 61 10.1002/dc.20784 18335555 \n5. Folk GS Abbondanzo SL Childers EL Foss RD Plasmablastic lymphoma: a clinicopathologic correlation Ann Diagn Pathol 2006 10 1 8 12 10.1016/j.anndiagpath.2005.07.009 16414538 \n6. Delecluse HJ Anagnostopoulos I Dallenbach F Hummel M Marafioti T Schneider U Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection Blood 1997 89 4 1413 20 9028965 \n7. Castillo JJ Reagan JL Plasmablastic lymphoma: a systematic review Sci World J 2011 11 687 96 10.1100/tsw.2011.59 \n8. Castillo J Pantanowitz L Dezube BJ HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases Am J Hematol 2008 83 10 804 9 10.1002/ajh.21250 18756521 \n9. Castillo JJ Winer ES Stachurski D Perez K Jabbour M Milani C Prognostic factors in chemotherapy-treated patients with HIV-associated Plasmablastic lymphoma Oncologist 2010 15 3 293 9 10.1634/theoncologist.2009-0304 20167839 \n10. Goto H Hagiwara S Hirai R Miyama T Honda H Tagashira A Case of relapsed AIDS-related plasmablastic lymphoma treated with autologous stem cell transplantation and highly active antiretroviral therapy Rare Tumors 2011 3 1 e11 10.4081/rt.2011.e11 21464873 \n11. Saba NS Dang D Saba J Cao C Janbain M Maalouf B Bortezomib in plasmablastic lymphoma: a case report and review of the literature Onkologie 2013 36 5 287 91 10.1159/000350325 23689224\n\n",
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"mesh_terms": "D000328:Adult; D001706:Biopsy; D001940:Breast; D001943:Breast Neoplasms; D051925:CD79 Antigens; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009055:Mouth; D009062:Mouth Neoplasms; D009364:Neoplasm Recurrence, Local; D000069293:Plasmablastic Lymphoma; D053668:Syndecan-1",
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"title": "Plasmablastic lymphoma of the oral cavity with breast recurrence: a case report.",
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"abstract": "Early relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an often unsuccessful therapeutic challenge. Since treatment options are few and efficacy is low, new approaches such as de novo allo-HSCT, targeted therapies and biomodulatory drugs have been developed, albeit prognosis is very poor. In this manuscript we present an unusual case of a patient with high-risk AML with an unbalanced jumping translocation and FLT3-TKD (low) mutation who presented with early relapse (FLT3 negative) after allo-HSCT, refractory to one cycle of azacytidine and discontinuation of immunosuppression (IS). As salvage therapy, the patient received a biomodulatory therapy consisting of low-dose azacytidine 75 mg/day (given s.c. d1-7 of 28), pioglitazone 45 mg/day orally, and all-trans-retinoic acid (ATRA) 45 mg/m2/day orally achieving a complete remission after two cycles of therapy. Even after cessation of treatment after 5 cycles, the patient remained in complete remission with full chimerism in peripheral blood and bone marrow for another 7 months. In conclusion, we report about an unusual case of long-lasting complete remission of early relapsed high-risk AML after allo-HSCT treated with azacytidine, pioglitazone and ATRA after standard of care treatment with HMA and discontinuation of IS failed.",
"affiliations": "Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany.",
"authors": "Kattner|Anna-Sophia|AS|;Holler|Ernst|E|;Herr|Wolfgang|W|;Reichle|Albrecht|A|;Wolff|Daniel|D|;Heudobler|Daniel|D|",
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"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00443\nOncology\nCase Report\nSuccessful Treatment of Early Relapsed High-Risk AML After Allogeneic Hematopoietic Stem Cell Transplantation With Biomodulatory Therapy\nKattner Anna-Sophia Holler Ernst Herr Wolfgang Reichle Albrecht Wolff Daniel Heudobler Daniel * Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany\nEdited by: Alfonso Pompella, University of Pisa, Italy\n\nReviewed by: Maria Christina Cox, Azienda Ospedaliera Sant'Andrea, Italy; Persio Dello Sbarba, University of Florence, Italy\n\n*Correspondence: Daniel Heudobler daniel.heudobler@ukr.deThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology\n\n\n23 4 2020 \n2020 \n10 44330 11 2019 12 3 2020 Copyright © 2020 Kattner, Holler, Herr, Reichle, Wolff and Heudobler.2020Kattner, Holler, Herr, Reichle, Wolff and HeudoblerThis 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.Early relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an often unsuccessful therapeutic challenge. Since treatment options are few and efficacy is low, new approaches such as de novo allo-HSCT, targeted therapies and biomodulatory drugs have been developed, albeit prognosis is very poor. In this manuscript we present an unusual case of a patient with high-risk AML with an unbalanced jumping translocation and FLT3-TKD (low) mutation who presented with early relapse (FLT3 negative) after allo-HSCT, refractory to one cycle of azacytidine and discontinuation of immunosuppression (IS). As salvage therapy, the patient received a biomodulatory therapy consisting of low-dose azacytidine 75 mg/day (given s.c. d1–7 of 28), pioglitazone 45 mg/day orally, and all-trans-retinoic acid (ATRA) 45 mg/m2/day orally achieving a complete remission after two cycles of therapy. Even after cessation of treatment after 5 cycles, the patient remained in complete remission with full chimerism in peripheral blood and bone marrow for another 7 months. In conclusion, we report about an unusual case of long-lasting complete remission of early relapsed high-risk AML after allo-HSCT treated with azacytidine, pioglitazone and ATRA after standard of care treatment with HMA and discontinuation of IS failed.\n\nacute myeloid leukemiarelapseallogeneic stem cell transplantationbiomodulatory treatmentanakoinosis\n==== Body\nIntroduction\nRelapse of AML, especially after allo-HSCT is difficult to treat as there are few therapeutic options promising sustained effects. Long-term survival in transplanted patients with AML relapse has been described as low as 10%. Aspects such as FMS-like tyrosine kinase 3 (FLT3) mutations or failure to respond to the first induction cycle, as was the case presented here, are adverse risk factors for relapse and outcome (1). FLT3 is a ligand-activated receptor tyrosine kinase expressed mainly in hematopoietic stem and progenitor cells (2). FLT3-TKD (tyrosine kinase domain) mutations, also present in our patient, are mostly point mutations in codons D835 and I836 leading to constitutive tyrosine phosphorylation with subsequent activation of FLT3 which leads to cell proliferation and is associated with poor prognosis (3–6). In FLT3-ITD (internal tandem duplication) mutated AML patients, low mutant-to-wildtype allelic ratio is associated with better overall survival (OS) compared to patients with high mutant-to-wildtype allelic ratio (7). However, less is known about TKD mutations. Their impact on survival does not seem as significant at this point (8, 9). Relapse within 6 months after allo-HSCT and high blast count in bone marrow are further risk factors for worse outcome (10). Established therapy regimens include hypomethylating agents (HMA) (11), discontinuation of IS and donor lymphocyte infusion (DLI) (12) as early preemptive or molecular recurrence treatment options while in cases of hematologic relapse, chemotherapy (13) and DLI are therapeutic options (14). In case of FLT3-ITD mutation, tyrosine kinase inhibitors (TKI) are a promising option leading to longterm survival in some patients (15). This sustained response was explained by an increase in IL15 production by AML cells acting synergistically in combination with allogeneic CD8+ T cell response in a mouse model of FLT3-ITD mutated AML (16). However, in case the mutation is lost during relapse, it is unclear whether these effects of TKI remain and generally speaking, data is limited at this point. Therefore, other therapeutic options are needed to further improve prognosis of relapsed patients after allo-HSCT. At our center, a biomodulatory regimen was developed showing efficacy in patients with refractory/relapsed AML (without allo-HSCT) in small case studies (17, 18) as well as an ongoing prospective randomized clinical trial (AMLSG26-16/AML-ViVA) (19). The biomodulatory regimen (termed APA) consists of low-dose azacytidine 75 mg/day (given s.c. d1–7 of 28), pioglitazone 45 mg/day orally, and all-trans-retinoic acid (ATRA) 45 mg/m2/day orally. In vitro experiments showed that the biomodulatory combination leads to a differentiation of AML blasts into neutrophil like cells capable of production of reactive oxygen species and phagocytosis (20), especially in relapsed/refractory AML patients with FLT3-ITD mutations. However, this is the first report on APA treatment of a patient that relapsed with high-risk AML (within 3 months) after allogeneic hematopoietic stem cell transplantation.\n\nCase Presentation\nThe 55-year old female patient first presented with increased tendency to bleed and respiratory infection. Past medical history consisted of pulmonary emphysema associated with smoking (40 pack years), allergy to ciprofloxacin and osteopenia. Peripheral blood count on admittance to our hospital showed pancytopenia with absolute neutropenia (0/nl) and myeloid blasts. Cytomorphology and flow cytometry confirmed bone marrow infiltration by AML (FAB M1) blasts in 42% of nucleated cells. Cytogenetic analysis revealed an unbalanced jumping translocation, a cytogenetic aberration where one chromosome segment has fused with two or more other chromosomes, associated with poor response to HMA and chemotherapy as well as poor survival (21). Molecular genetic testing diagnosed a FLT3-TKD low (low mutant-to-wildtype allelic ratio <0.5) mutation. The first induction cycle (cytarabine and daunorubicine 7 + 3 day schedule) failed to induce remission. Therefore, the 2nd induction cycle was changed to a high-dose cytarabine and mitoxantrone (HAM) regimen in combination with midostaurin (a FLT3 inhibitor) which has been shown to improve OS and event free survival (EFS) in FLT3-mutated AML patients in combination with chemotherapy (22). The following bone marrow aspirate detected minimal residual disease (MRD) with incomplete regeneration creating an adverse risk situation. The patient therefore proceeded to receive an allo-HSCT from a DQB1-mismatched unrelated donor with fludarabine, thiotepa, and busulfan as conditioning regimen. On day 30 post-transplant, complete remission was confirmed by bone marrow aspirate (with 100% chimerism). Signs of mild acute skin and gastrointestinal GvHD (which began day 53 post-transplant) were treated topically and with prednisolone (2.4 mg/kg/d) systemically. Signs of gastrointestinal GvHD ceased quickly and IS was reduced. Within routine follow-up bone marrow aspirate on day 89 after allo-HSCT, relapse of AML was diagnosed with an infiltration rate of 10% myeloid blasts in cytomorphological work-up (Figures 1A,D), which was confirmed by flow cytometry and chimerism analysis. The genetic work-up now showed a loss of the previously present FLT3-TKD mutation, which is known to happen in about 7% of patients with relapsed AML (23). As salvage therapy, the first cycle of azacytidine (75 mg/m2/d s.c. for days 1–7 q4w) was begun and concurrently, as there were no signs of GvHD, IS with prednisolone and cyclosporine were reduced and discontinued by day 105 post allo-HSCT. Despite discontinuation of IS, myeloid blasts in the peripheral blood further increased and GvHD remained absent. Infection during leucopenia was antibiotically treated with ciprofloxacin. An effort to increase leucocyte count by filgastrim (GCSF-support) was unsuccessful and due to thrombocytopenia, platelet transfusions became necessary. Two weeks after initiation of ciprofloxacin, the patient developed a maculopapular skin rash, treated with topical ointments. Whether this was a GvHD equivalent or an allergic reaction to ciprofloxacin was unclear. Sustained pancytopenia seemed suspicious for refractory disease, which was confirmed by bone marrow aspirate with ~50% blasts in cytomorphology and chimerism of 45.5% (Figures 1B,E). Therefore, the therapeutic regimen was altered to the biomodulatory treatment (APA) described above although ATRA dosage soon had to be reduced due to headaches. Within 3 weeks, the chimerism increased to 99.6% (considered full chimerism) and AML blasts had completely disappeared in the peripheral blood. The first APA cycle was complicated by urosepsis with Staphylococcus epidermidis, which was successfully treated with oral amoxicillin/clavulanic acid in an outpatient setting. After complete remission of infectious signs and symptoms and sustained absence of blasts in peripheral blood, the second cycle of APA was administered. During the second cycle, chronic GvHD (cGvHD) progressed with additional ocular (grade 1) involvement, treated with topical agents only. Response assessment via bone marrow aspirate after the second cycle again demonstrated complete remission in cytomorphology (Figures 1C,F) and flow cytometry. Because FLT3 mutation was lost at relapse, there was no MRD marker for molecular genetic analysis. However, chimerisms were 99.3 and 100% in bone marrow and peripheral blood, respectively, confirming complete remission. During the subsequent APA cycles, cGvHD remained unchanged with mild skin, oral and eye involvement. Treatment with APA was discontinued after 5 cycles due to sustained complete remission (validated by another bone marrow aspirate analysis) and patient wish. Unfortunately, almost 7 months after discontinuation of APA therapy, relapse of AML was diagnosed. Pancytopenia, increment in lactate dehydrogenase (LDH) and plummeting of chimerism had developed within 3 weeks, suggesting fast kinetics. Subsequently, a salvage therapy with azacytidine in combination with venetoclax was administered but unfortunately failed to induce a remission.\n\nFigure 1 Cytomorphology of bone marrow aspirates (A–C depict an overview of the slide; D–F show the cells at greater magnification; objective 63x). (A,D) Show a hypoplastic bone marrow after stem cell transplantation with up to 10% myeloblasts (marked by an arrow) resembling early relapse after allo-HSCT. Leukemic blasts display a basophilic cytoplasm frequently containing vacuoles. (B,E) (after one cycle of AZA) demonstrate a hypercellular marrow with ~50% of the previously described leukemic blasts (progressive disease). (C,F) (after two cycles of APA) show a normocellular marrow with an increased and left-shifted erythropoiesis, differentiated neutrophils and no evidence of an increased percentage of myeloblasts resembling complete remission.\n\nDiscussion and Conclusion\nThe biomodulatory combination therapy with AZA, ATRA, and PGZ rapidly lead to a complete remission in this high-risk AML patient with very poor prognosis after having had AML relapse within 3 months of allo-HSCT and failing therapy with HMA. In line with previous data, a complete response as well as cytomorphologic signs of differentiation were observed after only two cycles of therapy taking into account that the patient simultaneously developed cGvHD, which has been associated with a graft-vs.-leukemia effect. In this context, biomodulatory therapy might act synergistically with graft-vs.-leukemia (GvL) effect since differentiation of blasts may lead to (over)expression of antigens like proteinase 3 and other azurophil granule proteins which serve as targets for both autologous and allogeneic T-cell responses (24, 25). Induction of an interferon response as well as the up-regulation of major histocompatibility class-I (MHC-I) genes by DNA methyltransferase inhibition by azacytidine might further enhance the T-cell response (26, 27). Therefore, therapy with APA seems a promising option, especially for high-risk patients with poor prognosis and few therapeutic alternatives, even after allo-HSCT. To our knowledge this is the first report to show efficacy of this biomodulatory therapy in the post allo-HSCT setting. APA is currently being investigated within a prospective, randomized, clinical trial (AMLSG26-16/AML-ViVA, EudraCT number 2016-000421-39, ClinicalTrials.gov Identifier: NCT02942758).\n\nMethods\nAll follow-up genetic analyses (molecular genetic testing of FLT3-TKD low) have been performed within clinical routine diagnostics at MLL (Munich Leukemia Laboratory, Munich, Germany).\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nA-SK, DW, EH, WH, and AR treated the patient. A-SK and DH wrote the manuscript. All authors revised the manuscript critically, approved the final manuscript, and agreed to be accountable for all aspects of the manuscript.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Candoni A de Marchi F Zannier ME Lazzarotto D Filì C Dubbini MV . High prognostic value of pre-allogeneic stem cell transplantation minimal residual disease detection by WT1 gene expression in AML transplanted in cytologic complete remission\n. Leukemia Res. (2017 ) 63 :22 –7\n. 10.1016/j.leukres.2017.10.010 29096332 \n2. Grafone T Palmisano M Nicci C Storti S . An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment\n. Oncol Rev. (2012 ) 6 :e8 . 10.4081/oncol.2012.e8 25992210 \n3. Abu-Duhier FM Goodeve AC Wilson GA Care RS Peake IR Reilly JT . 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"references": "21886171;20699125;12394172;17965322;29055209;30658222;20670134;12200377;30542286;27026249;12551822;30651634;26141213;30483125;29096332;22167752;11290608;27895058;11442493;29431743;29339738;12036858;26317466;28644114;25992210;25261094",
"title": "Successful Treatment of Early Relapsed High-Risk AML After Allogeneic Hematopoietic Stem Cell Transplantation With Biomodulatory Therapy.",
"title_normalized": "successful treatment of early relapsed high risk aml after allogeneic hematopoietic stem cell transplantation with biomodulatory therapy"
} | [
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"abstract": "BACKGROUND\nTrastuzumab + chemotherapy is considered the standard therapy for advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer with mild manageable toxicity, on the basis of the results of a pivotal phase-III trial. Cerebrovascular events are not recognized as expected adverse effects of such therapy.\n\n\nMETHODS\nWe report the case of a 67-year-old, current-smoking male with stage-IV HER2-positive gastric cancer who suffered right middle cerebral artery (MCA) embolism after trastuzumab + chemotherapy. He received trastuzumab and cisplatin on Day 1, followed by a continuous 5-fluorouracil infusion for 5 days as a first-line treatment. Four days after chemotherapy initiation, he presented with left hemiplegia, and brain magnetic resonance imaging and magnetic resonance angiography revealed a right MCA occlusion. No further chemotherapy was administered because of worsening performance status.\n\n\nCONCLUSIONS\nThe present case, possibly the first such reported case, suggests the risk of development of embolism after trastuzumab + chemotherapy in HER2-positive advanced gastric cancer, although other factors should be considered.",
"affiliations": "Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. takahama_t@dotd.med.kindai.ac.jp.;Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. takedamasa2004@yahoo.co.jp.;Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. shin12470123@yahoo.co.jp.;Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. nakagawa@med.kindai.ac.jp.",
"authors": "Takahama|Takayuki|T|;Takeda|Masayuki|M|;Nishina|Shinichi|S|;Nakagawa|Kazuhiko|K|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D002945:Cisplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/s13104-015-1059-2",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 105910.1186/s13104-015-1059-2Case ReportA case of severe cerebral embolism after chemotherapy for HER2-positive gastric cancer Takahama Takayuki takahama_t@dotd.med.kindai.ac.jp Takeda Masayuki takedamasa2004@yahoo.co.jp Nishina Shinichi shin12470123@yahoo.co.jp Nakagawa Kazuhiko nakagawa@med.kindai.ac.jp Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511 Japan 26 3 2015 26 3 2015 2015 8 1004 2 2015 17 3 2015 © Takahama et al.; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTrastuzumab + chemotherapy is considered the standard therapy for advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer with mild manageable toxicity, on the basis of the results of a pivotal phase-III trial. Cerebrovascular events are not recognized as expected adverse effects of such therapy.\n\nCase presentation\nWe report the case of a 67-year-old, current-smoking male with stage-IV HER2-positive gastric cancer who suffered right middle cerebral artery (MCA) embolism after trastuzumab + chemotherapy. He received trastuzumab and cisplatin on Day 1, followed by a continuous 5-fluorouracil infusion for 5 days as a first-line treatment. Four days after chemotherapy initiation, he presented with left hemiplegia, and brain magnetic resonance imaging and magnetic resonance angiography revealed a right MCA occlusion. No further chemotherapy was administered because of worsening performance status.\n\nConclusion\nThe present case, possibly the first such reported case, suggests the risk of development of embolism after trastuzumab + chemotherapy in HER2-positive advanced gastric cancer, although other factors should be considered.\n\nKeywords\nIntracranial embolismChemotherapyGastric cancerHuman epidermal growth factor receptor 2issue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nThromboembolism is a known vascular toxicity associated with tumor chemotherapy. The combination of trastuzumab and chemotherapy has shown significant antitumor activity, with mild manageable toxicity in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer [1], whereas cerebral arterial embolism has not been recognized as a side effect expected with this regimen. We describe an unusual case of advanced gastric cancer, in which the patient developed right middle cerebral artery embolism after chemotherapy combined with trastuzumab.\n\nCase presentation\nA 67-year-old man was diagnosed with stage-IV gastric cancer with multiple liver and lymph node metastases, but no apparent brain metastases, in April 2013. The patient had no previous medical history of arrhythmia, ischemic heart disease, diabetes mellitus, or stroke, and he was not taking any daily medications. An echocardiogram before chemotherapy demonstrated no cardiac thrombus, no atrial/ventricular septal defects, no patent foramen ovale, no valvular vegetations, and a left ventricular ejection fraction (LVEF) of 67%. Immunohistochemical analysis showed a HER2-positive score of 3+ for a primary tumor. Thus, the patient was treated with trastuzumab, and cisplatin on day 1, with subsequent continuous infusion of 5-fluorouracil (5-FU) for 5 days. Although the patient did not experience any adverse events at the start of chemotherapy, 4 days afterward, he noticed a sudden onset of left hemiplegia and agitation. Laboratory testing showed grade-1 anemia (hemoglobin, 12.5 g/dL), increased number of platelets (452,000/μL), healthy levels of fibrinogen (235 mg/dL; reference range 150–340 mg/dL) and the prothrombin time–international normalized ratio (PT-INR) of 1.05 (reference range 0.90–1.10), and a slight increase in fibrin degradation product (FDP) levels to 10.3 μg/mL; reference range 0–4.0 μg/mL). An electrocardiogram showed a healthy sinus rhythm with no ST–T changes. Noncontrast brain computed tomography (CT) revealed a “dot sign” in the right middle cerebral artery (MCA) seen as a dot in the sylvian fissure (Figure 1A), which is known as an early CT marker of acute cerebral infarction. Brain magnetic resonance imaging and magnetic resonance angiography revealed an MCA occlusion (Figure 1B), consistent with a diagnosis of chemotherapy-induced grade-4 stroke. After consultation with a neurologist, emergency endovascular therapy with an aspiration catheter and balloon was performed. Removal of the clot did restore the blood flow; however, distal emboli still remained (Figure 1C). The patient concomitantly received argatroban and aspirin. No further chemotherapy was administered because of the deterioration in the performance status of the patient. He underwent extensive neurorehabilitation, which brought a slight improvement in his neurological status. One month after initiation of chemotherapy, his carcinoembryonic antigen level decreased from 15.4 ng/mL to 7.6 ng/mL (reference range 0.0–5.0); however, he developed jaundice because of the tumor burden due to liver metastasis. His condition worsened and he died 2.0 months after chemotherapy initiation.Figure 1 \nBrain images after the onset of cerebral infarction. A: Noncontrast brain computed tomography revealed a “dot” sign in the right middle cerebral artery (MCA; arrow) seen as a dot in the sylvian fissure. B: Brain magnetic resonance angiography (MRA) showing an occlusion of the right MCA (arrowhead) on the day of the stroke. C: Brain MRA 3 days after the stroke showing blood flow of the damaged area of the brain.\n\n\n\nDiscussion and conclusions\nThe combination of trastuzumab and chemotherapy is considered the standard of care for patients with HER2-positive advanced gastric cancer on the basis of the results of a pivotal phase-III trial, which showed the efficacy of trastuzumab combined with cisplatin plus capecitabine or 5-FU as a first-line therapy [1]. The toxicity profile is mild, and no severe thromboembolisms such as cerebral infarction have been reported to date. In the present case, the patient presented with MCA embolism on the fourth day of the first cycle of chemotherapy with 5-FU, cisplatin, and trastuzumab. The mechanism underlying the cerebrovascular event caused by a chemotherapy regimen is likely multifactorial, including tumor microemboli and thromboembolism. The proposed mechanism of tumor embolization is invasion of the pulmonary veins, with or without left atrial invasion [2]. In rare cases, a tumor may invade the venous circulation and spread to the left side of the heart through a patent foramen ovale, leading to systemic tumor embolization. The risk of tumor embolization in the present case appeared to be low because a chest CT scan had revealed no evidence of intrathoracic metastasis from the gastric cancer, and patent foramen ovale was not detectable on the echocardiogram.\n\nA possible explanation in the present case is that thromboembolism may be responsible for this cerebrovascular event, and several factors may be at work here. First, platelet activation, alteration of the clotting cascade, including hyperfibrinolysis, and disturbances of the prostacyclin–thromboxane homeostasis, increase the risk of thrombosis 4- to 6-fold in cancer patients compared with the general population [3]. Clinically significant disseminated intravascular coagulation is unlikely in the presence of healthy levels of fibrinogen and PT-INR; however, increased FDP levels may indicate the presence of a clot. Second, smoking likely contributes to an increased stroke risk via both acute effects on the risk of thrombus generation in narrowed arteries and via chronic effects related to an increased burden of atherosclerosis. Nevertheless, the present case had no other risk factors of stroke, such as hypertension, diabetes mellitus, hypercholesterolemia, and atrial fibrillation [4]. Third, the literature suggests that cisplatin-based chemotherapy has been associated with an increased risk of arterial thromboembolic events [5], although severe thromboembolism, similar to that in the present case, has not been reported as a side effect associated with this regimen. Fourth, congestive heart failure is associated with a relatively high risk of venous thromboembolism. Therefore, we should rule out the possibility of trastuzumab-related thromboembolism, which is associated with trastuzumab-related cardiotoxicity. Troponin I is a strong predictor of reduction in the LVEF in patients who received chemotherapy (mainly anthracycline-containing regimens). A study has demonstrated that troponin I is mainly detected in blood plasma soon after the first trastuzumab cycle among troponin-positive breast cancer patients who received trastuzumab-containing regimens [6-8]. These results suggest that trastuzumab-induced cardiotoxicity occurs in the early phase of chemotherapy. The present case had no signs or symptoms of congestive heart failure, and we did not perform further analysis such as echocardiography after the onset of cerebral infarction. Nonetheless, the possibility of trastuzumab-related thromboembolism due to cardiotoxicity should be taken into account in the present case.\n\nTrastuzumab in combination with platinum-based chemotherapy is a treatment option in patients with HER2-positive advanced gastric or those with cancer of the gastroesophageal junction. The present case suggests the possible risk of the development of cerebral embolism after chemotherapy initiation, although other factors should be considered. Further research is needed to elucidate the mechanisms underlying the neurovascular adverse events.\n\nPatient consent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images before the patient received chemotherapy.\n\nTakayuki Takahama and Masayuki Takeda contributed equally to this work.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nTT and SN was responsible for clinical management of the patient, acquisition of data, and drafting the manuscript; MT and KN were responsible for interpretation of data and critical revision of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank Enago (www.enago.jp) for the English language review.\n==== Refs\nReferences\n1. Bang YJ Van Cutsem E Feyereislova A Chung HC Shen L Sawaki A 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 7 10.1016/S0140-6736(10)61121-X 20728210 \n2. Al-Thenayan E Maghfoor I Complications of malignancy: case 1. Systemic tumor embolism from lung cancer at presentation J Clin Oncol 2004 22 372 3 10.1200/JCO.2004.12.053 14722045 \n3. Blom JW Doggen CJ Osanto S Rosendaal FR Malignancies, prothrombotic mutations, and the risk of venous thrombosis JAMA 2005 293 715 22 10.1001/jama.293.6.715 15701913 \n4. Mannami T Iso H Baba S Sasaki S Okada K Konishi M Cigarette smoking and risk of stroke and its subtypes among middle-aged Japanese men and women: the JPHC Study Cohort I Stroke 2004 35 1248 53 10.1161/01.STR.0000128794.30660.e8 15118170 \n5. Li SH Chen WH Tang Y Rau KM Chen YY Huang TL Incidence of ischemic stroke post-chemotherapy: a retrospective review of 10,963 patients Clin Neurol Neurosurg 2006 108 150 6 10.1016/j.clineuro.2005.03.008 16412836 \n6. Cardinale D Sandri MT Martinoni A Tricca A Civelli M Lamantia G Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy J Am Coll Cardiol 2000 36 517 22 10.1016/S0735-1097(00)00748-8 10933366 \n7. Cardinale D Sandri MT Colombo A Colombo N Boeri M Lamantia G Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy Circulation 2004 109 2749 54 10.1161/01.CIR.0000130926.51766.CC 15148277 \n8. Cardinale D Colombo A Torrisi R Sandri MT Civelli M Salvatici M Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation J Clin Oncol 2010 28 3910 6 10.1200/JCO.2009.27.3615 20679614\n\n",
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"issn_linking": "1756-0500",
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"medline_ta": "BMC Res Notes",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002945:Cisplatin; D017809:Fatal Outcome; D005472:Fluorouracil; D015870:Gene Expression; D006801:Humans; D020766:Intracranial Embolism; D008113:Liver Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D020768:Middle Cerebral Artery; D009367:Neoplasm Staging; D011859:Radiography; D018719:Receptor, ErbB-2; D013274:Stomach Neoplasms; D000068878:Trastuzumab",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "100",
"pmc": null,
"pmid": "25885256",
"pubdate": "2015-03-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10933366;14722045;15118170;20679614;15701913;16412836;20728210;15148277",
"title": "A case of severe cerebral embolism after chemotherapy for HER2-positive gastric cancer.",
"title_normalized": "a case of severe cerebral embolism after chemotherapy for her2 positive gastric cancer"
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"companynumb": "JP-MYLANLABS-2016M1004868",
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"abstract": "OBJECTIVE\nTo describe clinical characteristics of patients with rheumatic and musculoskeletal diseases (RMDs) and immunosuppressive therapies with Coronavirus disease 2019 (COVID-19) at an academic rheumatology center in Madrid and to identify baseline variables associated with a severe infection requiring hospitalization.\n\n\nMETHODS\nWe identified SARS-CoV-2 positive cases by polymerase chain reaction performed at our center within an updated RMDs database in our clinic. Additional RMDs patients were identified when they contacted the clinic because of a positive infection. Data extraction included diagnosis, demographics, immunosuppressive treatment, comorbidities, and laboratory tests. Comparisons between patients with or without hospitalization were performed. Multivariate logistic regression was used to analyze associations between baseline variables and need for hospitalization.\n\n\nRESULTS\nA total of 62 patients with COVID-19 and underlying RMDs were identified by April 24, 2020. Median age was 60.9 years, and 42% men. Forty-two patients required hospitalization; these were more frequently men, older and with comorbidities. There were no statistically significant between-group differences for rheumatologic diagnosis and for baseline use of immunosuppressive therapy except for glucocorticoids that were more frequent in hospitalized patients. Total deaths were 10 (16%) patients. In multivariate analysis, male sex (odds ratio [OR], 8.63; p = 0.018), previous lung disease (OR, 27.47; p = 0.042), and glucocorticoids use (> 5 mg/day) (OR, 9.95; p = 0.019) were significantly associated to hospitalization.\n\n\nCONCLUSIONS\nNeither specific RMD diagnoses or exposures to DMARDs were associated with increased odds of hospitalization. Being male, previous lung disease and exposure to glucocorticoids were associated with higher odds of hospitalization in RMDs patients.",
"affiliations": "Department of Rheumatology. Hospital General, Universitario Gregorio Marañón, 28007, Madrid, Spain. fernandojose.montero@salud.madrid.org.;Department of Rheumatology. Hospital General, Universitario Gregorio Marañón, 28007, Madrid, Spain.;Department of Rheumatology. Hospital General, Universitario Gregorio Marañón, 28007, Madrid, Spain.;Department of Rheumatology. Hospital General, Universitario Gregorio Marañón, 28007, Madrid, Spain.;Department of Rheumatology. Hospital General, Universitario Gregorio Marañón, 28007, Madrid, Spain.;Department of Rheumatology. Hospital General, Universitario Gregorio Marañón, 28007, Madrid, Spain.;Department of Rheumatology. Hospital General, Universitario Gregorio Marañón, 28007, Madrid, Spain.;Department of Rheumatology. Hospital General, Universitario Gregorio Marañón, 28007, Madrid, Spain.",
"authors": "Montero|Fernando|F|http://orcid.org/0000-0003-4594-7663;Martínez-Barrio|Julia|J|https://orcid.org/0000-0002-9670-1746;Serrano-Benavente|Belén|B|https://orcid.org/0000-0001-7805-1359;González|Teresa|T|https://orcid.org/0000-0003-4713-0737;Rivera|Javier|J|https://orcid.org/0000-0001-8147-5881;Molina Collada|Juan|J|https://orcid.org/0000-0001-5191-7802;Castrejón|Isabel|I|https://orcid.org/0000-0003-1811-2417;Álvaro-Gracia|Jose|J|https://orcid.org/0000-0002-0343-3747",
"chemical_list": "D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D000998:Antiviral Agents; D004338:Drug Combinations; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D006886:Hydroxychloroquine; D017963:Azithromycin; C502936:tocilizumab; D019438:Ritonavir",
"country": "Germany",
"delete": false,
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"issue": "40(10)",
"journal": "Rheumatology international",
"keywords": "Autoimmune diseases; COVID-19; Poor outcomes; Rheumatology",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D000998:Antiviral Agents; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D001327:Autoimmune Diseases; D017963:Azithromycin; D000073640:Betacoronavirus; D000086382:COVID-19; D015897:Comorbidity; D018352:Coronavirus Infections; D004338:Drug Combinations; D005260:Female; D005938:Glucocorticoids; D006760:Hospitalization; D006801:Humans; D006886:Hydroxychloroquine; D007166:Immunosuppressive Agents; D016015:Logistic Models; D061466:Lopinavir; D008171:Lung Diseases; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D058873:Pandemics; D011024:Pneumonia, Viral; D012189:Retrospective Studies; D019438:Ritonavir; D000086402:SARS-CoV-2; D012720:Severity of Illness Index; D012737:Sex Factors; D013030:Spain",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1593-1598",
"pmc": null,
"pmid": "32794113",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "31978945;32414804;32167524;32125452;32425234;32546811;32283152;32043983;32007143;16968120;32171076;32457048;32309814;32205336;32532753;32241793;32425260;32348641",
"title": "Coronavirus disease 2019 (COVID-19) in autoimmune and inflammatory conditions: clinical characteristics of poor outcomes.",
"title_normalized": "coronavirus disease 2019 covid 19 in autoimmune and inflammatory conditions clinical characteristics of poor outcomes"
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"abstract": "BRAT1-related neurodevelopmental disorders are characterized by heterogeneous phenotypes with varying levels of clinical severity. Since the discovery of BRAT1 variants as the molecular etiology of lethal neonatal rigidity and multifocal seizure syndrome (RMFSL, OMIM 614498), these variants have also been identified in patients with milder clinical forms including neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS, OMIM 618056), epilepsy of infancy with migrating focal seizures (EIMFS), and congenital ataxia (CA). This study aims to examine the consequences and pathogenicity of a novel homozygous splice site variant in BRAT1 in a patient presenting with migrating focal seizures since birth without prominent rigidity. The patient was born from a consanguineous marriage and has had seizures since the neonatal period. He presented with dysmorphic features, pontocerebellar hypoplasia, and migrating focal seizures. Despite supportive treatment, his symptoms rapidly progressed to intractable myoclonic seizures, bouts of apnea and bradycardia, and arrest of head growth, with no acquisition of developmental milestones. Clinical exome sequencing yielded a novel homozygous splice variant in BRAT1. Genetic analysis based on reverse transcription of the patient's RNA followed by PCR amplifications performed on synthesized cDNA and Sanger sequencing was undertaken, and the functional effect of a BRAT1 variant on splicing machinery was demonstrated for the first time. The severe clinical presentation of migrating focal seizures and pontocerebellar hypoplasia in the absence of rigidity further expands the genotypic and phenotypic spectrum of BRAT1-related neurodevelopmental disorders.",
"affiliations": "Department of Medical Genetics, Dr. Sami Ulus Maternity and Children's Training and Research Hospital, Ankara, Turkey. drfatmakurt@gmail.com.;Department of Medical Genetics, Dr. Sami Ulus Maternity and Children's Training and Research Hospital, Ankara, Turkey.;Division of Pediatric Intensive Care Unit, Dr. Sami Ulus Maternity and Children's Training and Research Hospital, Ankara, Turkey.;Division of Pediatric Intensive Care Unit, Dr. Sami Ulus Maternity and Children's Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Neurology, Dr. Sami Ulus Maternity and Children's Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Neurology, Dr. Sami Ulus Maternity and Children's Training and Research Hospital, Ankara, Turkey.",
"authors": "Colak|Fatma Kurt|FK|;Guleray|Naz|N|;Azapagasi|Ebru|E|;Yazıcı|Mutlu Uysal|MU|;Aksoy|Erhan|E|;Ceylan|Nesrin|N|",
"chemical_list": "C573230:BRAT1 protein, human; D009687:Nuclear Proteins",
"country": "Italy",
"delete": false,
"doi": "10.1007/s13760-020-01513-0",
"fulltext": null,
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"issn_linking": "0300-9009",
"issue": "120(6)",
"journal": "Acta neurologica Belgica",
"keywords": "BRAT1; Migrating focal seizure; Pontocerebellar hypoplasia; Splice variant",
"medline_ta": "Acta Neurol Belg",
"mesh_terms": "D003241:Consanguinity; D017809:Fatal Outcome; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins; D013036:Spasms, Infantile",
"nlm_unique_id": "0247035",
"other_id": null,
"pages": "1425-1432",
"pmc": null,
"pmid": "33040300",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26597089;25500575;27282648;25319849;23035047;26535877;22279524;26483087;26494257;31868227;29997391;27282546;29680930;28752061;27480663;30786674;30346566;26852664;29903031",
"title": "An intronic variant in BRAT1 creates a cryptic splice site, causing epileptic encephalopathy without prominent rigidity.",
"title_normalized": "an intronic variant in brat1 creates a cryptic splice site causing epileptic encephalopathy without prominent rigidity"
} | [
{
"companynumb": "TR-UCBSA-2020049146",
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"occurcountry": "TR",
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"activesubstancename": "PHENOBARBITAL"
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{
"abstract": "Ovarian pregnancy is a rare form of extra uterine pregnancy. Serous cyst adenoma is a benign variant of epithelial cell tumors of ovary. The coexistence of a cyst adenoma with an ovarian pregnancy in the same ovary is extremely rare. Some studies suggested that infertility or ovulation-inducing drugs can be involved in increased risk of ovarian tumors and ovarian pregnancies. A 28-year-old infertile woman presented with a ruptured ovarian pregnancy following ovulation induction with metformin. She had a concurrent benign serous cyst adenoma in the same ovary. Resection of both ovarian pregnancy and tumoral mass were performed. The ovary was preserved. Removal of gestational tissue and preservation of the involved ovary are the best options for management of ovarian pregnancy in young patient. Although there is an association between infertility/ovulation inducting medications and ovarian gestation, their connections with serous cyst adenoma are undetermined.",
"affiliations": null,
"authors": "Ebrahimi|Mahbod|M|;Akbari Asbagh|Firoozeh|F|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nInt J Fertil SterilInt J Fertil SterilRoyan InstituteInternational Journal of Fertility & Sterility2008-076X2008-0778Royan Institute Int-J-Fertil-Steril-8-85Case ReportGynecology and Female InfertilityPathologySimultaneous Serous Cyst Adenoma and Ovarian\nPregnancy in An Infertile Woman Ebrahimi Mahbod M.D.*Akbari Asbagh Firoozeh M.D.\n* Corresponding Address:\nP.O. Box: 1597856511Department of Obstetrics and GynecologyFaculty of MedicineTehran Women’s General HospitalTehran University of Medical SciencesTehranIran\nEmail: maeb214@yahoo.comApr-Jun 2014 9 3 2014 8 1 85 90 17 3 2013 2 6 2013 Any use, distribution, reproduction or abstract of this publication in any medium, with the exception of commercial purposes, is permitted provided the original work is properly citedThis is an open-access article distributed under the terms of the\nCreative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is properly cited.\nOvarian pregnancy is a rare form of extra uterine pregnancy. Serous cyst adenoma is\na benign variant of epithelial cell tumors of ovary. The coexistence of a cyst adenoma\nwith an ovarian pregnancy in the same ovary is extremely rare. Some studies suggested\nthat infertility or ovulation-inducing drugs can be involved in increased risk of ovarian\ntumors and ovarian pregnancies. A 28-year-old infertile woman presented with a ruptured\novarian pregnancy following ovulation induction with metformin. She had a concurrent\nbenign serous cyst adenoma in the same ovary. Resection of both ovarian pregnancy and\ntumoral mass were performed. The ovary was preserved. Removal of gestational tissue\nand preservation of the involved ovary are the best options for management of ovarian\npregnancy in young patient. Although there is an association between infertility/ovulation\ninducting medications and ovarian gestation, their connections with serous cyst adenoma\nare undetermined. \n\nInfertilityOvulation InductionEctopic PregnancyOvarian PregnancyMetforminCitationEbrahimi M, Akbari Asbagh F. Simultaneous serous cyst adenoma and ovarian pregnancy in an infertile\nwoman. Int J Fertil Steril. 2014; 8(1): 85-90.\n==== Body\nIntroduction\nOvarian pregnancy occurs when a fertilized\novum implants in or on the ovary. This entity is\na rare variant of extrauterine pregnancy and represents 1.1-3% of all ectopic pregnancies or one\novarian pregnancy per 7000-90000 live births (1-4)\n\nSerous cyst adenoma is a cystic ovarian tumor\ncontaining serous fluid and solid- tissue component. This tumor is benign form, presenting as\ncystic unilocular or multilocular ovarian mass with\nthin wall and minimal papillary projections (5).\n\nPolycystic ovarian syndrome (PCOS) is the most\ncommon endocrinopathy among subfertile women\n(6). The most prominent presenting characteristics\nare oligo/anovulation and hyperandrogenism (7).\nCurrently, metformin, an insulin-sensitizing agent,\nwas accepted as a favorable medication for ovulation induction in PCOS (8, 9).\n\nInfertility and subfertility managements including induction of ovulation seem to be responsible\ncauses in the occurrence of the ectopic pregnancies (10-12).\n\nIn some retrospective studies, an association has\nbeen found between fertility drugs use and ovarian\nneoplasia risk in infertile patients (13-15).\n\nThe case presented here is interesting in term of\nthe rarity of ovarian pregnancy and coincidence\nwith serous cyst ovarian tumor, and also occurring\nafter ovulation induction by metformin.\n\nCase report\nIn January 2013, a 28-year-old primigravida\nwoman with sever lower abdominal pain presented to the emergency room of our hospital (Tehran Women General Hospital, Tehran,\nIran). She suffered from vaginal spotting and lower abdominal pain for 5-6 consecutive days.\nShe revealed a history of primary infertility\nwith 3 years duration. Because of clinical and\nparaclinical manifestations of polycystic ovarian syndrome, metformin (1500 mg/day) has\nbeen prescribed for induction of ovulation since\n8 months ago. After starting this medication,\nshe developed regular menstruation pattern.\nHer last menstrual period was 25 days prior to\nadmission date. She had no previous history of\npelvic inflammatory disease, abdominal surgery, abortion, or use of any intrauterine contraceptive device (IUCD). Her hysterosalpingography (HSG) demonstrated an otherwise\nnormal image without uteroovarian fistula. On\ngeneral examination, she was pale. Abdominal\nexamination showed abdominal distention and\nguarding. On vaginal examination, the uterus\nwas normal in size and the cervix was tender\nin motion. There was a tenderous mass in deep\npalpation of right fornix. Clinical investigation\nshowed hematocrit level of 25.2%, and betahuman chorionic gonadotropin (β-hCG) titer of\n3569 m IU/mL. Vaginal ultrasonography demonstrated empty uterus with 6 mm endometrial\nthickness, free fluid in the peritoneal cavity,\nand a right sided heterogeneous adnexal mass\n(52×61 mm) beside the uterus. These findings\nwere suggestive of ruptured ectopic gestation.\nBased on the above findings, the patient underwent emergency laparotomy in which demonstrated an enlarged and bluish right ovary with\na 4 cm hemorrhagic and ruptured ovarian mass\nand a leaking hematoma on its surface. A 3×3\ncm multicystic structure was identified in the\nother side of right ovary and was presumed to\nbe a tumorous lesion. The uterus, both tubes\nand the left ovary appeared to be normal in appearance. The right tube had normal fimbriated\nend without dilation. There was no obvious\nevidence of endometriosis, metastatic lesions,\npelvic inflammation, or adhesion. We found\n1500 mL bloody fluid in abdominal cavity.\nThe diagnosis of ovarian pregnancy was made.\nTherefore, surgical resection of hemorrhagic\nmass with conservation of the right ovary was\ndone carefully. Because of bad looking appearance of the concurrent cyst in the right ovary,\novarian cystectomy and endometrial curetting\nwere performed, respectively. The final pathologic analysis revealed vascularized chorionic\nvilli and trophoblastic cells within ovarian paranchymal tissue (Figes1, 2). Histopathological\nstudy demonstrated that the excised cyst was\na benign serous cyst adenoma (Fig 3). The endometrial sample showed decidual change, but\nno gestational tissue. The post-operative course\nwas uneventful. On monitoring of β-hCG lev-\nels, they were undetectable (<5 m IU/ mL) on\nthe 21st\npostoperative day. The patient menstru-\nated 37 days after the surgical operation.\n\nFig 1 Photomicrograph identified trophoblastic cells within\nthe ovarian parenchyma (H&E); ×200.\n\nFig 2 Photomicrograph identified chorionic villi (H&E);\n×100.\n\nFig 3 Photomicrograph identified serous cyst adenoma\n(H&E); ×400.\n\nDiscussion\n\nOvarian pregnancy is a rare variant of ectopic\npregnancy (1- 4). This entity must be documented\nby the four criteria of Spiegelberg: I. separation of\nintact tubes from the ovaries, II. a gestational sac\noccupying the normal position of the ovary, III. the\novary and sac connected to the uterus by the uteroovarian ligament, and IV. ovarian tissue histologically demonstrated in the sac wall (16).\n\n Its true incidence is underestimated. Some\nof the suspected tubal pregnancies that are approached with conservative managements, without laparoscopic validation, are in fact ovarian\npregnancies (2, 10, 17). However, there is a rising in incidence of ovarian pregnancy in the last\ndecade, its true incidence is undetermined (3, 10,\n18). Furthermore, some studies suggested infer-\ntility and the medications, which are prescribed\nfor ovulation induction, were associated with\nan increased incidence of ovarian pregnancies\n(3, 10-12). The suspected predisposing factors\nwere increased levels of estrogen and progesterone after ovulation induction (19). However, the\nother reports did not support this hypothesis (2,\n10, 20, 21)\n\n The exact etiologic factors of increased risk of\novarian pregnancy after ART programs are unclear, but the most likely mechanisms are as follows: reverse migration of embryo after deep deposition, the use of large volumes of culture fluid\nduring embryo transfer (ET) procedures, difficult\nET, and tubal pathologies (12, 22-24).\n\n The risk of ovarian pregnancy in patients with\nendometriosis or using IUCDs is controversial (3,\n25). Unlike tubal pregnancy, the history of pelvic\ninflammatory disease does not increase the risk of\novarian pregnancy (2, 20, 21, 26).\n\nPreoperative diagnosis is a challenge to the clinician due to its rarity and lack of typical presenting\nsymptoms or documented risk factors (27). The\nclinical findings are similar to tubal pregnancy or\nhemorrhagic corpus luteal cyst (2, 28). The most\ncomplaints are abdominal pain and vaginal bleeding (3, 10). The increased vascularity of the ovary\nfacilitates more massive bleeding and hypovalemic shock (3, 18). The asymptomatic patients are\nincidentally discovered during post- in vitro fertilization (IVF) monitoring (2). The ovarian pregnancies could be multiple gestations or heterotopic\ntype (2, 29). There are very few recorded cases\nin which ovarian pregnancy reached viability (30).\n\nThe ultrasound features are ovarian enlargement with or without containing a double hyperechogenic ring along with yolk sac, fetal part, or\nfetal heart beat within ovary; fluid collection surrounding the ovary; and an empty uterus (2, 4, 20,\n31, 32). The sonographic differential diagnosis\nbetween ovarian pregnancy and a ruptured corpus luteal cyst or a hemorrhagic ovarian tumor is\ndifficult (2, 4, 27, 33). Although definite diagnosis is reached by laparoscopy or laparotomy, some\nof ovarian pregnancies are identifiable by vaginal\nultrasound scanning (10, 17). Ovarian pregnancies can be mistaken for hemorrhagic corpus luteal cysts or pregnancies in the distal part of tube\neven at laparoscopy or laparotomy (3). Since pregnancy induced tissue destruction and lesser tissue\nis available in conservative surgeries, postoperative diagnosis is also difficult (21). Therefore, the\nphysicians must exhibit a high degree of suspicion\nfor ovarian pregnancy when managing with pregnancy of unknown location.\n\nIn recent years, accurate and earlier diagnosis\nhas been performed by the application of vaginal\nultrasound scanning and quantitative hCG measurement (1, 28). So, the management procedures\nof ovarian pregnancy have evolved oopherectomy\nby open surgical procedures and removal of gestational products or ovarian wedge resection by the\nlaparoscopy and/or medical management using intramuscular or local injection of chemotherapeutic\nagents such as methotrexate (50 mg/m2) , hyperosmolar glucose, and prostaglandins, especially in\nyoung patients who have an intact ovarian pregnancy and a desire for future childbearing (2, 3,\n10, 17, 20, 29, 34-36). Application of these modalities in management of ovarian pregnancy decreases\nmaternal mortality and morbidity rates (34).\n\nSerous cyst adenoma is the most common benign epithelial cell tumor of ovary (5). In some\nretrospective epidemiologic studies, an association has been demonstrated between prolonged\ninfertility/use of ovulation inducing drugs and an\nincreased incidence of ovarian epithelial cell dysplasia and cancer (13-15, 37-40). The stimulation\nof ovulation and increased levels of estrogen and\nprogesterone explain the potential suspected relationship between the use of fertility medications\nand development of ovarian neoplasia (39)\n\nIn the other hand, a high frequency of hyperplasia and metaplasia in the ovarian epithelial surface and 2.5-fold increased risk of ovarian cancer\nhave been showed in women with PCOS (41, 42).\nAlthough the contradictory data were reported in\nthe other studies (40, 43-45, 46), like in a study\nby Brinton, the dosage and number of cycles of\novulation-inducing drugs were not associated with\nelevated risk (15). This difference is based on different study design, confusing factors such as duration and causes of infertility, parity, as well as\ntype and duration of medical therapy (33).\n\nIn some cohort studies, ovulation-inducing\ndrugs were related to an elevated risk of border\nline serous tumors (13, 40, 47). However, there is\na possible association between prolonged use of\nclomiphene citrate and invasive epithelial ovarian\ntumors (40). This relationship should be pointed\nout with caution. The confounding influence of infertility and nulliparity should be kept in mind. Additionally, the other authors did not confirm these\ndata in case-control studies (13, 15, 42, 48, 49).\n\nFertility experts frequently use metformin, an\ninsulin-sensitizing agent, as an ovulation-inducing\nmedication in PCOS (50, 51). Although its connection with ectopic gestation is reported (52), its\nassociation with serous cyst adenoma is undetermined. Some studies showed metformin use has\nbeen associated with a significant decrease in risk\nof prostate, pancreas, and breast cancer (53, 54);\nhowever, its molecular effect on ovarian tissue,\nand also, its effect on the risk of ovarian tumors\nremain undetermined (50). Although superovulation and increased serum levels of ovarian steroid\nhormones are the suspected pathogenesis of raising incidence of epithelial cell tumors following\ninduction ovulation, superovulation is very rare\nevent after metformin use (51); furthermore, estrdiol and progesterone serum levels are near the\nphysiologic levels in cycles after being induced by\nthis agent (50).\n\nHowever, to the best of our knowledge, this\nstudy is the first case report of coexistence of an\novarian pregnancy and a serous cyst adenoma\nin the same ovary following ovulation induction\nwith metformin. Review of the literature showed\nonly a few reports presenting the coincidence of\na serous cyst adenoma with an ectopic pregnancy.\nThey have been cases involving tubal or abdominal pregnancy coinciding with serous cyst adenoma (52, 55, 56). Vazquez et al. (55) reported tubal\npregnancy and ovarian serous cyst adenoma in a\n40-year-old patient. The pregnancy was happened\nafter induction of ovulation by clomiphene citrate.\nPricop et al. (56) presented a case with abdominal\npregnancy and serous cyst adenoma. Werlin et al.\n(52) reported a coincidence of tubal pregnancy\nwith a serous cyst adenoma in the same fallopian\ntube following induction ovulation with metformin, letrozol, and low-dose gonadotropin. After review of literature, we did not find original study\nor documented case report about relationship between the use of metformin and ovarian tumors.\n\nIn our case, the presenting signs and symptoms\nwere severe abdominal pain with vaginal spotting,\nelevated β-hCG, ovarian mass and empty uterus.\nShe fulfilled the criteria for ovarian pregnancy, as\nby Spiegelberg’s outlines. She had a concurrent benign serous cyst adenoma in the same ovary. Our\npatient was previously labeled with PCOS. Pregnancy happened following induction of ovulation\nwith metformin. In term of risk factors, infertility\nand the use of ovulation inducing drugs might be\nthe possible predisposing factors for the ovarian\npregnancy. The relationship between metformin\nand serous cyst adenoma is not clear. \n\nConclusion\nOvarian pregnancy is uncommon entity, which is difficult to diagnose. The microinvasive surgical\nprocedures and medical managements are effective therapeutic options in the treatment of unruptured ovarian pregnancies, especially in young patients. Although the current findings are not strong\nto support a link between fertility drugs and ovarian cancer, it seems to be an association between\nreduced fertility and increased neoplasia risk.\nCareful inspection of the ovaries at surgery indicated the high risk of ovarian tumors for patients\nwith long-standing history of infertility or fertility\nagents use in order to exclude the presence of a\nneoplasm. Moreover, further prospective, multicenter, and long follow-up studies considering all\nconfounding factors are necessary to improve our\nability for diagnosis and treatment of ovarian pregnancy, and to determine the patho-physiological\nmechanisms underlying the possible link between\ninfertility or the use of ovulation inducing drugs\nand ovarian tumors. \n\nThe authors would like to thank Dr. Izadi, Dr.\nShah- siah, and the staff of the Center of Research-\nes of Tehran Women’ s Hospital for their assistance\nin the preparation of this manuscript. 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"issn_linking": "2008-0778",
"issue": "8(1)",
"journal": "International journal of fertility & sterility",
"keywords": "Ectopic Pregnancy; Infertility; Metformin; Ovarian Pregnancy; Ovulation Induction",
"medline_ta": "Int J Fertil Steril",
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"title": "Simultaneous serous cyst adenoma and ovarian pregnancy in an infertile woman.",
"title_normalized": "simultaneous serous cyst adenoma and ovarian pregnancy in an infertile woman"
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"abstract": "Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for progressive marrow failure, myelodysplastic syndrome, or leukemia associated with dyskeratosis congenita (DC). HSCT for DC is limited by a high incidence of treatment-related mortality, thought to be related to underlying chromosomal instability and sensitivity to chemotherapy and radiation. We report our experience in 7 patients with DC who underwent allogeneic transplantation using a reduced-intensity conditioning (RIC) preparative regimen that contained chemotherapy only (no radiation). This RIC regimen, designed specifically for patients with DC, contained alemtuzumab, fludarabine, and melphalan (with melphalan at 50% reduced dosing), with the goal of decreasing toxicity and improving outcome. All 7 patients engrafted, with none developing mixed chimerism or rejection. Two patients experienced acute graft-versus-host disease (GVHD) and 1 went on to develop limited chronic GVHD of the skin. Five patients remain alive and well at a median follow-up of 44 months (range, 14 to 57 months). We conclude that a radiation-free RIC regimen results in durable engraftment, acceptable toxicity, and improved overall survival in patients with DC undergoing allogeneic HSCT.",
"affiliations": "Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Adam.nelson@cchmc.org.;Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Kids Cancer Centre, Sydney Children's Hospital, Randwick NSW Australia.;Division of Bone Marrow Transplantation and Immune Deficiency Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.",
"authors": "Nelson|Adam S|AS|;Marsh|Rebecca A|RA|;Myers|Kasiani C|KC|;Davies|Stella M|SM|;Jodele|Sonata|S|;O'Brien|Tracey A|TA|;Mehta|Parinda A|PA|",
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"issue": "22(5)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Dyskeratosis congenita; Hematopoietic stem cell transplantation; Reduced-intensity conditioning",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D018572:Disease-Free Survival; D019871:Dyskeratosis Congenita; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D012871:Skin Diseases; D015996:Survival Rate; D019172:Transplantation Conditioning",
"nlm_unique_id": "9600628",
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"pages": "884-8",
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"pmid": "26845033",
"pubdate": "2016-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
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"title": "A Reduced-Intensity Conditioning Regimen for Patients with Dyskeratosis Congenita Undergoing Hematopoietic Stem Cell Transplantation.",
"title_normalized": "a reduced intensity conditioning regimen for patients with dyskeratosis congenita undergoing hematopoietic stem cell transplantation"
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"abstract": "Paraneoplastic pemphigus (PNP) is an autoimmune bullous disease, which associates mainly with lymphoproliferative neoplasms. Bronchiolitis obliterans (BO) with progressive respiratory failure is a significant cause of death in PNP. We report a case of PNP associated with follicular lymphoma and BO, which showed findings suggesting coexistence of bullous pemphigoid (BP). The patient showed bullous and ulcerative lesions on the lips and oral cavity, and flaccid blisters on the trunk and thighs associated with anti-desmoglein (Dsg)3 antibodies. At later disease stage after commencement of treatment, anti-BP180 antibodies and tense blister formation were observed. It was proposed that persistent interface dermatitis is the first event in PNP, and subsequently induce the production of autoantibodies to Dsg and components of the basement membrane zone, resulting in both intraepidermal and subepidermal blisters. We speculate that interface dermatitis caused by autoreactive T cells induced autoantibody production against Dsg3, and subsequently against BP180.",
"affiliations": "Department of Dermatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.",
"authors": "Kanaoka|Miwa|M|;Matsukura|Setsuko|S|;Ishikawa|Hideyuki|H|;Matsuura|Midori|M|;Ishii|Norito|N|;Hashimoto|Takashi|T|;Aihara|Michiko|M|",
"chemical_list": "D001323:Autoantibodies; D001324:Autoantigens; C071894:DSG3 protein, human; D051184:Desmoglein 3; D024041:Non-Fibrillar Collagens; C040073:collagen type XVII",
"country": "England",
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"doi": "10.1111/1346-8138.12521",
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"issn_linking": "0385-2407",
"issue": "41(7)",
"journal": "The Journal of dermatology",
"keywords": "bronchiolitis obliterans; bullous pemphigoid; follicular lymphoma; paraneoplastic pemphigus",
"medline_ta": "J Dermatol",
"mesh_terms": "D001323:Autoantibodies; D001324:Autoantigens; D001989:Bronchiolitis Obliterans; D051184:Desmoglein 3; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D024041:Non-Fibrillar Collagens; D010257:Paraneoplastic Syndromes; D010391:Pemphigoid, Bullous; D013601:T-Lymphocytes",
"nlm_unique_id": "7600545",
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"pages": "628-30",
"pmc": null,
"pmid": "24985544",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paraneoplastic pemphigus associated with fatal bronchiolitis obliterans and appearance of anti-BP180 antibodies in the late stage of the disease.",
"title_normalized": "paraneoplastic pemphigus associated with fatal bronchiolitis obliterans and appearance of anti bp180 antibodies in the late stage of the disease"
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"abstract": "Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumor of the gastrointestinal tract involving both epithelial and neuroendocrine (NE) components, each of which represents at least 30% of the tumor. Because of the low frequency of this histotype, only a few cases have been described. In this report we discuss two cases treated with neoadjuvant chemotherapy: a pancreatic adenocarcinoma and a gastric adenocarcinoma. The histopathological specimens examined after surgery showed an additional NE component with a possible indication of the MANEC histotype. We hypothesize two possible explanations: tumor NE cells are more chemo-resistant than adenocarcinoma cells, and cytotoxic injury induces NE differentiation in tumor cells. The clinical significance and prognostic value of endocrine differentiation, however, remain controversial issues.",
"affiliations": "Department of Clinical Oncology, Fondazione Poliambulanza, Brescia, Italy.;Department of Pathology, Fondazione Poliambulanza, Brescia, Italy.;Department of Pathology, Fondazione Poliambulanza, Brescia, Italy.;Department of Clinical Oncology, Fondazione Poliambulanza, Brescia, Italy.;Department of Nuclear Medicine, Fondazione Poliambulanza, Brescia, Italy.;Department of Pathology, Fondazione Poliambulanza, Brescia, Italy.;Department of Clinical Oncology, Fondazione Poliambulanza, Brescia, Italy.",
"authors": "Oneda|Ester|E|;Liserre|Barbara|B|;Bianchi|Denise|D|;Rota|Luigina|L|;Savelli|Giordano|G|;Zorzi|Fausto|F|;Zaniboni|Alberto|A|",
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"doi": "10.1159/000501200",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000501200cro-0012-0434Case ReportDiagnosis of Mixed Adenoneuroendocrine Carcinoma (MANEC) after Neoadjuvant Chemotherapy for Pancreatic and Gastric Adenocarcinoma: Two Case Reports and a Review of the Literature Oneda Ester a*Liserre Barbara bBianchi Denise bRota Luigina aSavelli Giordano cZorzi Fausto bZaniboni Alberto aaDepartment of Clinical Oncology, Fondazione Poliambulanza, Brescia, ItalybDepartment of Pathology, Fondazione Poliambulanza, Brescia, ItalycDepartment of Nuclear Medicine, Fondazione Poliambulanza, Brescia, Italy*Ester Oneda, MD, Department of Clinical Oncology, Fondazione Poliambulanza, Bissolati street 57, IT–25124 Brescia (Italy), E-Mail ester.oneda@poliambulanza.itMay-Aug 2019 13 6 2019 13 6 2019 12 2 434 442 9 5 2019 14 5 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Mixed adenoneuroendocrine carcinoma (MANEC) is a rare tumor of the gastrointestinal tract involving both epithelial and neuroendocrine (NE) components, each of which represents at least 30% of the tumor. Because of the low frequency of this histotype, only a few cases have been described. In this report we discuss two cases treated with neoadjuvant chemotherapy: a pancreatic adenocarcinoma and a gastric adenocarcinoma. The histopathological specimens examined after surgery showed an additional NE component with a possible indication of the MANEC histotype. We hypothesize two possible explanations: tumor NE cells are more chemo-resistant than adenocarcinoma cells, and cytotoxic injury induces NE differentiation in tumor cells. The clinical significance and prognostic value of endocrine differentiation, however, remain controversial issues.\n\nKey Words\nMixed adenoneuroendocrine carcinomaNeoadjuvant chemotherapyNeuroendocrine differentiation\n==== Body\nIntroduction\nMixed adenoneuroendocrine carcinoma (MANEC) is a rare tumor with dual adenocarcinomatous and neuroendocrine differentiation, in which each component represents at least 30% of the tumor [1]. Diagnosis is mainly based on tumor cytology and architecture and is completed by immunostaining with specific neuroendocrine markers, such as chromogranin, synaptophysin, and CD56 (for the neuroendocrine component), combined with markers of non-endocrine differentiation, such as keratin 7 (for gastric tumors) and keratin 20, CDX2, and carcinoembryonic antigen (CEA) [2]. To date, according to literature, MANECs has been identified in various organs, such as the stomach [3], colon [4], biliary tract [5], pancreas, and even the uterine cervix [6]. A large retrospective case-matched study on patients with MANEC by Watanabe et al., reported 3.2% prevalence of MANEC among all patients with colorectal cancer, as determined from hospital records [7]. It is unclear whether MANEC is more biologically similar to the neuroendocrine or to the adenocarcinoma parts. However, it is an extremely rare tumor, with the majority of instance presented in case reports. Due to its rarity, few aspects regarding the origin or the best therapeutic options are known. The latest WHO recommendations suggest that MANECs should be treated as an adenocarcinoma; however, recent evidence, according to numerous authors, indicates that treatment should be based on the most aggressive histologic component [2, 8, 9]. Due to the rarity of these tumors, there is a significant ongoing debate regard the best treatment for MANECs. These tumors did not exhibit specific symptoms nor did specific radiological or laboratory tests of them reveal unique findings; hence, a diagnosis depends on postoperative histopathological and immunohistochemical studies. There is also conflicting evidence regarding the prognosis of patients with MANEC [10].\n\nIn this paper, we present two unusual cases of MANECs: one arising from the pancreas and one from the stomach. These diagnoses were made based on surgical specimens acquired after administration of neoadjuvant chemotherapy for adenocarcinoma tumors.\n\nCase Report\nCase 1\nFor a 54-years-old male high levels of transaminases were accidentally detected in a blood test. Therefore, an abdomen ultrasound (US) was performed and revealed a nodule in the head of the pancreas. In June 2018, computed tomography (CT) on the abdomen showed a neoplasm in the head of the pancreas that was in contact with the duodenal wall and featured an important dilatation of the extra-biliary and intra-biliary tracts of the liver, gallbladder and major pancreatic duct. Small lymph nodes were present near the pancreas. The patient was admitted to our hospital and underwent an endoscopic retrograde cholangiopancreatography (ERCP), with an insertion of biliary metallic prostheses, and an endoscopic ultrasound (EUS) biopsy. The cytological specimen confirmed the presence of malignant cells that were compatible with ductal adenocarcinoma.\n\nTo address the local extension of the disease, immediate surgery was not indicated. Instead, six cycles of FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan and oxaliplatin) chemotherapy were delivered, which resulted in a unique side effect of G1-like neuropathy in the hands. The reassessment using CT showed stable disease. However, the patient was hospitalized for a fever that was nonresponsive to antibiotic therapy, and diagnosed with cholangitis. Therefore, a biliary drain was placed using percutaneous transhepatic cholangiography (PTC). The bile culture showed the presence of Enterococcus faecalis, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. After delayed antibiotic therapy the patient no longer had a fever.\n\nOn November 2018, the patient underwent duodenum-cephalo-pancreasectomy with splenic vein tract resection, which was reconstructed with left renal vein segment interposition, and extensive right hemicolectomy with distal ileus-transverse anastomosis. Both biliodigestive and gastroenteric reconstruction in a single loop (following Child) and pancreatico-gastro anastomosis were performed.\n\nExamination of the surgical specimen revealed that the neoplasm involved the ampullary region. The proximal and distal resected margins, principal biliary duct and pancreatic margin were free from tumor involvement. Histopathological examination of the surgical specimen confirmed tumor infiltration into the duodenal wall to the mucosa and the adipose tissue anteriorly and posteriorly to the pancreas, <1 mm from the mesenteric vein and superior mesenteric artery. Metastases were present in 3 of the 25 regional lymph nodes. Angiolymphatic invasion, with perineural invasion was also present (ypT2N1, R1 stage). The tumor architecture was predominantly solid, consisting of clusters of glandular structures, with epithelial markers, such as CK19 and CK7, and neuroendocrine markers, such as synaptophysin and CD56. Focal mucus secretion was also seen in the same cells (focal PAS-D +). This pattern is characteristic of amphicrine MANEC, in which exocrine and neuroendocrine features are coexpressed by the same neoplastic cells, which show divergent differentiation as indicated by immunohistochemical or electron microscopic techniques [8]. The tumor cells were undifferentiated (G3) (Fig. 1).\n\nThe patient continued therapy with FOLFIRINOX for an additional four cycles and at the least assessment, he showed no evidence of recurrence.\n\nCase 2\nIn June 2018, a 73-years-old man underwent a fecal occult blood test (FOBT) in a screen used to prevent colorectal cancer, and the test result was positive. However, the colonoscopy was negative. The patient underwent a gastroscopy (missing documentation) that detected edematous and ulcerated mucosa that extended 5 cm (at 27 cm from the dental arch) and a neo-formation of approximately 4 cm with irregular margins at the level of the gastric curvature between the body and antrum, which was ulcerated. Histology revealed intestinal gastric adenocarcinoma and in situ squamous cell carcinoma with severe dysplasia of the esophagus. CT results showed thickening of the gastric antrum wall and of the small gastric curve and the presence of locoregional pathological lymph nodes. Positron emission tomography (PET) results showed intense accumulation of the metabolic tracer at the gastric wall, the small gastric curvature, and in two lymph node formations (cT1N1M0). The patient underwent four cycles of neoadjuvant chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT). CT results showed a reduction in the wall thickness of the gastric antrum and a reduction in the volume of regional lymph nodes. A near total laparoscopic gastrectomy (LAD D2) was performed in October 2018. Gross examination of the surgical specimen revealed a 20 mm × 10 mm tumor of the greater gastric curvature that invaded the gastric wall. The proximal and distal resected margins were free from tumor involvement. Histopathological examination of the surgical specimen confirmed tumor infiltration of mucosa, submucosa and muscularis, with metastasis found in 1 of 35 regional lymph nodes. Angiolymphatic invasion and peritumoral lymphocytic infiltrate, without perineural invasion, were also noted (ypT3N1, R0 stage). The tumor architecture was predominantly solid, consisting of clusters of glandular cells, marked by keratins 7, and clusters of tubular cells with endocrine morphology, marked by synaptophysin, CD 56 and chromogranin (Fig. 2). The neuroendocrine component represented more than 30% of the tumor; this pattern characterizes composite glandular-neuroendocrine mixed tumor (mixed adenocarcinoma-G1/G2 NET) [8]. The patient underwent four additional cycles of adjuvant chemotherapy with the FLOT scheme. The treatment was well tolerated, with G2 fatigue and G1 diarrhea which disappeared after the introduction of pancreatic enzyme therapy. Restaging through use of CT at the end of chemotherapy indicated no signs of recurrence of the underlying disease. The results from esophagogastroduodenoscopy (EGDS) showed irregular mucosal areas of the esophagus due to chronic esophagitis with an erosive character; normal results of gastric resection and regular gastric stump followed.\n\nDiscussion\nIn the presented cases, tumor cells with NE differentiation manifested in tumor postresection specimens after neoadjuvant chemotherapy, unlike the paired tumors in pretreatment biopsy/cytology specimens. The low cellularity of the basal specimens (determined by fine needle aspiration, in the first case, and by the lack of material of the biopsy, in the second case) did not reveal the presence or percentage of NE cells before the start of chemotherapy. Indeed, we know that tumors have heterogeneous population [11]. The genetic heterogeneity that derives from a large numbers of cell divisions with the emergence of multiple mutations translates into phenotypic heterogeneity. Neoadjuvant drugs can act as biologic selective killers. Increased NE cells have been reported in different types of tumors, such as colorectal and prostatic adenocarcinomas, after neoadjuvant therapy [12, 13, 14], and the extent of NE cells appears to be related to the degree of cytotoxic insult and treatment response. NE cell hyperplasia is observed in a variety of inflammatory conditions, such as chronic pancreatitis and inflammatory bowel disease, suggesting that NE cells may be more resistant to inflammatory injury. The resistance of endocrine cells to pathological conditions, such as inflammation or drug-induced toxicity, is a recognized phenomenon [15]. In benign conditions, resistance of preexisting endocrine cells to inflammatory injury is exemplified by the apparent islet cell aggregation seen when exocrine cells are lost because of inflammatory atrophy in chronic pancreatitis. Chemotherapy, which promotes inflammation, can also induce selective endocrine cell proliferation [16]. There are two main hypotheses to explain why NE differentiation increases in frequency and density in treated adenocarcinomas [17]. First, tumor cells with NE differentiation may be more resistant to the cytotoxic insult caused by neoadjuvant therapy [12, 14]. Second, cytotoxic injury may induce NE differentiation in tumor cells [12]. In the case of neoplasia, resistance of inherent endocrine cells in exocrine tumors to radiation and cytotoxic drugs has also been demonstrated in other organs, notably the prostate [18]. The endocrine cells are thought to represent a group of terminally differentiated cells that are in the quiescent stage of the cell cycle and are therefore less responsive to treatment effects. Recent studies have shown that NE-secreted products, such as serotonin, somatostatin, and bombesin, may influence tumor growth by promoting proliferation, invasiveness, metastatic potential, and angiogenesis and by conferring antiapoptotic capabilities in prostatic and colorectal carcinoma [19, 20]. A more likely explanation for the increase in endocrine cells with treatment, therefore, relates to the possibility of endocrine differentiation of tumor cells induced by cytotoxic insult. Indeed, it is well known that differentiation and growth arrest are often associated processes. It has been shown in the human prostatic cancer cell line LNCaP that interleukin-6 both mediates cell growth arrest and induces endocrine differentiation, indicating a connection between growth inhibition and endocrine differentiation in prostate cancer [18]. Cox et al. [21] showed that the androgen-independent LNCaP-derived cell line C4–2 also acquired endocrine characteristics in response to treatment with physiologic and pharmacologic agents that elevate intracellular cyclic adenosine monophosphate, indicating that cells representing later stages of tumor progression are also capable of differentiation. In light of these observations, for prostatic carcinoma cell lines, it is plausible to postulate that the increased endocrine cells in tumors with a more advanced treatment response might reflect the fact that tumor cells may respond to treatment by differentiation into endocrine cells thus acquire an endocrine phenotype. Moreover, in prostate cancer, Liu et al. discovered an immunocyte expression protein that induces inflammatory response gene expression and contributes to NE prostate cancer differentiation [22]. Trans-differentiation of cancer cells is also observed in lung adenocarcinoma after tyrosine kinase inhibitor (TKI) therapy. In those cases, the adenocarcinoma transforms into small-cell lung cancer (SCLC) when resistance develops [23]. The differentiation seems to start from the same EGFR mutation of the adenocarcinoma counterpart and develops activating mutations of PIK3CA, inactivating mutations of TP53, and RB1 loss [24].\n\nConclusions\nThe clinical significance of endocrine differentiation in post-treated adenocarcinomas is still a controversial issue. Unfortunately, most cases of MANEC seem to be missed through biopsy-based diagnosis (it is most often misdiagnosed as adenocarcinoma). Therefore, many patients with MANEC will receive neoadjuvant treatment as is established for adenocarcinoma [25, 26]. Of note, in the majority of missed MANEC cases, immunohistochemistry for neuroendocrine markers is not performed; therefore, it is impossible to establish any prognostic markers. Because of its dual histological profile, both the clinical behavior and management of MANEC are substantially different from those of adenocarcinoma and are primarily influenced by the contribution of each component as well as the type of cells in the neuroendocrine component. La Rossa et al. reported that patients with MANEC composed of large neuroendocrine cells have better survival and clinical behavior than patients with nonlarge neuroendocrine cells (small-to-intermediate or mixed large-to-intermediate cells) [27]. With regard to localized gastric MANEC, relatively good survival was observed in the two most-recent large Asian studies [28, 29]. A recent Chinese study [30] that compared the outcome of gastroesophageal junction neuroendocrine neoplasms (GEJ-NENs) with other gastric neuroendocrine neoplasms (NENs) showed that NEC was more aggressive, with poorly differentiated morphology, than adenocarcinoma [31] and had a shorter survival than MANEC (25.2 vs. 73.3 months) [30]. Shia et al. reported [32] that the absence of an associated adenocarcinoma component was predictive of a worse outcome; however, previous studies about gastric or colorectal MANEC reported that there was no statistically significant difference in survival between MANECs and NEC [33, 34]. In this study, a number of GEJ-NECs were mixed with high-grade adenocarcinoma, the outcome of which is better than with pure NECs. In fact, the metastatic patterns of the two entities are different: regional lymph node metastasis of MANEC is more common, and distant metastasis frequently occurrs in NEC, indicating that the behavior of NEC may be more aggressive. In contrast, the latest and largest Western study reported very poor survival rates of localized gastric MANEC [35]. In some studies of colorectal carcinomas, a poorer prognosis was observed in patients with tumors that harbored chromogranin-positive cells [36, 37, 38, 39], but in other studies, this outcome was not confirmed [40, 41, 42, 43, 44]. Currently, there is no consensus regarding the prognostic significance of NE cells after neoadjuvant chemotherapy, and more studies are needed. Due to the small number of cases of reported MANEC, the clinical behavior is unclear. At present, it is generally agreed that surgery is the first line of treatment for cases with a resectable tumor. After radical resection, multimodal treatment with adjuvant radiotherapy and/or chemotherapy should be performed if indicated. However, it is still not clear whether the postoperative course and ideal management of cases of MANEC differ from those of cases of adenocarcinoma only or neuroendocrine carcinoma only. Lee et al. proposed that treatment should focus on the more aggressive cells of the tumor because the clinical outcome of this mixed tumor follows that of the more aggressive cell type [36]. Following WHO recommendations, we treated our patients as if they were affected by adenocarcinoma because it represented the most aggressive histologic component.\n\nStatement of Ethics\nThe description of cases is retrospective, and the people involved maintained completely anonymous. The patients included in this case report had provided written informed consent to publish the images, and the authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFig. 1 A. The tumor consists of clusters of glandular structures (H&E stain, 40× magnification). B. Drop of mucus in violet near nuclei (PAS-D +). C. Cells marked by the neuroendocrine marker CD56 (10× magnification). D. Neoplastic cells marked by neuroendocrine marker synaptophysin.\n\nFig. 2 A. Morphology of the tumor in the neuroendocrine component (H&E stain, 2.5× magnification). B. Epithelial-glandular part of the tumor, CD56 negative. C. Details of the epithelial component (H&E stain, 10× magnification) D. Neoplastic cells marked by neuroendocrine marker synaptophysin in a double stain with ki67 for the neuroendocrine component.\n==== Refs\nReferences\n1 Kitajima T Kaida S Lee S Haruta S Shinohara H Ueno M Mixed adeno(neuro)endocrine carcinoma arising from the ectopic gastric mucosa of the upper thoracic esophagus World J Surg Oncol 2013 9 11 (1) 218 24139488 \n2 Harada K Sato Y Ikeda H Maylee H Igarashi S Okamura A Clinicopathologic study of mixed adenoneuroendocrine carcinomas of hepatobiliary organs Virchows Arch 2012 3 460 (3) 281 9 22358181 \n3 Gurzu S Kadar Z Bara T Bara T Jr Tamasi A Azamfirei L Mixed adenoneuroendocrine carcinoma of gastrointestinal tract: report of two cases World J Gastroenterol 2015 1 21 (4) 1329 33 25632209 \n4 Liu XJ Feng JS Xiang WY Kong B Wang LM Zeng JC Clinicopathological features of an ascending colon mixed adenoneuroendocrine carcinoma with clinical serosal invasion Int J Clin Exp Pathol 2014 8 7 (9) 6395 8 25337298 \n5 Acosta AM Hamedani FS Kajdacsy-Balla A Wiley EL Primary Mixed Adenoneuroendocrine Carcinoma of the Gallbladder in a 55-Year-Old Female Patient: A Case Report and Review of the Literature Int J Surg Pathol 2015 8 23 (5) 414 8 25838330 \n6 Solcia E Klöppel G Sobin LH Histopathological Typing of Endocrine Tumours 2000 2nd ed Berlin, Germany Springer \n7 Watanabe J Suwa Y Ota M Ishibe A Masui H Nagahori K Clinicopathological and Prognostic Evaluations of Mixed Adenoneuroendocrine Carcinoma of the Colon and Rectum: A Case-Matched Study Dis Colon Rectum 2016 12 59 (12) 1160 7 27824701 \n8 La Rosa S Marando A Sessa F Capella C Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract: an update Cancers (Basel) 2012 1 4 (1) 11 30 24213223 \n9 Acosta AM Wiley EL Primary biliary mixed adenoneuroendocrine carcinoma (MANEC). A short review Arch Pathol Lab Med 2016 10 140 (10) 1157 62 27684986 \n10 Düzköylü Y Aras O Bostancı EB Keklik Temuçin T Ulaş M Mixed Adeno-Neuroendocrine Carcinoma; Case Series of Ten Patients with Review of the Literature Balkan Med J 2018 5 35 (3) 263 7 29551754 \n11 Marusyk A Polyak K Tumor heterogeneity: causes and consequences Biochim Biophys Acta 2010 1 1805 (1) 105 17 19931353 \n12 Shia J Tickoo SK Guillem JG Qin J Nissan A Hoos A Increased endocrine cells in treated rectal adenocarcinomas: a possible reflection of endocrine differentiation in tumor cells induced by chemotherapy and radiotherapy Am J Surg Pathol 2002 7 26 (7) 863 72 12131153 \n13 Ahlgren G Pedersen K Lundberg S Aus G Hugosson J Abrahamsson PA Regressive changes and neuroendocrine differentiation in prostate cancer after neoadjuvant hormonal treatment Prostate 2000 3 42 (4) 274 9 10679756 \n14 Bonkhoff H Neuroendocrine cells in benign and malignant prostate tissue: morphogenesis, proliferation, and androgen receptor status Prostate Suppl 1998 8 (S8 Suppl) 18 22 9690659 \n15 Shia J Tickoo SK Guillem JG Qin J Nissan A Hoos A Increased endocrine cells in treated rectal adenocarcinomas: a possible reflection of endocrine differentiation in tumor cells induced by chemotherapy and radiotherapy Am J Surg Pathol 2002 7 26 (7) 863 72 12131153 \n16 Adlakha H Bostwick DG Paneth cell-like change in prostatic adenocarcinoma represents neuroendocrine differentiation: report of 30 cases Hum Pathol 1994 2 25 (2) 135 9 7509774 \n17 Wang KL Yang Q Cleary KR Swisher SG Correa AM Komaki R The significance of neuroendocrine differentiation in adenocarcinoma of the esophagus and esophagogastric junction after preoperative chemoradiation Cancer 2006 10 107 (7) 1467 74 16955509 \n18 Spiotto MT Chung TD STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells Prostate 2000 2 42 (3) 186 95 10639189 \n19 Abrahamsson PA Neuroendocrine differentiation in prostatic carcinoma Prostate 1999 5 39 (2) 135 48 10221570 \n20 Seretis E Gavrill A Agnantis N Golematis V Voloudakis-Baltatzis IE Comparative study of serotonin and bombesin in adenocarcinomas and neuroendocrine tumors of the colon Ultrastruct Pathol 2001 Nov-Dec 25 (6) 445 54 11783909 \n21 Cox ME Deeble PD Lakhani S Parsons SJ Acquisition of neuroendocrine characteristics by prostate tumor cells is reversible: implications for prostate cancer progression Cancer Res 1999 8 59 (15) 3821 30 10447001 \n22 Chen WY Zeng T Wen YC Yeh HL Jiang KC Chen WH Androgen deprivation-induced ZBTB46-PTGS1 signaling promotes neuroendocrine differentiation of prostate cancer Cancer Lett 2019 1 440-441 35 46 30312731 \n23 Ferrer L Giaj Levra M Brevet M Antoine M Mazieres J Rossi G A Brief Report of Transformation From NSCLC to SCLC: Molecular and Therapeutic Characteristics J Thorac Oncol 2019 1 14 (1) 130 4 30217489 \n24 Sequist LV Waltman BA Dias-Santagata D Digumarthy S Turke AB Fidias P Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors Sci Transl Med 2011 3 3 (75) 75ra26 \n25 van Hagen P Hulshof MC van Lanschot JJ Steyerberg EW van Berge Henegouwen MI Wijnhoven BP CROSS Group Preoperative chemoradiotherapy for esophageal or junctional cancer N Engl J Med 2012 5 366 (22) 2074 84 22646630 \n26 Cunningham D Allum WH Stenning SP Thompson JN Van de Velde CJ Nicolson M MAGIC Trial Participants Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N Engl J Med 2006 7 355 (1) 11 20 16822992 \n27 La Rosa S Marando A Furlan D Sahnane N Capella C Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers Am J Surg Pathol 2012 4 36 (4) 601 11 22314183 \n28 Kim BS Park YS Yook JH Kim BS Comparison of relapse-free survival in gastric neuroendocrine carcinoma (WHO grade 3) and gastric carcinoma Therap Adv Gastroenterol 2017 5 10 (5) 407 15 \n29 Ishida M Sekine S Fukagawa T Ohashi M Morita S Taniguchi H Neuroendocrine carcinoma of the stomach: morphologic and immunohistochemical characteristics and prognosis Am J Surg Pathol 2013 7 37 (7) 949 59 23759931 \n30 Zhang P Wang W Lu M Zeng C Chen J Li E Clinicopathological features and outcome for neuroendocrine neoplasms of gastroesophageal junction: A population-based study Cancer Med 2018 9 7 (9) 4361 70 30062861 \n31 Scardoni M Vittoria E Volante M Rusev B Bersani S Mafficini A Mixed adenoneuroendocrine carcinomas of the gastrointestinal tract: targeted next-generation sequencing suggests a monoclonal origin of the two components Neuroendocrinology 2014 100 (4) 310 6 25342539 \n32 Shia J Tang LH Weiser MR Brenner B Adsay NV Stelow EB Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? Am J Surg Pathol 2008 5 32 (5) 719 31 18360283 \n33 Ishida M Sekine S Fukagawa T Ohashi M Morita S Taniguchi H Neuroendocrine carcinoma of the stomach: morphologic and immunohistochemical characteristics and prognosis Am J Surg Pathol 2013 7 37 (7) 949 59 23759931 \n34 Jesinghaus M Konukiewitz B Keller G Kloor M Steiger K Reiche M Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas Mod Pathol 2017 4 30 (4) 610 9 28059096 \n35 La Rosa S Inzani F Vanoli A Klersy C Dainese L Rindi G Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms Hum Pathol 2011 10 42 (10) 1373 84 21531442 \n36 Lee HH Jung CK Jung ES Song KY Jeon HM Park CH Mixed exocrine and endocrine carcinoma in the stomach: a case report J Gastric Cancer 2011 6 11 (2) 122 5 22076213 \n37 Hamada Y Oishi A Shoji T Takada H Yamamura M Hioki K Endocrine cells and prognosis in patients with colorectal carcinoma Cancer 1992 6 69 (11) 2641 6 1571893 \n38 Syversen U Halvorsen T Mårvik R Waldum HL Neuroendocrine differentiation in colorectal carcinomas Eur J Gastroenterol Hepatol 1995 7 7 (7) 667 74 8590163 \n39 Yin J Liang Y Wang H [Significance of endocrine cells and their hormones in colorectal cancer] Zhonghua Zhong Liu Za Zhi 1997 5 19 (3) 192 5 10920894 \n40 Ferrero S Buffa R Pruneri G Siccardi AG Pelagi M Lee AK The prevalence and clinical significance of chromogranin A and secretogranin II immunoreactivity in colorectal adenocarcinomas Virchows Arch 1995 426 (6) 587 92 7655739 \n41 Lapertosa G Baracchini P Delucchi F Prevalence and prognostic significance of endocrine cells in colorectal adenocarcinomas Pathologica 1994 4 86 (2) 170 3 7936761 \n42 Mori M Mimori K Kamakura T Adachi Y Ikeda Y Sugimachi K Chromogranin positive cells in colorectal carcinoma and transitional mucosa J Clin Pathol 1995 8 48 (8) 754 8 7560204 \n43 Smith DM Jr Haggitt RC The prevalence and prognostic significance of argyrophil cells in colorectal carcinomas Am J Surg Pathol 1984 2 8 (2) 123 8 6322602 \n44 Paspala A Machairas N Prodromidou A Spartalis E Ioannidis A Kostakis ID Management of MANEC of the colon and rectum: A comprehensive review of the literature Mol Clin Oncol 2018 8 9 (2) 219 22 30101026\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "12(2)",
