article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "We report the case of a 76 year old lady with metastatic breast cancer, who presented to a hospice in severe distress from uncontrolled pain despite an increase in her opioid dose, alongside generalised hypersensitivity and delirium. The clinical presentation suggested opioid-induced hyperalgesia (OIH). After reduction of the opioid dose, our patient significantly improved to the extent she was discharged home a few weeks later. This report aims to increase awareness of OIH, a clinical phenomenon which remains poorly understood and probably under recognised.",
"affiliations": null,
"authors": "Wall|Jillian|J|;Chauhan|Alpna|A|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "England",
"delete": false,
"doi": "10.1080/15360288.2018.1546256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0288",
"issue": "32(2-3)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "Opioid-induced hyperalgesia; neurotoxicity; opiate; pain",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D001943:Breast Neoplasms; D000072716:Cancer Pain; D004305:Dose-Response Relationship, Drug; D005260:Female; D017051:Hospice Care; D006801:Humans; D006930:Hyperalgesia",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "158-160",
"pmc": null,
"pmid": "30592628",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Opioid-Induced Hyperalgesia.",
"title_normalized": "a case of opioid induced hyperalgesia"
} | [
{
"companynumb": "GB-PFIZER INC-2019240005",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "OXYCODONE"
},
"drugadditional": "1",
... |
{
"abstract": "The fatality of novel coronavirus disease 2019 (COVID-19) is precipitously increased in patients with underlying comorbidities or elderly people. Kidney transplant (KT) recipients are one of the vulnerable populations for infection. COVID-19 infection in KT recipients might be a complicated and awkward situation, but there has been a lack of reports concerning this group. Herein, we demonstrated two distinct cases with different clinical progress. The first case was a 36-year-old man who underwent KT 3 years ago. He was diagnosed with COVID-19 expressing relevant symptoms. Following administration of lopinavir/ritonavir and hydroxychloroquine with reduced immunosuppressant, he recovered from COVID-19. However, the unexpected fluctuations in tacrolimus trough levels needed to be managed because of drug-to-drug interaction. The second case was developed in a 56-year-old man without any symptoms. He received a second KT from an ABO-incompatible donor 8 years ago. He was diagnosed with COVID-19 by screening due to exposure history. During the hospitalization period, the chest infiltrative lesion showed a wax and wane, but he successfully recovered by administration of hydroxychloroquine with azithromycin. These apparently different cases suggest that assertive screening and management could improve the clinical course. In addition, antiviral agents should be used cautiously, especially in patients on calcineurin inhibitors.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.;Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.;Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.;Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.;Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.;Division of Infectious Disease, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.;Division of Infectious Disease, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.;Division of Infectious Disease, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.;Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.",
"authors": "Kim|Yaerim|Y|0000-0003-1596-1528;Kwon|Ohyun|O|;Paek|Jin H|JH|;Park|Woo Y|WY|;Jin|Kyubok|K|;Hyun|Miri|M|;Lee|Ji Y|JY|;Kim|Hyun A|HA|;Han|Seungyeup|S|0000-0002-7561-6534",
"chemical_list": "D000998:Antiviral Agents; D065095:Calcineurin Inhibitors; D004338:Drug Combinations; D007166:Immunosuppressive Agents; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D006886:Hydroxychloroquine; D017963:Azithromycin; D019438:Ritonavir; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15947",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "20(8)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; immunosuppressant; infection and infectious agents - viral; infectious disease; kidney (allograft) function/dysfunction; kidney transplantation/nephrology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D017963:Azithromycin; D000073640:Betacoronavirus; D000086382:COVID-19; D065095:Calcineurin Inhibitors; D018352:Coronavirus Infections; D004338:Drug Combinations; D004347:Drug Interactions; D006801:Humans; D006886:Hydroxychloroquine; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D019438:Ritonavir; D000086402:SARS-CoV-2; D016559:Tacrolimus; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2269-2275",
"pmc": null,
"pmid": "32337859",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "32015507;32037389;23459029;30619688;31996494;32164080;32247631;29453486;29477157;31986264;32214079;32205204;32337859;32091533;32104907;10421617;14632538;24364985;32003551;15673319",
"title": "Two distinct cases with COVID-19 in kidney transplant recipients.",
"title_normalized": "two distinct cases with covid 19 in kidney transplant recipients"
} | [
{
"companynumb": "KR-BAUSCH-BL-2020-016291",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe choice of the specific modality and treatment duration of renal replacement therapy (RRT) to adopt in metformin-associated lactic acidosis (MALA) is still debated. We aimed to verify if sustained low-efficiency dialysis (SLED) is a rational choice in patients with MALA and acute kidney injury (AKI).\n\n\nMETHODS\nWe collected serial serum metformin measurements, clinical parameters, and outcome data in ten consecutive patients (mean age 77 years [range 58-88], 5 males) admitted to our renal intensive care unit for suspected MALA associated with AKI and hemodynamic instability. Patients underwent a 16-h SLED session performed with either conventional dialysis machines or machines for continuous RRT (CRRT). A 2-compartment open-infusion pharmacokinetic model with first-order elimination was fitted to each subject's serum concentration-time data to model post-SLED rebound and predict the need for further treatments.\n\n\nRESULTS\nTwo patients died within 24 h after SLED start. Three patients needed one further dialysis session. Surviving patients (n = 8) were dialysis-free at discharge. Metformin levels were in the toxic range at baseline (median [range] 32.5 mg/l [13.6-75.6]) and decreased rapidly by the end of SLED (8.1 mg/l [4.5-15.8], p < 0.001 vs. baseline), without differences according to the dialysis machine used (p = 0.84). We observed a slight 4-h post-SLED rebound (9.7 mg/l [3.5-22.0]), which could be predicted by our pharmacokinetic model. Accordingly, we predicted that the majority of patients would need one additional dialysis session performed the following day to restore safe metformin levels.\n\n\nCONCLUSIONS\nA 16-h SLED session, performed with either conventional dialysis machines or CRRT machines, allows effective metformin removal in patients with MALA and AKI. However, due to possible post-SLED rebound in serum metformin levels, one additional dialysis treatment is required the following day in the majority of patients.",
"affiliations": "Acute and Chronic Renal Failure Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.;Acute and Chronic Renal Failure Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy. giuregolisti@gmail.com.;Renal Transplant Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.;Acute and Chronic Renal Failure Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.;Acute and Chronic Renal Failure Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.;Poison Control Centre and National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri Spa-SB, IRCCS Pavia Hospital and University of Pavia, Pavia, Italy.;Acute and Chronic Renal Failure Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.;Acute and Chronic Renal Failure Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.;Renal Transplant Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.;Acute and Chronic Renal Failure Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.",
"authors": "Greco|Paolo|P|;Regolisti|Giuseppe|G|http://orcid.org/0000-0002-9976-5681;Maggiore|Umberto|U|;Ferioli|Elena|E|;Fani|Filippo|F|;Locatelli|Carlo|C|;Parenti|Elisabetta|E|;Maccari|Caterina|C|;Gandolfini|Ilaria|I|;Fiaccadori|Enrico|E|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "Italy",
"delete": false,
"doi": "10.1007/s40620-018-00562-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-8428",
"issue": "32(2)",
"journal": "Journal of nephrology",
"keywords": "Acute kidney injury; Lactic acidosis; Metformin; Pharmacokinetics; Sustained low-efficiency dialysis",
"medline_ta": "J Nephrol",
"mesh_terms": "D000140:Acidosis, Lactic; D058186:Acute Kidney Injury; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D000079782:Hybrid Renal Replacement Therapy; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D008954:Models, Biological; D012307:Risk Factors; D066007:Toxicokinetics; D016896:Treatment Outcome",
"nlm_unique_id": "9012268",
"other_id": null,
"pages": "297-306",
"pmc": null,
"pmid": "30523561",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": "25538310;26731084;24599253;28417525;25762524;25860205;23499048;23518195;23990164;28223003;20215446;7306436;24847880;25347702;26882092;21241070;25536258;21617112;26062557;6691764;16423187;25983948;29609531;26800971;26337524;19487945;30280392",
"title": "Sustained low-efficiency dialysis for metformin-associated lactic acidosis in patients with acute kidney injury.",
"title_normalized": "sustained low efficiency dialysis for metformin associated lactic acidosis in patients with acute kidney injury"
} | [
{
"companynumb": "IT-BAUSCH-BL-2018-035977",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Serum levels of B cell-activating factor (BAFF) rise following rituximab (RTX) therapy in patients with rheumatoid arthritis (RA). Initiation of naive B cell return to the periphery and autoreactive B cell expansion leading to relapse after RTX may therefore be linked to interactions between BAFF and BAFF-binding receptors (BBR). Relationships between serum BAFF and BBR expression [(BAFFR, calcium signal modulating cyclophilic ligand interactor (TACI) and B cell maturation antigen (BCMA)] were determined on B cell subsets, defined using immunoglobulin (Ig)D/CD38. Twenty pre-RTX and 18 RA patients relapsing after B cell depletion were included. Results were analysed with respect to timing of relapse up to 7 months after peripheral B cell return (≥ 5 B cells/μl) and to serum BAFF levels. After B cell return, B cell populations from relapsing patients had significantly lower BAFFR+ expression compared to HC and pre-RTX patients. The percentage of BAFFR+ B cells increased with time after B cell return and was correlated inversely with serum BAFF levels. BAFFR expression remained reduced. The percentage of TACI+ memory B cells were lower in RA patients after RTX compared with healthy controls (HC). BCMA expression (% and expression) did not differ between patients and HC. Relapse following B cell return appeared largely independent of the percentage of BAFFR+ or percentage of BCMA+ B cells or serum BAFF levels. The lower percentage of TACI+ memory B cells may reduce inhibitory signalling for B cell differentiation. In patients relapsing at longer periods after B cell return, recovery of the B cell pool was more complete, suggesting that selection or expansion of autoreactive B cells may be needed to precipitate relapse.",
"affiliations": "Department of Rheumatology, University College London, London, UK.;Department of Rheumatology, University College London, London, UK.;Department of Rheumatology, University College London, London, UK.;Department of Rheumatology, University College London, London, UK.",
"authors": "Becerra|E|E|0000-0003-2628-469X;De La Torre|I|I|;Leandro|M J|MJ|;Cambridge|G|G|",
"chemical_list": "D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; C086966:TNFRSF17 protein, human; C505719:TNFSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1111/cei.13024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9104",
"issue": "190(3)",
"journal": "Clinical and experimental immunology",
"keywords": "B lymphocytes; rheumatoid arthritis; rituximab",
"medline_ta": "Clin Exp Immunol",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D016175:B-Lymphocyte Subsets; D005786:Gene Expression Regulation; D007156:Immunologic Memory; D000069283:Rituximab; D053303:Transmembrane Activator and CAML Interactor Protein",
"nlm_unique_id": "0057202",
"other_id": null,
"pages": "372-383",
"pmc": null,
"pmid": "28800164",
"pubdate": "2017-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19384869;16869000;16508933;20974656;15897279;27252261;22689315;15701725;25339550;11257159;15201414;19644860;21792840;24365380;23993191;20676093;21283146;18025170;11564773;17634409;17185325;21225699;17008130;16622478;22253030;17154264;17038469;20473756;21250838;22124120;19419560;18342003;17119122;22984268;17442944;3358796;22127692;17763423;12865416;20097906;17189244;20581016;27055777;12905467;16447239;9569065;16899196;16226112",
"title": "B cell phenotypes in patients with rheumatoid arthritis relapsing after rituximab: expression of B cell-activating factor-binding receptors on B cell subsets.",
"title_normalized": "b cell phenotypes in patients with rheumatoid arthritis relapsing after rituximab expression of b cell activating factor binding receptors on b cell subsets"
} | [
{
"companynumb": "GB-ROCHE-2086438",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nTo describe the results of photodynamic therapy (PDT) using a standard protocol, developed for treating choroidal neovascularization (CNV), for the treatment of circumscribed choroidal hemangioma (CCH).\n\n\nMETHODS\nA prospective, uncontrolled, consecutive case series of patients with symptomatic CCH that were treated using the standard PDT protocol was evaluated periodically with ophthalmic exams and echography.\n\n\nRESULTS\nNine CCH patients were included in the study. Mean tumor height decreased from 2.7 mm before treatment to 0.8 mm at the end of the follow-up period. Mean visual acuity improved from 6/15 to 6/12. Six patients required one PDT session, two patients two sessions, and one patient three sessions. Side effects included transient visual disturbances in two patients. One patient, who concomitantly presented with age-related macular degeneration, developed CNV.\n\n\nCONCLUSIONS\nThe standard PDT protocol is effective for the treatment of CCH. Complications are uncommon. Further studies should assess the optimal PDT protocol for the treatment of CCH.",
"affiliations": "Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.",
"authors": "Vicuna-Kojchen|Joaquin|J|;Banin|Eyal|E|;Averbukh|Edward|E|;Barzel|Israel|I|;Shulman|Marina|M|;Hemo|Itzhak|I|;Pe'er|Jacob|J|;Chowers|Itay|I|",
"chemical_list": "D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000095859",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-3755",
"issue": "220(6)",
"journal": "Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde",
"keywords": null,
"medline_ta": "Ophthalmologica",
"mesh_terms": "D000328:Adult; D000368:Aged; D002830:Choroid Neoplasms; D005260:Female; D006391:Hemangioma; D006801:Humans; D008297:Male; D008875:Middle Aged; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D011166:Porphyrins; D011446:Prospective Studies; D016896:Treatment Outcome; D014463:Ultrasonography; D000077362:Verteporfin; D014792:Visual Acuity",
"nlm_unique_id": "0054655",
"other_id": null,
"pages": "351-5",
"pmc": null,
"pmid": "17095878",
"pubdate": "2006",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Application of the standard photodynamic treatment protocol for symptomatic circumscribed choroidal hemangioma.",
"title_normalized": "application of the standard photodynamic treatment protocol for symptomatic circumscribed choroidal hemangioma"
} | [
{
"companynumb": "IL-BAUSCH-SYM-2013-09136",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERTEPORFIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer.\n\n\nMETHODS\nPatients were randomized to receive either CEF (cyclophosphamide 400 mg/m(2) IV, epirubicin 50 mg/m(2) IV, and fluorouracil 500 mg/m(2) IV on days 1 and 8), or CMF (cyclophosphamide 500 mg/m(2) IV, methotrexate 40 mg/m(2) IV, and fluorouracil 600 mg/m(2) IV on days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles.\n\n\nRESULTS\nA total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P =.01) and in the assessable subset (66% v 52%, respectively; P =.005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P =.0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectively; P =.01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P =.23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, required withdrawal from study of 15 patients on CEF (7%) and one patient on CMF.\n\n\nCONCLUSIONS\nThis CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer.",
"affiliations": "Department of Medical Oncology, Newcastle Mater Misericordiae Hospital, Waratah, Australia. mdspa@alinga.newcastle.edu.au",
"authors": "Ackland|S P|SP|;Anton|A|A|;Breitbach|G P|GP|;Colajori|E|E|;Tursi|J M|JM|;Delfino|C|C|;Efremidis|A|A|;Ezzat|A|A|;Fittipaldo|A|A|;Kolaric|K|K|;Lopez|M|M|;Viaro|D|D|;|||",
"chemical_list": "D003561:Cytarabine; D015251:Epirubicin; D003520:Cyclophosphamide; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2001.19.4.943",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "19(4)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D002945:Cisplatin; D003520:Cyclophosphamide; D003561:Cytarabine; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007275:Injections, Intravenous; D008727:Methotrexate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016019:Survival Analysis",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "943-53",
"pmc": null,
"pmid": "11181656",
"pubdate": "2001-02-15",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study.",
"title_normalized": "dose intensive epirubicin based chemotherapy is superior to an intensive intravenous cyclophosphamide methotrexate and fluorouracil regimen in metastatic breast cancer a randomized multinational study"
} | [
{
"companynumb": "AU-PFIZER INC-2017418007",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic disorder of Gαs activation. Fibroblast Growth Factor 23 (FGF23)-mediated hypophosphatemia is a feature of FD/MAS that has been associated with poor skeletal outcomes. Standard therapy includes oral phosphorus and vitamin D analogs; however, treatment is limited by potential adverse renal and gastrointestinal effects. Burosumab is a monoclonal antibody to FGF23 approved to treat patients with X-linked hypophosphatemia and tumor-induced osteomalacia. There is currently no safety or efficacy data to support burosumab use in patients with FD/MAS.\n\n\n\nA 7-year-old boy with severe FD/MAS presented with persistent hypophosphatemia and skeletal complications despite conventional treatment with oral phosphate and calcitriol. He was started on burosumab and achieved sustained normalization of serum phosphorus and marked improvement in alkaline phosphatase levels. This was accompanied by an encouraging clinical response, including decreased bone pain, improved muscle strength, and improved ambulation. No adverse effects of burosumab therapy were observed.\n\n\n\nThis is the first reported case of burosumab treatment in a patient with FD/MAS. The encouraging biochemical and clinical response in this patient highlights the need for future studies to explore the safety and efficacy of burosumab in the FD/MAS pediatric population.",
"affiliations": "Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.;Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA; National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, USA.;Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.;Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. Electronic address: alison.boyce@nih.gov.",
"authors": "Gladding|Anne|A|;Szymczuk|Vivian|V|;Auble|Bethany A|BA|;Boyce|Alison M|AM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23; C000601956:burosumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bone.2021.116004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-2763",
"issue": "150()",
"journal": "Bone",
"keywords": "FGF23; Hypophosphatemia; McCune-Albright syndrome; Osteomalacia; Rickets",
"medline_ta": "Bone",
"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D053098:Familial Hypophosphatemic Rickets; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D017674:Hypophosphatemia; D008297:Male",
"nlm_unique_id": "8504048",
"other_id": null,
"pages": "116004",
"pmc": null,
"pmid": "33984553",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "32504138;12952917;31196103;28188442;18685574;22640971;31673695;24316419;23532406;10365102;29791829;30645769;31104833;29947083;24550322;25123121;15005844;22247037;29669167;29924878;30124968;33338281",
"title": "Burosumab treatment for fibrous dysplasia.",
"title_normalized": "burosumab treatment for fibrous dysplasia"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP027293",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCITRIOL"
},
"drugadditional"... |
{
"abstract": "Checkpoint inhibitors (CPIs) have become standard of care for multiple types of malignancies and while end-stage renal disease is not a contraindication, these patients are frequently excluded from clinical trials. As a result, there is limited data regarding the safety and efficacy of CPI use in this patient population. In this case series, we report outcomes and adverse events in 8 patients on hemodialysis treated with CPIs. Treatment was overall well-tolerated with adverse events in 3 of 8 (37.5%) patients, with 1 (12.5%) having a grade 4 adverse event, which is comparable to the rate reported in literature for the overall population receiving CPI. No treatment related deaths were seen. Because of small sample size, efficacy data is limited. Further studies are needed in this patient population to elucidate the true incidence of adverse events and antitumor activity.",
"affiliations": "Department of Internal Medicine.;Pharmaceutical Care.;Department of Internal Medicine.",
"authors": "Jain|Jayanshu|J|;Stein|Jill|J|;Garje|Rohan|R|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000327",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "43(8)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000066491:Clinical Decision-Making; D019468:Disease Management; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007676:Kidney Failure, Chronic; D009369:Neoplasms; D011379:Prognosis; D006435:Renal Dialysis; D016896:Treatment Outcome",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "244-249",
"pmc": null,
"pmid": "32898386",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": null,
"title": "Evaluation of Checkpoint Inhibitors in Cancer Patients With End-stage Renal Disease on Hemodialysis: Case Series and Review of the Literature.",
"title_normalized": "evaluation of checkpoint inhibitors in cancer patients with end stage renal disease on hemodialysis case series and review of the literature"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-099784",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nTo analyze the impact of different classes of lupus nephritis as risk variables for maternal and fetal adverse outcomes in a cohort of pregnant lupus patients.\n\n\nMETHODS\nThis is a cohort study with retrospective and prospective data collection, conducted at the University Hospital of State University of Rio de Janeiro, Brazil, from 2011 to 2016. A total of 147 pregnancies of 137 systemic lupus erythematosus patients of whom 66 had lupus nephritis were included. Demographic and clinical features, as well as maternal and fetal outcomes were observed for each nephritis histological class among systemic lupus erythematosus patients and compared with those without nephritis. Categorical variables were expressed as absolute and relative frequencies and numerical variables as means and standard deviation. The chi-square test with Fisher's correction and Student's t-test were used for statistical analysis. A pvalue < 0.05 was considered statistically significant.\n\n\nRESULTS\nSystemic lupus erythematosus patients with proliferative nephritis (classes III/IV, n = 54) presented more frequent disease flares ( p = 0.02), continuous active disease during pregnancy and puerperium ( p = 0.006), hospitalization due to systemic lupus erythematosus ( p < 0.001), hospitalization not directly associated to systemic lupus erythematosus ( p = 0.04), higher frequency of cesarean delivery ( p = 0.03) and preeclampsia ( p = 0.01) than patients without nephritis. Permanent damage measured by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index was more frequent in classes III/IV than among the other patients. The frequency of adverse fetal outcomes such as prematurity and admission to neonatal intensive care unit were not different among systemic lupus erythematosus patients with or without nephritis. However, perinatal deaths were more frequent in patients with all classes of nephritis ( p = 0.003).\n\n\nCONCLUSIONS\nSystemic lupus erythematosus patients with proliferative nephritis (classes III/IV) have a higher frequency of adverse maternal outcomes. This is probably due to the major impact of proliferative forms of nephritis on women's global heath, which is corroborated by the higher Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index findings, although we cannot exclude the negative influence of disease activity for the maternal adverse events. The findings indicate a need for further lupus nephritis classification beyond the nonspecific term nephritis in the context of lupus pregnancy as the impact on maternal and fetal outcomes varies according to histological class.",
"affiliations": "1 Department of Obstetrics, State University of Rio de Janeiro, Brazil.;1 Department of Obstetrics, State University of Rio de Janeiro, Brazil.;1 Department of Obstetrics, State University of Rio de Janeiro, Brazil.;1 Department of Obstetrics, State University of Rio de Janeiro, Brazil.;1 Department of Obstetrics, State University of Rio de Janeiro, Brazil.;2 Department of Rheumatology, State University of Rio de Janeiro, Brazil.;2 Department of Rheumatology, State University of Rio de Janeiro, Brazil.",
"authors": "Rodrigues|B Costa|BC|https://orcid.org/0000-0002-7426-7491;Lacerda|M Ignacchiti|MI|;Ramires de Jesús|G R|GR|;Cunha Dos Santos|Flávia|F|;Ramires de Jesús|N|N|;Levy|R A|RA|;Klumb|E Mendes|EM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0961203319829825",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "28(4)",
"journal": "Lupus",
"keywords": "Systemic lupus erythematosus; nephritis; pregnancy; renal lupus",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D001938:Brazil; D002585:Cesarean Section; D015331:Cohort Studies; D005260:Female; D006760:Hospitalization; D006785:Hospitals, University; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D015931:Intensive Care, Neonatal; D008181:Lupus Nephritis; D066087:Perinatal Death; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D055815:Young Adult",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "492-500",
"pmc": null,