"journal": "Case reports in oncology",
"keywords": "Mixed adenoneuroendocrine carcinoma; Neoadjuvant chemotherapy; Neuroendocrine differentiation",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "434-442",
"pmc": null,
"pmid": "31275134",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10221570;10447001;10639189;10679756;10920894;11783909;12131153;1571893;16822992;16955509;18360283;19931353;21430269;21531442;22076213;22314183;22358181;22646630;23759931;24139488;24213223;25337298;25342539;25632209;25838330;27684986;27824701;28059096;28507599;29551754;30062861;30101026;30217489;30312731;6322602;7509774;7560204;7655739;7936761;8590163;9690659",
"title": "Diagnosis of Mixed Adenoneuroendocrine Carcinoma (MANEC) after Neoadjuvant Chemotherapy for Pancreatic and Gastric Adenocarcinoma: Two Case Reports and a Review of the Literature.",
"title_normalized": "diagnosis of mixed adenoneuroendocrine carcinoma manec after neoadjuvant chemotherapy for pancreatic and gastric adenocarcinoma two case reports and a review of the literature"
} | [
{
"companynumb": "IT-SA-2019SA285661",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Essential thrombocythemia is well-known to transform to other myeloid disorders, such as leukemia; however, the risk for development of lymphoma is not as well studied. This case report discusses a 76-year-old man with a history of prefibrotic post-essential thrombocythemia myelofibrosis on ruxolitinib, who developed anemia, thrombocytopenia, and leukocytosis with peripheral blasts. Results of a bone marrow biopsy and PET and CT scans revealed stage IV leukemic diffuse large B-cell lymphoma. Several days after cessation of ruxolitinib, the patient developed fevers, hypotension, and low-grade disseminated intravascular coagulation, and subsequently developed spontaneous tumor lysis syndrome, which resulted in death. This case is unique in several aspects: it highlights the rare possibility of lymphomatous transformation of myeloproliferative disorders, an unusual presentation of lymphoma masquerading as leukemia, and the possibility of ruxolitinib withdrawal syndrome. Additionally, this case serves as a reminder that the use of novel therapies should be adopted after a thorough assessment of long-term risks, including those associated with abrupt withdrawal.",
"affiliations": "From the Department of Internal Medicine, Division of Hematology-Oncology; Department of Pathology and Microbiology; and Human Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.;From the Department of Internal Medicine, Division of Hematology-Oncology; Department of Pathology and Microbiology; and Human Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.;From the Department of Internal Medicine, Division of Hematology-Oncology; Department of Pathology and Microbiology; and Human Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.;From the Department of Internal Medicine, Division of Hematology-Oncology; Department of Pathology and Microbiology; and Human Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.;From the Department of Internal Medicine, Division of Hematology-Oncology; Department of Pathology and Microbiology; and Human Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.;From the Department of Internal Medicine, Division of Hematology-Oncology; Department of Pathology and Microbiology; and Human Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.;From the Department of Internal Medicine, Division of Hematology-Oncology; Department of Pathology and Microbiology; and Human Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.;From the Department of Internal Medicine, Division of Hematology-Oncology; Department of Pathology and Microbiology; and Human Genetics Laboratory, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.",
"authors": "Bhatt|Vijaya Raj|VR|;Bociek|R Gregory|RG|;Yuan|Ji|J|;Fu|Kai|K|;Greiner|Timothy C|TC|;Dave|Bhavana J|BJ|;Rajan|Sandeep K|SK|;Armitage|James O|JO|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.6004/jnccn.2015.0039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "13(3)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D001853:Bone Marrow; D017809:Fatal Outcome; D006801:Humans; D016130:Immunophenotyping; D008214:Lymphocytes; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009196:Myeloproliferative Disorders; D049268:Positron-Emission Tomography; D055728:Primary Myelofibrosis; D013920:Thrombocythemia, Essential; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "281-7",
"pmc": null,
"pmid": "25736004",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leukemic diffuse large B-cell lymphoma in a patient with myeloproliferative disorder.",
"title_normalized": "leukemic diffuse large b cell lymphoma in a patient with myeloproliferative disorder"
} | [
{
"companynumb": "US-INCYTE CORPORATION-2015IN001394",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RUXOLITINIB"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nTo evaluate a larger number of patients receiving a vancomycin-dosing regimen of 20 mg/kg IV every 8 h for Group B streptococcus (GBS) chemoprophylaxis and analyze maternal and neonatal cord blood levels at delivery.\n\n\nMETHODS\nWe prospectively enrolled every mother that entered labor with a positive GBS culture and a high-risk penicillin allergy with resistance to clindamycin or unknown sensitivity. Maternal and cord blood vancomycin levels were obtained at delivery. Time from last dose completion to delivery, number of doses administered and body mass index were assessed.\n\n\nRESULTS\nA total of 30 patients consented and 23 (77%) maternal levels and cord blood levels were therapeutic. There were eight patients where one or both maternal and/or cord blood values were non-therapeutic, but in six of these, there was a regimen violation regarding timing of the next dose or total dosage administered. Of the 24 patients where the regimen was correctly followed, 22 (92%) had therapeutic maternal and cord blood levels.\n\n\nCONCLUSIONS\nUsing a vancomycin-dosing regimen of 20 mg/kg IV every 8 h (maximum individual dose of 2 g) produces therapeutic levels in more than 75% of mother/newborn pairs and this can exceed 90% when dosing regimens are correctly followed.",
"affiliations": "a Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine , University of Tennessee Medical Center , Knoxville , TN , USA.;a Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine , University of Tennessee Medical Center , Knoxville , TN , USA.",
"authors": "Towers|Craig V|CV|;Weitz|Beth|B|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.1080/14767058.2017.1306049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": "31(8)",
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": "Group B streptococcus chemoprophylaxis; Vancomycin in pregnancy; infections in pregnancy; neonatal sepsis",
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": "D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011446:Prospective Studies; D014640:Vancomycin",
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "1021-1024",
"pmc": null,
"pmid": "28287001",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Transplacental passage of vancomycin.",
"title_normalized": "transplacental passage of vancomycin"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP000051",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection. Its use is promising, especially in low- and middle-income countries, because of a high resistance barrier and a good safety profile. Very recently, a World Health Organization safety signal has been raised regarding neural tube defects after the first-trimester exposure. Furthermore, to date, the experience is limited regarding the use of the other InSTI drugs (raltegravir and elvitegravir) during pregnancy. Our objective is to analyze the safety of InSTI drugs in pregnant women.\n\n\n\nNation-wide database cohort analysis.\n\n\n\nWe evaluated the risk of major birth defects according to EUROCAT classification in pregnant women, which had had a first-trimester exposure to dolutegravir, raltegravir, or elvitegravir.\n\n\n\nWe found a major birth defect rate of 1.9% in the general population between 2012 and 2016. As InSTI drugs are not used as first-line therapy in pregnant women, we found a very low exposure in this population. Among 49, 240, and 70 pregnancy outcomes exposed to dolutegravir, raltegravir, and elvitegravir, respectively, during the first trimester, there were 2, 3, and 1 major birth defects, respectively. There was no case of neural tube defect.\n\n\n\nDrug exposure to InSTI is limited in our nation-wide database. Nevertheless, our data do not support a pharmacovigilance signal on neural tube defects in women exposed to dolutegravir, raltegravir or elvitegravir during pregnancy. Owing to a small number of pregnancy outcomes, these results need to be confirmed with further studies.",
"affiliations": "Centre Régional de Pharmacovigilance, Hopital Cochin, Assistance Publique-Hopitaux de Paris, Paris, France.;EA7323, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.;Centre Régional de Pharmacovigilance, Hopital Cochin, Assistance Publique-Hopitaux de Paris, Paris, France.",
"authors": "Chouchana|Laurent|L|;Beeker|Nathanael|N|;Treluyer|Jean-Marc|JM|",
"chemical_list": "D044966:Anti-Retroviral Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; C509700:elvitegravir; C562325:dolutegravir",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0000000000002065",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-4135",
"issue": "81(4)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D015331:Cohort Studies; D000013:Congenital Abnormalities; D024882:Drug Resistance, Viral; D005260:Female; D005602:France; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D009436:Neural Tube Defects; D010078:Oxazines; D060735:Pharmacovigilance; D010879:Piperazines; D011247:Pregnancy; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "481-486",
"pmc": null,
"pmid": "31021990",
"pubdate": "2019-08-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Is There a Safety Signal for Dolutegravir and Integrase Inhibitors During Pregnancy?",
"title_normalized": "is there a safety signal for dolutegravir and integrase inhibitors during pregnancy"
} | [
{
"companynumb": "FR-009507513-1905FRA012398",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RALTEGRAVIR POTASSIUM"
},
"drugadditional": ... |
{
"abstract": "Thrombopoietin mimetics are new treatment options for patients with immune throm-bocytopenia (ITP). Because of their mechanism of action, long-term administration was envisioned in order to maintain effective thrombopoiesis. We report on 30 romiplostim treated patients: 13/27 responders (48%) achieved stable platelet counts on a mean romiplostim dose of 2.43 µg/kg and were able to stop romiplostim after a mean of 44.3 weeks (range 12-122) on therapy with sustained response maintained at a mean of 26 months (range 12-52). No bleeding events occurred during the observational period. No specific patient's features nor pattern of early response seemed to predict for sustained response. However, patients achieving safe platelet counts at lower dosages are probably worth a try of therapy tapering and discontinuation. Our observations support feasibility of romiplostim safe suspension in a relevant proportion of ITP patients.",
"affiliations": "Hematology and Transplant Unit , A.O. San Gerardo, University of Milan Bicocca ; Milan, Italy.;Hematology and Oncology Department, A.O. Ospedale Niguarda Cà Granda , Milan, Italy.;Hematology and Transplant Unit , A.O. San Gerardo, University of Milan Bicocca ; Milan, Italy.;Hematology and Transplant Unit , A.O. San Gerardo, University of Milan Bicocca ; Milan, Italy.;Hematology and Oncology Department, A.O. Ospedale Niguarda Cà Granda , Milan, Italy.;Hematology and Transplant Unit , A.O. San Gerardo, University of Milan Bicocca ; Milan, Italy.",
"authors": "Carpenedo|Monica|M|;Cantoni|Silvia|S|;Coccini|Veronica|V|;Fedele|Marilena|M|;Morra|Enrica|E|;Pogliani|Enrico Maria|EM|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2015.5673",
"fulltext": "\n==== Front\nHematol RepHematol RepHRHematology Reports2038-83222038-8330PAGEPress Publications, Pavia, Italy hr-2015-1-567310.4081/hr.2015.5673Case ReportFeasibility of Romiplostim Discontinuation in Adult Thrombopoietin-Receptor Agonist Responsive Patients with Primary Immune Thrombocytopenia: An Observational Retrospective Report in Real Life Clinical Practice Carpenedo Monica 1Cantoni Silvia 2Coccini Veronica 1Fedele Marilena 1Morra Enrica 2Pogliani Enrico Maria 11 Hematology and Transplant Unit, A.O. San Gerardo, University of Milan Bicocca; Milan, Italy2 Hematology and Oncology Department, A.O. Ospedale Niguarda Cà Granda, Milan, ItalyHematology and Transplant Unit, A.O San Gerardo and University of Milan Bicocca, Monza (MB), Italy. + 39.3283343608 - +39.02332539. mnc.carpenedo@gmail.com; m.carpenedo@hsgerardo.orgContributions: MC and SC designed the study, were the principal investigators, recruited the patients, were involved in data collection, analyzed the data, wrote and revised the manuscript; VC and MF were involved in data collection; EM and EMP supervised the project\n\nConflict of interests: MC and SC has participated in advisory boards and as speakers for Amgen and Glaxo SmithKleine. The remaining Authors declare no conflict of interest.\n\n24 2 2015 24 2 2015 7 1 567314 10 2014 18 11 2014 04 12 2014 ©Copyright M. Carpenedo et al.2015Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Thrombopoietin mimetics are new treatment options for patients with immune throm-bocytopenia (ITP). Because of their mechanism of action, long-term administration was envisioned in order to maintain effective thrombopoiesis. We report on 30 romiplostim treated patients: 13/27 responders (48%) achieved stable platelet counts on a mean romiplostim dose of 2.43 µg/kg and were able to stop romiplostim after a mean of 44.3 weeks (range 12-122) on therapy with sustained response maintained at a mean of 26 months (range 12-52). No bleeding events occurred during the observational period. No specific patient’s features nor pattern of early response seemed to predict for sustained response. However, patients achieving safe platelet counts at lower dosages are probably worth a try of therapy tapering and discontinuation. Our observations support feasibility of romiplostim safe suspension in a relevant proportion of ITP patients.\n\nKey words\nimmune thrombocytopeniathrombopoietin receptor agonistssustained response\n==== Body\nIntroduction\nIn at least some of immune thrombocytopenia (ITP) patients, thrombocytopenia is worsened by inappropriately low levels of platelet production, unable to compensate for the increased peripheral immune-mediated destruction of platelets. Until recently, management of ITP adult patients with platelet counts <30×109/L and/or bleeding signs has relied upon the use of drugs or procedures (i.e. splenectomy) aimed at decreasing B-cell and T-cell immune-response to autologous platelets and megakariocytes. The availability of thrombopoietin-receptor agonist (TPO-RA) has offered new opportunities for treating adult ITP patients acting on megakariocyte survival and production of platelets.1\n\nThrombopoietin-receptor agonist increase thrombopoiesis activating the c-Mpl receptor on bone marrow megakariocytes, thus providing an additional stimulus to increase their survival and platelet production.1\n\nResponse rates up to 90% in long-term follow-up studieshave been reported with both romiplostim and eltrombopag.2,3 However, platelet counts usually return to pretreatment levels upon discontinuation of treatment and long-term, if not life-long, administration was envisioned in order to maintain effective thrombopoiesis.\n\nIn recent years sporadic patients have been reported as being able to discontinue treatment with either romiplostim or eltrombopag without relapsing off-therapy.4-10 Most studies were not designed to assess feasibility of TPORA discontinuation and thus true prevalence of patients able to maintain remission off therapy can not be inferred.\n\nA French observational study confirms that romiplostim can be successfully discontinued:11 of the 28/54 responding patients, 8 remained in complete remission off therapy at a median follow up of 13,5 months (range 5-27). Data from a recently presented interim analysis of a phase 2 study of platelet response and remission rates in ITP patients receiving romiplostim show that 11 of 38 evaluable patients (29%) were able to maintain remission (i.e. 24 weeks of platelet counts ≥50×109/L) off any treatment.12\n\nWe report our experience with the peptibody romiplostim in a small series of patients unresponsive to immunosuppressive therapy who were treated with this TPO-RA for variable lengths of time. Some of these patients were able to discontinue therapy after achieving response, without relapsing at long-term follow-up.\n\nCase Report\nBetween September 2009 and May 2014 a total of 30 patients (11 M; mean age at romiplostim treatment 50.7 yrs, range 18-82) received romiplostim at two collaborating Centers. Patients with shorter follow-up on treatment with romiplostim or on eltrombopag are not included in the present analysis. Patient characteristics at the time of romiplostim administration are summarized in Table 1. Patients were defined either as non responders or refractory according to the International Working Party (IWP) proposed standardization of terminology for ITP.13 All patients are enrolled in a local Italian registry (REL-ITP registry), and informed consent to demographic and clinical data use is given at enrollment. The REL registry has received approval by the human subjects research review board of both participating hospitals.\n\nOverall, 27/30 patients (90%) responded to romiplostim according to IWP criteria.13 Of the 27 responders: 1 patient (#4) was lost to follow-up; 1 patient (#5) discontinued romiplostim due to acute myocardial infarction, at the time of SAE, romiplostim dose was 10 µg/kg/week and platelet counts were 84×109/L; in 5/27 patients (#6-10) romiplostim was used as bridge to splenectomy; 5/27 patients (#11-15) lost response at 11, 6, 11, 12 and 11 months respectively; neutralizing anti-romiplostim antibodies could be searched for in 3/5 patients; in three (#13, 14 and 15) the test yielded a positive result; the remaining two patients could not be tested; in 2/27 patients (#16 and 17) romiplostim administration is ongoing (56 and 12 months respectively); 13/27 patients (#18-30) achieved stable, safe platelet counts and were able to stop romiplostim after a mean of 43.3 weeks (range 12-122) on therapy with sustained response maintained at a mean of 28.8 months (range 15-55).\n\nData on patients who achieved stable response off therapy are summarized in Table 2. Strict platelet monitoring was maintained during follow up off therapy. In 7/13 patients a decreased platelet count compared to a previous control was found weeks from discontinuation of weekly romiplostim administration. These patients were re-exposed to a limited number of one shot low (1 or 2 mcg/kg) dose of romiplostim and regained a stable response, as shown for four patients in Figure 1.\n\nNo bleeding events occurred during the observational period. Patient #29 developed lower limb superficial phlebitis while on romiplostim 1 µg/kg on alternate weeks and warfarin was started; platelets were 135×109/L at the time of the event; screening for lupus anticoagulant, anti-phospholipids antibodies, anti-beta2glycoprotein1 was negative. Romiplostim was discontinued a month later because platelet counts remained stable at around 100×109/L. Three patients (#18,20,28) had received the last rituximab course 4, 6 and 33 weeks before starting romiplostim; one patient (#19) received a first course of romiplostim as bridge to splenectomy having failed steroids and cyclosporine; a week after surgery he relapsed with severe thrombocytopenia and was re-treated with romiplostim. He received a total of 7 romiplostim doses administered over a 22 week period of time; romiplostim was discontinued at 22 weeks from splenectomy since stable, ≥100×109/L platelet counts were achieved.\n\nBone marrow biopsies for detection of fibrous changes during romiplostim use were not performed since most of our patients received treatment for less than 18 months.\n\nDiscussion\nOverall, our experience with romiplostim in real life practice is in line with reported findings from controlled studies with 90% of patients (27/30) responding. However, in our experience the percentage of patients able to discontinue romiplostim without relapsing is noteworthy: 48%, if we consider the whole number of romiplostim responders (13 of 27 responders) and 65% if we consider only patients who received long-term treatment (13 of 20 patients) i.e. not considering patients receiving romiplostim as bridge to splenectomy, lost to follow-up, or who discontinued the drug because of SAE.\n\nIn 5 chronic ITP patients out of 13 long term responders, romiplostim seemed to be the only treatment responsible for sustained response. Indeed, it has been proposed that TPO-RA therapy may result in improved immune regulation by regulatory T cells (Tregs) possibly restoring immune tolerance.14\n\nSimilar immune-modulating effects have also been described for other treatment modalities (e.g. rituximab, high-dose dexamethasone, intravenous immunoglobulin) which result in sustained responses in a fraction of ITP patients.15,16\n\nIn the remaining 8 patients, response might have been either spontaneous (2 newly diagnosed and 3 persistent disease patients) or secondary to rituximab (2 patients) or splenectomy (1 patient). Nevertheless, use of romiplostim may be a treatment option for patients with persistently low platelet counts awaiting for platelet recovery, either it be spontaneous or secondary to disease-modifying treatments for which a possible late-response can be anticipated.\n\nNo specific patient’s features (e.g. age, ITP duration, lines of previous treatment) nor pattern of early response (e.g. dose requirements, time to response) seemed to consistently predict for sustained response off therapy. However, it seems that patients achieving safe platelet counts at lower dosages are probably worth a try of therapy tapering and discontinuation. Manufacturer dose adjustment rules allow romiplostim to be discontinued when appropriate and clinical judgment was used to manage patients.\n\nMoreover, it appears that TPO-RA do not cause tachyphylaxis. This has been specifically tested and demonstrated for eltrombopag and it is conceivable also for romiplostim:17 one of the patients presented by Newland5 received a single romiplostim dose after 11 weeks off therapy and regained high platelet counts; thereafter, hemostatic platelet counts were maintained without any therapy for 2 years. Similar results were observed in a fraction of our patients. All 7 patients who were reexposed to romiplostim weeks after weekly administration was stopped (Table 2 and Figure 1), regained a platelet response. Knowledge that TPO-RA can be safely administered on a on-demand basis without loss of effectiveness offers the possibility of re-exposing relapsed patients without the threat of these patients not being able to regain a response. Moreover, need of on demand therapy doesn’t seem to predict for lost of long-term response to romiplostim. This new finding is probably worth being taken into account in planning prospective studies of feasibility of romiplostim discontinuation.\n\nThe finding that at least 3 of 5 patients who abruptly lost response to romiplostim tested positive for neutralizing antibodies suggests that development of these antibodies may be a more frequent event than expected.\n\nBeing a retrospective observational study, our results should be interpreted with caution, but still they suggest that in a significant fraction of patients, in real world practice, sustained remission without disease recurrence may be obtained after a relatively short-term administration of romiplostim.\n\nConclusions\nTo date, because of their known mechanism of action, TPO-RA are thought to be effective only while the treatment is ongoing and the proper dose is being administered. However increasing reported evidence exists on the occurrence of sustained responses after TPORA discontinuation. Our observations support the proposal of using romiplostim as bridge to recovery, either it be spontaneous (e.g. in newly diagnosed or persistent ITP), TPO-RA induced or representing a late-response to previously administered treatments, rather than long-term treatment. This approach would have relevant clinical implications. First of all, concern about TPO-RA long-term sides effects (marrow fibrosis, increased risk of thrombotic events), especially in younger patients, would be greatly reduced. Moreover, treatment costs, which currently also limit their use18 would be less of an issue. If results on persistent remissions after short-term romiplostim use were to be confirmed in larger patient population, this approach could be used to defer or avoid splenectomy and to spare patients the untoward effects of prolonged immunosuppressive treatments. This would be especially beneficial in newly diagnosed severe ITP failing first line therapy with steroids. Future biological and intervention studies are needed in order to identify predictive factors of long term sustained response, allowing clinicians to tailor the best treatment for each ITP patient.\n\nAcknowledgments\nthe abstract was submitted, accepted and presented at 19th Congress of European Hematology Association, Milan, June 2014.\n\nFigure 1. Platelet count in 4 patients who achieved a sustained response after romiplostim discontinuation and a limited number of on-demand re-exposure to the drug.\n\nTable 1. Main characteristics of enrolled patients.\n\nPatient (sex, age)\tAge at diagnosis\tAge at start of first line\tN, P, C at romipl start\tN. of previous treatment*\tTime from any treatment to romiplostim**\t\n1 (F, 47)\t37\t37\tC\t4\t120\t\n2 (F, 71)\t69\t69\tC\t4\t24\t\n3 (F, 33)\t11\t15\tC\t4\t264\t\n4 (M, 66)\t48\t66\tC\t2\t5\t\n5 (M, 56)\t34\t34\tC\t4\t264\t\n6 (F, 22)\t20\t20\tP\t3\t7\t\n7 (M, 68)\t61\t61\tC\t2\t89\t\n8 (F, 58)\t57\t57\tC\t2\t12\t\n9 (F, 24)\t24\t24\tN\t2\t1\t\n10 (F, 50)\t50\t50\tN\t2\t3\t\n11 (M, 59)\t42\t42\tC\t4\t204\t\n12 (F, 55)\t55\t55\tN\t2\t2\t\n13 (F, 37)\t37\t37\tP\t2\t2\t\n14 (F, 38)\t38\t28\tP\t2\t6\t\n15 (M, 18)\t18\t18\tN\t2\t2\t\n16 (F, 65)\t56\t56\tC\t4\t108\t\n17 (M, 28)\t28\t28\tP\t2\t7\t\n18 (F, 60)\t60\t60\tP\t2\t3\t\n19 (M, 66)\t64\t64\tC\t3\t24\t\n20 (F, 69)\t69\t69\tN\t3\t3\t\n21 (M, 20)\t11\t11\tC\t2\t2\t\n22 (M, 67)\t67\t67\tN\t2\t3\t\n23 (M 42)\t41\t41\tN\t2\t2\t\n24 (F, 51)\t51\t51\tP\t2\t6\t\n25 (F, 55)\t47\t47\tC\t3\t96\t\n26 (F, 42)\t20\t20\tC\t5\t252\t\n27 (F, 42)\t42\t42\tP\t2\t5\t\n28 (M, 60)\t57\t57\tC\t4\t26\t\n29 (F, 82)\t79\t80\tC\t4\t32\t\n30 (F,72)\t72\t72\tP\t4\t9\t\nN, newly; P, persistent; C, chronic.\n\n*Any type of steroid is considered as a single line of therapy. IVIG given as isolated drug is considered as a single line of therapy. IVIG + steroid if given associated, is considered as a single line of therapy. Other possible therapies: Rituximab, Cyclosporin, Azathioprine, Vincristine.\n\n**Time elapsed (months) from any treatment required for ITP and romiplostim.\n\nTable 2. Characteristics of patients who achieved a sustained response after romiplostim discontinuation.\n\nPatient\tSex, age at R start\tPlt count at R start (xl09/L)\tMax dose R (mcg/kg)\tMean dose R (mcg/kg)\tLast dose R (mcg/kg) before suspension\tRe exposure: n. of on-demand R doses\tTime interval at re exposure after R stop (weeks)\tPlt at time of re-exposure (xl09/L)\tMin-max Plt after R definitive stop (xl09/L)\tDuration of R treatment (weeks)\tPlt at last follow up (xl09//L)\tTime (months) of therapy\t\n18\tF, 60\t2\t1\t1\t1\t0\tn.a\tn.a\t210-320\t12\t250\t55\t\n19*\tM, 66\t13\t7\t3,5\t2\t2\t4,+7\t12,25\t94-324\t22\t287\t31\t\n20\tF, 69\t4\t3\t1,5\t1\t10\t4 (10 wkly doses)\t63\t96-120\t37\t145\t19\t\n21\tM,20\t1\t6\t3,3\t5\t0\tn.a\tn.a\t194-334\t15\t243\t43\t\n22\tM, 67\t11\t5\t3,09\t2\t2\t4,+11\t67,64\t67-314\t25\t118\t35\t\n23\tM,42\t1\t7\t3,3\t3\t0\tn.a\tn.a\t207-355\t14\t134\t15\t\n24\tF, 51\t22\t7\t3,3\t1\t3\t3, +4, +4\t35,60,37\t84-153\t68\t128\t20\t\n25\tF,55\t20\t6\t3,8\t6\t0\tn.a\tn.a\t67-298\t122\t115\t19\t\n26*\tF, 42\t22\t5\t2,7\t2\t0\tn.a\tn.a\t243-411\t16\t210\t19\t\n27\tF,42\t21\t2\t1,8\t1\t2\t3,+ 3\t38,40\t52-120\t62\t87\t15\t\n28*\tM,60\t5\t3\t1,71\t1\t4\t12,+7,+4,+7\t31,42,76,91\t155-313\t63\t113\t44\t\n29*\tF, 82\t21\t1\t0,5\t1\t1\t10\t75\t63-289\t94\t107\t32\t\n30*\tF, 72\t10\t3\t2,09\t2\t0\tn.a\tn.a\t138-281\t27\t121\t28\t\nMean (range)\t56\t11.7\t4.3\t2.43\t2.1\t–\t–\t–\tmin 128\t\t158.3\t28.8\t\n\t(42-82)\t(1-22)\t(1-7)\t(0.5-3.8)\t(1-6)\t\t\t\t(52-243)\t44.3 (12-122)\t(87-287)\t(15-55)\t\nR, Romiplostim; Pit, platelet; n.a, not applicable. Mean dose of Romiplostim: it is calculated as the mean of all administered doses during all period of treatment.\n\n*Splenectomized patients.\n==== Refs\nReferences\n1. Kuter DJ \nThrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia . Ann Rev Med 2009 ;60 :193 -206 .19642221 \n2. Kuter DJ Bussel JB Newland A \nLong-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy . Br J Hematol 2013 ;161 :411 -23 .\n3. Saleh MN Bussel JB Cheng G \nSafety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study . Blood 2013 ;121 :537 -45 .23169778 \n4. Bussel JB Rodeghiero F Lyons R \nSustained hemostatic platelet counts in adults with immune thrombocytopenia (ITP) following cessation of treatment with the TPO receptor agonist romiplostim: report of 9 cases . Blood 2011 ;118 :3281 .\n5. Newland A Cervinek L Eggermann J \nSustained hemostatic platelet counts in adult patients with primary immune thrombocytopenia (ITP) following cessation of romiplostim – four European case studies . Haematologica 2011 ;96 :ABS237 .\n6. Ghadaki B Nazi I Kelton JG Arnold DM \nSustained remissions of immune throm-bocytopenia associated with the use of thrombopoietin receptor agonists . Transfusion 2013 ;53 :2807 -12 .23451917 \n7. Thachil J Salter I George JN \nComplete remission of refractory immune thrombocytopenia (ITP) with a short course of Romiplostim . Eur J Hematol 2013 ;91 :376 -7 .\n8. Bussel JB Wang X Eisen M \nCase studies of remission in adults with immune thrombocytopenia (ITP) following cessation of treatment with the TPO receptor agonist romiplostim . Blood 2013 ;122 :ABS328 .\n9. Bussel JB Saleh MN Wong RSM \nUpdate on the safety and efficacy of EXTENDed treatment with eltrombopag (EPAG) in adults with chronic immune thrombocytopenia (ITP) . Blood 2013 ;122 :ABS2315 .\n10. González-López TJ González-Porras JR Arefi M \nSustained response after short-medium-term treatment with eltrombopag in patients with ITP . Blood 2013 ;122 :ABS2323 .\n11. Mahévas M Fain O Ebbo M \nThe temporary use of thrombopoietin-receptor agonists may induce a prolonged remission in adult chronic immune thrombocytopenia. Results of a French observational study . Br J Hematol 2014 ;165 :865 -9 .\n12. Stasi R Newland A Godeau B \nAn interim analysis of a phase 2, single-arm study of platelet responses and remission rates in patients with immune thrombocytopenia (ITP) receiving romiplostim . Blood 2013 ;122 :ABS1074 .\n13. Rodeghiero F Stasi R Gernsheimer T \nStandardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group . Blood 2009 ;113 :2386 -93 .19005182 \n14. Bao W Bussel JB Heck S \nImproved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents . Blood 2010 ;116 :4639 -45 .20688957 \n15. Stasi R Cooper N Del Poeta G \nAnalysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab . Blood 2008 ;112 :1147 -50 .18375792 \n16. Ling Y Cao X Yu Z Ruan C \nCirculating dendritic cells subsets and CD4+ Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome . Eur J Hematol 2007 ; 79 :310 -6 .\n17. Bussel JB Psaila B Saleh MN \nEfficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura . Blood 2008 ;112 : ABS3431 .\n18. Zeng Y Duan X Xu J Ni X \nTPO receptor agonist for chronic idiopathic thrombocytopenic purpura . Cochrane Database Syst Rev 2011 ;CD008235 21735426\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2038-8322",
"issue": "7(1)",
"journal": "Hematology reports",
"keywords": "immune thrombocytopenia; sustained response; thrombopoietin receptor agonists",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "5673",
"pmc": null,
"pmid": "25852848",
"pubdate": "2015-02-24",
"publication_types": "D002363:Case Reports",
"references": "19642221;19005182;23822831;17692100;21735426;18375792;23451917;23432528;23169778;20688957;24725224",
"title": "Feasibility of romiplostim discontinuation in adult thrombopoietin-receptor agonist responsive patients with primary immune thrombocytopenia: an observational retrospective report in real life clinical practice.",
"title_normalized": "feasibility of romiplostim discontinuation in adult thrombopoietin receptor agonist responsive patients with primary immune thrombocytopenia an observational retrospective report in real life clinical practice"
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"abstract": "Disseminated nocardiosis is a rare, life-threatening disease. Particularly at risk are immunocompromised patients, highlighting the crucial role of host factors. Conventional intensive antibiotic treatment has improved survival rates, but the overall prognosis of patients with disseminated nocardiosis remains unsatisfactory. In this Grand Round, we present a case of severe nocardiosis that did not respond to standard therapy. The patient's condition deteriorated when antibiotic therapy was given alone and improved substantially only after coadministration of interferon gamma. We review the literature relevant to adjuvant interferon gamma therapy of nocardiosis and discuss its potential harms and benefits. Overall, we consider such treatment as beneficial and low risk if the patient is followed-up closely. We conclude that clinicians should consider this regimen in refractory cases of severe Nocardia infection.",
"affiliations": "Department of Gastroenterology, Infectious Disease and Rheumatology, Charité Universitätsmedizin Berlin, Germany; Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany. Electronic address: thomas.derungs@charite.de.;Department of Gastroenterology, Infectious Disease and Rheumatology, Charité Universitätsmedizin Berlin, Germany; Department of Respiratory Medicine, Evangelische Lungenklinik, Berlin, Germany.;Pathologie PathoTres, Berlin, Germany.;Department of Gastroenterology, Infectious Disease and Rheumatology, Charité Universitätsmedizin Berlin, Germany.",
"authors": "Derungs|Thomas|T|;Leo|Fabian|F|;Loddenkemper|Christoph|C|;Schneider|Thomas|T|",
"chemical_list": "D000277:Adjuvants, Pharmaceutic; D000900:Anti-Bacterial Agents; D007371:Interferon-gamma",
"country": "United States",
"delete": false,
"doi": "10.1016/S1473-3099(20)30920-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-3099",
"issue": "21(10)",
"journal": "The Lancet. Infectious diseases",
"keywords": null,
"medline_ta": "Lancet Infect Dis",
"mesh_terms": "D000277:Adjuvants, Pharmaceutic; D000818:Animals; D000900:Anti-Bacterial Agents; D004359:Drug Therapy, Combination; D006790:Host-Parasite Interactions; D006801:Humans; D007371:Interferon-gamma; D009615:Nocardia; D009617:Nocardia Infections",
"nlm_unique_id": "101130150",
"other_id": null,
"pages": "e334-e340",
"pmc": null,
"pmid": "34425068",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment of disseminated nocardiosis: a host-pathogen approach with adjuvant interferon gamma.",
"title_normalized": "treatment of disseminated nocardiosis a host pathogen approach with adjuvant interferon gamma"
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"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-321067",
"fulfillexpeditecriteria": "1",
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"abstract": "Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.\n\n\n\nExpression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.\n\n\n\nWe show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.\n\n\n\nHere, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy.",
"affiliations": "Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Clinic of paediatric Oncohematology, University Hospital of Padova, Padova, 35128, Italy.;Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, 35128, Italy.;Istituto Oncologico Veneto - IRCCS, Padova, 35128, Italy.;Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Department of paediatric, Centro Ricerca M. Tettamanti, University of Milano Bicocca, Fondazione MBBM, Monza, 20900, Italy.;Department of Women's and Children's Health, University of Padova, Padova, 35128, Italy.;Istituto di Ricerca paediatrica Città della Speranza-IRP, corso Stati Uniti 4, Padova, 35127, Italy. luca.persano@unipd.it.",
"authors": "Bortolozzi|Roberta|R|;Bresolin|Silvia|S|;Rampazzo|Elena|E|;Paganin|Maddalena|M|;Maule|Francesca|F|;Mariotto|Elena|E|;Boso|Daniele|D|;Minuzzo|Sonia|S|;Agnusdei|Valentina|V|;Viola|Giampietro|G|;Te Kronnie|Geertruy|G|;Cazzaniga|Giovanni|G|;Basso|Giuseppe|G|;Persano|Luca|L|",
"chemical_list": "D007527:Isoenzymes; D014750:Vincristine; D017258:Medroxyprogesterone Acetate; D010088:Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; D000074408:Aldo-Keto Reductases; C435496:AKR1C2 protein, human; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase",
"country": "England",
"delete": false,
"doi": "10.1038/s41416-018-0014-0",
"fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group UK London\n\n29515258\n14\n10.1038/s41416-018-0014-0\nArticle\nAKR1C enzymes sustain therapy resistance in paediatric T-ALL\nBortolozzi Roberta 1\nBresolin Silvia 1\nRampazzo Elena 12\nPaganin Maddalena 3\nMaule Francesca 1\nMariotto Elena 1\nBoso Daniele 1\nMinuzzo Sonia 4\nAgnusdei Valentina 5\nViola Giampietro 1\nte Kronnie Geertruy 1\nCazzaniga Giovanni 6\nBasso Giuseppe 13\nPersano Luca +390498215486 luca.persano@unipd.it\n\n2\n1 0000 0004 1757 3470 grid.5608.b Department of Women’s and Children’s Health, University of Padova, Padova, 35128 Italy\n2 Istituto di Ricerca paediatrica Città della Speranza–IRP, corso Stati Uniti 4, Padova, 35127 Italy\n3 0000 0004 1760 2630 grid.411474.3 Clinic of paediatric Oncohematology, University Hospital of Padova, Padova, 35128 Italy\n4 0000 0004 1757 3470 grid.5608.b Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, 35128 Italy\n5 0000 0004 1808 1697 grid.419546.b Istituto Oncologico Veneto - IRCCS, Padova, 35128 Italy\n6 0000 0001 2174 1754 grid.7563.7 Department of paediatric, Centro Ricerca M. Tettamanti, University of Milano Bicocca, Fondazione MBBM, Monza, 20900 Italy\n8 3 2018\n3 4 2018\n118 7 985994\n22 9 2017\n8 1 2018\n9 1 2018\n© Cancer Research UK 2018\nhttps://creativecommons.org/licenses/by/4.0/ Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International licence (CC BY 4.0).\nBackground\n\nDespite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.\n\nMethods\n\nExpression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.\n\nResults\n\nWe show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.\n\nConclusions\n\nHere, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy.\n\nSubject terms\n\nCancer therapeutic resistance\nAcute lymphocytic leukaemia\nissue-copyright-statement© Cancer Research UK 2018\n==== Body\npmcIntroduction\n\nThe nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2)–Kelch-like (ECH)-associated protein 1 (KEAP1) signaling pathway is a cellular system that protects cells from oxidative stress and insults from toxic xenobiotics.1 Indeed, the NRF2 axis is finely regulated in normal cells by acting as a surveillance system to prevent the accumulation of endogenous metabolites or hazardous substrates from the microenvironment. Nonetheless, in the past decade, multiple studies reported a significant overactivation of this pathway in many tumors suggesting a positive correlation between its enhanced activity and poor prognosis in cancer patients.1,2 Under basal conditions, NRF2 activity is repressed by binding to its inhibitor KEAP1, which leads to NRF2 proteasomal degradation through the CUL3-dependent ubiquitin ligase complex.3 Oxidation of KEAP1 mediated by oxidative stress or electrophilic agents induces the release of NRF2 and its translocation into the nucleus where it binds to ARE consensus sequences and transactivates a series of cytoprotective target genes, including aldo-keto reductase (AKR) family members.4\n\nThe superfamily of AKR enzymes catalyze the NADPH-dependent conversion of aldehydes and ketones to their corresponding alcohols. Thus, a wide variety of substrates that include simple carbohydrates, cellular metabolites, steroid hormones, endogenous prostaglandins, xenobiotic compounds, and chemotherapeutics are potential targets of these enzymes.5 The AKR1C subfamily includes four isoenzymes (AKR1C1-4) widely expressed in different human tissues, except for AKR1C4 that is liver-specific.6 Recent studies demonstrated that AKR1C1-3 are highly expressed in many human cancers including prostate,7 breast,4 glioma,8,9 neuroblastoma,10 lung,11,12 and acute myeloid leukemia (AML), where they mediate drug resistance, regulate cell differentiation, and promote cancer cell proliferation.13,14\n\nIn this context, it has been demonstrated that the pan AKR1C inhibitor medroxyprogesterone acetate (MPA), greatly enhances the anti-leukemic activity of bezafibrate, by inhibiting the prostaglandin D2 11b-ketoreductase activity of AKR1C enzymes, thus promoting growth arrest, apoptosis, and cell differentiation in AML cells.15 Moreover, different studies aimed to selectively inhibit specific AKR1C isoforms (i.e., AKR1C3) and revealed that inhibition of AKR1C3 alone is not adequate to exert an anti-leukemic effect in AML cells,16 thus reinforcing the hypothesis that redundant activity of AKR1C enzymes supports intracellular antioxidant response.\n\nIn acute lymphoblastic leukemia (ALL), AKR1C1-4 messenger RNA (mRNA) and protein expression has been correlated with cellular sensitivity to the mustard pro-drug PR-104A,17 the latter was reported to be converted and activated by AKR1C3 in a subset of cancer cell lines.18 Although Moradi Manesh et al.17 nicely demonstrated that AKR1C3 expression and enzymatic activity are more abundant in T-ALL compared to BCP-ALL xenografts, and positively correlate with the response to the mustard pro-drug PR-104A, little is known about the potential correlation between AKR1C1-3 expression and the response to standard treatment regimens in ALLs.\n\nRecent improvements in chemotherapeutic protocols for childhood ALL achieve a 5-year survival rate of about 80%.19 However, different studies identified a slower clearance of cancer cells during treatment in T-ALL compared to B-ALL,20 with more resistant tumors (high-risk T-ALL) showing a 7-year survival of only 40%.19 Therefore, the study of the mechanisms underlying drug response and the development of new therapeutic strategies for patients who poorly respond to current treatment protocols remains an important challenge in T-ALL. In this context, we hypothesised that AKR1C enzymes could perturb therapeutic success in T-lineage leukemia. We evaluated the expression and enzymatic activity of AKR1Cs in a large cohort of T-ALLs, finding a significant upregulation of AKR1C1-3 in “resistant” or “poorly responding” tumors. Moreover, we functionally validated the role exerted by these enzymes in controlling T-ALL cell response to chemotherapeutics by pharmacologically or genetically modulating their activity. Finally, we directly correlated the expression of AKR1C1-3 to chemotherapy response in patient-derived xenograft (PDX)-T-ALL samples.\n\nMaterials and Methods\n\nPrimary leukemia cell cultures\n\nT-cell acute lymphoblastic leukemia cells derived from bone marrow (BM) of patients were obtained after informed consent following the tenets of the Declaration of Helsinki and according to the guidelines of the ethics committee of the University of Padova, the Padova Academic Hospital, and the Italian Association of paediatrics Onco-Hematology (AIEOP). Diagnosis was obtained according to standard cytomorphology, cytochemistry, and immunophenotypic criteria.21 All analysed T-ALL samples were obtained after hemolysis of red blood cells at the time of diagnosis, before treatment. Derived T-ALL cells have then been subjected to total RNA and/or protein extraction according to standard procedures or were used for drug testing and injected in mice to generate PDX-T-ALL as described hereafter. T-ALL patients have been classified as therapy “responders” or “resistant” according to the minimal residual disease (MRD) molecularly detected at day 78 from the start of therapy.\n\nIn some experiments, primary and PDX-T-ALL cells were seeded at a concentration of 105 cells per well in 96-well microtiter plates and cultured in α-MEM medium supplemented with 10% FBS, 1% penicillin/streptomycin, 1% glutamine (all from Thermo Fisher Scientific, Waltham, MA), 10% human heat inactivated AB+ serum (Sigma-Aldrich S.r.l., Milan, Italy), human IL7 (20 ng/ml; R&D Systems, Minneapolis, MN), human Stem Cell Factor (SCF) (50 ng/ml), human FLT3-ligand (20 ng/ml; both from Peprotech, London, UK), and insulin (20 nM; Sigma-Aldrich S.r.l.). Cells were immediately exposed to the test compounds and cell survival was evaluated by MTT assay after 48 h. Clinical information of T-ALL patients, from whom cells included in this study derived, are provided as Suppl. Table S1.\n\nMeasurement of AKR1C enzymatic activity\n\nBone marrow or peripheral blood derived T-ALL blasts were obtained from cryopreserved samples from our collection. AKR1C enzymatic activity was measured as previously described.22,23 Briefly, cells were added to white 96-well plates at 2 × 105 cells per well in phenol red-free media and equilibrated at 37 °C in a 5% CO2 incubator for 1 h in the presence of coumberone (10 µM). Coumberol-derived fluorescence intensity was detected after 1–3 h of coumberone addition with a VICTOR3™ Multilabel Plate Reader (excitation: 385 nm; emission: 510 nm; Perkin Elmer, Waltham, MA) and normalised to cell density. The slopes of linear enzymatic reactions obtained by regression analyses have been considered as good surrogates for measuring enzymatic activity and thus reported in the manuscript graphs.\n\nGeneration of T-ALL xenografts\n\nTo establish xenografts, 6- to 9-week-old mice were injected intravenously (i.v.) with 107 T-ALL cells in 300 μl of Dulbecco’s phosphate buffered saline as previously described.24 NOD/SCID mice were purchased from Charles River (Wilmington, MA). Procedures involving animals and their care conformed to institutional guidelines that comply with national and international laws and policies (EEC Council Directive 86/609, OJ L 358, 12 December 1987) and were authorised by the local ethical committee. T-cell acute lymphoblastic leukemia cell engraftment was monitored by periodic blood drawings and flow cytometry analysis of CD5 and CD7 markers over a 5-month period or until clear leukemia initiation. T-cell acute lymphoblastic leukemia xenograft cells have been derived from engrafted mice spleens and then used for ex vivo experiments. Information regarding T-ALL patients from whom xenografts have been generated are summarised in Suppl. Table S1.\n\nCombined drug analysis\n\nLeukemia cell lines and primary cultures were treated with cytarabine (Aractyn; AraC), daunorubicin (Dauno), vincristine (VCR) (all from Pfizer, New York, NY) or l-asparaginase (Asp) (Sigma-Aldrich S.r.l.) in the presence or absence of MPA (Sigma-Aldrich S.r.l.), added to each drug solution at fixed combination ratios. Cell viability was determined after 48–72 h of treatment by MTT assay as described above. To determine the synergistic, additive, or antagonistic effects of drug combinations, we used CompuSyn software (ComboSyn Inc., Paramus, NJ; www.combosyn.com) based on the method of the combination index (CI) described by Chou.25 Synergy, additivity, and antagonism were defined by a CI <1, CI = 1, or CI >1, respectively. Where indicated for some experiments, T-ALL cell lines have been treated with tert-buthylhydroxyquinone (t-BHQ; Sigma-Aldrich S.r.l.) for 18 h at a final concentration of 5 μM.\n\nRESULTS\n\nAKR1C1-3 are overexpressed in T-ALL cells from therapy-resistant patients\n\nIn order to evaluate a potential role of AKR1C1-4 on the phenomenon of therapy resistance in T-ALL, we analysed the expression levels, at diagnosis, of a series of NRF2-AKR1C axis components including NRF2, KEAP1, CUL3, and AKR1C1-4 in 48 patients for which the transcriptional profile was generated (Suppl. Table S1). T-cell acute lymphoblastic leukemia samples were divided into two subgroups based on their response to first-line treatment (details in Suppl. Materials and Methods). In particular, T-ALL patients have been defined as therapy “responders” when showing absent MRD (MRDneg), molecularly detected at day +78 from induction therapy, or “resistant” if MRD >5 × 10−4 (MRDpos) was detected at the same time point. Indeed, evaluation of MRD levels allows the identification of disease persistence and is considered a powerful predictor of therapy response.19,20 We found that MRDpos patients display a significant higher expression of both NRF2 and AKR1C1-3 transcripts, together with a lower expression of the NRF2 inhibitors KEAP1 and CUL3 (Fig. 1a). As expected,6 AKR1C4 displayed low/absent expression in T-ALL samples (Suppl. Fig. S1). The expression of AKR1C isoenzymes (1–3) was significantly correlated (Fig. 1b). We then confirmed protein expression of AKR1C1-3 in a smaller set of MRDpos vs. MRDneg patients, showing that AKR1C1-3 proteins are overexpressed in MRDpos patient samples (Fig. 1c). Moreover, as a further validation, we measured the speed of the specific conversion of the ketone coumberone metabolite to coumberol (slope of linear enzymatic reaction) as a reliable surrogate of AKR1C1-3 enzyme activity.22,23 We found that AKR1C1-3 enzymatic function is enhanced in resistant MRDpos compared to MRDneg T-ALLs (Fig. 1d). Finally, to better characterise the extent of AKR1C1-3 activation in resistant T-ALL samples, we correlated the enzymatic activity of AKR1C isoenzymes (1–3) to their cognate mRNA expression levels obtained for the same patients, showing a highly concordance (Pearson r > 0.7) (Fig. 1e). These data support our hypothesis that AKR1C1-3 enzymes could modulate drug sensitivity in T-ALL cells as demonstrated by a clear-cut overexpression and activation in MRDpos T-ALL patients.Fig. 1 AKR1C1-3 are overexpressed/activated in T-ALLs from therapy-resistant patients. a Box plots showing expression of selected transcripts (as indicated) in MRDneg (n = 29) and MRDpos (n = 19) T-ALL samples at diagnosis. b Graphs reporting the linear correlation existing between the expression values of the single AKR1C isoenzymes. Correlation between the mRNA expression of AKR1C1 vs. AKR1C2 (left panel), AKR1C1 vs. AKR1C3 (middle panel), and AKR1C2 vs. AKR1C3 (right panel) are shown. c Western blot analysis of AKR1C1-3 protein expression in MRD subgroups. Relative densitometric values of bands normalised to GAPDH expression are reported below each protein analysed. d, e Box plot summarising the slope of linear coumberone conversion during time of T-ALL cells from MRDneg (n = 11) and MRDpos (n = 9) patients d and relative correlation with the mRNA expression of each AKR1C isoenzymes (AKR1C1-3) (n = 14). mRNA expression of AKR1C1 (left panel), AKR1C2 (middle panel), and AKR1C3 (right panel) vs. the calculated slope of linear coumberone conversion reactions are shown. e In correlation graphs, 95% confidence interval is indicated by dotted lines. Moreover, Pearson r and relative p values are reported\n\nInhibition of AKR1Cs sensitise T-ALL cell lines to vincristine treatment\n\nIn order to demonstrate the involvement of AKR1C1-3 in the phenomenon of drug resistance, we evaluated if AKR1C1-3 inhibition could enhance drug response in terms of cell viability. To this end, we used a panel of three T-ALL cell lines (CCRF-CEM, DND-41, and LOUCY, all expressing varied levels of AKR1C1-3 isoforms; Suppl. Fig S2A) that were treated with vincristine (VCR), l-asparaginase (ASP), daunorubicin (Dauno), and cytarabine (AraC), all compounds employed during T-ALL therapy,19 in combination with MPA, a pan AKR1C inhibitor.15,26 As expected, inhibition of AKR1C1-3 by MPA dramatically reduced AKR1C-dependent enzymatic activity as assessed by measurement of coumberone conversion (Suppl. Fig. S2B). Moreover, MPA administration was sufficient to sensitise all T-ALL cell lines examined for VCR treatment, displaying a calculated CI <1, and thus a synergistic action according to the Chou method25 (Fig. 2a, b, Suppl. Table S2, and Suppl. Fig. S2C–E). On the contrary, we did not observe any significant increase in efficacy of Dauno, AraC, and ASP treatments when combined with MPA (Fig. 2c–h and Suppl. Table S2). Interestingly, treatment with MPA alone demonstrated a strong reduction of cell viability of CCRF-CEM and DND-41 when used at very high concentrations (i.e., 100 µM), and showed efficacy to only some extent in LOUCY T-ALL cells, even if synergistic potential with VCR was maintained (Fig. 2a–h, Suppl. Table S2, and Suppl. Fig. S2E). We then further characterised the synergistic effect mediated by MPA/VCR combination by analyzing the mechanism of cell death induction after treatment with sub-lethal doses of the single drugs. Indeed, only the combination of both drugs (MPA + VCR) was able to induce a potent pro-apoptotic response in T-ALL cells, which showed a significant increase of apoptotic cells (by Annexin-V/PI staining) after treatment (Fig. 3a, Suppl. Fig. S3A, and Suppl. Fig. S4A).Fig. 2 Pan inhibition of AKR1C1-3 enzymes sensitises T-ALL cell lines to vincristine. Dose–response curves of MPA and its combination at constant molar ratio with vincristine (VCR; a), daunorubicin (Dauno; c), cytarabine (AraC; e), and l-asparaginase (Asp; g) in T-ALL cell lines. Cell viability was determined by MTT assay after 72 h of drug exposure. Data are expressed as mean ± S.E.M. of at least three independent experiments. Combination index (CI) values were calculated for each drug combination at effective dose (ED) 50 and ED75, respectively (b, d, f, and h)\n\nFig. 3 The combined MPA/VCR treatment increases apoptosis in T-ALL cell lines. a Analysis of apoptosis (by Annexin-V/PI staining) induced by MPA, VCR, and their combination (at same molar ratios as in Fig. 2) at the indicated concentrations 72 h post treatment. In particular, representative drug dosages shown in graphs have been selected in order to achieve a lethal effect of VCR/MPA combination around 75%. We considered as apoptotic/dead cells all cells being alternatively stained for Annexin-V, PI, or both. b Assessment of mitochondrial membrane potential after treatments. Cells were treated with the indicated concentration of compounds for 72 h, then stained with the fluorescent probe JC-1. c Evaluation of ROS production after treatments. Cells were treated with the indicated concentration of compound for 72 h and then stained with H2-DCFDA. All data are expressed as mean ± S.E.M. of at least three independent experiments. Statistical analysis was assessed by one-way ANOVA with Newman–Keuls multiple comparison post-test\n\nSince VCR treatment induces cell death via a mitochondrial pathway, thus generating a concurrent production of Reactive Oxygen Species (ROS),27 we evaluated if the combination with MPA produced a significant increase of mitochondrial membrane depolarisation (as measured by JC-1 probe) and ROS accumulation (as measured by DCF+ cells). VCR treatment, combined with MPA, induced a strong imbalance of mitochondrial potential (Fig. 3b, Suppl Fig. S3B, and Suppl. Fig. S4B) and a significant increase of cellular ROS content (Fig. 3c, Suppl. Fig. S3C, and Suppl. Fig. S4C), supporting the hypothesis that inhibition of the AKR1C1-3-dependent detoxifying mechanism may enhance the anti-cancer effect exerted by some chemotherapics (in particular of VCR).\n\nInhibition of AKR1C1-3 sensitise primary T-ALL cells to VCR treatment\n\nTo further validate the sensitisation effect exerted by AKR1C1-3 inhibition on VCR treatment, we treated 10 primary T-ALL cultures (derived from leukemia patients at diagnosis) with VCR alone or in combination with MPA. All primary cells tested exhibited a strong synergistic effect mediated by MPA/VCR combination, independently from their response to therapy at day 78, as shown by CI calculation in Fig. 4a (exact CI calculated at ED50 and ED75 and MRD status for each primary T-ALL culture are reported in Suppl. Table S3). Representative complete dose–response curve are shown for PT55, PT58, and PT60 (Fig. 4b–d).Fig. 4 MPA sensitise primary T-ALL cells to vincristine. a CI values calculated at ED50 and ED75 for the combination of MPA and VCR in 10 primary cell lines. Cell viability was evaluated by MTT assay after 48 h of treatment with VCR and MPA. b–d Representative complete dose–response curves of MPA and its combination with VCR for PT55, PT58, and PT60, respectively\n\nModulation of AKR1C1-3 expression regulates T-ALL response to VCR treatment\n\nIn order to verify if the enhanced anti-cancer effects observed after combination treatment with MPA/VCR is dependent on the inhibition of a specific AKR1C enzyme or either by their combined knockdown due to a shared redundant function, we transfected CCRF-CEM with specific siRNAs against each AKR1C (1–3) isoenzyme or obtained the combined gene silencing of all the three AKR1C isoforms by using two different siRNAs that consistently reduced all their protein expression in T-ALL cells, respectively (Fig. 5a and Suppl. Fig. S5A–C, left panels). Supporting the hypothesised redundancy of AKR1C1-3 enzymes16 and confirming the effects obtained with MPA treatment (Fig. 2a), only the combined silencing of all the AKR1C genes (C1, C2, and C3) strongly sensitised CCRF-CEM to VCR treatment (Fig. 5b and Suppl. Fig. S5A–C, right panels), however without directly affecting cell proliferation or viability (Suppl. Fig. S5D,E).Fig. 5 AKR1C1-3 levels affect response to vincristine in T-ALL cells. a, b After 48 h from electroporation with two different siRNAs against AKR1C1-3, CCRF-CEM cell lysates were analysed by immunoblotting with AKR1C1, AKR1C2, AKR1C3, and β-Actin-specific antibodies, showing the effective gene silencing of AKR1C enzymes a. Response of AKR1C-silenced CCRF-CEM cells to scalar doses of VCR (48 h) is reported b. c, d AKR1C1-3 activity was stimulated in CCRF-CEM by t-BHQ treatment (5 μM) for 18 h and then evaluated by WB c and calculation of the slope of linear coumberone conversion reaction d. e Dose–response curves of t-BHQ-stimulated and control CCRF-CEM exposed to scalar doses of VCR for 48 h. f Box plot showing the ex vivo response to VCR treatment in terms of cell viability of cells obtained from PPR (n = 4) and PGR (N = 3) T-ALL patient-derived xenografts (PDX-T-ALLs). g Correlation of AKR1C1-3 mRNA expression with the viability of PDTALL cells after ex vivo treatment with 100 nM VCR for 48 h is reported. 95% confidence interval is indicated by dotted lines. All data are expressed as mean ± S.E.M. of three independent experiments. In correlation graphs, Pearson r and relative p values are reported independently for PGR and PPR patient-derived PDX-T-ALLs\n\nIn a complementary way, we treated CCRF-CEM with the redox-cycling agent t-BHQ, known to induce transcriptional activation of NRF2, subsequent ARE-driven gene expression and consequent antioxidant protection.4 A short treatment of T-ALL cells with t-BHQ was sufficient to induce the overexpression of the three AKR1C isoenzymes (Fig. 5c) and a significant increase of their enzymatic activity assessed by coumberone conversion (Fig. 5d). In agreement with previous results, activation of AKR1C1-3 enzymes significantly protected CCRF-CEM from VCR treatment (Fig. 5e). Together, these data demonstrate that modulation of AKR1C1-3 might play a fundamental role in the mechanism of T-ALL response to VCR treatment.\n\nAKR1C1-3 expression is directly correlated to VCR resistance ex vivo of T-ALL xenografts\n\nIn order to functionally correlate the overexpression of AKR1C1-3 enzymes with the response to VCR also in T-ALL primary cells, we generated seven T-ALL xenografts (PDX-T-ALL) by injecting patient-derived cells into NOD/SCID mice as described.24 Grafted T-ALL cells were subjected to gene expression profiling in order to characterize the transcriptional levels of AKR1C1-4. As previously shown for T-ALL primary samples (Suppl. Fig. S1), also T-ALL-derived xenografts showed absent expression of AKR1C4 gene (data not shown). Moreover, confirming previous results, the mRNA levels of the single AKR1C isoenzymes were strictly correlated (Suppl. Fig. S6).\n\nIt has been previously suggested that the outcome of T-ALL patients could partially predict the response of PDXs to different chemotherapics, including VCR, both in vivo and ex vivo.28 Based on this suggestion, we decided to correlate AKR1C1-3 expression and VCR response separately in the group of PDX-T-ALLs generated from prednisone good responder (PGR) or prednisone poor responder (PPR, commonly stratified as high-risk) patients. As expected, PGR patients-derived PDX-T-ALLs displayed a significant higher ex vivo sensitivity to VCR treatment than PPR xenografts (Fig. 5f). In addition, both PDX-T-ALL subgroups displayed a direct correlation between AKR1C1-3 expression levels and the amount of surviving cells after VCR treatment (Fig. 5g), with the only exception for AKR1C3 correlation in PGR xenografts (Fig. 5g, right panel). Although based on a small number of samples, these results suggest the presence of a direct link between AKR1C1-3 activity and VCR resistance in T-ALL.\n\nT-ALL induction chemotherapy promotes activation of AKR1C1-3 and resistance to VCR\n\nIt has been recently demonstrated that cancer cells can transcriptionally regulate NRF2 and, consequently, AKR1C1-3 activity as a pro-survival response against drug treatments.4 Thus, in order to evaluate the potential establishment of such a resistance loop in our experimental setting, we measured the amount of coumberone conversion rate in all T-ALL cell lines after 24 h of treatment with ASP, VCR, Ara-C, and Dauno at sub-lethal concentrations. Only Dauno induced a significant increase in the production of fluorescent coumberol in all T-ALL cell lines. Instead, VCR treatment increased coumberone conversion rate only in DND-41 cells and Asp significantly augmented AKR1C-dependent enzymatic activity in both DND-41 and LOUCY cell lines. Ara-C did not induce any increase of AKR1C1-3 activity (Fig. 6a, c, e). We confirmed these results by Western Blot (WB), showing that Dauno-induced overexpression of AKR1C1-3 proteins in all the three T-ALL cell lines tested (Fig. 6b, d, f). In order to functionally validate these data, we pretreated DND-41 cells with Dauno, with consequent AKR1C1-3 enzymes overexpression and activation (Fig. 6c, d), and tested the response to VCR treatment. Indeed, a 24 h pretreatment of T-ALL cells with Dauno was sufficient to make these cells significantly more resistant to VCR treatment (Fig. 6g). These data corroborate the “open” hypothesis that treatment with certain drugs can influence the response to other agents by activating a NRF2-dependent surveillance system and establish a potential AKR1C-mediated drug resistance loop during T-ALL therapy and highlight the relevance of potential pharmacological inhibition of AKR1C1-3 as adjuvant treatment to current chemotherapy protocols.Fig. 6 T-ALL induction therapy increases AKR1C1-3 activity/expression in T-ALL cell lines. CCRF-CEM a, b, DND-41 c, d, and Loucy e, f cells were treated with VCR, Dauno, AraC, and Asp at the indicated doses for 24 h. After treatment, AKR1C1-3 activity was determined by calculating the slopes of the linear reaction of coumberol formation from non-fluorescent coumberone a, c, d and relative AKR1C1-3 protein expression determined by WB b, d, f. g Dose–response curves of Dauno-pre-treated (10 nM for 24 h) and control DND-41 cells exposed to scalar doses of VCR for 48 h. Data are expressed as mean ± S.E.M. of at least three independent experiments. Statistical analysis was assessed by one-way ANOVA with Newman–Keuls multiple comparison post-test\n\nDiscussion\n\nDespite of significant improvements in intensive combination chemotherapy and hematopoietic stem cell transplantation achieved in the last decades,19,29 a number of childhood T-ALL patients only partially respond to treatment, thus experiencing relapse and poor disease outcome.19,30 In this context, AKR1C1-3, being part of the NRF2-KEAP1 signaling pathway,4 are intimately linked with cancer biology and could participate in sustaining resistance to anti-cancer treatments.2,31 Given their intrinsic promiscuity of substrates,32 AKR1C enzymes have been extensively reported to increase cancer cell resistance to therapeutics in various human cancers, by reducing the intracellular levels of drug products, adducts, or compounds themselves. In this study, we investigated if AKR1C1-3 could contribute to therapy resistance in T-ALL by evaluating the potential impact of AKR1C1-3 expression and inhibition on drug sensitivity in T-ALL cell lines, primary cultures, and PDXs.\n\nMRD levels molecularly detected after induction therapy (day 78) are a good marker of treatment response and predictive of subsequent relapse of T-ALL patients.19 For this reason, we chose to analyse NRF2-AKR1C1-3 signaling activation in MRDneg vs. MRDpos (MRD >5 × 10−4) T-ALL patients at diagnosis as a reliable and representative distinction of therapy “sensitive” or “resistant” tumors, respectively. Our data clearly show that therapy-resistant T-ALL samples are endowed with a significant overexpression and/or activation of three AKR1C (1–3) isoenzymes, with augmented enzymatic activity being dependent on increased gene transcription (Fig. 1).\n\nExploring the relationship between NRF2 overactivation and drug resistance in cancer, Wang et al.33 previously demonstrated that the transient knockdown of NRF2, or its specific inhibition by KEAP1 overexpression, both strongly increased the susceptibility of lung cancer cells to different chemotherapics, including cisplatin, doxorubicin, and etoposide. Along this line, in our study, we demonstrate that inhibition of AKR1C1-3 function by the pan-AKR1C inhibitor MPA (Figs. 2, 3, and 4) or AKR1C-specific gene silencing (Fig. 5a, b) are sufficient to increase T-ALL cell sensitivity to VCR. This sensitisation effect was obtained by the specific inhibition of AKR1C1-3, without the need to counteract additional detoxifying genes, generally regulated by NRF2, thus indicating a major role of AKR1C family members in modulating drug response in T-ALL. In order to further sustain the direct involvement of AKR1C1-3 enzymes in chemotherapy resistance, we compared the mRNA expression of additional NRF2 targets, previously involved in drug metabolism, such as the glutamate-cysteine ligase catalytic subunit (GCLC), the glutamate-cysteine ligase modifier subunit (GCLM), or the UDP-glucuronosyltransferase 1A634,35 in MRDpos vs. MRDneg T-ALL patients. Gene expression data disclosed that the above mentioned genes were not overexpressed in MRDpos relative to MRDneg patients, thus questioning a potential role in sustaining therapy resistance in T-ALL (data not shown). In line with our results, AKR1C1-3 were reported to induce resistance to cisplatin in colon cancer36 and to repress the sensitivity to ATRA-induced differentiation37 or bezafibrate26 in AML.\n\nAs an additional result, we were able to directly correlate the expression of AKR1C enzymes with the degree of resistance to VCR ex vivo treatment of PDX-T-ALL cells (Fig. 5f, g). In particular, minimal changes in the balance of AKR1C expression were associated to a very different drug efficacy in terms of surviving cells after VCR treatment. This suggests that any little imbalance in the regulation of the AKR1C surveillance system may produce dramatic effects on cellular metabolism, especially during the onset or progression of resistant tumors. Intriguingly, our data clearly show that AKR1C1-3 enzyme levels mainly affect VCR response rather than other chemotherapeutics. Supporting these results, Rovini et al.38 previously reported that in parallel with their effects on the microtubule network, vinca alkaloids are able to directly interact with mitochondria, thus inducing an early collapse of mitochondrial potential, with a significant increase of ROS production and apoptosis. In the same conditions, DAUNO or AraC have been demonstrated not to directly affect mitochondrial stability.39 In this context, AKR1C enzymes may function as a scavenger of the VCR-dependent mitochondrial depolarisation, by directly counteracting ROS induced-cell damage and subsequent cell death. On the contrary, thanks to their structure, other drugs could be subjected to AKR1C reductase activity, nevertheless producing further toxic metabolites.40\n\nAKR1C1-3 expression has been reported to be induced by anti-cancer agents, thus producing a consequent enhancement of the resistance mechanisms engaged by cancer cells against standard chemotherapics and the activation of survival pathways, thus facilitating cancer progression. In particular, Wang et al.4 showed that different anti-cancer drugs displayed disparate degrees of NRF2 activation and AKR1C overexpression in A549 lung carcinoma cells, including drugs with no effect (i.e., methotrexate), a modest (i.e., cisplatin), or strong effect (i.e., BCNU).\n\nFurther exploring the connection between AKR1C1-3 and the phenomenon of drug resistance, we found that drugs (Dauno, VCR, and Asp) used as first-line treatment during induction therapy in paediatric T-ALL induced overexpression/activation of AKR1C1-3 (Fig. 6a–f). We established a treatment resistance loop to VCR in surviving cancer cells. Further, we reported that Daunorubicin induced overexpression/activation of AKR1C1-3 in all the three T-ALL cell lines tested (Fig. 6a–f), showing various degree of activation probably depending on the redox status (and thus GSH content) of each particular cell line, as previously suggested.4 Moreover, we showed that Dauno-induced AKR1C1-3 overexpression partially counteracted the effects exerted by VCR treatment (Fig. 6g), suggesting the potential antagonistic effect of combined AKR1C-inducing drugs.\n\nFrom a pharmacological point of view, the availability of novel AKR1C-selective inhibitors would be of value for multiple reasons including: (i) cancer chemoprevention; (ii) potential adjuvant therapies in combination with standard chemotherapics; (iii) direct single therapeutic interventions.41 In this context, given the involvement of AKR1C3 in steroid hormone metabolism,5 several laboratories performed structural studies in order to identify new potential inhibitors of AKR1C3 for the treatment of hormone-dependent cancers such as prostate or breast carcinomas.42–44 However, many previous studies support the notion that a pan-AKR1C inhibition is fundamental to exert an anti-cancer activity15,41,45 and, given the structural diversity of these inhibitors such as NCI-PI,16 MPA,15 and jasmonates,37 it is reasonable to conceive that the shared anti-leukemic action of these drugs can be attributed to their ability to inhibit AKR1C isoforms rather than to shared “off-target” effects. In line, pyrithione-based ruthenium complexes have been successfully synthesised, demonstrating a potent inhibition of AKR1C1-3 and cytotoxic effects in breast cancer cells.46\n\nIn conclusion, our results for the first time directly correlate the expression and activation of AKR1C enzymes to chemotherapy response in paediatric T-ALL, making AKR1C1-3 potential suitable targets for T-ALL therapy or either predictive markers of patient response to treatments at diagnosis. However, increasing efforts are needed in order to better characterize the genetic or epigenetic mechanisms underlying NRF2/AKR1C1-3 de-regulation in T-ALL before they could be exploited as reliable prognostic tools.\n\nFrom a therapeutic point of view, the future development of new AKR1C inhibitors, with possibly less side effects than MPA, that could be used in combination with the standard chemotherapeutics, may finally promote a more effective therapy response in T-ALL patients.\n\nElectronic supplementary material\n\nSupplementary data\n\nSupplementary Table S1\n\nElectronic supplementary material\n\nSupplementary information is available for this paper at 10.1038/s41416-018-0014-0.\n\nAcknowledgements\n\nWe are grateful to Professor William R. Wilson from Auckland Cancer Society Research Centre (The University of Auckland) for providing coumberone reagent and to Dr. Stefano Indraccolo from Veneto Institute of Oncology IOV-IRCCS and Chiara Borga from University of Padova for support in animal experiments. This work was supported by funds from Istituto di Ricerca paediatrica Città della Speranza, Cassa di Risparmio di Padova e Rovigo (CARIPARO) Foundation (project no. IRP13/05), and from the Italian Association for Cancer Research (AIRC; IG 19186) (to G.B.). S.B. was supported by Cariplo Foundation, AIRC and the Umberto Veronesi Foundation. F.M. is supported by a fellowship from AIRC.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n\n1. Jaramillo MC Zhang DD The emerging role of the Nrf2-Keap1 signaling pathway in cancer Genes Dev. 2013 27 2179 2191 10.1101/gad.225680.113 24142871\n2. 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Lyon RC Li D McGarvie G Ellis EM Aldo-keto reductases mediate constitutive and inducible protection against aldehyde toxicity in human neuroblastoma SH-SY5Y cells Neurochem. Int. 2013 62 113 121 10.1016/j.neuint.2012.10.007 23084985\n11. Miller VL Aldo-keto reductase family 1 member C3 (AKR1C3) is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma Int. J. Clin. Exp. Pathol. 2012 5 278 289 22670171\n12. Palackal NT Lee SH Harvey RG Blair IA Penning TM Activation of polycyclic aromatic hydrocarbon trans-dihydrodiol proximate carcinogens by human aldo-keto reductase (AKR1C) enzymes and their functional overexpression in human lung carcinoma (A549) cells J. Biol. Chem. 2002 277 24799 24808 10.1074/jbc.M112424200 11978787\n13. Mahadevan D Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemia Am. J. Hematol. 2006 81 779 786 10.1002/ajh.20690 16838325\n14. Birtwistle J The aldo-keto reductase AKR1C3 contributes to 7,12-dimethylbenz(a)anthracene-3,4-dihydrodiol mediated oxidative DNA damage in myeloid cells: implications for leukemogenesis Mutat. Res. 2009 662 67 74 10.1016/j.mrfmmm.2008.12.010 19162045\n15. Khanim FL Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia PLoS ONE 2009 4 e8147 10.1371/journal.pone.0008147 19997560\n16. Khanim F Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate Br. J. Cancer 2014 110 1506 1516 10.1038/bjc.2014.83 24569460\n17. Moradi Manesh D AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia Blood 2015 126 1193 1202 10.1182/blood-2014-12-618900 26116659\n18. Guise CP The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3 Cancer Res. 2010 70 1573 1584 10.1158/0008-5472.CAN-09-3237 20145130\n19. Schrappe M Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study Blood 2011 118 2077 2084 10.1182/blood-2011-03-338707 21719599\n20. Willemse MJ Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL Blood 2002 99 4386 4393 10.1182/blood.V99.12.4386 12036866\n21. Basso G Buldini B De Zen L Orfao A New methodologic approaches for immunophenotyping acute leukemias Haematologica 2001 86 675 692 11454522\n22. Jamieson SM A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia cells Biochem. Pharmacol. 2014 88 36 45 10.1016/j.bcp.2013.12.019 24434189\n23. Yee DJ Balsanek V Bauman DR Penning TM Sames D Fluorogenic metabolic probes for direct activity readout of redox enzymes: selective measurement of human AKR1C2 in living cells Proc. Natl Acad. Sci. USA 2006 103 13304 13309 10.1073/pnas.0604672103 16938874\n24. Agnusdei V Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts Leukemia 2014 28 278 288 10.1038/leu.2013.183 23774673\n25. Chou TC Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies Pharmacol. Rev. 2006 58 621 681 10.1124/pr.58.3.10 16968952\n26. Murray JA Combined bezafibrate and medroxyprogesterone acetate have efficacy without haematological toxicity in elderly and relapsed acute myeloid leukaemia (AML) Br. J. Haematol. 2010 149 65 69 10.1111/j.1365-2141.2009.08055.x 20067564\n27. Zamzami N Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death J. Exp. Med. 1995 182 367 377 10.1084/jem.182.2.367 7629499\n28. Liem NL Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies Blood 2004 103 3905 3914 10.1182/blood-2003-08-2911 14764536\n29. Locatelli F Schrappe M Bernardo ME Rutella S How I treat relapsed childhood acute lymphoblastic leukemia Blood 2012 120 2807 2816 10.1182/blood-2012-02-265884 22896001\n30. Nguyen K Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group study Leukemia 2008 22 2142 2150 10.1038/leu.2008.251 18818707\n31. Zeng CM Aldo-keto reductase AKR1C1-AKR1C4: functions, regulation, and intervention for anti-cancer therapy Front. Pharmacol. 2017 8 119 10.3389/fphar.2017.00119 28352233\n32. Jez JM Bennett MJ Schlegel BP Lewis M Penning TM Comparative anatomy of the aldo-keto reductase superfamily Biochem. J. 1997 326 625 636 10.1042/bj3260625 9307009\n33. Wang XJ Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2 Carcinogenesis 2008 29 1235 1243 10.1093/carcin/bgn095 18413364\n34. Satoh T McKercher SR Lipton SA Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs Free Radic. Biol. Med. 2013 65 645 657 10.1016/j.freeradbiomed.2013.07.022 23892355\n35. Bock KW Kohle C UDP-glucuronosyltransferase 1A6: structural, functional, and regulatory aspects Methods Enzymol. 2005 400 57 75 10.1016/S0076-6879(05)00004-2 16399343\n36. Matsunaga T Pathophysiological roles of aldo-keto reductases (AKR1C1 and AKR1C3) in development of cisplatin resistance in human colon cancers Chem. Biol. Interact. 2013 202 234 242 10.1016/j.cbi.2012.09.024 23165153\n37. Desmond JC The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs Cancer Res. 2003 63 505 512 12543809\n38. Rovini A Savry A Braguer D Carre M Microtubule-targeted agents: when mitochondria become essential to chemotherapy Biochim. Biophys. Acta 2011 1807 679 688 10.1016/j.bbabio.2011.01.001 21216222\n39. Andre N Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells Cancer Res. 2000 60 5349 5353 11034069\n40. Bains OS A correlation between cytotoxicity and reductase-mediated metabolism in cell lines treated with doxorubicin and daunorubicin J. Pharmacol. Exp. Ther. 2013 347 375 387 10.1124/jpet.113.206805 23995598\n41. Davies NJ AKR1C isoforms represent a novel cellular target for jasmonates alongside their mitochondrial-mediated effects Cancer Res. 2009 69 4769 4775 10.1158/0008-5472.CAN-08-4533 19487289\n42. Day JM Tutill HJ Purohit A Reed MJ Design and validation of specific inhibitors of 17beta-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis Endocr. Relat. Cancer 2008 15 665 692 10.1677/ERC-08-0042 18541621\n43. Penning TM Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors Mol. Cell. Endocrinol. 2006 248 182 191 10.1016/j.mce.2005.12.009 16417966\n44. Byrns MC Steckelbroeck S Penning TM An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies Biochem. Pharmacol. 2008 75 484 493 10.1016/j.bcp.2007.09.008 17950253\n45. Bunce CM Indomethacin potentiates the induction of HL60 differentiation to neutrophils, by retinoic acid and granulocyte colony-stimulating factor, and to monocytes, by vitamin D3 Leukemia 1994 8 595 604 7512172\n46. Kljun J Pyrithione-based ruthenium complexes as inhibitors of aldo-keto reductase 1C enzymes and anticancer agents Dalton Trans. 2016 45 11791 11800 10.1039/C6DT00668J 27357845\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D015089:20-Hydroxysteroid Dehydrogenases; D017668:Age of Onset; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000074408:Aldo-Keto Reductases; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases; D007527:Isoenzymes; D017258:Medroxyprogesterone Acetate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010088:Oxidoreductases; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D014407:Tumor Cells, Cultured; D014750:Vincristine; D023041:Xenograft Model Antitumor Assays",