"pmid": "30776967",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The impact of different classes of lupus nephritis on maternal and fetal outcomes: a cohort study of 147 pregnancies.",
"title_normalized": "the impact of different classes of lupus nephritis on maternal and fetal outcomes a cohort study of 147 pregnancies"
} | [
{
"companynumb": "BR-STRIDES ARCOLAB LIMITED-2019SP003620",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"dru... |
{
"abstract": "Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited genetic disorder caused by red cell enzymatic defects and is associated with haemolytic crisis when patients are exposed to oxidative agents (fava beans, drugs, infections). Hydroxychloroquine is suspected to trigger haemolytic crisis in G6PD-deficient patients, and off-label administration of this drug to patients infected with the novel coronavirus (SARS-CoV-2) could cause concern. We report here the first case of severe haemolytic crisis in a patient with G6PD deficiency, initiated by severe COVID-19 infection and hydroxychloroquine use. With worldwide spread of COVID-19, especially in regions with a high prevalence of G6PD deficiency, our case should alert physicians to this possible correlation.",
"affiliations": "Haematology Division, Department of Oncology, Geneva University Hospitals, Geneva, Switzerland.;Intensive Care Division, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland.;Intensive Care Division, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland.;Haematology Division, Department of Oncology, Geneva University Hospitals, Geneva, Switzerland.",
"authors": "Beauverd|Yan|Y|https://orcid.org/0000-0002-7971-4326;Adam|Yannick|Y|;Assouline|Benjamin|B|;Samii|Kaveh|K|",
"chemical_list": "D006886:Hydroxychloroquine",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13432",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "105(3)",
"journal": "European journal of haematology",
"keywords": "COVID-19; G6PD deficiency; SARS-CoV-2; coronavirus; haemolysis; hydroxychloroquine",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000368:Aged; D000073640:Betacoronavirus; D000086382:COVID-19; D015897:Comorbidity; D018352:Coronavirus Infections; D005955:Glucosephosphate Dehydrogenase Deficiency; D006461:Hemolysis; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "357-359",
"pmc": null,
"pmid": "32324284",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32150618;32324284;18177777;32205204;32205321;28556555",
"title": "COVID-19 infection and treatment with hydroxychloroquine cause severe haemolysis crisis in a patient with glucose-6-phosphate dehydrogenase deficiency.",
"title_normalized": "covid 19 infection and treatment with hydroxychloroquine cause severe haemolysis crisis in a patient with glucose 6 phosphate dehydrogenase deficiency"
} | [
{
"companynumb": "CH-TEVA-2020-CH-1827279",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"dru... |
{
"abstract": "A case of severe amlodipine overdose with only mild symptoms is described. Plasma concentrations of amlodipine were measured in serial samples by gas chromatography. There was no concomitant overdose. The present case is compared with previous reported cases of amlodipine overdose where patients all developed severe symptoms. We conclude that amlodipine overdose does not always cause severe symptoms.",
"affiliations": "Department of Internal Medicine, Odense University Hospital, Odense, Denmark. poggenborg@dadlnet.org",
"authors": "Poggenborg|René Panduro|RP|;Videbaek|Lars|L|;Jacobsen|Ib Abildgaard|IA|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "England",
"delete": false,
"doi": "10.1111/j.1742-7843.2006.pto_318.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-7835",
"issue": "99(3)",
"journal": "Basic & clinical pharmacology & toxicology",
"keywords": null,
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": "D000328:Adult; D017311:Amlodipine; D001794:Blood Pressure; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D006801:Humans; D008297:Male; D013406:Suicide, Attempted",
"nlm_unique_id": "101208422",
"other_id": null,
"pages": "209-12",
"pmc": null,
"pmid": "16930293",
"pubdate": "2006-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of amlodipine overdose.",
"title_normalized": "a case of amlodipine overdose"
} | [
{
"companynumb": "DK-LUPIN PHARMACEUTICALS INC.-2015-03618",
"fulfillexpeditecriteria": "2",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditi... |
{
"abstract": "Little is known about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnant women, fetuses, and neonates, especially when the virus is contracted early in pregnancy. The literature is especially lacking on the effects of SARS-CoV-2 on extremely preterm (<28 weeks gestation) infants who have underdeveloped immune systems. We report the case of an extremely preterm, 25-week 5-days old infant, born to a mother with severe COVID-19 (coronavirus disease-2019) pneumonia. In this case, there is no evidence of vertical transmission of SARS-CoV-2 based on reverse transcription-polymerase chain reaction testing, despite extreme prematurity. However, it appears that severe maternal COVID-19 may have been associated with extremely preterm delivery, based on observed histologic chorioamnionitis. This is the first reported case of an extremely preterm infant born to a mother with severe COVID-19 pneumonia who required intubation, and was treated with hydroxychloroquine, azithromycin, remdesivir, tocilizumab, convalescent plasma, inhaled nitric oxide, and prone positioning for severe hypoxemic respiratory failure prior to and after delivery of this infant. The infant remains critically ill with severe respiratory failure on high-frequency ventilation, inotropic support, hydrocortisone for pressor-resistant hypotension, and inhaled nitric oxide for severe persistent pulmonary hypertension with a right to left shunt across the patent ductus arteriosus and foramen ovale. Pregnant women or women planning to get pregnant should take all precautions to minimize exposure to SARS-CoV-2 to decrease adverse perinatal outcomes.",
"affiliations": "Keck School of Medicine of University of Southern California, LAC+USC Medical Center, Los Angeles, CA, USA.;Keck School of Medicine of University of Southern California, LAC+USC Medical Center, Los Angeles, CA, USA.;Keck School of Medicine of University of Southern California, LAC+USC Medical Center, Los Angeles, CA, USA.;Keck School of Medicine of University of Southern California, LAC+USC Medical Center, Los Angeles, CA, USA.;Keck School of Medicine of University of Southern California, LAC+USC Medical Center, Los Angeles, CA, USA.",
"authors": "Easterlin|Molly C|MC|0000-0003-0899-1083;De Beritto|Theodore|T|;Yeh|Amy M|AM|;Wertheimer|Fiona B|FB|;Ramanathan|Rangasamy|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2324709620946621",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620946621\n10.1177_2324709620946621\nCase Report\nExtremely Preterm Infant Born to a Mother With Severe COVID-19 Pneumonia\nhttps://orcid.org/0000-0003-0899-1083Easterlin Molly C. MD, MS1 De Beritto Theodore MD, MS1 Yeh Amy M. MD, MPH1 Wertheimer Fiona B. DO1 Ramanathan Rangasamy MD1 1 Keck School of Medicine of University of Southern California, LAC+USC Medical Center, Los Angeles, CA, USA\nMolly C. Easterlin, MD, MS, Department of Pediatrics, Division of Neonatology, LAC+USC Medical Center, 1200 North State Street, IRD Building-Room 820, Los Angeles, CA 90033-1029, USA. Email: measterlin@chla.usc.edu\n29 7 2020 \nJan-Dec 2020 \n8 232470962094662117 6 2020 30 6 2020 5 7 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis 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 page (https://us.sagepub.com/en-us/nam/open-access-at-sage).Little is known about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnant women, fetuses, and neonates, especially when the virus is contracted early in pregnancy. The literature is especially lacking on the effects of SARS-CoV-2 on extremely preterm (<28 weeks gestation) infants who have underdeveloped immune systems. We report the case of an extremely preterm, 25-week 5-days old infant, born to a mother with severe COVID-19 (coronavirus disease-2019) pneumonia. In this case, there is no evidence of vertical transmission of SARS-CoV-2 based on reverse transcription-polymerase chain reaction testing, despite extreme prematurity. However, it appears that severe maternal COVID-19 may have been associated with extremely preterm delivery, based on observed histologic chorioamnionitis. This is the first reported case of an extremely preterm infant born to a mother with severe COVID-19 pneumonia who required intubation, and was treated with hydroxychloroquine, azithromycin, remdesivir, tocilizumab, convalescent plasma, inhaled nitric oxide, and prone positioning for severe hypoxemic respiratory failure prior to and after delivery of this infant. The infant remains critically ill with severe respiratory failure on high-frequency ventilation, inotropic support, hydrocortisone for pressor-resistant hypotension, and inhaled nitric oxide for severe persistent pulmonary hypertension with a right to left shunt across the patent ductus arteriosus and foramen ovale. Pregnant women or women planning to get pregnant should take all precautions to minimize exposure to SARS-CoV-2 to decrease adverse perinatal outcomes.\n\nextremely pretermCOVID-19 pneumoniarespiratory failuretuberous sclerosiscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nLittle is known about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the fetus when the virus is contracted by the mother, especially early in gestation. While a series of 9 pregnant women demonstrated no vertical transmission of SARS-CoV-2 based on reverse transcription-polymerase chain reaction (RT-PCR) testing,1 other studies have reported elevated neonatal immunoglobulin M (IgM) antibodies, concerning for vertical transmission,2,3 and cases of symptomatic neonatal and infant COVID-19 (coronavirus disease-2019).4-6 However, these reports are lacking data on extremely preterm infants (<28 weeks gestation), who have underdeveloped immune systems, and therefore may be at a greater risk. The only report that examined the effects of maternal COVID-19 in extremely preterm fetuses presented a case of miscarriage during the second trimester, at 19 weeks’ gestation, that appeared related to placental infection with SARS-CoV-2.7 We report the case of an extremely preterm infant born to a mother with severe COVID-19 pneumonia at Los Angeles County+USC Medical Center in April 2020. Verbal HIPPA (Health Insurance Portability and Accountability Act) authorization and informed consent were obtained from the patient and from a legally authorized representative for anonymized patient information to be published in this article, per the recommendations of our institutional review board.\n\nCase Presentation\nMaternal Presentation\nA 22-year-old primigravida mother with placenta previa and a past medical history of tuberous sclerosis and multiple associated comorbidities (pulmonary lymphangioleiomyomatosis, left ventricular hamartomas, subependymal nodules, adenoma sebaceum, left partial and right total nephrectomy for angiomyolipoma, and leiomyosarcoma) carrying a fetus at 23+6 weeks was admitted with cough, fever, emesis, and abdominal pain. Four days earlier, she had tested positive for SARS-CoV-2 at another institution. One day after her positive SARS-CoV-2 test, she was admitted for observation due to productive blood-tinged cough and tachycardia, which resolved with rest and intravenous fluids, she was treated for a urinary tract infection, and discharged home the next day. Two days after discharge, she presented with lymphopenia, elevated transaminases and lipase, and chest X-ray showed multifocal pneumonia consistent with diagnosis of COVID-19 pneumonia (Table 1).\n\nTable 1. Laboratory Studies for Mother.\n\nBlood counts morning of delivery\tResult (reference range)\t\nWhite blood cell count (K/cmm)\t14.1 (4.5-10)\t\nNeutrophils\t87.4%\t\nLymphocytes\t7.3%\t\nMonocytes\t4.5%\t\nEosinophils\t0.7%\t\nBasophils\t0.1%\t\nAbsolute neutrophil count (K/cmm)\t12.3\t\nAbsolute lymphocyte count (K/cmm)\t1.0\t\nHemoglobin (g/dL)\t6.6a (12.0-14.6)\t\nHematocrit (%)\t19.5a (36.0-44.0)\t\nPlatelets (K/cmm)\t356 (160-360)\t\nCoagulation studies day of delivery\t\n Partial thromboplastin time (seconds)\t61.6b (24.4-36.6)\t\n Fibrinogen (mg/dL)\t1070 (237-481)\t\nArterial blood gas prior to delivery\t\n pH\t7.43\t\n pCO2 (torr)\t39\t\n paO2 (torr)\t57\t\n HCO3\t26\t\n Base excess\t1.5\t\n Lactate (mmol/L)\t0.8\t\nInitial inflammatory markers\t\n CRP (mg/L)\t229.7 (≤4.9)\t\n Procalcitonin (ng/mL)\t16.10 (≤0.09)\t\n Serum interleukin-6 (pg/mL)\t150.93 (<5.00)\t\n Ferritin (ng/mL)\t350 (10-150)\t\n D-dimer (µg/mL)\t3.27 (≤0.49)\t\nSARS-CoV-2 RT-PCR\t\n Initial deep nasopharyngeal swab\tPositive\t\n Brocheoalveolar lavage 31 days later\tNegative\t\nAbbreviations: CRP, C-reactive protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RT-PCR, reverse transcription-polymerase chain reaction.\n\na The patient received a packed red blood cell transfusion and hemoglobin was 7.4 g/dL prior to delivery. She also received packed red blood cell transfusion during delivery.\n\nb The patient was on a therapeutic heparin drip until 6 hours prior to delivery.\n\nShe was admitted for acute pancreatitis in the setting of COVID-19 pneumonia. She was started on hydroxychloroquine and azithromycin. The following evening her respiratory status deteriorated, with hypoxia despite nasal cannula support, and she was transferred to the intensive care unit (ICU) for initiation of high-flow nasal cannula. Two days later, she was intubated. She was ultimately treated with sedation, paralysis, prone positioning with a RotoProne bed and doughnut to avoid pressure on the uterus and fetus, inhaled nitric oxide, remdesivir, convalescent plasma, tocilizumab (monoclonal antibody against interleukin-6), and therapeutic anticoagulation. On hospital day 14, with the fetus at 25+5, she developed preeclampsia and concern for concealed abruption in the setting of placenta previa. Given maximal maternal medical support, following multidisciplinary discussions among the intensivists, obstetrical, and neonatal care providers about resuscitation and initiating care, betamethasone for fetal lung development and magnesium sulfate for neuroprotection were begun. A few hours later, an urgent Cesarean section was performed in her ICU bed for worsening maternal status. Propofol was added to ongoing pain and sedation management. Following delivery, maternal status initially improved but was ultimately complicated by bilateral pneumothoraces requiring chest tube placement, multiple bilateral pulmonary emboli, culture negative sepsis, and failed extubation requiring tracheostomy after 27 days of intubation.\n\nNeonatal Presentation\nAt 25+5 weeks, an 810 g appropriate for gestational age female fetus was delivered in a negative-pressure ICU room. All staff were wearing N-95 masks, face shields, gowns, foot covers, gloves, and bouffants. On delivery the infant was apneic, cyanotic, and with no heart rate. Amniotic fluid was meconium stained and there was a nuchal cord. Cord clamping was not delayed. The infant needed intubation, chest compressions, and 1 dose of epinephrine, with improvement in oxygen saturation and heart rate by 11 minutes of life. Apgar scores were 0, 2, 5, 5, 5 at 1, 5, 10, 15, and 20 minutes, respectively. A viral filter was used between the endotracheal tube and T-piece resuscitator to minimize aerosolization. The infant was transported in a transport isolette and admitted to a negative-pressure room in the neonatal ICU.\n\nSARS-CoV-2 testing with RT-PCR of tracheal aspirate immediately after admission and nasopharyngeal swab at 24 hours of life were negative. Initial chest X-ray was consistent with respiratory distress syndrome. The infant was placed on high-frequency oscillatory ventilation and given surfactant. Initial laboratory values (Table 2) were significant for coagulopathy requiring transfusion of cryoprecipitate, fresh frozen plasma, and packed red blood cells. The complete blood count and liver enzymes were normal and remained essentially within normal limits. Repeat SARS-CoV-2 testing on day of life 10 was also negative and the infant was moved out of negative-pressure isolation per the recommendation from infectious disease consultants. The infant did not receive maternal breast milk due to multiple maternal medications and lack of breast milk supply due to severe maternal illness. Placental pathology revealed a small placenta, and fetal membranes with chorionitis, stage 1, grade 2. The infant has grade 2 intraventricular hemorrhage, patent ductus arteriosus, and remains hospitalized. She also has findings suggestive of tuberous sclerosis complex and genetic testing is pending. The mother is a known case of tuberous sclerosis complex and is heterozygous for a pathogenic variant of the TSC2 gene.\n\nTable 2. Laboratory Studies for Neonate.\n\nBlood counts\tResult (reference range)\t\nWhite blood cell count (K/cmm)\t11.7 (9-30)\t\nNeutrophils\t48%\t\nBands\t11%\t\nLymphocytes\t28%\t\nMonocytes\t12%\t\nEosinophils\t1%\t\nAbsolute neutrophil count (K/cmm)\t6.9 (6.0-26.0)\t\nAbsolute lymphocyte count (K/cmm)\t3.3 (2.0-11.0)\t\nHemoglobin (g/dL)\t12.7 (13.5-21.9)\t\nHematocrit (%)\t38.6 (42.0-60.0)\t\nPlatelets (K/cmm)\t209 (150-350)\t\nCoagulation studies\t\n Prothrombin time (seconds)\t58.6 (11.8-14.4)\t\n INR\t6.8 (0.87-1.13)\t\n Partial thromboplastin time (seconds)\t98.8 (24.4-38.6)\t\n Fibrinogen (mg/dL)\t<60 (237-481)\t\nFirst blood gas\t\n pH\t6.93\t\n Base deficit\t−8.8\t\n Lactate (mmol/L)\t5.2\t\nInflammatory markers\t\n CRP (mg/L)\t0.2 (≤4.9)\t\n Procalcitonin (ng/mL)\t0.64 (≤0.09)\t\nSARS-CoV-2 RT-PCR\t\n Tracheal aspirate DOL 0\tNegative\t\n Deep nasopharyngeal swab DOL 1\tNegative\t\n Deep nasopharyngeal swab DOL 10\tNegative\t\nAbbreviations: INR, international normalized ratio; CRP, C-reactive protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RT-PCR, reverse transcription polymerase chain reaction; DOL, day of life.\n\nDiscussion and Conclusion\nThe effects of COVID-19 on the pregnant woman and fetus are not well known, especially if the infection occurs early in pregnancy, making patient counseling and clinical decision making difficult. To our knowledge, this is the first reported case of an extremely preterm infant born to a mother with severe COVID-19 pneumonia. Though limited by one case, this report provides some information on the effects of severe COVID-19 on birth outcomes, vertical transmission, and neonatal outcomes when SARS-CoV-19 infection is confirmed during the second trimester of pregnancy.\n\nIn terms of birth outcomes, although there appears to be an increased frequency of preterm labor and cesarean delivery for abnormal fetal heart rate tracings (likely related to severe maternal illness), outcomes have only been studied for women infected in the third trimester of pregnancy.8 In our case, severe COVID-19 pneumonia likely contributed to preterm delivery. Though this observation is only an association, it is indirectly supported by the finding of histologic chorioamnionitis, which may be due to SARS-CoV-2, as reported in another study that documented still birth in the second trimester, potentially related to SARS-CoV-2 infection of the placenta.7 Severity of maternal hypoxic respiratory failure may have also contributed to preterm delivery. To our knowledge, this is the only report of severe COVID-19 in pregnancy needing intubation.\n\nWith regard to vertical transmission, while a series of 9 pregnant women reported no vertical transmission of SARS-CoV-2 based on PCR testing of newborn throat swabs, amniotic fluid, cord blood, and breastmilk,1 others have reported elevated neonatal IgM antibodies, suggestive of vertical transmission in 1 and 2 neonates born to mothers with COVID-19, respectively, with the later report also showing elevated levels of the inflammatory cytokine interleukin-6 in all infants.2,3 In our case, based on RT-PCR testing of the tracheal aspirate at birth, and nasopharyngeal swabs on days of life 1 and 10, there was no evidence of vertical transmission despite extremely preterm status and the possible presence of tuberous sclerosis complex at birth, which appears to have an effect on the development and function of the innate and adaptive immune responses.9 However, in our case, testing of cord blood and placenta for SARS-CoV-2 was not performed due to severity of maternal illness and urgency of delivery in the ICU. Additionally, SARS-CoV-2 antibody testing is not currently available at our county institution or through the send out service to an outside laboratory. Although this additional testing may have provided more information, difficulties in diagnosing vertical transmission remains, as RNA PCR is not necessarily indicative of viable virus and IgM exhibits high cross-reactivity, which may lead to false-positive results.\n\nFinally, with regard to the effects of SARS-CoV-2 on the neonate, other reports have documented cases of symptomatic neonatal and infant COVID-19.4-6 In the study by Zhu et al, all infants tested negative for SARS-CoV-2 by RT-PCR of pharyngeal swabs after birth but presented with clinical symptoms, and laboratory and imaging abnormalities that could have been consistent with COVID-19.5 In the studies by Zeng et al, and Feld et al, the neonates and infants tested positive for COVID-19.4,6 However, the infants in the Feld study were admitted from home, where they likely contracted the virus, making this a different population with likely horizontal acquisition of infection from the community. In our case, potential postnatal transmission was negated by isolation from all family members and lack of breastmilk feeding.\n\nOur case also highlights the dilemma obstetricians and perinatologists have been facing during this COVID-19 pandemic related to antenatal steroids for prematurity. While there are concerns that antenatal steroids may worsen maternal condition, this has to be weighed against the benefits of steroids to the fetus.10,11 Initial guidelines from the Centers for Disease Control and Prevention and World Health Organization recommended against corticosteroids in COVID-19 patients unless indicated for other reasons, such as the management of chronic obstructive pulmonary disease or septic shock. This is because limited studies in patients with MERS (Middle East respiratory syndrome), SARS, and influenza had shown corticosteroids to be associated with prolonged viral replication, possible harms, or higher mortality. Based on this, the American College of Obstetricians and Gynecologists altered their recommendation for corticosteroids for fetal lung maturity in COVID-19 mothers, recommending steroids only before 34+0 weeks. However many guidelines, such as those from the National Institutes of Health and World Health Organization, have now been revised or are undergoing revision, as recent new preliminary data from a large, multicenter, randomized, open-label trial for hospitalized patients in the United Kingdom (currently unpublished and undergoing peer review) has shown that dexamethasone appears to be associated with decreased mortality in patients who are severely ill (mechanically ventilated or receiving oxygen support by noninvasive methods).12 However, the preliminary data also show that in COVID-19 patients not requiring respiratory support, corticosteroids were associated with no benefit and possible harm (nonsignificant increase in mortality), and that timing of administration of corticosteroids in relation to the onset of COVID-19 appeared to be of critical importance. Therefore, who receives steroids and at what point in illness requires serious consideration, especially in pregnant women, where the immune response may be different, and maternal versus fetal benefit has to be weighed. Due to rapidly worsening maternal status and anticipated delivery, the mother in our case received 1 dose of betamethasone 4 hours prior to delivery. More data are needed to better inform how to weigh the risks and benefits of giving antenatal steroids in COVID-19-positive pregnant women. This case additionally highlights dilemmas related to the safety of positioning pregnant patients prone, delivery to improve maternal respiratory status, and continuous versus intermittent monitoring of very preterm fetuses in the setting of maternal respiratory failure, given the unknown risks and benefits to the mother and fetus of intervening on fetal behalf.13 Ultimately, it is clear that in cases where there is potential for maternal acute respiratory failure, ongoing goals of care discussions with the family, designation of a health care proxy, and clear and frequent communication between the intensivists, obstetric, and neonatal teams is paramount.\n\nLimitations are the following: this is a report of a single case and amniotic fluid, placenta, cord blood, and breast milk were not tested for SARS-CoV-2. We did not find evidence of vertical transmission in this extremely preterm infant. Further studies of maternal-infant dyads are needed to understand the impact of SARS-CoV-2 on pregnancy and neonatal outcomes, especially early in pregnancy. This information will be important to help guide clinical counseling, decision making, and health policy for pregnant women and neonates.\n\nAuthor Contributions: Dr Easterlin conceptualized and designed the case report, drafted the initial manuscript, and reviewed and revised the manuscript.\n\nDrs De Beritto, Yeh, Wertheimer, and Ramanathan conceptualized and designed the case report, reviewed and revised the manuscript, and critically reviewed the manuscript for important intellectual content.\n\nAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: This case report complies with the guidelines for human studies and was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.\n\nInformed Consent: Verbal HIPAA (Health Insurance Portability and Accountability Act) authorization and informed consent were obtained from the patient and from a legally authorized representative for anonymized patient information to be published in this article, per the recommendations of our institutional review board.\n\nORCID iD: Molly C. Easterlin \nhttps://orcid.org/0000-0003-0899-1083\n==== Refs\nReferences\n1 \nChen H Guo J Wang C , et al\nClinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records\n. Lancet . 2020 ;395 :809 -815\n. doi:10.1016/S0140-6736(20)30360-3 32151335 \n2 \nDong L Tian J He S , et al\nPossible vertical transmission of SARS-CoV-2 from an infected mother to her newborn\n. JAMA . 2020 ;323 :1846 -1848\n. doi:10.1001/jama.2020.4621 \n3 \nZeng H Xu C Fan J , et al\nAntibodies in infants born to mothers with COVID-19 pneumonia\n. JAMA . 2020 ;323 :1848 -1849\n. doi:10.1001/jama.2020.4861 \n4 \nZeng L Xia S Yuan W , et al\nNeonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China\n. JAMA Pediatr . 2020 ;174 :722 -725\n. doi:10.1001/jamapediatrics.2020.0878 \n5 \nZhu H Wang L Fang C , et al\nClinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia\n. Transl Pediatr . 2020 ;9 :51 -60\n. doi:10.21037/tp.2020.02.06 32154135 \n6 \nFeld L Belfer J Kabra R , et al\nA case series of the 2019 novel coronavirus (SARS-CoV-2) in three febrile infants in New York\n. Pediatrics . 2020 ;146 :e20201056 . doi:10.1542/peds.2020-1056 32404431 \n7 \nBaud D Greub G Favre G , et al\nSecond-trimester miscarriage in a pregnant woman with SARS-CoV-2 infection\n. JAMA . 2020 ;323 :2198 -2200\n. doi:10.1001/jama.2020.7233 \n8 \nMullins E Evans D Viner RM O’Brien P Morris E \nCoronavirus in pregnancy and delivery: rapid review\n. Ultrasound Obstet Gynecol . 2020 ;55 :586 -592\n. doi:10.1002/uog.22014 32180292 \n9 \nYang H Wang X Zhang Y , et al\nModulation of TSC-mTOR signaling on immune cells in immunity and autoimmunity\n. J Cell Physiol . 2014 ;229 :17 -26\n. doi:10.1002/jcp.24426 23804073 \n10 \nThe American College of Obstetricians and Gynecologists . COVID-19 FAQs for obstetrician-gynecologists, obstetrics\n. Accessed May 2020 \nhttps://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetrics\n11 \nRasmussen SA Smulian JC Lednicky JA Wen TS Jamieson DJ \nCoronavirus disease 2019 (COVID-19) and pregnancy: what obstetricians need to know\n. Am J Obstet Gynecol . 2020 ;222 :415 -426\n. doi:10.1016/j.ajog.2020.02.017 32105680 \n12 \nHorby P Lim WS Emberson J , et al\nEffect of dexamethasone in hospitalized patients with COVID-19: preliminary report\n. doi:10.1101/2020.06.22.20137273 Published June 22, 2020. Accessed July 16, 2020 \nhttps://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1\n13 \nPacheco LD Saad AF Saade G \nEarly acute respiratory support for pregnant patients with coronavirus disease 2019 (COVID-19) infection\n. Obstet Gynecol . 2020 ;136 :42 -45\n. doi:10.1097/AOG.0000000000003929 32349051\n\n",