"nlm_unique_id": "0370635",
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"pages": "985-994",
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"pmid": "29515258",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "AKR1C enzymes sustain therapy resistance in paediatric T-ALL.",
"title_normalized": "akr1c enzymes sustain therapy resistance in paediatric t all"
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"companynumb": "IT-TEVA-2018-IT-900059",
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"abstract": "Sodium-glucose cotransporter 2 inhibitor (SGLT2i)-associated euglycaemic diabetic ketoacidosis (euDKA) is a serious and increasingly recognised complication of treatment with this class of oral hypoglycaemic agents and can present a diagnostic challenge, resulting in delayed recognition, inappropriate treatment and potentially life-threatening acidosis. We present two cases of patients developing SGLT2i-associated euDKA in the early postoperative period. We support ceasing SGLT2i for 72 hours preoperatively and would suggest continuing to withhold the medication until oral intake is restored, and recommend a wider awareness of SGLT2i-associated diabetic ketoacidosis (DKA) amongst patients and their healthcare providers with an emphasis on checking ketone levels irrespective of blood glucose levels in the postoperative setting.",
"affiliations": "Nephrologist, Newcastle Private Hospital; Senior Staff Specialist, Nephrology and Transplantation Unit, John Hunter Hospital; Conjoint Senior Lecturer, School of Medicine and Public Health, University of Newcastle; Newcastle, New South Wales.;Intensivist, Newcastle Private Hospital; Senior Staff Specialist, Intensive Care Unit, John Hunter Hospital; Conjoint Senior Lecturer, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales.;Endocrinologist, Newcastle Private Hospital; Senior Staff Specialist, Endocrine and Diabetes Unit, John Hunter Hospital; Newcastle, New South Wales.;Intensivist, Newcastle Private Hospital; Senior Staff Specialist, Intensive Care Unit, John Hunter Hospital; Conjoint Lecturer, School of Medicine and Public Health, University of Newcastle; Newcastle, New South Wales.",
"authors": "Chacko|B|B|;Whitley|M|M|;Beckmann|U|U|;Murray|K|K|;Rowley|M|M|",
"chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007659:Ketones; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X1804600212",
"fulltext": null,
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"issue": "46(2)",
"journal": "Anaesthesia and intensive care",
"keywords": "metabolic acidosis, euglycaemic diabetic ketoacidosis, SGLT2 inhibitors, postoperative",
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000368:Aged; D001786:Blood Glucose; D016883:Diabetic Ketoacidosis; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007659:Ketones; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "215-219",
"pmc": null,
"pmid": "29519226",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Postoperative euglycaemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors (gliflozins): a report of two cases and review of the literature.",
"title_normalized": "postoperative euglycaemic diabetic ketoacidosis associated with sodium glucose cotransporter 2 inhibitors gliflozins a report of two cases and review of the literature"
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"companynumb": "AU-EMD SERONO-9155459",
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"activesubstance": {
"activesubstancename": "EMPAGLIFLOZIN"
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... |
{
"abstract": "BACKGROUND\nPneumatosis intestinalis (PI) is a rare but critical condition in which gas is found in the bowel wall. Although organ transplant recipients have an increased PI risk because of long-term immunosuppression, alpha-glucosidase inhibitors (α-GI), a standard diabetes therapy, often contribute to PI. However, little is known about the postorgan transplantation relationship between PI and α-GI. To the best of our knowledge, this is the first reported case of PI in a lung transplant recipient treated with α-GI.\n\n\nMETHODS\nA 59-year-old man underwent hybrid (living-donor and cadaveric) lung transplantation (LTx). The patient was treated with prednisolone and tacrolimus as immunosuppressive therapy and α-GI for diabetes for 4 years. He developed asymptomatic PI 1031 days after transplantation without any acute abdominal finding. After excluding other possible causes of PI, his PI was attributed to α-GI. The suspected α-GI was immediately withdrawn. The patient was managed conservatively with bowel rest and oxygen therapy. After 11 days of α-GI discontinuation, PI improved, and the patient completely recovered.\n\n\nCONCLUSIONS\nPhysicians should keep this rare adverse drug reaction in mind when prescribing α-GI, particularly in patients with diabetes after organ transplantation and including LTx. The management strategy for asymptomatic PI caused by α-GI is the immediate discontinuation of α-GI therapy, followed by conservative management initiation.",
"affiliations": "Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Hokkaido, Japan; Department of Surgery, Kushiro City General Hospital, Kushiro, Hokkaido, Japan.;Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Hokkaido, Japan. Electronic address: katotatu@huhp.hokudai.ac.jp.;Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Surgery, Kushiro City General Hospital, Kushiro, Hokkaido, Japan.;Department of Surgery, Kushiro City General Hospital, Kushiro, Hokkaido, Japan.",
"authors": "Otsuka|Shinya|S|;Ujiie|Hideki|H|;Kato|Tatsuya|T|;Shiiya|Haruhiko|H|;Fujiwara-Kuroda|Aki|A|;Hida|Yasuhiro|Y|;Kaga|Kichizo|K|;Wakasa|Satoru|S|;Inoue|Rei|R|;Iimura|Yasuaki|Y|",
"chemical_list": "D065089:Glycoside Hydrolase Inhibitors; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.02.006",
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"issn_linking": "0041-1345",
"issue": "53(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000005:Abdomen; D002102:Cadaver; D065089:Glycoside Hydrolase Inhibitors; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D019520:Living Donors; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011006:Pneumatosis Cystoides Intestinalis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1379-1381",
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"pmid": "33712306",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumatosis Intestinalis After Living Donor Lung Transplantation Associated With Alpha-Glucosidase Inhibitor Treatment: A Case Report.",
"title_normalized": "pneumatosis intestinalis after living donor lung transplantation associated with alpha glucosidase inhibitor treatment a case report"
} | [
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"companynumb": "JP-ACCORD-221816",
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"activesubstancename": "VOGLIBOSE"
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{
"abstract": "The MEK inhibitor trametinib is globally approved for metastatic melanoma harboring BRAF mutations. There are no reports thus far on its use in children. Exome sequencing on a relapsed tumor sample from an 11-year-old male with progressive, multiply relapsed stage 4 neuroblastoma revealed NRASQ61K mutation. After demonstration of normal cardiac function, he was started on oral trametinib. On day 13 of treatment, echocardiogram showed moderate left ventricular dysfunction. Trametinib was discontinued on day 15 and oral lisinopril was started. Left ventricular function recovered to baseline 37 days after discontinuing trametinib. However, neuroblastoma showed further progression.",
"affiliations": "*Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY Divisions of †Cardiology ‡Hematology-Oncology, All Children's Hospital, St Petersburg, FL.",
"authors": "Modak|Shakeel|S|;Asante-Korang|Alfred|A|;Steinherz|Laurel J|LJ|;Grana|Nanette|N|",
"chemical_list": "D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human",
"country": "United States",
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"issue": "37(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D002648:Child; D020558:GTP Phosphohydrolases; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "9505928",
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"abstract": "Smoke inhalation injury portends increased morbidity and mortality in fire-exposed patients. Upper airway thermal burns, inflammation from lower airway irritants, and systemic effects of carbon monoxide and cyanide can contribute to injury. A standardized diagnostic protocol for inhalation injury is lacking, and management remains mostly supportive. Clinicians should maintain a high index of suspicion for concomitant traumatic injuries. Diagnosis is mostly clinical, aided by bronchoscopy and other supplementary tests. Treatment includes airway and respiratory support, lung protective ventilation, 100% oxygen or hyperbaric oxygen therapy for carbon monoxide poisoning, and hydroxocobalamin for cyanide toxicity. Due to its progressive nature, many patients with smoke inhalation injury warrant close monitoring for development of airway compromise.",
"affiliations": "Clinical Assistant Professor of Emergency Medicine, Stony Brook School of Medicine, Stony Brook, NY.;Clinical Assistant Professor, Residency Assistant Program Director, Department of Emergency Medicine, Stony Brook School of Medicine, Stony Brook, NY.",
"authors": "Otterness|Karalynn|K|;Ahn|Christine|C|",
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"abstract": "Ritualistic behaviors are common in obsessive compulsive disorder (OCD), while catatonic stupor occasionally occurs in psychotic or mood disorders. Schizoaffective disorder is a specific mental disorder involving both psychotic and affective symptoms. The syndrome usually represents a specific diagnosis, as in the case of the 10th edition of the International Classification of Diseases (ICD-10) or the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, symptom-based diagnosis can result in misdiagnosis and hinder effective treatment. Few cases of ritualistic behaviors and catatonic stupor associated with schizoaffective disorder have been reported. Risperidone and modified electroconvulsive therapy (MECT) were effective in our case.\n\n\n\nA 35-year-old man with schizoaffective disorder-depression was admitted to the hospital because of ritualistic behaviors, depression, and distrust. At the time of admission, prominent ritualistic behaviors and depression misled us to make the diagnosis of OCD. Sertraline add-on treatment exacerbated the psychotic symptoms, such as pressure of thoughts and delusion of control. In the presence of obvious psychotic symptoms and depression, schizoaffective disorder-depression was diagnosed according to ICD-10. Meanwhile, the patient unfortunately developed catatonic stupor and respiratory infection, which was identified by respiratory symptoms, blood tests, and a chest X-ray. To treat psychotic symptoms, catatonic stupor, and respiratory infection, risperidone, MECT, and ceftriaxone were administered. As a result, we successfully cured the patient with the abovementioned treatment strategies. Eventually, the patient was diagnosed with schizoaffective disorder-depression with ritualistic behaviors and catatonia. Risperidone and MECT therapies were dramatically effective.\n\n\n\nMaking a differential diagnosis of mental disorders is a key step in treating disease. Sertraline was not recommended for treating schizoaffective disorder-depression according to our case because it could exacerbate positive symptoms. Controversy remains about whether antipsychotics should be administered for catatonic stupor. However, more case studies will be needed. Risperidone with MECT was beneficial for the patient in our case.",
"affiliations": "Department of Affective Disorder, Shenzhen Kangning Hospital, Cuizhu Road, Luohu District, Shenzhen, 518020, China.;Department of Affective Disorder, Shenzhen Kangning Hospital, Cuizhu Road, Luohu District, Shenzhen, 518020, China.;Department of Affective Disorder, Shenzhen Kangning Hospital, Cuizhu Road, Luohu District, Shenzhen, 518020, China.;Department of Affective Disorder, Shenzhen Kangning Hospital, Cuizhu Road, Luohu District, Shenzhen, 518020, China. szyhc@163.com.",
"authors": "Bai|Yuanhan|Y|;Yang|Xi|X|;Zeng|Zhiqiang|Z|;Yang|Haichen|H|",
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"fulltext": "\n==== Front\nBMC PsychiatryBMC PsychiatryBMC Psychiatry1471-244XBioMed Central London 165510.1186/s12888-018-1655-5Case ReportA case report of schizoaffective disorder with ritualistic behaviors and catatonic stupor: successful treatment by risperidone and modified electroconvulsive therapy Bai Yuanhan baiyuanhan@163.com Yang Xi nichle@126.com Zeng Zhiqiang 312047880@qq.com Yang Haichen szyhc@163.com grid.452897.5Department of Affective Disorder, Shenzhen Kangning Hospital, Cuizhu Road, Luohu District, Shenzhen, 518020 China 13 3 2018 13 3 2018 2018 18 6715 10 2017 8 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nRitualistic behaviors are common in obsessive compulsive disorder (OCD), while catatonic stupor occasionally occurs in psychotic or mood disorders. Schizoaffective disorder is a specific mental disorder involving both psychotic and affective symptoms. The syndrome usually represents a specific diagnosis, as in the case of the 10th edition of the International Classification of Diseases (ICD-10) or the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, symptom-based diagnosis can result in misdiagnosis and hinder effective treatment. Few cases of ritualistic behaviors and catatonic stupor associated with schizoaffective disorder have been reported. Risperidone and modified electroconvulsive therapy (MECT) were effective in our case.\n\nCase presentation\nA 35-year-old man with schizoaffective disorder-depression was admitted to the hospital because of ritualistic behaviors, depression, and distrust. At the time of admission, prominent ritualistic behaviors and depression misled us to make the diagnosis of OCD. Sertraline add-on treatment exacerbated the psychotic symptoms, such as pressure of thoughts and delusion of control. In the presence of obvious psychotic symptoms and depression, schizoaffective disorder-depression was diagnosed according to ICD-10. Meanwhile, the patient unfortunately developed catatonic stupor and respiratory infection, which was identified by respiratory symptoms, blood tests, and a chest X-ray. To treat psychotic symptoms, catatonic stupor, and respiratory infection, risperidone, MECT, and ceftriaxone were administered. As a result, we successfully cured the patient with the abovementioned treatment strategies. Eventually, the patient was diagnosed with schizoaffective disorder-depression with ritualistic behaviors and catatonia. Risperidone and MECT therapies were dramatically effective.\n\nConclusion\nMaking a differential diagnosis of mental disorders is a key step in treating disease. Sertraline was not recommended for treating schizoaffective disorder-depression according to our case because it could exacerbate positive symptoms. Controversy remains about whether antipsychotics should be administered for catatonic stupor. However, more case studies will be needed. Risperidone with MECT was beneficial for the patient in our case.\n\nKeywords\nSchizoaffective disorderRitualistic behaviorsCatatonic stuporRisperidoneModified electroconvulsive therapySanming Project of Medicine in ShenzhenGrand No. SZSM201612006issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nDiagnosis is the first step toward correctly curing disease. Unlike internal or surgical diseases, mental disorders are largely symptom-based diagnoses [1, 2]. In the process of interviewing, syndromes are always associated with certain diagnoses according to the ICD-10 or DSM-5. Repetitive behaviors or ritualistic behaviors may be linked with OCD [3]. Immobility, mutism, negativism, and peculiar motor behavior represent catatonic stupor [1, 2], which is a psychotic diagnosis because approximately 10–15% patients with catatonic stupor meet the criteria for schizophrenia [4]. Typical ritualistic behaviors and catatonic stupor may represent OCD and psychotic disorders, respectively. However, these patients are not “textbook” cases, which means that complex and complicated symptoms may lead to misdiagnosis. Schizoaffective disorder is a specific mental disorder involving both psychotic and affective symptoms [5]. It is classified as “schizophrenia, schizotypal, and delusional disorders” by ICD-10 [1] and “schizophrenia spectrum and other psychotic disorders” by DSM-5 [2]. The complex symptomatology of schizoaffective disorder makes it highly likely that patients will be misdiagnosed.\n\nSertraline is a selective serotonin reuptake inhibitor [6] that is used to treat depression and OCD [7]. Previous studies have summarized the effective use of antidepressants in schizoaffective disorder [8]. However, the risk of exacerbation of positive symptoms of antidepressants should be considered [9–11]. A review of the treatments for catatonia has shown that MECT is effective, while antipsychotics remain controversial [12]. On the other hand, Huang et al. published other papers suggesting that the Lorazepam-Diazepam protocol can rapidly and safely relieve catatonia in schizophrenia, mood disorder, and organic lesions [13–15].\n\nIn this paper, we present the case of a patient who was initially suspected of having OCD but who actually suffered from schizoaffective disorder-depression with ritualistic behaviors and catatonic stupor. Sertraline exacerbated the psychotic symptoms. The ritualistic behaviors that were actually secondary to psychotic symptoms may have prevented us from making an accurate diagnosis. Finally, risperidone and MECT were effective strategies for this patient.\n\nCase presentation\nThe patient was a 35-year-old male. He was apparently normal before the age of 27 years without any medical problems. He was intellectually normal and worked as a security guard. He was never married and had no children, often living with his older sister. He had been smoking for approximately 10 years or more, denying alcohol or other psychoactive substance abuse. He is the third child, with one older brother and one older sister. His father often became drunk and violent, going outside for no reason, and committed suicide many years ago. There were no detailed records for his father because he failed to see a doctor.\n\nIn 2009, the patient gradually became depressive; showed diminished pleasure, insomnia, and fatigue; and was unwilling to talk to others. Meanwhile, he developed delusions of persecution and reference, which made him believe that someone had insulted him and planned to kill him without evidence. Later, he came to the outpatient clinic of our hospital and was prescribed paroxetine 20 mg/d and sulpiride 0.2 g/d. He took these drugs irregularly, with minimal improvement in depressive symptoms and delusions. In August 2013, the patient was sent to the hospital for schizoaffective disorder-depression. During the following month, with quetiapine 600 mg/d and lithium carbonate sustained-release tablet 0.6 g/d, his depressive and positive symptoms improved. Taking these drugs, he almost enjoyed normal life and work. Unfortunately, he discontinued these medications in May 2017. Again, the patient gradually developed fear of the sound of water, a lack of any pleasure and negative ideas, and claimed that he could not trust anyone. Furthermore, the patient performed ritualistic behaviors, such as walking with a specific order. Once again, he was sent to our hospital by his older sister. At the time of admission, the patient presented depressive symptoms as well as ritualistic behaviors and distrust.\n\nUpon admission, liver and kidney function, routine blood test, computed tomography (CT) of the head, and electrocardiograph (ECG) were normal. Depressive symptoms, delusions, and ritualistic behaviors were found upon psychiatric interview. By day 9 in the hospital, we followed outpatient therapeutic strategies with quetiapine 100 mg/d and lithium carbonate sustained-release tablet 0.6 g/d, observing that the depressive symptoms and distrust had moderately improved. However, the ritualistic behaviors gradually worsened. Before waking up, he would swing his arms up and down four times, did sit-ups four or five times, and sat at the edge of the bed for a few minutes, all of which took him approximately 8 min. These disturbed or interrupted behaviors made the patient anxious. Because of the predominant ritualistic behaviors, OCD was suspected first. Here, we wanted to reduce these behaviors by adding sertraline at a dose of 50 mg/d and titrating it to 100 mg/d.\n\nThen, the symptoms further worsened, and the patient developed agitation, pressure of thoughts, and delusion of control. He felt that his ritualistic behaviors gradually became out of control, realizing that “unknown thoughts” and “a black shadow” affected his mind. Meanwhile, he felt sad, and there was nothing that brought him pleasure. Considering the clinical picture and depressive and psychotic symptoms with equal importance, the diagnosis of schizoaffective disorder-depression was eventually made according to the ICD-10. Sertraline 100 mg/d was immediately ceased. We planned to change the ineffective quetiapine to risperidone, which was more effective on positive symptoms according to our own clinical experiences when the patient developed catatonia. Mutism, posturing, nonverbal communication, hyper-myotonia of the limbs, and saliva collected in the mouth were observed. Redness and swelling of the pharynx and hyperthermia (38 °C) were present. Routine blood tests showed that the white blood cell (WBC) count was 12.85 × 109/L (normal range 3.5–9.5 × 109/L), and the neutrophil granulocyte (NEUT) count was 10.6 × 109/L (normal range 1.8–6.3 × 109/L). Chest computed tomography indicated a high-density streak like a shadow in the lower lobe of the left lung, which was clear at admission. After the case discussion, we decided to initiate risperidone at a dose of 1 mg/d and gradually titrate it to 4 mg/d to control the positive symptoms. A twice-daily intravenous injection of ceftriaxone 1 g in 250 mL 0.9% physiological saline was administered to treat the respiratory infection. Meanwhile, MECT was added three times a week to ameliorate the catatonia. MECT was administered with the SPECTRUM-5000Q device used in the bilateral mode. The treatment parameters included frequency (30 Hz), stimulus duration (2.5 s), electric charge (120 Mc), energy (21.1 J), and constant current (800 mA). Vital signs were stable; specifically, body temperature was not over 37.2 °C before starting MECT in this patient. Before and during the MECT, anesthesia was induced with etomidate 10 mg and muscle relaxation with succinylcholine 50 mg, while arterial oxygen saturation, heart rate, and electrocardiogram were continuously monitored. Each time, the patient experienced adequate generalized seizures measured with an electroencephalogram. The patient was ventilated with 100% oxygen until the resumption of spontaneous respiration.\n\nOn hospital day 23, inflammation of the pharynx disappeared, and normal WBC and NEUT counts suggested that the respiratory infection had been clinically cured. Ceftriaxone was ceased when we found negative blood bacterial culture results. We continued risperidone and MECT (a total of nine times) treatments. The patient gradually began to talk with doctors and other patients, joining some activities in the ward. The pressure of thoughts and delusion of control almost disappeared. Furthermore, it took him less and less time to perform the ritualistic behaviors. On hospital day 31, we stopped MECT and added lithium carbonate sustained-release tablets 0.6 g/d. Oral risperidone 4 mg/d was introduced, in which the blood concentration was 8.7 μg/L (normal range 2–60 μg/L). No obvious side effects were observed. Finally, we titrated the lithium carbonate sustained-release tablets to 0.9 g/d and maintained risperidone 4 mg/d. The patient remained normopyretic, and his psychotic and depressive symptoms were stable. We told the patient to review and check the blood lithium carbonate concentration 1 week later in the outpatient setting.\n\nFor the publication of this case report, written informed consent was obtained from the patient and his older sister.\n\nDiscussion\nHere, we describe a case of schizoaffective disorder-depression with ritualistic behaviors and catatonia. After admission, we suspected a diagnosis of OCD because of the dominance of ritualistic behaviors and depression, as the patient reported that the ritualistic behaviors must be performed or else he would feel sad. The ritualistic behaviors proved to be secondary to delusion of control. The patient’s insomnia, fatigue, and unwillingness to talk to others were not explained by the ritualistic behaviors. Ultimately, we made a diagnosis of schizoaffective disorder-depression. The symptom-based diagnostic criteria [1, 2] as well as the multivariate symptoms made diagnosis and treatment difficult. Our case suggests that time, patience, and detailed observation are essential factors for making clinical decisions.\n\nSelective Serotonin Reuptake Inhibitors (SSRIs) are beneficial for depression and OCD [6], among which sertraline is an effective therapeutic strategy [7]. In early studies and guidelines, psychiatrists were concerned about the risk of exacerbating psychosis when prescribing antidepressants to schizophrenic patients [9–11]. Rebecca Schennach et al. identified the exacerbation of positive symptoms in patients with antidepressant augmentation compared with patients without any antidepressants during the course of the study, and patients with antidepressant add-on treatment suffered from more severe psychopathological symptoms and greater psychosocial impairments at discharge [16]. However, a recent review does not support these points, as no studies found that add-on antidepressants worsened positive symptoms [17]. Although many studies have described the use of antidepressants in schizophrenia with depression, controversies remain about whether to administer antidepressants for schizophrenia spectrum disorders. We suggest that therapeutic strategies for schizoaffective disorder-depression might not include additional antidepressants, for sertraline may have exacerbated positive symptoms in our case.\n\nCatatonia is a neuropsychiatric syndrome with psychomotor inhibition that occurs in approximately 8% of patients admitted for mental disorders, such as schizophrenia or mood disorders [18]. Schizophrenia and other psychotic spectrum disorders are more commonly presented as catatonia than mood disorders [19]. Catatonic stupor is a psychiatric emergency due to a broad range of complications [20, 21]. Neuroleptic malignant syndrome (NMS) typically presents with fever, muscle rigidity, and altered mental status [22] and should be differentiated from catatonic stupor complicated by respiratory infection. In this case, the clear consciousness of the patient with psychomotor inhibition, redness and swelling of the pharynx, fever without muscle rigidity, increased WBC and NEUT counts, and a high-density streak of shadowing in the lower lobe of left lung in the chest X-ray at admission suggested a status of catatonic stupor complicated by respiratory infection. Therefore, our case describes schizoaffective disorder-depression with catatonic stupor complicated by respiratory infection. Controlling the infection and improving the catatonic stupor were important in treating this patient. Three treatment strategies were employed in this case. Supportive measures included high-level nursing care, intravenous fluids, and gastrointestinal support to reduce the risk of bedsores and deep vein thrombosis caused by immobility and to improve poor nutrition and dehydration. Antibiotic treatment was considered due to the redness and swelling of the pharynx, hyperthermia, increased WBC and NEUT counts, and abnormal chest X-ray. These symptoms successfully responded to the administration of 7 days of ceftriaxone. MECT was an effective strategy for improving catatonic stupor [23, 24]. Although benzodiazepines proved to rapidly and effectively relieve catatonia, we did not prescribe these kinds of medications for the patient considering his poor nutrition, respiratory infection, and risk of respiratory inhibition. However, the role of antipsychotics in the treatment of catatonia is controversial. Several authors have suggested that antipsychotics may exacerbate the catatonic state and increase the risk of NMS [25, 26]. Studies have found that second-generation antipsychotics (SGAs) have weak γ-aminobutyric acid (GABA)-agonist activity and 5-hydroxytryptamine2 (5-HT2)-antagonism that could stimulate dopamine release in the prefrontal cortex and thus alleviate catatonic symptoms [20]. Several articles have suggested a beneficial effect of risperidone [27, 28]. A case report identified MECT together with olanzapine, which resulted in improvement of catatonic stupor [29]. Given the results of the abovementioned studies, risperidone was cautiously administered at a low dose (2 mg/d). Once catatonic stupor improved and MECT came to a stop, risperidone would be titrated from 2 to 4 mg/d to target residual psychotic symptoms, such as the pressure of thoughts and delusion of control. Furthermore, lithium carbonate is also an effective strategy for patients with schizoaffective disorder, as it can reduce the rate of re-hospitalization [30].\n\nConclusion\nHere, we describe a case of schizoaffective disorder-depression with secondary ritualistic behaviors complicated by catatonic stupor, which induces respiratory infection. Sertraline might not be recommended in patients with schizoaffective disorder to improve depression, which could have exacerbated the positive symptoms in our case. Supportive measures have an important role in the treatment of catatonic stupor. Once again, MECT has been shown to improve catatonic stupor. Although there is controversy over whether antipsychotics should be administered in the catatonic status, we considered risperidone to be beneficial in our case. Further studies should focus on the effectiveness and safety of antipsychotics associated with MECT in patients with catatonia.\n\nAbbreviations\n5-HT25-hydroxytryptamine2\n\nCTComputed tomography\n\nDSM-55th edition of Diagnostic and Statistical Manual of Mental Disorders\n\nECGElectrocardiograph\n\nGABAγ-aminobutyric acid\n\nICD-1010th edition of International Classification of Diseases\n\nMECTModified electroconvulsive therapy\n\nNEUTNeutrophil granulocyte\n\nNMSNeuroleptic malignant syndrome\n\nOCDObsessive compulsive disorder\n\nSGAsSecond-generation antipsychotics\n\nSSRIsSelective Serotonin Reuptake Inhibitors\n\nWBCWhite blood cell\n\nAcknowledgements\nWe would like to thank the patient and his older sister for their collaboration.\n\nFunding\nThis case report was partially supported by the Sanming Project of Medicine in Shenzhen (Grand No. SZSM201612006). The funding agency had no role in this case report; analysis or interpretation of data; or the preparation, review, or approval of the manuscript. We received no support from any pharmaceutical company or other industry.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nYHB and XY were involved in the management of the patient. ZQZ and HCY were the primary clinicians involved in the assessment, management, and follow-up of the patient. The article was written by YHB. YHB, XY, ZQZ, and HCY provided final approval of the version to be published and agreed 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. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nFor the publication of this case report, written informed consent was obtained from the patient and his older sister.\n\nCompeting interests\nWe have no conflicts of interest to declare with respect to the manuscript, including no financial, consultant, political, personal, religious, ideological, academic, intellectual, or other relationships that could lead to a conflict of interest.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. World Health Organization The ICD-10 classification of mental and behavioural disorders: diagnostic criteria for research 1993 Geneva World Health Organization \n2. American Psychiatric Association Diagnostic and statistical manual of mental disorders 2013 Washington, DC American Psychiatric Association \n3. Rapp AM Bergman RL Piacentini J McGuire JF Evidence-based assessment of obsessive–compulsive disorder J Cent Nerv Syst Dis 2016 8 13 29 10.4137/JCNSD.S38359 27594793 \n4. Taylor MA Fink M Catatonia in psychiatric classification: a home of its own Am J Psychiatry 2003 160 7 1233 1241 10.1176/appi.ajp.160.7.1233 12832234 \n5. Wilson JE Nian H Heckers S The schizoaffective disorder diagnosis: a conundrum in the clinical setting Eur Arch Psychiatry Clin Neurosci 2014 264 1 29 34 10.1007/s00406-013-0410-7 23625467 \n6. Motohashi N Selective serotonin reuptake inhibitor (SSRI) Nihon Rinsho 2001 59 8 1519 1522 11519151 \n7. 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Van Den Eede F Van Hecke J Van Dalfsen A Van den Bossche B Cosyns P Sabbe BG The use of atypical antipsychotics in the treatment of catatonia Eur Psychiatry 2005 20 5–6 422 429 10.1016/j.eurpsy.2005.03.012 15964746 \n28. Grenier E Ryan M Ko E Fajardo K John V Risperidone and lorazepam concomitant use in clonazepam refractory catatonia: a case report J Nerv Ment Dis 2011 199 12 987 988 10.1097/NMD.0b013e3182392d7e 22134459 \n29. Tan QR Wang W Wang HH Zhang RG Guo L Zhang YH Treatment of catatonic stupor with combination of modified electroconvulsive treatment and olanzapine: a case report Clin Neuropharmacol 2006 29 3 154 156 10.1097/01.WNF.0000220816.86478.84 16772815 \n30. Svarstad BL Shireman TI Sweeney JK Using drug claims data to assess the relationship of medication adherence with hospitalization and costs Psychiatr Serv 2001 52 6 805 811 10.1176/appi.ps.52.6.805 11376229\n\n",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28114315;19996245;24756319;25538636;11519151;16772815;12506260;7895634;22134459;15000267;27594793;12832234;1687176;15964746;23625467;25991654;28505669;23515153;19969591;11376229;23856388;7609820;28615768;26110120;7897404;27318812;21677256",
"title": "A case report of schizoaffective disorder with ritualistic behaviors and catatonic stupor: successful treatment by risperidone and modified electroconvulsive therapy.",
"title_normalized": "a case report of schizoaffective disorder with ritualistic behaviors and catatonic stupor successful treatment by risperidone and modified electroconvulsive therapy"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-169847",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
... |
{
"abstract": "A woman in her late 60s with disseminated histoplasmosis was treated with posaconazole because first-line therapies were not tolerated. She subsequently presented with decompensated heart failure, hypertension, and hypokalemia. Laboratory tests revealed low renin and aldosterone levels. A potential mechanism is inhibition of the enzyme 11β-hydroxysteroid dehydrogenase 2, with resultant apparent mineralocorticoid excess.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA kkuriakose6@gmail.com.;Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, Tennessee, USA.;Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.;Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.",
"authors": "Kuriakose|Kevin|K|0000-0003-2004-8311;Nesbitt|Whitney J|WJ|;Greene|Matthew|M|;Harris|Bryan|B|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D006913:Hydroxysteroid Dehydrogenases; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.02130-17",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "62(5)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "aldosterone; hypertension; hypokalemia; mineralocorticoid; posaconazole; pseudohyperaldosteronism",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D006333:Heart Failure; D006660:Histoplasmosis; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases; D006929:Hyperaldosteronism; D006973:Hypertension; D007008:Hypokalemia; D043204:Mineralocorticoid Excess Syndrome, Apparent; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29530850",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28167540;15242978;28131847;17125435;28533238;25049247;15066665;25950873;26668209;20385363;27014922;1922210",
"title": "Posaconazole-Induced Pseudohyperaldosteronism.",
"title_normalized": "posaconazole induced pseudohyperaldosteronism"
} | [
{
"companynumb": "US-009507513-1805USA002327",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "We conducted a multicentre, phase II study of interim positron emission tomography (PET) as a guide to risk-adapted therapy in high-risk patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients achieving negative fluorodeoxyglucose (FDG)-PET after three courses of R-MegaCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET-positive patients received two courses of R-IFE (rituximab, ifosfamide, etoposide) followed by BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem-cell transplantation. The primary endpoint was progression-free survival (PFS). 71 patients (median age 55 years, range 25-69) were enrolled. With a median follow-up of 42·8 months (range 7·2-58·4), the estimated 4-year PFS and overall survival (OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET (N = 36) had significantly better 3-year PFS than those with partial response (N = 30) [81% vs. 57%, Hazard ratio (HR) = 2·6, 95% confidence interval (CI) = 1·02-6·65] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3-year PFS (81% vs. 33%; HR = 6·9, 95% CI = 2·35-20·6) and OS (95% vs. 33%, HR = 19·4, 95% CI = 3·89-97·0) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria.",
"affiliations": "Department of Haematology, Hospital Virgen del Puerto, Plasencia, Spain.",
"authors": "Pardal|Emilia|E|;Coronado|Mónica|M|;Martín|Alejandro|A|;Grande|Carlos|C|;Marín-Niebla|Ana|A|;Panizo|Carlos|C|;Bello|José Luis|JL|;Conde|Eulogio|E|;Hernández|Miguel T|MT|;Arranz|Reyes|R|;Bargay|Joan|J|;González-Barca|Eva|E|;Pérez-Ceballos|Elena|E|;Montes-Moreno|Santiago|S|;Caballero|María Dolores|MD|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D003561:Cytarabine; D019788:Fluorodeoxyglucose F18; D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D008558:Melphalan; D002330:Carmustine; D007069:Ifosfamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13036",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "167(3)",
"journal": "British journal of haematology",
"keywords": "autologous stem cell transplantation; fluorodeoxyglucose positron emission tomography; lymphoma",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003561:Cytarabine; D018572:Disease-Free Survival; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D049268:Positron-Emission Tomography; D011241:Prednisone; D011379:Prognosis; D011446:Prospective Studies; D019275:Radiopharmaceuticals; D012074:Remission Induction; D000069283:Rituximab; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "327-36",
"pmc": null,
"pmid": "25066542",
"pubdate": "2014-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial.",
"title_normalized": "intensification treatment based on early fdg pet in patients with high risk diffuse large b cell lymphoma a phase ii geltamo trial"
} | [
{
"companynumb": "ES-AMGEN-ESPSP2014063258",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARMUSTINE"
},
"drugadditional": null,
... |
{
"abstract": "The patient was a 72-year-old man who exhibited an abnormal shadow in the stomach in a series of medical check-ups of the upper gastrointestinal in August 20XX. It was diagnosed as gastric cancer(type 1)of the greater curvature of the MU region. Total gastrectomy, D2-11p dissection, and Roux-en-Y reconstruction were performed in October 20XX. The tumor was p-T1bN3aM0, Stage ⅡB, Pap, Ly1c, V1a, 90×70mm, HER2 score 3. Six courses of S-1/CDDP were administered as adjuvant chemotherapy after consultation. Two years and 8 months after the surgery, PET-CT scan showed distant lymph node metastasis(left axilla, para-aortic)and left lung metastasis. Three courses of XP-Her after 2 years and 11 months, 19 courses of X-Her after 3 years and 2 months, and 7 courses of trastuzumab alone after 4 years and 4 months to 4 years and 9 months were canceled. Three years and 4 months after the surgery, the tumor showed PR, and it showed CR, 3 years and 8 months after the surgery. Eight years and 3 months after the surgery, the tumor continued to show CR. The adverse events were blood toxicity, WBC reduction Grade 1, neutropenia Grade 3, and anemia Grade 2. There have only been a few reports on CR after chemotherapy with XP-Her for lung metastasis of gastric cancer, with a review of the literature.",
"affiliations": "Dept. of Digestive and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center.",
"authors": "Koganezawa|Itsuki|I|;Katayanagi|So|S|;Nakagawa|Masashi|M|;Yokozuka|Kei|K|;Hikita|Kousuke|K|;Kobayashi|Toshimichi|T|;Kuwabara|Hiroshi|H|;Shigoka|Masatoshi|M|;Tabuchi|Satoshi|S|;Hisada|Masayuki|M|;Kawachi|Shigeyuki|S|",
"chemical_list": "D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D005743:Gastrectomy; D006801:Humans; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography; D013274:Stomach Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2592-2594",
"pmc": null,
"pmid": "32157009",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of CR Achieved by Chemotherapy for Distant Metastatic Lymph Nodes after Surgery for HER2 Positive Early Gastric Cancer.",
"title_normalized": "a case of cr achieved by chemotherapy for distant metastatic lymph nodes after surgery for her2 positive early gastric cancer"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-248896",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"dr... |
{
"abstract": "Dabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily.\nFive hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated.\nA total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55-21.2; p = 0.009), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events.\nThe results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.",
"affiliations": "1Department of Pharmacy, National Hospital Organization, Yokohama Medical Center, 3-60-2 Harajuku, Totsuka, Yokohama, Kanagawa 245-8575 Japan.;2Department of Pharmacy, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro, Tokyo, 153-8515 Japan.;2Department of Pharmacy, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro, Tokyo, 153-8515 Japan.;3Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510 Japan.;4Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba, 283-8555 Japan.;5Department of Pharmacy, National Hospital Organization, Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo, 152-8902 Japan.;Department of Pharmacy, Tamagawa Hospital, 4-8-1 Seta, Setagaya, Tokyo, 158-0095 Japan.;Department of Pharmacy, Tamagawa Hospital, 4-8-1 Seta, Setagaya, Tokyo, 158-0095 Japan.;5Department of Pharmacy, National Hospital Organization, Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo, 152-8902 Japan.;5Department of Pharmacy, National Hospital Organization, Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo, 152-8902 Japan.;Department of Pharmacy, Mishuku Hospital, 5-33-12 Kami-meguro, Meguro, Tokyo, 153-0051 Japan.;2Department of Pharmacy, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro, Tokyo, 153-8515 Japan.;Department of Pharmacy, Kohsei Chuo General Hospital, 1-11-7 Mita, Meguro, Tokyo, 153-8581 Japan.;2Department of Pharmacy, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro, Tokyo, 153-8515 Japan.;Department of Cardiovascular Medicine, Odawara Cardiovascular Hospital, 6-1-14 Yahagi, Odawara, Kanagawa 250-0873 Japan.",
"authors": "Akagi|Yuuki|Y|0000-0001-9015-2507;Chiba|Tatsuo|T|;Uekusa|Shusuke|S|;Kato|Hiroyoshi|H|;Yamamura|Shigeo|S|;Aoki|Yukiko|Y|;Enoki|Mizuho|M|;Ogawara|Yuka|Y|;Kasahara|Takanori|T|;Kimura|Yuki|Y|;Shimizu|Tadahiro|T|;Takeishi|Aiko|A|;Nakajima|Yuko|Y|;Kobayashi|Hideki|H|;Sugi|Kaoru|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40780-019-0145-3",
"fulltext": "\n==== Front\nJ Pharm Health Care SciJ Pharm Health Care SciJournal of Pharmaceutical Health Care and Sciences2055-0294BioMed Central London 14510.1186/s40780-019-0145-3Research ArticleRetrospective cohort study of the efficacy and safety of dabigatran: real-life dabigatran use including very low-dose 75 mg twice daily administration http://orcid.org/0000-0001-9015-2507Akagi Yuuki +81-45-851-2621akagi.yuuki.nb@mail.hosp.go.jp 1Chiba Tatsuo t-t-o@oha.toho-u.ac.jp 2Uekusa Shusuke shuusuke.uekusa@phar.toho-u.ac.jp 2Kato Hiroyoshi hirkato@phar.toho-u.ac.jp 3Yamamura Shigeo s_yama@jiu.ac.jp 4Aoki Yukiko yki_aoki@ntmc-hosp.jp 5Enoki Mizuho mi5zu5ho5@gmail.com 6Ogawara Yuka y09046624086@gmail.com 6Kasahara Takanori tkasahara@ntmc-hosp.jp 5Kimura Yuki yuki.kimura0113@gmail.com 5Shimizu Tadahiro jinroos93@hotmail.com 7Takeishi Aiko aiko87aiko62@gmail.com 2Nakajima Yuko thu10.thu20@gmail.com 8Kobayashi Hideki ct9akai@oha.toho-u.ac.jp 2Sugi Kaoru sugi@ojh.or.jp 91 grid.416239.bDepartment of Pharmacy, National Hospital Organization, Yokohama Medical Center, 3-60-2 Harajuku, Totsuka, Yokohama, Kanagawa 245-8575 Japan 2 grid.470115.6Department of Pharmacy, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro, Tokyo, 153-8515 Japan 3 0000 0000 9290 9879grid.265050.4Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510 Japan 4 grid.440885.5Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba, 283-8555 Japan 5 grid.416239.bDepartment of Pharmacy, National Hospital Organization, Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo, 152-8902 Japan 6 Department of Pharmacy, Tamagawa Hospital, 4-8-1 Seta, Setagaya, Tokyo, 158-0095 Japan 7 Department of Pharmacy, Mishuku Hospital, 5-33-12 Kami-meguro, Meguro, Tokyo, 153-0051 Japan 8 Department of Pharmacy, Kohsei Chuo General Hospital, 1-11-7 Mita, Meguro, Tokyo, 153-8581 Japan 9 Department of Cardiovascular Medicine, Odawara Cardiovascular Hospital, 6-1-14 Yahagi, Odawara, Kanagawa 250-0873 Japan 1 8 2019 1 8 2019 2019 5 175 1 2019 25 6 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily.\n\nMethods\nFive hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated.\n\nResults\nA total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55–21.2; p = 0.009), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events.\n\nConclusions\nThe results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.\n\nKeywords\nDabigatranAnticoagulantExcessive dose reductionThromboembolismNon-valvular atrial fibrillationRetrospective studyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nAtrial fibrillation (AF) is an arrhythmia commonly reported in the elderly. Cardiogenic ischemic stroke is often severe because it is characterized by larger lesions than other types of stroke, and its recurrence rate is higher than that of other stroke types [1]. Anticoagulant therapy with warfarin can reduce the risk of stroke by more than 60% in patients with moderate to high AF risk [2]. However, since the anticoagulant effect of warfarin is greatly affected by diet and many drugs [3], it fluctuates easily. In fact, consuming food and drinks containing vitamin K such as natto (fermented soybeans), chlorella, and aojiru (green juice), may reduce the anticoagulant effect, whereas the use of concomitant medications, such as antibiotics and CYP2C9 inhibitors, may enhance anticoagulant effect. In addition, the therapeutic range of warfarin is narrow; therefore, poor anticoagulation control is common. Because of these limitations, new direct oral anticoagulants (DOACs) that directly inhibit a single coagulation factor have been recently discovered. The DOACs dabigatran, rivaroxaban, apixaban, and edoxaban are currently available in Japan.\n\nDabigatran (Prazaxa®) is a direct thrombin inhibitor, which has been marketed in Japan since 2011. It is prescribed to prevent ischemic stroke and systemic embolism in patients with non-valvular AF. In the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) clinical trial, dabigatran (150 mg twice daily) was shown to be non-inferior to warfarin for the prevention of stroke and systemic embolism [4]. A subgroup analysis of Asian patients in the RE-LY trial showed that the rate of stroke or systemic embolism with dabigatran (150 mg twice daily) was lower than that with warfarin [5]. For patients with risk factors such as decreased renal function, advanced age, and history of gastrointestinal bleeding, the risk of hemorrhagic complications with dabigatran is higher; therefore, a dose reduction to 110 mg twice daily is recommended on the package insert of Prazaxa® [6, 7].\n\nHowever, very few patients are prescribed dabigatran at a very low dose of 75 mg twice daily, probably due to safety concerns. One of the reasons is that dabigatran is available on the market in Japan as a 75 mg capsule, not as a 150 mg capsule. The patients in the RE-LY trial were assigned to receive 150 mg or 110 mg twice-daily dabigatran or warfarin treatment regardless of renal function [4]. However, current clinical doses for AF in the United States of America depend on renal function: 150 mg of dabigatran twice daily for creatinine clearance over 30 mL/min and 75 mg twice daily for creatinine clearance of 15 to 30 mL/min [8]. The dose of 75 mg twice daily occasionally prescribed in Japan may be based on the American dose recommendation. Because 75 mg twice daily is not an approved dose of dabigatran in Japan and its efficacy and safety are unknown, the anticoagulant effect of dabigatran may decrease with the lower dose. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications with dabigatran, including the use of the 75 mg twice daily dose.\n\nMethods\nData sources\nFive differently sized hospitals in the Meguro or Setagaya areas of Tokyo were enrolled in this study (Toho University Ohashi Medical Center, National Hospital Organization Tokyo Medical Center, Tamagawa Hospital, Mishuku Hospital, and Kohsei Chuo General Hospital). This multicenter, retrospective cohort study was performed after approval from each hospital’s institutional review board (approval no. 15–46, Toho University Ohashi Medical Center; the representative hospital in our research team). Data were analyzed at the National Hospital Organization Yokohama Medical Center.\n\nInclusion and exclusion criteria\nThe subjects started dabigatran in any of the 5 hospitals between March 2011 and February 2014. We excluded patients who had a dabigatran prescription history of less than 1 month, were hospitalized except for cardiovascular and cerebrovascular diseases, and had no information available after hospital discharge. Subjects with a description of poor medication adherence (less than 80%) in their medical records were also excluded.\n\nData collection\nThe following data were collected: age, sex, body weight, serum creatinine, activated partial thromboplastin time (aPTT), starting dose of dabigatran, date (year and month) of dabigatran initiation, the therapy period of dabigatran, any previous anticoagulant therapy before starting dabigatran, history of bleeding, incidence of complications (heart failure, hypertension, diabetes, and cerebral vascular disease for CHADS2 scores [9]), concomitant medications [antiplatelet drugs (low-dose aspirin, ticlopidine, and clopidogrel) and P-glycoprotein inhibitors (verapamil, amiodarone, cyclosporine, tacrolimus, itraconazole, and clarithromycin)], and incidence of thromboembolic and bleeding events. Creatinine clearance (CCr) was calculated using the Cockcroft-Gault formula. Patients were classified into 3 groups: normal dabigatran dose (300 mg/day; 150 mg twice daily), low-dose dabigatran (220 mg/day; 110 mg twice daily), and very low-dose dabigatran (150 mg/day; 75 mg twice daily). The incidence of thromboembolic events included stroke, transient ischemic attacks (TIA), and systemic embolism as defined by the RE-LY trial. In addition, the patients were monitored for major and minor bleeding. Major bleeding was defined as a decrease in hemoglobin concentration ≥ 2.0 g/dL, transfusion of whole or concentrated blood, and symptomatic hemorrhage of a vital organ or intracranial hemorrhage [4], whereas minor bleeding was defined as other hemorrhagic events.\n\nPrimary and secondary outcomes\nThe primary outcomes were the incidence of thromboembolic events during the period between dabigatran initiation and December 2014. Side effects of bleeding were also investigated. Risk of developing cerebral infarction among the groups was adjusted by CHADS2 scores. As a secondary outcome, the effect of patient background on the incidence of thromboembolic events was also investigated.\n\nStatistical analysis\nT-test (quantitative variable), Fisher’s exact test (qualitative variable, values in any of cells are 10 or below), or chi-square test (qualitative variable, others) was used to estimate clinical characteristics of patients. We compared the risk between normal and low-dose dabigatran (150 mg and 110 mg twice daily) and very low-dose dabigatran (75 mg twice daily) because the incidence of thromboembolic events in the 75 mg twice daily group was assumed to be higher than that in the other groups. Multivariable logistic regression analysis was performed to estimate the thromboembolic and bleeding risk of excessive dose reduction of dabigatran, using variables which are selected by stepwise logistic regression method. Statistical analysis was carried out using JMP Pro 14.2.0 (SAS institute Japan Ltd), and p values below 5% were considered to be significant.\n\nResults\nPatients’ characteristics\nOne hundred and eighty seven patients (26.7%) received 150 mg dabigatran twice daily (normal dose group), and 488 patients (69.6%) received 110 mg twice daily (low-dose group). Only a few patients (26 patients, 3.7%) received 75 mg twice daily (very low-dose group). Clinical characteristics of patients in this study are shown in Table 1, and 150 and 110 mg twice daily groups are shown as one group as mentioned above. The average age of 150 and 110 mg twice daily group (normal dose and low-dose group) was 70.8 ± 10.8 years (mean ± S.D.); the lower dose was associated with a higher average age. The CCr of 150 and 110 mg twice daily group was 69.4 ± 25.3 mL/min; CCr declined in the lower dose groups.Table 1 Clinical characteristics of patients\n\nVariables\tTotal (n = 701)\t150 mg and 110 mg twice daily (n = 675)\t75 mg twice daily (n = 26)\tP-value\t\nAge, years\t71.1 ± 10.9\t70.8 ± 10.8\t78.6 ± 10.0\t0.004**\t\nGender, female (%)\t244 (34.8%)\t231 (34.2%)\t13 (50.0%)\t0.098*\t\nCreatinine clearance: Ccr (mL/min)\t68.7 ± 25.3\t69.4 ± 25.3\t53.5 ± 20.9\t0.003*\t\nHistory of bleeding\t79 (11.3%)\t74 (11.0%)\t5 (19.2%)\t0.191***\t\nNew users\t354 (50.5%)\t348 (51.6%)\t6 (23.1%)\t0.004***\t\nChange from warfarin\t232 (33.1%)\t222 (32.9%)\t10 (38.5%)\t0.532***\t\nC: Congestive heart failure\t138 (19.7%)\t128 (19.0%)\t10 (38.5%)\t0.002***\t\nH: Hypertension\t426 (60.8%)\t406 (60.1%)\t20 (76.9%)\t0.041**\t\nA: Aged 75 or older\t294 (41.9%)\t278 (41.2%)\t16 (61.5%)\t0.021**\t\nD: Diabetes Mellitus\t140 (20.0%)\t133 (19.7%)\t7 (26.9%)\t0.117***\t\nS: Stroke/TIA (2 points)\t185 (26.4%)\t177 (26.2%)\t8 (30.8%)\t0.327***\t\nCHADS2 score\t1.95 ± 1.35\t1.92 ± 1.33\t2.54 ± 1.77\t0.011*\t\nWith antiplatelet agents\t129 (18.4%)\t125 (18.5%)\t4 (15.4%)\t0.686***\t\nMean ± S.D., * t-test, ** Chi-square test, *** Fisher’s exact test\n\n\n\nOverall, half of the patients were new users of anticoagulant therapy, and one-third switched to dabigatran from warfarin. Warfarin and dabigatran were the only oral anticoagulants available in the first half of the study period. Other anticoagulants were available in the second half, but other DOACs are not prescribed much due to their recent availability in Japan.\n\nThromboembolic events\nThe incidence of thromboembolic events during this study period is shown in Table 2. Thromboembolism occurred in 4 patients (2.1%) in the normal dose group and in 11 patients (2.3%) in the low-dose group (15 patients in the normal and low-dose group). On the other hand, 3 of 26 patients (11.5%) in the very low-dose group had a thromboembolic event. The odds ratio of the 75 mg group to the 150 and 110 mg twice daily groups was 5.73 [95% confidence interval (CI), 1.55–21.2; p = 0.009]; however, the number of events was limited. The CHADS2 score in 150 and 110 mg twice daily group was 1.92 ± 1.33 (Table 1); the lower dose was associated with a higher CHADS2 score. The unit odds ratio of the CHADS2 score was 1.69 [95% CI, 1.21–2.37; p = 0.002].Table 2 Thromboembolic events by dabigatran dose and each factor\n\nFactor\tThromboembolism (+) (n = 18)\tThromboembolism (−) (n = 683)\tODDS ratio [95% CI], (P-value)\t\nVery low-dose (75 mg twice daily)\t3\t23\t5.73 [1.55–21.2], (0.009*)\t\nAge, years\t77.4 ± 13.5\t71.0 ± 10.8\t1.06 [1.01–1.12], (0.013*)\t\nGender, female\t10\t234\t2.40 [0.93–6.16], (0.069)\t\nCreatinine clearance: Ccr (mL/min)\t58.9 ± 23.5\t69.0 ± 25.3\t0.98 [0.96–1.02], (0.096)\t\nHistory of bleeding\t1\t78\t0.46 [0.06–3.45], (0.449)\t\nNew users\t8\t346\t1.28 [0.50–3.29], (0.604)\t\nChange from warfarin\t8\t224\t1.66 [0.65–4.27], (0.292)\t\nC: Congestive heart failure\t6\t132\t1.84 [0.67–4.99], (0.233)\t\nH: Hypertension\t9\t417\t0.56 [0.22–1.45], (0.231)\t\nA: Aged 75 or older\t13\t281\t3.16 [1.11–8.96], (0.031*)\t\nD: Diabetes Mellitus\t5\t135\t1.36 [0.47–3.90], (0.561)\t\nS: Stroke/TIA (2 points)\t10\t175\t3.24 [1.26–8.36], (0.015*)\t\nCHADS2 score\t2.94 ± 1.51\t1.92 ± 1.34\t1.69 [1.21–2.37], (0.002*)\t\nWith antiplatelet agents\t2\t127\t0.55 [0.12–2.43], (0.426)\t\n*P < 0.05\n\n\n\nThe incidence of thromboembolism was higher in patients with aged 75 years or older and stroke/TIA history. The factor of aPTT > 60 was not shown because some patients had incomplete data.\n\nAmong the factors shown in Table 2, the factors related to thromboembolic events were dose, age, A (aged 75 or older), S (stroke/TIA), and CHADS2 score. Dose, hypertension, aged 75 or older, and stroke/TIA history were selected as variables since the value of Akaike’s Information Criterion (AIC) was lower in this model. In these variables, dose and stroke/TIA history were selected by stepwise logistic regression method (Table 3).Table 3 Factors that influence thromboembolic events by stepwise logistic regression method\n\nFactor\tAdjusted ODDS ratio\t95% CI\tP-value\t\nVery low-dose (75 mg twice daily)\t6.88\t1.67–28.3\t0.008*\t\nH: Hypertension\t2.25\t0.83–6.12\t0.110\t\nA: Aged 75 or older\t2.76\t0.92–8.23\t0.068\t\nS: Stroke/TIA\t2.97\t1.11–7.94\t0.030*\t\n*P < 0.05\n\n\n\nBleeding events\nMajor bleeding events occurred in 11 patients (Table 4) during the study period: 3 intracranial hemorrhages, 7 gastrointestinal bleeding, and 1 anemia case with no identified bleeding source. Only 1 event occurred in the 150 mg twice daily group (0.5%), and the other events were reported in patients receiving 110 mg twice daily (2.0%). Hemorrhagic complications (any bleeding including minor bleeding) were observed in 57 patients, and no significant difference was observed among each group. In the 75 mg twice daily group, 3 patients had minor bleeding. The incidence of hemorrhagic complications may be higher in patients who had lower CCr, were new users, changed to dabigatran from warfarin, were aged 75 years or older, had a stroke/TIA history, or received antiplatelet agents (Table 5). New users, aged 75 or older, stroke/TIA history, and “with antiplatelet agents” were selected as variables since the value of AIC was lower in this model. In these variables, new users and “with antiplatelet agents” were selected by stepwise logistic regression method (Table 6).Table 4 Number of bleeding cases by dose of dabigatran\n\nClassification of bleeding\tTotal (n = 701)\t150 mg and 110 mg twice daily (n = 675)\t75 mg twice daily (n = 26)\tP-value\t\nMajor bleeding\t11 (1.6%)\t11 (1.6%)\t0 (0.0%)\t1.000\t\nAny bleeding\t57 (8.1%)\t54 (8.0%)\t3 (11.5%)\t0.461\t\nTable 5 Bleeding cases by dabigatran dose and each factor\n\nFactor\tBleeding (+) (n = 57)\tBleeding (−) (n = 644)\tODDS ratio [95% CI], (P-value)\t\nVery low-dose (75 mg twice daily)\t3\t23\t1.50 [0.44–5.16], (0.520)\t\nAge, years\t74.0 ± 9.0\t70.9 ± 11.0\t1.03 [1.00–1.06], (0.036*)\t\nGender, female\t19\t225\t1.07 [0.60–1.90], (0.808)\t\nCreatinine clearance: Ccr (mL/min)\t61.6 ± 29.4\t69.4 ± 24.9\t0.99 [0.97–1.01], (0.038*)\t\nHistory of bleeding\t9\t70\t1.53 [0.72–3.27], (0.264)\t\nNew users\t19\t335\t0.46 [0.26–0.82], (0.007*)\t\nChange from warfarin\t26\t206\t1.81 [1.05–3.12], (0.034*)\t\nC: Congestive heart failure\t12\t126\t1.01 [0.51–1.96], (0.987)\t\nH: Hypertension\t38\t388\t0.76 [0.42–1.39], (0.376)\t\nA: Aged 75 or older\t33\t261\t1.78 [1.02–3.10], (0.043*)\t\nD: Diabetes Mellitus\t9\t131\t0.67 [0.32–1.39], (0.282)\t\nS: Stroke/TIA (2 points)\t24\t161\t2.00 [1.15–3.51], (0.015*)\t\nCHADS2 score\t2.44 ± 1.34\t1.90 ± 1.34\t1.33 [1.09–1.61], (0.005*)\t\nWith antiplatelet agents\t17\t112\t2.02 [1.10–3.69], (0.022*)\t\n*P < 0.056\n\nTable 6 Factors that influence bleeding as side effect by stepwise logistic regression method\n\nFactor\tAdjusted ODDS ratio\t95% CI\tP-value\t\nNew users\t0.51\t0.27–0.91\t0.022*\t\nA: Aged 75 or older\t1.55\t0.87–2.79\t0.136\t\nS: Stroke/TIA\t1.71\t0.94–3.07\t0.081\t\nWith antiplatelet agents\t2.04\t1.07–3.75\t0.030*\t\n*P < 0.05\n\n\n\nDiscussion\nThe AF guidelines recommend the administration of anticoagulant drugs including dabigatran if the CHADS2 score is 1 or higher [9]. Although dabigatran can decrease the risk of a thrombus, there is a possibility of hemorrhagic side effects. Therefore, some patients may occasionally receive an excessively reduced dose of dabigatran, which is unapproved in Japan, to lower the risk of bleeding. It has been over 5 years since dabigatran was used clinically in Japan; thus, this analysis was performed and included patients using 75 mg twice daily.\n\nApproximately 70% of the subjects in this study received 110 mg dabigatran twice daily. This tendency is similar to that reported in other Japanese studies [10, 11]. Patients receiving this reduced dose were older and had a lower CCr than patients receiving 150 mg twice daily; therefore, it was inferred that age and renal function were considered when selecting the dose of dabigatran. In the 75 mg twice daily group (26 patients), only 6 patients were newly started on anticoagulant therapy, 7 patients had the dose of dabigatran reduced, and 10 patients were switched to dabigatran from warfarin. The reason for the dose reduction to 75 mg twice daily varied from case to case; however, almost all of the patients on the very low-dose in this study were older than 70 years except for 3 patients, and some of them had aPTT prolongation, minor bleeding such as anemia or bloody stool, or renal dysfunction, or were on the combination of dabigatran and an antiplatelet drug or a P-glycoprotein inhibitor. One or more of these factors were considered to be involved in the dabigatran dose reduction. On the other hand, 7 other patients did not have any factors other than advanced age; therefore, it is possible that their doses were reduced at the discretion of their physician [11].\n\nThe CCr of a few patients was less than 30 mL/min. These patients must be prevented from dabigatran use; however, a small number of inappropriate uses have been reported in the “real-world” [10–12]. It was assumed that there were unavoidable reasons such as when renal function was around the boundary line of contraindicative criteria, or when warfarin could not be used because of its side effect. It might be related to the fact that DOACs are sometimes prescribed at a reduced dose [11, 12].\n\nThe incidence of thromboembolism was approximately 2% in the 150 and 110 mg twice daily groups in our study. In the subgroup analysis of Asian patients in the RE-LY trial, the incidence of thromboembolic events was 1.39% in the 150 mg twice daily group and 2.50% in the 110 mg twice daily group (CHADS2 score, 2.2 ± 1.1) [5]. In a real-world observational study of Japanese patients in Tokyo Women’s Medical University Hospital, the incidence was 0.6% (95% CI, 0.08–2.3%; CHADS2 score, 1.9 ± 1.5) [11]. It was inferred that the incidence of thromboembolic events depends on the study design and patient background, including the CHADS2 score [13]. On the other hand, 3 of 26 patients (11.5%) in the 75 mg twice daily dabigatran group had a thromboembolic event (femoral vein thrombosis, lacunar infarction, and TIA), and the incidence was higher than others. Moreover, lacunar infarction occurred in one of the 3 patients, who was 96-years-old and with a CCr of 30 mL/min. The other patients were 80 years old and their CCr was over 50 mL/min. This illustrates why the very elderly and those with poor renal function may receive doses lower than that recommended on the package insert. In AF patients undergoing coronary revascularization with warfarin anticoagulant therapy, the incidence of stroke was 6.9% with a time in therapeutic range (TTR) ≥ 65%; however, the incidence of stroke increased to 15.1% with TTR < 65%. Inadequate control of warfarin’s anticoagulant effect leads to inadequate stroke prevention and markedly higher cumulative 5-year incidence of stroke and mortality rates [14]. Optimization of anticoagulant dose is crucial for stroke prevention.\n\nOverall, in our study, hemorrhagic side effects were observed in 57 patients (8.1%), among which 1 case (0.5%) in the 150 mg twice daily group and 10 cases (2.0%) in 110 mg twice daily group were major bleeding. In the 75 mg twice daily group, major bleeding was not observed, although it may be because the total number of cases was small. In the sub-analysis of Asian patients in the RE-LY trial, the rate of major bleeding was approximately 2.2% [5], and the total rate of serious hemorrhagic events in the post-marketing surveillance was 0.55% [10]. The incidence of hemorrhagic complications (any bleeding) may be higher in patients with lower CCr, aged 75 years or older, with stroke/TIA, or on antiplatelet agents (Table 5). Therapy change from warfarin to dabigatran was also found to be a risk factor for bleeding, perhaps because the patients who switched medication were poorly controlled with warfarin. In contrast, “New users” reduced the risk for bleeding. Major bleeding rates with dabigatran use were similar to those with warfarin use in real-world settings, and not in a randomized controlled trial [15].\n\nThree subjects who had a thromboembolic event were excluded from this study owing to poor adherence. One patient discontinued treatment owing to an itching sensation. The other 2 patients only took dabigatran once a day. The half-life of dabigatran is shorter than that of warfarin, which is an advantage since the drug withdrawal period in case of surgery is shorter with dabigatran. However, poor adherence will attenuate the anticoagulant effect of dabigatran, and the risk of cardiogenic cerebral infarction will temporarily increase. A limitation of this study is that, owing to its retrospective nature, adequate adherence survey could not be performed.\n\nConclusions\nIn this study, we analyzed the efficacy and safety of dabigatran including patients on a very low-dose of 75 mg twice daily. A limited number of patients were on this very low-dose, and none experienced a major bleed; however, 3 cases of thromboembolism occurred. In conclusion, the results suggest that sufficient anticoagulation efficacy may not be maintained when the dose of dabigatran is excessively reduced.\n\nAbbreviations\nAFAtrial fibrillation\n\nAICAkaike’s Information Criterion\n\naPTTActivated partial thromboplastin time\n\nCCrCreatinine clearance\n\nCIConfidence interval\n\nDOACDirect oral anticoagulant\n\nRE-LYRandomized evaluation of long-term anticoagulant therapy trial\n\nTIATransient ischemic attack\n\nTTRTime in therapeutic range\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors appreciate Toa Eiyo Company’s assistance with activities of our team; the Johnan Pharmacist Heart Conference.\n\nAuthors’ contributions\nYA, TC, and SU conceived the study. TC, SU, YA, ME, YO, TK, YK, TS, AT, and YN collected the data from medical records of each hospital. YA analyzed the data, and SY performed the statistical analyses. YA wrote the manuscript. YA, TC, SU, HK, and SY provided editorial review and contributed to discussions. All the authors have read and approved the final version of the manuscript.\n\nFunding\nThis study was supported by research funds of Toho University.\n\nAvailability of data and materials\nThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis multicenter retrospective cohort study was performed after having obtained approval from each hospital’s institutional review board (Delegate: Toho University Ohashi Medical Center, approval no. 15–46).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Hata J Tanizaki Y Kiyohara Y Kato I Kubo M Tanaka K Ten year recurrence after first ever stroke in a Japanese community: the Hisayama study J Neurol Neurosurg Psychiatry 2005 76 368 372 10.1136/jnnp.2004.038166 15716529 \n2. Hart RG Benavente O McBride R Pearce LA Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis Ann Intern Med 1999 131 492 501 10.7326/0003-4819-131-7-199910050-00003 10507957 \n3. Aosaki M, Iwade K, Echizen H. Information on proper use of warfarin. 3rd ed. Tokyo: Eisai Co., Ltd; 2006. p. 170–513.\n4. Connolly SJ Ezekowitz MD Yusuf S Eikelboom J Oldgren J Parekh A Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009 361 1139 1151 10.1056/NEJMoa0905561 19717844 \n5. Hori M Connolly SJ Zhu J Liu LS Lau CP Pais P Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation Stroke 2013 44 1891 1896 10.1161/STROKEAHA.113.000990 23743976 \n6. Wallentin L Yusuf S Ezekowitz MD Alings M Flather M Franzosi MG Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial Lancet 2010 376 975 983 10.1016/S0140-6736(10)61194-4 20801496 \n7. The package insert of Plazaxa® in Japan. Nippon Boehringer Ingelheim Co ., Ltd. http://www.bij-kusuri.jp/medicine_data/pxa_cap/pxa_cap_tenpu.htm. Accessed 26 Jan 2018.\n8. Graham DJ Reichman ME Wernecke M Zhang R Southworth MR Levenson M Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation Circulation 2015 131 157 164 10.1161/CIRCULATIONAHA.114.012061 25359164 \n9. Joint working group Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013) Circ J 2014 78 1997 2021 10.1253/circj.CJ-66-0092 24965079 \n10. Inoue H Uchiyama S Atarashi H Okumura K Koretsune Y Yasaka M Post- marketing surveillance on the long-term use of dabigatran in Japanese patients with nonvalvular atrial fibrillation: preliminary report of the J-dabigatran surveillance J Arrhythm. 2016 32 145 150 10.1016/j.joa.2015.11.008 27092197 \n11. Naganuma M Shiga T Nagao T Suzuki A Murasaki K Hagiwara N Effectiveness and safety of dabigatran versus warfarin in “real-world” Japanese patients with atrial fibrillation: a single-center observational study J Arrhythm 2017 33 107 110 10.1016/j.joa.2016.07.007 28416975 \n12. Lavoie K Turgeon MH Brais C Larochelle J Blais L Farand P Inappropriate dosing of direct oral anticoagulants in patients with atrial fibrillation J Atr Fibrillation 2016 9 1478 10.4022/jafib.1478 29250254 \n13. Quinn GR Severdija ON Chang Y Singer DE Wide variation in reported rates of stroke across cohorts of patients with atrial fibrillation Circulation. 2017 135 208 219 10.1161/CIRCULATIONAHA.116.024057 27799272 \n14. Goto K Nakai K Shizuta S Morimoto T Shiomi H Natsuaki M Anticoagulant and antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention Am J Cardiol 2014 114 70 78 10.1016/j.amjcard.2014.03.060 24925801 \n15. Larsen TB Rasmussen LH Skjøth F Due KM Callréus T Rosenzweig M Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study J Am Coll Cardiol 2013 61 2264 2273 10.1016/j.jacc.2013.03.020 23562920\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2055-0294",
"issue": "5()",
"journal": "Journal of pharmaceutical health care and sciences",
"keywords": "Anticoagulant; Dabigatran; Excessive dose reduction; Non-valvular atrial fibrillation; Retrospective study; Thromboembolism",
"medline_ta": "J Pharm Health Care Sci",
"mesh_terms": null,
"nlm_unique_id": "101672177",
"other_id": null,
"pages": "17",
"pmc": null,
"pmid": "31388437",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "10507957;15716529;19717844;20801496;23562920;23743976;24925801;24965079;25359164;27092197;27799272;28416975;29250254",
"title": "Retrospective cohort study of the efficacy and safety of dabigatran: real-life dabigatran use including very low-dose 75 mg twice daily administration.",
"title_normalized": "retrospective cohort study of the efficacy and safety of dabigatran real life dabigatran use including very low dose 75 mg twice daily administration"
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"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-103615",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"activesubstancename": "LANSOPRAZOLE"
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{
"abstract": "This phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with romosozumab treatment and was well tolerated.\n\n\nBACKGROUND\nFollow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of romosozumab therapy. We evaluated the use of zoledronate following romosozumab treatment.\n\n\nMETHODS\nThis phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various romosozumab doses or placebo from months 0-24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and β-CTX) and safety were evaluated for 24 months, up to month 72.\n\n\nRESULTS\nA total of 141 subjects entered the month 48-72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48-72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: - 0.8% from months 48-72; 12.8% from months 0-72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and β-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and β-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed.\n\n\nCONCLUSIONS\nA zoledronate follow-on regimen can maintain robust BMD gains achieved with romosozumab treatment.",
"affiliations": "Oregon Osteoporosis Center, 2881 NW Cumberland Road, Portland, OR 97210, USA. mmcclung.ooc@gmail.com.;Bethesda Health Research Center, Bethesda, MD, USA.;Laval University and CHU de Québec (CHUL) Research Centre, Québec City, QC, Canada.;University of Liège, Liège, Belgium.;Aarhus University Hospital, Aarhus, Denmark.;Amgen Inc., Thousand Oaks, CA, USA.;Amgen Inc., Thousand Oaks, CA, USA.;Amgen Inc., Thousand Oaks, CA, USA.;UCB Pharma, Brussels, Belgium.;Amgen Inc., Thousand Oaks, CA, USA.",
"authors": "McClung|M R|MR|;Bolognese|M A|MA|;Brown|J P|JP|;Reginster|J-Y|JY|;Langdahl|B L|BL|;Maddox|J|J|;Shi|Y|Y|;Rojeski|M|M|;Meisner|P D|PD|;Grauer|A|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D050071:Bone Density Conservation Agents; C557282:romosozumab; D000077211:Zoledronic Acid",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-020-05502-0",
"fulltext": "\n==== Front\nOsteoporos Int\nOsteoporos Int\nOsteoporosis International\n0937-941X 1433-2965 Springer London London \n\n5502\n10.1007/s00198-020-05502-0\nOriginal Article\nA single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab\nMcClung M. R. mmcclung.ooc@gmail.com 12 Bolognese M. A. 3 Brown J. P. 4 Reginster J.-Y. 56 Langdahl B. L. 7 Maddox J. 8 Shi Y. 8 Rojeski M. 8 Meisner P. D. 9 Grauer A. 8 1 grid.240531.10000 0004 0456 863XOregon Osteoporosis Center, 2881 NW Cumberland Road, Portland, OR 97210 USA \n2 grid.411958.00000 0001 2194 1270Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC Australia \n3 Bethesda Health Research Center, Bethesda, MD USA \n4 grid.23856.3a0000 0004 1936 8390Laval University and CHU de Québec (CHUL) Research Centre, Québec City, QC, Canada \n5 grid.4861.b0000 0001 0805 7253University of Liège, Liège, Belgium \n6 grid.56302.320000 0004 1773 5396King Saud University, Riyadh, Kingdom of Saudi Arabia \n7 grid.154185.c0000 0004 0512 597XAarhus University Hospital, Aarhus, Denmark \n8 grid.417886.40000 0001 0657 5612Amgen Inc., Thousand Oaks, CA USA \n9 grid.421932.f0000 0004 0605 7243UCB Pharma, Brussels, Belgium \n4 7 2020 \n4 7 2020 \n2020 \n31 11 2231 2241\n11 6 2019 8 6 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.Summary\nThis phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with romosozumab treatment and was well tolerated.\n\nIntroduction\nFollow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of romosozumab therapy. We evaluated the use of zoledronate following romosozumab treatment.\n\nMethods\nThis phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various romosozumab doses or placebo from months 0–24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and β-CTX) and safety were evaluated for 24 months, up to month 72.\n\nResults\nA total of 141 subjects entered the month 48–72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48–72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: − 0.8% from months 48–72; 12.8% from months 0–72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and β-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and β-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed.\n\nConclusion\nA zoledronate follow-on regimen can maintain robust BMD gains achieved with romosozumab treatment.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s00198-020-05502-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nAntiresorptiveBone mineral densityFollow-on regimenOsteoporosisRomosozumabAmgen Inc.Not applicableUCB PharmaNot applicableAstellasNot applicableissue-copyright-statement© International Osteoporosis Foundation and National Osteoporosis Foundation 2020\n==== Body\nIntroduction\nOsteoporosis is a chronic condition requiring long-term therapy, potentially involving sequential treatment regimens with different agents over a patient’s lifetime. Accumulating evidence supports treatment strategies that improve and then maintain bone mineral density (BMD) to desired goals, in order to reduce fracture risk [1–4].\n\nAntiresorptive drugs such as bisphosphonates and denosumab may be given for several years. These agents increase BMD but do not correct the deficits in trabecular microarchitecture [5, 6]. Notably, therapies that stimulate bone formation can quickly increase BMD and improve bone structure [7]. Regulatory recommendations limit the use of previously available anabolic agents, including the parathyroid hormone (PTH) analogue teriparatide and the PTH receptor agonist abaloparatide, to a combined 2 years of treatment in a patient’s lifetime [8, 9]; thus, limiting the use of these drugs for long-term management of osteoporosis. Additionally, the BMD gains achieved with teriparatide are lost upon discontinuing therapy, but these gains can be preserved or amplified when subjects are switched to alendronate or denosumab upon stopping teriparatide therapy [10, 11]. Similarly, BMD gains and fracture risk reduction observed with abaloparatide are maintained upon transitioning to alendronate [12]. As a result, current guidelines recommend following anabolic therapy with a potent antiresorptive agent [13, 14].\n\nRomosozumab is a monoclonal antibody that inhibits sclerostin and has a dual effect of increasing bone formation and decreasing bone resorption [15–17], and has also been shown to improve skeletal microarchitecture [18, 19]. In the first 24 months of this dose-finding phase 2 study in postmenopausal women with low bone mass, we evaluated the efficacy and safety of different romosozumab doses (70 mg, 140 mg, and 210 mg) administered by subcutaneous (SC) injection at 1- or 3-month intervals to identify the optimal romosozumab regimen [17, 20]. Treatment with romosozumab 210 mg monthly (QM) for 12 months was subsequently shown to significantly increase BMD and reduce fracture risk compared to placebo and to alendronate in women with postmenopausal osteoporosis in phase 3 studies [21, 22]. The fracture protection benefit of romosozumab was maintained during the subsequent interval of antiresorptive treatment. A phase 3 open-label study also demonstrated the efficacy and safety of romosozumab when administered to subjects previously treated with bisphosphonates [23]. Romosozumab has been approved in several countries, e.g., for the treatment of osteoporosis in the USA [24] and for the treatment of severe osteoporosis in the EU [25] in postmenopausal women at high risk for fracture.\n\nWe extended the current phase 2 study to investigate the effects of discontinuing romosozumab and switching to denosumab or placebo from months 24 to 36, observing that subjects receiving denosumab continued to accrue BMD, whereas BMD returned toward baseline levels when romosozumab was discontinued without follow-on therapy [20]. These data pointed to the need for antiresorptive follow-on therapy to maintain the large and rapid BMD gains from romosozumab treatment. Phase 3 studies have subsequently confirmed the efficacy of antiresorptive therapy such as denosumab or alendronate following romosozumab in both maintaining BMD and in preserving the benefit of the initial treatment with romosozumab on fracture risk [2, 21, 22].\n\nIn a prior extension of this phase 2 study, subjects received a second course of romosozumab 210 mg QM from months 36 to 48. Rapid and large BMD gains with romosozumab were observed in subjects who had received no active treatment in the 12 months prior [26]. The BMD response to romosozumab following denosumab was very small, but romosozumab prevented BMD declines following denosumab discontinuation. Recognizing the need for following romosozumab therapy with an antiresorptive agent, in the last stage of this phase 2 study, we evaluated the efficacy and safety of a single dose of zoledronate (also known as zoledronic acid) 5 mg upon stopping treatment with the second course of romosozumab. This report describes the results of this final segment of the study.\n\nMaterials and methods\nStudy design\nThis phase 2, international, multicenter, randomized, placebo-controlled, dose-finding, parallel-group study enrolled postmenopausal women aged 55 to 85 years with a low BMD (T-score of ≤ − 2.0 and ≥ − 3.5 at the lumbar spine, total hip, or femoral neck) [17]. Key exclusion criteria have been previously described [17] and are provided in Online Resource Supplemental Methods.\n\nTreatment groups in the romosozumab double-blind period (months 0 to 24), denosumab extension period (months 24 to 36), romosozumab second-course period (months 36 to 48), and zoledronate follow-on period (months 48 to 72) are presented in Fig. 1; additional details of the study design have been previously published [17]. Briefly, women were randomized to receive 1 of 5 dosing regimens of SC romosozumab or to receive 1 of 2 open-label comparators (oral alendronate 70 mg weekly [QW] or SC teriparatide 20 μg daily) (Fig. 1a). The remaining 52 women were randomly assigned to receive placebo injections QM or Q3M.Fig. 1 Study schema. a Subjects were randomized 1:1:1:1:1:1:1:1 to the first 24 months of treatment. Administration of placebo and the various romosozumab doses was blinded; alendronate and teriparatide were administered open-label. At month 24, subjects were rerandomized (1:1) within treatment group to placebo or denosumab (60 mg SC Q6M) for 12 months, followed by a 12-month second course of romosozumab 210 mg QM. b For subjects who reached month 48 of the study, eligibility for the month 48 to 72 zoledronate follow-on period was assessed by the investigator using a 3-step approach with no randomization. Subjects were assigned to no further active treatment if they (1) had been assigned to active treatment throughout the first 48 months (romosozumab any dose and schedule, followed by denosumab 60 mg Q6M, and then followed by romosozumab 210 mg QM); (2) had no clinical vertebral or fragility fracture between months 24 and 48; (3) had a BMD T-score > − 2.5 at the lumbar spine, total hip, or femoral neck at month 48; or (4) had any contraindication to zoledronate. All other subjects were assigned to receive a single IV dose of zoledronate 5 mg. aSubjects transitioned to romosozumab 140 mg QM at month 12, were randomized in the denosumab extension period, completed the study at month 36, and are not included in the present analysis. bSubjects completed the study at month 12 and are not included in the present analysis. cOf the subjects randomized to romosozumab 210 mg QM in the double-blind period, 12 entered the no further active treatment group and 17 entered the zoledronate group during the follow-on phase. IV intravenous, PO orally, QD every day, QM every month, Q3M every 3 months, QW every week, SC subcutaneous\n\n\n\nOn completing the 12-month double-blind treatment period, subjects in the romosozumab and placebo groups continued their assigned treatment for an additional 12 months [17, 20] (Fig. 1a). At month 24, eligible consenting subjects entered a 12-month extension phase and were rerandomized (1:1) to double-blind treatment with placebo or denosumab 60 mg (Amgen Inc., Thousand Oaks, CA) every 6 months (Q6M) (Fig. 1a). Subjects who completed the month 24 to 36 denosumab extension period entered a 12-month phase where they received open-label romosozumab 210 mg (Amgen Inc., Thousand Oaks, CA) QM through month 48 (romosozumab second-course period).\n\nSubjects who completed the month 36 to 48 romosozumab second-course period were then eligible to enter a 24-month extension (month 48 to 72 follow-on period) where they were assigned to either no further active treatment or to receive a single intravenous (IV) dose of zoledronate 5 mg at month 48 (Fig. 1a, b). Eligibility for the month 48 to 72 follow-on period was assessed by the investigator using a 3-step approach with no randomization. Subjects were assigned to no further active treatment if they (1) had been assigned to active treatment (romosozumab any dose and schedule, followed by denosumab 60 mg Q6M, and then followed by romosozumab 210 mg QM) throughout the first 48 months; (2) had no clinical vertebral or fragility fracture between months 24 and 48; (3) had a BMD T-score > − 2.5 at the lumbar spine, total hip, and femoral neck at month 48; or (4) had any contraindication to zoledronate. All other subjects were assigned to zoledronate which was administered at month 48, approximately 4 weeks after the month 47 dose of romosozumab.\n\nThe study protocol was approved by an independent ethics committee or institutional review board at each center, and the study was registered as a clinical trial with registration identification ClinicalTrials.gov NCT00896532. The study was conducted in accordance with International Conference on Harmonization guidelines on Good Clinical Practice and the principles of the Declaration of Helsinki. All subjects provided written informed consent.\n\nStudy procedures\nThe study procedures for assessing BMD, bone turnover markers, and other measures during the first 48 months of the study have been previously published [17, 20]. This report describes BMD measured at the lumbar spine and proximal femur by dual energy X-ray absorptiometry (Lunar, GE Medical Systems, Madison, WI, USA or Hologic, Hologic Inc., Bedford, MA, USA) at months 36, 39, 42, 48, 54, 60, 66, and 72. BioClinica (previously known as Synarc; Newark, CA, USA) analyzed the scans and provided quality control of the scans and scanners. Blood was collected and analyzed for serum chemistry, hematology, bone turnover markers, and antiromosozumab antibodies. Levels of the bone formation marker procollagen type I N-terminal propeptide (P1NP; UniQ P1NP RIA, Orion Diagnostica Oy, Espoo, Finland) and the bone resorption marker β-isomer of the C-terminal telopeptide of type I collagen (β-CTX; Serum CrossLaps ELISA, Nordic Bioscience Diagnostics, A/S, Herlev, Denmark) were assessed at months 36, 37, 39, 42, 45, 48, 51, 54, 60, 66, and 72. Serum levels of antiromosozumab antibodies were assessed at months 36, 39, 42, 45, 48, and 51. Samples were tested for romosozumab neutralizing activity in vitro in subjects who tested positive for binding antibodies, as previously described [16]. Adverse events were collected as observed by the investigator or reported by subjects. Potential cases of osteonecrosis of the jaw and atypical femoral fracture were adjudicated by independent committees.\n\nStudy outcomes\nResults of the study periods up to month 48 have been previously published [17, 20, 26]. This report focuses on results from the month 48 to 72 follow-on period, assessing the exploratory endpoints of the percentage change in BMD at the lumbar spine, total hip, and femoral neck and bone turnover markers (P1NP and β-CTX), and the safety of transitioning to zoledronate after 12 months of treatment with a second course of romosozumab.\n\nStatistical analysis\nThe efficacy set included subjects enrolled in the month 48 to 72 follow-on period, and data were analyzed according to the treatment allocation as determined by the assigned treatment sequence throughout the study. The safety set included all subjects who were enrolled in the month 48 to 72 follow-on period, and data were analyzed by treatment received rather than by treatment assigned.\n\nChanges in BMD and bone turnover markers were summarized separately for subjects assigned to no further active treatment and subjects assigned to zoledronate. Subjects assigned to no further active treatment who began receiving an alternative treatment for osteoporosis, as determined by the investigator, were censored 3 months after the start of the alternative treatment for BMD and at the start of alternative treatment for bone turnover markers. All endpoints were summarized descriptively. Percentage change in BMD from month 48 at months 54, 60, 66, and 72 and from the initial baseline (month 0) at months 48, 54, 60, 66, and 72 are presented as means and 95% confidence intervals. Percentage change in P1NP and β-CTX from month 48 at months 51, 54, 60, 66, and 72 and from the initial baseline (month 0) at months 51, 54, 60, 66, and 72 are presented as medians and interquartile ranges.\n\nSafety endpoints were summarized for subjects assigned to no further active treatment and subjects assigned to zoledronate using the safety analysis set for the month 48 to 72 follow-on period. For subjects assigned to no further active treatment, the start of the month 48 to 72 follow-on period was defined as the month 48 study visit, 4 weeks after the month 47 dose of romosozumab. All adverse events occurring on this date until the end of study date were reported in the follow-on period. For subjects assigned to zoledronate, the start of the month 48 to 72 follow-on period was defined as the date of the first dose of zoledronate. All adverse events that started on the day of the first dose of zoledronate or later were attributed to zoledronate and hence were reported in the follow-on period. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA; version 18.1).\n\nResults\nSubject disposition\nSubject disposition has been previously published for the month 0 to 24 romosozumab double-blind period and the month 24 to 48 extension period [17, 20], and is summarized through month 72 in Online Resource Fig. S1 (which includes all the study phases). Of the 313 subjects randomized to placebo (n = 52) and romosozumab (n = 261) in the month 0 to 24 romosozumab double-blind period, 167 entered the month 36 to 48 romosozumab second-course period. Of those, 141 entered the month 48 to 72 zoledronate follow-on period. A total of 51 of the 141 subjects who entered the follow-on period met the eligibility criteria to be assigned to no further active treatment. These include 1 subject who received placebo in the month 0 to 24 romosozumab double-blind period and was incorrectly assigned to no further active treatment in the follow-on period and 4 subjects who were assigned to no further active treatment but received alendronate for the treatment of bone loss that developed during the follow-on period. The remaining 90 subjects were assigned to receive a single IV dose of zoledronate 5 mg at month 48. These include 2 subjects who were incorrectly assigned to receive zoledronate and 3 subjects who were assigned to zoledronate but did not receive investigational product from months 48 to 72. Of the 51 subjects assigned to no further active treatment, 50 (98.0%) completed the month 48 to 72 follow-on period and 1 died (Online Resource Fig. S1). Of the 90 subjects assigned to zoledronate, 88 (97.8%) completed the month 48 to 72 follow-on period and 2 (2.2%) discontinued the study (1 after the subject was determined to be ineligible; 1 after consent was withdrawn) (Online Resource Fig. S1). All subjects enrolled in the month 48 to 72 follow-on period were included in the safety analysis except for the 3 subjects assigned to zoledronate who did not receive the therapy.\n\nBaseline characteristics\nAt the initial study baseline (month 0), demographic and key characteristics were well matched between subject groups entering the month 48 to 72 follow-on period (Table 1). At month 48, the baseline for the month 48 to 72 follow-on period reported here, subjects who had been on active treatment in the previous 48 months and were therefore assigned to no further active treatment in this follow-on period exhibited somewhat higher BMD T-score values and levels of both bone turnover markers than subjects assigned to zoledronate (Table 1). The differences in BMD T-score values and levels of both bone turnover markers between the groups might be due, in large part, to the difference in the therapies received between the two study groups during year 3 of the phase 2 study: the subjects assigned to no further active treatment had received denosumab during months 24 to 36 while almost all of the subjects in the zoledronate group had received placebo during that interval.Table 1 Baseline demographic and key characteristics for all subjects who entered the month 0 to 24 double-blind period and were assigned to no further active treatment or zoledronate from months 48 to 72\n\n\tInitial study baseline (month 0)\tMonth 48 baseline\t\n\tNo further active treatmenta (N = 51)\tZoledronate\n5 mg IV single doseb (N = 90)\tNo further active treatmenta (N = 51)\tZoledronate\n5 mg IV single doseb (N = 90)\t\nAge, mean (SD), years\t67.2 (6.4)\t65.8 (5.6)\t71.8 (6.4)\t70.3 (5.6)\t\nBMD T-score, mean (SD)\t\n Lumbar spine\t− 2.32 (0.54)\t− 2.34 (0.64)\t− 1.04 (0.88)\t− 1.28 (0.83)\t\n Total hip\t− 1.63 (0.61)\t− 1.42 (0.61)\t− 1.29 (0.65)\t− 1.16 (0.63)\t\n Femoral neck\t− 1.98 (0.54)\t− 1.86 (0.55)\t− 1.70 (0.56)\t− 1.63 (0.61)\t\nSerum P1NP, median (Q1, Q3), μg/L\t51.2 (37.4, 64.5)\t49.9 (39.2, 60.8)\t66.8 (51.0, 90.4)\t46.7 (33.2, 54.3)\t\nSerum β-CTX, median (Q1, Q3), ng/mL\t0.54 (0.42, 0.65)\t0.48 (0.37, 0.63)\t0.55 (0.44, 0.82)\t0.38 (0.30, 0.49)\t\nN = number of subjects assigned to treatment groups from months 48 to 72\n\nNo further active treatment: Subjects randomized to romosozumab (any dose or schedule) in the month 0–24 double-blind period, received denosumab 60 mg Q6M in the month 24–36 extension period, received a second course of romosozumab 210 mg QM from months 36 to 48, and received no further active treatment from months 48 to 72\n\nZoledronate 5 mg IV single dose: Subjects randomized to romosozumab (any dose or schedule) or placebo in the month 0 to 24 double-blind period, received denosumab or placebo in the month 24 to 36 extension period, received a second course of romosozumab 210 mg QM from months 36 to 48, and received a single IV dose of zoledronate 5 mg from months 48 to 72\n\naIncludes all subjects who enrolled in the month 48 to 72 follow-on phase assigned to no further active treatment including 1 subject who had been randomized to placebo in the initial 24 months and was incorrectly assigned to no further active treatment\n\nbIncludes 2 subjects who were incorrectly assigned to zoledronate from months 48 to 72 and 3 subjects who were assigned to zoledronate at month 48 but did not receive treatment\n\nβ-CTX β-isomer of the C-terminal telopeptide of type I collagen, BMD bone mineral density, IV intravenous, P1NP procollagen type 1 N-terminal propeptide, Q1 quartile 1, Q3 quartile 3, SD standard deviation\n\n\n\nEfficacy\nBone mineral density\nBMD results for the overall population entering the month 48 to 72 follow-on period are presented in Fig. 2 and Online Resource Table S1. In subjects assigned to no further active treatment (n = 51), lumbar spine BMD decreased from months 48 to 72 (percentage change [95% CI]: − 10.8% [− 12.1, − 9.5]), decreasing from a mean of 17.3% [15.2, 19.3] above initial baseline value at months 48 to 4.2% [2.3, 6.1]) above the initial baseline at month 72 (Fig. 2a, Online Resource Table S1). BMD gains at the total hip and femoral neck for this group were also reversed after romosozumab discontinuation. Total hip BMD decreased from months 48 to 72 (percentage change [95% CI]: − 6.4% [− 7.4, − 5.3]), and remained close to the initial baseline level at month 72 (percentage change [95% CI] from initial baseline: − 1.6% [− 2.8, − 0.3]) (Fig. 2b, Online Resource Table S1). Femoral neck BMD decreased from months 48 to 72 (percentage change [95% CI]: − 5.9% [− 7.2, − 4.7]), and remained close to the initial baseline level at month 72 (percentage change [95% CI] from initial baseline: − 1.2% [− 2.6, 0.2]) (Fig. 2c, Online Resource Table S1).Fig. 2 Percentage change in BMD at the lumbar spine, total hip, and femoral neck in all subjects who received romosozumab during months 36–48 and who were then assigned to no further active treatment (n = 51; a–c) or zoledronate (n = 90; d–f) from months 48 to 72. Data are mean (95% CI). BMD bone mineral density, CI confidence interval, DMAb denosumab, QM every month, Q6M every 6 months\n\n\n\nIn subjects assigned to zoledronate (n = 90), lumbar spine BMD was maintained through months 48 to 72 (percentage change [95% CI] from months 48 to 72: − 0.8% [− 1.6, 0]; percentage change [95% CI] from initial baseline to month 72: 12.8% [11.4, 14.3]) (Fig. 2d, Online Resource Table S1). Results for total hip and femoral neck also showed a similar pattern to results observed for the lumbar spine. Total hip BMD was maintained through months 48 to 72 (percentage change [95% CI] from month 48: 0.1% [− 0.5, 0.7]; percentage change [95% CI] from initial baseline to month 72: 4.2% [3.1, 5.3]) (Fig. 2e, Online Resource Table S1). Femoral neck BMD was maintained through months 48 to 72 (percentage change [95% CI] from month 48: 0.5% [− 0.4, 1.3]; percentage change [95% CI] from initial baseline to month 72: 4.4% [3.0, 5.8]) (Fig. 2f, Online Resource Table S1).\n\nBone turnover markers\nP1NP and β-CTX results for the overall population entering the month 48 to 72 follow-on period are presented in Fig. 3 and Online Resource Table S2. In subjects assigned to no further active treatment from months 48 to 72 (n = 51), median P1NP initially decreased but stayed above the initial baseline level until month 72, and median β-CTX increased initially then gradually decreased but remained above the initial baseline level until month 72 (Fig. 3a, b, Online Resource Table S2). In subjects assigned to zoledronate from months 48 to 72 (n = 90), median P1NP and β-CTX levels decreased but then moved toward initial baseline level by month 72 (Fig. 3c, d, Online Resource Table S2).Fig. 3 Percentage change in P1NP and β-CTX in all subjects who received romosozumab during months 36–48 and who were then assigned to no further active treatment (n = 51; a, b) or zoledronate (n = 90; c, d) from months 48 to 72. Data are median (Q1, Q3). β-CTX β-isomer of the C-terminal telopeptide of type I collagen, DMAb denosumab, IV intravenous, P1NP procollagen type I N-terminal propeptide, Q1 quartile 1, Q3 quartile 3, QM every month, Q6M every 6 months\n\n\n\nSubgroup analysis\nIn the subpopulation of 29 subjects (no further active treatment [n = 12]; zoledronate [n = 17]) who received romosozumab 210 mg QM during the first 24 months of the study, changes in BMD and bone turnover markers during the month 48 to 72 follow-on period were consistent with changes observed in the overall population (data not shown).\n\nSafety\nA summary of adverse events reported from months 48 to 72 is provided in Table 2. No subject discontinued investigational product or study due to an adverse event. There were no deaths in the zoledronate group versus 1 death in the no further active treatment group. No adverse events of hypocalcemia, hyperostosis, clinical vertebral fractures, adjudicated osteonecrosis of the jaw, or adjudicated atypical femoral fracture were reported in either treatment group. Fractures occurred in 4 subjects in the no further active treatment group and 2 subjects in the zoledronate group. Additional details of the safety assessment from months 48 to 72 are presented in the Online Resource Supplemental Results: Additional Safety.Table 2 Incidence of adverse events from months 48 to 72\n\n\tNo further active treatment (N = 51)a\nn (%)\tZoledronate 5 mg IV single dose(N = 87)b\nn (%)\t\nAll adverse events\t37 (72.5)\t73 (83.9)\t\nSerious adverse events\t8 (15.7)\t12 (13.8)\t\nDeath\t1 (2.0)\t0\t\nLeading to study discontinuation\t0\t0\t\nAdverse events of interest\t\n Osteoarthritis\t5 (9.8)\t7 (8.0)\t\n Potentially associated with hypersensitivity\t3 (5.9)\t3 (3.4)\t\n Malignancies\t0\t2 (2.3)\t\n Hyperostosis\t0\t0\t\n Hypocalcemia\t0\t0\t\n Osteonecrosis of the jawc\t0\t0\t\n Atypical femoral fracturec\t0\t0\t\nFragility fractured\t2 (3.9)\t2 (2.3)\t\nN = number of subjects in follow-on phase who did or did not receive at least 1 dose of zoledronate\n\nn = number of subjects reporting at least 1 event\n\nNo further active treatment: Subjects randomized to romosozumab (any dose or schedule) in the month 0 to 24 double-blind period, received denosumab 60 mg Q6M in the month 24 to 36 extension period, received a second course of romosozumab 210 mg QM from months 36 to 48, and received no further active treatment from months 48 to 72\n\nZoledronate 5 mg IV single dose: Subjects randomized to romosozumab (any dose or schedule) or placebo in the month 0 to 24 double-blind period, received denosumab or placebo in the month 24 to 36 extension period, received a second course of romosozumab 210 mg QM from months 36 to 48, and received a single IV dose of zoledronate 5 mg from months 48 to 72\n\naIncludes all subjects who enrolled in the month 48 to 72 follow-on phase assigned to no further active treatment (including 1 subject who had been randomized to placebo in the initial 24 months and was incorrectly assigned to no further active treatment)\n\nbData not shown for 3 subjects who were assigned to zoledronate at month 48 but did not receive treatment\n\ncPotential cases of osteonecrosis of the jaw and atypical femoral fracture were adjudicated by independent committees\n\ndNo further active treatment group: 1 radius and 1 fibula fracture; zoledronate group: 1 radius and 1 rib fracture\n\nIV intravenous, QM every month, Q6M every 6 months\n\n\n\nDiscussion\nOur study demonstrates that a single 5 mg dose of zoledronate preserves BMD for up to 2 years after stopping romosozumab and provides further insights into the potential treatment sequence with romosozumab. Simply stopping romosozumab, even after very large BMD gains, resulted in a decrease in BMD to levels slightly above (lumbar spine) or near (total hip) baseline. The BMD loss after stopping a 12-month course of romosozumab presented here is consistent with that previously reported after 2 years of romosozumab treatment [20]. In contrast, a single dose of IV zoledronate 5 mg generally maintained the BMD gains achieved after a second course of romosozumab 210 mg QM during months 36 to 48 at the lumbar spine and proximal femur.\n\nThe efficacy of a single dose of zoledronate over an interval of 24 months is consistent with previous studies demonstrating a long duration of the effect of zoledronate in preserving bone density [27–29]. Results from our study are also consistent with results from previous studies demonstrating the effectiveness of bisphosphonate therapy to prevent bone loss upon stopping estrogen, denosumab, or PTH receptor agonists [11, 12, 27, 30–32].\n\nThe findings from our study should be considered in the context of several limitations including the small sample sizes of the two treatment groups, short study follow-up periods, and use of surrogate outcomes (percentage changes in BMD and bone turnover markers) for efficacy evaluation. Additionally, we evaluated the effect of only the single 5 mg dose of zoledronate administered approximately 4 weeks after the last dose of romosozumab. However, the major strength of this phase 2 study, overall, is that it has provided safety and efficacy data for up to 2 consecutive years of treatment with romosozumab in postmenopausal women with low bone mass, information on the effects of stopping romosozumab therapy, and information on a second course of romosozumab treatment as well as clinically relevant patterns of using the antiresorptive agents denosumab and zoledronate following romosozumab therapy.\n\nOsteoporosis is a chronic disease requiring life-long management. Since all currently available osteoporosis therapies are reversible over variable time frames, there is a need to understand the proper sequence of treatments as romosozumab is incorporated into osteoporosis management. Recent studies demonstrate that therapy with anabolic or bone-forming agents that increase bone formation by stimulation of osteoblasts such as romosozumab, teriparatide, and abaloparatide in women with postmenopausal osteoporosis is more effective in reducing fracture risk than therapy with oral bisphosphonates [12, 21, 22, 33]. This has led expert opinion to suggest that the treatment sequence of a bone-forming agent, followed by a potent antiresorptive agent, be used more often to treat patients at high risk for fracture [34, 35]. Our current study provides additional evidence that transitioning patients from a treatment with romosozumab to a potent antiresorptive, in this case zoledronate, can maintain the robust BMD gains accrued with romosozumab treatment, similar to what has previously been demonstrated for denosumab and alendronate [21, 22]. There are no clear guidelines for choosing among these antiresorptive agents to follow romosozumab. That decision will depend upon the clinical characteristics of the patients and concerns about side effects and adherence to the various follow-on therapies.\n\nIn conclusion, the treatment sequence of romosozumab for 12 months followed by zoledronate preserves BMD for up to 2 years, is well tolerated, and is an option for patients with osteoporosis at high risk for fracture.\n\nElectronic supplementary material\nESM 1 (DOCX 238 kb).\n\n Publisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nRepresentatives of the sponsor, Amgen Inc., designed the study in collaboration with some of the study investigators and UCB Pharma, and performed analyses according to a prespecified statistical analysis plan. Amgen Inc. maintained the study database. The first author (MRM) and 2 authors from Amgen Inc. (AG and YS) take responsibility of the integrity of the data analysis. The first author (MRM) wrote the first draft of the manuscript; all authors contributed to subsequent drafts of the manuscript, participated in the analysis and/or interpretation of the data, and participated in the critical review and revision of the report. All authors approved the final version for submission. Lisa A. Humphries, PhD, of Amgen Inc. and Martha Mutomba (on behalf of Amgen Inc.) provided medical writing support.\n\nFunding information\nThis study was funded by Amgen Inc., UCB Pharma, and Astellas.\n\nCompliance with ethical standards\nConflicts of interest\nMRM has received consulting fees and honoraria from Amgen and consulting fees from Myovant. MAB has received contract fees from and has been a speaker for Amgen. JPB has received research funding from Amgen, Eli Lilly, Mereo Biopharma, Radius Health, and Servier; has received consulting fees from Amgen, Eli Lilly, Orimed, and Servier; and has received lecture fees from Amgen and Eli Lilly. J-YR has received research funding from IBSA-Genevrier, Mylan, CNIEL, and Radius Health; has received lecture fees from IBSA-Genevrier, Mylan, CNIEL, and Dairy Research Council; and has received consulting fees from or participated in paid advisory boards for IBSA-Genevrier, Mylan, Radius Health, and Pierre Fabre. BLL has received research funding from Amgen and Novo Nordisk; has received consulting fees from Amgen, Eli Lilly, and UCB; and has received lecture fees from Amgen, Eli Lilly, and UCB. JM, YS, and MR are employees of and hold stock in Amgen. PDM is an employee of and holds stock in UCB Pharma. AG was an employee of Amgen at the time of the study and holds stock in Amgen.\n\nData sharing\nQualified researchers may request data from Amgen clinical studies. Complete details are available at https://wwwext.amgen.com/science/clinical-trials/clinical-data-transparency-practices/.\n==== Refs\nReferences\n1. Ferrari S Adachi JD Lippuner K Zapalowski C Miller PD Reginster JY Torring O Kendler DL Daizadeh NS Wang A O'Malley CD Wagman RB Libanati C Lewiecki EM Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years Osteoporos Int 2015 26 2763 2771 10.1007/s00198-015-3179-x 26068295 \n2. Cosman F Crittenden DB Ferrari S Khan A Lane NE Lippuner K Matsumoto T Milmont CE Libanati C Grauer A FRAME study: the foundation effect of building bone with 1 year of romosozumab leads to continued lower fracture risk after transition to denosumab J Bone Miner Res 2018 33 1219 1226 10.1002/jbmr.3427 29573473 \n3. Austin M Yang YC Vittinghoff E Adami S Boonen S Bauer DC Bianchi G Bolognese MA Christiansen C Eastell R Grauer A Hawkins F Kendler DL Oliveri B McClung MR Reid IR Siris ES Zanchetta J Zerbini CA Libanati C Cummings SR Trial F Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures J Bone Miner Res 2012 27 687 693 10.1002/jbmr.1472 22095631 \n4. Bouxsein ML Eastell R Lui LY Wu LA de Papp AE Grauer A Marin F Cauley JA Bauer DC Black DM Project FBQ Change in bone density and reduction in fracture risk: a meta-regression of published trials J Bone Miner Res 2019 34 632 642 10.1002/jbmr.3641 30674078 \n5. Recker RR Delmas PD Halse J Reid IR Boonen S Garcia-Hernandez PA Supronik J Lewiecki EM Ochoa L Miller P Hu H Mesenbrink P Hartl F Gasser J Eriksen EF Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure J Bone Miner Res 2008 23 6 16 10.1359/jbmr.070906 17892374 \n6. Zebaze RM Libanati C Austin M Ghasem-Zadeh A Hanley DA Zanchetta JR Thomas T Boutroy S Bogado CE Bilezikian JP Seeman E Differing effects of denosumab and alendronate on cortical and trabecular bone Bone 2014 59 173 179 10.1016/j.bone.2013.11.016 24275677 \n7. Jiang Y Zhao JJ Mitlak BH Wang O Genant HK Eriksen EF Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure J Bone Miner Res 2003 18 1932 1941 10.1359/jbmr.2003.18.11.1932 14606504 \n8. Forteo (teriparatide injection) Prescribing Information (2012) Eli Lilly and Company, Indianapolis, IN, US. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021318s036lbl.pdf. Accessed 19 February 2020\n9. Tymlos™ (abaloparatide) Prescribing Information (2017) Radius health, Inc., Waltham, MA, US. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf. Accessed 19 February 2020\n10. Leder BZ Tsai JN Uihlein AV Wallace PM Lee H Neer RM Burnett-Bowie SA Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-switch study): extension of a randomised controlled trial Lancet 2015 386 1147 1155 10.1016/S0140-6736(15)61120-5 26144908 \n11. Niimi R Kono T Nishihara A Hasegawa M Kono T Sudo A Efficacy of switching from teriparatide to bisphosphonate or denosumab: a prospective, randomized, open-label trial JBMR Plus 2018 2 289 294 10.1002/jbm4.10054 30283910 \n12. Bone HG Cosman F Miller PD Williams GC Hattersley G Hu MY Fitzpatrick LA Mitlak B Papapoulos S Rizzoli R Dore RK Bilezikian JP Saag KG ACTIVExtend: 24 months of alendronate after 18 months of abaloparatide or placebo for postmenopausal osteoporosis J Clin Endocrinol Metab 2018 103 2949 2957 10.1210/jc.2018-00163 29800372 \n13. Cosman F de Beur SJ LeBoff MS Lewiecki EM Tanner B Randall S Lindsay R Foundation NO Clinician’s guide to prevention and treatment of osteoporosis Osteoporos Int 2014 25 2359 2381 10.1007/s00198-014-2794-2 25182228 \n14. Camacho PM, Petak SM, Binkley N, Clarke BL, Harris ST, Hurley DL, Kleerekoper M, Lewiecki EM, Miller PD, Narula HS, Pessah-Pollack R, Tangpricha V, Wimalawansa SJ, Watts NB (2016) American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis - 2016. Endocr Pract 22:1–42\n15. Padhi D Jang G Stouch B Fang L Posvar E Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody J Bone Miner Res 2011 26 19 26 10.1002/jbmr.173 20593411 \n16. Padhi D Allison M Kivitz AJ Gutierrez MJ Stouch B Wang C Jang G Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study J Clin Pharmacol 2014 54 168 178 10.1002/jcph.239 24272917 \n17. McClung MR Grauer A Boonen S Bolognese MA Brown JP Diez-Perez A Langdahl BL Reginster JY Zanchetta JR Wasserman SM Katz L Maddox J Yang YC Libanati C Bone HG Romosozumab in postmenopausal women with low bone mineral density N Engl J Med 2014 370 412 420 10.1056/NEJMoa1305224 24382002 \n18. Chavassieux P Portero-Muzy N Roux JP Horlait S Dempster DW Wang A Wagman RB Chapurlat R Reduction of cortical bone turnover and erosion depth after 2 and 3 years of denosumab: iliac bone histomorphometry in the FREEDOM trial J Bone Miner Res 2019 34 626 631 10.1002/jbmr.3631 30601581 \n19. Ominsky MS Brown DL Van G Cordover D Pacheco E Frazier E Cherepow L Higgins-Garn M Aguirre JI Wronski TJ Stolina M Zhou L Pyrah I Boyce RW Differential temporal effects of sclerostin antibody and parathyroid hormone on cancellous and cortical bone and quantitative differences in effects on the osteoblast lineage in young intact rats Bone 2015 81 380 391 10.1016/j.bone.2015.08.007 26261096 \n20. McClung MR Brown JP Diez-Perez A Resch H Caminis J Meisner P Bolognese MA Goemaere S Bone HG Zanchetta JR Maddox J Bray S Grauer A Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: a randomized, double-blind, phase 2, parallel group study J Bone Miner Res 2018 33 1397 1406 10.1002/jbmr.3452 29694685 \n21. Cosman F Crittenden DB Adachi JD Binkley N Czerwinski E Ferrari S Hofbauer LC Lau E Lewiecki EM Miyauchi A Zerbini CA Milmont CE Chen L Maddox J Meisner PD Libanati C Grauer A Romosozumab treatment in postmenopausal women with osteoporosis N Engl J Med 2016 375 1532 1543 10.1056/NEJMoa1607948 27641143 \n22. Saag KG Petersen J Brandi ML Karaplis AC Lorentzon M Thomas T Maddox J Fan M Meisner PD Grauer A Romosozumab or alendronate for fracture prevention in women with osteoporosis N Engl J Med 2017 377 1417 1427 10.1056/NEJMoa1708322 28892457 \n23. Langdahl BL Libanati C Crittenden DB Bolognese MA Brown JP Daizadeh NS Dokoupilova E Engelke K Finkelstein JS Genant HK Goemaere S Hyldstrup L Jodar-Gimeno E Keaveny TM Kendler D Lakatos P Maddox J Malouf J Massari FE Molina JF Ulla MR Grauer A Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial Lancet 2017 390 1585 1594 10.1016/S0140-6736(17)31613-6 28755782 \n24. EVENITY® (romosozumab-aqqg) US Prescribing Information (2019) Amgen Inc., Thousand Oaks, CA, US. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/evenity/evenity_pi_hcp_english.ashx. Accessed 24 February 2020\n25. EVENITY® (romosozumab) EU Summary of Product Characteristics (2019) Amgen Inc., Thousand Oaks, CA, US. https://www.ucb.com/_up/ucb_com_presscenter/documents/98f3864197f1030c.pdf. Accessed 24 February 2020\n26. Kendler DL Bone HG Massari FE Gielen E Palacios S Maddox J Yan C Yue S Dinavahi RV Libanati C Grauer A Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab Osteoporos Int 2019 30 2437 2448 10.1007/s00198-019-05146-9 31628490 \n27. Anastasilakis AD Papapoulos SE Polyzos SA Appelman-Dijkstra NM Makras P Zoledronate for the prevention of bone loss in women discontinuing denosumab treatment: a prospective 2-year clinical trial J Bone Miner Res 2019 34 2220 2228 10.1002/jbmr.3853 31433518 \n28. Grey A Bolland MJ Horne A Mihov B Gamble G Reid IR Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial CMAJ 2017 189 e1130 e1136 10.1503/cmaj.161207 28893875 \n29. McClung M Miller P Recknor C Mesenbrink P Bucci-Rechtweg C Benhamou CL Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial Obstet Gynecol 2009 114 999 1007 10.1097/AOG.0b013e3181bdce0a 20168099 \n30. Ascott-Evans BH Guanabens N Kivinen S Stuckey BG Magaril CH Vandormael K Stych B Melton ME Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy: a randomized controlled trial Arch Intern Med 2003 163 789 794 10.1001/archinte.163.7.789 12695269 \n31. Freemantle N, Satram-Hoang S, Tang ET, Kaur P, Macarios D, Siddhanti S, Borenstein J, Kendler DL, DAPS Investigators (2012) Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int 23:317–326\n32. Reid IR Horne AM Mihov B Gamble GD Bone loss after denosumab: only partial protection with zoledronate Calcif Tissue Int 2017 101 371 374 10.1007/s00223-017-0288-x 28500448 \n33. Kendler DL Marin F Zerbini CAF Russo LA Greenspan SL Zikan V Bagur A Malouf-Sierra J Lakatos P Fahrleitner-Pammer A Lespessailles E Minisola S Body JJ Geusens P Moricke R Lopez-Romero P Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial Lancet 2018 391 230 240 10.1016/S0140-6736(17)32137-2 29129436 \n34. Cosman F Nieves JW Dempster DW Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis J Bone Miner Res 2017 32 198 202 10.1002/jbmr.3051 27925287 \n35. McClung MR Using osteoporosis therapies in combination Curr Osteoporos Rep 2017 15 343 352 10.1007/s11914-017-0376-x 28667435\n\n",
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"issue": "31(11)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Antiresorptive; Bone mineral density; Follow-on regimen; Osteoporosis; Romosozumab",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D015519:Bone Density; D050071:Bone Density Conservation Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal; D000077211:Zoledronic Acid",
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"title": "A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab.",
"title_normalized": "a single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab"
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"abstract": "Intoxication from calcium channel blockers exhibits almost 50% mortality rates. Amlodipine is a long-acting dihydropyridine and inappropriate dosage poses a great threat for profound vasodilation, hypotension, and refractory vasopressor-resistant shock. A 72-year-old woman with unremarkable medical history presented to the emergency department due to amlodipine overdose after a suicide attempt attributed to COVID-19 pandemic severe anxiety disorder. Vital signs at presentation: heart rate 82 beats/ min, arterial pressure 72/55 mmHg, and oxygen saturation 98%. Resuscitation was initiated with intravenous infusion of normal saline 0,9%, noradrenaline, and calcium chloride, while activated charcoal was orally administrated; however, blood pressure remained at 70/45 mmHg. Abruptly, she experienced acute pulmonary edema and was finally intubated. We commenced high-dose insulin infusion with Dextrose 10% infusion to maintain euglycemic hyperinsulinemia. Hemodynamic improvement occurred after 30 min, systolic blood pressure raised to 95 mmHg, and decongestion was achieved with intravenous furosemide. Insulin effect was dose-dependent and patient's hemodynamic status improved after insulin uptitration. Eight days later, the patient was weaned from the mechanical ventilation and she was successfully discharged after 14 days. High-dose intravenous infusion of insulin up to 10 units/kg per hour appears as an inotropic agent possibly through alterations in myocardial metabolism of fatty acids and augmentation of insulin secretion and uptake. This regimen possibly exhibits additional vasotropic properties. We conclude that euglycemic hyperinsulinemia is a potentially advantageous treatment in CCB toxicity.",
"affiliations": "Cardiology Department, Athens Naval and Veterans Hospital, Mikras Asias 48, 11257, Athens, Greece. lkoliastasis@gmail.com.;Cardiology Department, Athens Naval and Veterans Hospital, Mikras Asias 48, 11257, Athens, Greece.;Cardiology Department, Athens Naval and Veterans Hospital, Mikras Asias 48, 11257, Athens, Greece.;Cardiology Department, Athens Naval and Veterans Hospital, Mikras Asias 48, 11257, Athens, Greece.;Cardiology Department, Athens Naval and Veterans Hospital, Mikras Asias 48, 11257, Athens, Greece.;Cardiology Department, Athens Naval and Veterans Hospital, Mikras Asias 48, 11257, Athens, Greece.;Cardiology Department, Athens Naval and Veterans Hospital, Mikras Asias 48, 11257, Athens, Greece.;Cardiology Department, Athens Naval and Veterans Hospital, Mikras Asias 48, 11257, Athens, Greece.",
"authors": "Koliastasis|L|L|http://orcid.org/0000-0002-7966-9174;Lampadakis|I|I|;Milkas|A|A|;Strempelas|P|P|;Sourides|V|V|;Kakava|K|K|;Tsioufis|P|P|;Papaioannou|S|S|",
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"title": "Refractory Shock from Amlodipine Overdose Overcomed with Hyperinsulinemia.",
"title_normalized": "refractory shock from amlodipine overdose overcomed with hyperinsulinemia"
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"abstract": "Angioimmunoblastic Lymphadenopathy with Dysproteinemia (AILD) is a rare benign reactive process which often follows exposure to certain drugs such as penicillin. Treatment with corticosteroids usually reverses the process, however there have been reports of 18% of cases evolving into non-Hodgkins lymphoma. In our case report, we present a relatively healthy woman with history of various drug hypersensitivities who developed AILD and resultant lymphoma after treatment with azithromycin. A review of the literature has failed to find reports of AILD following macrolide exposure. Clonality, not present in other forms of hyperplasia, is present in AILD and immunosuppression may account for this difference. It is difficult to say whether the drugs are simply coincidently associated or actually cause, maintain, or exacerbate clonality in AILD and facilitate malignant transformation.",
"affiliations": "John A. Burns School of Medicine, University of Hawaii, USA.",
"authors": "Sasaki|T Y|TY|;Sumida|K N|KN|",
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"title": "Angioimmunoblastic T-cell lymphoma (AIL-TCL) following macrolide administration.",
"title_normalized": "angioimmunoblastic t cell lymphoma ail tcl following macrolide administration"
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"abstract": "A 53-year-old man with active hepatitis C and cirrhosis presented with a vasculitic rash, myalgias, and fatigue, and was found to have an elevated cardiac troponin I up to 15.7 ng/mL with normal electrocardiogram, echocardiogram, and coronary angiogram prior to being discharged. Subsequently, during a similar presentation to another academically affiliated hospital, the patient had a normal cardiac troponin T (< 0.01 ng/mL). Upon his third presentation with significantly elevated troponin I to 15.98 ng/mL, the patient was found to have cryoglobulinemic vasculitis and elevated rheumatoid factor due to active hepatitis C, causing interference with the troponin I immunoassay. In conclusion, troponin I assays may have high false-positive values due to interference by rheumatoid factor and/or a polyclonal antibody found in cryoglobulinemia.",
"affiliations": "UC San Diego Department of Medicine - Pulmonary and Critical Care Fellowship, La Jolla, CA 92037-7381.;UC San Diego Department of Medicine - Division of Nephrology, San Diego, CA 92161-9111.;UC San Diego Department of Medicine - Division of Cardiovascular Medicine, La Jolla, CA 92037.",
"authors": "Odish|Mazen|M|;Beben|Tomasz|T|;Daniels|Lori B|LB|",
"chemical_list": "D015415:Biomarkers; D019210:Troponin I; D012217:Rheumatoid Factor",
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"pubdate": "2018-06-30",
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"title": "False-positive Troponin I Assay elevation due to occult Mixed Cryoglobulinemic Vasculitis.",
"title_normalized": "false positive troponin i assay elevation due to occult mixed cryoglobulinemic vasculitis"
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"abstract": "This case report describes hypoglycemia during methadone escalation in an 8-year-old girl with acute lymphatic leukemia. After a significant increase in the methadone dosage, the blood glucose decreased from 12 mmol/l to 1 mmol/l. Nutrition and other medications were meticulously checked and no other apparent explanation was found. There are few reports from the adult palliative setting which describe this serious side effect. This is to our knowledge, the first described pediatric case.",
"affiliations": "Department of Anesthesia and Intensive Care Medicine, PICU Section, Aarhus University Hospital, Arhus N, Denmark.;Department of Anesthesia and Intensive Care Medicine, PICU Section, Aarhus University Hospital, Arhus N, Denmark.",
"authors": "Gjedsted|J|J|;Dall|R|R|",
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"keywords": null,
"medline_ta": "Acta Anaesthesiol Scand",
"mesh_terms": "D000701:Analgesics, Opioid; D002648:Child; D005260:Female; D006801:Humans; D007003:Hypoglycemia; D008691:Methadone",
"nlm_unique_id": "0370270",
"other_id": null,
"pages": "1394-6",
"pmc": null,
"pmid": "26087717",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe hypoglycemia during methadone escalation in an 8-year-old child.",
"title_normalized": "severe hypoglycemia during methadone escalation in an 8 year old child"
} | [
{
"companynumb": "DK-MYLANLABS-2015M1038579",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Very little has been published on the use of romiplostim to treat primary immune thrombocytopenia (ITP), refractory to previous treatments, in children. The objective of this study was to determine its efficacy and safety in pediatric patients in a university general hospital. Retrospective, longitudinal observational study of pediatric patients on treatment with romiplostim. The principal efficacy variable was platelet count. Safety was evaluated by recording possible adverse reactions to the medication, monitoring the appearance of thrombosis, thrombocytopenia during dose reduction, hemorrhage, and myelodysplastic syndromes. Three patients in the authors' center have been treated with romiplostim (subcutaneous [SC], initial dose: 1 μg/kg/week) for ITP refractory to various treatments: 1 with newly diagnosed ITP and 2 with chronic ITP. Patients were followed up for 27 to 39 weeks after starting treatment. Responses were achieved in 7 to 28 days, and complete responses were maintained for 37% to 91% of the follow-up period, with median platelet counts between 40 × 10(3)/μL and 215 × 10(3)/μL. The adverse reactions observed during follow-up were headache and asthenia in one patient and mucocutaneous bleeding after dose suspension in another one. With regard to effectiveness, the response in the 3 patients was varied. The drug was considered to be safe, as there were only mild adverse reactions. Although further studies and long-term follow-up are required, these results show that romiplostim could be considered an alternative to immunosuppressive therapies, such as rituximab, or splenectomy in refractory chronic ITP.",
"affiliations": "Pharmacy Department, Gregorio Marañón University General Hospital, Madrid, Spain. vescudero.hgugm@salud.madrid.org",
"authors": "Escudero Vilaplana|Vicente|V|;Aragonés|Jorge Huerta|JH|;Fernández-Llamazares|Cecilia M|CM|;Bieler|Cristina Beléndez|CB|;Rodríguez|Silvia Manrique|SM|;Sáez|María Sanjuro|MS|",
"chemical_list": "D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim",
"country": "England",
"delete": false,
"doi": "10.3109/08880018.2011.629401",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "29(2)",
"journal": "Pediatric hematology and oncology",
"keywords": null,
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D013926:Thrombopoietin; D016896:Treatment Outcome",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "197-205",
"pmc": null,
"pmid": "22376020",
"pubdate": "2012-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of romiplostim for primary immune thrombocytopenia in children.",
"title_normalized": "use of romiplostim for primary immune thrombocytopenia in children"
} | [
{
"companynumb": "ES-AMGEN-ESPSP2015094142",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ROMIPLOSTIM"
},
"drugadditional": null,
... |
{
"abstract": "A 53-year-old woman who was diagnosed as suffering from depression was found dead in her bed. The autopsy revealed no morphological changes sufficient to explain death. Toxicological analysis was performed and the drugs trimipramine (2.33 mg/l), citalopram (4.81 mg/l) and zolpidem (0.07 mg/l) were identified in the femoral blood. A combined drug intoxication resulting in synergistic effects to cardiovascular disorders was proposed as the cause of death. An acute overdose and suicide was suggested by calculation of the parent drug to main metabolite ratios in femoral blood and liver tissue. The trimipramine to desmethyltrimipramine ratios were calculated to be 2.06 and 3.18, the citalopram to desmethylcitalopram ratios were 1.96 and 2.02.",
"affiliations": "Institute of Legal Medicine, Rheinische Friedrich-Wilhelms-University, Bonn, Germany. f.musshoff@uni-bonn.de",
"authors": "Musshoff|F|F|;Schmidt|P|P|;Madea|B|B|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D006993:Hypnotics and Sedatives; D011725:Pyridines; D015283:Citalopram; C046304:desmethylcitalopram; D014299:Trimipramine; D000077334:Zolpidem; C040606:desmethyltrimipramine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/s0379-0738(99)00183-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "106(2)",
"journal": "Forensic science international",
"keywords": null,
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D015283:Citalopram; D003863:Depression; D062787:Drug Overdose; D004357:Drug Synergism; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008099:Liver; D008875:Middle Aged; D011725:Pyridines; D013405:Suicide; D014299:Trimipramine; D000077334:Zolpidem",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "125-31",
"pmc": null,
"pmid": "10664899",
"pubdate": "1999-12-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatality caused by a combined trimipramine-citalopram intoxication.",
"title_normalized": "fatality caused by a combined trimipramine citalopram intoxication"
} | [
{
"companynumb": "DE-ALLERGAN-1680291US",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIMIPRAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "Cryptococcus neoformans is a ubiquitous encapsulated environmental yeast that can cause severe central nervous system disease, primarily in immune compromised hosts. In patients with AIDS, the spectrum of cryptococcal central nervous system disease includes meningitis, cystic lesions, and mass-like cryptococcomas. We report a fatal case of meningitis and cerebritis caused by C. neoformans in an AIDS patient refractory to multiple courses of liposomal amphotericin B despite immune recovery with antiretroviral therapy. This case highlights ongoing diagnostic and therapeutic challenges in the face of treatment failure for cryptococcal meningitis and reinforces the need for improved treatment approaches.",
"affiliations": "1 Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA.;1 Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA.;2 Department of Radiology, Yale University School of Medicine, New Haven, CT, USA.;3 Department of Pathology, Indiana University Health Pathology Laboratory, Indianapolis, IN, USA.;1 Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA.",
"authors": "Bandaranayake|Thilinie D|TD|0000-0001-6602-0096;Ogbuagu|Onyema E|OE|;Mahajan|Amit|A|;Vortmeyer|Alexander O|AO|;Villanueva|Merceditas S|MS|",
"chemical_list": "C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "England",
"delete": false,
"doi": "10.1177/0956462418773219",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "29(12)",
"journal": "International journal of STD & AIDS",
"keywords": "Cryptococcus neoformans; HIV; amphotericin B; meningitis",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000666:Amphotericin B; D023241:Antiretroviral Therapy, Highly Active; D001921:Brain; D003455:Cryptococcus neoformans; D017809:Fatal Outcome; D005334:Fever; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D016919:Meningitis, Cryptococcal; D008875:Middle Aged",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "1250-1254",
"pmc": null,
"pmid": "29749873",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal cryptococcal meningitis in an AIDS patient complicated with immune reconstitution syndrome refractory to prolonged amphotericin B treatment.",
"title_normalized": "fatal cryptococcal meningitis in an aids patient complicated with immune reconstitution syndrome refractory to prolonged amphotericin b treatment"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP010032",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nMatrix-associated autologous chondrocyte implantation (MACI(®)) is an innovative therapeutic option for the treatment of chondral and osteochondral lesions of the knee.\n\n\nMETHODS\nFifty-three patients (54 knees) with MRI-documented osteochondral lesions were treated with MACI(®). A clinical assessment was performed using VAS score, Lysholm score, and Tegner activity level after an average follow-up of 27 months (SD: 2.3). MRI scans were performed 12 and 24 months after surgery. Seventeen patients were reevaluated after an average time of 59 months (SD: 6.7) after surgery.\n\n\nRESULTS\nTwo years after transplantation, Lysholm score increased from a preoperative mean value of 70 (SD: 13.4) to 95 (SD: 6.4); the average VAS score decreased from a preoperative value of 5.2 (SD: 2.9) to 1.9 (SD: 2.1). The difference with respect to Tegner activity level did not prove to be significant. At 1 year, MRI scans documented a completely repaired defect with slight subchondral bone abnormality in 38 cases (70%). Satisfying outcomes were confirmed on 17 patients who were reevaluated 5 years after surgery. At 60 months, MRI scans showed complete integration with the surrounding native cartilage without any sign of detachment or bone marrow edema in 15 cases (88%).\n\n\nCONCLUSIONS\nThe MACI(®) technique is a safe and clinically effective procedure, which has been proven to be valuable in treating osteochondral defects even over the long term.\n\n\nMETHODS\nTherapeutic study, Level III-2 (retrospective cohort study).",
"affiliations": "U.O.S.D. Chirurgia Articolare Mininvasiva (Minimally Invasive Articular Surgery), Istituto Ortopedico G. Pini, Milan, Italy. alberto.ventura@doctoral.it",
"authors": "Ventura|Alberto|A|;Memeo|Antonio|A|;Borgo|Enrico|E|;Terzaghi|Clara|C|;Legnani|Claudio|C|;Albisetti|Walter|W|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00167-011-1575-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0942-2056",
"issue": "20(1)",
"journal": "Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA",
"keywords": null,
"medline_ta": "Knee Surg Sports Traumatol Arthrosc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001178:Arthroplasty; D001182:Arthroscopy; D002358:Cartilage, Articular; D019902:Chondrocytes; D015331:Cohort Studies; D005500:Follow-Up Studies; D048091:Guided Tissue Regeneration; D006801:Humans; D007718:Knee Injuries; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D012189:Retrospective Studies; D054457:Tissue Scaffolds; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9314730",
"other_id": null,
"pages": "121-6",
"pmc": null,
"pmid": "21681599",
"pubdate": "2012-01",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": "15911295;14716284;17371156;12810965;2918421;20185841;19572120;14967329;16170579;11192250;20360528;16770636;17698376;8078550;20042546;9276052;20446086;16632362;10818982;19966108;11603704;17257849;11745090;15855365;4028566;15930926",
"title": "Repair of osteochondral lesions in the knee by chondrocyte implantation using the MACI® technique.",
"title_normalized": "repair of osteochondral lesions in the knee by chondrocyte implantation using the maci technique"
} | [
{
"companynumb": "IT-VERICEL CORPORATION-VCEL-2017-000829",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AUTOLOGOUS CULTURED CHONDROCYTES\\SUS SCROFA COLLAG... |
{
"abstract": "BACKGROUND\nThere are already numerous B-cell depleting monoclonal anti-CD20 antibodies which have been used to reduce the inflammatory burden associated with multiple sclerosis (MS). We describe here our experience of treating MS-patients with B-cell depleting rituximab.\n\n\nMETHODS\nAll MS-patients (n = 72) who had received rituximab treatment for at least six months by January 2019 were identified from the patient charts at the Turku University Hospital. Information about MS disease subtype, disease severity, MR-imaging outcomes and B-cell counts were collected from the charts.\n\n\nRESULTS\nRituximab was well received and well tolerated by the patients. There were no serious infusion-related side effects. The most serious adverse event that led to treatment discontinuation was neutropenia. After rituximab initiation the annual number of relapses was decreased in the relapsing remitting and secondary progressive MS groups and the mean number of gadolinium-enhancing lesions was decreased in relapsing remitting MS. Our study confirms the usability of rituximab treatment for MS in the Finnish health care environment.\n\n\nCONCLUSIONS\nOff-label rituximab-treatment can be successfully used to reduce MS disease burden for the benefit of MS patients.",
"affiliations": "Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland. Electronic address: laura.airas@utu.fi.;Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland.;Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland.;Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland.;Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland.;Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland; Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland.",
"authors": "Airas|Laura|L|;Nylund|Marjo|M|;Mannonen|Iina|I|;Matilainen|Markus|M|;Sucksdorff|Marcus|M|;Rissanen|Eero|E|",
"chemical_list": "D018951:Antigens, CD20; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2020.101980",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "40()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "B-lymphocyte; CD20; MS treatment; Multiple sclerosis",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018951:Antigens, CD20; D001402:B-Lymphocytes; D005260:Female; D005387:Finland; D006785:Hospitals, University; D006801:Humans; D007155:Immunologic Factors; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D009503:Neutropenia; D056687:Off-Label Use; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "101980",
"pmc": null,
"pmid": "32066031",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Rituximab in the treatment of multiple sclerosis in the Hospital District of Southwest Finland.",
"title_normalized": "rituximab in the treatment of multiple sclerosis in the hospital district of southwest finland"
} | [
{
"companynumb": "FI-CELLTRION INC.-2019FI021747",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": "3... |
{
"abstract": "We report the case of a half-marathon runner who presented with exertional heatstroke (EHS), whose management was confounded by concurrent treatment of his bipolar disorder with olanzapine. Antipsychotics can have a profound effect on thermoregulation and can cause athletes to present with features of neuroleptic malignant syndrome in the setting of EHS. It is vital for medical providers to consider the thermoregulatory effects of all medications, including antipsychotics, when providing care during sporting events.",
"affiliations": "Department of Rehabilitation Medicine, and.;Sports Institute at UW Medicine and Department of Rehabilitation Medicine, University of Washington Medical Center, Seattle, Washington.",
"authors": "Gessel|Trevor|T|;Lin|Cindy Y|CY|",
"chemical_list": "D014150:Antipsychotic Agents; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1097/JSM.0000000000000750",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1050-642X",
"issue": "30(5)",
"journal": "Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine",
"keywords": null,
"medline_ta": "Clin J Sport Med",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D001833:Body Temperature Regulation; D018883:Heat Stroke; D006801:Humans; D008297:Male; D000081642:Marathon Running; D000077152:Olanzapine; D005082:Physical Exertion; D012420:Running",
"nlm_unique_id": "9103300",
"other_id": null,
"pages": "e166-e168",
"pmc": null,
"pmid": "31157624",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Exertional Heatstroke in a Marathon Runner Complicated by Concurrent Use of an Antipsychotic Medication Affecting Thermoregulation.",
"title_normalized": "exertional heatstroke in a marathon runner complicated by concurrent use of an antipsychotic medication affecting thermoregulation"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0111537",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": "3",
... |
{
"abstract": "High-dose tranexamic acid (TXA) can cause seizures in patients who have undergone pulmonary endarterectomy (PTE). Seizures secondary to TXA will resolve once the drug is excreted from the body, and the patients do not have to be on long-term anticonvulsants. The aim of the study is to find out if medication review in the hospital has led to deprescribing of anticonvulsants for TXA-associated seizures on discharge from the critical care unit (CCU) and hospital.\n\n\n\nThis is a single-centre retrospective study conducted at a tertiary cardiothoracic hospital between 2012 and 2017. The inclusion criteria consisted of all adult patients who have undergone PTE surgery. Patients who were started on anticonvulsants preoperatively or postoperatively for seizures secondary to organic causes were excluded.\n\n\n\nA total of 933 patients underwent PTE from January 2012 to August 2017. 25 patients had TXA-related seizures postoperatively and were started on anticonvulsant therapy, giving an incidence of 2.7%. 15 patients were discharged from the CCU without anticonvulsants. A further three patients had their anticonvulsants deprescribed in the ward before being discharged from the hospital.\n\n\n\nDeprescribing of anticonvulsants after benign seizures secondary to high-dose TXA is facilitated by verbal and written handover, which can be improved in our hospital. A detailed handover summary, as well as a discharge letter with clearly defined instructions for drug review, is needed to make deprescribing a more robust process.",
"affiliations": "Anaesthetics and Intensive Care, Royal Papworth Hospital, Cambridge, UK tanzihui1985@gmail.com.;Cardiothoracic Surgery, Royal Papworth Hospital, Cambridge, UK.;Cardiothoracic Surgery, Royal Papworth Hospital, Cambridge, UK.;Pharmacy, Royal Papworth Hospital, Cambridge, UK.;Anaesthetics and Intensive Care, Royal Papworth Hospital, Cambridge, UK.",
"authors": "Tan|Zihui|Z|;Ng|Choo Yen|CY|;Jenkins|David|D|;Barrow|Linda|L|;Valchanov|Kamen|K|",
"chemical_list": "D000927:Anticonvulsants; D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid",
"country": "England",
"delete": false,
"doi": "10.1136/ejhpharm-2018-001844",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2047-9956",
"issue": "27(6)",
"journal": "European journal of hospital pharmacy : science and practice",
"keywords": "convulsion; de-prescribing; prescribing; seizure; tranexamic acid",
"medline_ta": "Eur J Hosp Pharm",
"mesh_terms": "D000927:Anticonvulsants; D000933:Antifibrinolytic Agents; D000069340:Deprescriptions; D004305:Dose-Response Relationship, Drug; D004691:Endarterectomy; D006801:Humans; D011651:Pulmonary Artery; D012189:Retrospective Studies; D012640:Seizures; D062606:Tertiary Care Centers; D014148:Tranexamic Acid; D006113:United Kingdom",
"nlm_unique_id": "101578294",
"other_id": null,
"pages": "337-340",
"pmc": null,
"pmid": "33097616",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": "28032332;25324330;22234015;30422193;27774838;22611164;26580862;28063660;17565077;31156896;23814291;21412876;29869294;31157064;26244566",
"title": "Deprescribing practices for anticonvulsants after benign seizures secondary to high-dose tranexamic acid in a single, large UK cardiothoracic centre.",
"title_normalized": "deprescribing practices for anticonvulsants after benign seizures secondary to high dose tranexamic acid in a single large uk cardiothoracic centre"
} | [
{
"companynumb": "GB-PFIZER INC-2019217351",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRANEXAMIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe currently used macrolide immunosuppressants, i.e., cyclosporine and tacrolimus, exert considerable nephrotoxicity. We aimed to avoid the nephrotoxic effects by applying a cyclosporine-free regimen for the induction as well as for the maintenance treatment of renal allograft recipients using mycophenolate mofetil (MMF) as the primary immunosuppressant.\n\n\nMETHODS\nThirteen patients were converted from cyclosporine (CsA) to MMF monotherapy. For 4 weeks, MMF (2 g/day) was added to the CsA treatment, before CsA was tapered by weekly steps of 25 mg/day and without \"safeguard treatment\" with additional immunosuppressants. In a second approach, 12 patients older than 50 years, and receiving a renal graft from a donor older than 50 years, were treated primarily with MMF combined with steroids and an induction therapy using antithymocyte globulin, and without the addition of CsA.\n\n\nRESULTS\nThirteen long-term renal transplant patients could be converted from CsA to MMF monotherapy. Conversion resulted in an immediate and long-lasting improvement of their median creatinine values by 20%. No serious adverse events occurred. In the second cohort of 12 patients, MMF was used as the primary immunosuppressant. All patients are alive and no grafts were lost after 4 months (n= 12) and after 6 months (n=7). The median creatinine values achieved after 4 and 6 months were 1.16+/-0.25 and 1.30+/-0.21 mg/dl, respectively. One patient was converted to CsA because of a reversible rejection episode (8.3%), and another patient was converted because of cytomegalovirus disease. Major complications consisted of wound-healing disturbances (16.6%) and cytomegalovirus infections (41.6%).\n\n\nCONCLUSIONS\nMMF monotherapy can be safely applied as long-term maintenance immunosuppression with improvement of renal function. Steroids are not required as an adjunct to MMF. MMF monotherapy, in the absence of drug-related nephrotoxicity, is particularly beneficial for grafts derived from marginal donors, such as donors of advanced age.",
"affiliations": "Division of Transplant Surgery, Klinikum Grosshadern, Ludwig-Maximilian-University, Munich, Germany. BernZanker@aol.com",
"authors": "Zanker|B|B|;Schneeberger|H|H|;Rothenpieler|U|U|;Hillebrand|G|G|;Illner|W D|WD|;Theodorakis|I|I|;Stangl|M|M|;Land|W|W|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1097/00007890-199807150-00007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "66(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D016572:Cyclosporine; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D019233:Retreatment",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "44-9",
"pmc": null,
"pmid": "9679820",
"pubdate": "1998-07-15",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Mycophenolate mofetil-based, cyclosporine-free induction and maintenance immunosuppression: first-3-months analysis of efficacy and safety in two cohorts of renal allograft recipients.",
"title_normalized": "mycophenolate mofetil based cyclosporine free induction and maintenance immunosuppression first 3 months analysis of efficacy and safety in two cohorts of renal allograft recipients"
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "Rosuvastatin is a 3-hydroxy-3-methyl-glutaryl-CoA reductase enzyme inhibitor that is in wide use with few reported ocular adverse events.\n\n\n\nTo report a case of bilateral neurotrophic keratopathy associated with rosuvastatin therapy that dramatically improved following drug discontinuation.\n\n\n\nA 65-year-old female presented with painless diminution of vision in both eyes of gradual onset and progressive course for 1 month. She had recently started rosuvastatin therapy for hyperlipidemia. Examination revealed bilateral stage 2 neurotrophic keratopathy with impaired corneal sensation which was previously resistant to conservative ulcer treatment. Following discontinuation of rosuvastatin therapy, there was dramatic bilateral improvement in corneal sensation, size of the corneal ulcers, and visual acuity.\n\n\n\nRosuvastatin may result in reversible trigeminal nerve impairment and neurotrophic keratopathy.",
"affiliations": "Department of Ophthalmology, Faculty of Medicine, Cairo University, Cairo, Egypt. ayman_elnahri@hotmail.com.;Department of Ophthalmology, Faculty of Medicine, Cairo University, Cairo, Egypt.",
"authors": "Elnahry|Ayman G|AG|;Elnahry|Gehad A|GA|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000068718:Rosuvastatin Calcium",
"country": "Australia",
"delete": false,
"doi": "10.15586/jptcp.v26i2.627",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2561-8741",
"issue": "26(2)",
"journal": "Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharmacologie clinique",
"keywords": "cranial neuropathy; drug-induced ocular adverse event; neurotrophic keratopathy; rosuvastatin; trigeminal neuropathy",
"medline_ta": "J Popul Ther Clin Pharmacol",
"mesh_terms": "D000368:Aged; D003316:Corneal Diseases; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000068718:Rosuvastatin Calcium; D020433:Trigeminal Nerve Diseases; D014792:Visual Acuity",
"nlm_unique_id": "101530023",
"other_id": null,
"pages": "e38-e42",
"pmc": null,
"pmid": "31577084",
"pubdate": "2019-08-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "REVERSIBLE NEUROTROPHIC KERATOPATHY ASSOCIATED WITH ROSUVASTATIN THERAPY: A CASE REPORT.",
"title_normalized": "reversible neurotrophic keratopathy associated with rosuvastatin therapy a case report"
} | [
{
"companynumb": "EG-JUBILANT CADISTA PHARMACEUTICALS-2019JUB00391",
"fulfillexpeditecriteria": "1",
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"actiondrug": "1",
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"activesubstancename": "ROSUVASTATIN CALCIUM"
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... |
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"abstract": "Both human immunodeficiency virus (HIV) and antiretroviral therapy (ART) are associated with endocrine dysfunction (1). The term 'immune reconstitution inflammatory syndrome' (IRIS) describes an array of inflammatory conditions that occur during the return of cell-mediated immunity following ART. Graves' disease (GD) occurs rarely as an IRIS following ART. In this study, we describe the case of a 40-year-old Brazilian female who was diagnosed with HIV following admission with cryptococcal meningitis and salmonellosis. At this time, she was also diagnosed with adrenal insufficiency. Her CD4 count at diagnosis was 17 cells/µL which rose to 256 cells/µL over the first 3 months of ART. Her HIV viral load, however, consistently remained detectable. When viral suppression was finally achieved 21 months post diagnosis, an incremental CD4 count of 407 cells/µL over the following 6 months ensued. Subsequently, she was diagnosed with a late IRIS to cryptococcus 32 months following initial ART treatment, which manifested as non-resolving lymphadenitis and resolved with high-dose steroids. Following the initiation of ART for 45 months, she developed symptomatic Graves' hyperthyroidism. At this time, her CD4 count had risen to 941 cells/µL. She has been rendered euthyroid on carbimazole. This case serves to remind us that GD can occur as an IRIS post ART and typically has a delayed presentation.\nEndocrinologists should be aware of the endocrine manifestations of HIV disease, in particular, thyroid pathology. Endocrinologists should be aware that IRIS can occur following the initiation of ART. Thyroid dysfunction can occur post ART of which Graves' disease (GD) is the most common thyroid manifestation. GD as a manifestation of ART-induced IRIS can have a delayed presentation. Infectious disease physicians should be aware of endocrine manifestations associated with HIV and ART.",
"affiliations": "Department of Diabetes and Endocrinology, Dublin, Ireland.;Department of Infectious Diseases, Dublin, Ireland.;Department of Diabetes and Endocrinology, Dublin, Ireland.;Department of Diabetes and Endocrinology, Dublin, Ireland.;Department of Radiology, Mater Misericordiae University Hospital, Dublin, Ireland.;Department of Infectious Diseases, Dublin, Ireland.;Department of Diabetes and Endocrinology, Dublin, Ireland.",
"authors": "Ludgate|S|S|;Connolly|S P|SP|;Fennell|D|D|;Muhamad|M F|MF|;Welaratne|I|I|;Cotter|A|A|;McQuaid|S E|SE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573\nBioscientifica Ltd Bristol\n\n34612207\n10.1530/EDM-21-0094\nEDM210094\nAdult\nFemale\nHispanic or Latino - Central American or South American\nIreland\nThyroid\nThyroid\nGeneral Practice\nUnusual Effects of Medical Treatment\nUnusual Effects of Medical Treatment\nGraves’ disease associated with HIV disease and late immune reconstitution inflammatory syndrome following the initiation of antiretroviral therapy\nS Ludgate and others\nGraves’ with HIV and late IRIS following ART\nLudgate S 1\nConnolly S P 2\nFennell D 1\nMuhamad M F 1\nWelaratne I 3\nCotter A 24\nMcQuaid S E 14\n1 Department of Diabetes and Endocrinology, Dublin, Ireland\n2 Department of Infectious Diseases, Dublin, Ireland\n3 Department of Radiology, Mater Misericordiae University Hospital, Dublin, Ireland\n4 School of Medicine, University College Dublin, Dublin, Ireland\nCorrespondence should be addressed to S E McQuaid Email smcquaid@mater.ie\n14 9 2021\n2021\n2021 21-009421 7 2021\n14 9 2021\n© The authors\n2021\nThe authors\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..\nSummary\n\nBoth human immunodeficiency virus (HIV) and antiretroviral therapy (ART) are associated with endocrine dysfunction (1). The term 'immune reconstitution inflammatory syndrome' (IRIS) describes an array of inflammatory conditions that occur during the return of cell-mediated immunity following ART. Graves’ disease (GD) occurs rarely as an IRIS following ART. In this study, we describe the case of a 40-year-old Brazilian female who was diagnosed with HIV following admission with cryptococcal meningitis and salmonellosis. At this time, she was also diagnosed with adrenal insufficiency. Her CD4 count at diagnosis was 17 cells/µL which rose to 256 cells/µL over the first 3 months of ART. Her HIV viral load, however, consistently remained detectable. When viral suppression was finally achieved 21 months post diagnosis, an incremental CD4 count of 407 cells/µL over the following 6 months ensued. Subsequently, she was diagnosed with a late IRIS to cryptococcus 32 months following initial ART treatment, which manifested as non-resolving lymphadenitis and resolved with high-dose steroids. Following the initiation of ART for 45 months, she developed symptomatic Graves’ hyperthyroidism. At this time, her CD4 count had risen to 941 cells/µL. She has been rendered euthyroid on carbimazole. This case serves to remind us that GD can occur as an IRIS post ART and typically has a delayed presentation.\n\nLearning points\n\nEndocrinologists should be aware of the endocrine manifestations of HIV disease, in particular, thyroid pathology.\n\nEndocrinologists should be aware that IRIS can occur following the initiation of ART.\n\nThyroid dysfunction can occur post ART of which Graves' disease (GD) is the most common thyroid manifestation.\n\nGD as a manifestation of ART-induced IRIS can have a delayed presentation.\n\nInfectious disease physicians should be aware of endocrine manifestations associated with HIV and ART.\n\nPatient Demographics\n\nAdult\nFemale\nHispanic or Latino - Central American or South American\nIreland\nClinical Overview\n\nThyroid\nThyroid\nRelated Disciplines\n\nGeneral practice\nPublication Details\n\nUnusual effects of medical treatment\nOctober\n2021\n==== Body\npmcBackground\n\nIt is estimated that more than 33 million people live with HIV worldwide (1). Thyroid function test abnormalities are common in HIV-infected patients and other associated endocrine disorders include diabetes, adrenal insufficiency, hypogonadism and growth hormone deficiency (1, 2). ART is also associated with endocrinopathies, including low bone mineral density, weight gain, insulin resistance, type 2 diabetes mellitus, lipodystrophy and thyroid dysfunction (2).\n\nIRIS describes an array of inflammatory conditions, indicating the return of cell-mediated immune function. In the setting of HIV infection and initiation of ART, IRIS typically manifests as a paradoxical worsening of underlying opportunistic infection, with common pathogens including Mycobacterium tuberculosis and Cryptococcus neoformans meningitis (3). However, autoimmune thyroid disease can also occur as an IRIS. GD is the most reported manifestation, occurring in approximately 3% of women diagnosed with HIV and 0.2 % of men (4). In this study, we report a patient with HIV who developed GD as a delayed IRIS presentation.\n\nCase presentation\n\nA 40-year-old Brazilian lady was diagnosed with HIV in November 2016 after she was admitted to our tertiary centre with a 2-week history of fevers, headache and persistent vomiting. Past medical history included oesophagitis. She was nulliparous with no reported miscarriages and reported a regular menstrual cycle. Blood cultures were positive for Salmonella enteritis and initially grew a yeast that was subsequently identified as C. neoformans. Following normal CT brain, lumbar puncture was cryptococcal antigen positive and cerebral spinal fluid (CSF) samples subsequently cultured C. neoformans, confirming a diagnosis of cryptococcal meningitis. She was prescribed 2 weeks of IV ceftriaxone for salmonella bacteraemia, i.v. flyctosine and liposomal amphotericin B followed by fluconazole and high-dose steroids for Cryptococcus meningitis. HIV antibody/antigen was positive; nadir CD4+ and CD8+ T-cell counts were 17 cells/µL (4%, reference range: 540–1660) and 145 cells/µL (7%, reference range: 270–930), respectively; and initial HIV viral load was 1 804 502 copies/mL.\n\nFour weeks into admission, the patient became persistently hypotensive and developed nausea, vomiting, weakness and worsening fatigue. A diagnosis of primary adrenal insufficiency was made (peak cortisol post Synacthen® of 407 nmol/L, ACTH 111 ng/L (7–63)). Adrenal and TPO antibodies were negative, and CT adrenal showed no infiltrative process (Fig. 1). Symptoms resolved on hydrocortisone replacement. Figure 1 CT abdomen performed in 2016 demonstrating structurally normal adrenal glands (red arrows) at the time of diagnosis with no infiltrative process.\n\nART (darunavir/ritonavir plus tenofovir alafenadmide/emtricitabine) was deferred until 5 weeks post admission. Her CD4+ and CD8+ count increased to 153 cells/µL (18%) and 47 (40%) following 3 months of ART and remained stable around this level over the following months. HIV viral load remained consistently detectable at low levels for 17 months following the initiation of ART. No resistance-associated mutations were found on HIV-1 genotypic antiretroviral resistance testing.\n\nNineteen months post original diagnosis, in June 2018, she presented with cervical lymphadenopathy while abroad. She underwent a full investigation including a biopsy without a clear diagnosis. Commencement of high-dose steroids resulted in full resolution of cervical lymphadenopathy. HIV viral load became detectable at 47 copies/mL, and CD4+ count remained below the normal range at 219 cells/µL. ART was switched to Symtuza® (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) in August 2018, and CD4 count increased from 219 to 626 cells/µL over 6 months.\n\nIn July 2019, 32 months following original diagnosis, she re-presented with a recurrence of cervical lymphadenopathy (CD4+ count 585 cells/µL, undetectable HIV viral load). She underwent extensive workup, including a repeat lymph node biopsy which showed occasional fungal forms highly suspicious for Cryptococcus; however, the culture was negative. Following the investigation and lack of response to prolonged courses of fluconazole, a late immune reconstitution inflammatory syndrome (IRIS) to cryptococcus was diagnosed, with complete resolution of lymphadenopathy on high-dose steroids.\n\nForty-five months after original ART initiation and 18 months post viral suppression, she developed classical hyperthyroidism symptoms with weight loss, tremor and hair thinning with free T4 (FT4) 28.9 pmol/L (9-20) and thyroid-stimulating hormone (TSH) < 0.01 mIU/L (0.35–4.94) (Table 1) (Fig. 2). A diagnosis of GD was confirmed with a positive TSH receptor antibody (TRAB) 3.7 IU/L (<1.8). Thyroid peroxidase antibodies were negative. She had no extra-thyroidal manifestations. Prior TFTs and thyroid imaging were normal. Family history was negative for thyroid and autoimmune disease. As our patient had no symptoms of COVID-19 infection, there was no requirement to test for PCR, IgG or IgM of SARS-COV2. She was commenced on carbimazole 10 mg daily orally with education on the adverse effects. Thyroid ultrasound showed a structurally normal gland with increased vascularity (Fig. 3A, B, C, D and E). Figure 2 Graph of CD4+ cells/µL and viral load copies/mL log against months since initiation of ART.\n\nFigure 3 Ultrasound thyroid. (A) Transverse view of a normal isthmus and both middle lobes. (B) and (C) Longitudinal views of the structurally normal right lobe with increased vascularity on colour Doppler, which can be seen in the setting of Graves’ disease. (D) and (E) demonstrating the same findings in the left lobe.\n\nTable 1 Table of thyroid function tests prior to and throughout treatment with ART.\n\nMonths post original ART\tTSH, mIU/L\tFT4, pmol/L\t\n−1\t1.84\t9.8\t\n0\t0.45\t12.5\t\n1\t1.79\t10\t\n16\t1.75\t10.3\t\n28\t0.78\t10.8\t\n36\t0.46\t10.3\t\n45\t<0.01\t28.9\t\n48\t0.01\t12\t\n51\t3.11\t10.5\t\nReference range for TSH: 0.35–4.94 mIU/L; FT4: 9–20 pmol/L.\n\nOutcome and follow-up\n\nOur patient continues on ART and remains well controlled from an HIV perspective with a normal CD4 count and undetectable viral load under the care of the infectious diseases team.\n\nHer hyperthyroidism has responded well to carbimazole, and the carbimazole dose has been titrated down to 5 mg daily orally based on recent TFTs (FT4 10.5 pmol/L, TSH 3.11 mIU/L) (Table 1). She continues to follow-up in the endocrine outpatient clinic. TRAB will be repeated after 18–24 months of treatment with an attempt to cease carbimazole at this point if possible. Our patient is also regularly followed up for her adrenal insufficiency and is stable on hydrocortisone 10 mg twice daily. She has had no adrenal crisis, and her renin is satisfactory at 1.8 nmol/L/h with sodium in the normal range.\n\nDiscussion\n\nOwing to the myriad of clinical presentations of IRIS, a broad differential diagnosis needs to be excluded before a diagnosis of IRIS can be finalised. French et al. stipulate that IRIS cases must demonstrate initially advanced HIV with a low CD4+ count with positive virologic and immune response to ART and clinical evidence of an inflammatory condition among a number of other criteria (3). The timing of IRIS varies with the inciting pathogen. Our patient developed a delayed IRIS to cryptococcus 32 months following initial ART which is rare; however, it has previously been described in the literature (5).\n\nWhile abnormal TFTs are relatively common in patients with HIV, the rate of overt hyperthyroidism does not appear to differ from the general population. While some consider that autoimmune disease following ART is a coincidence, GD following ART has been reported in over 70 patients treated for HIV (4, 6, 7, 8). GD occurs in approximately 3% of women diagnosed with HIV and 0.2 % of men (4). While this represents a 1.5- to 2-fold increase from the general population, GD as an IRIS is more common following alemtuzumab treatment for multiple sclerosis where the incidence of thyroid autoimmunity, including GD, is 30–40% (9).\n\nWhile the pathogenesis for GD following ART is not fully understood, a number of possible mechanisms have been described. One mechanism is that CTLA-4 may play a role in T cell tolerance to thyroid autoantigens (6, 10). Thymic dysfunction has also been demonstrated (11). French et al found that soluble CD30, a marker of Th2 immune response, occurred alongside a rise in TRAB. The patient with post-ART GD in their study was found to have a rise in CD8+ T cells with naïve immunophenotype (11). The classical onset of GD following ART has been described as 12–36 months following treatment with a median onset of 21 months (2). It has been suggested that CD4+ cells increase in a biphasic pattern following ART initiation (2). A possible explanation for the delayed presentation of GD following ART may be the expansion of naïve CD4+ cells occurring months after the initial redistribution of memory CD4 cells from lymphoid tissue (2). Our patient underwent a change in ART 24 months prior to her diagnosis of GD, after which she had a measured increase in CD4+ count of 722 cells/µL (221 cells/µL at nadir of change in ART to 941 cells/µL prior to diagnosis).\n\nWe cannot be definitive if the GD was of new-onset independent of HIV status or if it occurred as part of an IRIS. However, the diagnosis of documented late IRIS to cryptococcus suggests that the GD is a consequence of ART immune reconstitution. The late-onset occurrence of autoimmunity is a common characteristic of different forms of immune reconstitution syndromes. Two cases of GD 48 months following ART have been reported in the literature (7, 8).\n\nOur patient had no extra-thyroidal manifestations. One study has suggested that Graves’ orbitopathy can occur in up to 25% of patients (8).\n\nThe management of GD following ART is similar to usual management. To our knowledge, there is no published work on the relapse rates in GD following ART. Our patient also had primary adrenal insufficiency felt to be connected to her cryptococcal infection given that adrenal antibodies were negative. Primary adrenal insufficiency is reported in 17% of hospitalised HIV inpatients.\n\nThis case highlights the importance of remaining vigilant for potential endocrine effects that can occur during clinical follow-up in HIV patients treated with ART. The occurrence of GD post ART is characterised by a delayed presentation (8). It is important that all physicians be aware of the signs and symptoms of adrenal insufficiency in the setting of non-specific symptoms. Clinicians should also be cognisant of the signs of hyper- and hypothyroidism as neither the European AIDS Clinical Society nor the American Academy of HIV medicine currently recommends the routine screening of thyroid function tests either at the initiation of or during ART. In 2019, the European Thyroid Association released guidelines on the management of thyroid dysfunction following immune reconstitution therapy. In these guidelines, it is recommended that TSH should be tested following ART for treatment of HIV; however, routine ongoing testing of TSH/FT4 in such patients is not advised unless clinically indicated by the presence of the symptoms of hypo- or hyperthyroidism (9). Cross-communication between endocrinologists and other specialities remains essential to the co-ordinated care of these patients.\n\nDeclaration of interest\n\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\n\nThis study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\n\nBoth written and informed consent have been obtained from the patient for publication of this case report.\n\nAuthor contribution statement\n\nS Ludgate – conducted the chart review, prepared the first draft of the manuscript and was involved in the treatment of the patient. S P Connolly – contributing author and infectious disease registrar involved in the treatment of the patient. D Fennell – contributing author to the final draft of the manuscript and endocrinology registrar involved in the treatment of the patient. M F Muhamad – contributing author to the final draft of the manuscript and endocrinology registrar involved in the treatment of the patient. I Welaratne – contributing author and radiology registrar involved in the preparation of the patient’s imaging. A Cotter – consultant Infectious Diseases physician and lead infectious disease physician caring for the patient and contributing author to the final draft of the manuscript. S E McQuaid – consultant Endocrinologist caring for patient, review and preparation of the manuscript.\n==== Refs\nReferences\n\n1 Kalra S Sleim H Kotwal N . Human immunodeficiency virus and the endocrine system. Indian Journal of Endocrinology and Metabolism 2011 15 231–233. (10.4103/2230-8210.85566)\n2 Hoffmann CJ Brown TT . Thyroid function abnormalities in HIV-infected patients. Clinical Infectious Diseases 2007 45 488–494. (10.1086/519978)17638201\n3 French MA Price P Stone SF . Immune restoration disease after antiretroviral therapy. AIDS 2004 18 1615–1627. (10.1097/01.aids.0000131375.21070.06)15280772\n4 Chen F Day SL Metcalfe RA Sethi G Kapembwa MS Brook MG Churchill D de Ruiter A Robinson S Lacey CJ Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease. Medicine 2005 84 98–106. (10.1097/01.md.0000159082.45703.90)15758839\n5 Hashimoto H Hatakeyama S Yotsuyanagi H . Development of cryptococcal immune reconstitution inflammatory syndrome 41 months after the initiation of antiretroviral therapy in an AIDS patient. AIDS Research and Therapy 2015 12 33. (10.1186/s12981-015-0075-6)26425133\n6 French M French MA . Immune reconstitution inflammatory syndrome: a reappraisal. Clinical Infectious Diseases 2009 48 101–107. (10.1086/595006)19025493\n7 Crum NF Ganesan A Johns ST Wallace MR . Graves disease: an increasingly recognized immune reconstitution syndrome. AIDS 2006 20 466–469. (10.1097/01.aids.0000196173.42680.5f)16439886\n8 Jariyawattanarat V Sungkanuparph S Sriphrapradang C . Characteristics of Graves disease in HIV-infected patients on antiretroviral therapy. Endocrine Practice 2020 26 612–618. (10.4158/EP-2019-0514)31968184\n9 Muller I Moran C Lecumberri B Decallonne B Robertson N Jones J Dayan CM . 2019 European Thyroid Association guidelines on the management of thyroid dysfunction following immune reconstitution therapy. European Thyroid Journal 2019 8 173–185. (10.1159/000500881)31602359\n10 Kavvoura FK Akamizu T Awata T Ban Y Chistiakov DA Frydecka I Ghaderi A Gough SC Hiromatsu Y Ploski R Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 2007 92 3162–3170. (10.1210/jc.2007-0147)17504905\n11 French MA Lewin SR Dykstra C Krueger R Price P Leedman PJ . Graves’ disease during immune reconstitution after highly active antiretroviral therapy for HIV infection: evidence of thymic dysfunction. AIDS Research and Human Retroviruses 2004 20 157–162. (10.1089/088922204773004879)15018703\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2021()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": null,