"fulltext_license": "CC BY-NC",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "COVID-19 pneumonia; extremely preterm; respiratory failure; tuberous sclerosis",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D058873:Pandemics; D011024:Pneumonia, Viral; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D047928:Premature Birth; D055815:Young Adult",
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"title": "Extremely Preterm Infant Born to a Mother With Severe COVID-19 Pneumonia.",
"title_normalized": "extremely preterm infant born to a mother with severe covid 19 pneumonia"
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"abstract": "AREN0321 evaluated the activity of vincristine and irinotecan (VI) in patients with newly diagnosed diffuse anaplastic Wilms tumor (DAWT) and whether a regimen containing carboplatin (regimen UH1) in addition to regimen I agents used in the National Wilms Tumor Study 5 (NWTS-5; vincristine, doxorubicin, cyclophosphamide, and etoposide plus radiotherapy) would improve patient outcomes.\n\n\n\nPatients with stage II to IV DAWT without measurable disease received regimen UH1. Patients with stage IV measurable disease were eligible to receive VI (vincristine, 1.5 mg/m2 per day intravenously on days 1 and 8; irinotecan, 20 mg/m2 per day intravenously on days 1-5 and 8-12 of a 21-day cycle) in an upfront window; those with complete (CR) or partial response (PR) had VI incorporated into regimen UH1 (regimen UH2). The study was designed to detect improvement in outcomes of patients with stage II to IV DAWT compared with historical controls treated with regimen I.\n\n\n\nSixty-six eligible patients were enrolled. Of 14 patients with stage IV measurable disease who received VI, 11 (79%) achieved CR (n = 1) or PR (n = 10) after 2 cycles. Doses of doxorubicin, cyclophosphamide, and etoposide were reduced midstudy because of nonhematologic toxicity. Four patients (6%) died as a result of toxicity. Four-year event-free survival, relapse-free survival, and overall survival rates were 67.7% (95% CI, 55.9% to 79.4%), 72.9% (95% CI, 61.5% to 84.4%), and 73.7% (95% CI, 62.7% to 84.8%), respectively, compared with 57.5% (95% CI, 47.6% to 67.4%; P = .26), 57.5% (95% CI, 47.6% to 67.4%; P = .048), and 59.2% (95% CI, 49.4% to 69.0%; P = .08), respectively, in NWTS-5.\n\n\n\nVI produced a high response rate in patients with metastatic DAWT. AREN0321 treatment seemed to improve outcomes for patients with stage II to IV DAWT compared with NWTS-5, but with increased toxicity. The UH2 regimen warrants further investigation with modifications to reduce toxicity.",
"affiliations": "Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Biostatistics, University of Florida, Gainesville, FL.;Department of Radiation Oncology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern Memorial Hospital, Chicago, IL.;Department of Biostatistics, University of Florida, Gainesville, FL.;Department of Radiology, University of Washington, Seattle, WA.;Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH.;Department of Pathology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.;Department of Pediatric Surgery, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI.;Department of Pediatric Hematology/Oncology, Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA.;Department of Pediatrics, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD.;Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.;University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN.;Department of Pharmaceutical Services, St Jude Children's Research Hospital, Memphis, TN.;University of Nebraska Medical Center, Omaha, NE.;Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO.;Department of Biostatistics, University of Florida, Gainesville, FL.;Departments of Pediatrics and Bioethics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.;Division of Oncology, Children's National Medical Center, Center for Cancer and Blood Disorders, George Washington University School of Medicine and Health Sciences, Washington, DC.",
"authors": "Daw|Najat C|NC|;Chi|Yueh-Yun|YY|;Kalapurakal|John A|JA|;Kim|Yeonil|Y|;Hoffer|Fredric A|FA|;Geller|James I|JI|;Perlman|Elizabeth J|EJ|;Ehrlich|Peter F|PF|;Mullen|Elizabeth A|EA|;Warwick|Anne B|AB|;Grundy|Paul E|PE|;Paulino|Arnold C|AC|;Gratias|Eric|E|;Ward|Deborah|D|;Anderson|James R|JR|;Khanna|Geetika|G|;Tornwall|Brett|B|;Fernandez|Conrad V|CV|;Dome|Jeffrey S|JS|;|||",
"chemical_list": "D014750:Vincristine; D000077146:Irinotecan",
"country": "United States",
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"doi": "10.1200/JCO.19.01265",
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"issn_linking": "0732-183X",
"issue": "38(14)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D009367:Neoplasm Staging; D010372:Pediatrics; D014750:Vincristine; D009396:Wilms Tumor; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "1558-1568",
"pmc": null,
"pmid": "32134700",
"pubdate": "2020-05-10",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "28795993;8164044;7652168;8107657;11996479;7978044;7931483;21051660;15111352;22927531;29211618;7480650;10219330;15868587;8889347;16710034;831755;10589779;17634492;29659330;18996004",
"title": "Activity of Vincristine and Irinotecan in Diffuse Anaplastic Wilms Tumor and Therapy Outcomes of Stage II to IV Disease: Results of the Children's Oncology Group AREN0321 Study.",
"title_normalized": "activity of vincristine and irinotecan in diffuse anaplastic wilms tumor and therapy outcomes of stage ii to iv disease results of the children s oncology group aren0321 study"
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"abstract": "CNNM2 (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD). We identified two new cases with CNNM2 novel de novo pathogenic variants, c.814T>C and c.976G>C. They both presented with infantile-onset epilepsy with DD and hypomagnesemia refractory to magnesium supplementation. To date, 21 cases with CNNM2-related disorders have been reported. We combined all 23 cases to analyze the features of CNNM2-related disorders. The phenotypes can be classified into three types: type 1, autosomal dominant (AD) inherited simple hypomagnesemia; type 2, AD inherited hypomagnesemia with epilepsy and ID/DD; and type 3, autosomal recessive (AR) inherited hypomagnesemia with epilepsy and ID/DD. All five type 1 cases had no epilepsy or ID/DD; they all had hypomagnesemia, and three of them presented with symptoms secondary to hypomagnesemia. Fifteen type 2 patients could have ID/DD and seizures, which can be controlled with antiseizure medications (ASMs); their variations clustered in the DUF21 domain of CNNM2. All three type 3 patients had seizures from 1 to 6 days after birth; the seizures were refractory, and 1/3 had status epilepticus; ID/DD in these AR-inherited cases was more severe than that of AD-inherited cases; they all had abnormalities of brain magnetic resonance imaging (MRI). Except for one patient whose serum magnesium was the lower limit of normal, others had definite hypomagnesemia. Hypomagnesemia could be improved after magnesium supplement but could not return to the normal level. Variations in the CBS2 domain may be related to lower serum magnesium. However, there was no significant difference in the level of serum magnesium among the patients with three different types of CNNM2-related disorders. The severity of different phenotypes was therefore not explained by decreased serum magnesium. We expanded the spectrum of CNNM2 variants and classified the phenotypes of CNNM2-related disorders into three types. We found that DUF21 domain variations were most associated with CNNM2-related central nervous system phenotypes, whereas hypomagnesemia was more pronounced in patients with CBS2 domain variations, and AR-inherited CNNM2-related disorders had the most severe phenotype. These results provide important clues for further functional studies of CNNM2 and provide basic foundations for more accurate genetic counseling.",
"affiliations": "Department of Pediatrics, Peking University First Hospital, Beijing, China.;Department of Pediatrics, Peking University First Hospital, Beijing, China.;Department of Pediatrics, Peking University First Hospital, Beijing, China.",
"authors": "Zhang|Han|H|;Wu|Ye|Y|;Jiang|Yuwu|Y|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2021.699568",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.699568\nPediatrics\nOriginal Research\nCNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance\nZhang Han\n\nWu Ye\n\nJiang Yuwu *\n\nDepartment of Pediatrics, Peking University First Hospital, Beijing, China\nEdited by: Joseph Sullivan, UCSF Benioff Children's Hospital, United States\n\nReviewed by: Maurizio Elia, Oasi Research Institute (IRCCS), Italy; Charles Marques Loureco, University of São Paulo Ribeirão Preto, Brazil\n\n*Correspondence: Yuwu Jiang jiangyuwu@bjmu.edu.cn\nThis article was submitted to Pediatric Neurology, a section of the journal Frontiers in Pediatrics\n\n16 9 2021\n2021\n9 69956823 4 2021\n17 8 2021\nCopyright © 2021 Zhang, Wu and Jiang.\n2021\nZhang, Wu and Jiang\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nCNNM2 (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD). We identified two new cases with CNNM2 novel de novo pathogenic variants, c.814T>C and c.976G>C. They both presented with infantile-onset epilepsy with DD and hypomagnesemia refractory to magnesium supplementation. To date, 21 cases with CNNM2-related disorders have been reported. We combined all 23 cases to analyze the features of CNNM2-related disorders. The phenotypes can be classified into three types: type 1, autosomal dominant (AD) inherited simple hypomagnesemia; type 2, AD inherited hypomagnesemia with epilepsy and ID/DD; and type 3, autosomal recessive (AR) inherited hypomagnesemia with epilepsy and ID/DD. All five type 1 cases had no epilepsy or ID/DD; they all had hypomagnesemia, and three of them presented with symptoms secondary to hypomagnesemia. Fifteen type 2 patients could have ID/DD and seizures, which can be controlled with antiseizure medications (ASMs); their variations clustered in the DUF21 domain of CNNM2. All three type 3 patients had seizures from 1 to 6 days after birth; the seizures were refractory, and 1/3 had status epilepticus; ID/DD in these AR-inherited cases was more severe than that of AD-inherited cases; they all had abnormalities of brain magnetic resonance imaging (MRI). Except for one patient whose serum magnesium was the lower limit of normal, others had definite hypomagnesemia. Hypomagnesemia could be improved after magnesium supplement but could not return to the normal level. Variations in the CBS2 domain may be related to lower serum magnesium. However, there was no significant difference in the level of serum magnesium among the patients with three different types of CNNM2-related disorders. The severity of different phenotypes was therefore not explained by decreased serum magnesium. We expanded the spectrum of CNNM2 variants and classified the phenotypes of CNNM2-related disorders into three types. We found that DUF21 domain variations were most associated with CNNM2-related central nervous system phenotypes, whereas hypomagnesemia was more pronounced in patients with CBS2 domain variations, and AR-inherited CNNM2-related disorders had the most severe phenotype. These results provide important clues for further functional studies of CNNM2 and provide basic foundations for more accurate genetic counseling.\n\nCNNM2\nepilepsy\nintellectual disability/developmental delay\nhypomagnesemia\nDUF21\n==== Body\npmcIntroduction\n\nMagnesium is an important cation in the human body. It is involved in the function of a variety of enzymes in cells and associated with the excitability of nerve cells and muscles. Magnesium transporter-associated genes include MMGT1, MAGT1, NIPAL1, NIPAL4, MRS2, CNNM2, and CNNM4. CNNM2, previously known as ACDP2 (Ancient Conserved Domain Protein 2), has been demonstrated to be related to magnesium homeostasis in humans (1). In 2011, Stuiver et al. reported that CNNM2 pathogenic variants could cause hereditary hypomagnesemia (2). Subsequently, epilepsy and intellectual disability/developmental delay (ID/DD) had been added to the spectrum of phenotypes of CNNM2 variants (3). Up to now, a total of five articles have reported 21 cases of CNNM2-related disorders (2–6). But the relationship between genotypes and phenotypes of CNNM2-related disorders remains unknown. In this study, we reported two new Chinese cases of hypomagnesemia with epilepsy and DD caused by novel identified de novo heterozygous variants. We also investigated the relationship between the phenotypes and the variant sites/mode of inheritance in all 23 cases related to CNNM2 mutations including two cases we found and 21 cases previously reported.\n\nMaterials and Methods\n\nParticipants\n\nTwo Chinese cases with infantile-onset epilepsy and global DD had been identified to have novel CNNM2 pathogenic variants. These two cases and previously reported 21 CNNM2 mutation-related cases were collected for all available data, including clinical manifestations, electroencephalogram (EEG), brain MRI, serum electrolytes, gene variants information, and mode of inheritance.\n\nVariation Analysis\n\nWritten informed consent was obtained from the parents of both patients. This study was approved by the institutional review boards of Peking University First Hospital. We collected 5 ml of peripheral venous blood from patients and their parents. Genomic DNA was extracted for trio-whole exome sequencing (WES). The pathogenicity of the variants was predicted by SIFT, PolyPhen-2, CADD, and MutationTaster. Variants were evaluated against the overall population in 1000 Genomes, gnomAD, and ExAC databases. The pathogenicity was classified according to variant classification standards based on the American College of Medical Genetics and Genomics (ACMG) guidelines, 2015.\n\nResults\n\nClinical Features\n\nCase 1\n\nCase 1 was a 2-year-old boy who carried a novel identified de novo missense heterozygous variant c.814T>C [p.Phe272Leu]. He still could not raise his head steadily at 6 months of age. His seizures started at 10 months after birth, mainly characterized by eyes gazing to the left side and perioral cyanosis, sometimes accompanied by jaw tremor, right lower limb raising, and hand tremor. EEG showed focal frontal epileptic discharge. Although ictal EEG of this patient was not available, the electrical-clinical features indicate that his seizures were focal seizures. The seizures were clustered, up to eight attacks per day, only 2–3 days per month. He had been seizure-free from 12 months of age by levetiracetam monotherapy. He had DD. When he was 1 year old, he could sit and crawl without others' help. He could walk without support from 1 year 3 months of age, but he still could not walk steadily now. He began to vocalize at 1 year old, but he could not make the sound of “babamama” till now. He had no apparent malformations. Brain MRI was normal. His initial serum magnesium was 0.56 mmol/L. After his seizures were completely controlled, he was diagnosed with causative gene and began to receive magnesium supplement at 1 year old. But diarrhea occurred after oral administration of magnesium, which was improved after suspension of magnesium supplementation. It was considered that diarrhea was related to gastrointestinal side effects of oral magnesium, so the treatment with magnesium supplementation was interrupted, and his parents did not monitor serum magnesium level for him regularly. During magnesium supplementation treatment, his highest serum magnesium was 0.62 mmol/L and he had no seizures, but no improvement in psychomotor development was observed.\n\nCase 2\n\nCase 2 was a 4-year-old girl who carried a novel identified de novo missense heterozygous variant c.976G>C [p.Val326Leu]. Her seizures started at 8 months after birth and always occurred during sleep. Seizures involved eye opening and fearful expression, eye and head turning left, and then tonic and clonic jerks of the four limbs. Seizures were accompanied by perioral cyanosis. Ictal EEG showed the seizure onset from the right hemisphere (Figure 1). She was treated with sodium valproate at first, and the frequency of seizures decreased. Levetiracetam and lamotrigine adjunctive therapy had not shown any effect. Treatment with oxcarbazepine was discontinued due to allergic rash. Lacosamide was started 1 month before the last follow-up. Now she is treated with sodium valproate and lacosamide, and no seizure was seen in the recent 1 month. Gesell's developmental scale revealed severe DD. When she was 4 years old, she could recognize animal pictures, but she could not speak their names. Now she still cannot say anything but “baba” and “mama”. Physical examination revealed no apparent malformations. Brain MRI was normal. Her initial serum magnesium was 0.44 mmol/L. She tolerates oral magnesium supplementation at a dose of 0.1–0.2 mmol/kg/day, and her serum magnesium elevated to 0.52 mmol/L. But her serum magnesium could not return to the normal level.\n\nFigure 1 Ictal electroencephalogram of case 2 showed the seizure onset from the right hemisphere.\n\nWhole Exome Sequencing Results\n\nBoth cases were identified de novo heterozygous variants in CNNM2 by trio-WES, which were c.814T>C [p.Phe272Leu] and c.976G>C [p.Val326Leu]. We used multiple in silico tools to analyze these variants' conservation, pathogenicity, and minor allele frequency (MAF). Finally, according to the ACMG guidelines, both variants were clarified as likely pathogenic (LP) (Table 1). Other pathogenic variants associated with hypomagnesemia, epilepsy, and ID/DD were not found by trio-WES.\n\nTable 1 Analysis of pathogenicity of the variants in CNNM2.\n\nCase\tGene\tVariant\tVariant origin\tMAF\tPolyPhen-2\tSIFT\tMutation Taster\tCADD\tEvidence\tCategory\t\n\t\t\t\t1000 Genomes\tExAC\tgnomAD\t\t\t\t\t\t\t\n1\tCNNM2\tc.814T>C [p.Phe272Leu]\tDe novo\tNE\tNE\tNE\t0.81\t0.13\tDC\t25.3\tPS2+PM2+PP3\tLP\t\n2\tCNNM2\tc.976G>C [p.Val326Leu]\tDe novo\tNE\tNE\tNE\t0.18\t0.01\tDC\t24.2\tPS2+PM2+PP3\tLP\t\nTranscript: NM_017649. NE, not existing; DC, disease causing; LP, likely pathogenic.\n\nPhenotype and Genotype Relation Analysis\n\nWe used “CNNM2” as the keyword to search on PubMed. Excluding variants of unknown significance or non-pathogenic, there are totally 23 cases with CNNM2-related disorders, including the two cases we reported here (2–6) (Table 2). The features of these cases can be classified into three types: type 1, autosomal dominant (AD)-inherited simple hypomagnesemia; type 2, AD-inherited hypomagnesemia with epilepsy and ID/DD; and type 3, autosomal recessive (AR)-inherited hypomagnesemia with epilepsy and ID/DD. Type 1, AD-inherited simple hypomagnesemia, was the first phenotype to be discovered. The onset of hypomagnesemia was insidious. The age at which hypomagnesemia was found varied from 1 to 16 years. Two of five cases of type 1 were asymptomatic, and their hypomagnesemia was detected in serum electrolyte tests; the other cases had atypical clinical symptoms associated with hypomagnesemia, including muscle spasms, headache, fatigue, and vertigo. Type 1 patients had no epilepsy or ID/DD. Their initial serum magnesium was 0.36–0.575 mmol/L; it was reported that the serum magnesium could be increased to 0.61–0.64 mmol/L in two cases by magnesium supplementation but could not return to the normal level. Type 2, AD-inherited hypomagnesemia with epilepsy and ID/DD, is the most common phenotype in cases with CNNM2 variant (15/23). Most of the cases are with seizures at onset. In type 2 cases, 86.7% (13/15) had epileptic seizures, and 93.3% (14/15) had ID/DD in the course of the disease. Based on limited available details, the age at seizure onset was 4 months to 1 year in most cases, but 16 years of age in one case. Their seizures showed good response to antiseizure medications (ASMs); multiple kinds of ASMs had been reported to be effective, including phenobarbital, valproic acid, clobazam, levetiracetam, and lacosamide. All type 2 patients had ID/DD, characterized by language expression dysfunction. Physical development was normal in type 2 cases. Physical examination revealed no apparent malformations. Brain MRI was normal except for corona radiata and centrum semiovale white matter T2 slightly hyperintense in one case. Of the cases, 93.3% had definite hypomagnesemia; their initial serum magnesium was 0.44–0.66 mmol/L. However, borderline hypomagnesemia was found in one case whose initial serum magnesium was 0.72 mmol/L. Hypomagnesemia could be improved after magnesium supplement but could not return to the normal level. Type 3, AR-inherited hypomagnesemia with epilepsy and ID/DD, was relatively rare. Only three cases had been reported. But this is the most severe type of CNNM2-related disorders. Their seizures onset from 1 to 6 days after birth, much earlier than that of type 2. They could have myoclonic seizures, generalized tonic–clonic seizures, and status epilepticus. In type 3 cases, multiple ASMs were used, but seizures were refractory; valproic acid, levetiracetam, lamotrigine, and topiramate may decrease the frequency of seizures. All type 3 cases had severe ID/DD, and language development was most severely delayed. They all had brain MRI abnormalities, including dysmyelination and progressive cerebral cortical atrophy. The patient who carried c.1642G>A homozygous variant had more severe clinical manifestations, including swallowing difficulties, recurrent aspiration pneumonias, bilateral optic disc pallor, bone metabolism disorder, and facial abnormalities, which were not seen in the two patients who carried c.364G>A homozygous variants. In contrast, hypomagnesemia was no more severe in this severe type than in the other two types. Initial serum magnesium was 0.38–0.5 mmol/L. Serum magnesium could be increased to 0.49–0.66 mmol/L after magnesium supplement but could not be corrected normal. Table 3 demonstrates the features of these three types of CNNM2-related disorders. We used one-way ANOVA to compare the initial serum magnesium in patients with three types of CNNM2-related disorders, and no significant difference was found (Figure 2). And we used the Mann–Whitney test to compare the initial serum magnesium in patients with epilepsy and ID/DD (type 2 and type 3) and without epilepsy and ID/DD (type 1); no significant difference was found either (Figure 3).\n\nTable 2 The variants and clinical phenotypes of patients with CNNM2-related disorders.\n\nCase\tVariant\tAmino acid changes\tHomo/ het\tMode of inheritance\tGender\tEpilepsy\tID/DD\tHypomagnesemia\tPhysical development\tOthers\t\n\t\t\t\t\t\tWith/without\tOnset age\tRefractory seizures\tEffective ASM\t\tInitial serum Mg (mmol/L)\tSerum Mg after supplementation (mmol/L)\tSymptoms\tMicrocephaly\tStructural abnormalities of brain\tMalnutrition\t\t\n1 (2)\tc.117delG\tp.Ile40SerfsX15\tHet\tAD\tM\t–\t\t\t\t–\t0.46\tNA\tMuscle spasms, headache\t–\t–\t–\t\t\n2 (2)\tc.117delG\tp.Ile40SerfsX15\tHet\tAD\tF\t–\t\t\t\t–\t0.51\t0.64\tMuscle spasms, stuttering LOC\t–\t–\t–\t\t\n3 (2)\tc.1703C>T\tp.Thr568Ile\tHet\tAD\tF\t–\t\t\t\t–\t0.52\tNA\t-\t–\t–\t–\t\t\n4 (2)\tc.1703C>T\tp.Thr568Ile\tHet\tAD\tM\t–\t\t\t\t–\t0.36\t0.61\tWeakness, vertigo, headache\t–\t–\t–\t\t\n5 (3)\tc.364G>A\tp.Glu122Lys\tHomo\tAR\tM\t+\t1 day\t+\tVPA, LTG\tSevere\t0.5\t0.66\t–\t+\tMyelination defects, opercularization defect, widened outer cerebrospinal liquor spaces, calcification of basal ganglia\t–\t\t\n6 (3)\tc.364G>A\tp.Glu122Lys\tHomo\tAR\tF\t+\t6 days\t+\tVPA, LEV\tSevere\t0.5\t0.54\t–\t+\tCalcification of basal ganglia\t–\t\t\n7 (3)\tc.1069G>A\tp.Glu357Lys\tHet\tAD\tF\t+\t7 months\t–\tPB\tModerate\t0.56\t0.56\t–\tNA\t–\t–\t\t\n8 (3)\tc.806C>G\tp.Ser269Trp\tHet\tAD\tF\t+\t1 year\t–\tVPA\tModerate\t0.44\t0.53\t–\tNA\t–\t–\t\t\n9 (3)\tc.1069G>A\tp.Glu357Lys\tHet\tAD\tM\t+\t4 months\t–\tCLB\tModerate\t0.5\t0.68\t–\tNA\t–\t–\t\t\n10 (3)\tc.988C>T\tp.Leu330Phe\tHet\tAD\tF\t+\t16 years\t–\tUnknown\tMild\t0.66\tUnknown\t–\tNA\t–\t–\t\t\n11 (4)\tc.1642G>A\tp.Val548Met\tHomo\tAR\tM\t+\t1 day\t+\tTPM\tSevere\t0.38\t0.49\t-\tNA\tCerebral cortical atrophy, global reduction of white matter\tNormal at birth; height, weight and head circumference all less than P3 at 15 years\tHypotonia, swallowing difficulties, recurrent aspiration pneumonias; bilateral optic disc pallor; abnormal bone metabolism; facial abnormalities\t\n12 (5)\tc.2384C>A\tp.Ser795*\tHet\tAD\tM\t–\t\t\t\t–\t0.575\tNA\t–\tNA\tNA\tNA\t\t\n13 (7)\tg.(?_104678237) _(104816721_?) del\t\tHet\tAD\tF\t+\tNA\tNA\tNA\t+\t0.63\t0.65\tNA\t\t–\tNA\t\t\n14 (7)\tg.104814162_ 104814164 del\t\tHet\tAD\tM\t+\tNA\tNA\tNA\t+\t0.57\tNA\tNA\tNA\t–\tNA\t\t\n15 (7)\tc.143T>C\tp.Leu48Pro\tHet\tAD\tM\t+\tNA\tNA\tNA\t–\t0.45\t0.53–0.66\tNA\tNA\t–\tNA\t\t\n16 (7)\tc.942C>G\tp.Tyr314*\tHet\tAD\tM\t–\t\t\t\t+\t0.48\tNA\tNA\tNA\t–\tNA\t\t\n17 (7)\tc.961_963del\tp.Leu321del\tHet\tAD\tM\t+\tNA\tNA\tNA\t+\t0.5\t0.51\tNA\tNA\t–\tNA\t\t\n18 (7)\tc.970G>A\tp.Val324Met\tHet\tAD\tM\t+\tNA\tNA\tNA\t+\t0.54\t0.52\tNA\tNA\t–\tNA\t\t\n19 (7)\tc.1253T>C\tp.Leu418Pro\tHet\tAD\tF\t+\tNA\tNA\tNA\t+\t0.49\t0.58\tNA\tNA\t–\tNA\t\t\n20 (7)\tc.2384C>T\tp.Ser795Leu\tHet\tAD\tF\t–\t\t\t\t+\t0.72\t0.7\tNA\tNA\t–\tNA\t\t\n21 (7)\tc.2389C>T\tp.Arg797*\tHet\tAD\tF\t+\tNA\tNA\tNA\t+\t0.57\t0.69\tNA\tNA\tCorona radiata and centrum semiovale white matter T2 slightly hyperintense\tNA\t\t\n22\tc.814T>C\tp.Phe272Leu\tHet\tAD\tM\t+\t6 months\t–\tLEV\t+\t0.56\t/\t–\t–\t–\t–\t\t\n23\tc.976G>C\tp.Val326Leu\tHet\tAD\tF\t+\t8 months\tUnknown\tVPA, LCM?\tSevere\t0.44\t0.52\t–\t–\t–\t–\t\t\nCase 1 is the father of case 2. Case 3 is the mother of case 4. Case 5 and case 6 were the two siblings of same suspected consanguineous parents. Case 11 was the sibling of consanguineous parents. Case 12 had two family members carrying the same variant, both with insidious hypomagnesemia. Case 15 had six family members carrying the same variant, they all presented with hypomagnesemia, but only three of them had defects in motor skills or speech, and none of them had seizures. ID/DD, intellectual disability/developmental delay; ASM, antiseizure medication; AD, autosomal dominant; AR, autosomal recessive; VPA, valproic acid; LEV, levetiracetam; LOC, locus of control; LTG, lamotrigine; PB, phenobarbital; CLB, clobazam; TPM, topiramate; LCM, lacosamide.