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101618943",
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"pmc": null,
"pmid": "34612207",
"pubdate": "2021-10-01",
"publication_types": "D016428:Journal Article",
"references": "19025493;17638201;31602359;22028990;15280772;17504905;16439886;26425133;15758839;31968184;15018703",
"title": "Graves' disease associated with HIV disease and late immune reconstitution inflammatory syndrome following the initiation of antiretroviral therapy.",
"title_normalized": "graves disease associated with hiv disease and late immune reconstitution inflammatory syndrome following the initiation of antiretroviral therapy"
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"companynumb": "IE-GILEAD-2021-0560707",
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"activesubstancename": "EMTRICITABINE\\TENOFOVIR ALAFENAMIDE FUMARATE"
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{
"abstract": "BACKGROUND\nThrombopoietin receptor agonists (TRAs) are effective treatments for immune thrombocytopenia (ITP). However, continuous therapy is generally required to maintain platelet (PLT) count responses.\n\n\nMETHODS\nIn this case series, we describe ITP patients from our practice who achieved durable responses to the TRAs romiplostim and eltrombopag. Patients were classified as having a definite TRA-induced remission if PLT counts increased above 100 × 10(9) /L after TRA treatment and remained above 100 × 10(9) /L even after the medication was discontinued; or a possible TRA-induced remission if PLT counts increased above 100 × 10(9) /L, remained elevated for at least 3 months after the medication was discontinued, but a subsequent relapse occurred or the effect of other disease-modifying therapies could not be excluded.\n\n\nRESULTS\nOf 31 patients with chronic ITP treated with TRAs in our practice, nine patients achieved a PLT count response with either romiplostim (n = 6) or eltrombopag (n = 3) that was maintained even after the medications were discontinued. Three patients met criteria for a definite TRA-induced remission, each after exposure to romiplostim. Patients had ITP for a median of 7.8 years and had failed a median of four prior therapies including eight patients who had a splenectomy. We documented a progressive decline in anti-glycoprotein IIbIIIa PLT autoantibodies in one patient while on treatment.\n\n\nCONCLUSIONS\nSome patients with ITP can achieve sustained PLT count responses after the use of TRAs. This observation raises the possibility that these agents may restore immune tolerance to PLT antigens in some patients and supports the practice of down titrating the dose.",
"affiliations": "Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Canadian Blood Services, Hamilton, Ontario, Canada.",
"authors": "Ghadaki|Bahareh|B|;Nazi|Ishac|I|;Kelton|John G|JG|;Arnold|Donald M|DM|",
"chemical_list": "D001323:Autoantibodies; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim; C520809:eltrombopag",
"country": "United States",
"delete": false,
"doi": "10.1111/trf.12139",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "53(11)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D001565:Benzoates; D001792:Blood Platelets; D002908:Chronic Disease; D005260:Female; D006801:Humans; D006834:Hydrazines; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin",
"nlm_unique_id": "0417360",
"other_id": "CAMS4132",
"pages": "2807-12",
"pmc": null,
"pmid": "23451917",
"pubdate": "2013-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20739054;22612239;21325604;22160066;17050891;21735426;21067381;17200219;22460421;22102266;21502541;22882226;20688957;18981291;17272505;21832276;22223819;15217831;22566601;20620441;19426124;19897578;22562409;10086776",
"title": "Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists.",
"title_normalized": "sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists"
} | [
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"abstract": "Organ transplant recipients living in endemic regions are at increased risk of Leishmania infections. Visceral leishmaniasis is the most common kind of presentation in the Mediterranean basin. Rarely, Leishmania infantum may cause localized mucosal disease. We present the first case, to our knowledge, of a liver transplant recipient with localized mucosal leishmaniasis. Twenty-two years after transplantation, a painless, very slow growing ulcer appeared on the inner side of the patient's upper lip. A biopsy performed in the community hospital showed non-specific chronic inflammation without neoplastic signs. Because of a high suspicion of malignancy, the patient was transferred to the referral hospital to consider complete excision. The excisional biopsy revealed a granulomatous inflammatory reaction together with intracellular Leishmania amastigotes within macrophages. Leishmaniasis was confirmed by the nested polymerase chain reaction assay. The clinical and laboratory findings did not suggest visceral involvement. The patient received meglumine antimoniate for 21 days without relevant adverse effects.",
"affiliations": "Infectious Diseases Unit (Internal Medicine), Universidad Autónoma de Madrid, HU Puerta de Hierro, Majadahonda, Madrid, Spain.;Infectious Diseases Unit (Internal Medicine), Universidad Autónoma de Madrid, HU Puerta de Hierro, Majadahonda, Madrid, Spain.;Plastic Surgery Department, HU Puerta de Hierro, Majadahonda, Madrid, Spain.;Microbiology Department, HU Puerta de Hierro, Majadahonda, Madrid, Spain.;Parasitology Department, Instituto Nacional de Salud \"Carlos III\", Majadahonda, Madrid, Spain.;Liver Transplantation Unit (Internal Medicine), Universidad Autónoma de Madrid, HU Puerta de Hierro, Majadahonda, Madrid, Spain.;Pathology Department, HU Puerta de Hierro, Majadahonda, Madrid, Spain.;Liver Transplantation Unit (Internal Medicine), Universidad Autónoma de Madrid, HU Puerta de Hierro, Majadahonda, Madrid, Spain.",
"authors": "Ramos|A|A|;Múñez|E|E|;García-Domínguez|J|J|;Martinez-Ruiz|R|R|;Chicharro|C|C|;Baños|I|I|;Suarez-Massa|D|D|;Cuervas-Mons|V|V|",
"chemical_list": "D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D008536:Meglumine; D000077485:Meglumine Antimoniate",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12380",
"fulltext": null,
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"issn_linking": "1398-2273",
"issue": "17(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Leishmania infantum; leishmaniasis; liver transplantation; meglumine antimoniate; mucocutaneous",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000981:Antiprotozoal Agents; D001706:Biopsy; D002294:Carcinoma, Squamous Cell; D003937:Diagnosis, Differential; D006801:Humans; D007891:Leishmania; D007897:Leishmaniasis, Mucocutaneous; D016031:Liver Transplantation; D008297:Male; D008536:Meglumine; D000077485:Meglumine Antimoniate; D008875:Middle Aged; D009055:Mouth; D009942:Organometallic Compounds; D016133:Polymerase Chain Reaction",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "488-92",
"pmc": null,
"pmid": "25816835",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mucosal leishmaniasis mimicking squamous cell carcinoma in a liver transplant recipient.",
"title_normalized": "mucosal leishmaniasis mimicking squamous cell carcinoma in a liver transplant recipient"
} | [
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"companynumb": "PHHY2015ES061511",
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"activesubstancename": "CYCLOSPORINE"
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"abstract": "Sildenafil is one of the commonest over the counter drugs which is orally taken by the people for sexual enhancement. It is an inhibitor of phosphodiesterase type 5 (PDE5) and results in engorgement of carpora cavernosa and help in erectile dysfunction. There are fewer adverse cutaneous drug reactions reported by sildenafil perhaps due to use of the drug without medical prescription. Here we are reporting a case of sildenafil induced hypersensitivity syndrome that is possibly the first one and reviewing the medical literature on type of adverse cutaneous drug eruption due to sildenafil and other PDE5 inhibitors.",
"affiliations": "Department of Dermatology, All India Institute of Medical Sciences, Gorakhpur, India.;Department of Dermatology, All India Institute of Medical Sciences, Gorakhpur, India.;Faculty, Mansoura Dermatology, Venereology & Leprology Hospital, Mansoura, Egypt.",
"authors": "Gupta|Sunil K|SK|0000-0001-6810-6483;Sushantika|Sushantika|S|;Abdelmaksoud|Ayman|A|0000-0003-4848-959X",
"chemical_list": "D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.13826",
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"issn_linking": "1396-0296",
"issue": "33(6)",
"journal": "Dermatologic therapy",
"keywords": "drug reaction; inflammatory disorders; pharmacology; pruritus; therapysystemic",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e13826",
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"pmid": "32543093",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sildenafil-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: Case report with review.",
"title_normalized": "sildenafil induced hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms case report with review"
} | [
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"companynumb": "IN-PFIZER INC-2020244400",
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"activesubstancename": "SILDENAFIL CITRATE"
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{
"abstract": "BACKGROUND\nPneumocystis jiroveci is an opportunistic infectious fungus in immunosuppressed patients, particularly in ones with acquired immunodeficiency syndrome (AIDS). The use of immunosuppressive drugs especially corticosteroids predisposes the transplanted patients to a variety of infectious diseases including Pneumocystis infection. In many developed countries, the incidence of Pneumocystis jiroveci pneumonia (PJP) is dwindling in transplant patients receiving appropriate prophylaxis. In this study, definitive diagnosis of Pneumocystis infection in a patient receiving kidney transplant was presented.\n\n\nMETHODS\nThe patient was a 45-year-old man with a history of kidney transplantation 24 years ago, admitted to a specialized hospital in Tehran because of fever and respiratory distress. Upon admission, the patient showed symptoms of unconsciousness and shortness of breath. Paraclinical tests and complementary examinations such as microscopic observation and molecular analysis confirmed the definitive diagnosis of Pneumocystis infection. Specific treatment with trimethoprim/sulfamethoxazole was carried out alongside other therapeutic measures; but unfortunately the patient did not respond to the specific treatment and died in the course of a progressive disease.\n\n\nCONCLUSIONS\nThe disease progress in these patients can still be fast and deadly. Applying rapid molecular diagnostic techniques to start appropriate and timely treatment is essential. Utilization of such diagnostic methods is recommended in our country.",
"affiliations": "Department of Parasitology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, IR Iran.;Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran.;Health Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran.;Department of Parasitology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, IR Iran.;Department of Parasitology, Medical School, Tarbiat Modares University, Tehran, IR Iran.;Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran.;Departmanet of Laboratory Sciences, Health Research Center, Birjand University of Medical Sciences, Birjand, IR Iran.;Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran.;Department of Parasitology, School of Medicine, Ilam University of Medical Sciences, Ilam, IR Iran.",
"authors": "Rezavand|Babak|B|;Hosseini|Mohammad Javad|MJ|;Izadi|Morteza|M|;Mahmoodzadeh Poornaki|Abbas|A|;Sadraei|Javid|J|;Einollahi|Behzad|B|;Rezaimanesh|Mohammad Reza|MR|;Bagheri|Ozra|O|;Abdi|Jahangir|J|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.5812/numonthly.13605",
"fulltext": "\n==== Front\nNephrourol MonNephrourol Mon10.5812/numonthlyKowsarNephro-urology Monthly2251-70062251-7014Kowsar 10.5812/numonthly.13605Case ReportLethal Pneumocystis jiroveci pneumonia 24 Years After Kidney Transplantation Rezavand Babak 1Hosseini Mohammad Javad 2*Izadi Morteza 3Mahmoodzadeh Poornaki Abbas 1Sadraei Javid 4Einollahi Behzad 5Rezaimanesh Mohammad Reza 6Bagheri Ozra 2Abdi Jahangir 71 Department of Parasitology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, IR Iran2 Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran3 Health Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran4 Department of Parasitology, Medical School, Tarbiat Modares University, Tehran, IR Iran5 Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran6 Departmanet of Laboratory Sciences, Health Research Center, Birjand University of Medical Sciences, Birjand, IR Iran7 Department of Parasitology, School of Medicine, Ilam University of Medical Sciences, Ilam, IR Iran* Corresponding author: Mohammad Javad Hosseini, Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran. Tel: +98-2188039883, Fax: +98-2188600062, E-mail: dr_mjhosseini@yahoo.com09 3 2014 3 2014 6 2 e1360515 7 2013 07 9 2013 30 12 2013 Copyright © 2014, Nephrology and Urology Research Center; Published by Kowsar Corp.2014This 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 work is properly cited.Introduction:\nPneumocystis jiroveci is an opportunistic infectious fungus in immunosuppressed patients, particularly in ones with acquired immunodeficiency syndrome (AIDS). The use of immunosuppressive drugs especially corticosteroids predisposes the transplanted patients to a variety of infectious diseases including Pneumocystis infection. In many developed countries, the incidence of Pneumocystis jiroveci pneumonia (PJP) is dwindling in transplant patients receiving appropriate prophylaxis. In this study, definitive diagnosis of Pneumocystis infection in a patient receiving kidney transplant was presented.\n\nCase Presentation:\nThe patient was a 45-year-old man with a history of kidney transplantation 24 years ago, admitted to a specialized hospital in Tehran because of fever and respiratory distress. Upon admission, the patient showed symptoms of unconsciousness and shortness of breath. Paraclinical tests and complementary examinations such as microscopic observation and molecular analysis confirmed the definitive diagnosis of Pneumocystis infection. Specific treatment with trimethoprim/sulfamethoxazole was carried out alongside other therapeutic measures; but unfortunately the patient did not respond to the specific treatment and died in the course of a progressive disease.\n\nDiscussion:\nThe disease progress in these patients can still be fast and deadly. Applying rapid molecular diagnostic techniques to start appropriate and timely treatment is essential. Utilization of such diagnostic methods is recommended in our country.\n\nKidney TransplantationPneumonia, Pneumocystis jiroveciPolymerase Chain Reaction\n==== Body\n1. Introduction\nPneumocystis jiroveci pneumonia (PJP) is a fatal disease in patients with AIDS and those receiving organ transplantations. The use of immunosuppressive drugs, especially steroids, makes transplant patients prone to various infectious diseases (1). Pneumocystis jiroveci is attached to type 1 pneumocytes of the lung. This causes a deficiency in oxygen exchange resulting in progressive shortness of breath and death if left untreated (2). In many developed countries, the incidence of PJP in immunosuppressed patients receiving appropriate prophylaxis is declining (3). Herein, we discuss a diagnostic report of fatal Pneumocystis in a 45-year-old patient receiving kidney transplant 24 years ago.\n\n2. Case Presentation\nThe 45-year-old patient was admitted in a specialized hospital in Tehran with loss of consciousness and symptoms of apnea due to hypoxia. Upon admission, the patient suffered from edema of the hands and legs accompanied with ataxia and low-grade fever. In physical examination, patient was tachypneic. In lung auscultation, fine crackles were remarkable especially in bases of both lungs. In initial examination, the patient’s spouse stated a history of cough and apnea from 10 days ago, aggravated in the last week. The coughs were dry and nonprovocative, and mixed with sputum and blood two days before admission to the hospital. The patient was cytomegalovirus (CMV)-positive with a history of kidney transplant 24 years ago, and had not received any prophylaxis against opportunistic infections. Furthermore, the medical record of the patient indicated a history of receiving three immunosuppressive drugs including cyclosporine, azathioprine and prednisolone after renal transplantation. Chest X-ray (CXR) showed diffuse bilateral perihilar opacity with extension to periphery of upper and lower lobes (Figure 1A). CT section images showed bilateral perihilar alveolar ground glass opacity with extension to periphery of upper and lower lobes. No evidence of cavitation, pleural effusion, abscess formation or adenopathy was observed (Figures 1B and 1C). In further studies, ultrasound of the body showed tense ascites in the abdominal region and an echogenic nodule 17 mm in diameter in the left lobe of the liver. In the laboratory setting, white blood cell (WBCs) and red blood cells (RBCs) counts were reported as 8.2 thous/cumm and 4.15 mL/cumm, respectively. The polymorphonuclear (PMN) cells count was remarkably increased (≈96%). Serum level of sodium and potassium was measured as 136 mEq/L and 5.4 mEq/L respectively, in which the serum level of potassium was higher than the standard values. The values of lactate dehydrogenase (LDH), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are presented in the Table 1. All three reported values were greater than standard. On the fifth day of hospitalization, the patient developed worsening shortness of breath and inability to lie down, and the arterial O2 was 69%. The patient was transferred to the intensive care unit; intubation was performed and the patient was connected to mechanical ventilation (MV). The lung lavage sample was positive for Pneumocystis jiroveci using gomori methenamine silver staining (Figure 2A). \n\nTable 1. LDH, CRP and ESR Values a\n\tResults\t\n\nLDH, IU/L\n\t1109\t\n\nCRP, mg/L\n\t59.9\t\n\nESR, mm/h\n\t16\t\na Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase.\n\nFigure 1. Chest X-ray and CT Section Images Results\nA. CXR of diffuse bilateral perihilar opacity with extension to periphery of upper and lower lobes; B, C. CT section images, bilateral perihilar alveolar ground glass opacity with extension to periphery of the upper and lower lobes.\n\nFigure 2. A. Pneumocystis cysts Stained With GMS Image Magnification 1000x; B. Molecular Amplification of Pneumocystis jiroveci\nLane 1, 100 bp ladder; Lane 2, Pneumocystis jiroveci nested PCR result using PAZ102-E, pAZ102 and L2 primers; Lane 3, primary Pneumocystis genome amplification using PAZ102-H and PAZ102-E primers; Lane 4, negative control; Lane 5, positive control.\n\n3.1. Molecular Laboratory\nGenome of bronchoalveolar lavage (BAL) samples obtained from the patient was extracted using Rima ® Zol FlexiGen kit manufactured by Teifara Company, Iran. The search for specific genome of Pneumocystis jiroveci was conducted based on replication of mtLSUrRNA gene. The initial amplification was performed using the initial primers pAZ-102-E and pAZ102-H. Nested polychain reaction (nested-PCR) was performed using the PCR product of the primary phase along with the internal primers pAZ-102-E and pAZ102-L2 (4). The presence of amplified genome was studied after electrophoresis in 1.5% agarose gel stained with ethidium bromide. In this study the positive control sample of Pneumocystis Jiroveci isolated and sequenced from human immunodeficiency virus (HIV)-positive patients in Iran with the code number JF733748,which is listed on the World Gene Bank, was used (5).\n\nThe Pneumocystis jiroveci genome appeared as a 346 bp specific band in the initial amplification, and as a 120 bp band in nested PCR (Figure 2B). After 16 days of hospitalization in the intensive care unit, the patient did not respond to specific treatment with trimethoprim/sulfamethoxazole regarding Centers for Disease Control and Prevention (CDC) standards, and died because of hypoxia and pneumothorax.\n\n3. Discussion\nTo date, the key principle in kidney transplantation has been suppression of allograft rejection. Hence, development of immunosuppressive agents is crucial for successful allograft function. To achieve an intense immunosuppression in the initial days after transplantation, immunosuppressive molecules are used for depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways aiding maintenance, and reversal of the established rejection (6). One of the inevitable effects of immunosuppressive drugs is undesired consequence of immunodeficiency. Immunodeficiency leads to characteristic infections (such as opportunistic infections) and cancers (7). With increasing the number of immunosuppressed patients in different communities, the importance of opportunistic infectious organisms has become highlighted for clinicians over time. PJP is a result of a dangerous opportunistic organism for patients with acquired immunosuppression, especially AIDS, cancer, and those receiving transplantation (8). The studies showed that the incidence of this disease among kidney transplant patients was 14% (9). Routine laboratory tests provide limited information. Measurement of serum LDH seems to be a useful test that increases during the infection, but this test is nonspecific and serum LDH increases in other conditions such as other pneumonias and lymphoma. Patients with LDH levels two to three times higher than normal have a considerably higher mortality (10). In patients with HIV, the relative risk of PJP is associated with their prophylaxis against Pneumocystis infection. If there is no prophylaxis for a patient with pneumonia, risk of recurrence of Pneumocystis carinii Pneumonia (PCP) one year after infection would be 70% (11). If trimethoprim/sulfamethoxazole (TMP/SMX) is administered for prophylaxis, the risk of recurrence of PJP will be reduced (12). The above report suggests that despite 24 years of transplant, the risk of opportunistic infections in transplant patients is still inevitable. Therefore, considering the probability of opportunistic infections in these patients is critical. The disease progress in these patients can still be fast and deadly. Applying rapid molecular diagnostic techniques to start appropriate and timely treatment is essential. Utilization of such diagnostic methods is recommended in our country.\n\nWe wish to acknowledge Arash Mohammadi for his valuable assistance.\n\nImplication for health policy makers/practice/research/medical education:Pneumocystis jiroveci is an opportunistic infectious fungus in immunosuppressed patients, particularly the ones with AIDS. In many developed countries, the incidence of Pneumocystis jiroveci pneumonia (PJP) is dwindling in transplant patients receiving appropriate prophylaxis.\n\nAuthors’ Contribution:Clinicians: Behzad Einollahi, Mohammad Javad Hosseini. Sample collection: Babak Rezavand. PCR performances: Babak Rezavand, Ozra Bagheri. Pathological laboratory procedures: Mohammad Reza Rezaimanesh, Abbas Mahmoodzadeh Poornaki. Manuscript wiring and preparation: Babak Rezavand, Javid Sadraei, Morteza Izadi. PCR results and slide analysis: Babak Rezavand.\n\nFinancial Disclosure:The authors declare no conflict of interest.\n\nFunding/Support:This study had no sponsor.\n==== Refs\nReferences\n1 Goto N Oka S Pneumocystis jirovecii pneumonia in kidney transplantation. Transpl Infect Dis. 2011 13 6 551 8 10.1111/j.1399-3062.2011.00691.x 22093172 \n2 Lanken PN Minda M Pietra GG Fishman AP Alveolar response to experimental Pneumocystis carinii pneumonia in the rat. Am J Pathol. 1980 99 3 561 88 6966893 \n3 Harris JR Balajee SA Park BJ Pneumocystis Jirovecii Pneumonia: Current Knowledge and Outstanding Public Health Issues. Curr Fungal Infect Rep. 2010 4 4 229 37 10.1007/s12281-010-0029-3 \n4 Wakefield AE Pixley FJ Banerji S Sinclair K Miller RF Moxon ER et al. Amplification of mitochondrial ribosomal RNA sequences from Pneumocystis carinii DNA of rat and human origin. Mol Biochem Parasitol. 1990 43 1 69 76 10.1016/0166-6851(90)90131-5 1705311 \n5 Sheikholeslami FM Sadraei J Farnia P Forozandeh M Kochak HE Rate of Pneumocystis pneumonia in Iranian HIV+ Patients with Pulmonary Infiltrates. Jundishapur J Microbiol. 2013 6 3 295 300 \n6 Hamburger J Renal transplantation: theory and practice. 1981 US Williams & Wilkins 683038729 \n7 Brent L A history of transplantation immunology. 1996 US Academic Press 008053399X \n8 Morris A Wei K Afshar K Huang L Epidemiology and clinical significance of pneumocystis colonization. J Infect Dis. 2008 197 1 10 7 10.1086/523814 18171279 \n9 Rodriguez M Fishman JA Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients. Clin Microbiol Rev. 2004 17 4 770 82 10.1128/CMR.17.4.770-782.2004 15489347 \n10 Quist J Hill AR Serum lactate dehydrogenase (LDH) in Pneumocystis carinii pneumonia, tuberculosis, and bacterial pneumonia. Chest J. 1995 108 2 415 8 10.1378/chest.108.2.415 \n11 Schneider MME Hoepelman AIM Schattenkerk JKME Nielsen TL van der Graaf Y Frissen JPHJ et al. A controlled trial of aerosolized pentamidine or trimethoprim–sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. N Engl J Med. 1992 327 26 1836 41 1360145 \n12 Zellweger C Opravil M Bernasconi E Cavassini M Bucher HC Schiffer V et al. Long-term safety of discontinuation of secondary prophylaxis against Pneumocystis pneumonia: prospective multicentre study. AIDS. 2004 18 15 2047 53 15577626\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2251-7006",
"issue": "6(2)",
"journal": "Nephro-urology monthly",
"keywords": "Kidney Transplantation; Pneumonia, Pneumocystis jiroveci; Polymerase Chain Reaction",
"medline_ta": "Nephrourol Mon",
"mesh_terms": null,
"nlm_unique_id": "101578609",
"other_id": null,
"pages": "e13605",
"pmc": null,
"pmid": "24783169",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports",
"references": "15489347;22093172;7634877;6966893;1360145;15577626;1705311;18171279",
"title": "Lethal Pneumocystis jiroveci pneumonia 24 Years After Kidney Transplantation.",
"title_normalized": "lethal pneumocystis jiroveci pneumonia 24 years after kidney transplantation"
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{
"abstract": "A clear link between mating type and virulence has been demonstrated for some fungal pathogens, but not for Aspergillus fumigatus as of yet. An association between mating type and invasiveness has recently been established. The mating type proportion (MAT1-1:MAT1-2) of 213 A. fumigatus strains was determined (48.5%:51.5%) and results were in agreement with previous studies. However, these percentages changed when the strain collection was divided into azole-susceptible and -resistant strains. The 163 susceptible strains kept these proportions, but among the 50 azole-resistant strains 60.0% MAT1-1 and 40% MAT1-2 were found. Moreover, looking at the clinical outcome associated to 27 azole-resistant strains, we found that MAT1-1 was linked to a high mortality rate (64%), whereas the rate associated to MAT1-2 genotype was markedly lower (15%). The pathogenicity linked to the Mat type was tested in a Galleria mellonella model of infection, showing that MAT1-1 strains were consistently more pathogenic than MAT1-2, independently of their susceptibility phenotype. This data would suggest that A. fumigatus mating type determination at the time of diagnosis could have a prognostic value in invasive aspergillosis.",
"affiliations": "Mycology Reference Laboratory, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain.;Mycology Reference Laboratory, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain.;Mycology Reference Laboratory, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain.;Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañon, Instituto de Investigacion Biomedica, Madrid, Spain.;Mycology Reference Laboratory, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain.",
"authors": "Monteiro|Maria Candida|MC|;Garcia-Rubio|Rocio|R|;Alcazar-Fuoli|Laura|L|;Peláez|Teresa|T|;Mellado|Emilia|E|http://orcid.org/0000-0002-9801-0260",
"chemical_list": "D001393:Azoles; D005656:Fungal Proteins",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.12720",
"fulltext": null,
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"issn_linking": "0933-7407",
"issue": "61(3)",
"journal": "Mycoses",
"keywords": "\nAspergillus fumigatus\n; mating type; virulence",
"medline_ta": "Mycoses",
"mesh_terms": "D000818:Animals; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D001393:Azoles; D004195:Disease Models, Animal; D005656:Fungal Proteins; D049770:Genes, Mating Type, Fungal; D005838:Genotype; D006801:Humans; D000072742:Invasive Fungal Infections; D007814:Larva; D007915:Lepidoptera; D011379:Prognosis; D014774:Virulence",
"nlm_unique_id": "8805008",
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"pages": "172-178",
"pmc": null,
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"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Could the determination of Aspergillus fumigatus mating type have prognostic value in invasive aspergillosis?",
"title_normalized": "could the determination of aspergillus fumigatus mating type have prognostic value in invasive aspergillosis"
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"abstract": "Opsoclonus-myoclonus-ataxia syndrome is a heterogeneous constellation of symptoms ranging from full combination of these three neurological findings to varying degrees of isolated individual sign. Since the emergence of coronavirus disease 2019 (COVID-19), neurological symptoms, syndromes, and complications associated with this multi-organ viral infection have been reported and the various aspects of neurological involvement are increasingly uncovered. As a neuro-inflammatory disorder, one would expect to observe opsoclonus-myoclonus syndrome after a prevalent viral infection in a pandemic scale, as it has been the case for many other neuro-inflammatory syndromes. We report seven cases of opsoclonus-myoclonus syndrome presumably parainfectious in nature and discuss their phenomenology, their possible pathophysiological relationship to COVID-19, and diagnostic and treatment strategy in each case. Finally, we review the relevant data in the literature regarding the opsoclonus-myoclonus syndrome and possible similar cases associated with COVID-19 and its diagnostic importance for clinicians in various fields of medicine encountering COVID-19 patients and its complications.",
"affiliations": "Department of Neurology, School of Medicine, Hazrat Rasool-E Akram General Hospital, Iran University of Medical Sciences, Tehran, Iran.;Ganjavian Hospital, Dezful University of Medical Sciences, Khuzestan Province, Dezful, Iran.;Fajr Hospital, AJA University of Medical Sciences, Tehran, Iran.;Ganjavian Hospital, Dezful University of Medical Sciences, Khuzestan Province, Dezful, Iran.;Amiralmomenin Hospital, Zabol University of Medical Sciences, Zabol, Iran.;Khatamolanbia Hospital, Shoushtar University of Medical Sciences, Khuzestan Province, Shoushtar, Iran.;Department of Neurology, School of Medicine, Hazrat Rasool-E Akram General Hospital, Iran University of Medical Sciences, Tehran, Iran.;Department of Neurology, School of Medicine, Hazrat Rasool-E Akram General Hospital, Iran University of Medical Sciences, Tehran, Iran.;Nikan Hospital, Tehran, Iran.;Department of Neurology, School of Medicine, Hazrat Rasool-E Akram General Hospital, Iran University of Medical Sciences, Tehran, Iran. mohammadroohani@gmail.com.",
"authors": "Emamikhah|Maziar|M|http://orcid.org/0000-0001-8375-5262;Babadi|Mansoureh|M|http://orcid.org/0000-0002-8907-1168;Mehrabani|Mehrnoush|M|;Jalili|Mehdi|M|;Pouranian|Maryam|M|http://orcid.org/0000-0003-3170-8442;Daraie|Peyman|P|;Mohaghegh|Fahimeh|F|;Aghavali|Sharmin|S|;Zaribafian|Maryam|M|;Rohani|Mohammad|M|http://orcid.org/0000-0002-5409-1804",
"chemical_list": "D000927:Anticonvulsants; D053139:Oseltamivir; D000077287:Levetiracetam; D006886:Hydroxychloroquine; D002998:Clonazepam; D014635:Valproic Acid; D017963:Azithromycin",
"country": "United States",
"delete": false,
"doi": "10.1007/s13365-020-00941-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-0284",
"issue": "27(1)",
"journal": "Journal of neurovirology",
"keywords": "COVID-19; Myoclonus; Opsoclonus; Parainfectious; SARS-CoV-2",
"medline_ta": "J Neurovirol",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001259:Ataxia; D017963:Azithromycin; D000086382:COVID-19; D002998:Clonazepam; D003371:Cough; D004417:Dyspnea; D005260:Female; D005334:Fever; D006801:Humans; D006886:Hydroxychloroquine; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D063806:Myalgia; D053578:Opsoclonus-Myoclonus Syndrome; D053139:Oseltamivir; D000086402:SARS-CoV-2; D014635:Valproic Acid",
"nlm_unique_id": "9508123",
"other_id": null,
"pages": "26-34",
"pmc": null,
"pmid": "33492608",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "32979582;31356293;15380156;32435811;32837962;22986354;23302805;33236791;33324968;32837961;33069310;32091533",
"title": "Opsoclonus-myoclonus syndrome, a post-infectious neurologic complication of COVID-19: case series and review of literature.",
"title_normalized": "opsoclonus myoclonus syndrome a post infectious neurologic complication of covid 19 case series and review of literature"
} | [
{
"companynumb": "IR-OXFORD PHARMACEUTICALS, LLC-2108581",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
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{
"abstract": "BACKGROUND\nParacetamol poisoning accounts for just under half of all self-poisoning cases that present to hospitals in England. Treatment with acetylcysteine is routine, yet recommendations regarding its use vary internationally and have recently been revised in England and Wales.\n\n\nMETHODS\nData on all cases of paracetamol poisoning presenting to an adult inner city emergency department between May 2011 and April 2012 were prospectively collected using the Bristol Self-harm Surveillance Register.\n\n\nRESULTS\nParacetamol overdoses accounted for 44% of adult self-poisoning cases. A quarter (26.9%) of patients required treatment with acetylcysteine and it was estimated that recent changes in treatment guidelines would increase that proportion to 32.6%. Paracetamol concentration was positively associated with the risk of any adverse reaction to acetylcysteine. 22.5% of patients experienced anaphylactoid reactions to acetylcysteine. There was no clear evidence of an association between risk of anaphylactoid reaction and blood paracetamol levels. Patients presenting with blood paracetamol levels greater than 200 mg/L at 4 h post-ingestion were at greater risk of repeat self-harm (HR 2.17, 95% CI 1.11 to 4.21, p=0.033).\n\n\nCONCLUSIONS\nThe recent changes in UK treatment guidelines are expected to increase the proportion of our population requiring acetylcysteine by 5.7%. We found no clear evidence that risk of anaphylactoid or more general adverse reaction to acetylcysteine was increased in patients presenting with lower blood paracetamol concentrations. Blood paracetamol level was highlighted as a potentially useful clinical indicator for risk of repeat self-harm.",
"affiliations": "School of Social and Community Medicine, University of Bristol, Bristol, UK.;Emergency Department, Bristol Royal Infirmary, Bristol, UK Faculty of Health and Life Sciences, University of the West of England, Bristol, UK.;Liaison Psychiatry, Bristol Royal Infirmary, Bristol, UK.;Liaison Psychiatry, Bristol Royal Infirmary, Bristol, UK.;Liaison Psychiatry, Bristol Royal Infirmary, Bristol, UK.;School of Social and Community Medicine, University of Bristol, Bristol, UK Liaison Psychiatry, Bristol Royal Infirmary, Bristol, UK.;School of Social and Community Medicine, University of Bristol, Bristol, UK.",
"authors": "Carroll|R|R|;Benger|J|J|;Bramley|K|K|;Williams|S|S|;Griffin|L|L|;Potokar|J|J|;Gunnell|D|D|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.1136/emermed-2013-202518",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1472-0205",
"issue": "32(2)",
"journal": "Emergency medicine journal : EMJ",
"keywords": "Clinical Management; Epidemiology; Poisoning, Deliberate Self; Self Harm",
"medline_ta": "Emerg Med J",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic; D000707:Anaphylaxis; D000931:Antidotes; D019468:Disease Management; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D004739:England; D005260:Female; D006786:Hospitals, Urban; D006801:Humans; D008297:Male; D017063:Outcome Assessment, Health Care; D011446:Prospective Studies; D014852:Wales",
"nlm_unique_id": "100963089",
"other_id": null,
"pages": "155-60",
"pmc": null,
"pmid": "24099830",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Epidemiology, management and outcome of paracetamol poisoning in an inner city emergency department.",
"title_normalized": "epidemiology management and outcome of paracetamol poisoning in an inner city emergency department"
} | [
{
"companynumb": "GB-JNJFOC-20150120469",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo investigate feasibility, morbidity and surgical mortality of a docetaxel-based chemotherapy regimen randomly administered before or after gastrectomy in patients suffering from locally-advanced resectable gastric cancer.\n\n\nMETHODS\nPatients suffering from locally-advanced (T3-4 any N M0 or any T N1-3 M0) gastric carcinoma, staged with endoscopic ultrasound, bone scan, computed tomography, and laparoscopy, were assigned to receive four 21 d/cycles of TCF (docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2) per day for days 1-14), either before (Arm A) or after (Arm B) gastrectomy. Operative morbidity, overall mortality, and severe adverse events were compared by intention-to-treat analysis.\n\n\nRESULTS\nFrom November 1999 to November 2005, 70 patients were treated. After preoperative TCF (Arm A), thirty-two (94%) resections were performed, 85% of which were R0. Pathological response was complete in 4 patients (11.7%), and partial in 18 (55%). No surgical mortality and 28.5% morbidity rate were observed, similar to those of immediate surgery arm (P = 0.86). Serious chemotherapy adverse events tended to be more frequent in arm B (23% vs 11%, P = 0.07), with a single death per arm.\n\n\nCONCLUSIONS\nSurgery following docetaxel-based chemotherapy was safe and with similar morbidity to immediate surgery in patients with locally-advanced resectable gastric carcinoma.",
"affiliations": "Division of Abdomino-pelvic Surgery, European Institute of Oncology, Via Ripamonti 435, I-20141 Milan, Italy. roberto.biffi@ieo.it",
"authors": "Biffi|Roberto|R|;Fazio|Nicola|N|;Luca|Fabrizio|F|;Chiappa|Antonio|A|;Andreoni|Bruno|B|;Zampino|Maria Giulia|MG|;Roth|Arnaud|A|;Schuller|Jan Christian|JC|;Fiori|Giancarla|G|;Orsi|Franco|F|;Bonomo|Guido|G|;Crosta|Cristiano|C|;Huber|Olivier|O|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v16.i7.868",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "16(7)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D018572:Disease-Free Survival; D000077143:Docetaxel; D019160:Endosonography; D005060:Europe; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil; D005743:Gastrectomy; D006801:Humans; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011877:Radionuclide Imaging; D013274:Stomach Neoplasms; D043823:Taxoids; D013997:Time Factors; D036542:Tomography, Spiral Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "868-74",
"pmc": null,
"pmid": "20143466",
"pubdate": "2010-02-21",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "17440161;17978289;15856477;3390683;16135489;8336183;15273542;17051604;17143028;17334715;8402053;17075117;11957040;10188901;12699095;16550575;15256239;16921048;10533448;17664469;12679305;16997150;8864093;9632861;16761937;11952590;15082726;16822992;15028313",
"title": "Surgical outcome after docetaxel-based neoadjuvant chemotherapy in locally-advanced gastric cancer.",
"title_normalized": "surgical outcome after docetaxel based neoadjuvant chemotherapy in locally advanced gastric cancer"
} | [
{
"companynumb": "IT-SA-2021SA093112",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 21-year-old male patient with no history of systemic disease or drug use presented to our clinic with redness and pain in the right eye. Best corrected visual acuity was 20/20 in both eyes. Inflamed pinguecula was observed on slit-lamp examination and the patient was prescribed ophthalmic nepafenac eye drops. After instilling the drops that day and the next day, the patient presented again due to pruritus and rash. Upon consultation with the dermatology department, the patient was diagnosed with drug-induced allergic urticaria and the nepafenac drops were discontinued. Although urticaria has been reported as a side effect after systemic non-steroidal anti-inflammatory drug (NSAID) use, such a reaction has not been reported with an ophthalmic NSAID and ours is the first reported case of urticaria following ophthalmic nepafenac use. This unique case highlights the fact that ophthalmologists must also keep urticaria in mind as a potential side effect when prescribing this drug.",
"affiliations": "Aksaray University Aksaray Training and Research Hospital, Ophthalmology Clinic, Aksaray, Turkey.;Aksaray University Aksaray Training and Research Hospital, Dermatology Clinic, Aksaray, Turkey.;Osmangazi University Faculty of Medicine, Department of Ophthalmology, Eskişehir, Turkey.",
"authors": "Yaşar|Erdoğan|E|https://orcid.org/0000-0001-5129-9397;Öztürk Kara|Deniz|D|https://orcid.org/0000-0003-4679-7476;Yıldırım|Nilgün|N|https://orcid.org/0000-0001-6506-0336",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/tjo.78614",
"fulltext": "\n==== Front\nTurk J OphthalmolTurk J OphthalmolTJOTurkish Journal of Ophthalmology2149-86952149-8709Galenos Publishing 10.4274/tjo.7861419070Case ReportA Case of Allergic Urticaria After Ophthalmic Nepafenac Use Yaşar Erdoğan 1*https://orcid.org/0000-0001-5129-9397Öztürk Kara Deniz 2https://orcid.org/0000-0003-4679-7476Yıldırım Nilgün 3https://orcid.org/0000-0001-6506-0336\n1 Aksaray University Aksaray Training and Research Hospital, Ophthalmology Clinic, Aksaray, Turkey\n2 Aksaray University Aksaray Training and Research Hospital, Dermatology Clinic, Aksaray, Turkey\n3 Osmangazi University Faculty of Medicine, Department of Ophthalmology, Eskişehir, Turkey* Address for Correspondence: Aksaray University, Aksaray Training and Research Hospital, Clinic of Ophthalmology Clinic, Aksaray, Turkey GSM: +90 530 060 86 49 E-mail:dr.e.yasar@gmail.com6 2018 28 6 2018 48 3 146 149 4 7 2017 8 1 2018 ©Turkish Journal of Ophthalmology, Published by Galenos Publishing.2018This 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 work is properly cited.A 21-year-old male patient with no history of systemic disease or drug use presented to our clinic with redness and pain in the right eye. Best corrected visual acuity was 20/20 in both eyes. Inflamed pinguecula was observed on slit-lamp examination and the patient was prescribed ophthalmic nepafenac eye drops. After instilling the drops that day and the next day, the patient presented again due to pruritus and rash. Upon consultation with the dermatology department, the patient was diagnosed with drug-induced allergic urticaria and the nepafenac drops were discontinued. Although urticaria has been reported as a side effect after systemic non-steroidal anti-inflammatory drug (NSAID) use, such a reaction has not been reported with an ophthalmic NSAID and ours is the first reported case of urticaria following ophthalmic nepafenac use. This unique case highlights the fact that ophthalmologists must also keep urticaria in mind as a potential side effect when prescribing this drug.\n\nNepafenac allergic urticaria\n==== Body\nIntroduction\nNon-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in oral, intramuscular and topical (skin and ophthalmic) forms for a variety of indications. Ophthalmic NSAIDs currently in use include nepafenac, ketorolac tromethamine, diclofenac sodium, bromfenac and flurbiprofen. A study performed in rabbit eyes demonstrated the distribution of ophthalmic nepafenac in the cornea, aqueous humor, iris, ciliary body and choroid.1 These ophthalmic drugs are used in the management of inflammatory ocular diseases, allergic conjunctivitis and postoperative pain following refractive and cataract surgery and in the treatment of cystoid macular edema after cataract surgery.2,3,4,5,6\n\nAdverse effects of ophthalmic NSAIDs include corneal melting,7,8,9,10 ocular tissue hemorrhage,7 blurred vision, photophobia, posterior capsule opacity, foreign body sensation, dry eye and increased intraocular pressure.11 Adverse effects involving the pulmonary, gastrointestinal, dermatologic, renal, cardiovascular, hematologic, pulmonary and central nervous systems have been reported after topical, intramuscular and oral administration.12,13,14,15,16,17,18,19 Here we present urticaria as a previously unreported adverse effect of an ophthalmic NSAID.\n\nCase Report\nA 21-year-old male patient presented to our clinic with pain and redness in his right eye. On physical examination, visual acuity using Snellen chart was 20/20 in both eyes and intraocular pressures were 14 and 15 mmHg in the right and left eyes, respectively. On slit-lamp biomicroscopic examination, minimally inflamed pinguecula was noted on the nasal conjunctiva of the right eye. No pathology was observed in the left eye except pinguecula (Figure 1a, b). Fundus examination revealed no pathology in either eye. The patient reported no disease or drug use in his systemic medical history. Treatment was initiated with ophthalmic nepafenac (Nevanac 0.1%, Alcon) four times daily and the patient was scheduled for follow-up one week later. The next day, the patient returned to the outpatient clinic due to redness and itching on his body. He stated that an itchy rash had formed on his trunk and arms the previous day, approximately 1-2 hours after instilling the nepafenac eye drop and he had been treated for allergy that night in the emergency department. A similar reaction had occurred 1-2 hours after instilling the drop that morning and the dermatology department was consulted. Erythematous, edematous plaque lesions were observed on the arms, neck and abdomen on dermatologic examination and the patient was diagnosed with allergic urticaria by the dermatologist (Figure 2a, b, c). The dermatologist instructed the patient to discontinue the nepafenac drops and prescribed oral antihistamines to treat the urticaria. The ophthalmology department recommended preservative-free lubricating drops and scheduled the patient for follow-up. At follow-up three days later, the patient’s skin lesions and symptoms had completely regressed and his ocular complaints had also improved.\n\nDiscussion\nNSAIDs act by inhibiting the enzyme cyclooxygenase (COX), thus reducing the synthesis of prostaglandin, prostacyclin and leukotriene from arachidonic acid. There are two forms of COX. COX-1 is generally found in all tissues and plays a protective role by regulating the action of prostaglandins. COX-2 increases inflammation by stimulating immune system cells and other tissues in the presence of various stimuli such as mitogens, inflammatory cytokines and tumor promoters.20\n\nOphthalmic NSAIDs currently in use include nepafenac, ketorolac tromethamine, diclofenac sodium, bromfenac and flurbiprofen. The chemical designation of nepafenac is 2-amino-3-benzoylbenzeneacetamine and it is available as a 0.1% suspension. Ophthalmic nepafenac is the only prodrug among the NSAIDs. It is deaminated to form amfenac, a potent COX inhibitor. Ophthalmic nepafenac targets the anterior segment and intraocular vascular tissues. An in vivo study in humans showed nepafenac had a significantly shorter time to peak anterior chamber concentration after instillation on the cornea, followed by amfenac, ketorolac and bromfenac.21 Ophthalmic nepafenac takes effect approximately 15 minutes after topical application and lasts more than 8 hours.22 Quantitative plasma concentrations of nepafenac and amfenac were measured in subjects 2-3 hours after ocular administration and mean steady-state C-max values of the drugs were 0.310±0.104 ng/mL and 0.422±0.121 ng/mL, respectively. Ophthalmic diclofenac has been associated with corneal melting in studies of the ophthalmic side effects of topical NSAIDs.7 In another study, topical ketorolac and bromfenac were associated with severe corneal damage and the authors suggested that patients with corneal damage should be asked about their use of these agents.8,9 Topical nepafenac has also been associated with corneal melting.10 Ophthalmic NSAIDs may prolong bleeding time by impairing platelet aggregation, thus leading to hemorrhage in ocular tissues.7 Therefore, caution is warranted when using ophthalmic NSAIDs long-term in patients using systemic NSAIDs, patients who smoke or use alcohol and in elderly and pediatric populations. In a study of the ocular side effects of nepafenac, ocular adverse events that occurred at rates of at least 1% included blurred vision, photophobia, posterior capsular opacity, foreign body sensation, dry eye and increased intraocular pressure.11\n\nAdverse effects have also been reported after using topical and intramuscular NSAIDs. In one of these reports, a patient with asthma history experienced an asthma attack after using piroxicam topical gel (NSAID) for knee pain.15 Another patient with no history of gastric ulcer developed gastric ulcer perforation four days after starting intramuscular ketorolac (NSAID) treatment for traumatic humerus and femur fracture.16 The systemic side effects of oral NSAIDs on the gastrointestinal, renal, cardiovascular, hematological, pulmonary and central nervous systems have been demonstrated in various studies.17,18,19,20 Dermatologic side effects include urticaria, morbilliform and vesiculobullous eruptions, exfoliative erythroderma, erythema multiforme, Steven Johnson syndrome and toxic epidermal necrosis.21,22Urticaria occurs as the result of mediator release from mast cells or basophils after contact with a triggering stimulus. These mediators induce vasodilation and transudation from small vessels, which causes the development of the characteristic erythematous, edematous, itchy papules and plaques. Many factors are implicated in the etiology of urticaria. The main etiological causes of acute urticaria are drugs, food and infections. It is usually possible to determine the etiology based on only a detailed history. Nearly all drugs can cause urticaria but the most common are antimicrobials (penicillin, sulfonamides), analgesics and antiinflammatory drugs (acetylsalicylic acid, NSAIDs, opiates), angiotensin converting enzyme (ACE) inhibitors and blood products.23,24 In a study conducted in rabbits, it was determined that ocular instillation of 0.5% (50 µL) diclofenac resulted in a peak plasma concentration of 185 ng/mL after 15 minutes at the earliest.25 In addition, it has been shown in rabbits that 7-10% of ophthalmic flurbiprofen enters the ocular circulation, while 74% passed to the systemic circulation.26 Urticaria is a known adverse effect of systemic NSAID use and we believe that our patient developed it after the ophthalmic NSAID entered the systemic circulation via the conjunctival vessels and nasolacrimal duct. Although there are previous reports of allergic urticaria after oral NSAID use,23,24 our case is novel as the first reported case in the literature of allergic urticaria as an adverse event after ophthalmic NSAID use.\n\nEthics\n\nInformed Consent: Patient-confirmed approval was obtained. In addition, written approval has been received for the presentation of the patient as a case report.\n\nPeer-review: Externally and internally peer-reviewed.\n\nAuthorship Contributions\n\nSurgical and Medical Practices: Erdoğan Yaşar, Concept: Nilgün Yıldırım, Design: Deniz Öztürk Kara, Data Collection or Processing: Erdoğan Yaşar, Analysis or Interpretation: Nilgün Yıldırım, Literature Search: Deniz Öztürk Kara, Writing: Erdoğan Yaşar.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n\nFigure 1a Inflamed pinguecula in the right eye\nFigure 1b Pinguecula in the left eye\nFigure 2 Erythematous and edematous plaques on the patient’s right arm (a), left arm (b), and upper trunk (c)\n==== Refs\nReferences\n1 Gamache DA Graff G Brady MT Spellman JM Yanni JM Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I.assessment of anti-inflammatory efficacy Inflammation. 2000 24 357 370 10850857 \n2 Waterbury LD Flach AJ Comparison of ketorolac tromethamine, diclofenac sodium and loteprednol etabonate in an animal model of ocular inflammation J Ocul Pharmacol Ther. 2006 22 155 159 16808675 \n3 Yaylali V Demirlenk I Tatlipinar S Ozbay D Esme A Yildirim C Ozden S Comparative study of 0.1% olopatadine hydrochloride and 0.5% ketorolac tromethamine in the treatment of seasonal allergic conjunctivitis. Acta Ophthalmol Scand 2003 81 378 382 12859265 \n4 Price MO Price FW Effi cacy of topical ketorolac tromethamine 0.4% for control of pain or discomfort associated with cataract surgery Curr Med Res Opin. 2004 20 2015 2019 15701218 \n5 Rajpal RK Cooperman BB Analgesic efficacy and safety of ketorolac after photorefractive keratectomy. Ketorolac Study Group J Refract Surg 1999 15 661 667 10590004 \n6 Rho DS Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac J Cataract Refract Surg. 2003 29 2378 2384 14709300 \n7 Gaynes BI Fiscella R Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: a safetu review Drug Saf. 2002 25 233 250 11994027 \n8 Asai T Nakagami T Mochizuki M Hata N Tsuchiya T Hotta Y Three cases of corneal melting after instillation of a new nonsteroidal anti-inflammatory drug Cornea. 2006 25 224 227 16371788 \n9 Mian SI Gupta A Pineda R 2nd Corneal ulceration and perforation with ketorolac tromethamine (Acular®) use after PRK Cornea. 2006 25 232 234 16371790 \n10 Wolf EJ Kleiman LZ Schrier A Nepafenac-associated corneal melt J Cataract Refract Surg. 2007 33 1974 1975 17964407 \n11 Lane SS Modi SS Lehmann RP Holand EJ Nepafenac ophthalmic suspension 0.1% for prevention of ocular inflammation associated with cataract surgery J Cataract Refract Surg. 2007 33 53 57 17189793 \n12 Chan TY Severe asthma attacks precipitated by NSAIDs Ann Pharmacother. 1995 29 199 \n13 Estes LL Fuhs DW Heaton AH Butwinick CS Gastric ulcer perforation associated with use of injectable keterolac Ann Pharmacother. 1993 27 42 43 8431619 \n14 Brooks PM In: Klippel JH Dieppe PA NSAIDs Textbook of Rheumatology, (2th ed) London Harcourt Publisher Ltd 2000 1 6 \n15 Kawai S Kojima F Kusunoki N Recent Advances in Nonsteroidal Anti-Inflammatory Drugs Allergology International. 2005 54 209 215 \n16 Vonkeman HE van de Laar MA Nonsteroidal Anti-Inflammatory Drugs: Adverse Effects and Their Prevention Semin Arthritis Rheum. 2010 39 294 312 18823646 \n17 Simon RA NSAIDs (including aspirin): Allergic and pseudoallergic reactions. UpToDate 2009 \n18 Moore DE Drug-induced cutaneous photosensitivity Drug Saf. 2002 25 345 372 12020173 \n19 Su M Nagdev A Nonsteroidal antiinflammatory drug (NSAID) poisoning. UpToDate 2009 \n20 Norman RJ Wu R The potential danger of COX-2 inhibitors Fertil Steril. 2004 81 493 494 15037388 \n21 Walters T Raizman M Ernest P Guyton J Lehmann R In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac and bromfenac J Cataract Refract Surg. 2007 33 1539 1545 17720067 \n22 Stewart WC Stewart R Maxwell WA Cavanqh HD Walters TR Saqer DP Meuse PA Preoperative and postoperative clinical evaluation of nepafenac 0.1% ophthalmic suspension for postcataract inflammation [abstract] Asaio J. 2005 \n23 Caffarelli C Cuomo B Cardinale F Barberi S Dascola CP Agostinis F Franceschini F Bernardini R Aetiological Factors Associated with Chronic Urticaria in Children:A Systematic Review Acta Derm Venereol. 2013 93 268 272 23224228 \n24 Muller BA Urticaria and Angioedema: A Practical Approach Am Fam Physician. 2004 69 1123 1128 15023012 \n25 Ling TL Combs DL Ocular bioavailability and tissue distribution of (14C) ketorolac tromethamine in rabbits J Pharm Sci. 1987 76 289 294 3598886 \n26 Tang-Liu DD Liu SS Weinkam RJ Ocular and systemic bioavailability of ophthalmic flurbiprofen J Pharmacokinet Biophurm. 1984 12 611 626\n\n",
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"issn_linking": "2149-8709",
"issue": "48(3)",
"journal": "Turkish journal of ophthalmology",
"keywords": " allergic; urticaria; Nepafenac",
"medline_ta": "Turk J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101686048",
"other_id": null,
"pages": "146-149",
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"pubdate": "2018-06",
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"title": "A Case of Allergic Urticaria After Ophthalmic Nepafenac Use.",
"title_normalized": "a case of allergic urticaria after ophthalmic nepafenac use"
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"abstract": "Chronic thromboembolic pulmonary hypertension (CTEPH) involves non-resolving thromboemboli in the pulmonary arteries. Treatment for CTEPH includes lifelong anticoagulation and determination of patients who have disease which is operable versus inoperable. Pulmonary arterial hypertension (PAH) targeted therapies are oftentimes used as a bridge to pulmonary thromboendarterectomy (PTE), though riociguat is the only Food and Drug Administration (FDA)-approved therapy for CTEPH. There is a paucity of data regarding the efficacy of other PAH therapies, particularly as a bridge to PTE. Here, we present a case report of severe CTEPH related to ventriculoatrial shunt in which intravenous treprostinil was used as a bridge to PTE.",
"affiliations": "Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, USA cattraam@ucmail.uc.edu.;Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, USA.",
"authors": "Cattran|Ashley|A|;Elwing|Jean|J|http://orcid.org/0000-0001-6199-1707",
"chemical_list": "D011464:Epoprostenol; C427248:treprostinil",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235806",
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"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "pulmonary embolism; pulmonary hypertension",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002908:Chronic Disease; D004691:Endarterectomy; D011464:Epoprostenol; D006801:Humans; D006976:Hypertension, Pulmonary; D011655:Pulmonary Embolism",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
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"pmid": "33766958",
"pubdate": "2021-03-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful use of intravenous treprostinil as a bridge to pulmonary thromboendarterectomy.",
"title_normalized": "successful use of intravenous treprostinil as a bridge to pulmonary thromboendarterectomy"
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"abstract": "BACKGROUND\nCongenital hemophilia A is a recessive inherited hemorrhagic disorder. According to the activity of functional coagulation factors, the severity of hemophilia A is divided into three levels: mild, moderate and severe. The first bleeding episode in severe and moderate congenital hemophilia A occurs mostly in early childhood and mainly involves soft tissue and joint bleeds. At present, there are limited reports on severe congenital hemophilia A with low factor XII (FXII) activity during the neonatal period.\n\n\nMETHODS\nA 13-day-old neonate was admitted to the hospital with hematoma near the joints of both upper arms. Coagulation tests showed he had low activity of factor VIII (FVIII) and FXII. He was diagnosed with congenital hemophilia A and treated with human coagulation factor VIII (recombinant FVIII). Although the hematoma became smaller, FVIII activity was only increased to a certain extent and FXII activity decreased gradually. Unfortunately, the child responded poorly to recombinant human coagulation factor VIII and his guardian rejected prophylactic inhibitors and genetic testing and refused further treatment. Three months later, the child developed intracranial hemorrhage (ICH) due to low FVIII activity.\n\n\nCONCLUSIONS\nIn hemophilia A, the presence of FVIII inhibitors, drug concentration and testing are three important aspects that must be considered when FVIII activity does not reach the desired level. Early positive disease treatment and prophylaxis can decrease the frequency of bleeding and improve quality of life. We recommend that pregnant women with a family history of hemophilia A undergo early prenatal and neonatal genetic testing.",
"affiliations": "Department of Neonatology, Maoming People's Hospital, Weimin Road, Maonan District, Maoming, 525000, Guangdong, China.;Department of Neonatology, Maoming People's Hospital, Weimin Road, Maonan District, Maoming, 525000, Guangdong, China.;Department of Neonatology, Maoming People's Hospital, Weimin Road, Maonan District, Maoming, 525000, Guangdong, China. haiyanfeng90@163.com.",
"authors": "Lei|Baoyu|B|;Liang|Chuang|C|;Feng|Haiyan|H|http://orcid.org/0000-0002-1747-5470",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13052-021-01137-x",
"fulltext": "\n==== Front\nItal J Pediatr\nItal J Pediatr\nItalian Journal of Pediatrics\n1824-7288\nBioMed Central London\n\n1137\n10.1186/s13052-021-01137-x\nCase Report\nCongenital hemophilia A with low activity of factor XII: a case report and literature review\nLei Baoyu\nLiang Chuang\nhttp://orcid.org/0000-0002-1747-5470\nFeng Haiyan haiyanfeng90@163.com\n\nDepartment of Neonatology, Maoming People’s Hospital, Weimin Road, Maonan District, Maoming, 525000 Guangdong China\n11 10 2021\n11 10 2021\n2021\n47 20413 4 2020\n27 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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.\nBackground\n\nCongenital hemophilia A is a recessive inherited hemorrhagic disorder. According to the activity of functional coagulation factors, the severity of hemophilia A is divided into three levels: mild, moderate and severe. The first bleeding episode in severe and moderate congenital hemophilia A occurs mostly in early childhood and mainly involves soft tissue and joint bleeds. At present, there are limited reports on severe congenital hemophilia A with low factor XII (FXII) activity during the neonatal period.\n\nCase presentation\n\nA 13-day-old neonate was admitted to the hospital with hematoma near the joints of both upper arms. Coagulation tests showed he had low activity of factor VIII (FVIII) and FXII. He was diagnosed with congenital hemophilia A and treated with human coagulation factor VIII (recombinant FVIII). Although the hematoma became smaller, FVIII activity was only increased to a certain extent and FXII activity decreased gradually. Unfortunately, the child responded poorly to recombinant human coagulation factor VIII and his guardian rejected prophylactic inhibitors and genetic testing and refused further treatment. Three months later, the child developed intracranial hemorrhage (ICH) due to low FVIII activity.\n\nConclusions\n\nIn hemophilia A, the presence of FVIII inhibitors, drug concentration and testing are three important aspects that must be considered when FVIII activity does not reach the desired level. Early positive disease treatment and prophylaxis can decrease the frequency of bleeding and improve quality of life. We recommend that pregnant women with a family history of hemophilia A undergo early prenatal and neonatal genetic testing.\n\nKeywords\n\nCongenital hemophilia A\nFactor VIII\nFactor XII\nInhibitor\nNeonate\nHigh-level Hospital Construction Research Project of Maoming People's Hospitalissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nCongenital hemophilia A is an inherited hemorrhagic disorder caused by the x-linked chromosome factor VIII (FVIII) and it occurs in 0.01% of newborns. Thirty percent of these patients have spontaneous mutations in FVIII and do not have a family history of hemophilia A [1, 2]. In an observational cohort study consisting of 679 patients with severe or moderate hemophilia A, the researchers found that the first bleeding episode in hemophilia A occurred at the median age of 0.82 years in severe disease and 1.47 years in moderate disease [3]. Acute joint hemorrhage is a common symptom. Patients often suffer from repeated bleeding and chronic joint injury [4]. In addition, in 1–4% of patients, intracranial hemorrhage could be the first symptom [5]. When the FVIII activity is < 1%, repeated episodes of spontaneous bleeding occur in approximately 50–60% of patients [6]. Primary prevention in patients with severe hemophilia A can reduce the progression of arthropathy [7].\n\nIt is found that the lower the FVIII activity in the body, the more frequent bleeding episodes [5]. The severity of hemophilia is classified according to the activity of functional coagulation factors, with 5–40% being mild, 1–5% being moderate and < 1% being severe [8, 9]. Currently, the main prevention and treatment method is to use plasma-derived or recombinant FVIII products [9]. In addition, bleeding episodes could also be treated with activated prothrombin complex concentrate (aPCC) or recombinant activating factor VII (rFVIIa) [10]. Here, we report the case of a very early onset of severe neonatal congenital hemophilia A and perform a brief literature review on its mechanism.\n\nCase presentation\n\nWe encountered a 13-day-old neonatal patient with congenital hemophilia A with low FXII activity. At first, he was admitted for hematoma near the joints of both upper arms. Blood test results showed that activated partial thromboplastin time (APTT) was prolonged without extended prothrombin time (PT) and the activity of factors VIII, IX, XI and XII was low, especially the activity of FVIII (0.7%) and factor XII (15.3%). The newborn had a family history of hemophilia A, with an uncle diagnosed with hemophilia A. The neonate was diagnosed with congenital hemophilia A. After admission, he was treated with human coagulation factor VIII with standard dosage according to the guidelines for the management of hemophilia [11, 12]. In general, each unit of FVIII/kg per 8–12 h infused intravenously raises plasma FVIII levels by approximately 2% in the absence of an inhibitor [11, 12]. After 5 days of treatment, the APTT returned to normal and the hematomas became smaller. But the FVIII activity of this patient did not reach the desired level, remaining below 20%, and FXII gradually decreased (Fig. 1). We believed that the plasma factor peak level response was inadequate and that the duration of administration needed to be longer. However, despite the continued risk of bleeding, the family members stopped treatment and refused further prophylactic inhibitors and genetic testing due to financial and other reasons. Fig. 1 After treatment with human coagulation factor VIII for 5 days, FVIII activity was not significantly increased and FXII gradually decreased\n\nProphylaxis prevents bleeding and joint destruction and must be initiated 2–3 times per week [11]. Unfortunately, 3 months after all of the treatments were discontinued, he developed convulsions and brain CT scanning revealed intracranial hemorrhage (Fig. 2). Fig. 2 Three months after initial presentation, brain CT scanning showed intracranial hemorrhage\n\nDiscussion and conclusions\n\nReports of neonatal patients with low FVIII:C and FXII:C are relatively rare. In this case, the neonate’s FVIII activity did not reach the desired level with treatment, and his FXII activity gradually decreased. This case presents some of the challenges of treating patients with hemophilia A. Our patient had severe hemophilia A with FXII deficiency and may have had chromosome and gene mutations. To address these challenges, this paper reviews some new knowledge about congenital hemophilia A and FXII. Currently, three important aspects, namely, the presence of FVIII inhibitors, drug concentration and genetic testing, must be considered when poor treatment response occurs in hemophilia A.\n\nThe newborn had low FVIII activity. However, after treatment with human coagulation factor VIII, the activity of FVIII did not increase significantly, as inhibition of FVIII may have occurred. The presence of inhibitors is a common adverse effect of human coagulation factor VIII therapy in patients with hemophilia [13, 14]. Generally, 30 % of patients with severe hemophilia A may develop inhibitors during the first 20 days of exposure to recombinant coagulation factor VIII [15]. The presence of inhibitors may be an immune response to foreign proteins in patients with severe hemophilia A [16]. The inhibitor development depends on the proper activation of antigen-presenting cells (APCs) that encounter FVIII in the periphery, which is a T-cell-dependent process [9]. The total risk of developing inhibitors over a lifetime is 25–40% for severe hemophilia and 5–15% for moderate/mild hemophilia A [16]. However, inhibitors can be produced without previous treatment with human coagulation factor VIII or with only a small amount of blood components [17]. Besides, high doses of recombinant FVIII therapy and surgery may increase the risk of inhibitor development in patients with non-severe hemophilia A [18]. In general, the emergence of inhibitors increases the risk of progressive and disabling joints disease. The sensitive inhibitor screening or the Nijmegen modification method of Bethesda should be used for screening [14, 19, 20].\n\nDespite the potential for the production of inhibitors, the benefits of recombinant coagulation factor VIII still seem to outweigh the risks [21], and better treatment with recombinant FVIII product is possible. Studies have shown that patients treated with factor VIII containing von Willebrand factor (VWF) have a lower incidence of inhibitor production than patients treated with recombinant FVIII product [17]. This may be because the von Willebrand factor obscures the inhibitor epitope in the concentrate, resulting in a longer half-life of the product [14]. Another study suggested that when patients with hemophilia A had inhibitors, clinicians could initiate an immune tolerance induction (ITI) protocol to reduce levels of the inhibitor [14, 22]. A randomized trial showed that ITI eliminated anti-FVIII alloantibodies in about two-thirds of patients [23].\n\nElimination of inhibitors is important because some asymptomatic patients remain at risk of severe bleeding or life-threatening conditions until the inhibitors are eliminated. Prednisolone has been reported to achieve a complete immunosuppressive response (CR) in some patients [14]. Recombinant FVIII concentrates that produce fewer inhibitors are under study, and a new treatment option for hemophilia patients with inhibitors is the bispecific monoclonal antibody emicizumab [5].\n\nResearch findings have shown that plasma-derived or full-length recombinant FVIII have a half-life of between 6 and 25 h [24]. A regimen of lower doses of prophylaxis given more frequently may be an effective option to decrease the frequency of bleeding, joint disease and intracranial hemorrhage. Recombinant FVIII, which effectively prevent spontaneous bleeding, must be injected intravenously three times a week or every other day to maintain FVIII levels ≥1% in patients with severe hemophilia A [25, 26]. Weight-adjusted clearance (CL) of FVIII is related to age and weight. From infancy to adulthood, CL decreases with age and/or weight, and the terminal half-life increases accordingly [27]. Extended plasma half-life FVIII products can produce higher FVIII plasma levels and reduce the number of intravenous injections, which increase the possibility of a more active lifestyle [28]. Currently, half-life extension technology for Fc-fusion proteins or modification with polyethylene glycol (PEG) can prolong the plasma half-life of FVIII, as with efmoroctocog alfa and BAX 855 [26, 29]. Coagulation FVIII produced by Fc fusion technology has few adverse effects because the components of the fusion peptide are plasma proteins, causing fewer allergic reactions [25].\n\nAccurate testing of FVIII is critical for guiding clinical treatment. The test results for coagulation factors are greatly affected by laboratory test methods, and the reason for variation between laboratories is not the bias of instrument calibration, but the differences in reagents, instruments used and test design. The following sampling protocol is recommended for more effective detection of inhibitors: FVIII samples were taken at pre-dose, 15 min, 30 min and at 3, 6, 9, 24, 28 and 32 h post-dose administration to obtain more test information [14]. Results of experiments have shown that test designs for three samples produce more stable results than designs that test only one or two of the diluents. It is recommended that at least three different sample diluents be used in each FVIII:C (FVIII activity) assay with a commutable lyophilised FVIII:C calibrator, which results in a limited reduction of the inter-laboratory variation [30]. However, there are no comparable data to reliably predict an individual patient’s FVIII:C level to guide clinical treatment. Current studies have shown that adults and adolescents need less FVIII/kg than young children to maintain serum drug concentrations. Personalized drug delivery is therefore more suitable in clinical practice [24].\n\nActivated factor XII (Hageman factor, FXII) can trigger the internal coagulation pathway [31], which is measured by APTT [32]. Hageman factor deficiency is usually an autosomal recessive disorder but can be autosomal dominant. Matsushita et al. reported a female patient with hemophilia with an FXII deficiency who had an extremely inactivated normal X chromosome [33]. The exact prevalence of Hageman factor deficiency is not known because patients are normally asymptomatic. Hageman factor deficiency is usually detected by chance in coagulation assay results that isolated prolonged APTT or unexplained coagulation disease [32, 34].\n\nFXII plays an important role in the coagulation system. FXII respectively drives the contact system to initiate coagulation and inflammation through the intrinsic coagulation pathway and the bradykinin-producing kallikrein-kinin system [35]. Humans and animals with low FXII activity have a normal hemostatic ability, but animal models show that FXII is involved in the thrombotic process [36]. FXII was associated with thromboembolic complications, but it was only rarely associated with severe hemorrhagic disease [32].\n\nFXII activity is generally lower in Asians. Deficiency of FXII is an autosomal recessive disorder, but few cases have been reported. Alleles in homozygotes or complex heterozygotes are associated with very low FXII activity (< 1%) compared to unaffected individuals [34]. The autosomal recessive genetic diseases can be prevented by avoiding intermarriage, which requires counselling and education [32]. The average FXII activity depends on the race of the person. One study showed that 95% of healthy Chinese subjects had FXII activity between 47 and 160.25%, and identified some mutations associated with low FXII activity [34].\n\nIn addition, results of the coagulation assays are highly age-dependent and must be used to ensure the correct evaluation of coagulation assays in children, especially in the first year of life [37]. For newborns, coagulation factors are already low and gradually increase to adult levels after 6 months [38–40]. On the whole, the low FXII:C in hemophilia A is related to race and age, which is determined by chromosomal and genetic testing.\n\nUnfortunately, the newborn described in this report had a family history of hemophilia A, and the child’s mother did not receive a prenatal genetic diagnosis, nor did she agree to have the child tested for inhibitors and genetic mutations as soon as possible after birth. In one study, Chen et al. developed a noninvasive prenatal diagnosis (NIPD) method for Hemophilia A by sequencing a small target region [41]. A genetic diagnosis can help couples at risk of hemophilia reduce their anxiety about childbirth. The obstetrician must discuss the birth plan with the expectant mother [5]. Hemophilia A is diagnosed by informational gene tracking and/or measurement of fetal FVIII: C level [42]. Determination of a woman’s genetic and phenotypic status before pregnancy is optimal so that she can understand her options and the requirements for a safe delivery [43–45].\n\nIn conclusion, this paper presents the case of a newborn with severe neonatal congenital hemophilia A with FXII deficiency. This case highlights the importance of FVIII inhibitors, serum recombinant FVIII concentration and testing in hemophilia A. Prophylaxis treatment is an effective option for decreasing the frequency of bleeding and improving quality of life. We suggest that expectant mothers identified as congenital hemophilia A gene carriers test their fetuses for the FVIII or FXII activity levels and that newborns undergo genetic testing as soon as possible after birth to assess for the risk of the disease.\n\nAbbreviations\n\nFVIII Factor VIII\n\nICH Intracranial hemorrhage\n\naPCC Activated Prothrombin complex concentrate\n\nrFVIIa Recombinant activating factor VII\n\nFVIII:C FVIII activity\n\nFXII Factor XII\n\nFXII:C FXII activity\n\nVWF Von Willebrand factor\n\nCR Complete remission\n\nCL Weight-adjusted clearance\n\nPEG Polyethylene glycol\n\nAPTT Activated partial thromboplastin time\n\nPT Prothrombin time\n\nFXIIa Free factor XIIa\n\nNIPD Noninvasive prenatal diagnosis\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\n(I) Conception and design: Haiyan Feng; (II) Provision of study materials: All of the authors; (III) Manuscript writing: All of the authors; (IV) All of the authors read and approved the final manuscript.\n\nFunding\n\nThis work was supported by the High-level Hospital Construction Research Project of Maoming People’s Hospital.\n\nAvailability of data and materials\n\nAll of the data presented in this article can be found in our hospital.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nThe neonate’s guardians consented to publication of this case.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nBaoyu Lei and Chuang Liang contributed equally to this work.*Correspondence should be addressed to Haiyan Feng (haiyanfeng90@163.com).\n==== Refs\nReferences\n\n1. 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[Chinese guidelines on the treatment of hemophilia (version 2020)] Zhonghua Xue Ye Xue Za Zhi 2020 41 265 271 32295333\n13. Messori A Peyvandi F Mengato D Mannucci PM Incidence of low-titre factor VIII inhibitors in patients with haemophilia a: meta-analysis of observational studies Haemophilia. 2017 23 2 e87 e92 10.1111/hae.13193 28220685\n14. Hay CRM Brown S Collins PW Keeling DM Liesner R The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre doctors organisation Br J Haematol 2006 133 6 591 605 10.1111/j.1365-2141.2006.06087.x 16704433\n15. Klamroth R A new era of treatment for patients with haemophilia a? Hamostaseologie. 2017 37 3 216 218 10.5482/HAMO-16-07-0028 27885373\n16. Tieu P Chan A Matino D Molecular mechanisms of inhibitor development in hemophilia Mediterr J Hematol Infect Dis 2020 12 1 e2020001 10.4084/mjhid.2020.001 31934311\n17. Peyvandi F Mannucci PM Garagiola I El-Beshlawy A Elalfy M Ramanan V A randomized trial of factor VIII and neutralizing antibodies in hemophilia A N Engl J Med 2016 374 21 2054 2064 10.1056/NEJMoa1516437 27223147\n18. van Velzen AS Eckhardt CL Peters M Leebeek FWG Escuriola-Ettingshausen C Hermans C Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study J Thromb Haemost 2017 15 7 1422 1429 10.1111/jth.13711 28440011\n19. White GC 2nd Rosendaal F Aledort LM Lusher JM Rothschild C Ingerslev J Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the international society on thrombosis and Haemostasis Thromb Haemost 2001 85 560 10.1055/s-0037-1615621 11307831\n20. Pinto P Shetty S Lacroix-Desmazes S Bayry J Kaveri S Ghosh K Antibody profile in Indian severe haemophilia a patients with and without FVIII inhibitors Immunol Lett 2016 169 93 97 10.1016/j.imlet.2015.09.013 26433059\n21. Lusher JM Arkin S Abildgaard CF Schwartz RS Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. safety, efficacy, and development of inhibitors. Kogenate previously untreated patient study group N Engl J Med 1993 328 7 453 459 10.1056/NEJM199302183280701 8421474\n22. DiMichele DM Hoots WK Pipe SW Rivard GE Santagostino E International workshop on immune tolerance induction: consensus recommendations Haemophilia 2007 13 Suppl 1 1 22 10.1111/j.1365-2516.2007.01497.x 17593277\n23. Hay CRM DiMichele DM International Immune Tolerance S. The principal results of the International Immune Tolerance Study: a randomized dose comparison Blood 2012 119 6 1335 1344 10.1182/blood-2011-08-369132 22101900\n24. Collins PW Fischer K Morfini M Blanchette VS Bjorkman S International prophylaxis study group pharmacokinetics expert working G Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia Haemophilia 2011 17 1 2 10 10.1111/j.1365-2516.2010.02370.x 20731726\n25. Mancuso ME, Mannucci PM. Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias. Drug Des Devel Ther. 2014;8:365–71.\n26. Tiede A Half-life extended factor VIII for the treatment of hemophilia A J Thromb Haemost 2015 13 S176 SS79 10.1111/jth.12929 26149020\n27. Bjorkman S Blanchette VS Fischer K Oh M Spotts G Schroth P Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring J Thromb Haemost 2010 8 4 730 736 10.1111/j.1538-7836.2010.03757.x 20398185\n28. Mannucci PM Benefits and limitations of extended plasma half-life factor VIII products in hemophilia A Expert Opin Investig Drugs 2020 29 3 1 7 10.1080/13543784.2020.1723547\n29. Mahlangu J Young G Hermans C Blanchette V Berntorp E Santagostino E Defining extended half-life rFVIII-A critical review of the evidence Haemophilia 2018 24 3 348 358 10.1111/hae.13438 29633467\n30. van den Besselaar AM Haas FJ Kuypers AW Harmonisation of factor VIII:C assay results: study within the framework of the Dutch project 'Calibration 2000′ Br J Haematol 2006 132 1 75 79 10.1111/j.1365-2141.2005.05829.x 16371022\n31. Vorlova S Koch M Manthey HD Cochain C Busch M Chaudhari SM Stegner D Yepes M Lorenz K Nolte MW Nieswandt B Zernecke A Coagulation factor XII induces pro-inflammatory cytokine responses in macrophages and promotes atherosclerosis in mice Thromb Haemost 2017 117 1 176 187 10.1160/TH16-06-0466 27786338\n32. Chaudhry LA El-Sadek WYM Chaudhry GA Al-Atawi FE Factor XII (Hageman factor) deficiency: a rare harbinger of life threatening complications Pan Afr Med J 2019 33 39 10.11604/pamj.2019.33.39.18117 31384354\n33. Matsushita T Takamatsu J Kagami K Takahashi I Sugiura I Hamaguchi M Kamiya T Saito H A female hemophilia a combined with hereditary coagulation factor XII deficiency: a case report Am J Hematol 1992 39 2 137 141 10.1002/ajh.2830390212 1550105\n34. Han Y Zhu T Jiao L Hua B Cai H Zhao Y Normal range and genetic analysis of coagulation factor XII in the general Chinese population Thromb Res 2015 136 2 440 444 10.1016/j.thromres.2015.06.012 26105808\n35. Maas C Renne T Coagulation factor XII in thrombosis and inflammation Blood. 2018 131 17 1903 1909 10.1182/blood-2017-04-569111 29483100\n36. Nickel KF Long AT Fuchs TA Butler LM Renne T Factor XII as a therapeutic target in thromboembolic and inflammatory diseases Arterioscler Thromb Vasc Biol 2017 37 1 13 20 10.1161/ATVBAHA.116.308595 27834692\n37. Liu J Dai Y Yuan E Li Y Wang Q Wang L Su Y Paediatric reference intervals for common coagulation assays in Chinese children as performed on the STA-R coagulation analyzer Int J Lab Hematol 2019 41 5 697 701 10.1111/ijlh.13098 31424160\n38. Andrew M Paes B Milner R Johnston M Mitchell L Tollefsen DM Powers P Development of the human coagulation system in the full-term infant Blood. 1987 70 1 165 172 10.1182/blood.V70.1.165.165 3593964\n39. Andrew M Paes B Milner R Johnston M Mitchell L Tollefsen DM Castle V Powers P Development of the human coagulation system in the healthy premature infant Blood. 1988 72 5 1651 1657 10.1182/blood.V72.5.1651.1651 3179444\n40. Toulon P Berruyer M Brionne-François M Grand F Lasne D Telion C Arcizet J Giacomello R de Pooter N Age dependency for coagulation parameters in paediatric populations. Results of a multicentre study aimed at defining the age-specific reference ranges Thromb Haemost 2016 116 1 9 16 10.1160/TH15-12-0964 26988943\n41. Chen C, Sun J, Yang Y, Jiang L, Guo F, Zhu Y, et al. Noninvasive prenatal diagnosis of hemophilia A by a haplotype-based approach using cell-free fetal DNA. Biotechniques. 2020. 10.2144/btn-019-0113.\n42. Sasanakul W Chuansumrit A Ajjimakorn S Krasaesub S Sirachainan N Chotsupakarn S Kadegasem P Rurgkhum S Cost-effectiveness in establishing hemophilia carrier detection and prenatal diagnosis services in a developing country with limited health resources Southeast Asian J Trop Med Public Health 2003 34 4 891 898 15115107\n43. Street AM Ljung R Lavery SA Management of carriers and babies with haemophilia Haemophilia 2008 14 Suppl 3 181 187 10.1111/j.1365-2516.2008.01721.x 18510540\n44. Lavery S Preimplantation genetic diagnosis of haemophilia Br J Haematol 2009 144 3 303 307 10.1111/j.1365-2141.2008.07391.x 19036080\n45. Tizzano EF Barcelo MJ Baena M Cornet M Vencesla A Mateo J Rapid identification of female haemophilia a carriers with deletions in the factor VIII gene by quantitative real-time PCR analysis Thromb Haemost 2005 94 3 661 664 10.1160/TH05-03-0144 16268486\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1720-8424",