\n\nTable 3 Three types of CNNM2-related disorders and their features.\n\nType\t1\t2\t3\t\nPhenotype\tAD-inherited simple hypomagnesemia\tAD-inherited hypomagnesemia with epilepsy and ID/DD\tAR-inherited hypomagnesemia with epilepsy and ID/DD\t\nNumber of cases\t5/23\t15/23\t3/23\t\nAge of onset\t1–16 years\t5/6 4 months−1 year, 1/6 16 years\t1–6 days\t\nEpilepsy\t-\t13/15\nFocal seizures, easy to control with ASMs\t3/3\nMultiple forms, refractory seizures, may have status epilepticus\t\nPsychomotor development\tNormal\t14/15\nMild to severe ID/DD, language expression inability\t3/3\nSevere ID/DD, nonverbal\t\nApparent malformations\t–\t–\tMay have facial abnormalities\t\nBrain MRI abnormalities\t–\t–\t+\t\nHypomagnesemia\t+\t+\t+\t\nInitial serum magnesium (mmol/L)\t0.36–0.575\t0.44–0.72\t0.38–0.5\t\nOthers\t\t\tSwallowing difficulties, recurrent aspiration pneumonias; bilateral optic disc pallor; abnormal bone metabolism\t\nMode of inheritance\tAD\tAD\tAR\t\nAD, autosomal dominant; ID/DD, intellectual disability/developmental delay; AR, autosomal recessive; ASM, antiseizure medication.\n\nFigure 2 Initial serum magnesium in patients with three types of CNNM2-related disorders. No significant difference was found. p = 0.3496.\n\nFigure 3 Initial serum magnesium in patients with epilepsy and ID/DD (type 2 and type 3) and without epilepsy and ID/DD (type 1). No significant difference was found. p = 0.3905. ID/DD, intellectual disability/developmental delay.\n\nCNNM2 is located on chromosome 10q24.32. CNNM2 protein is a transmembrane protein on the cell membrane and is composed of 875 amino acids. CNNM2 contains one DUF21 domain, two CBS domains, and one CNBH (Cyclic Nucleotide-Binding Homology) domain (8). Variants caused CNNM2-related disorders type 1 were frameshift variant, missense variant, and stop-gain variant. The changed amino acids were located on various domains and include extracellular segment near the N-terminal, the second CBS domain, and the CNBH domain, but were not within the DUF21 domain (Figure 4). Variants caused CNNM2-related disorders type 2 included missense variants, stop-gain variants, deletion variant, and two deletion copy number variants (CNVs). Of the variant site, 75% is located in or immediately adjacent to the DUF21 domain. All variants that caused CNNM2-related disorders type 3 were missense variants. One variant was located on the extracellular segment near the N-terminal, and another was located on the second CBS domain, whereas the latter variants cause a more severe phenotype. It was noteworthy that all variants located in DUF21 domain caused type 2 of CNNM2-related disorders. Among all 23 cases, patients with variants on CBS domain had lower serum magnesium, but the difference was not significant (Figure 5).\n\nFigure 4 The structure of CNNM2 and the sites of variations. Blue, AD-inherited simple hypomagnesemia; red, AR-inherited hypomagnesemia with epilepsy and ID/DD; green: AD-inherited hypomagnesemia with epilepsy and ID/DD; black box, our cases. AD, autosomal dominant; AR, autosomal recessive; ID/DD, intellectual disability/developmental delay.\n\nFigure 5 Initial serum magnesium of patients with variants of different domains. We used one-way ANOVA to compare the difference. p = 0.20.\n\nDiscussion\n\nMagnesium plays an important role in the human body. It is the fourth most abundant cation and is a constituent of a variety of enzymes in the body that are involved in various important metabolic processes including DNA synthesis, protein synthesis, and oxidative phosphorylation (9). Besides, magnesium ions (Mg2+) have an inhibitory effect on the excitability of nerve cells in the central nervous system, skeletal muscle, and myocardium. Normal serum magnesium is 0.7–1.1 mmol/L. Neuromuscular irritability, tremor, hypokalemia, and hypocalcemia present when serum magnesium is less than 0.7 mmol/L. If serum magnesium is less than 0.4 mmol/L, hypomagnesemia can cause more severe clinical symptoms, including tetany, nystagmus, seizures, mental disorders, and arrhythmias (10). CNNM2 has been demonstrated to play a role in magnesium homeostasis in humans (1).\n\nWe summarized and clarified phenotypes of CNNM2-related disorders into three types: AD-inherited simple hypomagnesemia; AD-inherited hypomagnesemia with epilepsy and ID/DD; and AR-inherited hypomagnesemia with epilepsy and ID/DD. Type 1, AD-inherited simple hypomagnesemia, has an insidious onset without epilepsy and ID/DD. Some type 1 cases had symptoms associated with hypomagnesemia, including muscle spasms, headache, fatigue, and vertigo; however, the others were asymptomatic. Type 2, AD-inherited hypomagnesemia with epilepsy and ID/DD, mostly presented with ASM-effective seizures at onset at the age of 4 months to 1 year, and ID/DD is characterized by language expression inability. Type 3, AR-inherited hypomagnesemia with epilepsy and ID/DD, presented with more severe phenotypes. Multiple forms of seizures present at 1–6 days after birth, including status epilepticus. The seizures were refractory. ID/DD of type 3 is more severe than type 2. Patients with type 3 could have brain and facial abnormalities. Therefore, CNNM2-related disorders should be considered if a patient presented with any one of the three phenotypes.\n\nAll patients who carried pathogenic variants in CNNM2 had hypomagnesemia. Some of them were asymptomatic. However, serum magnesium could not be corrected to the normal level by magnesium supplement. There was no significant difference in serum magnesium levels between different types of cases. Hypomagnesemia could not be correlated to seizures directly in these cases, because the seizures could not be controlled by magnesium supplement. Differences in the severity could not be explained by differences in the degree of decreased serum magnesium. The phenotype of AR-inherited hypomagnesemia with epilepsy and ID/DD was more severe than that of AD-inherited, which suggests that the causative variant of CNNM2 may be loss of function (LOF). Some pathogenic missense variants have been proved as LOF variants (6). However, this conclusion still needs further functional studies to be confirmed. In AD-inherited CNNM2-related disorders, the basis of abnormal protein function caused by pathogenic variants may be haploinsufficiency.\n\nCNNM2 is highly expressed in the brain and kidney, while it is widely expressed in various organs including the digestive tract, cardiovascular system, lungs, endocrine glands, and blood cells (11). CNNM2 variants may lead to serum magnesium reduction by attenuating the reabsorption of magnesium at the distal convoluted tubule in the kidney (2). However, the exact function of CNNM2 protein and its mechanism are still unknown. CNNM2 contains one DUF21 domain, two CBS domains, and one CNBH domain (1). The DUF21 domain contains three transmembrane structures and one intramembrane structure, and the specific function is currently unknown. However, this domain is present in all proteins of the CNNM family and is highly conserved from prokaryotic to eukaryotic cells, suggesting that it may have an important biological function. The two CBS domains (also known as Bateman modules) are demonstrated to be closely related to the function of the protein (12). They may dimerize by binding with Mg2+-ATP and alter the conformation of the CNNM2 protein (8). Inactivation of the CNBH domain can cause loss of CNNM2 function (13); however, the function of this domain is unknown. It is thought that its dimerization can assist the CBS domain to function. The mechanisms by which CNNM2 regulates magnesium homeostasis are still under discussion.\n\nMost investigators suggest that CNNM2 itself is a transporter for Mg2+ (8). Immunohistochemical staining of human kidney sections confirmed that CNNM2 is expressed in the distal convoluted tubule, which is the last site of Mg2+ reabsorption (2). Low magnesium caused high expression of Cnnm2 on the lateral side of the basement membrane of the distal convoluted tubule in the rat kidney, suggesting that CNNM2 may be related to the transport of magnesium from within renal tubular epithelial cells into capillaries. Thereafter, in HEK293 cell line-based experiments, it was found that the influx of sodium ions was decreased in cells transfected with the CNNM2 p.Thr568Ile mutation (a mutation causing hereditary hypomagnesemia) compared with wild type. Therefore, it is thought that CNNM2 protein is involved in the reverse transport of magnesium and sodium ions in the distal convoluted tubule of the kidney, transporting magnesium ions from within renal tubular epithelial cells to capillaries (14). Besides, Tremblay's (15) and Miki's (16) team found that the interaction between CNNMs and PRL (phosphatases of the regenerating liver) was associated with tumorigenesis in 2014. PRL is a molecule highly expressed in solid and hematologic tumor cells (17, 18). PRLs can form complexes with CNNMs, thereby inhibiting the activity of CNNM to transport Mg2+ extracellularly, increasing the intracellular concentration of Mg2+, and promoting the growth of tumor cells. In breast cancer cells, when the intracellular Mg2+ concentration is low, the expression of PRL-1 can be increased. PRL-1 can anchor the CBS domain, after which the charge interaction between two adjacent proteins alters the conformation of the CBS domain, which causes changes in the structure of the transmembrane region of the protein, allowing magnesium ion influx. Also, Mg2+-ATP can bind to the CBS domain as the intracellular Mg2+ concentration increases, to maintain the state of transporter opening. However, this mechanism cannot explain the mechanism of CNNM2 in the distal convoluted tubule of the kidney. And the function and role of CNNM2 in the central nervous system are still unknown. Some investigators have also suggested that CNNM2 is not a Mg2+ transporter per se but a factor affecting Mg2+ transporters (7).\n\nDifferent phenotypes of CNNM2-related disorders are associated with different modes of inheritance and different domains in which variation occurs. Variation of AD-inherited simple hypomagnesemia (type 1) contains a frameshift variant located near the N-terminal (p.Ile40SerfsX15), a missense variant in the CBS domain (p.Thr568Ile), and a stop-gain variant located in the CNBH domain, where p.Ile40SerfsX15 and p.Ser795* can cause changes in mRNA and protein length, and the structurally abnormal mRNA and proteins may be degraded, causing a decrease in intracellular CNNM2 expression, which affects the transmembrane transport of magnesium. p.Thr568Ile is located in the CBS2 domain in the core region of the CNNM2, which is highly conserved, and the variation may cause a loss in CNNM2 function. Variation of AD-inherited hypomagnesemia with epilepsy and ID/DD (type 2) included missense variants, stop-gain variants, deletion variant, and two heterozygous deletion CNVs. Most of them (p.Ser269Trp, p.Phe272 Leu, p.Tyr314*, p.Leu321del, p.Val324Met, p.Val326Leu, p.Leu330Phe, p.Glu357Lys, and p.Leu418Pro) clustered in the DUF21 domain, the transmembrane structure of CNNM2 with unknown function. And five of the nine variant sites are located in the intramembrane structure. These patients had manifestations of central nervous system involvement independent of hypomagnesemia, including ID/DD and epilepsy, suggesting that functional abnormalities in DUF21 domain may be more closely related to neurological function. The pathogenic mechanism may be abnormal transmembrane structure caused by mutations, rather than a decreased expression of CNNM2, causing abnormal neuron excitability. This suggests that in addition to affecting magnesium reabsorption in the kidney, the function of CNNM2 may also include participating in the regulation of neural cell excitability in the central nervous system, and the important core of regulatory function may be the transmembrane region DUF21. p.Leu48Pro is located near the N-terminal, and this site was located in a region that crosses the endoplasmic reticulum (ER) membrane during protein transport (6). This suggested that p.Leu48Pro may affect the transport of CNNM2 protein to the cell membrane, which in turn reduced the amount of CNNM2 protein on the cell membrane. However, p.Ser795Leu and p.Arg 797* are located in the CNBH domain, and another pathogenic variant at Ser795 (p.Ser795*) was related to type 1 CNNM2-related disorders. This may suggest that the region near Ser795 has a relatively important effect on the function of the CNBH domain. But the pathogenic mechanisms of these three variants could not yet be well-explained. Variations of AR-inherited hypomagnesemia with epilepsy and ID/DD (type 3) are missense variants, including p.Glu122Lys located between the N-terminal and DUF21 domain and p.Val548Met located in CBS domain. p.Glu122Lys is adjacent to the DUF21 domain, and this variant causes a change in the charge of the amino acid residue, suggesting that some regions of the N-terminal of CNNM2 may form some interaction with the DUF21 domain electrostatically, which, like the variants of type 2, alters the membrane structure of DUF21 domain, causing changes in neuron membrane excitability, resulting in similar central nervous system manifestations. p.Val548Met is located in the CBS domain of CNNM2, and this variant causes the most significant decrease in serum magnesium and the most severe neurological phenotype, suggesting that this variant site may be the core position of the CBS domain, and the amino acid changes caused by this variant significantly affect the function of the CNNM2. The patient carried p.Val548Met had initial serum magnesium of 0.38 mmol/L; however, considering that p.Thr568Ile carriers had equally severe hypomagnesemia but did not develop any central nervous system phenotype, this indicated that the remarkable hypomagnesemia per se cannot explain the severe phenotype of the central nervous system in this patient. Therefore, the mechanism by which p.Val548Met leads to severe CNS phenotypes may be at least partially related to the DUF21 domain, as in type 2 cases.\n\nAlthough all patients with CNNM2-related disorders had hypomagnesemia, the serum magnesium was different in each case, which may be related to the protein domain where the variant was located. Among the 23 reported cases, those with variants in the CBS domain had lower serum magnesium levels, and the lowest two had variants both located in the CBS2 domain (p.Val548Met and p.Thr568Ile). This suggests an important role for the CBS domain in the Mg2+ transport function of CNNM2.\n\nIn summary, we reported two cases first in the Chinese population with hypomagnesemia, epilepsy, and DD caused by novel de novo heterozygous variants in CNNM2 (c.814T>C [p.Phe272Leu] and c.976G>C [p.Val326Leu]). We summarized and classified the phenotypes of CNNM2-related disorders into three types. We found that CNNM2 related central nervous system phenotypes were most associated with DUF21 domain variations, whereas hypomagnesemia was more pronounced in patients with CBS2 domain variations, and AR-inherited CNNM2-related disorders had the most severe phenotype. The limitation of our study is the relatively small sample size. The features summarized from 23 patients might not be the real characteristics for such a complicated disease. More cases and further biological functional studies are needed to confirm, modify, and interpret our findings. However, our findings provide important clues for mechanism studies of CNNM2-related disorder and provide the possibility for accurate genetic counseling.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nWritten informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nYJ: study design and revision of the manuscript. YW and YJ: collection of clinical and WES data. HZ: follow up the patients' information and analyses and draft preparation. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by the National Key Research and Development Program of China (grant numbers: 2020YFA0804003, 2016YFC1306201, and 2016YFC0901505), by the National Natural Science Foundation of China (grant numbers: 81971211, 12026606, and 81601131), by Beijing Natural Science Foundation (grant number: 7212109), by the Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases (grant number: BZ0317), and by the Fundamental Research Funds for the Central Universities (grant numbers: BMU2017JI002, BMU2018XY006, and PKU2017LCX06). The authors declare no competing financial interests. The funding agencies had no role in the study design, the experiments, analysis, or interpretation of data, the writing of the report, or the decision to submit the article for publication.\n\nConflict of Interest\n\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\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n==== Refs\nReferences\n\n1. de Baaij JH Stuiver M Meij IC Lainez S Kopplin K Venselaar H . Membrane topology and intracellular processing of cyclin M2 (CNNM2). J Biol Chem. (2012) 287 :13644–55. 10.1074/jbc.M112.342204 22399287\n2. Stuiver M Lainez S Will C Terryn S Gunzel D Debaix H . CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia. Am J Hum Genet. (2011) 88 :333–43. 10.1016/j.ajhg.2011.02.005 21397062\n3. Arjona FJ de Baaij JH Schlingmann KP Lameris AL van Wijk E Flik G . CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. PLoS Genet. (2014) 10 :e1004267. 10.1371/journal.pgen.1004267 24699222\n4. Accogli A Scala M Calcagno A Napoli F Di Iorgi N Arrigo S . CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations. Eur J Med Genet. (2019) 62 :198–203. 10.1016/j.ejmg.2018.07.014 30026055\n5. Garcia-Castano A Madariaga L Anton-Gamero M Mejia N Ponce J Gomez-Conde S . Novel variant in the CNNM2 gene associated with dominant hypomagnesemia. PLoS ONE. (2020) 15 :e0239965. 10.1371/journal.pone.0239965 32997713\n6. Franken GAC Muller D Mignot C Keren B Lévy L Tabet AC . The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2). Hum Mutat. (2021) 42 :473–86. 10.1002/humu.24182 33600043\n7. Sponder G Mastrototaro L Kurth K Merolle L Zhang Z Abdulhanan N . Human CNNM2 is not a Mg(2+) transporter per se. Pflugers Arch. (2016) 468 :1223–40. 10.1007/s00424-016-1816-7 27068403\n8. Chen YS Kozlov G Fakih R Yang M Zhang Z Kovrigin EL . Mg(2+)-ATP sensing in CNNM, a putative magnesium transporter. Structure. (2020) 28 :324–335.e4. 10.1016/j.str.2019.11.016 31864811\n9. Laires MJ . Role of cellular magnesium in health and human disease. Front Biosci. (2004) 9 : 262–76. 10.2741/1223 14766364\n10. Van Laecke S . Hypomagnesemia and hypermagnesemia. Acta Clin Belg. (2019) 74 :41–7. 10.1080/17843286.2018.1516173 30220246\n11. Gimenez-Mascarell P Gonzalez-Recio I Fernandez-Rodriguez C Oyenarte I Muller D Martinez-Chantar ML . Current structural knowledge on the CNNM family of magnesium transport mediators. Int J Mol Sci. (2019) 20 :1135. 10.3390/ijms20051135 30845649\n12. Corral-Rodriguez MA Stuiver M Abascal-Palacios G Diercks T Oyenarte I Ereno-Orbea J . Nucleotide binding triggers a conformational change of the CBS module of the magnesium transporter CNNM2 from a twisted towards a flat structure. Biochem J. (2014) 464 :23–34. 10.1042/BJ20140409 25184538\n13. Chen YS Kozlov G Fakih R Funato Y Miki H Gehring K . The cyclic nucleotide-binding homology domain of the integral membrane protein CNNM mediates dimerization and is required for Mg(2+) efflux activity. J Biol Chem. (2018) 293 :19998–20007. 10.1074/jbc.RA118.005672 30341174\n14. Funato Y Miki H . Molecular function and biological importance of CNNM family Mg2+ transporters. J Biochem. (2019) 165 :219–25. 10.1093/jb/mvy095 30476181\n15. Hardy S Uetani N Wong N Kostantin E Labbe DP Begin LR . The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis. Oncogene. (2015) 34 :986–95. 10.1038/onc.2014.33 24632616\n16. Yamazaki D Miyata H Funato Y Fujihara Y Ikawa M Miki H . The Mg2+ transporter CNNM4 regulates sperm Ca2+ homeostasis and is essential for reproduction. J Cell Sci. (2016) 129 :1940–9. 10.1242/jcs.182220 27006114\n17. Hardy S Wong NN Muller WJ Park M Tremblay ML . Overexpression of the protein tyrosine phosphatase PRL-2 correlates with breast tumor formation and progression. Cancer Res. (2010) 70 :8959–67. 10.1158/0008-5472.CAN-10-2041 20841483\n18. Julien SG Dube N Hardy S Tremblay ML . Inside the human cancer tyrosine phosphatome. Nat Rev Cancer. (2011) 11 :35–49. 10.1038/nrc2980 21179176\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-2360",
"issue": "9()",
"journal": "Frontiers in pediatrics",
"keywords": "CNNM2; DUF21; epilepsy; hypomagnesemia; intellectual disability/developmental delay",
"medline_ta": "Front Pediatr",
"mesh_terms": null,
"nlm_unique_id": "101615492",
"other_id": null,
"pages": "699568",
"pmc": null,
"pmid": "34604137",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "30341174;24699222;27068403;14766364;25184538;30026055;33600043;32997713;30476181;27006114;24632616;20841483;31864811;21179176;30845649;22399287;30220246;21397062",
"title": "CNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance.",
"title_normalized": "cnnm2 related disorders phenotype and its severity were associated with the mode of inheritance"
} | [
{
"companynumb": "CN-TEVA-2022-CN-2014154",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "4",
... |
{
"abstract": "Familial pancreatic adenocarcinoma (PDAC) is most commonly related to inheritance of a pathogenic BRCA variant (J Med Genet 2005;42:711-719). The National Comprehensive Cancer Network recommends germline testing for patients diagnosed with PDAC and recommends platinum-based chemotherapy as the preferred initial systemic therapy for patients harboring a pathogenic BRCA germline variant with PDAC (https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455). PDACs related to pathogenic BRCA germline variants typically demonstrate BRCA loss of heterozygosity (LOH), which results in ineffective DNA damage repair due to a lack of normal BRCA gene product activity. By causing DNA damage, platinum-based therapies have been shown to be highly effective therapies (Cancer Cell 2010;18:499-509, Gen Med 2015;17:569). In contrast, platinum-based therapies would be predicted to be significantly less effective for PDACs in patients with pathogenic BRCA germline variants who have cancers that lack BRCA LOH. Poly (ADP-ribose) polymerase 1 (PARP) is also key to effective DNA repair. The Food and Drug Administration has approved PARP inhibitors for patients carrying germline pathogenic BRCA variants and metastatic breast cancer or ovarian cancer (Ann Oncol 2019;30:558-566, J Clin Oncol 2015;33:244-250). PARP inhibitors would again be expected to be far less effective in patients who carry pathogenic BRCA germline variants with breast and ovarian cancers (those that lack BRCA LOH) than in those with BRCA-related breast and ovarian cancers (which typically demonstrate BRCA LOH), because PARP is involved in DNA repair. Here, we present a patient harboring a pathogenic BRCA germline variant whose PDAC grew rapidly during platinum-based therapy and lacked BRCA LOH and therefore was not likely BRCA related. Given the molecular fingerprint of BRCA-related PDAC in patients with pathogenic BRCA germline variants and the mechanism of action of platinum-based therapies and PARP inhibitors, this case underscores the importance of future studies aimed at determining whether the lack of BRCA LOH in PDACs in pathogenic BRCA germline variant carriers is a biomarker of less responsiveness to platinum-based chemotherapy and PARP inhibitors. KEY POINTS: Platinum-based therapy or Poly (ADP-ribose) polymerase 1 (PARP) inhibitor therapies are highly effective systemic therapy options for most patients with pancreatic adenocarcinoma who carry a germline pathogenic BRCA variant. In the case presented here, a patient carrying a germline pathogenic BRCA variant saw rapid progression of his pancreatic adenocarcinoma while on platinum-based therapy. Next-generation sequencing confirmed that his pancreatic cancer was likely not related to BRCA loss of heterozygosity (LOH). Studies are needed to determine, in patients who harbor germline pathogenic BRCA variants, whether similar cancers (i.e., those that lack BRCA LOH) are less responsive to platinum-based or PARP inhibitor therapies than are those more common BRCA-related cancers (i.e., those that demonstrate LOH).",
"affiliations": "Department of Internal Medicine, Oncology Division, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.;Pathology and Diagnostic Medicine, Foundation Medicine, Inc, Cambridge, Massachusetts, USA.",
"authors": "Sorscher|Steven|S|https://orcid.org/0000-0001-7408-0646;Ramkissoon|Shakti|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/onco.13912",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "26(11)",
"journal": "The oncologist",
"keywords": "BRCA; Loss of heterozygosity; Pancreatic cancer; Poly (ADP-ribose) polymerase 1",
"medline_ta": "Oncologist",
"mesh_terms": null,
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "916-918",
"pmc": null,
"pmid": "34309133",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "26000489;21934105;21821475;28831036;21561347;21056012;31157963;32444418;32343890;31976786;16141007;28825726;26775620",
"title": "Rapid Progression of Metastatic Pancreatic Adenocarcinoma During Platinum-Based Therapy in a Patient Harboring a Pathogenic BRCA2 Germline Variant.",
"title_normalized": "rapid progression of metastatic pancreatic adenocarcinoma during platinum based therapy in a patient harboring a pathogenic brca2 germline variant"
} | [
{
"companynumb": "US-MYLANLABS-2022M1021095",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "Ocular decompression retinopathy (ODR) is a relatively rare entity with variable prognosis depending on extent and pre-existing condition. This article describes profile of two cases with a brief review of the condition.\n\n\n\nCase 1 highlights extensive choroidal detachment with subhyaloid haemorrhage and multiple intra-retinal hemorrhages in the posterior pole seen on first post-operative day in a 6 year old child with congenital glaucoma who underwent Trab & Trab. Case 2 describes multiple intraretinal hemorrhages seen at posterior pole on second post-operative day in a 24 year old pregnant lady with post traumatic cataract and secondary glaucoma who underwent cataract extraction with Cionni ring. Both patients had complete resolution of the haemorrhages with topical steroids.\n\n\n\nOcular decompression retinopathy is mostly seen after operations on cases with advanced glaucoma and those with vulnerable blood flow fluidics. Adequate precautions to prevent this entity should be adopted during surgery and management of the manifest entity is conservative with good prognosis.",
"affiliations": null,
"authors": "Singh|Kirti Singh|KS|;Bhattacharyya|Mainak|M|;Wali|Keerti|K|;Rana|Kartik|K|;Jain|Divya|D|",
"chemical_list": null,
"country": "Nepal",
"delete": false,
"doi": "10.3126/nepjoph.v9i2.19269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2072-6805",
"issue": "9(18)",
"journal": "Nepalese journal of ophthalmology : a biannual peer-reviewed academic journal of the Nepal Ophthalmic Society : NEPJOPH",
"keywords": null,
"medline_ta": "Nepal J Ophthalmol",
"mesh_terms": "D002648:Child; D005260:Female; D005901:Glaucoma; D006068:Gonioscopy; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D011183:Postoperative Complications; D011247:Pregnancy; D011248:Pregnancy Complications; D012164:Retinal Diseases; D012166:Retinal Hemorrhage; D014821:Vitrectomy; D055815:Young Adult",
"nlm_unique_id": "101505288",
"other_id": null,
"pages": "194-198",
"pmc": null,
"pmid": "29634712",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ocular Decompression Retinopathy : A Case Series.",
"title_normalized": "ocular decompression retinopathy a case series"
} | [
{
"companynumb": "IN-FRESENIUS KABI-FK201905758",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TIMOLOL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe prognosis of acute lymphoblastic leukemia (ALL) is poor in older adults and elderly patients, and subtype-oriented prospective trials are scarce in these patients. We present the results of three prospective parallel subtype-oriented protocols in fit patients older than 55 years.\n\n\nMETHODS\nIn 2008, three prospective phase II trials in patients older than 55 years were activated: ALLOLD07 for Philadephia (Ph) chromosome-negative ALL, ALLOPH07 for Ph-positive ALL, and BURKIMAB08 for mature B-ALL. Early death (ED), complete remission (CR), disease-free survival (DFS), overall survival (OS) and toxicity were analyzed.\n\n\nRESULTS\n56, 53 and 21 patients from the ALLOLD07, ALLOPH07 and BURKIMAB08 trials, respectively, were evaluable. CR was 74%, 87% and 70%, with an ED rate of 13%, 11% and 15%, respectively. The medians of DFS were 8 and 38 months for ALLOLD07 and ALLOPH07 protocols, not being achieved in the BURKIMAB08 trial (p=0.001), and the median OS was 12, 37 and 25 months, respectively (p=0.030). Neutropenia, thrombocytopenia and infections were less frequent in the ALLOPH07 trial vs. ALLOLD07 and BURKIMAB trials, and renal toxicity and mucositis were more frequent in the BURKIMAB08 trial vs. the ALLOLD07 and ALLOPH07 trials. ECOG score and WBC count had prognostic significance for OS in ALLOPH07 and BURKIMAB08 trials, whereas no prognostic factors were identified in ALLOLD07 protocol.\n\n\nCONCLUSIONS\nSubtype-oriented treatment had an impact in the outcome of older adults with ALL. The poorest outcome was observed in Ph-negative non-Mature B-cell ALL patients, for whom improvements in therapy are clearly needed.",
"affiliations": "Hematology Department of Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Universitat Autònoma de Barcelona, Spain. Electronic address: jribera@iconcologia.net.;Hematology Department of Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Universitat Autònoma de Barcelona, Spain.;Hematology Department of Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Universitat Autònoma de Barcelona, Spain.;Hematology Department of Hospital General Universitario de Alicante, Alicante, Spain.;Hematology Department of Hospital Universitario y Politécnico La Fe. Valencia, Spain.;Hematology Department of Hospital Central de Asturias, Oviedo, Spain.;Hematology Department of Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Hematology Department of Hospital Universitario Lucus Augusti, Lugo, Spain.;Hematology Department of Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Universitat Autònoma de Barcelona, Spain.;Hematology Department of Hospital de Sant Pau, Barcelona, Spain.;Hematology Department of Hospital Doce de Octubre, Madrid, Spain.;Hematology Department of Hospital Clínico, Valencia, Spain.;Hematology Department of Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Universitat Autònoma de Barcelona, Spain.;Hematology Department of Hospital Vall d'Hebron, Barcelona, Spain.;Hematology Department of Institut Català d'Oncologia-Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain.;Hematology Department of Hospital Universitario de Getafe, Getafe, Spain.;Hematology Department of Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain.;Hematology Department of Hospital Marqués de Valdecilla, Santander, Spain.;Hematology Department of Hospital Son Llàtzer, Palma de Mallorca, Spain.;Hematology Department of Hospital Arnau de Vilanova, Lleida, Spain.;Hematology Department of Hospital Ramón y Cajal, Madrid, Spain.;Hematology Department of Hospital Madrid Norte Sanchinarro, Madrid, Spain.;Hematology Department of Hospital Verge de la Cinta, Tortosa, Spain.;Hematology Department of Hospital Universitario Doctor Peset, Valencia, Spain.;Hematology Department of Hospital General Universitario Morales Meseguer, Murcia, Spain.;Hematology Department of Institut Català d'Oncologia-Hospital Joan XXIII, Tarragona, Spain.;Hematology Department of Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Universitat Autònoma de Barcelona, Spain.",
"authors": "Ribera|Josep-Maria|JM|;García|Olga|O|;Oriol|Albert|A|;Gil|Cristina|C|;Montesinos|Pau|P|;Bernal|Teresa|T|;González-Campos|José|J|;Lavilla|Esperanza|E|;Ribera|Jordi|J|;Brunet|Salut|S|;Martínez|María-Pilar|MP|;Tormo|Mar|M|;Genescà|Eulàlia|E|;Barba|Pere|P|;Sarrà|Josep|J|;Monteserín|María-Carmen|MC|;Soria|Beatriz|B|;Colorado|Mercedes|M|;Cladera|Antònia|A|;García-Guiñón|Antoni|A|;Calbacho|María|M|;Serrano|Alfons|A|;Ortín|Xavier|X|;Pedreño|María|M|;Amigo|Maria-Luz|ML|;Escoda|Lourdes|L|;Feliu|Evarist|E|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "41()",
"journal": "Leukemia research",
"keywords": "Acute lymphoblastic leukemia; Elderly; Risk-adapted therapy",
"medline_ta": "Leuk Res",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "12-20",
"pmc": null,
"pmid": "26686475",
"pubdate": "2016-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Feasibility and results of subtype-oriented protocols in older adults and fit elderly patients with acute lymphoblastic leukemia: Results of three prospective parallel trials from the PETHEMA group.",
"title_normalized": "feasibility and results of subtype oriented protocols in older adults and fit elderly patients with acute lymphoblastic leukemia results of three prospective parallel trials from the pethema group"
} | [
{
"companynumb": "PHHY2018ES176284",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Guillain-Barre syndrome is an acute immune-mediated demyelinating, polyneuropathy, which is usually provoked by a preceding infection. Guillain-Barre syndrome lies within the spectrum of disimmune neuropathies and usually occurs in immunocompromised patients because it is theoretically contradictory. Guillain-Barre syndrome in liver transplant recipients has been rarely reported. Here, we present a case of a patient who had undergone a deceased donor liver transplant and who developed symptoms of Guillain-Barre syndrome in the posttransplant period. We postulated that reactivation of varicella-zoster virus in our patient triggered the autoimmune-related peripheral neuropathy leading to Guillain-Barre syndrome; another etiology for this complication may be autoimmune hepatitis, as also shown in our patient.",
"affiliations": "From the Department of General Surgery, Post Graduate institute of Medical Education & Research, Chandigarh, India.",
"authors": "Ramavath|Krishna|K|;Behera|Arunanshu|A|;Kaman|Lileswar|L|;Dahiya|Divya|D|;Tandup|Cherring|C|;Singh|Virendra|V|;Rathod|Srinath S|SS|;Talukdar|Shibojit|S|;Taneja|Sunil|S|;Pattnaik|Bramhadatt|B|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2020.0286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "19(11)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": null,
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "1238-1240",
"pmc": null,
"pmid": "33952175",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Guillain-Barre Syndrome in Orthotopic Liver Transplant Recipient.",
"title_normalized": "guillain barre syndrome in orthotopic liver transplant recipient"
} | [
{
"companynumb": "IN-STRIDES ARCOLAB LIMITED-2022SP006151",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nHepatitis E virus (HEV) may be resistant to immunosuppression reduction and ribavirin treatment in kidney transplant recipients because of mutant strains and severe side effects of ribavirin which conduct to dose reduction. Sofosbuvir efficacy is controversial. Peg-interferon 2 alpha (PEG-IFN) is currently contraindicated due to a high risk of acute humoral and cellular rejection. The present study assessed, for the first time, the effect of PEG-IFN in a kidney transplant recipient infected with HEV.\n\n\nMETHODS\nThe patient had chronic active HEV that was resistant to immunosuppression reduction and optimal ribavirin treatment. He developed significant liver fibrosis. PEG-IFN was administered for 10 months, and it was well tolerated and did not induce rejection. A sustained virological response was obtained.\n\n\nCONCLUSIONS\nWe conclude that prolonged treatment with PEG-IFN in kidney transplant recipients infected with HEV could be considered as a salvage option.",
"affiliations": "Department of Gastroenterology, University Hospital, Avenue de la côte de Nacre, 14000, Caen, France.;Department of Gastroenterology, University Hospital, Avenue de la côte de Nacre, 14000, Caen, France. louise.lebedel@gmail.com.;Department of Nephrology, University Hospital, Caen, France.;Department of Gastroenterology, University Hospital, Avenue de la côte de Nacre, 14000, Caen, France.;Department of Gastroenterology, University Hospital, Avenue de la côte de Nacre, 14000, Caen, France.;Department of Virology, University Hospital, Caen, France.;Department of Gastroenterology, University Hospital, Avenue de la côte de Nacre, 14000, Caen, France.",
"authors": "Ollivier-Hourmand|I|I|;Lebedel|L|L|http://orcid.org/0000-0002-0218-5542;Lecouf|A|A|;Allaire|M|M|;Nguyen|T T N|TTN|;Lier|C|C|;Dao|T|T|",
"chemical_list": "D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-020-05212-2",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect. Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5212\n10.1186/s12879-020-05212-2\nCase Report\nPegylated interferon may be considered in chronic viral hepatitis E resistant to ribavirin in kidney transplant recipients\nOllivier-Hourmand I. 1 http://orcid.org/0000-0002-0218-5542Lebedel L. louise.lebedel@gmail.com 1 Lecouf A. 2 Allaire M. 13 Nguyen T. T. N. 1 Lier C. 4 Dao T. 1 1 grid.411149.80000 0004 0472 0160Department of Gastroenterology, University Hospital, Avenue de la côte de Nacre, 14000 Caen, France \n2 grid.411149.80000 0004 0472 0160Department of Nephrology, University Hospital, Caen, France \n3 grid.7452.40000 0001 2217 0017Inserm U1149, Center for Research on Inflammation, Faculté de Médecine Xavier Bichat, Université Paris Diderot, Sorbonne Paris Cité, Paris, France \n4 grid.411149.80000 0004 0472 0160Department of Virology, University Hospital, Caen, France \n16 7 2020 \n16 7 2020 \n2020 \n20 52213 2 2020 29 6 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\nHepatitis E virus (HEV) may be resistant to immunosuppression reduction and ribavirin treatment in kidney transplant recipients because of mutant strains and severe side effects of ribavirin which conduct to dose reduction. Sofosbuvir efficacy is controversial. Peg-interferon 2 alpha (PEG-IFN) is currently contraindicated due to a high risk of acute humoral and cellular rejection. The present study assessed, for the first time, the effect of PEG-IFN in a kidney transplant recipient infected with HEV.\n\nCase presentation\nThe patient had chronic active HEV that was resistant to immunosuppression reduction and optimal ribavirin treatment. He developed significant liver fibrosis. PEG-IFN was administered for 10 months, and it was well tolerated and did not induce rejection. A sustained virological response was obtained.\n\nConclusions\nWe conclude that prolonged treatment with PEG-IFN in kidney transplant recipients infected with HEV could be considered as a salvage option.\n\nKeywords\nHepatitis EKidney transplantationInterferonRibavirinRejectionissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nInfection with hepatitis E virus (HEV) is a global public health problem that causes important morbidity and mortality, particularly in immunosuppressed patients. HEV genotype 1 and HEV genotype 2 are obligate human pathogens transmitted by the faecal-oral route via contaminated water in developing countries. In European countries, HEV genotype 3 (HEV3) and HEV genotype 4 (HEV4) are dominant and transmitted by a zoonotic route, primarily via consumption of contaminated pig meat or direct contact [1, 2].\n\nIn most European cases, HEV infection is a mild sub-clinical hepatitis and self-limiting infection that resolves spontaneously. Less than 5% [1] of patients infected with HEV3 develop symptoms of acute hepatitis, such as jaundice, elevated liver enzymes or fatigue. Progression to acute liver failure is rare, but it is more common in patients with chronic liver disease. Immunosuppressed patients may fail to clear HEV infection, which is responsible for chronic hepatitis [1–3]. HEV is also associated with extrahepatic manifestations. The most important manifestations are neurological (5.5% of patients infected by HEV3), such as Guillain-Barré syndrome, neuralgic amyotrophy, and acute meningoencephalitis [2]. Some cases of membranous and membranoproliferative glomerulonephritis were observed [1] in immunosuppressed patients infected by HEV3. HEV also induces haematological disorders, severe thrombocytopenia and aplastic anaemia.\n\nThe seroprevalence of HEV in solid organ transplant (SOT) recipients varies from 2 to 44% [2, 4]. A European study reported that the seroprevalence of HEV was roughly the same in the general population and SOT recipients and fluctuated between 7 to 17% and 8 to 18%, respectively, according to the serological test used [5]. When SOT recipients are infected with HEV, 66% will develop chronic hepatitis, which will lead to cirrhosis within 2–3 years in 14% [2, 4]. All cases of chronic HEV infection in SOT recipients were diagnosed in patients infected by HEV3 or HEV4, which supports a zoonotic mode of transmission. The sources of transmission of HEV3 in SOT patients are similar to the general population, i.e., the consumption of contaminated meat or direct contact. A few cases of HEV transmission via blood transfusions or infected graft were reported [2, 4].\n\nA treatment algorithm for chronic HEV infection in immunosuppressed transplant patients, based on EASL guidelines published in 2018 [1], is presented in Fig. 1. Immunosuppression reduction generally allows a clearing of the virus in 32% of cases [1, 3, 4, 6]. When chronic HEV persists despite immunosuppression reduction, the first line treatment is at least a 3-month course of ribavirin (RBV). An initial median daily dose of 600 mg RBV achieved a sustained virological response (SVR) (defined as undetectable HEV RNA in the serum at least 6 months after the completion of treatment) in 78% of cases. The RBV dose varies widely between studies (400–1200 mg/d) depending on weight, haemoglobin and glomerular filtration rate adaptations [1–4, 6–8]. In patients with persisting replication in the serum and stools, an additional 3 months of treatment is proposed. In the absence of viral clearance at 6 months, Peg-interferon (PEG-IFN) may be considered only in liver transplant (LTR) patients, but not other transplant patients. In practice, the second line treatment is often an increase in RBV to 1200 mg/day for a 6–9 months [1, 3, 4], which allows an 85% SVR [1, 4]. This dose of RBV may induce anaemia, which requires erythropoietin (EPO) in 40% of patients and sometimes blood transfusions [1, 3, 4, 6, 8]. The 25% treatment failure in SOT are generally linked to RBV dose reduction due to severe side effects and mutant strains, such as HEV polymerase variant (G1634R) [1, 6, 7].\nFig. 1 Treatment algorithm for solid organ transplant patients with chronic HEV infection (adapted from EASL Guidelines 2018)\n\n\n\nOther treatments were tested after RBV failure, such as sofosbuvir, which decreased HEV viral load, but its ability to cure HEV infection, even in combination with RBV, remains controversial [9–12]. To date, a single case of SVR with sofosbuvir plus RBV was observed in a kidney transplant recipient (KTR) [10].\n\nPEG IFN 2 alpha was used in LTR patients infected by hepatitis C (HCV) with a 50% SVR, but it was contra-indicated in other SOTs due to a higher expected risk of acute humoral and cellular rejection [4, 13–16]. Similarly, PEG-IFN was successfully prescribed in 5 LTR patients infected by HEV [3] but not in other SOTs.\n\nWe report a case of chronic HEV infection in a kidney transplant recipient treated with PEG-IFN after failure of a decrease in immunosuppression level associated with a well-performed RBV treatment. The patient did not present cellular or humoral graft rejection and was cured from HEV.\n\nCase presentation\nA 47-year-old KTR was diagnosed with chronic genotype 3i (determination of genotype by sequencing of ORF2 region [17]) HEV infection 4.5 years after transplantation for an undetermined glomerulonephritis. At the time of diagnosis, alanine aminotransferase was 117 IU/L, HEV plasma viral load (VL) was 6 log IU/mL (Altona Diagnostics / RealStar® HEV RT-PCR kit) and liver stiffness measurement (LSM) was 10.6 kPa on transient elastography.\n\nThe beginning of the infection was at least 2 years prior because a plasma sample at that time was retrospectively found to be positive for HEV with a viral load of 6.54 log IU/mL. The patient had no extrahepatic manifestations of HEV infection. He was treated with tacrolimus (TAC) 1 mg X 2/day (d) (trough level (TL) 12.3 ng/ml) and mycophenolate mofetil (MMF) 750 mg X 2/d. TAC was reduced to 0.5 mg X 2/d (TL 4.2 ng/ml). At the same time, RBV 800 mg/d was introduced (58 kg, haemoglobin (Hb) 14.7 g/dL) but suspended after 2 weeks because of anaemia (Hb 8.0 g/dL) that required 2 units of packed red blood cells at week (W) 4 (Hb 6.8 g/dL) and EPO 10,000 IU weekly. After this short RBV course, transaminases were normalized, and HEV viremia was undetectable.\n\nHowever, HEV viremia was detectable 2 months later (3.75 log IU/mL). RBV (200 mg/d) was reintroduced (W0) and increased to a maximum of 800 mg/d with many adjustments to Hb levels and an injection of EPO 30,000 IU/wk. Due to a low TL (2.25 ng/mL), TAC was increased to 1 mg × 2/d (TL 9 ng/ml). At W11, plasma VL was 2 log IU/mL. At W22, the patient received another packed red blood cell treatment for symptomatic anaemia (Hb 7.8 g/dL). EPO was increased to 30,000 IU × 2/wk. At W23, the plasma VL was undetectable. RBV at 400 mg–600 mg/d was continued with EPO 30,000 IU × 2/wk., until W31, but plasma VL became positive again (2.50 log IU/mL) and treatment was stopped. To identify mutations associated with RBV failure, sequencing of the polymerase region was made at the French National Reference Center for HEV (Pr Jacques Izopet, Toulouse) by the Sanger method [18]. The sequencing of the polymerase region revealed the presence of 3 mutations (V1479I - Y1587F - G1634G/R). Seven months after the end of RBV treatment, viremia remained positive, LSM was 12.6 kPa, and liver biopsy showed fibrosis progression (METAVIR score A1F2). PEG-IFN (90 μg/wk. subcutaneously) was introduced for 2 weeks, then 135 μg/wk., with close monitoring of serum creatinine and proteinuria. Immunosuppression was also reduced to MMF 500 mg × 2/d and TAC 0.5 mg × 2/d (TL 6.8 ng/ml) then modified for TAC-XR 0.5 mg/d due to a high TL (9.2 ng/ml). After 6 weeks of treatment, no sign of cellular rejection or donor-specific HLA antibodies (DSAs) were observed, and HEV viremia and faecal RT-PCR were negative. Immunosuppressive therapy was re-increased (TAC-XR 1 mg/day then 2 mg/day) due to a low TL TAC-XR (3.1 ng/mL), and PEG-IFN was continued 3 months after faecal RT-PCR was negative, for a total administration of 6 months. LSM at the end of treatment was 6.3 kPa, and RT-PCR remained negative in plasma and faeces. HEV remains undetectable in plasma and faeces 16 months after PEG-IFN discontinuation (Fig. 2). LSM was 5.1 kPa, and no sign of kidney rejection was observed (DSA negative).\nFig. 2 Evolution of viral load HEV and Tacrolimus \n\n\n\nDiscussion and conclusions\nThis paper is the first report of chronic HEV infection treated with PEG-IFN in a KTR. The most remarkable result was that the patient was cured of HEV without kidney rejection. The patient underwent careful surveillance. Tolerance was good compared with RBV alone. PEG-IFN was administered for approximately 10 months, and it was not associated with any sign of graft rejection during the course of treatment or after 16 months. Late rejection has been described, especially in longer lengths of therapy in chronic HCV, and an extended close monitoring was required [16]. We also administered PEG-IFN in 2 HEV-infected heart transplants without any graft rejection (unpublished personal data), but treatment was unsuccessful.\n\nTherapeutic alternatives in cases of intolerance or immunomodulation and RBV failure in SOTs remain unknown. Our patient was already treated according to standard recommendations: immunosuppression was lowered as much as possible, and the doses and duration of RBV were optimized most of the time, with adjunctive administration of EPO and blood transfusion when necessary. The results of the use of sofosbuvir alone or in combination with daclatasvir failed to demonstrate efficiency in vivo [9]. The use of sofosbuvir in association with RBV was not conclusive. In the single case of an SVR using sofosbuvir plus RBV in a KTR, RBV was doubled from 600 mg/d to 1200 mg/d during the combined therapy, so the RBV alone may be responsible for SVR [10].\n\nRapid progression towards cirrhosis is frequent in immunosuppressed patients, especially in kidney and heart transplant recipients [19, 20]. PEG-IFN was used as an alternative to RBV monotherapy in liver transplant recipients. However, it was successfully prescribed in only 5 patients [3]. In contrast, because of its immunomodulatory effect, PEG-IFN was associated with a high risk of humoral and cellular rejection and renal failure in the context of HCV in kidney and liver transplant recipients, and it is contraindicated for SOT recipients other than the liver [3, 4]. Here, PEG-IFN successfully cured chronic HEV. RT-PCR was undetectable in plasma and faeces after 6 weeks. PEG-INF for chronic HEV in LTR was administered for 3 to 12 months in a previous study, and the dose varied from 135 to 180 μg/week [3]. We empirically prolonged treatment 12 weeks after virological clearance for a total of 6 months.\n\nPEG-IFN treatment was successful despite the occurrence of 3 HEV polymerase variants, including the G1634R variant, after RBV treatment. RBV applies mutagenic pressure, which may result in an increment in quasispecies diversity or viral excretion in non-responding patients. The variants selected by RBV are characterized by mutations or single nucleotide variations (SNV). In a study of 63 SOT patients with chronic hepatitis E (genotype 3), the authors found that although its proportion was increased in patients whose RBV treatment failed, the presence of the SNV G1634R did not compromise the response to a second RBV treatment [7]. Another study highlighted the emergence of SNV G1634R during RBV treatment and subsequent treatment failure, and suggested that this mutation contributed to resistance [6].\n\nIn conclusion, in cases of RBV first line treatment failure (associated with a decrease of immunosuppression), prolonged treatment with PEG-IFN in kidney transplant recipients infected by HEV may be safe without acute or delayed graft rejection.\n\nAbbreviations\nDDay\n\nDSAsDonor-specific HLA antibody\n\nEPOErythropoietin\n\nHbHaemoglobin\n\nHCVHepatitis C Virus\n\nHEVHepatitis E Virus\n\nKTRKidney transplant recipient\n\nLSMLiver stiffness measurement\n\nLTRLiver transplant recipients\n\nMMFMycophenolate mofetil\n\nPEG-IFNPeg-interferon 2 alpha\n\nRBVRibavirin\n\nSNVSingle nucleotide variations\n\nSOTSolid organ transplant\n\nSVRSustained virological response rate\n\nTACTacrolimus\n\nTLTrough level\n\nVLPlasma viral load\n\nWWeek\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nIOH and LL had full access to all data and take responsibility for the integrity of data and the accuracy of data reported. Report concept: IOH. Acquisition of data: IOH, LL, CL, TTNN. Analysis and interpretation of data: IOH, CL, AL, MA. Drafting of the manuscript: IOH, LL, TD. Critical revision of the manuscript for important intellectual content and final approval of the version to be published: IOH, LL, AL, MA, TTNN, CL, TD.\n\nFunding\nNo financial support was provided for this work.\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\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\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 of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. European Association for the Study of the Liver EASL clinical practice guidelines on hepatitis E virus infection J Hepatol 2018 68 1256 1271 10.1016/j.jhep.2018.03.005 29609832 \n2. Kamar N Izopet J Rostaing L Hepatitis E virus infection Curr Opin Gastroenterol 2013 29 271 278 10.1097/MOG.0b013e32835ff238 23507918 \n3. Abbas Z Afzal R Hepatitis E: when to treat and how to treat Antivir Ther 2014 19 125 131 10.3851/IMP2705 24192696 \n4. Te H Doucette K Viral hepatitis: guidelines by the American society of transplantation infectious disease community of practice Clin Transpl 2019 33 e13514 10.1111/ctr.13514 \n5. Hartl J Otto B Madden RG Webb G Woolson KL Kriston L Hepatitis E seroprevalence in Europe: a meta-analysis Viruses 2016 8 211 10.3390/v8080211 \n6. Debing Y Ramière C Dallmeier K Piorkowski G Trabaud MA Lebossé F Hepatitis E virus mutations associated with ribavirin treatment failure result in altered viral fitness and ribavirin sensitivity J Hepatol 2016 65 499 508 10.1016/j.jhep.2016.05.002 27174035 \n7. Lhomme S Kamar N Nicot F Ducos J Bismuth M Garrigue V Mutation in the hepatitis E virus polymerase and outcome of ribavirin therapy Antimicrob Agents Chemother 2015 60 1608 1614 10.1128/AAC.02496-15 26711757 \n8. Luciani L Deharo P Aherfi S Chalvignac V Borentain P Colson P Hepatitis E virus infection in heart transplant recipients, Southeastern France Clin Res Hepatol Gastroenterol 2019 43 108 111 10.1016/j.clinre.2018.09.010 30497845 \n9. Donnelly MC Imlach SN Abravanel F Ramalingam S Johannessen I Petrik J Sofosbuvir and daclatasvir anti-viral therapy fails to clear HEV viremia and restore reactive T cells in a HEV/HCV co-infected liver transplant recipient Gastroenterology 2017 152 300 301 10.1053/j.gastro.2016.05.060 27883881 \n10. Drinane M Jing Wang X Watt K Sofosbuvir and ribavirin eradication of refractory hepatitis E in an immunosuppressed kidney transplant recipient Hepatology 2019 69 2297 2299 10.1002/hep.30428 30549275 \n11. Kamar N Pan Q No clear evidence for an effect of sofosbuvir against hepatitis E virus in organ transplant patients Hepatology 2019 69 1846 1847 10.1002/hep.30546 \n12. Todesco E Mazzola A Akhavan S Abravanel F Poynard T Roque-Afonso AM Chronic hepatitis E in a heart transplant patient: sofosbuvir and ribavirin regimen not fully effective Antivir Ther 2018 23 463 465 10.3851/IMP3227 29504509 \n13. Kamar N Rostaing L Abravanel F Garrouste C Esposito L Cardeau-Desangles I Pegylated interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation Clin Infect Dis 2010 50 e30 e33 10.1086/650488 20113176 \n14. Haagsma EB Riezebos-Brilman A van den Berg AP Porte RJ Niesters HG Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b Liver Transpl 2010 16 474 477 10.1002/lt.21926 20373458 \n15. Nakano R Ohira M Ishiyama K Ide K Kobayashi T Tahara H Acute graft rejection and formation of de novo donor-specific antibodies triggered by low cyclosporine levels and interferon therapy for recurrent hepatitis C infection after liver transplantation: a case report Transplant Proc 2017 49 1634 1638 10.1016/j.transproceed.2017.05.006 28838454 \n16. Selzner N Guindi M Renner EL Berenguer M Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients J Hepatol 2011 55 207 217 10.1016/j.jhep.2010.11.012 21145865 \n17. Legrand-Abravanel F Mansuy JM Dubois M Hepatitis E virus genotype 3 diversity, France Emerg Infect Dis 2009 15 1 110 114 10.3201/eid1501.080296 19116067 \n18. Kamar N, Abravanel F, Behrendt P, Hofmann J, Pageaux GP, Barbet C, et al. Ribavirin for hepatitis E virus infection after organ transplantation: a large European retrospective multicenter study. Clin Infect Dis. 2019:ciz953. 10.1093/cid/ciz953 Epub ahead of print. PMID: 31793638.\n19. Koning L Pas SD de Man RA Balk AH de Knegt RJ ten Kate FJ Clinical implications of chronic hepatitis E virus infection in heart transplant recipients J Heart Lung Transplant 2013 32 78 85 10.1016/j.healun.2012.10.008 23260707 \n20. Gérolami R Moal V Colson P Chronic hepatitis E with cirrhosis in a kidney-transplant recipient N Engl J Med 2008 358 859 860 10.1056/NEJMc0708687 18287615\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "20(1)",