"issue": "47(1)",
"journal": "Italian journal of pediatrics",
"keywords": "Congenital hemophilia A; Factor VIII; Factor XII; Inhibitor; Neonate",
"medline_ta": "Ital J Pediatr",
"mesh_terms": null,
"nlm_unique_id": "101510759",
"other_id": null,
"pages": "204",
"pmc": null,
"pmid": "34635150",
"pubdate": "2021-10-11",
"publication_types": "D016428:Journal Article",
"references": "31384354;24729686;17593277;3179444;27223147;11307831;15115107;27562315;31424160;31996009;25059285;24893572;31990229;11396445;27885373;22776238;28440011;1550105;28220685;22101900;31994162;28793786;31934311;20731726;18510540;27786338;27125646;16704433;19036080;26433059;26149020;26105808;27487799;32295333;26988943;27834692;29483100;32020842;20398185;3593964;26582077;29633467;16268486;8421474;16371022",
"title": "Congenital hemophilia A with low activity of factor XII: a case report and literature review.",
"title_normalized": "congenital hemophilia a with low activity of factor xii a case report and literature review"
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"abstract": "BACKGROUND\nOwing to the technical difficulty of pathological diagnosis, imaging is still the most commonly used method for clinical diagnosis of para-aortic lymph node metastasis (PALM) and evaluation of therapeutic effects in gastric cancer, which leads to inevitable false-positive findings in imaging. Patients with clinical PALM may have entirely different pathological stages (stage IV or not), which require completely different treatment strategies. There is no consensus on whether surgical intervention should be implemented for this group of patients. In particular, the value of D2 gastrectomy in a multidisciplinary treatment (MDT) approach for advanced gastric cancer with clinical PALM remains unknown.\n\n\nOBJECTIVE\nTo investigate the value of D2 gastrectomy in a MDT approach for gastric cancer patients with clinical PALM.\n\n\nMETHODS\nIn this real-world study, clinico-pathological data of all gastric cancer patients treated at the Cancer Hospital, Chinese Academy of Medical Sciences between 2011 and 2016 were reviewed to identify those with clinically enlarged PALM. All the clinico-pathological data were prospectively documented in the patient medical record. For all the gastric cancer patients with advanced stage disease, especially those with suspicious distant metastasis, the treatment methods were determined by a multidisciplinary team.\n\n\nRESULTS\nIn total, 48 of 7077 primary gastric cancer patients were diagnosed as having clinical PALM without other distant metastases. All 48 patients received chemotherapy as the initial treatment. Complete or partial response was observed in 39.6% (19/48) of patients in overall and 52.1% (25/48) of patients in the primary tumor. Complete response of PALM was observed in 50.0% (24/48) of patients. After chemotherapy, 45.8% (22/48) of patients received D2 gastrectomy, and 12.5% (6/48) of patients received additional radiotherapy. The postoperative major complication rate and mortality were 27.3% (6/22) and 4.5% (1/22), respectively. The median overall survival and progression-free survival of all the patients were 18.9 and 12.1 mo, respectively. The median overall survival of patients who underwent surgical resection or not was 50.7 and 12.8 mo, respectively. The 3-year and 5-year survival rates were 56.8% and 47.3%, respectively, for patients who underwent D2 resection. Limited PALM and complete response of PALM after chemotherapy were identified as favorable factors for D2 gastrectomy.\n\n\nCONCLUSIONS\nFor gastric cancer patients with radiologically suspicious PALM that responds well to chemotherapy, D2 gastrectomy could be a safe and effective treatment and should be adopted in a MDT approach for gastric cancer with clinical PALM.",
"affiliations": "Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.;Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.;Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.;Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.;Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.;Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. yibinxie_2003@163.com.",
"authors": "Zheng|Xiao-Hao|XH|;Zhang|Wen|W|;Yang|Lin|L|;Du|Chun-Xia|CX|;Li|Ning|N|;Xing|Gu-Sheng|GS|;Tian|Yan-Tao|YT|;Xie|Yi-Bin|YB|",
"chemical_list": null,
"country": "United States",
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"doi": "10.3748/wjg.v25.i19.2338",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v25.i19.pg233810.3748/wjg.v25.i19.2338Retrospective StudyRole of D2 gastrectomy in gastric cancer with clinical para-aortic lymph node metastasis Zheng Xiao-Hao Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaZhang Wen Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaYang Lin Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaDu Chun-Xia Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaLi Ning Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaXing Gu-Sheng Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaTian Yan-Tao Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaXie Yi-Bin Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. yibinxie_2003@163.comAuthor contributions: All authors helped to perform the research; Zheng XH and Xie YB contributed to study conception and design as well as manuscript writing; Zheng XH and Xing GS contributed to data collection; Zheng XH contributed to data analysis; Zheng XH, Zhang W, Yang L, Du CX, Li N, Tian YT, and Xie YB contributed to performing the treatment.\n\nSupported by the CAMS Initiative for Innovative Medicine, No. 2016-I2M-1-007.\n\nCorresponding author: Yi-Bin Xie, MD, Professor, Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuannanli, Chaoyang District, Beijing 10021, China. yibinxie_2003@163.com\n\nTelephone: +86-10-8778712\n\n21 5 2019 21 5 2019 25 19 2338 2353 14 3 2019 17 4 2019 29 4 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.2019This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nOwing to the technical difficulty of pathological diagnosis, imaging is still the most commonly used method for clinical diagnosis of para-aortic lymph node metastasis (PALM) and evaluation of therapeutic effects in gastric cancer, which leads to inevitable false-positive findings in imaging. Patients with clinical PALM may have entirely different pathological stages (stage IV or not), which require completely different treatment strategies. There is no consensus on whether surgical intervention should be implemented for this group of patients. In particular, the value of D2 gastrectomy in a multidisciplinary treatment (MDT) approach for advanced gastric cancer with clinical PALM remains unknown.\n\nAIM\nTo investigate the value of D2 gastrectomy in a MDT approach for gastric cancer patients with clinical PALM.\n\nMETHODS\nIn this real-world study, clinico-pathological data of all gastric cancer patients treated at the Cancer Hospital, Chinese Academy of Medical Sciences between 2011 and 2016 were reviewed to identify those with clinically enlarged PALM. All the clinico-pathological data were prospectively documented in the patient medical record. For all the gastric cancer patients with advanced stage disease, especially those with suspicious distant metastasis, the treatment methods were determined by a multidisciplinary team.\n\nRESULTS\nIn total, 48 of 7077 primary gastric cancer patients were diagnosed as having clinical PALM without other distant metastases. All 48 patients received chemotherapy as the initial treatment. Complete or partial response was observed in 39.6% (19/48) of patients in overall and 52.1% (25/48) of patients in the primary tumor. Complete response of PALM was observed in 50.0% (24/48) of patients. After chemotherapy, 45.8% (22/48) of patients received D2 gastrectomy, and 12.5% (6/48) of patients received additional radiotherapy. The postoperative major complication rate and mortality were 27.3% (6/22) and 4.5% (1/22), respectively. The median overall survival and progression-free survival of all the patients were 18.9 and 12.1 mo, respectively. The median overall survival of patients who underwent surgical resection or not was 50.7 and 12.8 mo, respectively. The 3-year and 5-year survival rates were 56.8% and 47.3%, respectively, for patients who underwent D2 resection. Limited PALM and complete response of PALM after chemotherapy were identified as favorable factors for D2 gastrectomy.\n\nCONCLUSION\nFor gastric cancer patients with radiologically suspicious PALM that responds well to chemotherapy, D2 gastrectomy could be a safe and effective treatment and should be adopted in a MDT approach for gastric cancer with clinical PALM.\n\nGastric cancerPara-aortic lymph nodeMultidisciplinaryGastrectomyConversionNeoadjuvant\n==== Body\nCore tip: The value of surgical resection in gastric cancer with radiologically overt para-aortic lymph node metastasis (PALM) is still not clear. Current controversial issues include the extent of resection (D1, D2, D2 + para-aortic lymph node metastasis dissection, or D3), surgical timing, and identification of optimal surgical candidates. This study confirmed the benefit of D2 gastrectomy after chemotherapy in select patients. Limited PALM at baseline and complete response of PALM after chemotherapy were proposed as criteria for selecting patients who will potentially benefit from D2 gastrectomy, which should be useful for future clinical trials.\n\nINTRODUCTION\nGastric cancer is the fifth most common cancer and the third leading cause of mortality among all cancers worldwide. Gastric cancer with para-aortic lymph node metastasis (PALM) is considered a metastatic disease, and its prognosis remains poor after isolated surgical treatment. However, pathological diagnosis of enlarged para-aortic lymph nodes (PAN) is difficult. Certain methods, such as endoscopic ultrasound, B-ultrasound, or computed tomography (CT) guided fine needle aspiration, are theoretically feasible for pathological diagnosis of suspicious PALM. PAN biopsy is an invasive and technically difficult manipulation and thus is not typically used for clinical diagnosis of PALM in most institutes. In addition, positive lymph nodes will disappear or shrink after preoperative treatment, which makes it difficult to re-biopsy the original nodes during follow-up. Despite the inevitable false-positive findings, imaging is still the most commonly used noninvasive method for clinical diagnosis of PALM and preoperative evaluation of therapeutic effects.\n\nHowever, due to the fact that suspicious lymph node enlargement can be the result of inflammatory lymphadenopathy or malignancy, patients with radiologically overt PALM may have entirely different pathological stages (stage IV or not), which will require completely different treatment strategies. And the best clinical practice for patients with clinical PALM remains controversial for over ten years. Early this century, Sasako et al[1] conducted prophylactic D3 resection in advanced stage gastric cancer patients without radiologically overt PALM, and according to their results published in 2008, extended resection is not necessary. At the same time, through retrospective studies, other researchers have shown that D2 gastrectomy plus para-aortic lymph node dissection (PAND) might result in satisfactory outcomes in a highly select group of patients with PAN enlargement. Results reported by Tokunaga et al[2] and Roviello et al[3] in 2010 further complicate this issue. Both studies showed that even after extended D3 resection, the 5-year survival rates of patients with pathologically positive PAN were as low as 13.0% and 17.0%, respectively, not to mention the extremely high complication rate. Moreover, the phase III clinical trial REGATTA, in which patients with clinical PALM were enrolled, showed that chemotherapy alone was better than D1 gastrectomy followed by chemotherapy[4]. The above studies indicate that D1, D2 plus PAND, or D3 with adjuvant chemotherapy all failed to prolong the survival of patients with pathological PALM.\n\nRecently, as preoperative chemotherapy was adopted into studies, Japanese oncologists reported an encouraging 5-year survival rate of 53% in gastric cancer with PALM treated by D2 gastrectomy with PAND after neoadjuvant chemotherapy. However, developing a safe and standard D2 plus PAND protocol after chemotherapy was challenging, and to date, only a few surgeons worldwide can perform it expertly. In addition, only 10% of patients who underwent D2 plus PAND had a pathologically positive PAN. Therefore, whether their method is the best solution for radiologically evident PALM is up for debate. Wang et al[5] considered patients with a good response to chemotherapy and PAN shrinkage to < 1.0 cm for D2 gastrectomy without PAND, and the surgery group had a non-inferior outcome compared with the Japanese results. More recently, several small studies have also reported improved survival through resection without metastasectomy after conversional chemotherapy. These results indicate that extensive resection might not be the only way to improve prognosis and D2 gastrectomy can provide a choice for select patients[6,7].\n\nIn our center, management of suspicious stage IV gastric cancer is determined by a multidisciplinary team. After conversional chemotherapy, the subsequent treatment method for patients with enlarged PAN prior to treatment is decided according to the response to chemotherapy. However, D3 or D2 resection plus PAND is not routinely recommended due to high morbidity and mortality. For those with enlarged PALM that cannot be controlled by chemotherapy, additional radiotherapy is recommended. In this study, we sought to determine the value of D2 gastrectomy in a multidisciplinary treatment approach for patients with clinical PALM based on data from this single center.\n\nMATERIALS AND METHODS\nPatients\nIn total, 7077 patients were diagnosed with gastric adenocarcinoma at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2011 to December 2016. We searched the clinico-pathological database for primary gastric adenocarcinoma patients with suspiciously enlarged lymph nodes in the para-aortic region documented in medical records prospectively. The inclusion criteria for this study were as follows: pathologically confirmed gastric adenocarcinoma with PAN enlargement; clinical T3-4 disease; no evidence of concurrent metastasis other than that in PAN, including distant hematogenous metastasis, distant lymph node metastasis, peritoneal metastasis and so on; esophageal invasion less than 3 cm; ECOG performance status of 0 or 1; sufficient oral intake and adequate organ function according to records at first visit; no previous malignancies; and pathologically confirmed HER2-negative gastric adenocarcinoma. In addition, patients who underwent reduction surgery or had positive lavage cytology were excluded, while palliative surgery to address severe uncontrollable complications during chemotherapy was allowed. This retrospective study was approved by the Ethics Committee of Cancer Institute and Hospital, Chinese Academy of Medical Sciences, and the need for informed consent was waived.\n\nBaseline evaluation\nContrast-enhanced thoracic/abdominal/pelvic CT, upper gastrointestinal tract endoscopy, and endoscopic ultrasonography (EUS) with or without positron emission tomography and CT (PET-CT) were conducted as the pretreatment workup. Both the clinical tumor stage (cT) and the clinical nodal stage (cN) were diagnosed via EUS and enhanced CT. Classification of TNM stage was defined according to the 8th edition of the American Joint Committee on Cancer Staging Manual. The clinical stage was evaluated by a multidisciplinary team based on all the radiological results.\n\nThe major criterion for clinical positive nodes on CT and EUS was solitary nodes ≥ 8 mm in minor diameter. The supplementary criteria for clinical PALM on EUS were as follows: echo-poor, roundish, or well-demarcated nodes. The supplementary criteria for clinical PALM on CT were as follows: Marked enhancement in the portal venous phase; cluster nodes regardless of the enhancement pattern; certain metastasis-associated enhancement patterns, such as central necrosis and heterogeneous enhancement; and highly clinically suspicious lymph nodes that did not satisfy the above criteria. The nodal size and anatomic location (station numbers) of all the suspicious lymph nodes were recorded. The lymph node station was classified using the fifteenth edition of the Japanese Classification of Gastric Carcinoma.\n\nChemotherapy and radiotherapy schedule\nThe chemotherapy regimens for this cohort of patients included S-1 plus oxaliplatin (SOX), docetaxel/oxaliplatin/S-1 (DOS), docetaxel/capecitabine/oxaliplatin (DOX), docetaxel/cisplatin/S-1 (DCS), capecitabine and oxaliplatin (XELOX), S-1 monotherapy, paclitaxel monotherapy, 5-fluorouracil (5-FU)/leucovorin (LV)/oxaliplatin (FOLFOX), irinotecan/5-FU/LV/oxaliplatin (FOLFOXIRI), and taxane/oxaliplatin.\n\nPatients began receiving four cycles of adjuvant chemotherapy within 45 d after D2 gastrectomy, under the same regimen used preoperatively. For patients who were not suitable or unwilling to receive surgical resection, chemotherapy was continued. Second-line chemotherapy was administered when disease progression or recurrence was observed. Radiotherapy was not routinely recommended by the multidisciplinary team unless the presence of acute symptoms indicated a need for radiotherapy during chemotherapy or patients had an incomplete response (CR) of PALM after perioperative chemotherapy.\n\nTumor response and toxicity criteria\nAll the enrolled patients were treated with chemotherapy initially and then subjected to CT after every two cycles of chemotherapy for the first six cycles and every 2 mo thereafter. Patients were reevaluated by the multidisciplinary team, and after evaluation, D2 gastrectomy was recommended to patients who had responded well to treatment. Clinical response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and the response of the primary tumor was assessed according to the fifteenth edition of the Japanese Classification of Gastric Carcinoma[8,9]. After chemotherapy, PAN disappearance or shrinkage to < 8 mm on CT was regarded as CR of PALM. Unless otherwise specified, all the diameters in this study refer to the short-axis diameter. The largest PAN was recorded as the index node, and the index nodes in the short axis is recorded as the index diameter. If all the enlarged lymph nodes disappeared in imaging, the index diameter was documented as a default value (5 mm) according to the RECIST 1.1. Two experienced radiologists were asked to evaluate the CT scans to document the overall response, response of the primary tumor, and the metastatic sites. Adverse events were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v 4.0.\n\nFollow-up\nAll the patients were followed via contrast-enhanced thoracic/abdominal/pelvic CT and blood testing every 3 mo for the first 3 years and every 6 mo thereafter.\n\nSurgical procedure\nExploration and lavage cytology examination were carried out to exclude patients with other non-curable factors before gastrectomy. Distal, proximal, or total gastrectomy with D2 dissection was performed based on the tumor location. The PAN were not removed intentionally. The pathological response grading was based on the Mandard tumor grading system (TRG). Tumor staging and dissection range were in accordance with the eighth edition of the AJCC Cancer Staging Manual[10]. Postoperative complications were recorded according to the Clavien-Dindo classification.\n\nStatistical analysis\nThe primary outcome was overall survival (OS, survival time from diagnosis to death from any cause), and the secondary outcome was progression-free survival (PFS, time from diagnosis to disease progression). Categorical data are presented as absolute and relative frequencies calculated using a chi-square test. Differences were determined by a Wilcoxon rank-sum test for non-normally distributed continuous variable (the short axis diameter of lymph nodes). We constructed violin plots of index diameter to analyze the index diameter distribution according to clinical factors. The Kaplan-Meier method was used to generate survival curves. All statistical tests were two-sided, and a P-value less than 0.05 was considered statistically significant. Analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, United States).\n\nRESULTS\nPatient characteristics\nBetween January 2011 and December 2016, 301 of 7077 gastric cancer patients were identified with PALM based on their medical history and were reevaluated by radiologists (Figure 1). A total of 209 patients were excluded because of a lack of concurrent PALM as the single non-curable factor. In addition, 19 patients with incomplete baseline information and 25 patients incompatible with the clinical inclusion criteria were also excluded. Finally, 48 patients with PALM as the single non-curable factor were included in this real-world study (Figure 1). Baseline information is shown in Table 1. The mean age at diagnosis was 57.2 years (range, 27-76 years), and male patients comprised the majority (81.3%). The common characteristics of the patients with radiological PAN enlargement were poor tumor differentiation and late tumor and nodal stage. In addition, major clinico-pathological characteristics were not significantly different between patients receiving or not receiving D2 gastrectomy.\n\nTable 1 Characteristics of the patients at baseline\n\nVariable\t≥ 60 yr old\t< 60 yr old\t\nGender\t\t\t\nMale\t21 (91.3)\t18 (72.0)\t\nFemale\t2 (8.7)\t7 (28.0)\t\nTumor location\t\t\t\nLower\t2 (8.7)\t4 (16.0)\t\nMiddle\t9 (39.1)\t12 (48.0)\t\nUpper\t12 (52.2)\t9 (36.0)\t\nClinical tumor stage\t\t\t\nT4\t22 (95.7)\t23 (92.0)\t\nT3\t1 (4.3)\t2 (8.0)\t\nClinical nodal stage\t\t\t\nN2-3\t18 (78.3)\t21 (84.0)\t\nN0-1\t5 (21.7)\t4 (16.0)\t\nMacroscopic type\t\t\t\n4\t4 (17.4)\t3 (12.0)\t\n1-3 or 5\t19 (82.6)\t22 (88.0)\t\nDifferentiation\t\t\t\nPoorly differentiated\t18 (78.3)\t23 (92.0)\t\nWell differentiated\t5 (21.7)\t2 (8.0)\t\nPerformance status\t\t\t\n0\t6 (26.1)\t11 (44.0)\t\n1\t17 (73.9)\t14 (56.0)\t\nFigure 1 Flow chart. CT: Computed tomography; SOX: S-1 plus oxaliplatin; DOS: Docetaxel/oxaliplatin/S-1; DOX: Docetaxel/capecitabine/oxaliplatin; DCS: Docetaxel/cisplatin/S-1; XELOX: Capecitabine/oxaliplatin; FOLFOX: 5-fluorouracil/leucovorin/oxaliplatin; FOLFOXIRI: Irinotecan/5-fluorouracil/leucovorin/oxaliplatin.\n\nChemotherapy and adverse events\nOf the 48 patients included, 17 were treated with SOX, 8 with DOS, 6 with DOX, 6 with DCS, 4 with XELOX, 2 with FOLFOX, 2 with taxane/oxaliplatin, and 3 with other regimens (S-1, paclitaxel monotherapy, or FOLFOXIRI). Among the 22 patients who underwent D2 gastrectomy after perioperative chemotherapy, 5 received DOS, 4 received SOX, 4 received DCS, 3 received XELOX, 2 received DOX, 2 received taxane/oxaliplatin, 1 received FOLFOX, and 1 received S-1 monotherapy. Following resection, 18 patients received adjuvant chemotherapy using the same regimen that was used preoperatively, and the other 4 patients did not receive adjuvant chemotherapy. Respectively, 6 and 8 patients among the patients who underwent D2 gastrectomy or not received less than six cycles of chemotherapy in total (Figure 1).\n\nAdverse events associated with chemotherapy are listed in Table 2. The most frequent adverse events were anorexia (68.8%) and nausea (68.8%), most of which occurred at grade 1 or 2. Neutropenia was observed, with the most frequent adverse events being grade 3 or higher. One treatment-related death was reported in a patient who died of acute pulmonary embolism during the first cycle of initial chemotherapy.\n\nTable 2 Adverse events of preoperative chemotherapy\n\n\tGrade\tTotal\tGrade ≥ 3 (%)\t\nToxicity\t1\t2\t3\t4\t5\t\nDiarrhea\t4\t2\t2\t0\t0\t8\t4.2\t\nMalaise\t9\t1\t0\t0\t0\t10\t0.0\t\nAnorexia\t22\t10\t1\t0\t0\t33\t2.1\t\nNausea\t20\t11\t2\t0\t0\t33\t4.2\t\nVomiting\t6\t4\t0\t0\t0\t10\t0.0\t\nPeripheral sensory neuropathy\t13\t4\t0\t0\t0\t17\t0.0\t\nRash\t1\t0\t1\t0\t0\t2\t2.1\t\nThromboembolic event\t0\t0\t0\t0\t1\t1\t2.1\t\nAnemia\t11\t2\t3\t0\t0\t16\t6.3\t\nThrombocytopenia\t7\t6\t4\t1\t0\t18\t10.4\t\nLeukopenia\t11\t14\t3\t1\t0\t29\t8.3\t\nNeutropenia\t7\t5\t9\t4\t0\t25\t27.1\t\nFebrile neutropenia\t4\t0\t0\t0\t0\t4\t0.0\t\nLymph node information and response assessment\nDetails related to lymph nodes at the first visit and at the time of best response during chemotherapy are listed in Table 3. The most common PAN station was No. 16b1 in 34 of 48 patients, followed by No. 16a2 (24/48). Overall, 27.1% (13/48) of patients had more than two para-aortic node stations involved. According to the RECIST 1.1 criteria, 26 patients had target lesions at baseline, while the other 22 patients had non-target lesions. The objective overall response rate in this group was 39.6% (19 of 48, Table 3). Response of the primary tumor was observed in 25 (52.1%) patients, and CR of metastatic sites was observed in 24 (50.0%) patients.\n\nTable 3 Lymph node information at baseline and after chemotherapy\n\nVariable\tNo. of patients (%)\t\nAt baseline\nPAN station involved number\t\t\n1-2\t35 (72.9)\t\n3-4\t13 (27.1)\t\nPAN station involved\t\t\nn16a1\t8 (16.7)\t\nn16a2\t24 (50.0)\t\nn16b1\t34 (70.8)\t\nn16b2\t9 (18.8)\t\nClinical response after chemotherapy\t\t\nOverall (RECIST)\t\t\nTarget lesions\t\t\nCR\t2 (4.2)\t\nPR\t16 (33.3)\t\nSD\t6 (12.5)\t\nPD\t2 (4.2)\t\nNon-target lesions only\t\t\nCR\t1 (2.1)\t\nNon-CR/Non-PD\t19 (39.6)\t\nPD\t2 (4.2)\t\nPrimary lesions (JGCA)\t\t\nCR\t3 (6.3)\t\nPR\t22 (45.8)\t\nSD\t19 (39.6)\t\nPD\t4 (8.3)\t\nMetastatic lesions\t\t\nCR\t24 (50.0)\t\nNon-CR\t24 (50.0)\t\nPAN: Para-aortic node; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; NE: Not evaluable; RECIST: Response Evaluation Criteria in Solid Tumors (version 1.1); JGCA: Japanese Gastric Cancer Association.\n\nSurgical decision making\nViolin plots of the distribution of the short axis diameter of the largest PAN distributed by whether the patient underwent D2 resection or not are shown in Figure 2A (baseline) and Figure 2C (after initial chemotherapy). Violin plots of the distribution of the short axis diameter of the largest PAN distributed by whether more than 2 PAN stations were involved or not are shown in Figure 2B (baseline) and Figure 2D (after initial chemotherapy). The distributions in both treatment groups and PAN stations significantly varied at baseline (chemotherapy vs chemotherapy plus D2 gastrectomy, P = 0.01, Figure 2A; PAN stations 1-2 vs 3-4, P = 0.001, Figure 2B) but were not significantly different after chemotherapy (chemotherapy vs chemotherapy plus D2 gastrectomy, P = 0.29, Figure 2C; PAN stations 1-2 vs 3-4, P = 0.06, Figure 2D). The correlation between CR of all clinical PALM and clinical characteristics is displayed in Table 4. The largest PAN in the short axis at baseline (≥15 mm vs < 15 mm), overall response (RECIST), and response of the primary lesion (JGCA) were correlated with CR of PALM. Considering the diameter of the index nodes, a CR was observed in 3 of 12 patients with PAN ≥ 15 mm (25%) and in 10 of 26 patients with PAN ≥ 10 mm (38.5%).\n\nFigure 2 Violin plots of index diameter distribution of all patients. A: Violin plots of index diameter distribution at baseline of patients who underwent D2 resection or not; B: Violin plots of index diameter distribution at baseline of patients with involvement of more than two para-aortic lymph node stations or not; C: Violin plots of index diameter distribution of patients who underwent D2 resection or not after initial chemotherapy; D: Violin plots of index diameter distribution after initial chemotherapy of patients with involvement of more than two para-aortic lymph node stations or not. CA: Chemotherapy alone; C+D2G: Chemotherapy plus D2 gastrectomy; PAN: Para-aortic lymph node.\n\nTable 4 Demographic characteristics and response of para-aortic nodes\n\nVariable\tn\tResponse of PAN\tP-value\tTreatment\tP-value\t\nComplete response\tResidual tumor\tWith D2 resection\tWithout D2 resection\t\nTumor location\t0.5647\t\t\t0.0931\t\nUpper\t21\t10 (41.7)\t11 (45.8)\t\t7 (31.8)\t14 (53.8)\t\t\nMiddle\t21\t12 (50.0)\t9 (37.5)\t\t10 (45.5)\t11 (42.3)\t\t\nLower\t6\t2 (8.3)\t4 (16.7)\t\t5 (22.7)\t1 (3.8)\t\t\nClinical tumor stage\t0.5510\t\t\t0.4545\t\nT3\t3\t2 (8.3)\t1 (4.2)\t\t2 (9.1)\t1 (3.8)\t\t\nT4\t45\t22 (91.7)\t23 (95.8)\t\t20 (90.9)\t25 (96.2)\t\t\nClinical nodal stage\t0.2673\t\t\t0.1640\t\nN0-1\t9\t6 (25.0)\t3 (12.5)\t\t6 (27.3)\t3 (11.5)\t\t\nN2-3\t39\t18 (75.0)\t21 (87.5)\t\t16 (72.7)\t23 (88.5)\t\t\nMacroscopic type\t0.2199\t\t\t0.5158\t\n1-3 or 5\t41\t22 (91.7)\t19 (79.2)\t\t18 (81.8)\t23 (88.5)\t\t\n4\t7\t2 (8.3)\t5 (20.8)\t\t4 (18.2)\t3 (11.5)\t\t\nNo. of PAN stations involved\t0.1044\t\t\t0.0012\t\n1-2\t35\t20 (83.3)\t15 (62.5)\t\t21 (95.5)\t14 (53.8)\t\t\n3-4\t13\t4 (16.7)\t9 (37.5)\t\t1 (4.5)\t12 (46.2)\t\t\nLargest PAN in short-axis\t0.0822\t\t\t0.0899\t\n< 10 mm\t22\t14 (58.3)\t8 (33.3)\t\t13 (59.1)\t9 (34.6)\t\t\n≥ 10 mm\t26\t10 (41.7)\t16 (66.7)\t\t9 (40.9)\t17 (65.4)\t\t\nLargest PAN in short-axis\t0.0455\t\t\t0.0026\t\n< 15 mm\t36\t21 (87.5)\t15 (62.5)\t\t21 (95.5)\t15 (57.7)\t\t\n≥ 15 mm\t12\t3 (12.5)\t9 (37.5)\t\t1 (4.5)\t11 (42.3)\t\t\nOverall (RECIST)\t0.0109\t\t\t0.1405\t\nCR + PR\t19\t10 (41.7)\t9 (37.5)\t\t7 (31.8)\t12 (46.2)\t\t\nSD + PD\t10\t1 (4.2)\t9 (37.5)\t\t3 (13.6)\t7 (26.9)\t\t\nNE\t19\t13 (54.2)\t6 (25.0)\t\t12 (54.5)\t7 (26.9)\t\t\nPrimary lesions (JGCA)\t0.0431\t\t\t0.1405\t\nCR + PR\t25\t16 (66.7)\t9 (37.5)\t\t14 (63.6)\t11 (42.3)\t\t\nSD + PD\t23\t8 (33.3)\t15 (62.5)\t\t8 (36.4)\t15 (57.7)\t\t\nPAN: Para-aortic node; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; NE: Not evaluable; RECIST: Response Evaluation Criteria in Solid Tumors (version 1.1); JGCA: Japanese Gastric Cancer Association.\n\nOf the 24 patients with CR of PALM, only 66.7% (16/24) achieved CR or partial response (PR) in the primary tumor. All 24 patients were recommended to receive surgical resection, and 14 patients with CR of PALM underwent D2 gastrectomy, while 8 patients with well-responded PALM also received D2 gastrectomy at the request of the patient. Among the 22 patients who received D2 gastrectomy, 2 exhibited CR, 5 exhibited PR, 2 exhibited stable disease (SD), 1 exhibited progressive disease (PD), and 12 were not evaluable considering the overall response; 2 exhibited CR, 12 exhibited PR, 7 exhibited SD, and 1 exhibited PD considering the response of the primary tumor. Among patients with an index node larger than 15 mm at the first visit, only 1 of 12 underwent D2 gastrectomy, and among patients with more than two PAN stations involved at baseline, only 1 of 13 underwent D2 gastrectomy.\n\nIn addition, six patients received radiotherapy as recommended by the multidisciplinary team in total. Among them, two patients received preoperative radiotherapy, three received adjuvant radiotherapy, and one received palliative radiotherapy.\n\nSurgical outcomes\nLavage cytology was routinely performed, and positive lavage cytology was considered an incurable factor. Therefore, patients with positive cytology were excluded. For the 22 patients who ultimately underwent D2 gastrectomy, the median number of preoperative chemotherapy cycles was 4 [interquartile range (IQR), 3-5]. The median blood loss was 150 mL (IQR, 100-200 mL), and the median surgery time was 195 min (IQR, 170-214 min). Surgical and pathological data are listed in Table 5. Postoperative complications occurred in 27.3% (6/22) of patients, including abdominal infection (2/22), lymphatic fistula (1/22), pneumonia (1/22), anastomotic leakage (1/22), and sudden cardiac death (1/22). One patient with a history of heart disease died of sudden cardiac death on postoperative day 28. Patients without CR of PALM were regarded as having an R1/R2 resection, and thus, R0 resection was achieved in 63.6% of patients. Three patients presented a pathological CR, and the pathological response rate was 68.2%.\n\nTable 5 Surgical and pathological findings\n\nVariable\tChemotherapy plus surgery\t\nResidual tumor\t\t\nR0\t14 (63.6)\t\nR1-R2\t8 (36.4)\t\nSurgery approach\t\t\nLaparoscopy\t8 (36.4)\t\nOpen\t14 (63.6)\t\nExtent of gastric resection\t\t\nDistal\t11 (50.0)\t\nProximal\t3 (13.6)\t\nTotal\t7 (31.8)\t\nMultiple organ resection\t1 (4.5)\t\nMacroscopic type\t\t\n1-3 or 5\t18 (81.8)\t\n4\t4 (18.2)\t\nHistological type\t\t\nIntestinal or mixed\t11 (50.0)\t\nDiffuse\t11 (50.0)\t\nMandard grade\t\t\n1-2\t2 (9.1)\t\n3\t13 (59.1)\t\n4-5\t7 (31.8)\t\nTumor depth\t\t\nypT0\t2 (9.1)\t\nypT1a\t1 (4.5)\t\nypT1b\t1 (4.5)\t\nypT2\t1 (4.5)\t\nypT3\t6 (27.3)\t\nypT4a\t10 (45.5)\t\nypT4b\t1 (4.5)\t\nLymph node metastases\t\t\nypN0\t7 (31.8)\t\nypN1\t5 (22.7)\t\nypN2\t2 (9.1)\t\nypN3a\t5 (22.7)\t\nypN3b\t3 (13.6)\t\nSurvival\nOverall, 9 patients experienced recurrence after surgery during the follow-up period, with 7 patients experiencing recurrence within 1 year. The progressive sites included four cases of PAN recurrence, one case of hepatic metastasis, one case of peritoneal metastasis, and one case of malignant ascites. Two patients relapsed after 1 year, including one with lung recurrence and one with mediastinal lymph node metastasis. Distant lymph node metastasis was the most common site of recurrence and occurred in 55.6% (5/9) of cases.\n\nSurvival plots are presented in Figure 3. The median follow-up period was 16.2 months (range, 2.8-72.4 mo). The 3-year OS rate for all patients was 36.9% [95% confidence interval (CI): 21.2-52.6], the 3-year PFS rate of all patients was 27.6% (95%CI: 13.5-41.6), and the median OS and PFS were 18.9 and 12.1 mo, respectively (Figure 3A). The survival time of those who received D2 gastrectomy was much longer than that of patients who did not undergo gastrectomy (median OS: 50.7 mo vs 12.8 mo, P = 0.0003, Figure 3B; median PFS: 27.4 mo vs 7.8 mo, P = 0.0002, Figure 3C; 3-year survival rate: 56.8% (95%CI: 33.2-80.4) vs 19.0% (95%CI: 0.02-35.9)). The 5-year survival rate for the D2 gastrectomy patients reached 47.3% (95%CI: 21.4-73.3). The survival difference according to overall response was not significant (Figure 4D). However, according to the response of the primary tumor, the median OS of patients who responded well was significantly better than that of those who responded poorly (50.7 mo vs 11.5 mo, P < 0.0001, Figure 3E), and according to the response of PALM, the median OS of patients with CR of PALM was much better than that of patients without CR of PALM (50.7 mo vs 14.0 mo, P = 0.0051, Figure 3F). Differences in survival according to the index diameter (≥ 15 mm vs < 15 mm) and the stations involved (total PAN stations involved: > 2 vs 1-2) at baseline and the pathological response (Mandard TRG: 1-3 vs 4-5) were not significant in univariate analyses (data not shown).\n\nFigure 3 Kaplan-Meier curves for survival of the gastric cancer patients with clinically positive para-aortic node metastasis. A: Overall survival and progression-free survival of all patients; B: Overall survival of patients who underwent chemotherapy with or without D2 resection; C: Progression-free survival of patients who underwent chemotherapy with or without D2 resection; D: Overall survival of all patients assessed by overall response; E: Overall survival of all patients assessed by chemotherapy response of the primary tumor; F: Overall survival of all patients assessed by chemotherapy response of the metastatic para-aortic lymph node. CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; NE: Not evaluable.\n\nFigure 4 Computed tomography images of a gastric cancer patient with clinically positive para-aortic node metastasis who has survived for more than 70.1 mo. A: At baseline; B: Incomplete response of para-aortic lymph nodes after two cycles of preoperative chemotherapy (1.5 mo after initial treatment); C: After D2 gastrectomy (2.2 mo after initial treatment); D: Follow-up after adjuvant chemoradiotherapy (70.1 months after initial treatment).\n\nData of patients who survived more than 3 years are listed in Table 6. Among them, two underwent chemotherapy alone, while the other six received interventions via D2 gastrectomy. The surgical groups were characterized as having non-target PAN (short diameter < 15 mm), no more than two PAN stations involved at baseline, and CR of PALM after chemotherapy (range, 2-11 cycles) with or without the aid of radiotherapy (Table 6). One patient underwent D2 gastrectomy with an 11 mm left PAN (R1 resection) and received adjuvant radiotherapy to control the enlarged PAN. As a result, the suspicious PAN diminished dramatically, and the patient has been alive for 68 months after surgery without recurrence (Figure 4).\n\nTable 6 Long-term survivors (more than 3 years)\n\nTherapy\tPAN\t\tResponse\t\tSurvival\t\n\tTarget\tSN\t\tOverall\tPrimary\tPAN\t\tSR\tOS\tPFS\tStatus\t\nC+S+C\tNT\t1\t\tNE\tPR\tCR\t\t\t65.1\t65.1\tAlive\t\nC+S+C\tNT\t1\t\tPR\tPR\tCR\t\t\t72.4\t72.4\tAlive\t\nC+S+C\tNT\t1\t\tNE\tPR\tCR\t\t\t62.1\t62.1\tAlive\t\nC+S+C\tNT\t2\t\tCR\tCR\tCR\t\tL\t52.8\t16.8\tAlive\t\nC+S+CRT\tNT\t2\t\tNE\tSD\tNN\t\t\t70.1\t70.1\tAlive\t\nC+S+CRT\tNT\t2\t\tPR\tPR\tCR\t\tPAN\t50.7\t16.2\tDead\t\nC\tT\t3\t\tCR\tCR\tCR\t\tNA\t37.8\t20.9\tAlive\t\nC\tT\t3\t\tPR\tPR\tNN\t\tNA\t36.3\t36.3\tAlive\t\nC: Chemotherapy; S: D2 gastrectomy; CRT: Chemoradiotherapy; PAN: Para-aortic node; NT: Non-target lesions; SN: Para-aortic node station involved number; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; NE: Not evaluable; NC: Non-complete response; SR: Sites of recurrence; L: Lung; OS: Overall survival; PFS: Progression-free survival.\n\nDISCUSSION\nChemotherapy is considered the primary choice for treatment of stage IV gastric cancer, but the prognosis remains poor. Surgery is not routinely recommended, except for palliative reasons. Under some conditions, treatment of clinical stage IV gastric cancer with a single incurable factor, such as PALM, positive lavage cytology, and sole liver metastasis, can be controversial. Unlike other incurable factors, PAN lesions are difficult for a biopsy, and the diagnosis and follow-up primarily depend on CT or PET-CT scanning. Thus, there is confusion concerning clinico-pathological issues in gastric cancer with suspicious PALM.\n\nCurrently, except PET-CT, clinical PALM is primarily diagnosed based on the enlarged diameter in the short axis of PAN[8,9]. In previously published studies, different enrollment criteria and distribution bias have compromised the comparability of results[11-15]. Although the current criteria for clinically positive lymph nodes on imaging examination, such as CT or EUS, are mainly based on lymph node measurement in the short axis[16-20], the cut-off value varies dramatically across different studies[12,21]. In this study, we selected a minimal axial diameter of 8 mm or greater as the main criterion for diagnosis of clinical lymph node metastasis, which is widely accepted in several studies and has shown a sensitivity and specificity of up to 85% and 95%, respectively[13-15,22]. In addition, the diameter of index nodes (equal to the largest clinically positive lymph nodes) was used to help us determine clinically positive PALM during treatment, because a change in the short diameter has been shown to be significantly correlated with pathological outcomes[23].\n\nThe incidence of metastases in the PAN was found to be only 8.5% in the JCOG 9501 trial, and thus, for the majority of gastric cancer patients without radiologically positive PALM, curative D2 surgery is adequate[1]. However, whether this method is suitable for patients with CR of PALM after chemotherapy remains unknown. In the present study, we defined PALM disappearance or shrinkage to < 8 mm in the short axis as clinical CR. Moreover, the survival of patients with clinical CR of PALM exhibited better survival than patients with positive PALM after chemotherapy. These results confirmed that CR of PALM was associated with a good prognosis and was a favorable factor for D2 resection. In addition, according to our results, a short axis < 8 mm can be chosen as the cut-off value for clinically negative PAN after che-motherapy, which is a stricter criterion than that in previous studies[5,8].\n\nCurrent response evaluation criteria also lead to difficulties in response evaluation of gastric cancer patients with isolated PALM. In this study, 26 advanced gastric cancer patients with isolated PALM were absent from the classification of target lesions in RECIST 1.1, which regards primary tumors and lymph nodes < 15 mm as non-measurable[8]. After chemotherapy, 19 patients were considered inevaluable leading to a response rate of only 39.6%. We further analyzed the response by stratifying the primary tumor and PALM separately. The response of primary tumor was evaluated based on the 15th edition of the Japanese Classification of Gastric Carcinoma. While for PALM, we considered lymph node disappearance or shrinkage to < 8 mm as clinical CR after chemotherapy. Under the adjusted response evaluation system, we found that a good response of the primary tumor or CR of PALM was significantly correlated with better survival (Figure 3E and F).\n\nWhether surgical resection is needed for stage IV gastric cancer remains controversial. PALM is classified as a relatively early type in stage IV gastric cancer, is associated with a lower tumor burden than other organ and peritoneal metastases[24], and could be considered as the most suitable type for surgery among all the types of stage IV gastric cancer[25,26]. In this group, the long-term OS of those who underwent D2 resection was much better than that of those who did not. The main reason was attributed to R0 resection and the difference in response to chemotherapy. Patients with a lower tumor burden or incurability de novo, which was characterized as a smaller tumor size, fewer metastatic lymph nodes, or fewer metastatic lymph node stations in gastric cancer with clinical PALM, are more prone to achieve CR of metastasis (Table 4); therefore, D2 gastrectomy was performed, resulting in a better prognosis. Kaito et al[27] found that involvement of a greater number of PAN stations was associated with a poorer prognosis. To date, most studies on surgical interventions in gastric cancer with clinical PALM have been limited to no more than two PAN stations (No. 16a2/16b1)[2,5,24,27-33]. Lymph node size was also found to be an independent prognostic factor for gastric cancer[21]. In the present study, we found that 58.3% (21/36) of patients with an index diameter less than 15 mm achieved CR after chemotherapy and then received surgical resection. We found confounding factors in both the station number and baseline lymph node size. Although patients with a higher metastatic burden, characterized as having a greater number of PAN stations involved and larger PAN size, did not show a significant impact on OS, they showed fewer chances of CR of PALM and fewer surgical decision made by the multidisciplinary team.\n\nThe extent of lymph node resection has long been a debated question. Japanese researchers tend to perform D2 resection plus PAND for advanced stage gastric cancer with overt PALM after chemotherapy; however, their results were not significantly better than those of the study that chose D2 gastrectomy. Many retrospective studies have reported a clinical benefit of curative D2 gastrectomy for patients with stage IV gastric cancer, who exhibited a CR of distant metastasis after chemotherapy without extensive resection[28,34,35].\n\nWe chose D2 resection as the surgical method for three reasons. First, no more than 10% of patients have radiologically occult metastasis in the para-aortic region, which indicates that D2 resection is adequate for most patients. Meanwhile, the most common recurrence site is para-aortic region even after PAND [27,30]. In this study, patients who underwent D2 surgery had a 22.7% lymph node recurrence rate, which is comparable to the 24.6%-30.0% lymph node recurrence rate of patients who underwent D2 gastrectomy plus PAND in previous studies. More importantly, the prognosis of pathologically positive patients was poor, therefore we did not think that PAND was necessary. Second, D3 or D2 plus PAND after chemotherapy has not been fully demonstrated in clinical studies, and is accompanied by a higher rate of morbidity and mortality even in the Japanese studies. Only a few gastrointestinal surgeons worldwide are experts at this complicated procedure[36-39]. Finally, with the development of radiotherapy, new techniques can provide excellent local control rates to limit lymph node metastasis.\n\nA similar phase II study conducted by Wang et al[5] also chose D2 resection as the surgical method and achieved an encouraging 1-year PFS rate of 47.8%, indicating non-inferior survival compared with neoadjuvant therapy plus extended dissection[31]. However, in our real-world study, the survival outcome was much more aggressive. The 3- and 5-year survival rates for patients who underwent D2 resection were 56.8% and 47.3%, respectively. In this study, the chemotherapy regimens and the compliance of perioperative chemotherapy varied. We think that the individualized chemotherapy regimens and the necessary radiotherapy targeted to each individual also contributed to the remarkable survival outcomes. In contrast, in some clinical trials, it is compulsory for patients to receive two or four cycles of chemotherapy regardless of whether it is the best timing[31,33,40,41].\n\nARTICLE HIGHLIGHTS\nResearch background\nPara-aortic lymph node metastasis (PALM) is classified as stage IV gastric cancer with a dismal outcome after isolated surgical treatment. However, the treatment issues for patients with clinical para-aortic lymph node (PAN) enlargement are complex, as PAN enlargement can represent either inflammatory lymphadenopathy or malignant metastasis. In recent years, the role of surgery in multidisciplinary treatment (MDT) of gastric cancer with clinical PALM has been recognized. Nevertheless, the effect of D2 gastrectomy treatment has not yet been fully studied.\n\nResearch motivation\nThe benefit of addition of D2 gastrectomy to MDT and the unsettled clinico-pathological issues in gastric cancer with clinical PALM need to be discussed.\n\nResearch objectives\nThe present study aimed to determine whether D2 resection can be adopted for gastric cancer with radiologically overt PALM and to identify criteria of enrollment and response evaluation and find a best treatment strategy for this group of patients.\n\nResearch methods\nWe collected clinical and pathological data of gastric cancer patients with clinically positive PALM, including detailed information on PAN and clinical response. The short axis diameter of the largest PAN in every individual patient was recorded, and clinical response in the primary tumor and the metastatic sites was evaluated separately. Surgical decision making in accordance with the status of PALM after chemotherapy and survival data were documented.\n\nResearch results\nD2 gastrectomy improved the prognosis of select patients, especially those with complete response (CR) of PALM. Patients with long-term survival were characterized as having limited PALM at baseline and CR of PALM after chemotherapy. For patients without CR of clinical PALM, radiotherapy may be considered as an option to complement D2 resection.\n\nResearch conclusions\nChemotherapy followed by D2 gastrectomy may be a promising strategy for treating select gastric cancer patients with radiologically suspicious PALM. Patients with limited PALM at baseline and CR of PALM after chemotherapy may be good candidates for D2 gastrectomy. Large-scale, multicenter, randomized studies are needed to confirm the feasibility of addition of D2 gastrectomy to a practical MDT plan for patients with clinical PALM.\n\nResearch perspectives\nAlthough we confirmed the benefit of D2 gastrectomy in gastric cancer patients with enlarged PALM, the problem of whether dissection of the para-aortic region is necessary remains unresolved. D2 gastrectomy has limitations as it greatly depends on good response of the metastatic lesions. Currently, a surgical strategy seems promising for gastric cancer with clinical PALM, but the best clinical practice should be identified in future research.\n\nInstitutional review board statement: This study was reviewed and approved by the Ethics Committee of CAMS.\n\nInformed consent statement: The need for informed consent was waived because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.\n\nConflict-of-interest statement: All authors declare no conflicts of interest related to this article.\n\nData sharing statement: No additional data are available.\n\nPeer-review started: March 14, 2019\n\nFirst decision: March 27, 2019\n\nArticle in press: April 29, 2019\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: China\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B, B\n\nGrade C (Good): C\n\nGrade D (Fair): D\n\nGrade E (Poor): 0\n\nP-Reviewer: Matowicka-Karna J, alebi Bezmin Abadi A, Tanabe S S-Editor: Yan JP L-Editor: Wang TQ E-Editor: Ma YJ\n==== Refs\n1 Sasako M Sano T Yamamoto S Kurokawa Y Nashimoto A Kurita A Hiratsuka M Tsujinaka T Kinoshita T Arai K Yamamura Y Okajima K Japan Clinical Oncology Group D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer N Engl J Med 2008 359 453 462 18669424 \n2 Tokunaga M Ohyama S Hiki N Fukunaga T Aikou S Yamaguchi T Can superextended lymph node dissection be justified for gastric cancer with pathologically positive para-aortic lymph nodes? Ann Surg Oncol 2010 17 2031 2036 20182811 \n3 Roviello F Pedrazzani C Marrelli D Di Leo A Caruso S Giacopuzzi S Corso G de Manzoni G Super-extended (D3) lymphadenectomy in advanced gastric cancer Eur J Surg Oncol 2010 36 439 446 20392590 \n4 Fujitani K Yang HK Mizusawa J Kim YW Terashima M Han SU Iwasaki Y Hyung WJ Takagane A Park DJ Yoshikawa T Hahn S Nakamura K Park CH Kurokawa Y Bang YJ Park BJ Sasako M Tsujinaka T REGATTA study investigators Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): A phase 3, randomised controlled trial Lancet Oncol 2016 17 309 318 26822397 \n5 Wang Y Yu YY Li W Feng Y Hou J Ji Y Sun YH Shen KT Shen ZB Qin XY Liu TS A phase II trial of Xeloda and oxaliplatin (XELOX) neo-adjuvant chemotherapy followed by surgery for advanced gastric cancer patients with para-aortic lymph node metastasis Cancer Chemother Pharmacol 2014 73 1155 1161 24748418 \n6 Okabe H Ueda S Obama K Hosogi H Sakai Y Induction chemotherapy with S-1 plus cisplatin followed by surgery for treatment of gastric cancer with peritoneal dissemination Ann Surg Oncol 2009 16 3227 3236 19777180 \n7 Beom SH Choi YY Baek SE Li SX Lim JS Son T Kim HI Cheong JH Hyung WJ Choi SH Jung M Kim HS Jeung HC Chung HC Rha SY Noh SH Multidisciplinary treatment for patients with stage IV gastric cancer: The role of conversion surgery following chemotherapy BMC Cancer 2018 18 1116 30442107 \n8 Schwartz LH Bogaerts J Ford R Shankar L Therasse P Gwyther S Eisenhauer EA Evaluation of lymph nodes with RECIST 1.1 Eur J Cancer 2009 45 261 267 19091550 \n9 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L Kaplan R Lacombe D Verweij J New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 19097774 \n10 Amin MB Edge S Greene F Byrd DR Brookland RK Washington MK Gershenwald JE Compton CC Hess KR Sullivan DC Jessup JM Brierley JD Gaspar LE Schilsky RL Balch CM Winchester DP Asare EA Madera M Gress DM Meyer LR AJCC Cancer Staging Manual. 8th ed. Springer International Publishing 2017 XVII, 1032 \n11 Dorfman RE Alpern MB Gross BH Sandler MA Upper abdominal lymph nodes: Criteria for normal size determined with CT Radiology 1991 180 319 322 2068292 \n12 Fukuya T Honda H Hayashi T Kaneko K Tateshi Y Ro T Maehara Y Tanaka M Tsuneyoshi M Masuda K Lymph-node metastases: Efficacy for detection with helical CT in patients with gastric cancer Radiology 1995 197 705 711 7480743 \n13 Joo I Kim SH Ahn SJ Lee ES Shin CI Lee HJ Yang HK Preoperative tumor restaging and resectability assessment of gastric cancers after chemotherapy: Diagnostic accuracy of MDCT using new staging criteria Abdom Radiol (NY) 2017 42 2807 2815 28643135 \n14 Marrelli D Mazzei MA Pedrazzani C Di Martino M Vindigni C Corso G Morelli E Volterrani L Roviello F High accuracy of multislices computed tomography (MSCT) for para-aortic lymph node metastases from gastric cancer: A prospective single-center study Ann Surg Oncol 2011 18 2265 2272 21267792 \n15 Kwee RM Kwee TC Imaging in assessing lymph node status in gastric cancer Gastric Cancer 2009 12 6 22 19390927 \n16 Fairweather M Jajoo K Sainani N Bertagnolli MM Wang J Accuracy of EUS and CT imaging in preoperative gastric cancer staging J Surg Oncol 2015 111 1016 1020 25872753 \n17 Feng XY Wang W Luo GY Wu J Zhou ZW Li W Sun XW Li YF Xu DZ Guan YX Chen S Zhan YQ Zhang XS Xu GL Zhang R Chen YB Comparison of endoscopic ultrasonography and multislice spiral computed tomography for the preoperative staging of gastric cancer - results of a single institution study of 610 Chinese patients PLoS One 2013 8 e78846 24223855 \n18 Hwang SW Lee DH Lee SH Park YS Hwang JH Kim JW Jung SH Kim NY Kim YH Lee KH Kim HH Park DJ Lee HS Jung HC Song IS Preoperative staging of gastric cancer by endoscopic ultrasonography and multidetector-row computed tomography J Gastroenterol Hepatol 2010 25 512 518 20370729 \n19 Mehmedović A Mesihović R Saray A Vanis N Gastric cancer staging: EUS and CT Med Arch 2014 68 34 36 24783909 \n20 Mocellin S Marchet A Nitti D EUS for the staging of gastric cancer: A meta-analysis Gastrointest Endosc 2011 73 1122 1134 21444080 \n21 Tokunaga M Sugisawa N Tanizawa Y Bando E Kawamura T Terashima M The impact of preoperative lymph node size on long-term outcome following curative gastrectomy for gastric cancer Ann Surg Oncol 2013 20 1598 1603 23117474 \n22 De Manzoni G Marrelli D Baiocchi GL Morgagni P Saragoni L Degiuli M Donini A Fumagalli U Mazzei MA Pacelli F Tomezzoli A Berselli M Catalano F Di Leo A Framarini M Giacopuzzi S Graziosi L Marchet A Marini M Milandri C Mura G Orsenigo E Quagliuolo V Rausei S Ricci R Rosa F Roviello G Sansonetti A Sgroi G Tiberio GA Verlato G Vindigni C Rosati R Roviello F The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015 Gastric Cancer 2017 20 20 30 \n23 Lee SM Kim SH Lee JM Im SA Bang YJ Kim WH Kim MA Yang HK Lee HJ Kang WJ Han JK Choi BI Usefulness of CT volumetry for primary gastric lesions in predicting pathologic response to neoadjuvant chemotherapy in advanced gastric cancer Abdom Imaging 2009 34 430 440 18546037 \n24 Park IH Kim SY Kim YW Ryu KW Lee JH Lee JS Park YI Kim NK Park SR Clinical characteristics and treatment outcomes of gastric cancer patients with isolated para-aortic lymph node involvement Cancer Chemother Pharmacol 2011 67 127 136 20221601 \n25 Yoshida K Yamaguchi K Okumura N Tanahashi T Kodera Y Is conversion therapy possible in stage IV gastric cancer: The proposal of new biological categories of classification Gastric Cancer 2016 19 329 338 26643880 \n26 Yamaguchi K Yoshida K Tanaka Y Matsuhashi N Tanahashi T Takahashi T Conversion therapy for stage IV gastric cancer-the present and future Transl Gastroenterol Hepatol 2016 1 50 28138617 \n27 Kaito A Kinoshita T Tokunaga M Sunagawa H Watanabe M Sugita S Tonouchi A Sato R Abe I Akimoto T Prognostic Factors and Recurrence Pattern of Far-advanced Gastric Cancer with Pathologically-positive Para-aortic Lymph Nodes Anticancer Res 2017 37 3685 3692 28668861 \n28 Sato Y Ohnuma H Nobuoka T Hirakawa M Sagawa T Fujikawa K Takahashi Y Shinya M Katsuki S Takahashi M Maeda M Okagawa Y Naoki U Kikuch S Okamoto K Miyamoto H Shimada M Takemasa I Kato J Takayama T Conversion therapy for inoperable advanced gastric cancer patients by docetaxel, cisplatin, and S-1 (DCS) chemotherapy: A multi-institutional retrospective study Gastric Cancer 2017 20 517 526 27553665 \n29 Kodera Y Kobayashi D Tanaka C Fujiwara M Gastric adenocarcinoma with para-aortic lymph node metastasis: A borderline resectable cancer? Surg Today 2015 45 1082 1090 25366353 \n30 Fujiwara Y Omori T Demura K Miyata H Sugimura K Ohue M Kobayashi S Takahashi H Doki Y Yano M A Multidisciplinary Approach for Advanced Gastric Cancer with Paraaortic Lymph Node Metastasis Anticancer Res 2015 35 6739 6745 26637890 \n31 Tsuburaya A Mizusawa J Tanaka Y Fukushima N Nashimoto A Sasako M Stomach Cancer Study Group of the Japan Clinical Oncology Group Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis Br J Surg 2014 101 653 660 24668391 \n32 He Q Ma L Li Y Li G A pilot study of an individualized comprehensive treatment for advanced gastric cancer with para-aortic lymph node metastasis BMC Gastroenterol 2016 16 8 26782354 \n33 Ito S Sano T Mizusawa J Takahari D Katayama H Katai H Kawashima Y Kinoshita T Terashima M Nashimoto A Nakamori M Onaya H Sasako M A phase II study of preoperative chemotherapy with docetaxel, cisplatin, and S-1 followed by gastrectomy with D2 plus para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis: JCOG1002 Gastric Cancer 2017 20 322 331 27299887 \n34 Yamaguchi K Yoshida K Tanahashi T Takahashi T Matsuhashi N Tanaka Y Tanabe K Ohdan H The long-term survival of stage IV gastric cancer patients with conversion therapy Gastric Cancer 2018 21 315 323 28616743 \n35 Seo HS Song KY Jung YJ Park SM Jeon HM Kim W Chin HM Kim JJ Kim SK Chun KH Kim JG Lee JH Lee HH Kim DJ Yoo HM Kim CH Kim EY Park CH Catholic Gastric Cancer Study Group (CGCSG) Radical Gastrectomy After Chemotherapy May Prolong Survival in Stage IV Gastric Cancer: A Korean Multi-institutional Analysis World J Surg 2018 42 3286 3293 29717344 \n36 Günther K Horbach T Merkel S Meyer M Schnell U Klein P Hohenberger W D3 lymph node dissection in gastric cancer: Evaluation of postoperative mortality and complications Surg Today 2000 30 700 705 10955732 \n37 Bostanci EB Kayaalp C Ozogul Y Aydin C Atalay F Akoglu M Comparison of complications after D2 and D3 dissection for gastric cancer Eur J Surg Oncol 2004 30 20 25 14736518 \n38 Morita S Fukagawa T Fujiwara H Katai H The clinical significance of para-aortic nodal dissection for advanced gastric cancer Eur J Surg Oncol 2016 42 1448 1454 26876636 \n39 Tamura S Takeno A Miki H Lymph node dissection in curative gastrectomy for advanced gastric cancer Int J Surg Oncol 2011 2011 748745 22312521 \n40 Yoshikawa T Sasako M Yamamoto S Sano T Imamura H Fujitani K Oshita H Ito S Kawashima Y Fukushima N Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer Br J Surg 2009 96 1015 1022 19644974 \n41 Yoshikawa T Morita S Tanabe K Nishikawa K Ito Y Matsui T Fujitani K Kimura Y Fujita J Aoyama T Hayashi T Cho H Tsuburaya A Miyashita Y Sakamoto J Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer Eur J Cancer 2016 62 103 111 27244537\n\n",
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"keywords": "Conversion; Gastrectomy; Gastric cancer; Multidisciplinary; Neoadjuvant; Para-aortic lymph node",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001011:Aorta; D005260:Female; D005500:Follow-Up Studies; D005743:Gastrectomy; D006801:Humans; D008197:Lymph Node Excision; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011183:Postoperative Complications; D000077982:Progression-Free Survival; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D015996:Survival Rate",
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"pages": "2338-2353",
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"pubdate": "2019-05-21",
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"title": "Role of D2 gastrectomy in gastric cancer with clinical para-aortic lymph node metastasis.",
"title_normalized": "role of d2 gastrectomy in gastric cancer with clinical para aortic lymph node metastasis"
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"abstract": "Aim\nTo report the first case of cardiac tamponade related to Infliximab induction therapy in an Ulcerative Colitis patient.\nMethods\nReview of published case reports.\nResults\nThis complication was likely due to a type 3 hypersensitivity immune-complex reaction resulting in a reactive pericardial effusion\nDiscussion\nThough rare, this case demonstrates how autoimmune reaction to anti-TNF𝛼 therapy can initially mimic infection, as our patient presented with tachycardia, hypotension, raised inflammatory and infective markers and fever.",
"affiliations": "Department of Gastroenterology & Clinical Medicine, Tallaght University Hospital/Trinity College Dublin, Dublin 24;Department of Gastroenterology & Clinical Medicine, Tallaght University Hospital/Trinity College Dublin, Dublin 24;Department of Cardiology, Tallaght University Hospital/Trinity College Dublin, Dublin 24;Department of Gastroenterology & Clinical Medicine, Tallaght University Hospital/Trinity College Dublin, Dublin 24;Department of Gastroenterology & Clinical Medicine, Tallaght University Hospital/Trinity College Dublin, Dublin 24",
"authors": "O’Morain|N|N|;Kumar|L|L|;O’Carroll-Lolait|C|C|;Alakkari|A|A|;Ryan|B|B|",
"chemical_list": "D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "Ireland",
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"issn_linking": "0332-3102",
"issue": "3(112)",
"journal": "Irish medical journal",
"keywords": null,
"medline_ta": "Ir Med J",
"mesh_terms": "D015551:Autoimmunity; D002305:Cardiac Tamponade; D003093:Colitis, Ulcerative; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008875:Middle Aged; D010490:Pericardial Effusion; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0430275",
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"pages": "902",
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"pmid": "31124350",
"pubdate": "2019-03-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Infliximab Induced Cardiac Tamponade",
"title_normalized": "infliximab induced cardiac tamponade"
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"companynumb": "IE-PFIZER INC-2019263501",
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"abstract": "Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5-FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. We encountered an esophageal carcinoma patient who developed hyperammonemia when receiving 5-FU-containing chemotherapy but did not exhibit any of the other common adverse effects of 5-FU treatment. At the onset of hyperammonemia, laboratory tests revealed high dihydropyrimidine dehydrogenase (DPD) activity and rapid 5-FU clearance. Our findings suggested that 5-FU hypermetabolism may be one of the key mechanisms responsible for hyperammonemia during 5-FU treatment.",
"affiliations": "Department of Hematology and Oncology, Suzuka General Hospital, Yamanohana, Yasuzuka, Suzuka, Mie Prefecture 1275-53, Japan.;Department of Pharmacy, Mie University Hospital, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan.",
"authors": "Nagaharu|Keiki|K|;Ikemura|Kenji|K|;Yamashita|Yoshiki|Y|;Oda|Hiroyasu|H|;Ishihara|Mikiya|M|;Sugawara|Yumiko|Y|;Tamaru|Satoshi|S|;Mizuno|Toshiro|T|;Katayama|Naoyuki|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/7510901",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2016/7510901Case ReportA Case of Hyperammonemia Associated with High Dihydropyrimidine Dehydrogenase Activity Nagaharu Keiki \n1\n\n*\nIkemura Kenji \n2\nYamashita Yoshiki \n3\nOda Hiroyasu \n3\nIshihara Mikiya \n3\nSugawara Yumiko \n3\nTamaru Satoshi \n3\nMizuno Toshiro \n3\nKatayama Naoyuki \n3\n1Department of Hematology and Oncology, Suzuka General Hospital, Yamanohana, Yasuzuka, Suzuka, Mie Prefecture 1275-53, Japan2Department of Pharmacy, Mie University Hospital, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan3Department of Hematology and Oncology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, Mie Prefecture 514-8507, Japan*Keiki Nagaharu: keiki.nagaharu@gmail.comAcademic Editor: Raffaele Palmirotta\n\n2016 19 4 2016 2016 75109019 10 2015 20 12 2015 Copyright © 2016 Keiki Nagaharu 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.Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5-FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. We encountered an esophageal carcinoma patient who developed hyperammonemia when receiving 5-FU-containing chemotherapy but did not exhibit any of the other common adverse effects of 5-FU treatment. At the onset of hyperammonemia, laboratory tests revealed high dihydropyrimidine dehydrogenase (DPD) activity and rapid 5-FU clearance. Our findings suggested that 5-FU hypermetabolism may be one of the key mechanisms responsible for hyperammonemia during 5-FU treatment.\n==== Body\n1. Introduction\nIn 1957, Heidelberger et al. reported the use of 5-FU as a new antitumoral drug [1], and at present, 5-FU is one of the most commonly used anticancer drugs around the world. A combination of cisplatin and 5-FU is often used for first-line chemotherapy in unresectable cases of advanced esophageal carcinoma. As is the case for other anticancer drugs, the most common side effects of 5-FU, such as diarrhea, mucositis, neutropenia, and anemia, are due to its effects on the bone marrow and gastrointestinal epithelium. These common adverse effects are observed in more than half of the patients treated with 5-FU-containing regimens [2]. On the other hand, the prevalence of 5-FU-induced hyperammonemia has been reported to range within 5.7%–7.0% [3–5]. The exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. Herein, we report a patient who developed recurrent hyperammonemia.\n\n2. Case Report\nA 60-year-old man presented with a 1-month history of progressively worsening discomfort during swallowing. His medical history included treated gastric cancer (5 years earlier) and emphysema. The patient reported that he had smoked approximately 20 cigarettes per day since the age of 20. Laboratory tests did not detect hepatic disorders or renal problems. Upper gastrointestinal endoscopy revealed an ulcerative lesion with elevated distinct borders in the lower esophagus, and endoscopic ultrasound detected serosal invasion. The lesion was diagnosed as a squamous cell carcinoma from a biopsy. A positron emission tomography (PET) examination confirmed lung metastasis. As a result, the patient was clinically staged as cT3N1M1 and was treated with 5-FU and cisplatin. However, his obstructive swallowing problems continued to worsen. We next administered concurrent radiotherapy as a palliative treatment. The treatment regimen (FP regimen) consisted of 5-FU at a dose of 800 mg/m2 on days 1–5 and cisplatin at a dose of 80 mg/m2 on day 1 and was repeated every 28 days. The patient did not exhibit specific adverse effects during the first course of treatment. After the completion of that, a second course of the same regimen was started. However, the patient fell unconscious 72 hours after the initiation of treatment.\n\nOn physical examination, he was unconscious (Glasgow Coma Scale: E1V3M5) and afebrile and had a pulse rate of 69 bpm and a blood pressure of 111/61 mmHg. There were no signs of mucositis. A neurological examination did not detect paralysis or abnormal reflexes. The patient's laboratory data revealed hyperammonemia, mild hyponatremia, and a high blood urea nitrogen (BUN) level. Other findings are shown in Table 1. Radiological assessments including computed tomography (CT) and magnetic resonance imaging (MRI) scans of the patient's head did not detect any apparent cause of the patient's condition. On the following day, his condition normalized with only normal saline hydration, and he did not exhibit sequelae. We subsequently diagnosed the patient with 5-FU-related hyperammonemia.\n\nAt the onset of hyperammonemia, the patient's serum 5-FU concentration during the unconscious state was significantly lower (13 ng/mL) than the normal range (500–600 ng/mL). In 5-FU metabolism, approximately 80% of infused 5-FU is degraded by DPD, the initial and rate-limiting enzyme in the catabolism of pyrimidine bases, and this process produces ammonia as the end product. Due to the rapid clearance of 5-FU, we evaluated the patient's DPD activity using the urinary dihydrouracil to uracil ratio (DHU/U). Table 2 shows the patient's DPD activity and a high DHU/U ratio, which indicated that his 5-FU metabolism had not been suppressed.\n\nWe concluded that continuing with the FP regimen would be harmful to the patient. He was subsequently treated with taxane-based treatment, which resulted in PD. He died approximately six months after being diagnosed due to cancer progression.\n\n3. Discussion\nOur patient developed hyperammonemia without other adverse effects. Laboratory examination revealed a high DHU/U ratio. Although urinary DHU/U is an indirect method to assess DPD activity, his high DPD activity was supported by his undetectably low serum 5-FU concentration and the absence of most of the common adverse effects of 5-FU treatment (including diarrhea, mucositis, neutropenia, and anemia). These findings suggested that rapid metabolism of 5-FU may cause faster than normal accumulation of ammonia.\n\nPrevious studies have investigated the relationship between DPD activity and 5-FU toxicity [7–11]. Clinically severe 5-FU toxicity was reported in a family with DPD deficiency [12]. Moreover, relatively low DPD activity was reported to be a risk factor for severe cytotoxic adverse effects [7]. On the other hand, Kim et al. described a case of hyperammonemia with high DPD synthesis, similar to our case [13]. Although the etiology for acquisition of high DPD is unknown, Li et al. demonstrated that exposure to 5-FU causes resistance to 5-FU, with upregulation of DPD activity, using a human colorectal carcinoma xenograft nude mouse model [14]. In the present and previous cases, the first administration of 5-FU may have induced upregulation of DPD activity.\n\nThere are some limitations in our hypothesis. First, we were unable to assess the actual DPD activity in the liver tissue. Because it was reported that hepatic DPD activity is correlated with the urinary DHU/U ratio, we indirectly analyzed the patient's DPD activity using the urinary DHU/U ratio, as was performed in a previous study [6]. Although urine and salivary DHU/U ratios were reported to be good predictors of the adverse effect of 5-FU [7, 15], further investigation is required to establish a method for precise DPD evaluation. Second, the DPD activity before treatment was not evaluated. Thus, we were unable to identify whether the high DPD of our case was congenital or acquired. As mentioned above, the absence of hyperammonemia during his first course suggested acquired high DPD. However, previous reports also performed the same regimen without incidence of hyperammonemia [13]. This suggests that other factors may be required for development of hyperammonemia. Third, we did not evaluate genetic analysis of DPD and other enzymes in our case. Kim et al. reported genetic mutations of thymidylate synthetase which is the main target enzyme of 5-FU in their hyperammonemia cases [16]. Not only catabolic enzymes but also the target of 5-FU may play a role in hyperammonemia.\n\nIn conclusion, the present case suggested that high DPD activity may be a trigger of hyperammonemia. While this report suggested a possible mechanism for such hyperammonemia, the exact mechanism remains unknown, and further investigation on the association between hyperammonemia and DPD activity is warranted.\n\nAcknowledgment\nThe authors thank their patient's family for allowing them to write about the case for the benefit of the future patients.\n\nAbbreviation\n5-FU:5-Fluorouracil\n\nDPD:Dihydropyrimidine dehydrogenase\n\nCT:Computed tomography\n\nBUN:Blood urea nitrogen\n\nMRI:Magnetic resonance imaging\n\nDHU/U:Dihydrouracil to uracil ratio.\n\nConflict of Interests\nThe authors declare that they have no competing interests.\n\nAuthors' Contribution\nKeiki Nagaharu participated in the treatment of the patient in this case report and drafted the paper. Kenji Ikemura assisted in the examination of catabolites. Yoshiki Yamashita participated in the treatment of the patient. Hiroyasu Oda, Mikiya Ishihara, Yumiko Sugawara, and Satoshi Tamaru participated in the planning of treatment. Toshiro Mizuno and Naoyuki Katayama supervised and assisted in drafting the paper. All authors read and approved the final paper.\n\nTable 1 Laboratory findings.\n\n \tDay of onset \tThe following day\t[Normal range]\t\n[Peripheral blood]\t \t \t \t\n WBC\t8080/µL\t5180/µL\t3500–9000/µL\t\n RBC\t382 × 104/µL\t414 × 104/µL\t376–500 × 104/µL\t\n Hb\t15.3 g/dL\t12.9 g/dL\t11.3–15.2 g/dL\t\n Ht\t33.3%\t37.0%\t33.4–44.9%\t\n MCV\t87.2 fL\t89.4 fL\t82.7–101 fL\t\n Plt\t26.3 × 104/µL\t25.6 × 104/µL\t13.0–36.9 × 104/µL\t\n[Coagulation test]\t \t \t \t\n APTT\t31.0 sec\t \t25.0–45.0 sec\t\n PT\t14.2 sec\t \t13.5–15.0 sec\t\n D-dimer\t0.66 µg/mL\t \t<0.50 µg/mL\t\n[Biochemistry]\t \t \t \t\n TP\t6.2 g/dL\t5.6 g/dL\t6.5–8.5 g/dL\t\n Alb\t3.4 g/dL\t3.4 g/dL\t4.1–5.3 g/dL\t\n AST\t20 IU/L\t20 IU/L\t10–35 IU/L\t\n ALT\t25 IU/L\t23 IU/L\t10–35 IU/L\t\n LDH\t182 IU/L\t155 IU/L\t110–225 IU/L\t\n \nγ-GTP\t \t50 IU/L\t8–60 IU/L\t\n T-Bil\t0.6 mg/dL\t0.60 mg/dL\t0.2–1.3 mg/dL\t\n Glu\t101 mg/dL\t \t80–120 mg/dL\t\n BUN\t34 mg/dL\t31 mg/dL\t9.6–22.0 mg/dL\t\n Cre\t0.95 mg/dL\t1.09 mg/dL\t<1.20 mg/dL\t\n Na\t129 mEq/L\t136 mEq/L\t138–145 mEq/L\t\n K\t2.6 mEq/L\t3.1 mEq/L\t3.4–4.7 mEq/L\t\n Cl\t93 mEq/L\t97 mEq/L\t99–108 mEq/L\t\n CRP\t0.47 mg/dL\t0.44 mg/dL\t<0.30 mg/dL\t\n NH3\n\t131 µg/dL\t44 µg/dL\t<18 µg/dL\t\n 5-FU concentration\t13 ng/mL\t<10 ng/mL\t600 ng/mL (steady state)\t\nLaboratory findings revealed hyperammonemia and mild hyponatremia. Serum concentration of 5-FU was low.\n\nTable 2 Urinary analysis of dihydrouracil and uracil.\n\n \tDihydrouracil\tUracil\tRatio\t\nPatient's value\t5.325 µg/mL\t0.495 µg/mL\t10.75\t\nNormal range [6]\t1.7–13.1 µg/mL\t4–30 µg/mL\t0.3–0.77\t\nUrinary DHU/U was much higher than normal. These findings supported the high activity of dihydropyrimidine dehydrogenase.\n==== Refs\n1 Heidelberger C. Chaudhuri N. K. Danneberg P. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds Nature 1957 179 4561 663 666 10.1038/179663a0 2-s2.0-33745464490 13418758 \n2 Tsuji K. Yasui H. Onozawa Y. Modified folfox-6 therapy for heavily pretreated advanced gastric cancer refractory to fluorouracil, irinotecan, cisplatin and taxanes: a retrospective study Japanese Journal of Clinical Oncology 2012 42 8 686 690 10.1093/jjco/hys084 2-s2.0-84865103319 22693245 \n3 Liaw C.-C. Liaw S.-J. Wang C.-H. Chiu M.-C. Huang J.-S. Transient hyperammonemia related to chemotherapy with continuous infusion of high-dose 5-fluorouracil Anti-Cancer Drugs 1993 4 3 311 315 10.1097/00001813-199306000-00003 2-s2.0-0027318815 8358058 \n4 Yeh K. H. Cheng A. L. High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy British Journal of Cancer 1997 75 3 464 465 2-s2.0-0031025605 9020500 \n5 Nobuhiro M. Takashi G. Takanori M. Risk factors for hyperammonemia during mFOLFOX6 treatment Gan To Kagaku Ryoho 2013 40 4 483 487 23848016 \n6 Sparidans R. W. Bosch T. M. Jörger M. Schellens J. H. M. Beijnen J. H. Liquid chromatography–tandem mass spectrometric assay for the analysis of uracil, 5,6-dihydrouracil and β -ureidopropionic acid in urine for the measurement of the activities of the pyrimidine catabolic enzymes Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences 2006 839 1-2 45 53 10.1016/j.jchromb.2006.02.016 2-s2.0-33745947684 16513432 \n7 van Kuilenburg A. B. P. Haasjes J. Richel D. J. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene Clinical Cancer Research 2000 6 12 4705 4712 2-s2.0-0034488052 11156223 \n8 Wettergren Y. Carlsson G. Odin E. Gustavsson B. Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5-fluorouracil-based chemotherapy Cancer 2012 118 11 2935 2943 10.1002/cncr.26595 2-s2.0-84861337759 22020693 \n9 Gamelin M. Boisdron-Celle M. Guérin-Meyer V. Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: a potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage Journal of Clinical Oncology 1999 17 4 1105 1110 2-s2.0-0032940053 10561167 \n10 Nakayama Y. Matsumoto K. Inoue Y. Correlation between the urinary dihydrouracil-uracil ratio and the 5-FU plasma concentration in patients treated with oral 5-FU analogs Anticancer Research 2006 26 5 3983 3988 2-s2.0-33750713063 17094430 \n11 Kristensen M. H. Pedersen P. Mejer J. The value of dihydrouracil/uracil plasma ratios in predicting 5-fluorouracilrelated toxicity in colorectal cancer patients Journal of International Medical Research 2010 38 4 1313 1323 10.1177/147323001003800413 2-s2.0-77957732473 20926004 \n12 Harris B. E. Carpenter J. T. Diasio R. B. Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome Cancer 1991 68 3 499 501 2-s2.0-0025990479 1648430 \n13 Kim Y.-A. Chung H. C. Choi H. J. Rha S. Y. Seong J. S. Jeung H.-C. Intermediate dose 5-fluorouracil-induced encephalopathy Japanese Journal of Clinical Oncology 2006 36 1 55 59 10.1093/jjco/hyi214 2-s2.0-32244443581 16436463 \n14 Li L.-H. Dong H. Zhao F. The upregulation of dihydropyrimidine dehydrogenase in liver is involved in acquired resistance to 5-fluorouracil European Journal of Cancer 2013 49 7 1752 1760 10.1016/j.ejca.2012.12.013 2-s2.0-84876134544 23313143 \n15 Carlsson G. Odin E. Gustavsson B. Wettergren Y. Pretherapeutic uracil and dihydrouracil levels in saliva of colorectal cancer patients are associated with toxicity during adjuvant 5-fluorouracil-based chemotherapy Cancer Chemotherapy and Pharmacology 2014 74 4 757 763 10.1007/s00280-014-2553-2 2-s2.0-84905300079 25102934 \n16 Kim S.-R. Park C.-H. Park S. Park J.-O. Lee J. Lee S.-Y. Genetic polymorphisms associated with 5-fluorouracil-induced neurotoxicity Chemotherapy 2010 56 4 313 317 10.1159/000320032 2-s2.0-77955523615 20714149\n\n",