"journal": "BMC infectious diseases",
"keywords": "Hepatitis E; Interferon; Kidney transplantation; Rejection; Ribavirin",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D024882:Drug Resistance, Viral; D016751:Hepatitis E; D016752:Hepatitis E virus; D006521:Hepatitis, Chronic; D006801:Humans; D016898:Interferon-alpha; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012074:Remission Induction; D012254:Ribavirin; D000072230:Sustained Virologic Response; D066027:Transplant Recipients; D016896:Treatment Outcome",
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"pubdate": "2020-07-16",
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"title": "Pegylated interferon may be considered in chronic viral hepatitis E resistant to ribavirin in kidney transplant recipients.",
"title_normalized": "pegylated interferon may be considered in chronic viral hepatitis e resistant to ribavirin in kidney transplant recipients"
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"abstract": "BACKGROUND\nTo describe an unusual case of Cushing's disease with spontaneous axial pain due to multiple consecutive vertebral fractures which led to secondary deformity that required surgical treatment.\n\n\nMETHODS\nA 43-year-old man was referred to our service with back pain without previous trauma. He was diagnosed of refractory arterial hypertension and we observed centripetal obesity during exploration. With clinical findings and laboratory studies, ACTH-dependent Cushing's syndrome due to a pituitary microadenoma was diagnosed and the patient underwent an endoscopic-assisted endonasal transsphenoidal resection. Dual energy X-ray absorptiometry (DXA) revealed spine and hip osteoporosis. Moreover, X-ray, MR and CT showed multiple vertebral osteoporotic compression fractures in thoracic and thoracolumbar area. Secondary kyphosis thoracolumbar deformity and sagittal imbalance was treated by two-level Smith-Petersen osteotomies (SPO) and instrumented posterolateral arthrodesis T10-L3 using fenestrated pedicles screws with polymethyl methacrylate (PMMA). At six years of follow-up dual energy X-ray absorptiometry (DXA) recovered normal values (T-score lumbar spine L2-L4 1.4 and T-score hip -1.9) and X-ray study showed an adequate sagittal vertebral axis.\n\n\nCONCLUSIONS\nOsteoporosis is a common feature of CD and fractures occur in 30-50% of cases. Treating the underlying cause reduces the risk of new fractures. Medical therapy is usually enough but consecutive multiple vertebral fractures related to glucocorticoid excess may lead to secondary painful deformity.\n\n\nCONCLUSIONS\nVertebral compression fractures result from secondary corticoid-induced osteoporosis in Cushing's disease. Early detection and treatment of primary disease decreases the risk of new fractures. However, unusual secondary spinal deformity or disability may require surgery.",
"affiliations": "Complejo Hospitalario Universitario de Albacete, Department of Orthopedics, Spine Unit, Albacete, Spain. Electronic address: jramirez02003@me.com.;Complejo Hospitalario Universitario de Albacete, Department of Orthopedics, Spine Unit, Albacete, Spain. Electronic address: davidcop80@gmail.com.;Complejo Hospitalario Universitario de Albacete, Endocrinologist Department, Albacete, Spain. Electronic address: clamaso@sescam.jccm.es.;Hospital Universitario Dr. Peset, Department of Orthopedics, Chief of Endocrinologic Department, Valencia, Spain. Electronic address: cmorillas@telefonica.net.",
"authors": "Ramírez-Villaescusa|José|J|;Ruiz-Picazo|David|D|;Oliveira|Cristina Lamas|CL|;Morillas-Ariño|Carlos|C|",
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"doi": "10.1016/j.ijscr.2020.09.182",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30855-5\n10.1016/j.ijscr.2020.09.182\nCase Report\nSecondary thoracolumbar deformity and sagittal imbalance due to osteoporosis in a young man with Cushing’s disease: A case report\nRamírez-Villaescusa José jramirez02003@me.coma⁎ Ruiz-Picazo David davidcop80@gmail.coma Oliveira Cristina Lamas clamaso@sescam.jccm.esb Morillas-Ariño Carlos cmorillas@telefonica.netc a Complejo Hospitalario Universitario de Albacete, Department of Orthopedics, Spine Unit, Albacete, Spain\nb Complejo Hospitalario Universitario de Albacete, Endocrinologist Department, Albacete, Spain\nc Hospital Universitario Dr. Peset, Department of Orthopedics, Chief of Endocrinologic Department, Valencia, Spain\n⁎ Corresponding author at: C/Hermanos Falcó 37, 02006, Albacete, Spain. jramirez02003@me.com\n29 9 2020 \n2020 \n29 9 2020 \n76 134 138\n1 9 2020 25 9 2020 25 9 2020 © 2020 The Author(s)2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Vertebral fractures are frequent due to osteoporosis in Cushing disease.\n\n• Treating de primary cause of the disease reduces the risk of new fractures.\n\n• Surgical treatment may be needed for secondary deformity.\n\n\n\nIntroduction\nTo describe an unusual case of Cushing’s disease with spontaneous axial pain due to multiple consecutive vertebral fractures which led to secondary deformity that required surgical treatment.\n\nPresentation of case\nA 43-year-old man was referred to our service with back pain without previous trauma. He was diagnosed of refractory arterial hypertension and we observed centripetal obesity during exploration. With clinical findings and laboratory studies, ACTH-dependent Cushing’s syndrome due to a pituitary microadenoma was diagnosed and the patient underwent an endoscopic-assisted endonasal transsphenoidal resection. Dual energy X-ray absorptiometry (DXA) revealed spine and hip osteoporosis. Moreover, X-ray, MR and CT showed multiple vertebral osteoporotic compression fractures in thoracic and thoracolumbar area. Secondary kyphosis thoracolumbar deformity and sagittal imbalance was treated by two-level Smith-Petersen osteotomies (SPO) and instrumented posterolateral arthrodesis T10-L3 using fenestrated pedicles screws with polymethyl methacrylate (PMMA). At six years of follow-up dual energy X-ray absorptiometry (DXA) recovered normal values (T-score lumbar spine L2–L4 1.4 and T-score hip -1.9) and X-ray study showed an adequate sagittal vertebral axis.\n\nDiscussion\nOsteoporosis is a common feature of CD and fractures occur in 30–50% of cases. Treating the underlying cause reduces the risk of new fractures. Medical therapy is usually enough but consecutive multiple vertebral fractures related to glucocorticoid excess may lead to secondary painful deformity.\n\nConclusion\nVertebral compression fractures result from secondary corticoid-induced osteoporosis in Cushing’s disease. Early detection and treatment of primary disease decreases the risk of new fractures. However, unusual secondary spinal deformity or disability may require surgery.\n\nKeywords\nCushing’s diseaseMultiple vertebral fracturesSagittal imbalanceSurgical treatment\n==== Body\n1 Introduction\nEndogenous Cushing’s syndrome (CS) is a rare disease. In a European population-based study, the annual incidence was 2–4 cases per million inhabitants per year [1]. Cushing’s disease (CD) due to ACTH pituitary hyperproduction is the most frequent cause of endogenous CS and 1.2–1.7 cases per million per year have been reported, about three times more frequent than the one caused by an adrenal tumour [1,2]. CS due to an adrenal or pituitary tumour occurs mainly between 25 to 45-years, with the female-to-male incidence ratio being approximately 5:1.\n\nIn CD there is a pituitary ACTH hypersecretion and increased ACTH plasma levels, originated by a pituitary adenoma, often undetected through image techniques, which stimulate bilateral adrenal hyperplasia with cortisol hypersecretion and consequently cortisol circadian rhythm lost [3]. CD signs and symptoms depend directly on persistently high cortisol plasma levels, most of them being present in general population (arterial hypertension, central obesity, diabetes or insulin resistance) so it is often difficult to make a diagnosis [3]. Early diagnosis is important as the high rate of comorbidity and mortality in CD patients can be avoided if treated at an early stage.\n\nBone disease a common feature of CS and there is a variable risk of osteoporosis of 50–90% [4,5]. Fractures occur in 30–50% of the cases, being more frequent in men than in women (2), especially in thoracic and lumbar spine [4,5] and are strongly correlated with the degree and duration of hypercortisolism [6]. Dual X-ray absorptiometry (DXA) is the standard non-invasive technique for measuring bone mineral density (BMD) at the lumbar spine (L2–L4) and hip, as it allows the assessment of the risk of fractures if there is osteoporosis, as well as improvement after response to medical treatment or resolution of the cause in secondary osteoporosis.\n\nVertebral fractures in CD are usually treated conservatively, as every other osteoporotic fracture, and surgical treatment is infrequently needed [7]. Treating the primary cause could prevent new fractures [8].\n\nWe present a case with consecutive thoracolumbar vertebral fractures which led to a secondary kyphotic thoracolumbar deformity treated by arthrodesis and corrective posterior osteotomies. This report is line with the SCARE criteria [9].\n\n2 Presentation of case\nA 43-year-old man was referred to our hospital due to lumbar pain without previous trauma. He was previously diagnosed of refractory arterial hypertension. The initial exam did not reveal neurological deficit. The patient showed signs such as abdominal perimeter increase, abdominal violaceous striae, thin skin, weight loss more significant in the last month, intense proximal weakness in the lower limbs, ecchymosis, toenails, and armpits fungal lesions, erythema and moon facies, all happening over the course of one year. The patient had never taken any corticoids. After that, he was diagnosed of a nosocomial respiratory infection due to influenza A virus treated with oseltamivir.\n\nX-ray and computerised tomography (TC) showed rib and multiple vertebral compression fractures in thoracic T6 level, thoracolumbar T11, T12, L1, L2 and L4, L5 lumbar levels. Magnetic resonance (MR) confirmed multiple vertebral fractures without malignant signs, which suggested osteoporotic fractures (Fig. 1). Dual energy X-ray absorptiometry (DXA) showed osteoporosis in spine and hip (lumbar spine T-score -2.7 and femoral neck T-score -3.1) (Fig. 2).Fig. 1 A/B: Standing full spine x-ray preoperative antero-posterior and sagittal view. A: No coronal imbalance or angular deformities showed in AP view. B: Sagittal view: Multiples vertebral fractures were observed in thoracic, lumbar and consecutives in thoracolumbar area leads to TLK (T10-L2) 25° and sagittal vertical axis (SVA) 13 cm. C/D/E/F: TC preoperative sagittal view shows loss of vertebral body height and kyphosis in thoracolumbar area and sagittal views of MR T1, T2-weighted and STIR sequences without oedema suggesting acute lesion.\n\nFig. 1Fig. 2 DXA changes through follow-up. Dual energy X-ray absorptiometry (DXA) recovered a normal value in the L2-L4 lumbar spine (T-score 1.4) and an osteopenic value in the hip (T-score -1.9) at six years of follow-up.\n\nFig. 2\n\nWhen Cushing’s syndrome was suspected, the patient was referred to the endocrinologist for a confirmation study and the following analytic studies were performed. Cortisol rhythm: Serum cortisol 38.4 μg/dl (8 h), 38.7 μg/dl (23 h) (normal value 6–30 μg/dl), Urinary free cortisol: 1616.8 μg/24 h (normal value 4.3–176 μg/24 h), ACTH: 104 pg/mL (normal value 7–63 pg/ml). ACTH-dependent Cushing’s disease was confirmed. Low-dose (0.5 mg every 6 h for two days) and high-dose (8 mg single dose) dexamethasone suppression tests did not suppress cortisol levels (35.8 μg/dl after low dose and 33.7 μg/dl after high dose of dexamethasone). Pituitary function was preserved, except for hypogonadotropic hypogonadism secondary to hypercortisolism. Brain MR identified a 5 mm pituitary microadenoma and bilateral inferior petrosal sinus sampling showed a central to peripheral ACTH gradient (>2 basally and >3 post-ACTH), thus confirming Cushing’s disease.\n\nThe patient was initially treated with anti-hypertensive medical therapy, ketoconazole, and testosterone. Moreover, teriparatide treatment was also started to treat osteoporosis. However, the patient started to have spine and neck erythema and non-puriginic painful thorax. He was treated by the dermatologist because of the lesions’ deterioration which had expanded to the trunk, limbs, head, and neck, with some blisters appearing in areas of friction with associated epidermolysis and Nikolsky sign [10]. The biopsy confirmed toxic epidermal necrolysis (TEN) related to medical treatment, probably related to oseltamivir [11].\n\nThe patient underwent an endoscopic-assisted endonasal trans-sphenoidal excision of the pituitary adenoma by the neurosurgical team, with hypercortisolism resolution and development of secondary adrenal insufficiency, which required hydrocortisone substitutive treatment for 15 months.\n\nAfter three months, the patient presented forward inclination of the trunk and had difficulties for standing or walking. CT and MR showed multiple vertebral compression fractures in thoracic T6, thoracolumbar T11, T12, L1, L2 and lumbar L4, L5 levels without cleft or vacuum signs and diffuse hypointense in T1-weighted and T2-weighted sequences, which excluded osteonecrosis. However, X-ray full standing spine showed thoracolumbar kyphosis and disabling sagittal deformity. Spinal parameters were: Sagittal vertical axis (SVA) 13 cm, thoracic kyphosis T2-T12 (TK) 32°, thoracolumbar kyphosis T10-L2 (TLK) 25°, lumbar lordosis L1-S1 (LL) 28°. Pelvic parameters: Pelvic incidence (PI) 40°, sacral slope (SS) 25° and pelvic tilt (PT) 15° (Fig. 1).\n\nSurgical treatment was decided and with general anaesthesia by posterior approach we perform a T10-L3 posterolateral arthrodesis using autologous bone and two-level posterior Smith-Petersen corrective osteotomies (SPO) [12]. Weak intraoperative bone was observed so fenestrated pedicle screws reinforced with PMMA were used to increase the insertional torque and pull-out strength preventing instrumentation failure. The procedure was performed for a main author.\n\nAt six years of follow-up the patient had no standing or walking pain and he recovered his previous working activity. Dual energy X-ray absorptiometry (DXA) recovered a normal value in the L2-L4 lumbar spine (T-score 1.4) and an osteopenic value in the hip (T-score -1.9) at six years of follow-up (Fig. 2). X-ray study showed an adequate SVA 6.9 cm, TK (T2-T12) of 28°, and TLK (T10-L2) 16° and LL of 36° (Fig. 3). Although physiological thoracolumbar kyphosis wasn’t recovered it was well tolerated.Fig. 3 A/B: Standing full spine x-ray postoperative antero-posterior and sagittal view. C/D: Coronal and sagittal views at end of follow-up, showing T10-L3 arthrodesis with fenestrated screws and PMMA, adequate balance, well positioned implants without osteolysis or proximal junctional faillure. E/F/G: MR T1, T2-weighted and STIR sagittal sequences don’t show news fractures at six-years of follow-up.\n\nFig. 3\n\n3 Discussion\nOsteoporosis is a common feature in Cushing’s disease, with a highly variable prevalence (50–90%) and vertebral fractures can be the first clinical manifestation, as it was in our patient [8]. A high number of pathologic vertebral fractures in different locations and evolutive stages, as in our case, have been related to endogenous hypercortisolism bone disease and its vertebral trabecular bone preference [13]. Higher serum cortisol levels and longer duration of hypercortisolism confer a higher fracture risk [6]. Glucocorticoid excess affects osteoblast differentiation and function leading to bone loss and increase in fracture risk. Also, it affects osteocyte number and function, inducing apoptosis and reducing mineral matrix with an increase in lacunar size [14]. As a consequence, there is a disproportionate loss of bone strength in relation to bone mass especially in trabecular sites [13].\n\nTreating the underlying cause reduces the risk of new fractures, but it may persist, since complete bone mineral density recovery is not always achieved [15]. Furthermore, fractures may develop even in the presence of normal or low-normal bone mineral density (BMD). DXA has been proposed as the standard BMD measuring technique. It allows the assessment of initial treatment response as well as long-term recovery. Bone mass recovery after successful treatment of Cushing’s syndrome may take 5–10 years [16,17].\n\nAnalgesics and bracing conservative therapy can be useful for isolated or multiple acute osteoporotic vertebral fractures. Reinforcement techniques such as percutaneous vertebroplasty (PVP) or balloon-kyphoplasty (BKP), are generally accepted treatment for vertebral compression fractures, if pain remains after six weeks. Reinforcement techniques, when compared to conservative treatment, achieve better pain relief, functional recovery and quality of life after one-year follow-up, although no differences are found in long-term pain relief [18]. Moreover, thoracolumbar kyphosis may not be corrected or even increase after PVP or BKP in transitional thoracolumbar area [19].\n\nIn our case, reinforcement techniques weren’t considered because MR showed multiple vertebral fractures with isointense signal in T1 and T2 weighted sequences suggesting long-term evolution. However, isolated vertebral osteoporotic fractures are more frequent in the thoracolumbar area and can be associated with poor evolution signs with cleft or vacuum signs presence indicating osteonecrosis [20]. These findings weren’t present in our case and malignant signs were ruled out. Furthermore, multiples and consecutive fractures can lead to progressive local or regional deformity causing pain, disability and increase neurologic risk and decompression or realignment techniques associated with instrumentation can be required to restore sagittal balance [21]. Fusion levels and length can be conditioned by the number of fractures in deformity, apex of deformity and the presence of old fractures or previous degenerative changes, in the thoracic or lumbosacral area. Osteotomy type can be chosen depending on deformity shape (whether sharp or round), rigidity and amount of correction [12]. For the treatment of sagittal deformity, the kyphotic thoracolumbar segment was included and in the instrumented upper vertebra election, only one vertebra upper to the fractured one (T11) was elected (T10) to avoid the thoracic apical area and its complications such as proximal junctional kyphosis or proximal junctional failure. The presence of consolidated and without kyphosis compression fracture in T6 allowed us not extending the fusion to the upper thoracic area. When electing the lower instrumented vertebra, we considered L3 as a stable vertebra due to it is below the most compressed inferior vertebra (L2), the need of preserving as many lumbar levels as possible and to avoid extending fusion to S1 due to the presence of degenerative changes in L5-S1 segment.\n\nIn this case, apart from thoracic vertebral fractures, multiple consecutive vertebral thoracolumbar fractures led to secondary painful kyphosis of 25° and sagittal imbalance, specially standing or walking. Due to moderate and flexible deformity, Smith-Petersen osteotomies (SPO) were performed at the apex of the deformity with shortening of the posterior column (16° postoperative TLK) and postoperative SVA of 6.9 cm. In the presence of poor bone quality, pedicle screw instrumentation can be unsuccessful due to implant loosening or breaking. In patients with postmenopausal osteoporosis, teriparatide treatment for at least one month prior to surgery can be effective maximizing the purchase of pedicle screws by increasing their insertional torque. However, teriparatide had to be stopped in our patient after a few days of treatment, since he developed TEN. Finally, oseltamivir was confirmed as the cause of epidermal disorder [11]. Reinforcement techniques with PMMA or fenestrated screws decrease pull-out risk and were used in this patient due to his low mineral density [22].\n\n4 Conclusion\nVertebral fractures are the most frequent bone lesions associated with Cushing’s disease, which often improve after treatment of this disease. Early diagnosis is important as the high rate of comorbidity and mortality in CD patients can be avoided if treated at an early stage. The conservative therapy can be useful for isolated or multiple osteoporotic vertebral fractures. However, when there is a late diagnosis and/or severe lesion, surgery may be required, in order to address secondary vertebral deformity.\n\nDeclaration of Competing Interest\nJosé Ramírez-Villaescusa has nothing to disclose.\n\nDavid Ruiz-Picazo has nothing to disclose.\n\nCristina Lamas-Oliveira has nothing to disclose.\n\nCarlos Morillas-Ariño has nothing to disclose.\n\nFunding\nThis Research did not receive and specific grant form funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nThe paper is a case report, and therefore does not require ethics approval.\n\nConsent\nInformed consent has been obtained from the patient, and all identifying details have been omitted.\n\nAuthor contribution\nJosé Ramírez-Villaescusa: Study concept, acquisition and analysis of data and writing the paper.\n\nDavid Ruiz-Picazo: Acquisition and analysis of data.\n\nCristina Lamas-Oliveira: Data analysis interpretation and revision of the article.\n\nCarlos Morillas-Ariño: Data analysis interpretation and revision of the article.\n\nRegistration of research studies\nNA.\n\nGuarantor\nJosé Ramírez-Villaescusa.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nAcknowledgments\nThe authors thank Ana Ramirez-Villaescusa, Alejandro Garcia Alonso y Ana Ramirez-Martinez for they support in the translation of this paper.\n==== Refs\nReferences\n1 Lindholm J. Juul S. Jørgensen J.O.L. Astrup J. Bjerre P. Feldt-Rasmussen U. Incidence and late prognosis of Cushing’s syndrome: a population-based study J. Clin. Endocrinol. Metab. 86 1 2001 7 \n2 Valassi E. Santos A. Yaneva M. Tóth M. Strasburger C.J. Chanson P. The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics Eur. J. Endocrinol. 165 3 2011 383 392 21715416 \n3 Carroll T.B. Findling J.W. The diagnosis of Cushing’s syndrome Rev. Endocr. Metab. Disord. 11 2 2010 147 153 20821267 \n4 Kaltsas G. Makras P. Skeletal diseases in Cushing’s syndrome: osteoporosis versus arthropathy Neuroendocrinology 92 1 2010 60 64 20829620 \n5 Mancini T. Doga M. Mazziotti G. Giustina A. Cushing’s syndrome and bone Pituitary 7 4 2004 249 252 16010458 \n6 Tauchmanova L. Rossi R. Nuzzo V. del Puente A. Esposito-del Puente A. Pizzi C. Bone loss determined by quantitative ultrasonometry correlates inversely with disease activity in patients with endogenous glucocorticoid excess due to adrenal mass Eur. J. Endocrinol. 2001 241 247 11517003 \n7 Freehill A.K. Lenke L. Severe kyphosis secondary to glucocorticoid-induced osteoporosis in a young adult with Cushing’s disease. A case report and literature review Spine 24 2 1999 189 193 9926392 \n8 Vestergaard P. Lindholm J. Jorgensen J. Hagen C. Hoeck H. Laurberg P. Increased risk of osteoporotic fractures in patients with Cushing’s syndrome Eur. J. Endocrinol. 1 2002 51 56 \n9 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n10 Urbano F.L. Nikolsky’s sign in autoimmune skin disorders Hosp. Phys. 2001 23 24 \n11 González-Ramos J. Lamas C. Bellón T. Ruiz-Bravo E. Ramírez E. Lerma V. Oseltamivir-induced toxic epidermal necrolysis in a patient with Cushing’s disease Indian J. Dermatol. Venereol. Leprol. 5 86 2020 515 518 \n12 Schwab F. Blondel B. Chay E. Demakakos J. Lenke L. Tropiano P. The comprehensive anatomical spinal osteotomy classification Neurosurgery 74 1 2014 112 120 24356197 \n13 O’Brien C.A. Jia D. Plotkin L.I. Bellido T. Powers C.C. Stewart S.A. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength Endocrinology 145 4 2004 1835 1841 14691012 \n14 Canalis E. Mazziotti G. Giustina A. Bilezikian J.P. Glucocorticoid-induced osteoporosis: pathophysiology and therapy Osteoporos. Int. 18 10 2007 1319 1328 17566815 \n15 Faggiano A. Pivonello R. Filippella M. Somma C.D. Jr F.O. Lombardi G. Spine abnormalities and damage in patients cured from Cushing’s disease Pituitary 4 2001 53 161 \n16 Di Somma C. Pivonello R. Loche S. Faggiano A. Klain M. Salvatore M. Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing’s disease: a prospective study Clin. Endocrinol. 58 3 2003 302 308 \n17 Kristo C. Jemtland R. Ueland T. Godang K. Bollerslev J. Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing’s syndrome: a prospective, long-term study Eur. J. Endocrinol. 154 1 2006 109 118 16381999 \n18 Rousing R. Hansen K.L. Andersen M.O. Jespersen S.M. Thomsen K. Lauritsen J.M. Twelve-months follow-up in forty-nine patients with acute/semiacute osteoporotic vertebral fractures treated conservatively or with percutaneous vertebroplasty: a clinical randomized study Spine 35 5 2010 478 482 20190623 \n19 Chou K.-N. Lin B.-J. Wu Y.-C. Liu M.-Y. Hueng D.-Y. Progressive kyphosis after vertebroplasty in osteoporotic vertebral compression fracture Spine 39 1 2014 68 73 24108287 \n20 Tsujio T. Nakamura H. Terai H. Hoshino M. Namikawa T. Matsumura A. Characteristic radiographic or magnetic resonance images of fresh osteoporotic vertebral fractures predicting potential risk for nonunion: a prospective multicenter study Spine 36 15 2011 1229 1235 21217433 \n21 Buchowski J.M. Kuhns C.A. Bridwell K.H. Lenke L.G. Surgical management of posttraumatic thoracolumbar kyphosis Spine J. 8 4 2008 666 677 17662662 \n22 Aydogan M. Ozturk C. Karatoprak O. Tezer M. Aksu N. Hamzaoglu A. The pedicle screw fixation with vertebroplasty augmentation in the surgical treatment of the severe osteoporotic spines J. Spinal Disord. Tech. 22 6 2009 444 447 19652573\n\n",
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"keywords": "Cushing’s disease; Multiple vertebral fractures; Sagittal imbalance; Surgical treatment",
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"title": "Secondary thoracolumbar deformity and sagittal imbalance due to osteoporosis in a young man with Cushing's disease: A case report.",
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"abstract": "Extended-release medications are widely prescribed across the spectrum of medical specialties; however, there is heterogeneity in how they are formulated. Commonly, they consist of an insoluble matrix or shell from which drug elutes, which may then be observed by patients when excreted in feces. We describe the case of a patient who ingested a large amount of extended-release bupropion tablets and subsequently passed a large number of these so-called \"ghost tablets\" in his stool.\n\n\n\nA 19-year-old male presented in status epilepticus following intentional overdose of an unknown substance. He had prolonged QRS and QT intervals on ECG, hypotension requiring vasopressors, and tachycardia, and progressed to cardiac arrest and respiratory failure. On hospital day 4, he passed several large bowel movements containing apparent tablets. Serum bupropion and hydroxybupropion levels performed on serum taken at time of admission were 1800 ng/mL and 4200 ng/mL, respectively. Case Discussion: \"Ghost tablets,\" the insoluble remnant of some extended-release dosage forms, have been previously reported to appear in patients' stool in the course of therapeutic dosing. We present the case of a considerable quantity of these ghost tablets recovered from stool following a large bupropion XL overdose.\n\n\n\nHealthcare providers should be aware of the potential for this phenomenon to occur in poisoned patients. It should be documented as physical evidence of overdose in addition to clinical evidence.",
"affiliations": "a Indiana Poison Center , Indiana University Health Methodist Hospital , Indianapolis , IN , USA.;b Department of Emergency Medicine , Indiana University School of Medicine , Indianapolis , IN , USA.;a Indiana Poison Center , Indiana University Health Methodist Hospital , Indianapolis , IN , USA.",
"authors": "Overberg|Adam|A|;Purpura|Andrea|A|;Nanagas|Kristine|K|",
"chemical_list": "D003692:Delayed-Action Preparations; D013607:Tablets; D016642:Bupropion",
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"issue": "57(2)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "CNS and psychological; bupropion; dosage forms; extended release; pharmaceuticals",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D016642:Bupropion; D003692:Delayed-Action Preparations; D062787:Drug Overdose; D005243:Feces; D006801:Humans; D008297:Male; D013607:Tablets; D055815:Young Adult",
"nlm_unique_id": "101241654",
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"pages": "141-142",
"pmc": null,
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"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Ghost tablet\" husks excreted in feces in large bupropion XL overdose.",
"title_normalized": "ghost tablet husks excreted in feces in large bupropion xl overdose"
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"abstract": "Itraconazole is well known for carrying a black-box warning for new or worsening congestive heart failure. Single cases of other cardiac- and fluid-related disturbances have been reported periodically since its issuance. We describe a large cohort of patients on itraconazole experiencing a breadth of cardiac- and fluid-related toxicities, ranging from new-onset hypertension to cardiac arrest. A retrospective, single-center, large case series at a large tertiary medical center was conducted. Patients with itraconazole and cardiac toxicity-including hypertension, cardiomyopathy, reduced ejection fraction, and edema-in medical record between January 1, 1999, and May 21, 2019, were identified and assigned a Naranjo score; 31 patients were included with a Naranjo score of 5 or higher. There were slightly more male subjects than female subjects, average age was 66, and all subjects were Caucasian. Median time until presentation of adverse effects was 4 weeks (range: 0.3 to 104 weeks). Most common symptom was edema (74% of patients), followed by heart failure without and with preserved ejection fraction (19.4% and 22.6% of patients, respectively). Worsening or new hypertension was also common (25.8% of patients). Rarer were pulmonary edema, pericardial effusion, and cardiac arrest that occurred in 1 patient. In most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%), resulting in improvement or resolution of symptoms. In 4 cases, the adverse effect did not resolve. Itraconazole can cause a range of possible serious cardiac and fluid-associated adverse events. Dose decrease or cessation usually resulted in symptomatic improvement or reversal.",
"affiliations": "Department of Pharmacy, Mayo Clinic, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic, Rochester, MN.;Division of Cardiology, Mayo Clinic, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic, Rochester, MN.;Department of Pharmacy, Mayo Clinic, Rochester, MN.",
"authors": "Teaford|Hilary R|HR|;Abu Saleh|Omar M|OM|;Villarraga|Hector R|HR|;Enzler|Mark J|MJ|;Rivera|Christina G|CG|",
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"doi": "10.1016/j.mayocpiqo.2020.05.006",
"fulltext": "\n==== Front\nMayo Clin Proc Innov Qual Outcomes\nMayo Clin Proc Innov Qual Outcomes\nMayo Clinic Proceedings: Innovations, Quality & Outcomes\n2542-4548\nElsevier\n\nS2542-4548(20)30098-9\n10.1016/j.mayocpiqo.2020.05.006\nCase Report\nThe Many Faces of Itraconazole Cardiac Toxicity\nTeaford Hilary R. PharmD a\nAbu Saleh Omar M. MBBS b\nVillarraga Hector R. MD c\nEnzler Mark J. MD b\nRivera Christina G. PharmD rivera.christina@mayo.edu\n@MsSmallsO\na∗\na Department of Pharmacy, Mayo Clinic, Rochester, MN\nb Division of Infectious Diseases, Mayo Clinic, Rochester, MN\nc Division of Cardiology, Mayo Clinic, Rochester, MN\n∗ Correspondence: Address to Christina G. Rivera, PharmD, Department of Pharmacy, 200 First Street, Rochester, MN 55905. rivera.christina@mayo.edu@MsSmallsO\n15 8 2020\n10 2020\n15 8 2020\n4 5 588594\n17 3 2020\n21 4 2020\n4 5 2020\n© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.\n2020\nMayo Foundation for Medical Education and Research\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nItraconazole is well known for carrying a black-box warning for new or worsening congestive heart failure. Single cases of other cardiac- and fluid-related disturbances have been reported periodically since its issuance. We describe a large cohort of patients on itraconazole experiencing a breadth of cardiac- and fluid-related toxicities, ranging from new-onset hypertension to cardiac arrest. A retrospective, single-center, large case series at a large tertiary medical center was conducted. Patients with itraconazole and cardiac toxicity—including hypertension, cardiomyopathy, reduced ejection fraction, and edema—in medical record between January 1, 1999, and May 21, 2019, were identified and assigned a Naranjo score; 31 patients were included with a Naranjo score of 5 or higher. There were slightly more male subjects than female subjects, average age was 66, and all subjects were Caucasian. Median time until presentation of adverse effects was 4 weeks (range: 0.3 to 104 weeks). Most common symptom was edema (74% of patients), followed by heart failure without and with preserved ejection fraction (19.4% and 22.6% of patients, respectively). Worsening or new hypertension was also common (25.8% of patients). Rarer were pulmonary edema, pericardial effusion, and cardiac arrest that occurred in 1 patient. In most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%), resulting in improvement or resolution of symptoms. In 4 cases, the adverse effect did not resolve. Itraconazole can cause a range of possible serious cardiac and fluid-associated adverse events. Dose decrease or cessation usually resulted in symptomatic improvement or reversal.\n\nAbbreviations and Acronyms\n\nADR, adverse drug event\nCHF, congestive heart failure\nCV, cardiovascular\nCYP, Cytochrome-P\nEF, ejection fraction\nFDA, Food and Drug Administration\nHFpEF, heart failure with preserved ejection fraction\nHFrEF, heart failure with reduced ejection fraction\n==== Body\nItraconazole is a triazole antifungal commonly used to treat serious fungal infections. In 2001, the Food and Drug Administration (FDA) issued a black-box warning to itraconazole labeling about the risk of new or exacerbated congestive heart failure (CHF).1 The FDA warning stated that itraconazole should not be used for onychomycosis in patients with ventricular dysfunction because of negative inotrope activity seen in healthy human volunteers and dogs.2 Although not fully understood, proposed mechanisms of this effect include mitochondrial toxicity.3 Following the initial publication describing 58 cases of itraconazole-associated cardiac failure,1 related cases have periodically been reported.4, 5, 6, 7 Particularly concerning are cases of CHF in the setting of no previous cardiac risk factors.5,6 Although CHF is the most commonly described form of cardiotoxicity, reports generally consisting of 1 to 2 patients suggest the scope of toxicity spans more widely. Case reports of cardiovascular (CV) or fluid disorders attributed to itraconazole include peripheral edema,8 polyuria,9 hypertension,10, 11, 12 and cardiac arrest:13 the latter typically involving concomitant QT-prolonging medications.\n\nWe sought to describe the patients seen at our institution in the last 2 decades with widely defined CV- or fluid-related adverse effects that we determined to be probably systematically related to the use of itraconazole and describe their outcomes.\n\nMethods\n\nThis single-center retrospective, descriptive study was conducted at Mayo Clinic Rochester. Institutional review board approval was obtained. Charts of all adult patients with itraconazole orders were queried between January 1, 1999, and May 21, 2019, using the Mayo Clinic Unified Data Platform.14 Patients without research authorization in Minnesota were excluded. Clinical notes were searched for terms itraconazole and hypertension, cardiomyopathy, reduced ejection fraction, or edema. Identified patients were reviewed, and the Naranjo adverse drug event (ADE) scoring tool15 was used to rate the likelihood of an itraconazole-associated ADE by 2 clinical pharmacists reviewing cases independently. If the pharmacist was unable to determine a score clearly, an infectious diseases physician provided input. Patients with Naranjo scores ≥5 (probable or definite ADE) were included. Patients scoring <5 (possible or doubtful ADE) were excluded. Data collected included patient age, sex, race, itraconazole indication, itraconazole- dosing history, itraconazole start date per prescription record and provider documentation for internal and the latter only for external initiation, itraconazole formulation at time of CV toxicity, clinician response, CV-toxicity resolution, itraconazole/hydroxy-itraconazole level, cardiac comorbidities, and pharmacogenomics results. Predefined cardiac comorbidities included cardiac arrhythmias, established coronary artery disease, cardiomyopathy, diabetes, hypertension, or hyperlipidemia. Concomitant medications were screened for potential alternative causes and Naranjo points assigned accordingly. CV toxicity was defined as complete resolution: no further signs, symptoms, or test results indicating adverse effect; partial resolution: ≥ 1 sign, symptom, or test result indicating adverse effect and severity has improved or number of symptoms decreased since presentation; no resolution: signs, symptoms, and/or test results continue at same frequency and severity or worsen.\n\nSerum drug levels were performed in the majority of patients at steady state (1 to 3 weeks following initiation of drug or change in dose). Itraconazole and its primary active metabolite— hydroxy-itraconazole—levels were assessed on site. Drug assay was performed by liquid chromatography-tandem mass spectrometry from a single serum sample. Laboratory reference suggests goals of >0.5 μg/mL for a localized infection and >1 μg/mL for systemic infections, with no defined upper limit. Results of each individual component were available via the electronic medical record laboratory section. Itraconazole and hydroxy-itraconazole results were summed and compared with the total to the aforementioned goal values. We reported the highest sum of itraconazole and hydroxy-itraconazole during a single assay recorded for each patient within the study time frame. This result was usually the serum level at the time of occurrence of the ADE.\n\nResults\n\nOf the initial 69 patients identified with itraconazole and a cardiac- or fluid-related ADE, 31 cases that scored ≥ 5 by Naranjo scale were included. Physician input on scoring was obtained on 1 of the included cases and 3 of the excluded cases. There were slightly more men than women, with an average age of 66, and all were Caucasian. The most common cardiac comorbidities were hypertension (22%) and cardiac arrhythmia (25%), whereas only 1 patient had baseline cardiomyopathy. The most common itraconazole indication was Histoplasmosis infection (48.4%) with pulmonary source (51.6%). Disseminated fungal infections were also frequent. In only 1 case was itraconazole used for prophylaxis (Table 1). The average total serum itraconazole level was 5.2 μg/mL (range: 1.8 to 11.7 μg/mL).Table 1 Patient Characteristics\n\nCharacteristic\tTotal (N=31)\nN (%)\t\nSex, Male\t17 (54.8)\t\nAge, median (IQR), years\t66 (56, 70)\t\nRace\t\t\n Caucasian\t31 (100)\t\nCardiovascular comorbidities\t\t\n Cardiac arrhythmia\t8 (25.8)\t\n Cardiomyopathy\t1 (3.2)\t\n Coronary artery disease\t5 (16.1)\t\n Hypertension\t7 (22.6)\t\n Dyslipidemia\t3 (9.7)\t\nIndication\t\t\n Pulmonary\t16 (51.6)\t\n Disseminated\t12 (38.7)\t\n Tenosynovitis\t2 (6.5)\t\n Prophylaxis\t1 (3.2)\t\nOrganism\t\t\n Histoplasma\t15 (48.4)\t\n Aspergillus\t2 (6.5)\t\n Coccidioides\t3 (9.7)\t\n Blastomyces\t5 (16.1)\t\n Prophylaxis\t1 (3.2)\t\n Cryptococcus\t1 (3.2)\t\n Other Fungal NOS\t4 (12.9)\t\nNaranjo Score, median (range) points\t7 (5-9)\t\nIQR = interquartile range; NOS = not otherwise specified.\n\nTable 2 Summary of CV Toxicity Characteristicsa\n\nCharacteristic\tTotal (N=31)\nN (%)\t\nCV toxicity type\t\t\n CHF with reduced EF\t6 (19.4)\t\n CHF with preserved EF\t7 (22.6)\t\n Hypertension\t8 (25.8)\t\n Edema\t23 (74.2)\t\n Pericardial effusion\t1 (3.2)\t\n Other\t8 (25.8)\t\nClinician initial action\t\t\n Continue itraconazole regimen\t2 (4.5)\t\n Discontinue itraconazole\t23 (74.2)\t\n Modify itraconazole dose\t6 (19.4)\t\nOutcome\t\t\n Complete resolution\t17 (54.8)\t\n Partial resolution\t9 (29)\t\n No resolution\t4 (12.9)\t\n Unknown\t1 (3.2)\t\nClinician subsequent action taken\t\t\n Yes\t6 (19.4)\t\n No\t26 (80.6)\t\nCV = cardiovascular; CHF = congestive heart failure; EF = ejection fraction.\n\na Percentages add up to >100%, as many patients had ≥1 CV toxicity.\n\nTable 3 Descriptions of Patient Cases\n\nID\tAge\tSex\tCV comorbiditiesb\tITRA indication\tCV toxicity type\tNaranjo Score\tTime to ADE (weeks)\tITRA oral dosec\tFormulation\tITRA Loadd\tITRA + H-ITRA levele (μg/mL)\tClinician action Regarding ITRA\tResolution\t\n1\t70\tM\t3,5\tPulmonary histoplasmosis\tright heart failure, edema\t9\t6\t200 mg BID\tcapsule\tYes\t2\tDiscontinue\tpartial\t\n2\t67\tM\t\tDisseminated histoplasmosis\tHTN\t8\t2\t200 mg BID\tcapsule\tYes\t2.9\tDiscontinue\tcomplete\t\n3\t33\tM\t\tDisseminated Blastomyces\tpleural effusions, pulmonary edema, SOB\t8\t8\tUnknown\tliquid\tUnknown\t6.2\tDiscontinue\tunknown\t\n4\t65\tM\t\tPulmonary histoplasmosis\tHFpEF, edema\t8\t2\t200 mg BID\tliquid\tYes\t11.5\tModify dose\tcomplete\t\n5\t84\tM\t3\tPulmonary histoplasmosis and Blastomyces\tHTN\t8\t5\t200 mg BID\tcapsule\tYes\t4.3\tDiscontinue\tpartial\t\n6\t77\tM\t\tPulmonary histoplasmosis\tedema, pleural effusion\t8\t8\t200 mg BID\tcapsule\tUnknown\t10.1\tDiscontinue\tcomplete\t\n7\t52\tF\t5\tPulmonary Blastomyces\tHTN, edema, hypokalemia, and metabolic acidosis\t8\t7\t100 mg BID\tcapsule\tYes\t7.8\tDiscontinue\tcomplete\t\n8\t68\tF\t1\tPulmonary Aspergillus\tHFpEF, HTN, edema\t7\t8\t200 mg BID\tcapsule\tNo\t4.8\tModify dose\tpartial\t\n9\t70\tF\t\tPisseminated histoplasmosis\tHTN, edema\t7\t34\t200 mg BID\tcapsule\tNo\t5.9\tDiscontinue\tcomplete\t\n10\t65\tM\t1,2\tPisseminated Blastomyces\tHFpEF, edema, pulmonary edema\t7\t3\t200 mg BID\tcapsule\tYes\t4.8\tDiscontinue\tcomplete\t\n11\t66\tF\t1\tPulmonary (NOS)\tHFpEF, edema\t7\t1\t200 mg BID\tcapsule\tYes\t5.6\tDiscontinue\tcomplete\t\n12\t72\tF\t1,5,6\tPulmonary Aspergillus\tHFpEF, edema\t7\t3.5\t200 mg BID\tcapsule\tNo\t-\tDiscontinue\tcomplete\t\n13\t69\tM\t1,6\tPenosynovitis (NOS)\tHFrEF, edema\t7\t3\t200 mg BID\tcapsule\tNo\t4.5\tDiscontinue\tcomplete\t\n14\t66\tF\t\tPisseminated Coccidioides\tedema\t7\t1\t200 mg BID\tcapsule\tYes\t3.1\tDiscontinue\tcomplete\t\n15\t50\tM\t\tPulmonary histoplasmosis\tedema, SOB\t7\t1.5\t200 mg BID\tcapsule\tNo\t5.9\tDiscontinue\tcomplete\t\n16\t53\tF\t3,6\tDisseminated histoplasmosis\tHFrEF, edema\t7\t4\tUnknown\tunknown\tUnknown\t2.3\tDiscontinue\tno resolution\t\n17\t63\tM\t\tProphylaxis\tHFrEF, edema\t7\t69\t300 mg BID\tcapsule\tYes\t2.5\tDiscontinue\tcomplete\t\n18\t71\tF\t5\tPulmonary histoplasmosis\tHTN, edema\t7\t4\t200 mg BID\tcapsule\tNo\t5.6\tDiscontinue\tpartial\t\n19\t57\tF\t\tPulmonary histoplasmosis\tedema\t6\t3\t200 mg BID\tcapsule\tYes\t7.5\tContinue regimen\tno resolution\t\n20\t73\tM\t5\tPulmonary Crytococcus\tHFrEF\t6\t104\t200 mg BID\tcapsule\tNo\t-\tContinue regimen\tno resolution\t\n21\t50\tF\t1\tPulmonary Coccidioides\tedema\t6\t1\t200 mg BID\tcapsule\tYes\t3\tDiscontinue\tcomplete\t\n22\t55\tF\t1\tDisseminated histoplasmosis\tHTN, pericardial effusion\t6\t24\t200 mg BID\tcapsule\tYes\t4.3\tModify dose\tpartial\t\n23\t54\tM\t3\tPulmonary histoplasmosis\tedema\t6\t0.3\t200 mg BID\tcapsule\tYes\t-\tDiscontinue\tcomplete\t\n24\t69\tM\t5\tPulmonary (NOS)\tHTN\t6\tunknown\tUnknown\tunknown\tUnknown\t-\tDiscontinue\tcomplete\t\n25\t63\tM\t\tDisseminated Blastomyces\tedema, nocturia\t6\t67\t200 mg BID\tliquid\tNo\t3.5\tModify dose\tpartial\t\n26\t66\tF\t\tPulmonary histoplasmosis\tHFrEF\t6\t4\t200 mg QD\tliquid\tNo\t2.9\tDiscontinue\tpartial\t\n27\t73\tF\t3\tDisseminated histoplasmosis\tedema\t6\t104\t200 mg BID\tcapsule\tYes\t6.8\tModify dose\tno resolution\t\n28\t70\tM\t\tDisseminated Blastomyces\tHFpEF, edema\t5\t2\t200 mg BID\tcapsule\tNo\t-\tDiscontinue\tpartial\t\n29\t64\tM\t5\tDisseminated Coccidioides\tedema\t5\t2.5\t400 mg BID\tcapsule\tYes\t4.8\tModify dose\tpartial\t\n30\t60\tF\t1\tTenosynovitis histoplasmosis\tHFrEF, cardiac arrest\t5\t30\t100 mg BID\tliquid\tNo\t11.7\tDiscontinue\tcomplete\t\n31\t21\tM\t\tDisseminated histoplasmosis\tedema\t5\t3\t300 mg BID\tliquid\tYes\t1.8\tDiscontinue\tcomplete\t\nADE = adverse drug event; BID = twice daily; CV = cardiovascular; HFrEF = heart failure with reduced ejection fraction (left-ventricular ejection fraction ≤40%); H-ITRA = hydroxy-itraconazole; HTN = hypertension; ID = identification; NOS = not otherwise specified; ITRA = itraconazole; SOB = shortness of breath.\n\nb Defined risk factors include arrhythmia = 1, cardiomyopathy = 2, coronary artery disease = 3, diabetes = 4, hypertension = 5, or hyperlipidemia = 6.\n\nc Dose at time of adverse drug event.\n\nd 200 mg PO TID for at least 3 days at beginning of therapy.\n\ne Highest total (itraconazole + hydroxyitraconazole) level recorded.\n\nThe median time from itraconazole initiation until adverse effect presentation was 4 weeks (range: 0.3 to 104 weeks). The most common symptom was edema in 74% of patients, followed by heart failure with and without preserved ejection fraction (HFpEF and HFrEF, respectively) in just under a quarter of patients each. Worsening or new hypertension was present in 25.8% of patients. Rarer, but notable, were pulmonary edema and pericardial effusion; cardiac arrest occurred in 1 patient (Table 2). Most patients experienced more than 1 ADE, and, typically, these presented simultaneously.\n\nIn most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%) in response to perceived itraconazole toxicity. Complete resolution occurred in just over half the patients (54%) and partial resolution in 30%. In the cases with partial resolution, 20% of the time the clinician took an additional action in an attempt to resolve, most commonly discontinuing itraconazole after the dose had first been decreased. In 4 cases (12.9%), the identified toxicity did not resolve. Half the HFpEF cases resolved partially, and half resolved fully. For HFrEF, 2 patients had no resolution, 1 had partial resolution, and 3 had complete resolution. A summary of the 31 cases is presented in Table 3.\n\nWe describe below 3 cases of heightened interest. Patient 1 demonstrates a combination of severe, concerning cardiac toxicities occurring at a moderate serum itraconazole level. Patient 7 experienced serious cardiac toxicity in the setting of elevated itraconazole levels, possibly related to her pharmacogenomic (CYP450) genotype. Patient 25 experienced dose-dependent nocturia, an effect not previously described in the literature.\n\nPatient 1\n\nA 70-year-old man from Minnesota, with a history of coronary artery disease requiring coronary artery bypass surgery in 2010 and pulmonary sarcoidosis diagnosed in 1996, was hospitalized for acute hypoxic respiratory failure. Bronchoscopy with transbronchial biopsy showed necrotizing granuloma and fungal elements consistent with Histoplasma capsulatum. Histoplasma urinary antigen results were positive. He started itraconazole liquid 200 mg every 8 hours for 3 days, followed by 200 mg orally every 12 hours. Five weeks later, the total serum itraconazole level was 3.1 μg/mL.\n\nSix weeks later, he was hospitalized with progressive shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, bilateral lower-limb swelling, and N-terminal-pro brain natriuretic hormone of 6066 pg/mL. A transthoracic echo revealed severe right-ventricular enlargement with moderate to severe decrease in systolic function, severely dilated inferior vena cava, and mild tricuspid regurgitation. Troponins were negative, whereas electrocardiogram revealed new evidence of prolonged QT interval and multifocal atrial tachycardia.\n\nItraconazole was transitioned to voriconazole and later fluconazole for 1 year. Two years later, a repeat transthoracic echo showed improvement in the right-ventricular size but remained mildly dilated.\n\nPatient 7\n\nA 52-year-old former nurse from Minnesota with a history of hypertension presented with muscle weakness, bone pain, and diarrhea following a trip to Florida. Chest computed tomography demonstrated left lower-lobe cavitary lesion and right upper-lobe ground-glass nodule. Blastomyces urine antigen was low positive (0.35 ng/mL). Itraconazole (capsule formulation), 200 mg every 8 hours for 3 days, followed by 200 mg twice daily, was initiated for possible blastomycosis. Ten days later, the combined itraconazole/hydroxy-itraconazole serum level was 4.8 μg/mL. The itraconazole dose was decreased to 200 mg in the morning and 100 in the evening, resulting in a total itraconazole serum level of 7.8 μg/mL. The itraconazole dose was further reduced to 100 mg, twice daily.\n\nOne month later, the patient reported increased blood pressure, new-onset dyspnea, slight swelling in her hands and feet, mouth ulcers, and poor appetite. Repeat total itraconazole level was 6.5 μg/mL. The itraconazole dose was further decreased to 100 mg daily. Shortness of breath progressed to dyspnea with minimal exertion and difficulty speaking. She reported chest pain, reported to emergency care, and was found to be in respiratory acidosis and hypokalemic, with serum potassium 2.8 mmol/L without known cause. Itraconazole was stopped, and subsequently her blood-pressure control improved, but dyspnea symptoms waxed and waned. Seventeen days later, her total itraconazole serum level was 1.4 μg/mL. Several months later, pharmacogenomics testing revealed CYP3A4 genotype∗1/∗22, which is associated with reduced 3A4 function. Approximately 2 years later, she was newly diagnosed with HFpEF at an outside institution.\n\nPatient 25\n\nA 63-year-old man from Wisconsin, with a history of pulmonary sarcoidosis, hyperlipidemia, benign prostate hypertrophy, and mild idiopathic low CD4, presented with a history of recurrent blastomycosis treated with itraconazole for 2 years, dosed at 100 mg twice daily. He had a pulmonary relapse of blastomycosis and was retreated with itraconazole capsules 200 mg twice daily, which now was associated with frequent nocturia of 4 to 5 times nightly. Because of the marked nocturia, the itraconazole was decreased to 100 mg twice daily. With this dose reduction, nocturia improved to 1 to 2 times per night. Total serum itraconazole on this dose was 3.5 μg/mL. His history was unremarkable for heart failure, fluid retention, or peripheral edema. Following completion of 18 months’ treatment dosing, the itraconazole dose was decreased to 100 mg, once daily, for lifelong secondary prophylaxis, which led to a decrease in nocturia to 1 time nightly. Nocturia completely resolved with itraconazole 100 mg, 3 times weekly. The patient was switched to fluconazole for secondary prophylaxis in early 2019.\n\nDiscussion\n\nThis study is the largest of its kind to detail itraconazole-related toxicity comprehensively at a single center since the FDA warning was issued nearly 20 years ago. Although the notion of cardiac- and fluid-related toxicity associated with itraconazole is known, the variety in patient presentations and specific sequelae were significant findings. Although some patients experience classic reduced ejection fraction, others demonstrated preserved ejection fraction. A possible mechanism is itraconazole damage to myofibroblasts or mitochondrial dysfunction, as seen with anthracycline cardiotoxicity.16,17 In addition, fluid retention and hypertension, as experienced by Patient 25, may be related to mineralocorticoid excess. Thompson et al. have postulated that itraconazole inhibition of 11β-hydroxysteroid dehydrogenase 2 may lead to this effect.18 In a few cases, clinicians did not recognize itraconazole as a risk, and patients experienced ongoing negative outcomes.\n\nThe clinical implications of pharmacogenomic variability on itraconazole metabolism have not been thoroughly explored. At this time, there are no Clinical Pharmacogenetics Implementation Consortium guidelines to direct clinician response to pharmacogenomic testing results on itraconazole use and dosing, although drug metabolic pathways suggest a potential influence.19,20 Itraconazole undergoes hepatic metabolism primarily by CYP3A4, forming more than 30 metabolites, including hydroxy-itraconazole, which has antifungal activity. All metabolites are also inhibitors of CYP3A4, having higher affinity for CYP3A4 than the parent drug.20 Patient 7’s pharmacogenomics indicated reduced CYP3A4 activity, which may have played a role in increased itraconazole exposure and, ultimately, cardiac toxicity.\n\nLimitations\n\nThis study has several limitations, chiefly a lack of data on total itraconazole use during the study time frame to determine an exact rate of incidence. One-year sample revealed 316 unique patients issued itraconazole at Mayo Clinic Rochester, suggesting that these toxicities are infrequent. We did not seek to quantify specific patient risk factors or biochemical makers but see these as areas for future exploration. In addition, all the patients in this report were Caucasians, which may limit generalizability of our findings to non-Caucasian patient populations.\n\nConclusion\n\nOver a 20-year span, itraconazole was the probable cause of 31 serious cardiac and fluid disorders at our institution.\n\nGrant Support: Funding Support: The Mayo Midwest Pharmacy Research Committee provided funding for the pubication fee.\n\nPotential Competing Interests: The authors report no competing interests.\n==== Refs\nReferences\n\n1 Ahmad S. Singer S. Leissa B. Congestive heart failure associated with itraconazole Lancet 357 9270 2001 1766 1767 11403818\n2 Janssen. Sporonax (itraconazole) package insert 2001 Princeton, NJ\n3 Cleary J.D. Stover K.R. Farley J. Daley W. Kyle P.B. Hosler J. Cardiac toxicity of azole antifungals Pharmacol Pharm 04 03 2013 362 368\n4 Okuyan H. Altin C. Heart failure induced by itraconazole Indian J Pharmacol 45 5 2013 524 24130392\n5 Abraham A.O. Panda P.K. Itraconazole induced congestive heart failure, a case study Curr Drug Saf 13 1 2017 59 61\n6 Paul V. Rawal H. Cardiotoxicity with itraconazole BMJ Case Rep 2017 2017 2 3\n7 Rodrigo-Troyano A. Mediavilla M. Garin N. Guell R. Heart failure induced by itracaonazole Med Clin 148 2 2017 69 70\n8 Lestner J.M. Roberts S.A. Moore C.B. Howard S.J. Denning D.W. Hope W.W. Toxicodynamics of itraconazole: implications for therapeutic drug monitoring Clin Infect Dis 49 6 2009 928 930 19681707\n9 Chiang C.-T. Chan H.-L. Therapeutic and safety evaluation of 200 mg/day itraconazole for 7 days in the treatment of recalcitrant superficial mycoses: a preliminary report J Dermatol Treat 10 4 1999 241 244\n10 Hoffmann W.J. McHardy I. Thompson G.R. Itraconazole induced hypertension and hypokalemia: Mechanistic evaluation Mycoses 61 5 2018 337 339 29385285\n11 Fung S.-L. Chau C.-H. Yew W.-W. Cardiovascular adverse effects during itraconazole therapy Eur Respir J 32 1 2008 240 18591345\n12 Denolle T. Azizi M. Massart C. Zennaro M.C. HTA sous itraconazole: une nouvelle cause d’HTA iatrogène Ann Cardiol Angeiol (Paris) 63 3 2014 213 215 24952675\n13 Tsimogianni A.M. Andrianakis I. Betrosian A. Douzinas E. Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report J Med Case Rep 5 1 2011 333 21801420\n14 Chute C.G. Beck S.A. Fisk T.B. Mohr D.N. The Enterprise Data Trust at Mayo Clinic: a semantically integrated warehouse of biomedical data J Am Med Inform Assoc 17 2 2010 131 135 20190054\n15 Naranjo C.A. Busto U. Sellers E.M. A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 30 2 1981 239 245 7249508\n16 Bollong M.J. Yang B. Vergani N. Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis Proc Natl Acad Sci USA 114 18 2017 4679 4684 28416697\n17 Varga Z.V. Ferdinandy P. Liaudet L. Pacher P. Drug-induced mitochondrial dysfunction and cardiotoxicity Am J Physiol Heart Circ Physiol 309 9 2015 H1453 H1467 26386112\n18 Hoffman W.J. McHardy I. Thompson G.R. III Itraconazole induced hypertension and hypokalemia: mechanistic evaluation Mycoses 61 5 2018 337 339 29385285\n19 Clinical Pharmacogenetics Implementation Consortium [Internet] 2019 Stanford University & St. Jude Children’s Research Hospital Stanford [cited October 21, 2019]. Available from: https://cpicpgx.org/guidelines/\n20 Ashbee H.R. Gilleece M.H. Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics Bone Marrow Transplant 47 7 2012 881 894 21785468\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2542-4548",