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"title": "A Case of Hyperammonemia Associated with High Dihydropyrimidine Dehydrogenase Activity.",
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"abstract": "Suppurative thyroiditis is uncommon in the pediatric population and particularly rare to be caused by fungi. We present a case of Candida tropicalis thyroiditis in an adolescent male with acute lymphocytic leukemia that led to disseminated candidiasis, thyroid storm and eventual total thyroidectomy for source control.",
"affiliations": "From the Section of Infectious Diseases, Department of Pediatrics.;From the Section of Infectious Diseases, Department of Pediatrics.;Section of Hematology Oncology, Department of Pediatrics.;Section of Hematology Oncology, Department of Pediatrics.;Department of Otolaryngology, Division of Pediatric Otolaryngology.;Section of Endocrinology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;Section of Endocrinology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.;From the Section of Infectious Diseases, Department of Pediatrics.;From the Section of Infectious Diseases, Department of Pediatrics.",
"authors": "Niles|Denver|D|;Boguniewicz|Juri|J|;Shakeel|Omar|O|;Margolin|Judith|J|;Chelius|Daniel|D|;Gupta|Meenal|M|;Paul|David|D|;King|Katherine Y|KY|;McNeil|J Chase|JC|",
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"issue": "38(10)",
"journal": "The Pediatric infectious disease journal",
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"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000293:Adolescent; D041022:Candida tropicalis; D002177:Candidiasis; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013958:Thyroid Crisis; D013965:Thyroidectomy; D013969:Thyroiditis, Suppurative; D016896:Treatment Outcome",
"nlm_unique_id": "8701858",
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"pages": "1051-1053",
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"pmid": "31365478",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Candida tropicalis Thyroiditis Presenting With Thyroid Storm in a Pediatric Patient With Acute Lymphocytic Leukemia.",
"title_normalized": "candida tropicalis thyroiditis presenting with thyroid storm in a pediatric patient with acute lymphocytic leukemia"
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"companynumb": "US-SERVIER-S20003094",
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"abstract": "Everolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC.\nPatients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated.\nThe median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1-28.0) ng/mL and 14.8 (6.4-58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26-288) and 235 days (95% CI, 28-291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436).\nThis study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.",
"affiliations": "1Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.;1Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.;2Department of Urology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.;1Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.;1Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.;2Department of Urology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.;1Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.",
"authors": "Takasaki|Shinya|S|;Yamaguchi|Hiroaki|H|0000-0003-3021-6120;Kawasaki|Yoshihide|Y|;Kikuchi|Masafumi|M|;Tanaka|Masaki|M|;Ito|Akihiro|A|;Mano|Nariyasu|N|",
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"fulltext": "\n==== Front\nJ Pharm Health Care SciJ Pharm Health Care SciJournal of Pharmaceutical Health Care and Sciences2055-0294BioMed Central London 13510.1186/s40780-019-0135-5Research ArticleLong-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study Takasaki Shinya takasaki_shinya@hosp.tohoku.ac.jp 1http://orcid.org/0000-0003-3021-6120Yamaguchi Hiroaki yamaguchi@hosp.tohoku.ac.jp 1Kawasaki Yoshihide kawasaki@uro.med.tohoku.ac.jp 2Kikuchi Masafumi mkikuchi@hosp.tohoku.ac.jp 1Tanaka Masaki ms-tanaka@hosp.tohoku.ac.jp 1Ito Akihiro itoaki@uro.med.tohoku.ac.jp 2Mano Nariyasu mano@hosp.tohoku.ac.jp 11 0000 0004 0641 778Xgrid.412757.2Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan 2 0000 0001 2248 6943grid.69566.3aDepartment of Urology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan 12 3 2019 12 3 2019 2019 5 612 12 2018 21 2 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEverolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC.\n\nMethods\nPatients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated.\n\nResults\nThe median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1–28.0) ng/mL and 14.8 (6.4–58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26–288) and 235 days (95% CI, 28–291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436).\n\nConclusions\nThis study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.\n\nKeywords\nEverolimusmTORPharmacokineticsRenal cell carcinomaTherapeutic drug monitoringhttp://dx.doi.org/10.13039/501100001691Japan Society for the Promotion of ScienceJP16H00518Takasaki Shinya issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nTyrosine kinase inhibitors and mammalian target of rapamycin inhibitors (mTORi) are molecular targeted drugs for metastatic renal cell carcinoma (mRCC) [1]. Although these targeted drugs of mRCC show higher objective response rate and significantly prolong a median progression-free survival (PFS), various adverse events such as diarrhea, fatigue, vomiting, myelosuppression, and interstitial pneumonia are frequently induced [1]. Recently, personalized medicine for cancer using therapeutic drug monitoring (TDM) is recommended to maximize the efficacy of anticancer drugs, and several evidence of TDM of molecular target drugs such as imatinib and sunitinib have been demonstrated [2, 3].\n\nAn mTORi everolimus used for mRCC has already been adapted for TDM in other applications such as the prevention of organ rejection after transplantation [4, 5], and for the treatment of tuberous sclerosis complex [6, 7] and various forms of cancer [8–10]. Everolimus is very effective, but its therapeutic blood concentration range is narrow and the variability of pharmacokinetics among individuals is high. Therefore, it is appropriate to perform individualized medical treatment using TDM [11]. In transplantation settings, trough level of everolimus should be maintained at 3–8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitor and glucocorticoid) and at 6–10 ng/mL when used without calcineurin inhibitor [11–16]. In the treatment of tuberous sclerosis complex, it is recommended that everolimus concentrations should be managed at 5–15 ng/mL [7, 11, 17]. But, in cancer, there is little evidence of TDM for everolimus in actual clinical practice [11].\n\nPresently, there are several reports on the pharmacokinetics/pharmacodynamics studies of everolimus in cancer [11, 18–20]. Deppenweiler et al. reported that everolimus trough level between 11.9 and 26.3 ng/mL was associated with increase in PFS and decrease in the risk of toxicity [18]. A meta-analysis study by Noguchi et al. demonstrated that the risk of pulmonary adverse events is associated with the administration of everolimus in Japanese patients [19]. Moreover, another meta-analysis study reported the relationship between an increase in everolimus trough level and antitumor effect or risk of high-grade adverse events [20]. However, in cancer patients, there has been no report of monitoring the blood levels of everolimus on a long-term. The dose of everolimus may be reduced following the occurrence of clinically significant hematological or other adverse events. In addition, everolimus blood concentration has been reported to be affected by interaction between drugs [11]. Drugs that alleviate various symptoms will be used for cancer patients with the progress of their symptoms, but these such as antiepileptic drugs may cause drug-drug interactions. That is, in clinical practice, events that may affect everolimus blood concentrations often occur even during everolimus treatment. It is important to evaluate the relationship between everolimus blood level and long-term clinical outcomes. Therefore, in this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC.\n\nMethods\nPatients\nThe subjects of this study were prospectively recruited from mRCC patients for whom everolimus therapy was scheduled at Tohoku University Hospital from April 2012 to December 2016.\n\nChemicals\nEverolimus and d4-everolimus as internal standard were purchased from Toronto Research Chemicals (Toronto, ON, Canada). Acetonitrile, methanol, ammonium formate, zinc sulfate, and formic acid were obtained from Wako Pure Chemical Industries (Osaka, Japan). Water was purified using a PURELAB Ultra Genetic system (Organo, Tokyo, Japan).\n\nMeasurement of everolimus blood concentration\nThe administration schedule of everolimus in this study was in a fasting state. Whole blood samples were obtained just before taking everolimus after day 8 of reaching the steady state of everolimus [21, 22], the sampling was scheduled weekly during hospitalization. For outpatient, the samples were collected for each visit. Everolimus blood concentrations were measured by modifying a previously validated assay [23]. In brief, 100 μL of whole blood sample was mixed with 50 μL of a methanol solution of 100 ng/mL d4-everolimus as an internal standard and preprocessed by 200 μL methanol and 50 μL of 0.2 M zinc sulfate. The samples were centrifuged at 15,000×g for 5 min, the supernatants were analyzed by a column-switching liquid chromatography/tandem mass spectrometry system. Analytes were trapped and concentrated at the inlet edge of Shim-pack MAYI-C8 (10 mm × 4.6 mm i.d., 50 μm, GL Sciences, Tokyo, Japan) using the mobile phase [2 mM ammonium formate and 0.1% formic acid in water-methanol (41:9, v/v)] at a flow rate 0.5 mL/min. Then, analytes were separated on Luna® phenyl-hexyl column (50 mm × 2 mm i.d., 5 μm, Phenomenex, Torrance, CA, USA) using the mobile phase [2 mM ammonium formate and 0.1% formic acid in water-methanol (1:9, v/v)] at a flow rate 0.2 mL/min. The analysis was performed in selected reaction monitoring mode: m/z 975.4 to 542.2 for everolimus; m/z 979.5 to 542.2 for d4-everolimus. The quantitative range of everolimus was 1–50 ng/mL. The observed intra-day and inter-day precision and accuracy were below 6.6% and within ±6.8%, respectively. Samples with everolimus blood concentrations higher than the calibration curve range were diluted in saline.\n\nEvaluation of safety\nAdverse events by everolimus therapy were evaluated according to Common Terminology Criteria for Adverse Events version 4.0. The relationship between everolimus blood concentration and everolimus discontinuation or dose reduction due to adverse events was assessed, and everolimus blood concentrations on day 8 and just before discontinuation or dose reduction of everolimus therapy were used for analysis. In addition, the median value of everolimus blood concentration on day 8 was used to classify into two groups, high group and low group, and the association with adverse events was evaluated.\n\nEvaluation of efficacy\nTime to treatment failure (TTF) was defined as the period from the initiation of everolimus therapy to cessation for any cause (including disease progression or adverse events). Progression-free survival (PFS) was defined as the time from the start of everolimus treatment to the objective detection of disease progression or death. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the efficacy of everolimus (TTF and PFS) was evaluated in the groups.\n\nStatistical analysis\nThe cut-off date for this analysis was March 2017. Patients whose blood samples were not obtained after day 8 from the start of everolimus treatment were excluded from the analysis. Continuous variables were compared between two groups by the Wilcoxon rank sum test, and categorical variables were compared by the chi-squared test or Fisher’s exact test. Correlations between everolimus blood concentration on day 8, and age, body surface area (BSA), body mass index (BMI), and estimated glomerular filtration rate (eGFR) were evaluated using Spearman’s rank correlation coefficient. TTF and PFS were estimated using Kaplan-Meier curves and compared using the log-rank test. Differences were considered significant at P < 0.05. All statistical analyses were performed using JMP pro 13.1.0 software (SAS Institute Inc., Cary, NC, USA).\n\nResults\nPatients\nTen patients with mRCC, who were being administered everolimus, were evaluated in this study. The characteristics of the patients are shown in Table 1. The median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1–28.0) ng/mL and 14.8 (6.4–58.4) ng/mL, respectively with no significant difference between these values (P = 0.3594). Fluctuations in the blood level of everolimus were also observed in some patients. Correlation coefficients between concentration/dose (C/D) and age, BSA, BMI, and eGFR are indicated in Fig. 1. No significant correlation between C/D ratio and each parameter was observed.Table 1 Patients’ characteristics\n\n\tTotal\tContinuation\tDiscontinuation or dose reduction by adverse events\tP value\t\nPatients, n\t10\t4\t6\t\t\nAge (years)a\t63 (32–74)\t61 (51–64)\t65 (32–74)\t0.3329 b\t\nMale/Female\t5/5\t1/3\t4/2\t0.5238 c\t\nBody weight (kg)a\t57.7 (46.0–65.8)\t58.9 (51.3–63.4)\t52.9 (46.0–65.8)\t0.4555 b\t\nBody surface area (m2)a\t1.57 (1.37–1.74)\t1.59 (1.47–1.70)\t1.56 (1.37–1.74)\t0.7476 b\t\nBody mass index (kg/m2)a\t22.1 (16.3–26.2)\t23.0 (20.9–26.2)\t21.2 (16.3–23.8)\t0.2410 b\t\nAspartate aminotransferase (UI/L)a\t27 (16–43)\t29 (17–43)\t27 (16–42)\t0.6689 b\t\nAlanine aminotransferase (UI/L)a\t17 (12–47)\t26 (12–47)\t17 (13–42)\t1.0000 b\t\nSerum creatinine (mg/dL)a\t0.84 (0.61–1.47)\t0.68 (0.61–0.92)\t0.99 (0.66–1.47)\t0.0691 b\t\neGFR (mL/min/1.73 m2)a\t64.9 (38.2–113.0)\t70.0 (64.5–76.0)\t50.9 (38.2–113.0)\t0.3938 b\t\nECOG PS, n\t\n0\t6\t2\t4\t0.7143 c\t\n1\t3\t2\t1\t\t\n2 or more\t1\t0\t1\t\t\nNumber of prior systemic therapies, n\t\n 2\t1\t1\t0\t0.3333 c\t\n 3\t7\t2\t5\t\t\n 4 or more\t2\t1\t1\t\t\nInitial dose, n\t\n 10 mg/day\t8\t2\t6\t0.1333c\t\n 7.5 mg/day\t1\t1\t0\t\t\n 5 mg/day\t1\t1\t0\t\t\nEverolimus blood concentration on day 8 after starting everolimus administration (ng/mL)a\t15.3 (8.1–28.0)\t8.2 (8.1–9.8)\t18.0 (13.7–28.0)\t0.0139b\t\nEverolimus blood concentration just before discontinuation or dose reduction (ng/mL)a\t14.8 (6.4–58.4)\t9.7 (6.4–17.1)\t22.9 (12.5–58.4)\t0.0142b\t\nChange of everolimus blood concentration just before discontinuation or dose reduction from day 8 (absolute value, ng/mL)a\t1.65 (0.03–36.60)\t2.00 (0.03–8.90)\t1.40 (0.20–36.60)\t0.3374b\t\neGFR: estimated glomerular filtration rate, ECOG PS: Eastern Cooperative Oncology Group Performance Status, a: Values are reported as median (range), b: Continuous variables evaluated by Wilcoxon rank sum test and c: categorical variables by Fisher exact test\n\nFig. 1 The relationship between the concentration-to-dose (C/D) ratio of everolimus on day 8 and patients’ demographic data. Demographic data include age, body surface area (BSA), body mass index (BMI), and estimated glomerular filtration rate (eGFR) and the relationship was analyzed with Spearman’s rank correlation coefficient\n\n\n\nSafety\nAs shown in Table 1, patients (n = 6) with discontinuation or dose reduction by adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with continuation on both the day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). The profile of adverse events that occurred in this study is indicated in Table 2, eight patients (80%) had adverse events of all grades and five patients (50%) had adverse events of grade 3 or 4. In addition, we divided the patients into two groups (low level group, ≤ 15.3 ng/mL and high level group, > 15.3 ng/mL) on the basis of the blood concentration of everolimus on day 8 using the median value, and the safety of the drug was evaluated in the two groups of patients. In the low level group (n = 5), patients with adverse events of all grades were 3 (60%) and those with adverse events of grade 3 or 4 were 2 (40%). In the high level group (n = 5) of everolimus, patients with adverse events of all grade were 5 (100%) and those with adverse events of grade 3 or 4 were 3 (60%). For the grade 3 or 4 adverse events, pneumonitis and leukopenia were confirmed in two patients, one from the low level group and the other from the high level group. In the high level group, grade 3 hyperglycemia, hypoalbuminemia, and increased γ-glutamyltransferase were observed in one patient, which we have previously reported [24]. Table 3 shows the mean value ± standard deviation (SD) of everolimus blood concentration for each patient, everolimus blood concentration at the time of discontinuation or dose reduction, and the adverse events that caused discontinuation or dose reduction.Table 2 Relationship between adverse events and everolimus blood concentration\n\n\tTotal (n = 10)\tEverolimus blood concentration just before discontinuation or dose reduction (ng/mL)\t\n≤ 15.3 (n = 5)\t> 15.3 (n = 5)\t\n\tAll grades\tGrade 3 or 4\tAll grades\tGrade 3 or 4\tAll grades\tGrade 3 or 4\t\nNumber of patients\t\n Any event\t8\t5\t3\t2\t5\t3\t\n Fatigue\t1\t0\t0\t0\t1\t0\t\n Nausea\t1\t0\t0\t0\t1\t0\t\n Vomiting\t1\t0\t0\t0\t1\t0\t\n Mucosal inflammation\t5\t0\t2\t0\t3\t0\t\n Diarrhea\t1\t0\t0\t0\t1\t0\t\n Rash\t2\t0\t1\t0\t1\t0\t\n Pneumonitis\t4\t2\t2\t1\t2\t1\t\n Increased aspartate aminotransferase\t2\t0\t0\t0\t2\t0\t\n Increased alanine transaminase\t2\t0\t0\t0\t2\t0\t\n Increased alkaline phosphatase\t3\t0\t0\t0\t3\t0\t\n Increased γ-glutamyltransferase\t1\t1\t0\t0\t1\t1\t\n Leukopenia\t3\t2\t1\t1\t2\t1\t\n Neutropenia\t2\t0\t1\t0\t1\t0\t\n Thrombocytopenia\t2\t0\t0\t0\t2\t0\t\n Anemia\t2\t0\t0\t0\t2\t0\t\n Hypoalbuminemia\t1\t1\t0\t0\t1\t1\t\n Hyperglycemia\t2\t1\t0\t0\t2\t1\t\nTable 3 Everolimus blood concentration at the time of discontinuation or dose reduction by adverse events\n\nPatient number\tNumber of measurements\tEverolimus blood concentration,\nMean ± SD (ng/mL)\tDiscontinuation or dose reduction by adverse events\t\nDiscontinuation or dose reduction\tDate (day)\tEverolimus blood concentration (ng/mL)\tAdverse events\t\nPat.1\t22\t11.2 ± 4.6\t\t\t\t\t\nPat.2\t9\t16.4 ± 6.2\tDiscontinuation\t147\t17.5\tAST (G2), ALT (G2), ALP (G2), Hyperglycemia (G2), Mucosal inflammation (G2), Fatigue (G2),\t\nPneumonitis (G1), Diarrhea (G1), Leukopenia (G1), Neutropenia (G1)\t\nPat.3\t2\t13.1 ± 0.6\tDiscontinuation\t26\t12.5\tPneumonitis (G3), Mucosal inflammation (G2)\t\nPat.4\t4\t27.9 ± 18.0\tDose reduction\t15\t58.4\tHyperglycemia (G3), Hypoalbuminemia (G3), γ-GTP (G3), AST (G2), ALP (G2), ALP (G1)\t\nDiscontinuation\t41\t19.1\tAST (G1), ALT(G1), ALP(G1)\t\nPat.5\t15\t8.4 ± 2.5\t\t\t\t\t\nPat.6\t3\t10.2 ± 0.6\t\t\t\t\t\nPat.7\t12\t18.8 ± 4.8\tDiscontinuation\t265\t20.4\tLeukopenia (G3), Thrombocytopenia (G2)\t\nPat.8\t3\t8.2 ± 0.5\t\t\t\t\t\nPat.9\t4\t27.6 ± 4.9\tDiscontinuation\t98\t35.4\tPneumonitis (G3), Mucosal inflammation (G2)\t\nPat.10\t5\t18.7 ± 1.3\tDose reduction\t16\t17.1\tMucosal inflammation (G2), ALP (G1), Nausea (G1), Vomiting (G1)\t\nDiscontinuation\t93\t19.5\tALP (G1), Nausea (G1)\t\nAST: Increased aspartate aminotransferase, ALT: Increased alanine transaminase, ALP: Increased alkaline phosphatase, γ-GTP: Increased γ-glutamyltransferase\n\n\n\nEfficacy\nMedian TTF and PFS of all the patients (n = 10) were 96 days [95% confidence interval (CI), 26–288] and 235 days (95% CI, 28–291). Subgroup analysis using median value (15.3 ng/mL) of everolimus blood concentration on day 8 showed that the TTF of patients with > 15.3 ng/mL (n = 5) was not significantly different from that of patients with ≤15.3 ng/mL (n = 5; P = 0.5622; Fig. 2a). Similarly, the PFS of patients with > 15.3 ng/mL was not significantly different from that of patients with ≤15.3 ng/mL (P = 0.3436; Fig. 2b).Fig. 2 The relationships between everolimus blood concentration and efficacy. Efficacy was evaluated as time to treatment failure (TTF) (A) and progression-free survival (PFS) (B) with the Kaplan-Meier method and the log-rank test\n\n\n\nClinical application to measurement of everolimus blood concentration\nA case of drug-drug interaction detected by the measuring of blood concentration of everolimus is indicated in Fig. 3. Pat.1 in Table 3 is a 52-year-old Japanese female diagnosed with cell carcinoma 5 years ago. She underwent a partial right nephrectomy for clear cell carcinoma and the following year, her lung metastasis was discovered and sequentially treated with interferon and sunitinib. The sunitinib therapy was changed to everolimus when she was diagnosed with brain metastasis. The patient was administered carbamazepine for neurologic symptoms and prednisolone for cerebral edema associated with brain metastasis. Other concomitant medications were lansoprazole, domperidone, rebamipide, sodium ferrous citrate, and probucol. There were few adverse events of grade 2 or more after the initiation of everolimus 10 mg. The average trough concentration of everolimus in concomitant medications at the start of everolimus was 7.3 ng/mL in patients, whereas the mean level of patients treated with 10 mg of everolimus in a clinical trial was 13.2 ng/mL [22]. Therefore, administration of carbamazepine, prednisolone, and lansoprazole was discontinued because of its ability to induce cytochrome P450 (CYP) 3A4 [25–27]—the main metabolic enzyme of everolimus [11]. Considering less interaction with CYP3A4, carbamazepine was switched to levetiracetam [28], lansoprazole was changed to rabeprazole [29], and prednisolone was stopped after dose reduction. After discontinuing these drugs (carbamazepine, prednisolone, and lansoprazole), the blood concentration of everolimus gradually increased. There were no serious adverse events and no significant change in liver and kidney function during this everolimus treatment, and everolimus therapy lasted for half a year.Fig. 3 Changes in blood concentration of everolimus before and after combination with concomitant drugs (carbamazepine, prednisolone, and lansoprazole). *Prednisolone was reduced from 10 mg/day to 5 mg/day at the same time as carbamazepine and lansoprazole termination, and was discontinued after 1 week\n\n\n\nDiscussion\nIn this study, everolimus blood levels of the patients with discontinuation or dose reduction by adverse events were significantly higher than the patients with continuation (Table 1). Deppenweiler et al. reported that everolimus trough levels higher than 26.3 ng/mL were associated with increased risk of adverse events [18]. In the patients (Pat.2, Pat.4, Pat.7, Pat.9, and Pat.10) who exceeded the average everolimus blood level of 16.4 ng/mL, there was discontinuation or dose reduction in the everolimus therapy due to adverse events (Table 3). Everolimus treatment was discontinued in Pat.3 due to grade 3 pneumonitis even though the everolimus level was 13.1 ng/mL, which was not higher than that of other patients (Table 3). Subsequently, Pat.3 was diagnosed with interstitial pneumonia and because symptoms might continue to develop in the patient, steroid pulse therapy was required. The toxic range of interstitial pneumonia by everolimus may be lower than other adverse events, therefore it is better to increase the number of cases and verify in the future. In many cases, TDM of everolimus is considered useful in predicting the occurrence of adverse events.\n\nIn this study, there was no significant difference between the median blood everolimus concentration on day 8 (15.3 ng/mL) and just before discontinuation or dose reduction of that therapy (14.8 ng/mL). These values were almost equal to the mean trough value 15.99 ng/mL [19] and 15.65 ng/mL [20] in previous reports. However, the everolimus levels fluctuated largely in Pat 4 (21.8 to 58.4 ng/mL) and Pat.9 (28.0 to 35.4 ng/mL). They had serious adverse events leading to dose reduction and discontinuation. In addition, Pat.1 had fluctuations in everolimus levels due to drug-drug interaction (Fig. 3). In cancer treatment, various supportive therapies are used, and this may cause drug-drug interaction. For instance, antiepileptic drugs are sometimes used for symptomatic relief, but because of many interactions that can occur between drugs, caution is needed in the administration anticancer drugs [11]. Hence, since intra-individual variations in everolimus pharmacokinetics are large and it is affected by concomitant drugs or food components, routine TDM may be effective for everolimus therapy [11]. In addition, large inter-individual variations were also observed in this study (Fig. 1 and Table 3). It is known that the pharmacokinetics of everolimus is affected by drugs and food, as well as intra-individual [11]. To date, there is not sufficient clinical evidence that inter-individual its differences in metabolic enzymes and transporters affect everolimus pharmacokinetics [11].\n\nRavaud et al. [20] and Deppenweiler et al. [18] reported that everolimus blood level was directly correlated with the antitumor effect, but in this study, there was no significant difference between the TTF and PFS of the high everolimus level group and those of the low everolimus level group (Fig. 2). However, there were some differences between this study and the previous ones. The reports of Ravaud et al. [20] are based on the results of a phase II and III clinical trials, but our patients had worse performance status and more prior systemic therapies than those of the trial. In the research of Deppenweiler et al., the diagnosis of the patients was mainly breast cancer (n = 42, 77.8%) and few patients with kidney cancer (n = 10, 18.5%) [18], and the relationship between everolimus blood level and antitumor effect may differ depending on the type of cancer. In addition, our study involved only Japanese patients who were also less in number than in the previous studies.\n\nThe limitation of the present study was that, it was a small case study and unlike clinical trials, patients with poor performance status or many prior systemic therapies made it difficult to evaluate efficacy. Further studies on the pharmacokinetics/pharmacodynamics of everolimus are required to determine the clinical utility of TDM in oncology settings. Moreover, it is necessary to evaluate the significance of everolimus TDM by a randomized comparative study between TDM group and non-TDM group. This information would help to maximize the therapeutic potential of everolimus TDM for cancer while minimizing severe adverse events.\n\nConclusions\nThe present study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and it showed that everolimus blood level correlate with adverse events in Japanese patients with mRCC. The relation with efficacy was not sufficiently evaluated due to the small number of cases in this study. It is necessary to study further in the future. Consequently, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events in Japanese patients with mRCC.\n\nAbbreviations\nBMIBody mass index\n\nBSABody surface area\n\nC/Dconcentration-to-dose\n\nCIconfidence interval\n\neGFRestimated glomerular filtration rate\n\nmRCCMetastatic renal cell carcinoma\n\nmTORiMammalian target of rapamycin inhibitor\n\nPFSProgression-free survival\n\nSDStandard deviation\n\nTDMTherapeutic drug monitoring\n\nTTFTime to treatment failure\n\nAcknowledgements\nWe appreciate all the staff of Tohoku University Hospital who participated in this study.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll the data generated or analyzed in this study are included in the published article.\n\nAuthors’ contributions\nST was the main contributor in the conception and preparation of the manuscript. YK and AI collected blood samples. ST, MK, and MT measured everolimus blood concentration. ST, HY, and YK analyzed the relationship between everolimus blood concentration and clinical outcomes. HY and NM revised the manuscript critically. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Tohoku University Graduate School of Medicine (No. 2011–634). A clear written consent was obtained from each patient prior to start of the study.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients. Am J Transplant 2010;10:1401–1413.\n6. Bissler JJ Kingswood JC Radzikowska E Zonnenberg BA Frost M Belousova E Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial Lancet. 2013 381 817 824 10.1016/S0140-6736(12)61767-X 23312829 \n7. Franz DN Belousova E Sparagana S Bebin EM Frost M Kuperman R Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial Lancet. 2013 381 125 132 10.1016/S0140-6736(12)61134-9 23158522 \n8. Motzer RJ Escudier B Oudard S Hutson TE Porta C Bracarda S Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial Lancet. 2008 372 449 456 10.1016/S0140-6736(08)61039-9 18653228 \n9. Pavel ME Hainsworth JD Baudin E Peeters M Horsch D Winkler RE Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study Lancet. 2011 378 2005 2012 10.1016/S0140-6736(11)61742-X 22119496 \n10. Baselga, J., Campone, M., Piccart, M., Burris, H.A., 3rd, Rugo, H.S., Sahmoud, T. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520–529.\n11. Shipkova M Hesselink DA Holt DW Billaud EM van Gelder T Kunicki PK Therapeutic drug monitoring of Everolimus: a consensus report Ther Drug Monit 2016 38 143 169 10.1097/FTD.0000000000000260 26982492 \n12. Kovarik JM Eisen H Dorent R Mancini D Vigano M Rouilly M Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure J Heart Lung Transplant 2003 22 1117 1125 10.1016/S1053-2498(02)01221-4 14550821 \n13. Starling RC Hare JM Hauptman P McCurry KR Mayer HW Kovarik JM Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling Am J Transplant 2004 4 2126 2131 10.1046/j.1600-6143.2004.00601.x 15575918 \n14. Budde K Lehner F Sommerer C Arns W Reinke P Eisenberger U Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study Am J Transplant 2012 12 1528 1540 10.1111/j.1600-6143.2012.03994.x 22642473 \n15. 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"fulltext_license": "CC BY",
"issn_linking": "2055-0294",
"issue": "5()",
"journal": "Journal of pharmaceutical health care and sciences",
"keywords": "Everolimus; Pharmacokinetics; Renal cell carcinoma; Therapeutic drug monitoring; mTOR",
"medline_ta": "J Pharm Health Care Sci",
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"nlm_unique_id": "101672177",
"other_id": null,
"pages": "6",
"pmc": null,
"pmid": "30906563",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "10722121;12944570;14550821;14748618;15135093;15258107;15575918;18332470;18653228;20455882;21047224;21334736;22119496;22149876;22642473;22927532;23158522;23312829;24332451;24895078;24928190;25141173;25521535;26982492;28174388;28219073;28473246;28596261;8877250",
"title": "Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study.",
"title_normalized": "long term relationship between everolimus blood concentration and clinical outcomes in japanese patients with metastatic renal cell carcinoma a prospective study"
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... |
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"abstract": "Variants in Phosphomannomutase 2 (PMM2) lead to PMM2-CDG, the most frequent congenital disorder of glycosylation (CDG). We here describe the disease course of a ten-month old patient who presented with the classical PMM2-CDG symptoms as cerebellar hypoplasia, retinitis pigmentosa, seizures, short stature, hepato- and splenomegaly, anaemia, recurrent vomiting and inverted mamillae. A severe form of tetralogy of Fallot was diagnosed and corrective surgery was performed at the age of 10 months. At the end of the cardiopulmonary bypass, a sudden oedematous reaction of the myocardium accompanied by biventricular pump failure was observed immediately after heparin antagonization with protamine sulfate. The patient died seven days after surgery, since myocardial function did not recover on ECMO support. We here describe the first patient carrying the homozygous variant g.18313A > T in the PMM2 gene (NG_009209.1) that either can lead to c.394A > T (p.I132F) or even loss of 100 bp due to exon 5 skipping (c.348_447del; p.G117Rfs*4) which is comparable to a null allele. Proliferation and doubling time of the patient's fibroblasts were affected. In addition, we show that the induction of cellular stress by elevating the cell culture temperature to 40 °C led to a decrease of the patients' PMM2 transcript as well as PMM2 protein levels and subsequently to a significant loss of residual activity. We assume that metabolic stressful processes occurring after cardiac surgery led to the drop of the patient's PMM activity below a life-sustaining niveau which paved the way for the fatal outcome.",
"affiliations": "Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.;Department of Pediatric Cardiology, University Hospital RWTH, Aachen, Germany.;Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.;Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.;Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.;Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.;Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.;Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.;Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.;Centre for Organismal Studies (COS), Glycobiology, Heidelberg University, Heidelberg, Germany.;Department of Pediatric Heart Surgery, University Hospital RWTH, Aachen, Germany.;Department of Pediatric Cardiology, University Hospital RWTH, Aachen, Germany.;Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.",
"authors": "Görlacher|Marlen|M|;Panagiotou|Eleftheria|E|;Himmelreich|Nastassja|N|;Hüllen|Andreas|A|;Beedgen|Lars|L|;Dimitrov|Bianca|B|;Geiger|Virginia|V|;Zielonka|Matthias|M|;Peters|Verena|V|;Strahl|Sabine|S|;Vázquez-Jiménez|Jaime|J|;Kerst|Gunter|G|;Thiel|Christian|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ymgmr.2020.100673",
"fulltext": "\n==== Front\nMol Genet Metab Rep\nMol Genet Metab Rep\nMolecular Genetics and Metabolism Reports\n2214-4269 Elsevier \n\nS2214-4269(20)30119-1\n10.1016/j.ymgmr.2020.100673\n100673\nResearch Paper\nFatal outcome after heart surgery in PMM2-CDG due to a rare homozygous gene variant with double effects\nGörlacher Marlen a1 Panagiotou Eleftheria b1 Himmelreich Nastassja a Hüllen Andreas a Beedgen Lars a Dimitrov Bianca a Geiger Virginia a Zielonka Matthias a Peters Verena a Strahl Sabine c Vázquez-Jiménez Jaime d Kerst Gunter b Thiel Christian Christian.thiel@med.uni-heidelberg.dea⁎ a Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany\nb Department of Pediatric Cardiology, University Hospital RWTH, Aachen, Germany\nc Centre for Organismal Studies (COS), Glycobiology, Heidelberg University, Heidelberg, Germany\nd Department of Pediatric Heart Surgery, University Hospital RWTH, Aachen, Germany\n⁎ Corresponding author at: Centre for Child and Adolescent Medicine, Pediatrics I, University of Heidelberg, Heidelberg, Germany. Christian.thiel@med.uni-heidelberg.de1 Görlacher & Panagiotou contributed equally.\n\n\n07 11 2020 \n12 2020 \n07 11 2020 \n25 10067323 10 2020 23 10 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Variants in Phosphomannomutase 2 (PMM2) lead to PMM2-CDG, the most frequent congenital disorder of glycosylation (CDG). We here describe the disease course of a ten-month old patient who presented with the classical PMM2-CDG symptoms as cerebellar hypoplasia, retinitis pigmentosa, seizures, short stature, hepato- and splenomegaly, anaemia, recurrent vomiting and inverted mamillae. A severe form of tetralogy of Fallot was diagnosed and corrective surgery was performed at the age of 10 months. At the end of the cardiopulmonary bypass, a sudden oedematous reaction of the myocardium accompanied by biventricular pump failure was observed immediately after heparin antagonization with protamine sulfate. The patient died seven days after surgery, since myocardial function did not recover on ECMO support. We here describe the first patient carrying the homozygous variant g.18313A > T in the PMM2 gene (NG_009209.1) that either can lead to c.394A > T (p.I132F) or even loss of 100 bp due to exon 5 skipping (c.348_447del; p.G117Rfs*4) which is comparable to a null allele. Proliferation and doubling time of the patient's fibroblasts were affected. In addition, we show that the induction of cellular stress by elevating the cell culture temperature to 40 °C led to a decrease of the patients' PMM2 transcript as well as PMM2 protein levels and subsequently to a significant loss of residual activity. We assume that metabolic stressful processes occurring after cardiac surgery led to the drop of the patient's PMM activity below a life-sustaining niveau which paved the way for the fatal outcome.\n\nKeywords\nCongenital disorder(s) of glycosylationPMM2Phosphomannomutase 2Splicing variantExon skippingN-glycosylation\n==== Body\n1 Introduction\nCongenital disorders of glycosylation (CDG) are about 140 genetic defects in glycoprotein and glycolipid glycosylation as well as glycosaminoglycans and GPI-anchor synthesis ([19]; [8]). Within the protein N-glycosylation, PMM2-CDG (about 900 reported patients) is by far the most common CDG [22].\n\nIn PMM2-CDG (OMIM: 601785) the conversion of mannose-6-phosphate to mannose-1-phosphate by the cytosolic phosphomannomutase 2 (PMM2) is affected. This reduces GDP-mannose, an essential nucleotide-activated sugar substrate for the early steps in N-glycosylation [28]. This leads to the accumulation of shortened dolichol-linked oligosaccharides (Man1-5GlcNAc2-PP-Dol) and subsequently to reduced provision of full-length dolichol-linked oligosaccharides (Glc3Man9GlcNAc2-PP-Dol) needed for the transfer onto the nascent glycoprotein by the oligosaccharyl transferase complex. As a consequence, glycosylation sites on glycoproteins are partially non-occupied by N-glycans leading to protein N-hypoglycosylation, indicated by a CDG type 1 pattern of serum transferrin after isoelectric focusing or HPLC separation.\n\nPMM2-CDG is a multisystem disease including neurological involvement and variable dysmorphism such as prominent forehead, long face, epicanthal folds, almond-shaped eyes, short nose, anteverted nares, long philtrum, thin upper lip, high-arched palate, large and protruding ears, microcephaly or macrocephaly, abnormal fat pads, inverted mamillae and cryptorchidism in boys [1]. The severity of the clinical presentation is mainly attributed to the patient's biallelic variant status and thus the residual activity of PMM2.\n\nPMM2 is a 28 kDa protein (NP_000294.1) encoded by 741 bp (NM_000303.3). The PMM2 gene (NG_009209.1) comprises eight exons and spans about 20 kbp on chromosome 16p13.2. Nearly 200 intronic and exonic variants are already associated with PMM2-CDG (see NCBI, ClinVar: https://www.ncbi.nlm.nih.gov/clinvar), most of them result in amino acid substitutions affecting the enzymatic conversion of mannose-6-phosphate or the stability of the protein.\n\nHere we describe the first PMM2-CDG patient with homozygosity for variant NG_009209.1:g.18313A > T which provokes two effects: shortening of the protein length by exon splicing and an amino acid alteration of the PMM2 protein composition due to a nucleotide substitution.\n\n2 Materials and methods\n2.1 Patient material\nThe study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committees of the Medical Faculty Aachen. Written informed consent was obtained from the parents for biochemical and sequencing analysis. The parents also consented to molecular testing (Sanger sequencing) of their own PMM2 status. Written informed consent was also obtained for the use of clinical information.\n\n2.2 Isoelectric focusing and SDS-PAGE of serum transferrin\nIsoelectric focusing of serum transferrin was carried out as described by Niehues and co-workers [20].\n\n2.3 Cell culture and cell collecting\nPatient and control fibroblasts were cultured in Dulbecco's modified Eagle's medium (high glucose, Life Technologies) supplemented with 10% fetal calf serum (PAN Biotech) and 1% Pen/Strep at 5% CO2 at 37 °C. Growth medium was changed every 72 h. Two days before running the assays, 2 × 106 fibroblasts were seeded and cultivated under the above-mentioned conditions at 37 °C and 40 °C, respectively. After 48 h cells were collected by scraping and used for the isolation of proteins and total RNA.\n\n2.4 PMM and MPI activity assay\nPMM activity was determined in control and patient fibroblasts. To isolate proteins, the scraped cells were solubilized (50 mM Hepes, pH 7.1) and centrifuged (45 min at 45,000 rpm and 4 °C). 30 μg of protein from the supernatant was used for the assay. PMM activity was determined via a coupled photometric assay at 340 nm for 120 min as described [14]. The photometric assay was performed at 37 °C and 40 °C, respectively. The MPI activity was also performed in a photometric assay with 30 μg protein as described [20].\n\n2.5 Analysis of dolichol-linked oligosaccharides\n1 × 106 fibroblasts derived from a control and the patient were cultured, and labelled with [2−3H]mannose for 30 min. Dolichol-linked oligosaccharides (LLO) were extracted and analysed by HPLC [27].\n\n2.6 SDS-PAGE and Western blot\nSDS-PAGE (10%) and Western blot were performed with the same protein material isolated for the PMM activity assay (see above). 10 μg of protein of the patient and controls were used per lane. Further procedure was as described previously [11]. All antibodies were diluted in PBS-T (0.1% Tween in PBS). Primary antibodies used were anti-PMM2 (rabbit anti human, polyclonal; Proteintech) in a 1:1000 dilution and anti-β-actin (mouse anti human; polyclonal, Sigma-Aldrich) in a 1:10,000 dilution. As secondary antibodieswe used anti-rabbit IgG conjugated with horseradish peroxidase (HRP) for PMM2 detection (Santa Cruz) and anti-mouse IgG-HRP for β-actin (Santa Cruz). Both secondary antibodies were diluted 1:10,000 in PBS-T. Protein signals were detected by light emission with Pierce™ ECL Western blotting substrate. Quantification of signal strength was performed by using ImageJ (www.imagej.nih.gov).\n\n2.7 Variant analysis in PMM2\nTotal RNA was extracted from control and patient fibroblasts (incubated at 37 °C) using the RNAeasy kit (Qiagen). First strand cDNA of PMM2 (NM_000303.3) was synthesized from 0.5 μg of total RNA with Omniscript reverse transcriptase (Qiagen) and the primer hPMM2_R1 (5’-GACTGCACATGCCTGGCATAG-3′). In a first round of PCR the cDNA was amplified with primers PMM2_F1 (5’-CGGAAGTTCCGGGCCGAGT-3′) and PMM2_R1 by using the HotStar-Taq-Polymerase kit (Qiagen). In a nested PCR, primers were PMM2_F2 (5’-CTCGTGCCAACGTGTCTTGTA-3′) and PMM2_R2 (5’-GCAGAGCCTGCCTAGGCTG-3′). Thermo Cycler conditions were: 94 °C for 1 min, followed by 35 cycles with 94 °C for 30 s, 55 °C for 30 s and 72 °C for 1.5 min.\n\nGenomic DNA from control and patient fibroblasts was isolated with the Genomic DNA Isolation Kit (Sigma-Aldrich). 100 ng of genomic DNA was used for amplification of PMM2 exon 5 (NG_009209.1) in two rounds of PCR with primers PMM2_ Ex5-6_F1 (5’-GCTGAGAAACATTGACCACACT-3′) together with PMM2_Ex5-6_R1 (5-CATACTTCATTATCAATAGCTCAC-3′) and PMM2_Ex5-6_F2 (5’-GCTGTTTATCTATGATGTTGCCCAA-3′) paired with PMM2_Ex5-6_R2 (5’-TGGGTATCCAAGTTTGGAACAC-3′) under the above-mentioned conditions. cDNA and exon PCR products were separated on 1% agarose gels and fragments were isolated with the peqGOLD (PeQLab) gel extraction kit. Variant analysis was performed by Sanger sequencing. The variant was uploaded to ClinVar Submission Wizard (SUB6890963; www.ncbi.nlm.nih.gov/clinvar/).\n\n2.8 Quantitative real-time PCR (qRT-PCR)\nTotal RNA was extracted from patient and control fibroblasts incubated at 37 °C and 40 °C using the MasterPure RNA purification kit (Epicentre Biotechnologies). One μg of RNA was reverse transcribed using random hexamer primers (Invitrogen) and the RevertAid Reverse Transcriptase (Thermo Scientific). Quantitative real-time PCR was performed with SensiFAST SYBR No-ROX-Mix (Bioline) with 50 ng cDNA in a CFX Connect Real-Time System (Bio Rad) with the following parameters: step 1: 95 °C, 15 s; step 2: 95 °C, 15 s; step 3: 60 °C, 1 min; step 4: 72 °C 10 s; step 5: 65 °C to 100 °C, 5 min; step 6: hold on 4 °C. Steps 2–4 were repeated 35 times. Primers were qPCR_PMM2_Ex5-8_F (5’-TGTCCCCTATTGGAAGAAGC-3′), qPCR_PMM2_Ex5-8_R (5’-GATCTCATGGTCATTGCC-3′) and qPCR_PMM2_Ex6-8_F (5’CAGATCTACGGAAAGAGT3’) together with qPCR_PMM2_Ex6-8_R (5’GATCTCATGGTCATTGCC3’). PMM2 expression was normalized against the gene expression of Ras-related protein (RAB7A) by using primers RAB7A_qPCR_F (5’-TGGGAGATTCTGGAGTCGGG-3′) combined with RAB7A_qPCR_R (5’-CACACCGAGAGACTGGAACC-3′).\n\n2.9 Immunofluorescence studies\nOne day before preparation, 6 × 104 fibroblasts were seeded on glass cover slips. Immunofluorescence was carried out as described (Hansske et al., 2001). Cells were stained with antibodies against PMM2 (Proteintech, rabbit anti-human, 1:400 in PBS-T) and MPI (Sigma Aldrich, mouse anti-human, 1:500). After incubation with fluorochrome-conjugated secondary antibodies (Alexa Fluor 488, ThermoFisher, goat anti-rabbit, 1:500; Alexa Fluor 568, ThermoFisher, goat anti-mouse, 1:500), respectively, cells were mounted with Mowiol and analysed by confocal fluorescence microscopy.\n\n2.10 Cell proliferation studies by live cell monitoring\nCell proliferation was assessed by following the manufacturer's guidelines using the XCelligence device (ACEA Biosciences). We seeded 1000 cells to the measuring cavities and cultured them under standard conditions for 120 h. Cell density was computer-based recorded every 30 min. Quantification was carried out with slope values (1/h) measured during the logarithmic growth phase according to the manufacturer's guidelines.\n\n2.11 Statistics\nWith exception of the LLO analysis, all experiments have been repeated at least three times. Data were analysed using Student's t-test for single comparisons or one-way ANOVA followed by Bonferroni's test for multiple comparisons. Significances of p values: *p ≤ 0.05; **p ≤ 0.005; ***p ≤ 0.001. Data are displayed as means ± standard deviation (SD).\n\n3 Results\n3.1 Patient report\nThis 10 month-old boy from related Turkish parents was referred for treatment of tetralogy of Fallot with severely hypoplastic infundibulum, pulmonary valve and pulmonary artery branches (Fig. 1). The patient showed also a small stature, inverted mamillae, bilateral radial aplasia, right-sided clubfoot, left-sided drop foot, retinitis pigmentosa, hepatosplenomegaly, cerebellar hypoplasia, reduced signals in the T2 sequence in consensus with white matter abnormality and generalized muscular hypotonia. Laboratory findings showed thrombocytopenia and increased serum transaminases. Because of recurrent hypoxemic spells, a modified Blalock-Taussig-shunt was placed at the age of six weeks. The postoperative course was uneventful. The boy showed neither thrombotic nor bleeding complications on standard antiplatelet therapy. At six months of age, a balloon angioplasty of the shunt and the hypoplastic pulmonary valve was performed. Corrective surgery at this time was not performed because the boy showed significant comorbidities: recurrent vomiting, leading to a failure to thrive, seizures necessitating anticonvulsive therapy and a presumably viral encephalitis. Corrective surgery was postponed until ten months of age and after this surgery and during weaning from cardiopulmonary bypass, transesophageal echocardiography (TOE) showed no residual defects and a good biventricular function. In order to reverse the anticoagulant effects of heparin at the end of the surgery, protamine sulphate was administered.. Shortly after, intensified catecholamine support was needed to stabilize the patient. TOE revealed increasing thickening of the myocardium of both ventricles compatible with biventricular edema and a severely reduced biventricular function, possibly due to microthrombotic cardiac ischemia. The patient was put on cardiopulmonary support by extracorporeal membrane oxygenation (ECMO). However, due to persistent non-recovery of biventricular function followed by multiorgan failure the boy died seven days after surgery. In respect to the multiple morphological stigmata and the unusual clinical course after cardiac surgery, diagnostic laboratory tests were initiated.Fig. 1 Intra-operative transesophageal echocardiography showed significant hypertrophy with increased septum thickness. Numbers indicate the penetration depth of echo in cm.\n\nFig. 1\n\n3.2 Isoelectric focusing of serum transferrin revealed a CDG-I pattern\nInitial CDG diagnostics was conducted by isoelectric focusing of serum transferrin which revealed a CDG type 1 pattern (Fig. 2A: elevated asialotransferrin (8%, ref. val. 0% - 2%) and disialotransferrin (16%, ref. val. 5% - 13%), and decreased tetrasialotransferrin (21%, ref. val. 30% - 55%; see [7] for ref. values)).Fig. 2 A Isoelectric focussing of serum transferrin revealed elevated amounts of disialo- and asialotransferrin in case of the patient (lane 4), indicating a CDG-I disease. As internal standards also a healthy control (lane 1) and CDG-I (lane 2) as well as CDG-II patients' samples (lane 3) are included. B Sanger Sequencing of PMM2 exon 5 showed homozygosity for variant c.394A > T (p.I132F) in the patient. The parents are heterozygous carriers. C Due to the loss of exon 5, amplification of the PMM2 cDNA by RT-PCR revealed a 100 bp shorter PCR product in case of the patient than in the control. D PMM2 protein alignment demonstrated Ile132 as a highly conserved amino acid in a highly conserved stretch through different species. E Schematic intron-exon structure of PMM2 from exon 3 to exon 7 (gDNA) and the spliced mRNA fragment (mRNA) of a healthy control and the patient with deletion of exon 5 leading to a shift in the open reading frame and a mutated C-terminus ending in Lys-Lys-Arg-Lys-Lys-Ile-* (short: KKRKKI*). F PMM2 activity analysis of a control and the patient. At 37 °C the patient's activity was reduced to 7%, whereas at 40 °C, the activity was only 3% as compared to the value measured at 37 °C. G Western blot analysis for PMM2 of control and patient fibroblasts. In comparison to the control, the patient's PMM2 expression was clearly reduced to 19% at 37 °C and further declined to 10% at 40 °C. H PMM2 qRT-PCR studies of control and patient fibroblasts. At 37 °C the PMM2 expression in the patient cells was diminished to 47% compared to the control, whereas only 4% residual PMM2 transcript level could be detected at 40 °C in case of the patient. I HPLC analysis of LLOs derived from control (in blue) and patient's fibroblasts (in orange) after metabolic labelling with [2-3H]mannose displayed accumulations of shortened oligosaccharide structures Man2-5 (Man2-5GlcNAc2-PP-Dol) accompanied by depletion of the full-length oligosaccharide Glc3. (Glc3Man9GlcNAc2-PP-Dol). J – L Analysis of cell growth. (J) XCelligence device analysis of cell proliferation of a control (blue) and the patient (orange) measured over 5 days. (K) PMM2-deficient cells needed about 1,25 times longer for doubling compared to control fibroblasts and showed a significantly reduced cell proliferation (L).\n\nUsed symbols: Image 1 = dolichol, Image 2 = galactose, Image 3 = N-Acetylglucosamine, Image 4 = mannose, Image 5 = glucose, Image6 = sialic acid\n\nFig. 2\n\n3.3 Sanger sequencing of the PMM2 gene identified a rare homozygous variant\nAnalysis of the patient's PMM2 gene by Sanger sequencing showed the homozygous variant NG_009209.1:g.18313A > T in exon 5. Both parents are carriers for the mutation. Interestingly, on cDNA level two different effects were provoked. First, base exchange c.394A > T leads to amino acid substitution p.I132F (Fig. 2B). Second, exon 5 was spliced out, whereby 100 bp (c.348-447 bp) were skipped and the PMM2 open reading frame was significantly altered (Fig. 2C and D). Concerning the amino acid substitution, isoleucin 132 is a highly conserved amino acid from Homo sapiens to Xenopus tropicalis (Fig. 2D), indicating its important role for function. Regarding the loss of 100 bp by deletion of exon 5, three alternative amino acids would be introduced after arginine 116. The patient's PMM2 would then be terminated due to a premature stop codon (Fig. 2E), leading to a protein with a theoretical molecular weight of 13.5 kDa (correlating with a loss of 51% of the wildtype protein size).\n\n3.4 Reduced PMM activity due to diminished PMM2 protein and reduced PMM2 transcript levels\nThe PMM activity in fibroblasts at the physiological relevant 37 °C was significantly reduced to 7.4% (± 1.3%; n = 6; ***p < 0.001; controls (100.0% ± 22.6%)) (Fig. 2F). MPI activity was normal (data not shown).\n\nIn Western blot analysis of fibroblasts, the patient's PMM2 expression was significantly reduced to 19.4% (± 11.8%; n = 6; ***p < 0.001; controls (100.0% ± 23.8%)) (Fig. 2G). Notably, no additional protein band was observed at 13.5 kDa in the patient. We also like to mention that the localization of the patient's PMM2 was not affected since it co-localizes with the cytosolic MPI in immunofluorescence analysis. Also, it was not mislocalized into the nucleus (data not shown). To further elucidate whether the PMM activity reduction was due to an impact on the patient's PMM2 mRNA level, qRT-PCR studies were performed. Normalized to RAB7 of the control (103.0% ± 27.0%), the quantity of the patient's PMM2 mRNA of the missense variant carrying transcript was significantly diminished (47.0% ± 8.5%; n = 9; ***p ≤ 0.001) (Fig. 2H). Additional qPCR analyses of the transcript with loss of exon 5 revealed almost the same significant reduction of mRNA expression level (42.0% ± 7.0%; n = 9; ***p ≤ 0.001) (data not shown). Next, we analysed the cells' doubling time and proliferation. Comparison of the slope values measured during the logarithmic growth phase (between 55 h to 110 h) showed that the patient's fibroblasts needed 1.25 times longer doubling time (29.9 h ± 1.8 h) than the control (23.9 h ± 0.3 h; n = 3; ***p ≤ 0,002; Fig. 2J). Besides, the proliferation of the patient's fibroblasts (0,017 ± 0,004) was significantly reduced to 44.7% ± 10.5% (controls 0,038 ± 0,004; n = 3; ***p ≤ 0,002) (Fig. 2K).\n\nPutting stress on the cells by incubating them at 40 °C and repeating the analyses on the transcript and protein level, we found that the patient's PMM2 protein expression dropped by 53.1% to 10.3% (± 6.9%; n.s.) in comparison to the data measured at 37 °C (Fig. 2G). This phenomenon was accompanied by an almost equivalent loss (minus of 54.1%) of PMM activity to 3.4% (± 0.3%; n = 6; ***p < 0.001) (Fig. 2F). Additionally, our qRT-PCR analysis revealed that due to the temperature increase in cell culture, the patient's PMM2 missense variant carrying transcript declined to 4.0% (± 0.3%; n = 9; ***p < 0.001) which is equal to a minus of 91.5% in comparison to the amount measured at 37 °C (Fig. 2H). Concerning the patient's PMM2 transcript level without exon 5, we detected 7.0% (± 2.7%; n = 9; ***p < 0.001; data not shown).In addition, LLO analysis revealed significant accumulations of shortened dolichol-linked oligosaccharides (esp. Man3-5GlcNAc2-PP-Dol; Fig. 2I), pointing to a severe impact of the patient's PMM2 deficiency on the early steps of glycoprotein biosynthesis.\n\n4 Discussion\nThe present patient was homozygous for the variant NG_009209.1:g.18313A > T in exon 5 of the PMM2 gene. To our knowledge this is the first time that homozygosity for this variant was found. Accordingly, database search revealed no entry in e.g. ClinVar or Ensemble. We found only one patient in the literature who was compound-heterozygous for c.394A > T (p.I132F) and c.338C > T (p.P113L) [17]. The closely related variant c.395 T > C (p.I132T) was found in 12 patients and was then associated with c.422G > A (p.R141H; 7 cases; Matthijs et al.,1998; [6,17,29]), c.368G > A (p.R123Q; 3 cases; [4,6,17,29]), c.620 T > C (p.F207S; 1 case, [24]) and c.58C > T (p.P20S; [17]). These patients consistently showed a severe phenotype. There is no information available about premature deaths.\n\nOn the cDNA level, we found that variant NG_009209.1:g.18313A > T leads to c.394A > T and subsequently to amino acid exchange p.I132F but as well to pseudosplicing of 100 bp (c.348_447del; p.G117Rfs*4) which comprised the complete exon 5 of the PMM2 gene. This is in accordance with a former study on a compound-heterozygous patient (c.394A > T and c.338C > T) showing that NG_009209.1:g.18313A > T was a splicing enhancer sequence [17]. Due to the exon loss and the subsequent shift in the open reading frame, a significantly shortened PMM2 protein of 13.5 kDa would be generated in which amino acids glycine 117, threonine 118 and phenylalanine 119 are changed into lysine 117, lysine 118 and isoleucine 119 before a premature termination occurred. Thereby this mutated protein would end in a KKRKK(I*) sequence, a single (monopartite) stretch of basic amino acids which displays a consensus motif for a nuclear localization signal in heat shock events [16]. However, we neither detected the shortened 13.5 kDa PMM2 by Western blot nor in the nucleus by immunofluorescence studies which indicates that it was not present. Whether already the shortened mRNA was degraded by nonsense mediated mRNA decay or the truncated protein by the unfolded protein response as quality control system of the cell, remains outside the scope of this manuscript. In addition, due to the fact that amino acids arginine123, arginine134 and arginine141 which are needed for substrate binding of GDP-mannose at the active side of the enzyme would be affected [2], we estimate that this protein would have had no activity. This is in line with experimental data for the most common amino acid substitution (p.R141H) in PMM2-CDG, originating from another base pair variant in exon 5, which leads to a protein with no enzymatic activity [13]. According to Andreotti and coworkers [2], p.I132F does not affect the active site of PMM2. Besides, the structural prediction of the PMM2 dimer by PDBePISA [15] indicates that variant p.I132F is buried in the structure and is not found at the protein interface (supplementary figure). However, computational simulation with DynaMut [23] predicts a destabilization of the protein (ΔΔG: −0.492 kcal/mol) and hence supports the assumption that the homozygous mutation p.I132F reduces both, the protein dynamics and the stability resulting from vibrational entropy changes (supplementary figure). Although two differently mutated PMM2 proteins can form heterodimers where one subunit stabilizes the other in a complementary fashion [3], we assume that this kind of dimerization is prevented in the presented patient due to homozygosity of variant p.I132F, which might be an additional explanation for the severity of this case. As the low residual PMM activity (7%) in the patient's fibroblasts arose from the full-length PMM2 protein carrying the p.I132F substitution only, we rate it as one of the severe PMM2 mutations [18,30].\n\nInflammation, remodelling and proliferation are important process in wound healing. This begins between day 4 and 5 after injury or surgery with the migration of fibroblasts into the wound matrix [26]. Since we found that the cell doubling time was significantly enhanced which was accompanied by a significantly reduced proliferation rate, we expect a general impact on the course of the healing.\n\nIt is well known that surgery can lead to wide and severe metabolic disarrangements as increased oxygen and energy consumption, hormonal imbalance, hyperglycaemia, hyperlactatemia, increased glutamate, aspartate and free fatty acid concentrations as well as increased systemic inflammation [9,12]. More recent studies even showed that after cardiac surgery extensive changes in the N-glycosylation of total plasma proteins are initiated within the first three days after the onset of the normal systemic inflammation [21]. Although this glycan-dependent mechanism is not completely understood, it nonetheless emphasises the importance of a functional glycosylation machinery during the stressful period of healing.\n\nNo plasma or serum sample was taken during surgery to test for respective N-glycan changes. But when we put stress on the patient's fibroblasts by elevating the incubation temperature to 40 °C, we significantly reduced the PMM2 transcript and protein level. Strikingly, the residual PMM2 activity hereby fell to 3.4%. Since fibroblasts generally show higher activities then, for example, leukocytes [10], one cannot rule out an even more severe effect of hyperthermia on the activity in other organs. However, a surgical wound and its surrounding exhibit a significant increase in wound temperature [25]. So, we suppose that at least the heart region around the surgery scar was impacted by an extremely low PMM2 activity, being insufficient for the glycosylation-dependent curing and proliferation processes which in combination could have led to the patient's bad outcome at day 7 after surgery.\n\nProtamine is an antidote routinely used to antagonize the heparin effect after surgery. Whether the patient's strong response to protamine administration during weaning from the cardiopulmonary bypass was directly related to the PMM2 glycosylation defect, is unclear. Reports with experiences from surgeries of other CDG patients are rare. However, protamine administration itself is associated with immunological and inflammatory alterations, and may induce an anaphylactic response with hypotension, bradycardia, pulmonary vasoconstriction, and allergy [5].\n\nIn conclusion, we consider homozygosity for the variant NG_009209.1:g.18313A > T to be life threatening, not only during surgery but also during a normal infection with fever, due to the temperature sensitivity of PMM2 transcripts. Since the majority of PMM2-CDG variants are not completely biochemically studied, more studies esp. under hyperthermia conditions are needed. Besides, a moderate cooling of the surgery area should be considered as potential benefit for (CDG) patients carrying thermolabile variants. Moreover, due to potential side-effects during surgeries, replacement of heparin and protamine application by e.g. bivalirudin, a direct thrombin inhibitor, should be considered for patients suffering from CDG or other severe metabolic defects.\n\nThe following are the supplementary data related to this article.Fig. S1 In silico structure prediction of wildtype and mutated PMM2 proteins. (A) Predicted impact of p.I132F on PMM2 protein conformation. Blue represents a rigidification of the structure. (B and C) Interactomic interactions in wildtype and mutated PMM2 proteins. Isoleucine 132 (B, wildtype) and phenylalanine (C, mutated) are colored in light-blue and are shown together with the interacting amino acid residues. (D) PDBePISA prediction of the PMM2 (PDB 2AMY) homodimer. Red circles indicate the site of mutation.\n\nFig. S1\n\nFunding\nThis study was supported by the 10.13039/501100001659Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; Forschungsgruppe FOR 2509, Project-ID TH1461/7–1 to CT and STR 443/6–1 to SS) and the 10.13039/501100000780European Commission (E-Rare-3 Joint Transnational Call 2018/ EUROGLYCAN-OMICS in association with the 10.13039/501100001659Deutsche Forschungsgemeinschaft, Project-ID TH1461/9–1).\n\nContributions\nMG: Planned and conducted experiments, contributed to the writing of the manuscript. NH, AH, LB, BD, VG: Conducted experiments. EP, GK, MZ, VP, SS, JVJ: Collected data and contributed to the interpretation of the results. CT: Planning of experiments, interpretation of data and writing of the manuscript.\n\nDeclaration of Competing Interest\nThe authors declare that there is no conflict of interests.\n==== Refs\nReferences\n1 Altassan R. Péanne R. Jaeken J. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: diagnosis, treatment and follow up J. Inherit. Metab. Dis. 42 2019 5 28 30740725 \n2 Andreotti G. Cabeza de Vaca I. Poziello A. Monti M.C. Guallar V. Cubellis M.V. Conformational response to ligand binding in phosphomannomutase2: insights into inborn glycosylation disorder J. Biol. Chem. 289 2014 34900 34910 25324542 \n3 Andreotti G. Monti M.C. Citro V. Cubellis M.V. Heterodimerization of two pathological mutants enhances the activity of human phosphomannomutase2 PLoS One 10 2015 e0139882 \n4 Arnoux J.B. Boddaert N. Valayannopoulos V. Risk assessment of acute vascular events in congenital disorder of glycosylation type Ia Mol Genet. Metab. 93 2008 444 449 \n5 Boer C. Meesters M.I. Veerhoek D. Vonk A.B.A. Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review Br. J. Anaesth. 120 2018 914 927 29661409 \n6 De Lonlay P. Seta N. Barrot S. A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases J. Med. Genet. 38 1 2001 14 19 10.1136/jmg.38.1.14 11134235 \n7 Dimitrov B. Himmelreich N. Hipgrave Ederveen A.L. Cutis laxa, exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG Mol. Genet. Metab. 123 2018 364 374 29396028 \n8 Ferreira C.R. Van Karnebeek C.D.M. Vockley J. Blau N. A proposed nosology of inborn errors of metabolism Genet Med. 21 2019 102 106 29884839 \n9 Finnerty C.C. Mabvuure N.T. Ali A. Kozar R.A. Herndon D.N. The surgically induced stress response JPEN J. Parenter. Enteral Nutr. 37 2013 21S-9S \n10 Grünewald S. Schollen E. Van Schaftingen E. Jaeken J. Matthijs G. High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency) Am. J. Hum. Genet. 68 2001 347 354 11156536 \n11 Himmelreich N. Dimitrov B. Geiger V. Novel variants and clinical symptoms in four new ALG3-CDG patients, review of the literature, and identification of AAGRP-ALG3 as a novel ALG3 variant with alanine and glycine-rich N-terminus Hum. Mutat. 40 2019 938 951 31067009 \n12 Jakob S.M. Ensinger H. Takala J. Metabolic changes after cardiac surgery Curr Opin Clin Nutr Metab Care. 4 2 2001 Mar 149 155 11224661 \n13 Kjaergaard S. Skovby F. Schwartz M. Carbohydrate-deficient glycoprotein syndrome type 1A: expression and characterisation of wild type and mutant PMM2 in E. coli Eur. J. Hum. Genet. 7 1999 884 888 10602363 \n14 Körner C. Lehle L. von Figura K. Abnormal synthesis of mannose 1-phosphate derived carbohydrates in carbohydrate-deficient glycoprotein syndrome type I fibroblasts with phosphomannomutase deficiency Glycobiology 8 2 February 1998 165 171 9451026 \n15 Krissinel E. Henrick K. Inference of macromolecular assemblies from crystalline state J. Mol. Biol. 372 2007 774 797 17681537 \n16 Lange A. Mills R.E. Lange C.J. Stewart M. Devine S.E. Corbett A.H. Classical nuclear localization signals: definition, function, and interaction with importin alpha J. Biol. Chem. 282 2007 5101 5105 17170104 \n17 Le Bizec C. Vuillaumier-Barrot S. Barnier A. A new insight into PMM2 mutations in the French population Hum. Mutat. 25 2005 504 505 \n18 Matthijs G. Schollen E. Van Schaftingen E. Cassiman J.J. Jaeken J. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A Am. J. Hum. Genet. 62 3 1998 542 550 10.1086/301763 9497260 \n19 Ng B.G. Freeze H.H. Perspectives on glycosylation and its congenital disorders Trend. Genet. 34 6 2018 466 476 10.1016/j.tig.2018.03.002 TIG \n20 Niehues R. Hasilik M. Alton G. Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy J. Clin. Invest. 101 7 1998 1414 1420 10.1172/JCI2350 9525984 \n21 Novokmet M. Lukić E. Vučković F. Ðurić Ž. Keser T. Rajšl K. Remondini D. Castellani G. Gašparović H. Gornik O. Lauc G. Changes in IgG and total plasma protein glycomes in acute systemic inflammation Sci. Rep. 4 2014 Mar 11 4347 24614541 \n22 Peanne R. de Lonlay P. Foulquier F. Congenital disorders ofglycosylation (CDG): quo vadis? Eur. J. Med. Genet. 61 2018 643 663 29079546 \n23 Rodrigues C.H. Pires D.E. Ascher D.B. DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability Nucleic Acids Res. 46 2018 W350 W355 29718330 \n24 Shanti B. Silink M. Bhattacharya K. Congenital disorder of glycosylation type Ia: heterogeneity in the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency J. Inherit. Metab. Dis. 32 2009 241 251 10.1007/s10545-009-1180-2 \n25 Siah C.R. Childs C. Chia C.K. Cheng K.F.K. An observational study of temperature and thermal images of surgical wounds for detecting delayed wound healing within four days after surgery J. Clin. Nurs. 28 2019 2285 2295 30791157 \n26 Son D. Harijan A. Overview of surgical scar prevention and management J. Korean Med. Sci. 29 6 2014 751 24932073 \n27 Thiel C. Rind N. Popovici D. Hoffmann Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip Hum. Mutat. 33 2012 485 487 22213132 \n28 Van Schaftingen E. Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I FEBS Lett. 377 1996 318 320 10.1016/0014-5793(95)01357-1 \n29 Vuillaumier-Barrot S. Hetet G. Barnier A. Identification of four novel PMM2 mutations in congenital disorders of glycosylation (CDG) Ia French patients J. Med. Genet. 37 8 2000 579 580 10.1136/jmg.37.8.579T 10922383 \n30 Yuste-Checa P. Gámez A. Brasil S. Desviat L.R. Ugarte M. Pérez-Cerdá C. Pérez B. The effects of PMM2-CDG-causing mutations on the folding, activity, and stability of the PMM2 protein Hum. Mutat. 36 2015 851 860 26014514\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4269",
"issue": "25()",
"journal": "Molecular genetics and metabolism reports",
"keywords": "Congenital disorder(s) of glycosylation; Exon skipping; N-glycosylation; PMM2; Phosphomannomutase 2; Splicing variant",
"medline_ta": "Mol Genet Metab Rep",
"mesh_terms": null,
"nlm_unique_id": "101624422",
"other_id": null,
"pages": "100673",
"pmc": null,
"pmid": "33209585",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "29718330;25324542;10922383;26488408;15844218;26014514;29884839;24009246;24932073;9497260;18093857;30791157;24614541;9525984;22213132;10602363;17170104;9451026;17681537;19396570;11156536;29079546;29606283;30740725;11224661;11134235;8549746;29661409;29396028;31067009",
"title": "Fatal outcome after heart surgery in PMM2-CDG due to a rare homozygous gene variant with double effects.",
"title_normalized": "fatal outcome after heart surgery in pmm2 cdg due to a rare homozygous gene variant with double effects"
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"abstract": "Salmonellosis is characterized by gastroenteritis and enteric fever in humans and affects various organs, particularly in endemic regions and in immunocompromised patients. Here, we report on a 45-year-old male patient with multifocal osteomyelitis, pneumonia and colonic ulcers caused by Salmonella typhi infection. The patient was admitted to our outpatient department with dysuria, fever and hip pain and had been treated with prednisolone and methotrexate for pemphigus vulgaris for two months. After Salmonella typhi was isolated in the urine culture, the patient was hospitalized and treated according to the antibiogram. However, despite antibiotherapy, the patient's ongoing complaints suggested an existing resistance problem or a rare or atypical involvement of Salmonella spp. As immunosuppressive agents were not used in high doses or for prolonged periods, this disease course and severity were not expected. For an infectious process with an atypical course or multiorgan involvement, particularly in endemic regions and immunocompromised patients, salmonellosis should be considered in the differential diagnosis.",
"affiliations": "Department of Infectious Diseases and Clinical Microbiology, Gaziantep University Faculty of Medicine, Gaziantep, Turkey. Electronic address: ayseozlem_ornek@hotmail.com.;Alanya Alaaddin Keykubat University, Education and Research Hospital, Antalya, Turkey.",
"authors": "Mete|Ayşe Özlem|AÖ|;Tekin Şahin|Sema|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jiph.2020.09.005",
"fulltext": null,
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"issn_linking": "1876-0341",
"issue": "13(11)",
"journal": "Journal of infection and public health",
"keywords": "Multifocal osteomyelitis; Salmonella typhi; Salmonellosis",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010019:Osteomyelitis; D012480:Salmonella Infections; D012485:Salmonella typhi; D014435:Typhoid Fever",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "1787-1790",
"pmc": null,
"pmid": "33051159",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A rare case of salmonellosis with multifocal osteomyelitis and pulmonary involvement.",
"title_normalized": "a rare case of salmonellosis with multifocal osteomyelitis and pulmonary involvement"
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"companynumb": "NVSC2020TR297261",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstancename": "METHOTREXATE"
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"abstract": "Sacubitril/Valsartan (Sac/Val) was proven more effective than enalapril for symptomatic patients with heart failure (HF) with reduced ejection fraction (HFrEF). This study aimed to investigate eligibility, titration, and tolerability for Sac/Val in a real-world clinical setting.\n\n\n\nThis retrospective cohort study consists of two parts. In Part 1 (eligibility study), all patients discharged from Sahlgrenska University Hospital due to HF were consecutively included during 1 year. Data from the patients' medical records were collected. Patients were adjudicated to be eligible based on European Society of Cardiology (ESC) criteria for angiotensin receptor neprilysin inhibitor (ARNI) with the exception of N-terminal (NT)-proBNP levels. Patients who received <50% of target dose angiotensin-converting enzyme/angiotensin receptor blocker and otherwise fulfilled ESC criteria were adjudicated to be potentially eligible. In Part 2 (tolerability study), all patients receiving Sac/Val during the same period were included. Medical data regarding dose, titration, and adverse effects and events were registered. A total of 1355 patients (mean age 78 ± 13 years) were hospitalized for HF and 619 patients had an EF ≤40%. Twenty percent were eligible for initiation of ARNI, and additionally 8% were potentially eligible. In all 95 patients (mean age 65 ± 12 years) were initiated with Sac/Val, which correlates to 13%. The patients who were initiated were younger (65 years), more often had dilated cardiomyopathy (31%), more often were on guideline-directed medical therapy, and had a higher frequency of cardiac resynchronization therapy and implantable cardioverter-defibrillator compared with the patients who did not receive Sac/Val. Of the initiated patients, 59% reached target dose of Sac/Val, and 15% discontinued due to adverse effects. The most common cause of discontinuation was benign gastrointestinal adverse effects, followed by elevated creatinine, malaise, and vertigo. Female gender [odds ratio (OR) 3.58; 95% CI 1.07-2.00; P = 0.038] and NT-proBNP ≥ median level (OR 0.48; 95% CI 0.26-0.90; P = 0.021) was associated with termination of the medication.\n\n\n\nAmong HFrEF patients in this real-world cohort, 20% were eligible for ARNI; however, only 13% received the treatment. Sac/Val was well tolerated, but 41% of the patients did not reach target dose. How this affects outcome is not known and needs further investigation.",
"affiliations": "Department of Molecular and Clinical Medicine/Cardiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Molecular and Clinical Medicine/Cardiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.;Department of Molecular and Clinical Medicine/Cardiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.",
"authors": "Nordberg Backelin|Charlotte|C|;Fu|Michael|M|;Ljungman|Charlotta|C|",
"chemical_list": "D000613:Aminobutyrates; D001713:Biphenyl Compounds; D004338:Drug Combinations; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination",
"country": "England",
"delete": false,
"doi": "10.1002/ehf2.12644",
"fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822 John Wiley and Sons Inc. Hoboken \n\n10.1002/ehf2.12644\nEHF212644\nESCHF-19-00313\nOriginal Research Article\nOriginal Research Articles\nEarly experience of Sacubitril–Valsartan in heart failure with reduced ejection fraction in real‐world clinical setting\nEarly experience of Sacubitril‐ValsartanC.N. Backelin et al.Nordberg Backelin Charlotte \n1\ncharlotte.backelin@vgregion.se Fu Michael \n1\n Ljungman Charlotta \n1\n \n1 \nDepartment of Molecular and Clinical Medicine/Cardiology, Institute of Medicine, Sahlgrenska Academy\nUniversity of Gothenburg\nGöteborg\nSweden\n\n* \nCorrespondence to: Charlotte Nordberg Backelin, Department of Molecular and Clinical Medicine/Cardiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden. Tel: +46313427577. Email: charlotte.backelin@vgregion.se\n\n06 2 2020 \n6 2020 \n7 3 10.1002/ehf2.v7.31049 1055\n20 9 2019 17 1 2020 26 1 2020 © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of CardiologyThis 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\nAims\nSacubitril/Valsartan (Sac/Val) was proven more effective than enalapril for symptomatic patients with heart failure (HF) with reduced ejection fraction (HFrEF). This study aimed to investigate eligibility, titration, and tolerability for Sac/Val in a real‐world clinical setting.\n\nMethods and results\nThis retrospective cohort study consists of two parts. In Part 1 (eligibility study), all patients discharged from Sahlgrenska University Hospital due to HF were consecutively included during 1 year. Data from the patients' medical records were collected. Patients were adjudicated to be eligible based on European Society of Cardiology (ESC) criteria for angiotensin receptor neprilysin inhibitor (ARNI) with the exception of N‐terminal (NT)‐proBNP levels. Patients who received <50% of target dose angiotensin‐converting enzyme/angiotensin receptor blocker and otherwise fulfilled ESC criteria were adjudicated to be potentially eligible. In Part 2 (tolerability study), all patients receiving Sac/Val during the same period were included. Medical data regarding dose, titration, and adverse effects and events were registered. A total of 1355 patients (mean age 78 ± 13 years) were hospitalized for HF and 619 patients had an EF ≤40%. Twenty percent were eligible for initiation of ARNI, and additionally 8% were potentially eligible. In all 95 patients (mean age 65 ± 12 years) were initiated with Sac/Val, which correlates to 13%. The patients who were initiated were younger (65 years), more often had dilated cardiomyopathy (31%), more often were on guideline‐directed medical therapy, and had a higher frequency of cardiac resynchronization therapy and implantable cardioverter–defibrillator compared with the patients who did not receive Sac/Val. Of the initiated patients, 59% reached target dose of Sac/Val, and 15% discontinued due to adverse effects. The most common cause of discontinuation was benign gastrointestinal adverse effects, followed by elevated creatinine, malaise, and vertigo. Female gender [odds ratio (OR) 3.58; 95% CI 1.07–2.00; P = 0.038] and NT‐proBNP ≥ median level (OR 0.48; 95% CI 0.26–0.90; P = 0.021) was associated with termination of the medication.\n\nConclusions\nAmong HFrEF patients in this real‐world cohort, 20% were eligible for ARNI; however, only 13% received the treatment. Sac/Val was well tolerated, but 41% of the patients did not reach target dose. How this affects outcome is not known and needs further investigation.\n\nChronic heart failureEligibilityHFrEFPharmacological TreatmentSacubitril–ValsartanTolerabilityNovartis (SE) 10.13039/100004336Västra Götalandsregionen 10.13039/100007212ALFGBG‐878221Novartis 10.13039/100004336Swedish government and the country councils, the ALF‐agreement source-schema-version-number2.0cover-dateJune 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:31.05.2020\n\n\nNordberg Backelin , C. \n, \nFu , M. \n, and \nLjungman , C. \n (2020 ) Early experience of Sacubitril–Valsartan in heart failure with reduced ejection fraction in real‐world clinical setting\n. ESC Heart Failure , 7 : 1049 –1055\n. 10.1002/ehf2.12644 .\n==== Body\n1 Introduction\nHeart failure (HF) is a syndrome that affects approximately 26 million patients worldwide,1 and the prevalence is estimated to approximately 2% in the western world. 2, 3 In Sweden, it is among the most common causes of hospitalization.4 Despite guideline‐directed medical therapy (GDMT) including ACE inhibitor (ACEI) or angiotensin II receptor blocker (ARB) together with beta‐blocker (BB) and mineral corticoid receptor antagonist (MRA), both mortality and morbidity remain high.3, 5\n\n\nSacubitril/Valsartan, an angiotensin receptor neprilysin inhibitor (ARNI) is a novel treatment of HF with reduced ejection fraction (HFrEF) and was shown in the PARADIGM‐HF trial to be more effective than enalapril for symptomatic HFrEF patients in reducing mortality and morbidity.6 However, the HF population in real‐world differs from patients in randomized controlled trials in many aspects. The population in the PARADIGM‐HF trial was younger and excluded patients who could not tolerate enalapril 20 mg daily during a run‐in phase in the trial. This raised serious concern of applicability of the trial results in a real‐world setting in which the main body of HF population do not tolerate target dose of GDMT.7, 8 Therefore, it remains uncertain what proportion of patients with HF that would be eligible for ARNI, and if so, how well is ARNI tolerated? In this study, we sought to assess the representativeness of the PARADIGM‐HF trial in a real‐world population of patients with HFrEF by investigating eligibility and tolerability of ARNI during the early implementation in Sahlgrenska University Hospital in Gothenburg, Sweden.\n\n2 Methods\nThis retrospective cohort study was made in two parts: eligibility and tolerability study. The study complies with the Declaration of Helsinki and was approved by the Swedish ethical committee.\n\n2.1 Eligibility study\nAll patients from Sahlgrenska University Hospital (Mölndal, Sahlgrenska, and Östra Hospital) who were hospitalized in any ward and discharged with the main diagnosis of HF (ICD10 I.50) were consecutively included from the 1st of November 2016 until the 31st of October 2017. The hospitals have a catchment area of approximately 800 000 people. We manually extracted data from the hospital's medical records according to a standardized protocol. Data from the time of hospitalization regarding age, gender, ejection fraction, laboratory results, blood pressure, aetiology and duration of HF, medical therapy, dosing, and device therapy were registered and then later validated by a second reviewer. Comorbidities were registered from the text of the journals.\n\nPatients with left ventricular ejection fraction (LVEF) ≤40% were considered fully eligible for ARNI if they fulfilled the safety criteria of S‐Potassium (s‐K) ≤5.2 mmol/L, estimated glomerulation filtration rate (eGFR) ≥30 mL/h/L, and 73 m2 and systolic blood pressure (SBP) of ≥100 mmHg and were treated with BB and at least 50% of target dose of ACEI/ARB. Patients were considered potentially eligible for ARNI if the ACEI/ARB dose were <50% of target dose. We considered all patients symptomatic because they were hospitalized due to HF. The eGFR was calculated with the chronic kidney disease epidemiology collaboration formula.9\n\n\n2.2 Tolerability study\nAll patients from the eligibility study who were prescribed ARNI, either during hospitalization or during follow up at the outpatient clinic, were included. To this cohort, we added patients with HFrEF from the HF outpatient clinic who were initiated with ARNI during the same period of time. This made the cohort more numerous and also more comparable with the paradigm study in which only ambulatory patients were included. The titration of ARNI was performed in a nurse‐based HF outpatient clinic. Information of titration rate, all adverse effects, hospitalizations, mortality, laboratory results, blood pressure, medication, dosage, and discontinuation were collected from the hospital's medical records during the titration period. The follow‐up period regarding mortality was 12 months after initiation.\n\n2.3 Statistical analysis\nCategorical variables are presented as numbers (n) and percentages (%). For continuous variables mean, standard deviation, median (min; max) is presented. For comparison between the groups, Fisher's exact test was used for dichotomous variables, and the Mann–Whitney U‐test was used for continuous variables. The impact of selected variables [age, sex, SBP, diastolic blood pressure, ischemic heart disease, N‐terminal (NT)‐proBNP, renal disease, number of different types of comorbidities, and the starting doses of Sac/Val registered at first up‐titration] on the incidence of discontinuation of ARNI was evaluated by applying age‐adjusted univariable logistic regression. Odds ratio (OR) and 95% confidence interval (CI) were presented along with area under the receiver operating characteristic curve, area under the curve for receiver operating characteristic curve, as a goodness‐of‐fit statistics.\n\nAll tests were two tailed and conducted at 0.05 significance level. All analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).\n\n3 Results\n3.1 Eligibility study\nDuring 1 year, 1355 patients were hospitalized due to HF of which 603 patients had LVEF >40%, 619 patients had LVEF ≤40%, and 133 patients had missing data of LVEF. There were 64 patients with missing data of SBP (n = 36), eGFR (n = 21), or s‐K (n = 7), leaving 555 patients included in the eligibility study. Of the patients, 62.9% were diagnosed with HF for 6 months or longer, and the most common aetiology of HF was ischemic heart disease (43%; n = 237). The mean age was 74.0 ± 13.9 years, and the median age was 76.0 years (min; max 18.0; 100.0). Of the patients, 30.5% were women.\n\nMedication with ACEI or ARB were used by 376 (67.7%) patients, and 208 (37.5%) were prescribed ≥50% of target dose of ACEI or ARB. Of the patients 88,5% (n = 491) were on treatment with BB, and 42.7% (n = 237) were on MRA.\n\nIn the hospital cohort, 111 patients (20%) were fully eligible for initiation of ARNI according to ESC criteria with the exception of NT‐proBNP level. Additional 45 (8%) of the patients were considered potentially eligible. The main reason for not being fully eligible is insufficient basic medication, predominantly ACEI and ARB.\n\n3.2 Tolerability study\nIn the tolerability part of the study, 73 patients from the hospital cohort and 22 patients from the outpatient ward, in total 95 patients, were initiated and up‐titrated with ARNI (Figure\n1). Comparison between the groups, in total 577 patients (555 from the hospital cohort and 22 from the outpatient ward), is shown in Table 1a. The patients who were treated with ARNI were younger, with lower NT‐proBNP, and more often on GDMT (100% with BB and 100% with MRA) Table 1b. The aetiology was more often dilated cardiomyopathy in the ARNI group. Of the patients initiated on ARNI, 58.9% reached target dose after up‐titration. Adverse effects of ARNI during the titration period are illustrated in Figure 2. Of the patients, 25% (n = 24) were rehospitalized for HF, and the mortality rate was 12% (n = 11) during the 1 year of follow up. With the exception of discontinuation due to death, mechanical assist, or heart transplantation, 14.7% discontinued ARNI medication. The most common cause of discontinuation was gastrointestinal adverse effects, followed by elevated creatinine, malaise, and vertigo (Figure\n3). Age‐adjusted logistic regression analysis showed that female gender (OR 3.58; 95% CI 1.07–2.00; P = 0.038) and a NT‐proBNP higher than the median level of 2860 ng/L (OR 0.48; 95% CI 0.26–0.90; P = 0.021) predicted discontinuation of the treatment.\n\nFigure 1 Inclusions of patients in the tolerability part of the study and the up‐titration of ARNI. Data is presented in numbers. ARNI, angiotensin receptor neprilysin inhibitor\n\nFigure 2 Adverse events during up‐titration of angiotensin receptor neprilysin inhibitor. Data is presented in numbers and percentage. Patients can have multiple adverse events and be registered several times\n\nTable 1a Patient characteristics\tTotal (n = 577)\tHospitalized non‐ARNI patients (n = 482)\tARNI patients (n = 95)\t\nP‐value\t\nMale\t402 (69.7%)\t327 (67.8%)\t75 (78.9%)\t\t\nFemale\t175 (30.3%)\t155 (32.2%)\t20 (21.1%)\t0.038\t\nAge\t73.8 (13.6)\t75,4 (13.2)\t65,4 (12.2)\t<0.0001\t\n76.0 (18.0; 100.0)\t78.0 (18.0; 100.0)\t66.0 (36.0; 86.0)\t\n\nn = 577\t\nn = 482\t\nn = 95\t\nSBP and lab results\t\t\t\t\t\nSBP (mmHg)\t129.3 (23.0)\t131.7 (23.0)\t116.6 (18.7)\t<0.0001\t\n129.0 (68.0; 224.0)\t130.0 (68.0; 224.0)\t116.0 (80.0; 180.0)\t\n\nn = 573\t\nn = 482\t\nn = 91\t\nPotassium (mmol/L)\t4.2 (0.54)\t4.2 (0.52)\t4.5 (0.55)\t<0.0001\t\n4.2 (2.20; 7.10)\t4.1 (2.20; 7.10)\t4.5 (2.90; 6.10)\t\n\nn = 572\t\nn = 482\t\nn = 90\t\nNT‐proBNP (ng/L)\t9172 (13 371)\t9945 (14 249)\t5627 (7308)\t<0.0001\t\n5680 (66; 218 000)\t6420 (87; 218 000)\t2860 (66; 34 200)\t\n\nn = 441\t\nn = 362\t\nn = 79\t\neGFR (CKD‐EPI)\t59.6 (29.2)\t58.8 (29.1)\t63.6 (29.2)\t0.10\t\n57.8 (4.3; 292.2)\t56.7 (4.3; 292.2)\t61.9 (24.3; 265.9)\t\n\nn = 576\t\nn = 482\t\nn = 94\t\nAetiology of HF\t\t\t\t\t\nHypertension\t102 (17.7%)\t87 (18.0%)\t15 (15.8%)\t0.72\t\nIHD\t237 (41.1%)\t210 (43.6%)\t27 (28.4%)\t0.0076\t\nDCM\t65 (11.3%)\t35 (7.3%)\t30 (31.6%)\t<0.0001\t\nHCM\t3 (0.5%)\t1 (0.2%)\t2 (2.1%)\t0.14\t\nValve disease\t28 (4.9%)\t24 (5.0%)\t4 (4.2%)\t1.00\t\nARNI, angiotensin receptor neprilysin inhibitor; CKD‐EPI, chronic kidney disease epidemiology collaboration; DCM, dilated cardiomyopathy; EF, ejection fraction; eGFR, estimated glomerulation filtration rate; HCM, hypertrophic cardiomyopathy; HF, heart failure; IHD, ischemic heart disease; NT‐proBNP, N‐terminal pro BNP; SBP, systolic blood pressure.\n\nTable 1a Comparison of non‐ARNI patients and ARNI patients. For categorical variables, n (%) is presented. For continuous variables, mean (SD)/median (min; max)/n= is presented.\n\nTable 1b Comorbidities\tTotal (n = 577)\tHospitalized non‐ARNI patients (n = 482)\tARNI patients (n = 95)\t\nP‐value\t\nNumber of different types of comorbidities\t2.6 (1.41)\t2.6 (1.43)\t2.2 (1.25)\t0.011\t\n2.0 (0.00; 6.00)\t3.0 (0.00; 6.00)\t2.0 (0.00; 6.00)\t\n\nn = 577\t\nn = 482\t\nn = 95\t\nHypertension\t280 (48.5%)\t249 (51.7%)\t31 (32.6%)\t0.0009\t\nMyocardial infarction\t233 (40.4%)\t199 (41.3%)\t34 (35.8%)\t0.38\t\nAtrial fibrillation\t293 (50.8%)\t248 (51.5%)\t45 (47.4%)\t0.54\t\nDiabetes type 1\t9 (1.6%)\t7 (1.5%)\t2 (2.1%)\t0.90\t\nDiabetes type 2\t162 (28.1%)\t138 (28.6%)\t24 (25.3%)\t0.59\t\nStroke\t74 (12.8%)\t64 (13.3%)\t10 (10.5%)\t0.59\t\nRenal disease\t124 (21.5%)\t111 (23.0%)\t13 (13.7%)\t0.052\t\nCOPD\t60 (10.4%)\t58 (12.0%)\t2 (2.1%)\t0.0022\t\nAsthma\t25 (4.3%)\t23 (4.8%)\t2 (2.1%)\t0.38\t\nSleep apnea\t33 (5.7%)\t25 (5.2%)\t8 (8.4%)\t0.32\t\nMalign cancer\t94 (16.3%)\t84 (17.4%)\t10 (10.5%)\t0.12\t\nValve disease\t98 (17.0%)\t90 (18.7%)\t8 (8.4%)\t0.016\t\nRA\t16 (2.8%)\t14 (2.9%)\t2 (2.1%)\t0.99\t\nThyroid disease\t67 (11.6%)\t57 (11.8%)\t10 (10.5%)\t0.88\t\nMedication\t\t\t\t\t\nBeta blockers\t515 (89.3%)\t420 (87.1%)\t95 (100.0%)\t<0.0001\t\nMRA\t278 (48.2%)\t183 (38.0%)\t95 (100.0%)\t<0.0001\t\nIvabradine\t3 (0.5%)\t1 (0.2%)\t2 (2.1%)\t0.14\t\nLoop diuretics\t447 (77.5%)\t391 (81.1%)\t56 (58.9%)\t<0.0001\t\nAnticoagulant\t280 (48.5%)\t229 (47.5%)\t51 (53.7%)\t0.32\t\nDevice\t\t\t\t\t\nPacemaker\t51 (8.8%)\t50 (10.4%)\t1 (1.1%)\t0.0016\t\nCRT without ICD\t27 (4.7%)\t23 (4.8%)\t4 (4.2%)\t1.00\t\nCRT with ICD\t39 (6.8%)\t21 (4.4%)\t18 (18.9%)\t<0.0001\t\nICD without CRT\t43 (7.5%)\t27 (5.6%)\t16 (16.8%)\t0.0010\t\nARNI, angiotensin receptor neprilysin inhibitor; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; MRA, mineralcorticoid receptor antagonist; RA, rheumatoid arthritis.\n\nTable 1b Comparison of non‐ARNI patients and ARNI patients.For categorical variables, n (%) is presented. For continuous variables, mean (SD)/median (min; max)/n= is presented.\n\nFigure 3 Reasons for discontinuation of angiotensin receptor neprilysin inhibitor during follow up, 1 year after initiation. Data is presented in numbers\n\n4 Discussion\nDuring the first year of introduction of ARNI in Sahlgrenska University Hospital, 13% of the hospitalized HFrEF patients were initiated with ARNI, despite that 20% of the patients were eligible and 28% were potentially eligible. Side effects and discontinuation rates were comparable to those observed in the PARADIGM‐HF trial.\n\nIn the PARADIGM‐HF trial, there was a single‐blind run‐in period, during which all patients received enalapril at target dose, followed by a single‐blind run‐in period during which all patients received Sac/Val at target dose. This was to ensure an acceptable side‐effect profile of the study drug at target doses and to minimize discontinuation rates in the trial. However, this raised serious concern about representativeness of the trial in the real‐world clinical setting. Moreover, similar inclusion and exclusion criteria were adopted by European and Swedish guideline recommendations for selecting patients for ARNI. However, in our daily clinical practice, it is impossible to provide run‐in prior to initiation of ARNI. More than one third of the HF patients in this study did not tolerate the target dose. Therefore, experience of early implementation of ARNI is important.\n\nIn our study, 20–28% of all hospitalized HF patients were eligible, and this is in line with previous studies.10, 11, 12 However, a recent publication from the Swedish Heart failure Registry showed that 34–76% of the patients were eligible to ARNI.13 The patients registered in the Swedish Heart failure Registry are real‐world patients but still a selected group from cardiology clinics with an interest of HF.\n\nIn our study, all hospitalized HF patients, from all clinics, not only cardiology wards, at the hospitals were consecutively included and might reflect the “real‐world” HF population in a more correct manor.\n\nAnother recent Swedish study comparing eligible and noneligible patients showed that eligible patients had lower all‐cause mortality than those who were noneligible although they still had higher mortality compared with the PARADIGM‐HF trial population.14\n\n\nThe patients from our cohort who were initiated with ARNI were younger, more often had dilated cardiomyopathy as the aetiology, with a lower NT‐proBNP, and more often were on GDMT (100% with BB, 100% with MRA, and a higher frequency of CRT/ICD) compared with the patients who did not receive ARNI. This means that patients treated with ARNI, during the first year of introduction, were highly selected. Accordingly, great potential exists for further improvement in clinical implementation of ARNI in a broader HFrEF population.\n\nWe have shown that ARNI was well tolerated among this selected group. Only 14.7% of the patients discontinued treatment, and the most common cause of discontinuation was surprisingly benign gastrointestinal side effects. Women had a greater risk of discontinuation. Among adverse events, high potassium and elevation of creatinine occurred in 16% and 14% of the patients, respectively, and these numbers are in line with the PARADIGM‐HF study.6 The strict selection of HFrEF patients for initiation of ARNI is not optimal but is apparent from the clinical reality of today. At present, many HFrEF patients, including patients from this study, are to a large extent on suboptimal medical therapy although the majority of the patients were diagnosed with HF for 6 months or more. Only around 1/3 were on target dose of BB and renin–angiotensin–aldosterone system inhibitor. Because the baseline therapy is far from optimal, adding treatment with ARNI is not the first step based on available guidelines. This under treatment is an international problem and has been shown repeatedly in previous studies.7, 15, 16 There is also a large variation in prescriptions of ACEI/ARB reported in Swedish Heart failure Registry between older and younger patients (70% and 90%, respectively). The annual reports are available at http://www.SwedeHF.se.\n\nIf more patients get GDMT in accurate dose, it is possible that more would be eligible to ARNI as the next step according to the guidelines. Another possibility is that more patients would improve and then not be eligible for ARNI. At present, available international and national guidelines vary because of uncertainty about how to manage dose level of background therapy with ACEI/ARB before initiation of ARNI. However, it is shown that the benefit of Sac/Val, over Enalapril, was consistent regardless of background therapy or BB dose.17 Therefore, increasing the awareness of under treatment among physicians at all levels is an urgent matter and should receive high priority.\n\nOnly 58.9% of the patients reached target dose of ARNI, lower than in the TITRATION study in which 75.9% reached target dose.18 This most likely illustrate the differences between randomized controlled trials and clinical practice. The effect of a lower dose is not known despite subgroup analysis from the PARADIGM‐HF trial showed that Sac/Val is still more effective than enalapril if both are in lower dose.19 Further studies are warranted to investigate the effect of lower dosage. However, in the TITRATION study, a more careful titration approach seemed beneficial in reaching target dose in patients with lower blood pressure.\n\nThe readmission rate of our ARNI population was higher than in PARADIGM‐HF even though follow‐up time was shorter. The possible explanation might be that our cohort is frailer compared with the patients in the PARADIGM‐HF trial because the majority of our patients were hospitalized due to HF and had almost 10‐fold higher NT‐proBNP levels on average. The readmission rate in the PIONEER study, which also included hospitalized patients, was 8% in 8 weeks, suggesting a higher readmission rate in hospitalized HF patients.20 However, the mortality rate in this study was in line with PARADIGM‐HF and other previous studies.21\n\n\n5 Limitations\nOur study has included only a limited number of patients. However, a consecutive inclusion was applied without any exclusions to ensure representativeness from real‐world clinical settings. The number of patients who received ARNI is small, but this was from the first year of implementation of Sac/Val. Despite some data missing, all data in this study were validated by reviewing patients' medical records by two reviewers.\n\n6 Conclusions\nIn the present study, from a cohort of patients with HFrEF, 20% are fully and 28% are potentially eligible for ARNI. However, only 13% received the treatment. ARNI was well tolerated, but 41% of the patients did not reach target dose. How this affects outcome is not known. The use of GDMT in accurate dose in a real‐world clinical setting is far from optimal in patients with HFrEF. Our study highlights the immediate need for improved HF therapy in real world.\n\nConflict of interest\nMichael Fu and Charlotta Ljungman have received honoraria for lectures by Novartis. 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"fulltext_license": "CC BY-NC",
"issn_linking": "2055-5822",
"issue": "7(3)",
"journal": "ESC heart failure",
"keywords": "Chronic heart failure; Eligibility; HFrEF; Pharmacological Treatment; Sacubitril-Valsartan; Tolerability",
"medline_ta": "ESC Heart Fail",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000613:Aminobutyrates; D001713:Biphenyl Compounds; D004338:Drug Combinations; D005260:Female; D006333:Heart Failure; D006801:Humans; D008875:Middle Aged; D012189:Retrospective Studies; D013318:Stroke Volume; D000068756:Valsartan",
"nlm_unique_id": "101669191",
"other_id": null,
"pages": "1049-1055",
"pmc": null,
"pmid": "32030899",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28244205;30415601;31789711;27618854;28386917;31132222;28834669;32030899;30903545;27170530;29033112;19414839;27283779;23978433;24863749;17699180;27095461;27748494;28087688;25176015;29345425;26619183",
"title": "Early experience of Sacubitril-Valsartan in heart failure with reduced ejection fraction in real-world clinical setting.",
"title_normalized": "early experience of sacubitril valsartan in heart failure with reduced ejection fraction in real world clinical setting"
} | [
{
"companynumb": "NVSC2020SE190881",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SACUBITRIL\\VALSARTAN"
},
"drugadditional": null,
... |
{
"abstract": "Nocardia otitidis-cavarium is rarely isolated as an infectious pathogen in the western world. We report on a 71-year-old Caucasian man with membranous glomerulonephritis who presented with several seemingly unrelated clinical symptoms that, after laborious diagnostics, turned out to be caused by disseminated infection with N. otitidis-cavarium. This case highlights the variable clinical presentations that can occur in nocardial infections and underscores the need to search for rare pathogens in patients taking immunosuppressive medication.",
"affiliations": "Department of Medicine, Renal Division, University Medical Center Freiburg, Freiburg, Germany.;Department of Medicine, Renal Division, University Medical Center Freiburg, Freiburg, Germany.",
"authors": "Grahammer|Florian|F|;Fischer|Karl-Georg|KG|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D015433:Glomerulonephritis, Membranous; D006801:Humans; D007166:Immunosuppressive Agents; D007868:Leg Dermatoses; D008169:Lung Abscess; D008297:Male; D008271:Mycetoma; D009615:Nocardia; D011014:Pneumonia; D011859:Radiography",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26220982",
"pubdate": "2015-07-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12539073;2745762;15280400;15342974;7815796;16582679;8055469;4790942;15882201;16614249;3952335",
"title": "Pulmonary infiltrate and painful nodular leg lesions in a patient with membranous glomerulonephritis.",
"title_normalized": "pulmonary infiltrate and painful nodular leg lesions in a patient with membranous glomerulonephritis"
} | [
{
"companynumb": "DE-BAXTER-2015BAX054966",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.",
"affiliations": "Department of Pharmacy, Kobe University Hospital, Japan. Electronic address: takaito@med.kobe-u.ac.jp.;Department of Pharmacy, Kobe University Hospital, Japan. Electronic address: yamakz@med.kobe-u.ac.jp.;Division of Urology, Graduate School of Medicine, Kobe University, Japan. Electronic address: satoshi.ogawa0704@gmail.com.;Division of Urology, Graduate School of Medicine, Kobe University, Japan. Electronic address: jfuru@med.kobe-u.ac.jp.;Division of Urology, Graduate School of Medicine, Kobe University, Japan. Electronic address: harada1971@gmail.com.;Division of Urology, Graduate School of Medicine, Kobe University, Japan. Electronic address: masato@med.kobe-u.ac.jp.;Department of Pharmacy, Kobe University Hospital, Japan. Electronic address: omurat@med.kobe-u.ac.jp.;Department of Pharmacy, Kobe University Hospital, Japan. Electronic address: iyano@med.kobe-u.ac.jp.",
"authors": "Ito|Takahiro|T|;Yamamoto|Kazuhiro|K|;Ogawa|Satoshi|S|;Furukawa|Junya|J|;Harada|Kenichi|K|;Fujisawa|Masato|M|;Omura|Tomohiro|T|;Yano|Ikuko|I|",
"chemical_list": "D000068338:Everolimus; D000077210:Sunitinib; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1016/j.dmpk.2020.05.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1347-4367",
"issue": "35(5)",
"journal": "Drug metabolism and pharmacokinetics",
"keywords": "Bayesian analysis; Everolimus; Metastatic renal cell carcinoma; Renal transplantation; Sunitinib; Tacrolimus",
"medline_ta": "Drug Metab Pharmacokinet",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell; D003131:Combined Modality Therapy; D000068338:Everolimus; D006801:Humans; D007680:Kidney Neoplasms; D016030:Kidney Transplantation; D008297:Male; D000077210:Sunitinib; D016559:Tacrolimus",
"nlm_unique_id": "101164773",
"other_id": null,
"pages": "405-409",
"pmc": null,
"pmid": "32788078",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Model-based assessment of pharmacokinetic changes of sunitinib, tacrolimus, and everolimus in a patient with metastatic renal cell carcinoma after renal transplantation.",
"title_normalized": "model based assessment of pharmacokinetic changes of sunitinib tacrolimus and everolimus in a patient with metastatic renal cell carcinoma after renal transplantation"
} | [
{
"companynumb": "JP-STRIDES ARCOLAB LIMITED-2020SP012864",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": ... |
{
"abstract": "Eosinophilic fasciitis is a rare disease from the group of scleroderma-like connective tissue diseases with unclear etiopathogenesis. It may be occasionally accompanied with other eosinophilic or autoimmune dysfunctions (1,2). Lack of international diagnostic criteria and treatment consensus may lead to diagnostic and therapeutic difficulties. The 61-year-old man with no significant personal or family pathological history was admitted to the Dermatology Department presenting persistent induration for several months as well as erythema and pain of the shins that gradually extended to thighs and forearms, with limited mobility of peripheral joints. (Figure 1) Additional tests showed leukocytosis with 16% eosinophilia, elevated CRP, and hypergammaglobulinemia. Borrelia burgdorferi antibodies (classes IgM and IgG) were negative twice. A biopsy that included deep fascia was taken for histopathological examination. Antinuclear antibody screening was negative, but the direct immunofluorescence showed complexes in the dermo-epidermal junction and around the vessels. The diagnostics conducted toward malignant process showed no disturbing abnormalities (i.e. tumor markers in serum, chest, and abdomen computed tomography imaging, panendoscopy). The treatment was carried out with cephalosporin and nonsteroidal anti-inflammatory drugs (NSAIDs). The condition did not improve much but was stable. Histopathological results were indicative of eosinophilic fasciitis with fibrous thickening of deep fascia and perivascular infiltrations of plasma cells and lymphocytes; oral prednisone was initiated and the condition begin to improve. After 12 weeks, we observed disease progression with fever and very hard and cyanic skin lesions, which presented as an orange peel with linear furrows over the superficial venous vessels (Figure 2). The lesions extended to the trunk and caused troubles in moving. A complex rehabilitative intervention was started to minimize the inflammatory fascial restrictions. The prednisolone dose was increased, and oral methotrexate was added. After two weeks, the patient suffered from abdominal pain and periodic bleeding diarrhea. Methotrexate was suspected of inducing gastrointestinal adverse effects, and antipyretic NSAIDs were completely withdrawn. Colonoscopy showed features of mucosal edema with erythema, and histopathological examination revealed eosinophilic colitis. The patient was referred to a gastroenterologist, and methotrexate was ceased and switched to azathioprine. In summary, the consensus therapy of the rheumatologist, dermatologist, and gastroenterologist consisted of prednisolone and azathioprine. As of this writing, the patient's condition is gradually improving. The most characteristic symptoms of eosinophilic fasciitis is sudden onset with induration, sclerosis, and pain of the skin, with subcutaneous tissue and fascia usually appearing on the upper and lower limbs (3,4). The skin surface forms a characteristic orange peel appearance. The \"groove\" sign refers to the linear furrows over the superficial vessels of the extremities (1). Typical abnormalities are eosinophilia, elevated CRP, and hypergammaglobulinemia. The presence of eosinophilia is the most characteristic feature, occurring in 60-93% cases, but it is not necessary for diagnosis (1,5). Antinuclear antibodies are commonly absent with positive lesional direct immunofluorescence (6). If antinuclear antibodies are positive, it is recommended to broaden the diagnostic process to include other connective tissue diseases. Eosinophilia must be differentiated from hematological disorders and paraneoplastic syndrome. (4,6). Eosinophilic colitis is an eosinophilic gastrointestinal disease (EGID). It is the least frequent manifestation of EGID. It may be associated with connective tissue diseases, mostly systemic sclerosis - to our knowledge, there is no information in the literature about coexisting eosinophilic fasciitis. (7,8). The case described herein demonstrated that such a connection may occur. In treatment, it is important to prevent the patient from contractures and to maintain joint mobility by appropriate physiotherapy (2,9). The fascia forms a functional integral and continuous structure. Inflammation of one part of it changes the elasticity of the whole and produces fascial restrictions with movement limitation and pain. The fascia is profusely innervated, which favors constriction as a result of inflammation, and is also poorly vascularized which disrupts its regeneration (9,10). Myofascial techniques improve fascia elasticity by breaking up the tissue adhesions caused by inflammation (11). Eosinophilic fasciitis is a rare clinical entity, but knowing the possible clinical symptoms and laboratory abnormalities should help in taking the appropriate diagnostic path. It is important to treat the patient with attention to all concomitant diseases in consultation with different specialists.",
"affiliations": "Monika Bilewicz-Stebel, MD, Department of Internal Medicine, Dermatology and Allergology, Curie-Skłodowskiej 10, 41-800 Zabrze, Poland; bil.ste@hotmail.com.",
"authors": "Bilewicz-Stebel|Monika|M|;Bergler-Czop|Beata|B|;Stebel|Robert|R|;Weryńska-Kalemba|Maria|M|;Matuszewska|Anna|A|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D011239:Prednisolone; D001379:Azathioprine",
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1330-027X",
"issue": "28(3)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D001379:Azathioprine; D003937:Diagnosis, Differential; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004802:Eosinophilia; D005208:Fasciitis; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D011239:Prednisolone",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "190-192",
"pmc": null,
"pmid": "33422175",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Eosinophilic Fasciitis - Clinical Features and Therapeutic Management.",
"title_normalized": "eosinophilic fasciitis clinical features and therapeutic management"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-322466",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
{
"abstract": "We report a 12-year-old male with Prader-Willi syndrome (PWS) and 47, XYY syndrome. Genetic work up revealed 47, XYY karyotype. PWS diagnosis was made by polymerase chain reaction methylation and maternal uniparental disomy (mUPD) was determined to be the etiology. Review of distinct behavioral features, possible interplay between the two syndromes and considerations for diagnoses are presented. To our knowledge, this is the first report of behavioral features in PWS with comorbid 47, XYY.",
"affiliations": "Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.;Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.;Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.;Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.;Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.;Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.;Autism and Obsessive Compulsive Spectrum Program, Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.",
"authors": "Palkar|Pooja|P|;Kabasakalian|Anahid|A|;Taylor|Bonnie|B|;Doernberg|Ellen|E|;Ferretti|Casara Jean|CJ|;Uzunova|Genoveva|G|;Hollander|Eric|E|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5582/irdr.2016.01043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2186-3644",
"issue": "5(3)",
"journal": "Intractable & rare diseases research",
"keywords": "47; Prader-Willi syndrome; XYY; attention deficit hyperactivity disorder; autism spectrum disorder",
"medline_ta": "Intractable Rare Dis Res",
"mesh_terms": null,
"nlm_unique_id": "101586847",
"other_id": null,
"pages": "235-7",
"pmc": null,
"pmid": "27672550",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": "25558953;23810129;16038620;3688028;11925360;16941227;9394132;22876265",
"title": "Behavioral phenotype in a child with Prader-Willi syndrome and comorbid 47, XYY.",
"title_normalized": "behavioral phenotype in a child with prader willi syndrome and comorbid 47 xyy"
} | [
{
"companynumb": "US-UCBSA-2016049311",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Serotonin toxicity is a state of central nervous system (CNS) excitation classically featuring altered mental status, neuromuscular excitation, and autonomic instability. While retrospective studies and reviews have characterized serotonin toxicity in adults, there have been no systematic reviews of serotonin toxicity in pediatric populations. The goal of this review was to use published case reports to describe serotonin toxicity in pediatric patients and to consider the impact of age on clinical presentation. A search for case reports of serotonin toxicity in patients younger than 18 years was conducted. Cases were systematically screened for inclusion using serotonin toxicity diagnostic tools, and a meta-analysis of case characteristics was conducted. Sixty-six cases of serotonin toxicity in pediatric patients were reviewed. Only 56.1% met diagnostic criteria for serotonin toxicity on all three of the most commonly used diagnostic tools. Antidepressants were found to be the most common trigger of toxicity, implicated in 78.8% of cases. While onset of toxicity was rapid following overdose, toxicity was more likely to be delayed in the setting of medication titration (71.8% vs. 0%, p < 0.0001). Signs of neuromuscular excitation were prevalent, occurring in 92.4% of cases with 81.8% showing the full triad of neuromuscular symptoms, altered mental status, and autonomic instability. The only age-related differences occurred in relation to activation symptoms (more likely to be reported in children than in adolescents) and seizures (less likely to be reported in children than in adolescents or toddlers). Treatment was primarily supportive in nature, although 25.8% of patients received cyproheptadine. In all but one reviewed case, the patient survived. The presentation of serotonin toxicity in the pediatric population is similar to that seen in adults. Treatment is supportive with most patients achieving full recovery. Further exploration of the age-related differences in serotonin activity within the CNS is needed.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA.;Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA.;Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA.",
"authors": "Hutchison|Lisa|L|;Hartman|Jacob S|JS|;Lerea|Yehuda|Y|",
"chemical_list": "D000928:Antidepressive Agents; D012701:Serotonin",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2020.0176",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "31(6)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": "antidepressants; children and adolescents; serotonin syndrome; serotonin toxicity",
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000928:Antidepressive Agents; D002675:Child, Preschool; D062787:Drug Overdose; D006801:Humans; D012640:Seizures; D012701:Serotonin; D020230:Serotonin Syndrome",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "394-403",
"pmc": null,
"pmid": "33909452",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review",
"references": null,
"title": "Serotonin Toxicity in Children and Adolescents: A Systematic Review and Meta-Analysis of Cases.",
"title_normalized": "serotonin toxicity in children and adolescents a systematic review and meta analysis of cases"
} | [
{
"companynumb": "US-BAUSCH-BL-2021-018900",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VILAZODONE"
},
"drugadditional": "3",
... |
{
"abstract": "Cerebellum is known to play an important role in coordination and motor functions. In some resent studies it is also considered to be involved in modulation of mood, cognition and psychiatric disorders. Dandy Walker Malformation is a congenital malformation that is characterized by hypoplasia or aplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of the posterior fossa. When the volume of posterior fossa is normal, the malformation is called Dandy Walker Variant. Case is a 32 year old male with a 12 year history of Bipolar I Disorder presented with manic and depresive symptoms, including dysphoric and depressive affect, anhedonia, suicidal thoughts and behaviours, thoughts of fear about future, overtalkativeness and graphomania, increased energy, irregular sleep, loss of appetite, increased immersion in projects, irritability, agressive behavior, impulsivity. Cranial Magnetic Resonance Imaging was compatible to the morphological features of Dandy Walker Variant.",
"affiliations": "Ankara Atatürk Research and Training Hospital, Bilkent, Ankara, Turkey.;Ankara Atatürk Research and Training Hospital, Bilkent, Ankara, Turkey.;Ankara Atatürk Research and Training Hospital, Bilkent, Ankara, Turkey.",
"authors": "Can|Serdar Suleyman|SS|;Karakaş Uğurlu|Görkem|G|;Cakmak|Selcen|S|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4306/pi.2014.11.3.336",
"fulltext": "\n==== Front\nPsychiatry InvestigPsychiatry InvestigPIPsychiatry Investigation1738-36841976-3026Korean Neuropsychiatric Association 10.4306/pi.2014.11.3.336Case ReportDandy Walker Variant and Bipolar I Disorder with Graphomania Can Serdar Suleyman Karakaş Uğurlu Görkem Çakmak Selcen Ankara Atatürk Research and Training Hospital, Bilkent, Ankara, Turkey.Correspondence: Serdar Suleyman Can, MD. Ankara Atatürk Research and Training Hospital, Bilkent street 3, Ankara 06800, Turkey. Tel: +05324091262, Fax: +90 312 291 27 26, serdarsccan@yahoo.com7 2014 21 7 2014 11 3 336 339 20 5 2013 03 8 2013 29 8 2013 Copyright © 2014 Korean Neuropsychiatric Association2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cerebellum is known to play an important role in coordination and motor functions. In some resent studies it is also considered to be involved in modulation of mood, cognition and psychiatric disorders. Dandy Walker Malformation is a congenital malformation that is characterized by hypoplasia or aplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of the posterior fossa. When the volume of posterior fossa is normal, the malformation is called Dandy Walker Variant. Case is a 32 year old male with a 12 year history of Bipolar I Disorder presented with manic and depresive symptoms, including dysphoric and depressive affect, anhedonia, suicidal thoughts and behaviours, thoughts of fear about future, overtalkativeness and graphomania, increased energy, irregular sleep, loss of appetite, increased immersion in projects, irritability, agressive behavior, impulsivity. Cranial Magnetic Resonance Imaging was compatible to the morphological features of Dandy Walker Variant.\n\nDandy walkerBipolar disorderCerebellum\n==== Body\nINTRODUCTION\nCerebellum is known to play an important role in coordination and motor functions.1 In some resent studies it is also considered to be involved in modulation of mood,2 cognition and psychiatric disorders.3 From this aspect it is clear to understand that the cerebellum has a regulatory function on enhancing and suplementing other brain functions throughout direct and indirect circuits.4,5,6 According to different sources of evidence, the cerebellum may be altered in many psychiatric disorders including schizophrenia, bipolar disorder, unipolar depression, anxiety and attention deficit hyperactivity disorder.5,7\n\nDandy Walker Malformation is a congenital malformation that is characterized by hypoplasia or aplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of the posterior fossa. When the volume of posterior fossa is normal, the malformation is called Dandy Walker Variant (DWV).8\n\nBipolar Disorder is a chronic and a life-long condition which is characterized by unusual shifts in mood state, energy level and behavior9 and psychotic symptoms such as hallucinations and delusions.10 Cerebellum is suggested to interfere in the pathophysiology of bipolar disorder.11 Cerebellum has connections via thalamus to the dorsolateral prefrontal cortex, medial prefrontal cortex, parietal and superior areas, anterior cingulate and the posterior hypothalamus. These are the areas associated with cognition and behavior.12,13\n\nCerebellum also has connections to limbic system that can provide changes in emotion and affects.14 A clinical study, 'cerebellar cognitive affective syndrome', patients with posterior and vermal cerebellar lesions were described to have executive dysfunctions, behavioral disinhibition and emotional dysregulation.15 In the literature there is a case report including a manic episode associated mega cisterna magna, a posterior fossa malformation which affects cerebellum.16\n\nWe aimed to report a case of a 32 year-old-man who has Bipolar I Disorder with Dandy Walker Variant.\n\nCASE\nThe patient A, a 32 year old male with a 12 years history of Bipolar I Disorder presented with manic and depressive symptoms, including dysphoric and depressive affect, anhedonia, suicidal thoughts and behaviours, thoughts of fear about future, overtalkativeness and graphomania, increased energy, irregular sleep, loss of appetite, increased immersion in projects, irritability, agressive behavior, impulsivity in May 2013. He was complaining about decreased functionality, distractibility, sadness, thoughts of suiside, aggresivity, loss of interest to his environment, forgetfulness.\n\nHe had a history of three manic and a depressive episodes which he was diagnosed as Bipolar I Disorder. No alcohol and subtance abuse was reported.\n\nThe first episode of the disorder had come into existence with the delusions of grandiosity and reference, increased self esteem, hyperactivity, flight of ideas, impulsivity, irritability, decreased need for sleep when he admitted to an outpatient psychiatry clinic 12 years ago. At that time, he was diagnosed as 'psychotic disorder' and given antipsychotics (risperidone) and anticholinergic durg (biperiden). He went on a remission period, but incompliance occured. He undergone two other manic episodes especially including impulsivity, agressive behaviors, graphomania, overtalkativeness, distractibility and irritability. He was diagnosed as 'Bipolar I Disorder' and given mood stabilizators (Lithium carbonate, sodium valproat), antipsychotics (olanzapine, risperidone), anticholinergic drug (biperiden) and he stayed in hospital three times during that manic period.\n\nOn follow up visits he showed depressive and cognitive symptoms like depressive affect, decreased energy levels, psychomotor retardation, hypersomnia, unwillingness, attention and working memory deficits, anhedonia, hopelessness, thoughts of guilt and fear about future life. And then olanzapine and biperiden were stopped. When using citalopram some hypomanic symptoms like excessive talking, decreased need for sleep, euphoric affect and sexual disfunction occured. Then aripiprazole 10 mg/day, bupropione 150 mg/day were added to the treatment and citalopram was stopped day by day. In the following days he was hospitalized, because his symptoms didn't show a decline. When he was discharged from hospital, his treatment was aripiprazole 5 mg/day, duloxetine 60 mg/day, sodium valproate 1250 mg/day. Cognitive and depressive symptoms repeated 3 months after discharging from hospital. His treatment was changed to lithium 1200 mg/day, venlafaxine 225 mg/day, quetiapine 600 mg/day at outpatient clinic. On follow up he expressed depressive and hypomanic symptoms including dysphoric and depressive affect, anhedonia, suicidal thoughts and behaviours, thoughts of fear about future, overtalkativeness and graphomania, increased energy, irregular sleep, decreased appetide, increased immersion in projects, irritability, agressive behavior, impulsivity. Venlafaxine treatment was stopped for the reason of manic symptoms. He didn't show response to lithium carbonate therapy. So lithium carbonate treatment changed with sodium valproate.\n\nFinally, he had been followed-up the inpatient clinic for two months in 2013 May to June. After 5 weeks treatment of sodium valproate 1250 mg/day, quetiapine 500 mg/day his depressive and manic symptoms improved well. On the other hand his cognitive symptoms like working memory, attention and learning deficit remained unchanged.\n\nNeurological examination and electroensephalography were normal. Cranial Magnetic Resonance Imaging was compatible to the morphological features of Dandy Walker Variant. Bender Gestalt Visual Motor Sensation Scale (BGVMSS), Benton Visual Motor Memory Scale (BVMMS), Weschler Memory Scale (WMS) were applied to examine the organisity. Attention, working memory deficit and difficulty in learning were observed in WMS. BVMMS showed signs of cerebral organic pathology like significant turning mistakes and perseverations. All of them were compatible with a cerebral organic pathology. Young Mania Rating Scale (YMRS) performed before and after the treatment. During the treatment YMRS scores showed decrease from 26 to 13. Minnesota Multiphasic Personality Inventory (MMPI) was also administered to the patient. MMPI results were valid and showed an increase in hypocondriac and histrionic scales (Figures 1,2,3).\n\nDISCUSSION\nMental symptoms have been associated with Dandy Walker Variant in recent studies. A large variety of mental symptoms ranging from psychotic to cognitive and emotional were defined earlier.17,18 Although Dandy Walker Syndrome is usually detected in the early childhood, the patient did not state any neurologic symptom till 20 years.\n\nCerebellar vermis neurons plays a role in mood modulation.19 Cerebellar vermis pathologies may be associated with changes of mood and behaviors.20 In this case we diagnose Bipolar I Disorder presented with emotional, behavioral and cognitive changes with a cerebellar vermian and hemispheral atrophy and mega cysterna magna. This case may contibute to the association between cerebellar vermian pathology and behavioral, mood and cognitive changes.\n\nHypergraphy is an inappropriate and a permenant writing behavior. It is considered to be a compulsive activity that results from the lesions of globus pallidus and bilateral frontal lobes.21 Hypergraphy have been reported about 8% of patients who had temporal lobe epilepsy. It is also a symptom of manic and hypomanic episodes of Bipolar Disorder.22 In addition to these knowledges compulsive writing behavior can be observed in schizophrenia and frontotemporal dementia.10 In light of the review of the literature, any studies couldn't be found about the association between dandy walker variant or other cerebellar malformations and hypergraphy.\n\nNeuropsychiatric studies supports that the cognitive symptoms like language (including speech perception, lexical retrieval and working memory), temporal processing, implicit learning and memory and visual spatial attention defficits may be a result of cerebellar lesions,23 but the role of cerebellum in the cognitive process have not been clearly known.9 In the present case Weschler Memory Scale was applied to the patient and as a result; attention, working memory and learning deficits were observed. These findings compatible with the idea of association between cerebellar pathology and attention, learning and memory deficits.\n\nFigure 1 Enlargement of cisterna magna, 4th ventricle and vermian agenesia.\n\nFigure 2 Enlargement of cisterna magna and other cisternal structures.\n\nFigure 3 Cerebellar hemispheral hipoplasia and enlargement of foliums.\n==== Refs\n1 Schmahmann JD An emerging concept. The cerebellar contribution to higher function Arch Neurol 1991 48 1178 1187 1953406 \n2 Brambilla P Harenski K Nicoletti M Mallinger AG Frank E Kupfer DJ MRI study of posterior fossa structures and brain ventricles in bipolar patients J Psychiatr Res 2001 35 313 322 11684138 \n3 Schmahmann JD Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective, syndrome J Neuropsychiatry Clin Neurosci 2004 16 367 378 15377747 \n4 Andreasen NC Pierson R The Role of the cerebellum in schizophrenia Biol Psychiatry 2008 64 81 88 18395701 \n5 Schmahmann JD Weilburg JB Sherman JC The neuropsychiatry of the cerebellum-insights from the clinic Cerebellum 2007 6 254 267 17786822 \n6 Ribas GC Neuroanatomic basis of behavior: history and recent contributions Rev Bras Psiquiatr 2007 29 63 71 17435932 \n7 Bugalho P Correa B Viana-Baptista M Role of the cerebellum in cognitive and behavioural control: scientific basis and investigation models Acta Med Port 2006 19 257 267 17234089 \n8 Mytilinaios DG Tsamis KI Njau SN Polyzoides K Baloyannis SJ Neuropathological findings in Dandy Walker variant Dev Neurorehabil 2010 13 64 67 20067347 \n9 Baldaçara L Borgio JGF Lacerda ALT Jackowski AP Cerebellum and psychiatric disorders Rev Bras Psiquiatr 2008 30 281 289 18833430 \n10 Goes FS Sadler B Toolan J Zamoizki RD Modimore FM Mackinron DF Psychotic features in bipolar and unipolar depression Bipolar Disord 2007 9 901 906 18076541 \n11 Strakowski SM Adler CM DelBello MP Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disord 2002 4 80 88 12071513 \n12 Dolan RJ A cognitive affective role for the cerebellum Brain 1998 121 545 546 9577383 \n13 Middleton FA Strick PL Cerebellar output channels Int Rev Neurobiol 1997 41 61 82 9378611 \n14 Schutter DJ van Honk J The cerebellum on the rise in human emotion Cerebellum 2005 4 290 294 16321885 \n15 Schmahmann ID Sherman JC The cerebellar cognitive affective syndrome Brain 1998 121 561 579 9577385 \n16 Turan T Beşirli A Asdemir A Özsoy S Eşel E Manic episode associated with mega cisterna magna Psychiatry Investig 2010 7 305 307 \n17 Turner SJ Poole R Nicholson MR Ghadiali EJ Schizophrenia like psychosis and Dandy-Walker variant Schizophr Res 2001 48 365 367 11368032 \n18 Ferentinos PP Kontaxakis VP Havaki-Kontaxaki BJ Paplos KG Papa DA Soldatos CR Refractoriness to psychosis andprominent cognitive deficits in a patient with mega-cisterna magna Prog Neuropsychopharmacol Biol Psychiatry 2007 31 561 563 17150294 \n19 Mills NP Delbello MP Adler CM Stracowski SM MRI analysis of cerebellar vermal abnormalities in bipolar disorder Am J Psychiatry 2005 162 1530 1532 16055777 \n20 Richter S Schoch B Kaiser O Groetschel H Dimitrova A Hein-Kropp C Behavioral and affectve changes in children and adolescents with chronic cerebellar lesions Neurosci Lett 2005 381 102 107 15882798 \n21 Cambier J Masson C Benammou S Robine B Graphomania. Compulsive graphic activity as a manifestation of fronto-callosal glioma Rev Neurol (Paris) 1988 144 158 164 3368690 \n22 Schachter SC Holmes GL Kasteleijn-Nolst Trenite DGA Behavioral Aspects of Epilepsy: Principles NewYork Demos Medical Publishing 2008 \n23 Justus TC Ivry RB The cognitive neuropsychology of the cerebellum Int Rev Psychiatry 2001 13 276 282\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-3684",
"issue": "11(3)",
"journal": "Psychiatry investigation",
"keywords": "Bipolar disorder; Cerebellum; Dandy walker",
"medline_ta": "Psychiatry Investig",
"mesh_terms": null,
"nlm_unique_id": "101242994",
"other_id": null,
"pages": "336-9",
"pmc": null,
"pmid": "25110509",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": "11368032;20067347;18076541;17234089;15377747;9577385;17786822;15882798;18395701;9577383;1953406;11684138;17150294;9378611;3368690;12071513;16055777;17435932;21253417;18833430;16321885",
"title": "Dandy walker variant and bipolar I disorder with graphomania.",
"title_normalized": "dandy walker variant and bipolar i disorder with graphomania"
} | [
{
"companynumb": "PHHY2014TR129474",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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"activesubstancename": "LITHIUM CARBONATE"
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{
"abstract": "BACKGROUND\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening adverse drug reaction.\n\n\nOBJECTIVE\nTo increase awareness of the potential for recurrence in patients with a history of DRESS syndrome and provide a brief review of the clinical characteristics, diagnosis, and management of this disease process.\n\n\nMETHODS\nThe authors selected and reviewed salient articles on the topic and incorporated pertinent information from the patient's clinical course.\n\n\nRESULTS\nA case of recurrent DRESS triggered by a structurally unrelated drug is presented, followed by discussion of the clinical characteristics, diagnosis, and management. Clinical pearls and pitfalls are emphasized for the practicing allergist, clinical immunologist, and fellow-in-training.\n\n\nCONCLUSIONS\nThe most important steps in the treatment of this condition are the identification and removal of the offending agent. Providers should be aware of the potential for recurrent DRESS and recognize the importance of prompt management.",
"affiliations": "Allergy, Immunology and Immunizations Service, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.",
"authors": "Spriet|Sarah|S|;Banks|Taylor A|TA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.2500/aap.2015.36.3903",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1088-5412",
"issue": "36(6)",
"journal": "Allergy and asthma proceedings",
"keywords": null,
"medline_ta": "Allergy Asthma Proc",
"mesh_terms": "D000328:Adult; D019468:Disease Management; D063926:Drug Hypersensitivity Syndrome; D004802:Eosinophilia; D005260:Female; D006801:Humans",
"nlm_unique_id": "9603640",
"other_id": null,
"pages": "501-5",
"pmc": null,
"pmid": "26534757",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Drug reaction with eosinophilia and systemic symptoms syndrome.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms syndrome"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0055102",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
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"drugadditional": nul... |
{
"abstract": "BACKGROUND\nVulvodynia is a difficult condition to treat due to both the uncertain etiology of the disorder and poorly available therapies. This difficulty leads to a disproportionately high prevalence and cost of treatment for this condition. Candida vulvovaginitis is a frequent co-present diagnosis in vulvodynia patients. Whether through treatment of co-present, candida vulvovaginitis or by systemic interaction, itraconazole has been proposed as a treatment for vulvodynia.\n\n\nOBJECTIVE\nTo describe objective change in vulvodynia pain in a cohort of patients treated with itraconazole.\n\n\nMETHODS\nThis study was a retrospective cohort study comprised of women diagnosed with vulvodynia who were treated with itraconazole between January 1, 2011 and October 17, 2017. Patients had failed fluconazole treatment and had negative fungus cultures for >2 months before itraconazole treatment. All other vulvovaginal disorders were excluded.\n\n\nMETHODS\nThe main outcome measure was the change in pain before and after treatment as measured by cotton swab testing.\n\n\nRESULTS\n106 patients met inclusion criteria. Average pain reduction for the entire cohort was 60.7%. Patients who continued itraconazole for 5 to 8 weeks demonstrated a 69.6% reduction in cotton swab test pain. Pain reduction as a percentage of total patients showed complete resolution of pain in 37.7% of patients and >50% reduction in 66.0% of patients. Two-sample paired T-tests for means analysis of pain scores disproved the null hypothesis (P < .01, α = 0.01) and showed a 50% reduction in pain to be significant (P = 0.043, α = 0.05). Two-tailed Wilcoxon signed rank test also demonstrated rejection of the null hypothesis (α = 0.05).\n\n\nCONCLUSIONS\nItraconazole therapy is associated with a significant reduction in vulvovaginal pain in patients with negative fungus cultures and no other identifiable disease in this pilot study. A randomized placebo-controlled trial is warranted. Rothenberger R, Jones W, MacNeill C. Itraconazole Improves Vulvodynia in Fungus Culture-Negative Patients Post Fluconazole Failure. J Sex Med 2021;9:100383.",
"affiliations": "Penn State University College of Medicine Hershey, PA, USA. Electronic address: rothenrr@ucmail.uc.edu.;Department of Obstetrics and Gynecology - Penn State University College of Medicine, Hershey, PA, USA.;Department of Obstetrics and Gynecology - Penn State University College of Medicine, Hershey, PA, USA; Harvard Vanguard Medical Associates, Burlington, MA.",
"authors": "Rothenberger|Rodger|R|;Jones|Wendy|W|;MacNeill|Colin|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.esxm.2021.100383",
"fulltext": "\n==== Front\nSex Med\nSex Med\nSexual Medicine\n2050-1161\nElsevier\n\nS2050-1161(21)00063-5\n10.1016/j.esxm.2021.100383\n100383\nOriginal Research\nPain\nItraconazole Improves Vulvodynia in Fungus Culture-Negative Patients Post Fluconazole Failure\nRothenberger Rodger MD rothenrr@ucmail.uc.edu\n1⁎\nJones Wendy CRNP 2\nMacNeill Colin MD 23\n1 Penn State University College of Medicine Hershey, PA, USA\n2 Department of Obstetrics and Gynecology – Penn State University College of Medicine, Hershey, PA, USA\n3 Harvard Vanguard Medical Associates, Burlington, MA\n⁎ Corresponding Author: Rodger Rothenberger, MD, University of Cincinnati Medical Center, PO Box 670526, Cincinnati, OH 45267-0526, 231 Albert. Sabin Way, Tel: 6 10 620 3936, Fax: (513) 558-5705 rothenrr@ucmail.uc.edu\n09 7 2021\n8 2021\n09 7 2021\n9 4 10038320 12 2020\n22 4 2021\nCopyright © 2021 The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine.\n2021\nThe Authors\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nVulvodynia is a difficult condition to treat due to both the uncertain etiology of the disorder and poorly available therapies. This difficulty leads to a disproportionately high prevalence and cost of treatment for this condition. Candida vulvovaginitis is a frequent co-present diagnosis in vulvodynia patients. Whether through treatment of co-present, candida vulvovaginitis or by systemic interaction, itraconazole has been proposed as a treatment for vulvodynia.\n\nAim\n\nTo describe objective change in vulvodynia pain in a cohort of patients treated with itraconazole.\n\nMethods\n\nThis study was a retrospective cohort study comprised of women diagnosed with vulvodynia who were treated with itraconazole between January 1, 2011 and October 17, 2017. Patients had failed fluconazole treatment and had negative fungus cultures for >2 months before itraconazole treatment. All other vulvovaginal disorders were excluded.\n\nMain outcome measure\n\nThe main outcome measure was the change in pain before and after treatment as measured by cotton swab testing.\n\nResults\n\n106 patients met inclusion criteria. Average pain reduction for the entire cohort was 60.7%. Patients who continued itraconazole for 5 to 8 weeks demonstrated a 69.6% reduction in cotton swab test pain. Pain reduction as a percentage of total patients showed complete resolution of pain in 37.7% of patients and >50% reduction in 66.0% of patients. Two-sample paired T-tests for means analysis of pain scores disproved the null hypothesis (P < .01, α = 0.01) and showed a 50% reduction in pain to be significant (P = 0.043, α = 0.05). Two-tailed Wilcoxon signed rank test also demonstrated rejection of the null hypothesis (α = 0.05).\n\nConclusions\n\nItraconazole therapy is associated with a significant reduction in vulvovaginal pain in patients with negative fungus cultures and no other identifiable disease in this pilot study. A randomized placebo-controlled trial is warranted.\n\nRothenberger R, Jones W, MacNeill C. Itraconazole Improves Vulvodynia in Fungus Culture-Negative Patients Post Fluconazole Failure. J Sex Med 2021;9:100383\n\nKey Words\n\nVulvodynia\nVulvovaginitis\nItraconazole\nFluconazole\nAzole\nAntifungal\nAbbreviations: CVV, Candida vulvovaginitis\nCVVC, Chronic vulvovaginal candidiasis\n==== Body\nINTRODUCTION\n\nVulvodynia, vulvar pain of undetermined origin of 3 or more months duration,1 is a difficult condition to treat due the uncertain etiology of the disorder and to poorly available therapies. With a prevalence of 7-8% and an estimated cost per patient of greater than $8800, the estimated an annual cost of vulvodynia is $102-$117 billion per year in the United States2, 3, 4 Vulvodynia should be differentiated from chronic vulvovaginal candidiasis (CVVC), a chronic vulvovaginal pain related to a vulvar or vaginal Candida.5 The distinction is clouded by the frequently found history of CVVC in vulvodynia patients, the overlapping symptom of vulvar vestibule burning in patients with vulvodynia and with CVVC, and the frequently found history in CVVC patients of symptomatic improvement with fluconazole that diminishes over the course of the condition and leads the clinician to suspect the diagnosis is now vulvodynia. Indeed, a study of clinic discharge diagnoses in vulvovaginal specialty clinics reported a large proportion of patients were discharged with 2 diagnoses: vulvodynia and vaginal candidiasis. It has been proposed that studies considering vulvodynia should include fungal cultures or some other test for fungal infection in the inclusion/exclusion criteria and the data analysis.6, 7, 8\n\nItraconazole is a potent antifungal agent that, by the same mechanism as fluconazole, inhibits ergosterol synthesis (causing a fungicidal effect). Though Itraconazole and fluconazole both are triazole antifungals, they are structurally distinct and elicit different reactions systemically. The question posed in this paper involves whether itraconazole, thus far unstudied in vulvodynia, can be used in the treatment of vulvodynia. Itraconazole has been utilized in the treatment of non-fungal conditions before, with active study being undertaken in its treatment of basal cell carcinoma, prostate, non-small cell lung cancer, triple-negative breast cancer, and ovarian cancers.9 The mechanism by which it acts systemically is unclear with numerous possibilities suggested but none confirmed. These authors favor a mechanism of mTOR pathway modulation and thereby changes in angiogenesis and nerve growth.10 Within the realm of pain indications, however, with the exception of a clinical trial being undertaken in the treatment of chronic pain,11 there has been, as of yet, very little study. Does itraconazole decrease fungal culture-negative vulvodynia pain?\n\nMETHODS\n\nThis study is a retrospective cohort study which specifically examined women diagnosed with vulvodynia and who were treated with itraconazole. The primary outcome was defined as an objective reduction in cotton swab test of the vulvar vestibule for pain. Cotton swab testing was performed as described by Bergeron et al. in 2001. The labia majora and labia minora were palpated (right, left, and midline) followed by six vestibular sites in a clockwise fashion: 12 o'clock, then 12-3, 3-6, 6, 6-9, and 9-12 o'clock.12 Pain score was recorded as the maximal pain value in a 10 point pain scale during this testing (10 being the greatest pain and 0 being no pain). We postulated that pain reduction scores of >50%, if achieved, would outperform all previously reported placebo effects in vulvodynia.13 This cohort of patients was selected from patients who had first been treated with up to 200 mg daily of fluconazole for 6 to 8 weeks with insufficient reduction in vulvar pain and subsequently desired further treatment for continued vulvovaginal pain and elected to initiate treatment with itraconazole. This cohort of patients was obtained through a search of the electronic medical record pharmacy records for all patients prescribed itraconazole at Penn State Hershey Medical Center. Both providers prescribed itraconazole at a dose of 400 mg per day14 to all patients involved in this study.\n\nInclusion criteria comprised of all patients who were administered itraconazole by the second and third authors between the dates of January 1, 2011 and October 17, 2017. All subjects were over 18 years of age, female in gender, and carried the diagnosis of vulvodynia using the ISSVD definition of vulvodynia.1 From this cohort of patients treated with itraconazole, all patients with both negative fungus cultures for >2 months before itraconazole initiation and previous treatment with up to 200 mg daily of fluconazole for 6 to 8 weeks were selected. It was this cohort of fungus culture-negative, fluconazole refractory, vulvodynia patients who were treated with itraconazole that was examined in this study.\n\nExclusion criteria included patients with any identifiable vulvovaginal disease, such as lichen sclerosis or lichen planus and lichen simplex chronicus. Antibiotic therapy during the itraconazole treatment period and the lack of pain with cotton swab examination at the initiation of itraconazole treatment were also treated as an exclusion criterion. Baseline liver disease was treated as an exclusion criterion as well. All patients under the age of 18 were excluded. Patients whom received other treatments for vulvodynia such as alternative oral and/or topical medications, physical therapy, and surgery were excluded.\n\nData on pain, as determined through maximal pain score on cotton swab palpation of the vulvar vestibule before and after treatment with itraconazole was collected from medical record entries at clinic visits, following up every 3 to 4 weeks with liver function tests (LFTs) at each visit. These before and after pain data points for each treatment were contrasted to create a percent reduction in pain. Data regarding the duration of treatment with itraconazole and discontinuation of itraconazole due to side effects were also collected.\n\nStatistical analysis utilized the two-tailed Wilcoxon signed rank test to determine the significance of the change in pain scores with itraconazole administration. The two-sampled paired t-test for means was also completed to both reject the null hypothesis and to demonstrate significance to a 50% reduction in pain scores. Statistics performed using the Microsoft Excel Software (version 2019 16.0.6742.2048. Redmond, WA. Microsoft Corp.)\n\nOf the patients studied, not reported in the above figures are 3 patients who discontinued itraconazole due to gastrointestinal side-effects (frequent bowel movements), 1 patient who discontinued treatment due to elevated LFTs, and 1 patient who discontinued itraconazole after a seizure during the treatment period. It should be noted that liver function testing was conducted for all patients prior to initiation of itraconazole treatment and at follow up appointment(s). Elevated LFTs normalized after itraconazole discontinuation.\n\nThis research was approved by the Penn State Hershey Medical Center Institutional Review Board before data collection with a waiver of informed consent.\n\nRESULTS\n\nPatient characteristics of age, weight, BMI, and menopausal status were recorded from the time of itraconazole initiation. Participants ranged from 18 to 86 years of age with an average age of 39.9 years. Of the 106 Participants, 77 patients were premenopausal and 29 patients were postmenopausal. Average weight was 69.9 kg and average BMI was 25.4 kg/m2. Data was normally distributed with a kurtosis of -0.6 and a skewness z value of -0.6.\n\nThe 106 patients who received itraconazole were found to have a 60.7% reduction in pain in response to cotton swab testing. Interestingly, we observed that pain reduction increased with duration of itraconazole therapy. In Table 1 one can see the varying duration of itraconazole therapy and change in maximal pain on cotton swab testing. The optimal therapeutic window is 5 to 6 weeks of therapy with a 69.7% reduction in pain. With longer duration of therapy the benefit of maintenance itraconazole continued, with similar reductions in pain observed in the 8 and 9+ week treatment groups. These reductions in pain may be nonsignificant due to the small number of participants and lack of control group, however, they appear to indicate a correlation between these periods of itraconazole therapy and reduction of symptoms.Table 1 Reduction in pain associated with number of weeks of treatment\n\nTable 1\t% Reduction in Pain (standard deviation)\t95% Confidence Interval\tNumber of Patients\t\nOverall Average\t60.7 (39.0)\t7.52\t106\t\nLess than 4 Weeks Treatment\t36.6 (43.2)\t36.1\t8\t\n4 Weeks of Treatment\t52.0 (44)\t20.0\t21\t\n5-6 Weeks of Treatment\t69.6 (31.9)\t10.6\t37\t\n8 Weeks of Treatment\t58.4 (44)\t19.1\t23\t\n9+ Weeks of Treatment\t66.6 (34)\t17.6\t17\t\n\nTwo-sample paired T-tests for means were undertaken to examine both pre-treatment and post-treatment objective pain scores, whether the null hypothesis could be rejected and whether significance could be proven to a >50% pain reduction. Null hypothesis was disproven (P < .01, α = 0.01) and a decrease in patients’ objective pain score by greater than 3 (correlating with a 50% reduction in pain) was demonstrated (P = .038, α = 0.05). Two-tailed Wilcoxon signed rank test also demonstrated rejection of the null hypothesis (α = 0.05).\n\nPain reduction as a percentage of total patients studied can be seen in Table 2. Overall, 37.7% of patients in this study underwent complete resolution of symptoms, and 53.8% of patients had a greater than 60% reduction in pain. A lack of symptom reduction was observed in 9.43% of patients, and in 3.77% of patients, an increase in pain was observed.Table 2 Pain reduction as a percentage of total patients studied\n\nTable 2% Reduction\tPercent of total patients\t\n100%\t37.7\t\n60 % or more\t53.8\t\n>50%\t66.0\t\n<50%\t34.0\t\n0%\t9.43\t\nSymptoms Worsened\t3.77\t\n\nDISCUSSION\n\nThis study demonstrates that the use of itraconazole in fungus culture-negative vulvodynia patients is associated with a reduction or elimination of vestibular pain as objectively measured by the cotton swab test. Our examination of dose and duration of treatment demonstrated that treatment for 5 or more weeks with a dosage of 400 mg of itraconazole (dispersed as 200 mg twice per day) was deemed the most effective. In this study, the pain scores of patients with chronic vulvar pain were collected before and after initiation of a daily dose of itraconazole. To our knowledge this is the first report of a significant reduction in objectively tested vulvar pain associated with itraconazole treatment and is striking in its complete or almost complete amelioration of pain in a large percentage of patients.\n\nA limitation of this work is the retrospective study design and the lack of a control group causing the palpable placebo effect in the vulvodynia patient population to cloud the impact of this data. An understanding of this placebo effect through the literature on vulvodynia may ameliorate this concern. In the systematic review conducted by Dr. JC Andrews interventions available for vulvodynia were examined and the placebo effect in vulvodynia, defined as an absolute effect of >50% decline in pain score, was found to range from 14% to 33%, with a median of 22%.13 We applied this benchmark to determine whether the primary outcome has been achieved. Using these median and maximal values of the projected placebo effect, this study offers benefit at this >50% benchmark to 66.0% of patients (see Table 2). This substantial benefit extends well past the placebo effect. The mechanism for this Itraconazole efficacy in vulvodynia is uncertain. It is possible itraconazole is active against a small population of yeast that do not grow in culture; alternatively, itraconazole may reduce vulvodynia pain through an anti-inflammatory or other systemic effect yet undocumented since its synthesis in 1980.\n\nThe possibility that these patients have a yet unculturable fungus present in their vulvovaginal region status post 4 to 6 weeks of fluconazole treatment remains present. This possible causative organism remains plausible due to the problematic nature of the universal treatment of CVVC with fluconazole. CVV is most commonly caused by Candida albicans, however, non-albicans candida is the causative agent in approximately 10% of CVV and has shown resistance to azole antifungals such as fluconazole.15 Itraconazole has a similar coverage when compared to fluconazole with the addition of coverage in dimorphic fungal pathogens, dermatophytes, and molds. Itraconazole also tends to concentrate in the skin and nails, accumulating 20 times higher concentrations in these tissues. It has been previously found to not offer clear benefit when compared to fluconazole for vulvovaginal infections and has been deemed to have increased side-effects, variable gastric absorption, and less predictable drug levels causing relegation to use after fluconazole treatment failure. The caveat to these statements is that itraconazole used with this high a dosage and duration has not been previously reported in CVV patients.16 The possibility that this is a treatment for a yet unculturable pathogen exists.\n\nAlternatively, if one were to consider these patients as having had a negative infectious etiology satisfactorily proven negative cultures before itraconazole initiation, it is reasonable to consider other mechanisms by which itraconazole could reduce vulvodynia pain. Pathologically, hyperinnervation and nociceptor sensitization in the vulva is a well-described characteristic of vulvodynia. It can be hypothesized that it is through a limitation of this mechanism that itraconazole could exert an effect in decreasing or eliminating vulvodynia pain.6 In murine models, it has been shown that inhibition of angiogenesis in vaginal tissues is likely to inhibit the development of accompanying perivascular nociceptive nerve fibers and hyperinnervation.17 These findings raise the possibility that inhibition of angiogenesis in the vulva could reasonably be accomplished by itraconazole.\n\nItraconazole was first identified as an inhibitor of angiogenesis in 2007 by the US food and drug administration and has since been researched as a possible anti-cancer therapy.9 Itraconazole has been shown to decrease angiogenesis through action on the mTOR signaling pathway, specifically through mTORC1.10 This same mTORC1 plays an active role in inflammation-related angiogenesis in the body18 and nerve growth factor protein expression in Schwann cells.19 The likelihood that modulation of these inhibitory functions by itraconazole is supported by the theorized mechanism for the induction of pain in vulvodynia patients that of infection and/or trauma causing an initial insult which induces inflammation, leading to angiogenesis, nerve fiber proliferation and chronic pain.\n\nFurther study in the form of randomized control trials with long-term follow up to 6- and 12-months post-treatment is warranted to detect long-term remission, along with an examination of differing dosages of itraconazole. The implication that an organic and treatable cause exists for vulvodynia with an effective treatment would have substantial practice-altering implications.\n\nStatement of Authorship\n\nRodger Rothenberger: Conceptualization, Methodology, Formal Analysis, Investigation, Data Curation, Writing – Original Draft, Writing – Review and Editing; Wendy Jones: Conceptualization, Investigation; Colin MacNeill: Conceptualization, Investigation, Validation, Data Curation, Writing – Review and Editing, Visualization, Supervision.\n\nConflict of Interest: All authors have no conflicts of interest to disclose.\n\nFunding: No external source of funding was provided. Patient's insurance and the patients themselves purchased itraconazole for treatment of their vulvovaginal pain.\n\nResearch approved by the Penn State University College of Medicine Institutional Review Board.\n\nPatient Consent: Research was approved by the Penn State College of Medicine Institutional Review Board prior to initiation of chart review with a waiver of informed consent.\n==== Refs\nREFERENCES\n\n1 Bornstein J Goldstein AT Stockdale CK 2015 ISSVD, ISSWSH, and IPPS consensus terminology and classification of persistent vulvar pain and vulvodynia J Sex Med 13 2016 607 612 10.1016/j.jsxm.2016.02.167 27045260\n2 Xie Y Shi L Xiong X Economic burden and quality of life of vulvodynia in the United States Curr Med Res Opin 28 2012 601 608 22356119\n3 Harlow BL Kunitz CG Nguyen RHN Prevalence of symptoms consistent with a diagnosis of vulvodynia: population-based estimates from two geographical regions Am J Obs Gynecol 210 2014 10.1016/j.ajog.2013.09.033 Prevalence\n4 United States Census Bureau. Quick facts: population estimates, 2017.\n5 Hong E Dixit S Fidel PL Vulvovaginal candidiasis as a chronic disease J Low Genit Tract Dis 18 2014 31 38 10.1097/lgt.0b013e318287aced 23760143\n6 Reed BD Plegue MA Sen A Nerve growth factor and selected cytokines in women with and without vulvodynia J Low Genit Tract Dis 22 2018 139 146 10.1097/LGT.0000000000000377 29570566\n7 Belayneh M, Sehn E, Korownyk C. Tools for practice: recurrent vulvovaginal candidiasis. 2017;63.\n8 Chew SY Than LTL. Vulvovaginal candidosis: contemporary challenges and the future of prophylactic and therapeutic approaches Mycoses 59 2016 262 273 10.1111/myc.12455 26765516\n9 Tsubamoto H Ueda T Inoue K Repurposing itraconazole as an anticancer agent (Review) Oncol Lett 14 2017 1240 1246 10.3892/ol.2017.6325 28789339\n10 Head SK Shi WQ Yang EJ Simultaneous targeting of NPC1 and VDAC1 by itraconazole leads to synergistic inhibition of mTOR signaling and angiogenesis ACS Chem Biol 12 2017 174 182 10.1021/acschembio.6b00849 28103683\n11 Biogen. Effect of itraconazole on the pharmacokinetics of BIIB074. Available at: https://clinicaltrials.gov/ct2/show/NCT02698267?term=Effect+of+Itraconazole+on+the+Pharmacokinetics+of+BIIB074&rank=1. Accessed May 1, 2021.\n12 Bergeron S, Binik YM, Khalife S, Pagidas K. Vulvar vestibulitis syndrome : reliability of diagnosis and evaluation of current diagnostic criteria. 2001;98:45-51.\n13 Andrews JC. Vulvodynia interventions-systematic review and evidence grading Obstet Gynecol Surv 66 2011 299 315 10.1097/OGX.0b013e3182277fb7 21794194\n14 Sobel JD.Candida Vulvovaginitis: Treatment. (Barbieri RL, Kauffman CA, Eckler K, eds.). Post TW (Ed); 2021\n15 Deorukhkar SC Saini S Mathew S. Non-albicans candida infection: an emerging threat Interdiscip Perspect Infect Dis 2014 2014 615958 10.1155/2014/615958\n16 Nett JE Andes DR. Antifungal agents: spectrum of activity, pharmacology, and clinical indications Infect Dis Clin NA 30 2016 51 83 10.1016/j.idc.2015.10.012\n17 Barry CM Huilgol KK Haberberger R V New models to study vulvodynia: hyperinnervation and nociceptor sensitization in the female genital tract Neural Regen Res 13 2018 2096 2097 30323133\n18 Faes S Santoro T Demartines N Evolving significance and future relevance of anti-angiogenic activity of mTOR inhibitors in cancer therapy Cancers (Basel) 9 2017 152 10.3390/cancers9110152\n19 Cheng M Lv X Zhang C DNMT1, a novel regulator mediating mTORC1/mTORC2 pathway-induced NGF expression in schwann Cells Neurochem Res 43 2018 2141 2154 10.1007/s11064-018-2637-1 30229399\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-1161",
"issue": "9(4)",
"journal": "Sexual medicine",
"keywords": "Antifungal; Azole; Fluconazole; Itraconazole; Vulvodynia; Vulvovaginitis",
"medline_ta": "Sex Med",
"mesh_terms": null,
"nlm_unique_id": "101631053",
"other_id": null,
"pages": "100383",
"pmc": null,
"pmid": "34246854",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "25404942;21794194;28789339;30323133;24080300;22356119;28103683;30229399;28615397;29570566;26739608;29104248;26765516;27045260;23760143;11430955",
"title": "Itraconazole Improves Vulvodynia in Fungus Culture-Negative Patients Post Fluconazole Failure.",
"title_normalized": "itraconazole improves vulvodynia in fungus culture negative patients post fluconazole failure"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2021US287507",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,... |
{
"abstract": "In recent years, several publications have demonstrated the interest and the usefulness of pharmacogenetics in forensic toxicology. However, this approach remains namely focused on DNA-based phenotype, which may potentially lead to misinterpretation. Other determinants such as co-medication or physiological parameters may also impact the phenotype. This article aims to highlight the importance of considering such determinants in forensic toxicology, through the original case of a heroin-related fatality.\n\n\n\nEthanol concentration determination and toxicological screening were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection and gas chromatography with mass spectrometry detection. CYP2C19 and CYP2D6 genotypes were determined by Taqman® real-time PCR analyses.\n\n\n\nFemoral blood analyses revealed the presence of ethanol, morphine, codeine, venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), paroxetine, and risperidone. 6-acetylmorphine was also identified in urine. VEN, paroxetine and risperidone were quantified at supra-therapeutic or toxic blood concentrations. NDV was not quantified. The metabolic ratio of VEN (ODV to VEN) was exceptionally low (about 0.7). Pharmacogenetics testing showed that the patient was heterozygous for the CYP2C19*2 loss-of-function allele, which predict an intermediate metabolism for CYP2C19. None of the deficient CYP2D6 alleles investigated were identified. Those results suggest an extensive CYP2D6-metabolism phenotype.\n\n\n\nA discrepancy was seen between the results of the genomic evaluation and the observed metabolic ratio of VEN. This tends to exclude a genetic origin and lead us to formulate other hypotheses, such as phenoconversion that may have been induced by drug interaction involving patients' regular medications. Phenoconversion is as a complex phenomenon that leads to genotype-phenotype mismatch without any genetic abnormality particularly described for cytochromes P450 2D6 and 2C19. Although transient, phenoconversion can have a significant impact on the analysis and interpretation of genotype-focused clinical outcomes correlation and in forensic toxicology conclusions.",
"affiliations": "Service de Pharmacologie-Toxicologie Pharmacovigilance, CHU Angers, Angers, France; Université d'Angers, Angers, France. Electronic address: Guillaume.drevin@chu-angers.fr.;Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Limoges, France.;Université d'Angers, Angers, France; Institut de Médecine légale, CHU Angers, Angers, France.;Service de Pharmacologie-Toxicologie Pharmacovigilance, CHU Angers, Angers, France; Université d'Angers, Angers, France; Laboratoire MitoVasc, UMR INSERM 1083 CNRS 6015, Angers, France.;Service de Pharmacologie-Toxicologie Pharmacovigilance, CHU Angers, Angers, France.",
"authors": "Drevin|G|G|;Picard|N|N|;Jousset|N|N|;Briet|M|M|;Abbara|C|C|",
"chemical_list": "D018490:Serotonin Agents; D017374:Paroxetine; D000069470:Venlafaxine Hydrochloride; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.fsigen.2020.102433",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1872-4973",
"issue": "51()",
"journal": "Forensic science international. Genetics",
"keywords": "Forensic; Personalized medicine; Pharmacogenetics; Phenoconversion",
"medline_ta": "Forensic Sci Int Genet",
"mesh_terms": "D000328:Adult; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D053593:Forensic Toxicology; D006579:Heterozygote; D006801:Humans; D008297:Male; D017374:Paroxetine; D010597:Pharmacogenetics; D010641:Phenotype; D018967:Risperidone; D018490:Serotonin Agents; D019966:Substance-Related Disorders; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "101317016",
"other_id": null,
"pages": "102433",
"pmc": null,
"pmid": "33278816",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pitfalls and challenges associated with phenoconversion in forensic toxcicology.",
"title_normalized": "pitfalls and challenges associated with phenoconversion in forensic toxcicology"
} | [
{
"companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2021-00775",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAROXETINE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nThe long term treatment of VIH/SIDA puts down majors risks among which the happening of virological failure or resistance to the anti-retroviral treatment at the patient.\n\n\nOBJECTIVE\nTo study the cases of resistance to antiretroviral to a cohort of 70 patients of the social hygiene of Dakar.\n\n\nMETHODS\nThis is a retrospective study of the medical records of 70 patients followed in the social hygiene of Dakar during 24 mouths. Data were gathered with the help of form having following variables: The period of meadow inclusion; The period of inclusion; The period of rebound virological; The rate of CD4 count; The viral load and weight of patients.\n\n\nRESULTS\nAverage of age in inclusion is of 47.5 years with a sex ratio of the women HIV 1 was dominant. Two cases of virological failure were found or (2.8%). The patient 1 was the stade II of the classification of the with as therapeutic class 2INTI + 2 INNTI. It was in stage asymptomatic with as therapeutic protocol DDI + 3TC + NVP. The patient 2 was at the stade III of the whom that is to say at the stade in AIDS with as therapeutic class: 2INTI + 1IP with the protocol of treatment DDI + 3TC +IND.\n\n\nCONCLUSIONS\nThe virological failure to the newly infected persons noticed more and more in the world poses a problem of public health because it constitutes a threat for the success of the programs of treatment of the HIV/AIDS.",
"affiliations": "Institut d’Hygiene Sociale de Dakar, Dakar/Fann, Senegal. pgallo92000@yahoo.fr",
"authors": "Sow|P G|PG|;Ndiaye|I P|IP|;Soumare|M|M|;Dieye|A M|AM|;Traore|I|I|;Diallo|F B|FB|",
"chemical_list": "D044966:Anti-Retroviral Agents",
"country": "Mali",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0464-7874",
"issue": "26(3)",
"journal": "Le Mali medical",
"keywords": null,
"medline_ta": "Mali Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012675:Senegal; D017211:Treatment Failure",
"nlm_unique_id": "18420390R",
"other_id": null,
"pages": "48-52",
"pmc": null,
"pmid": "22766411",
"pubdate": "2011",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Study of two cases of virological failure antiretrovirals in the Institute of Social Hygiene (ISH) of Dakar.",
"title_normalized": "study of two cases of virological failure antiretrovirals in the institute of social hygiene ish of dakar"
} | [
{
"companynumb": "PHHY2015SN154100",
"fulfillexpeditecriteria": "1",
"occurcountry": "SN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": null,
"drug... |
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