"issue": "4(5)",
"journal": "Mayo Clinic proceedings. Innovations, quality & outcomes",
"keywords": "ADR, adverse drug event; CHF, congestive heart failure; CV, cardiovascular; CYP, Cytochrome-P; EF, ejection fraction; FDA, Food and Drug Administration; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction",
"medline_ta": "Mayo Clin Proc Innov Qual Outcomes",
"mesh_terms": null,
"nlm_unique_id": "101728275",
"other_id": null,
"pages": "588-594",
"pmc": null,
"pmid": "33083707",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": "7249508;21785468;21801420;26386112;29385285;19681707;27914674;11403818;24952675;24130392;28416697;20190054;18591345;28971777",
"title": "The Many Faces of Itraconazole Cardiac Toxicity.",
"title_normalized": "the many faces of itraconazole cardiac toxicity"
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"abstract": "Radiation-associated sarcomas are rare and aggressive types of sarcomas that can occur after exposure to ionizing radiation. We examine a case of radiation-associated undifferentiated/unclassified soft-tissue sarcoma with primary disease in the chest wall. The optimal treatment of these patients is surgical resection if possible; however, the role of chemotherapy has not been well defined. The patient described herein had a central tumor in the chest wall. Since many of these patients have borderline resectable tumors, the use of neoadjuvant chemotherapy may be helpful to downstage the tumors for possible surgical resection. In this case, doxorubicin plus ifosfamide chemotherapy was employed with a favorable therapeutic effect prior to being resected. To our knowledge this is the first report of greater than 90% necrosis in a patient with radiation-associated undifferentiated/unclassified soft-tissue sarcoma treated with chemotherapy for a borderline resectable mass.",
"affiliations": "Internal Medicine, LAC + USC Medical Center, Glendale, CA, USA.;Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.;Pathology, Keck Medical Center, University of Southern California, Los Angeles, CA, USA.;Diagnostic Radiology, Keck Medical Center, University of Southern California, Los Angeles, CA, USA.",
"authors": "Patel|Ronak|R|;Hu|James|J|;Chopra|Shefali|S|;Lee|Christopher|C|",
"chemical_list": null,
"country": "England",
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"doi": "10.1177/2036361318821763",
"fulltext": "\n==== Front\nRare TumorsRare TumorsRTUsprtuRare Tumors2036-36052036-3613SAGE Publications Sage UK: London, England 10.1177/203636131882176310.1177_2036361318821763Case ReportNeoadjuvant chemotherapy for radiation-associated soft-tissue sarcoma: A case report Patel Ronak 1Hu James 2Chopra Shefali 3Lee Christopher 41 Internal Medicine, LAC + USC Medical Center, Glendale, CA, USA2 Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA3 Pathology, Keck Medical Center, University of Southern California, Los Angeles, CA, USA4 Diagnostic Radiology, Keck Medical Center, University of Southern California, Los Angeles, CA, USARonak Patel, Internal Medicine, LAC + USC Medical Center, 224 W Dryden St, Apt 116, Glendale, CA 91202, USA. Email: ronakprakashpatel@gmail.com06 1 2019 2019 11 203636131882176314 6 2018 6 12 2018 © The Author(s) 20192019SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.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).Radiation-associated sarcomas are rare and aggressive types of sarcomas that can occur after exposure to ionizing radiation. We examine a case of radiation-associated undifferentiated/unclassified soft-tissue sarcoma with primary disease in the chest wall. The optimal treatment of these patients is surgical resection if possible; however, the role of chemotherapy has not been well defined. The patient described herein had a central tumor in the chest wall. Since many of these patients have borderline resectable tumors, the use of neoadjuvant chemotherapy may be helpful to downstage the tumors for possible surgical resection. In this case, doxorubicin plus ifosfamide chemotherapy was employed with a favorable therapeutic effect prior to being resected. To our knowledge this is the first report of greater than 90% necrosis in a patient with radiation-associated undifferentiated/unclassified soft-tissue sarcoma treated with chemotherapy for a borderline resectable mass.\n\nSarcomaradiation-induced sarcomaundifferentiated pleomorphic sarcomaneoadjuvant chemotherapy sarcomaradiation sarcomaradiation-associated sarcomaradiation-associatedradiation-associated soft-tissue sarcomacover-dateJanuary-December 2019\n==== Body\nIntroduction\nWith improved local, systemic, and supportive therapies, cancer patients are surviving longer. Such treated patients are at greater risk of secondary malignancies including radiation-associated malignancies. These malignancies are most prevalent in patients treated for breast, lymphoma, head and neck, and gynecologic cancers who have received prior radiation therapy (RT).1 A small proportion of these secondary malignancies will be diagnosed as sarcoma. The exact origin of radiation-associated sarcomas (RAS) is of some debate, but they are considered to be cancers of mesenchymal origin, and involve cells that can mature into smooth muscle, skeletal muscle, fibrous tissue, bone, cartilage, and blood vessels.2 RAS can present anywhere from 2 to 57 years after treatment, with a median of 13.6 years, and are characterized by a high mortality rate.3 They can also present at any site including head and neck, chest, retroperitoneum, pelvis, and extremity. In matched cohort studies, RAS has a worse outcome than primary soft-tissue sarcomas (STS) in terms of 5-year disease-specific survival (44% vs 66%). In addition, central location, achievement of incomplete surgical resection, and lessened use of RT were associated with poorer outcomes in RAS.4 Since complete surgical resection and central location are characteristic of RAS, neoadjuvant chemotherapy with the goal of stabilizing tumor growth and metastasis is an important adjunct to therapy. We report the results and outcome of a patient who presented to our institution with a borderline resectable radiation-associated undifferentiated/unclassified soft-tissue sarcoma (RA-USTS).\n\nCase description\nA 58-year-old male diagnosed with Hodgkin’s disease 30 years ago received mantle field and para-aortic radiation without chemotherapy. A computed tomography (CT) scan done in August 2015 showed no evidence of disease. In Jan 2017, he presented with left shoulder pain which did not respond to medications and physical therapy. CT showed a large left upper lobe necrotic soft tissue mass protruding through the chest wall between the first and the second ribs with underlying expansion of the left first rib and extension into the pectoral space and neck (Figure 1). The chest wall/lung mass was biopsied via core needle in June and showed spindle cells that immunohistochemically (IHC) stained negative for AE1/AE3, S100, desmin, smooth muscle actin, and CAM 5.2. It was classified as undifferentiated spindle cell sarcoma of at least intermediate grade according to FNCLCC (Figure 2). Neoadjuvant therapy consisting of AIM: adriamycin 75 mg/m2 and ifosfamide 7500 mg/m2 with mesna was started. He received two cycles of AIM in July with side effects of anemia requiring transfusion and neutropenia. CT scan in August showed minimal decrease in the size of the tumor (Figure 3). After recovery from his side effects, he was given one dose of liposomal doxorubicin 30 mg/m2 with plan for surgical resection. He tolerated the liposomal doxorubicin well and on 21 September 2017, he underwent uncomplicated left chest wall resection, left upper lobectomy, and chest wall reconstruction with prolene mesh. He was discharged in good condition without complications. The completely resected specimen showed negative margins and 95% necrosis within the remaining tumor measuring 9 × 7 × 4 cm3 (Figure 4). He reported feeling well until he was admitted on 19 October 2017 for shortness of breath and diagnosed with an ST Elevation Myocardial Infarction which required three drug-eluting stents and a pericardial window for a large effusion. He subsequently underwent cardiac arrest on 29 October 2017 and was on ECMO until he was decannulated on 1 November 2017. He then had a pacemaker placed on 2 November 2017. CT chest on 10 November 2017 showed no evidence of disease. His chest wall mesh from the surgery became infected with MDR Pseudomonas which required a mesh explantation on 13 November 2017. Despite maximum ICU care with mechanical ventilation and vasopressors, the patient passed away several months later.\n\nFigure 1. CT chest with contrast, pre-chemotherapy. (a) Superior aortic arch. (b) Carina.\n\nCT chest with contrast at the level of the superior aortic arch (a) and carina (b) prior to treatment demonstrates a large soft tissue mass (asterisk) within the left anterior hemithorax. There is invasion of the mass into the left upper lobe and the superior chest wall (arrows).\n\nFigure 2. Undifferentiated spindle cell sarcoma. HE stained section; 200×.\n\nPathology: on the pretreatment needle core biopsy the tumor was composed of spindle cells with a mitotic count of 3/10 HPF. No necrosis was seen on the limited core needle biopsy. IHC stains performed showed the tumor cells to be negative for AE1/AE3, S100, desmin, smooth muscle actin, and CAM 5.2. Given the appearance and the IHC profile, the tumor was best classified as an undifferentiated spindle cell sarcoma, at least intermediate grade based on the FNCLCC grading system.\n\nFigure 3. CT chest with contrast, post two cycles of AIM. (a) Superior aortic arch. (b) Carina.\n\nCT chest with contrast at the level of the superior aortic arch (a) and carina (b) following two cycles of AIM again demonstrates a soft tissue mass (asterisk) within the left anterior hemithorax. The mass is not significantly changed in size, but there is relative decreased enhancement reflecting treatment-related necrosis, as well as decreased invasion into the superior chest wall. There has been interval development of a small posteriorly loculated pleural effusion (arrowhead).\n\nFigure 4. Area of fibrosis with no viable sarcoma seen HE stained section; 100×.\n\nPathology: on the post treatment, resection specimen there was marked therapy effect with approximately 95% fibrosis and necrosis with very few areas of residual tumor cells.\n\nDiscussion\nIonizing radiation has been known to be associated with secondary cancers since the early 1800s with RAS first being reported early in the 20th century.5 Diagnostic criteria for RAS described by Cahan et al.6 in 1948 included: (1) the development of sarcoma within a radiation field, (2) an asymptomatic interval from the end of radiation to the development of the second malignancy, and (3) the histologic confirmation of a diagnosis of sarcoma from biopsies of the lesion. Currently, RAS account for 3%–5% of all sarcomas and the most common subtype is RA-USTS.4 Radiation risk for all sarcomas is evident at a dose above 5 Gy with a 10.7-fold increase at doses of 60 Gy or higher.7 Since RAS are most often high-grade, 5-year survival rates range from 17% to 58% for RAS compared with a much higher 54% to 76% for de novo sarcomas.4 The current case illustrates the challenges that can be encountered in treating such patients.\n\nStandard of care for RA-USTS involves surgical resection with attempt for clear margins. The benefit of chemotherapy is not clear in these patients, but since many patients have borderline resectable tumors and are at high risk for distant metastases, neoadjuvant systemic therapy may play a role in overall management. Although the response to chemotherapy for RAS is not well known, some authors argue that neoadjuvant systemic therapy for RAS should be dictated by the risk of distant metastasis, especially for sarcomas that are high grade and greater than 5 cm in size.8 Standard systemic therapy with anthracycline-based chemotherapy is often used alone or in combination for high-grade sarcomas.9 Standard dose doxorubicin plus intermediate dose ifosfamide was used in this case, but was changed to a more tolerable low-dose liposomal doxorubicin 30 mg/m2 due to symptomatic arrhythmias from underlying coronary artery disease (CAD). Although there is no demonstrated benefit for use of liposomal doxorubicin in the neoadjuvant setting for sarcoma, there is demonstrated efficacy for the advanced metastatic setting with better tolerability.10,11\n\nIn the present case, our patient was able to receive a limited number of cycles of chemotherapy prior to undergoing a complete margin negative resection. Our original plan was to give a total of 5 cycles; however our patient passed away from known CAD, which also is a well-documented risk of RT.12 His cardiac morbidity obviated any protracted use of doxorubicin, but other patients may benefit from additional cycles. This patient was found to have 95% necrosis of his tumor. The significance of a high percent necrosis has been suggested to be a good prognosticator for survival, but overall the data are still controversial.8 Of note, CT imaging did not show a significant reduction in size, but this is not unusual in STS as other changes demonstrating therapeutic effect have been described13 (Figure 3). An effective regimen with a goal of downstaging tumors with neoadjuvant treatment so that surgical resection may be possible, is a reasonable option for those who can tolerate the chemotherapy and with good functional status (ECOG < 2).\n\nThe molecular pathogenesis and development of RAS is poorly understood. Earlier studies have implicated DNA aberrations in p53 and Retinoblastoma (Rb) genes.14 Other research has suggested that radiation-associated carcinogenesis may also be related to the tumor microenviroment as bystander cells often demonstrate chromosomal instability.2 There has also been a suggestion that RAS are less responsive to chemotherapy than de novo STS. Rumenapp et al.15 looked at radiation-associated osteosarcomas and found these tumors respond poorly to chemotherapy and are associated with genome-wide loss of heterozygosity. This relative chemoresistance has also been reported by others.16 Although the response of our current patient could represent a selection bias, we believe that future patients that present with RAS should not be excluded from doxorubicin plus ifosfamide if they can tolerate it. Thus, given the heterogeneity of molecular findings in RAS patients and the dearth of literature on chemotherapy responses, further study is needed to identify patients who might respond to standard chemotherapy.\n\nConclusion\nRAS and cardiac disease are unfortunate long-term consequences for many patients who have undergone RT. This has led to treatments aimed at reducing the use of RT without loss of efficacy; such as in patients with Hodgkin’s lymphoma or breast cancer.17 There is limited data on the effectiveness of systemic treatment in RAS. Since the incidence of RAS will continue to rise, especially with improved therapies and supportive care, management guidelines will be important in managing this unique set of patients who may also suffer from the morbidity of cardiac disease. This is the first reported case to our knowledge of a greater than 90% necrosis in a patient with RA-USTS.\n\nWe would like to thank Dr Shefali Chopra and Dr Christopher Lee for their help with the pathology and radiology captions, respectively, for the manuscript.\n\nDr Ronak Patel wrote the first draft of the manuscript. Dr James Hu reviewed and edited the manuscript and approved the final version of the draft.\n\nConflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: No formal ethical committee was used; all patient identifiers withheld.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Obtained.\n\nTrial registration: Not applicable.\n==== Refs\nReferences\n1 \nBrady MS Gaynor JJ Brennan MF. \nRadiation-associated sarcoma of bone and soft tissue . Arch Surg \n1992 ; 127 (12 ): 1379 –1385 .1365680 \n2 \nThiagarajan A Iyer N. \nRadiation-induced sarcomas of the head and neck . World J Clin Oncol \n2014 ; 5 (5 ): 973 –981 .25493233 \n3 \nBjerkehagen B Smeland S Walberg L et al \nRadiation-induced sarcoma: 25-year experience from the Norwegian Radium Hospital . Acta Oncol \n2008 ; 47 (8 ): 1475 –1482 .18607853 \n4 \nBjerkehagen B Småstuen MC Hall KS et al \nWhy do patients with radiation-induced sarcomas have a poor sarcoma-related survival? \nBr J Cancer \n2012 ; 106 (2 ): 297 –306 .22173669 \n5 \nGonzalez AB Kutsenko A Rajaraman P. \nSarcoma risk after radiation exposure . Clin Sarcoma Res \n2012 ; 2 (1 ): 18 .23036235 \n6 \nCahan WG Woodard HQ Higinbotham NL et al \nSarcoma arising in irradiated bone: report of eleven cases. 1948 . Cancer \n1998 ; 82 (1 ): 8 –34 .9428476 \n7 \nWong F Boice J JrAbramson D et al \nCancer incidence after retinoblastoma. Radiation dose and sarcoma risk . Am J Ophthalmol \n1998 ; 125 (2 ): 1262 –1267 .\n8 \nPatel SR. \nRadiation-induced sarcoma . Curr Treat Opt Oncol \n2000 ; 1 (3 ): 258 –261 .\n9 \nRawat S. \nRadiation induced sarcomas in head and neck , https://www.slideshare.net/shehrawat/radiation-induced-sarcomas-in-head-and-neck (accessed 17 September 2011 ).\n10 \nO’Shaughnessy JA. \nPegylated liposomal doxorubicin in the treatment of breast cancer . Clin Breast Cancer \n2003 ; 4 (5 ): 318 –328 .14715106 \n11 \nXing M Yan F Yu S et al \nEfficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy in advanced breast cancer: a meta-analysis of ten randomized controlled trials . PLoS ONE \n2015 ; 10 (7 ): e0133569 .26204517 \n12 \nBorges N Kapadia SR. \nRadiation-induced CAD: incidence, diagnosis, and management outcomes , https://www.acc.org/latest-in-cardiology/articles/2018/05/24/01/44/radiation-induced-cad (accessed 21 September 2018 ).\n13 \nLucasa DR Kshirsagara MP Biermannb JS et al \nHistologic alterations from neoadjuvant chemotherapy in high-grade extremity soft tissue sarcoma: clinicopathological correlation , http://theoncologist.alphamedpress.org/content/13/4/451.full.html (accessed 1 April 2008 ).\n14 \nBrachman DG Hallahan DE Beckett MA et al \nP53 gene mutations and abnormal retinoblastoma protein in radiation-induced human sarcomas . J Cancer Res \n1991 ; 51 (23 ): 6393 –6396 .\n15 \nRumenapp C Smida J Gonzalez-Vasconcellos I et al \nSecondary radiation-induced bone tumours demonstrate a high degree of genomic instability predictive of a poor prognosis . Curr Genom \n2012 ; 13 (6 ): 433 –437 .\n16 \nDineen SP Roland CL Feig R et al \nRadiation-associated undifferentiated pleomorphic sarcoma is associated with worse clinical outcomes than sporadic lesions . Ann Surg Oncol \n2015 ; 22 (12 ): 3913 –3920 .25743327 \n17 \nNational Comprehensive Cancer Network . Breast cancer (version 1.2018), https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (accessed 21 September 2018 ).\n\n",
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"journal": "Rare tumors",
"keywords": "Sarcoma; neoadjuvant chemotherapy sarcoma; radiation sarcoma; radiation-associated; radiation-associated sarcoma; radiation-associated soft-tissue sarcoma; radiation-induced sarcoma; undifferentiated pleomorphic sarcoma",
"medline_ta": "Rare Tumors",
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"pages": "2036361318821763",
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"pubdate": "2019",
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"title": "Neoadjuvant chemotherapy for radiation-associated soft-tissue sarcoma: A case report.",
"title_normalized": "neoadjuvant chemotherapy for radiation associated soft tissue sarcoma a case report"
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"abstract": "Immune checkpoint blockade has emerged as a highly effective treatment for patients with metastatic melanoma and cutaneous squamous cell carcinoma. Nivolumab blocks the interactions between programmed cell death protein 1 and programmed death ligand 1 allowing for activation of a latent immune response against the malignancy. Ipilimumab binds to and blocks cytotoxic T-lymphocyte-associated protein 4, alleviating the negative regulation of T-cell activation that is mediated by that checkpoint. Combination therapy with nivolumab and ipilimumab is associated with longer overall survival at 5 years compared with nivolumab monotherapy. Solid organ transplant recipients have a significantly higher risk of malignancies compared with the general population. There is limited data surrounding the efficacy of combination immunotherapy in solid organ transplant recipients, as these patients were excluded from seminal trials due to risk of organ rejection.\n\n\n\nHere we present four cases of combination immunotherapy in kidney transplant recipients. Three patients had metastatic melanoma, and one patient had metastatic cutaneous squamous cell carcinoma. Two patients had radiographic responses from immunotherapy, one patient had stable disease, and one patient had disease progression. Only one patient had biopsy-proven rejection. At last follow-up, three patients had functioning grafts, though one required hemodialysis after treatment, and one patient succumbed to disease, but graft function remained intact throughout her course.\n\n\n\nThese cases describe the use of ipilimumab and nivolumab combination immunotherapy for cutaneous malignancies in kidney transplant recipients. They highlight the potential to preserve kidney graft function while effectively treating the disease.\n\n\n\nNCT03816332.",
"affiliations": "Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA.;Department of Pathology and Cell Biology, Division of Renal Pathology, Columbia University Irving Medical Center, New York, New York, USA.;Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA.;Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, New York, USA.;Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, New York, USA.;Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA.;Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA.;Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, New York, USA.;Ocean Renal Associates, Brick, New Jersey, USA.;Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, New York, USA.;Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, New York, USA rdc2150@cumc.columbia.edu.",
"authors": "Trager|Megan H|MH|0000-0002-7330-1627;Coley|Shana M|SM|0000-0002-2152-5469;Dube|Geoffrey|G|;Khan|Shaheer|S|;Ingham|Matthew|M|;Samie|Faramarz H|FH|;Geskin|Larisa J|LJ|;McDonnell|Diana|D|;Brouder|Daniel|D|;Saenger|Yvonne|Y|;Carvajal|Richard|R|",
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"doi": "10.1136/jitc-2020-000908",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32503950\njitc-2020-000908\n10.1136/jitc-2020-000908\nCase Report\n1506\n2518 1619\nCombination checkpoint blockade for metastatic cutaneous malignancies in kidney transplant recipients\nhttp://orcid.org/0000-0002-7330-1627Trager Megan H 1 http://orcid.org/0000-0002-2152-5469Coley Shana M 2 Dube Geoffrey 3 Khan Shaheer 4 Ingham Matthew 4 Samie Faramarz H 1 Geskin Larisa J 1 McDonnell Diana 4 Brouder Daniel 5 Saenger Yvonne 4 Carvajal Richard 4 1 Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA\n2 Department of Pathology and Cell Biology, Division of Renal Pathology, Columbia University Irving Medical Center, New York, New York, USA\n3 Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA\n4 Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, New York, USA\n5 Ocean Renal Associates, Brick, New Jersey, USA\nCorrespondence to Dr Richard Carvajal; rdc2150@cumc.columbia.edu\n2020 \n4 6 2020 \n8 1 e00090805 5 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2021http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background\nImmune checkpoint blockade has emerged as a highly effective treatment for patients with metastatic melanoma and cutaneous squamous cell carcinoma. Nivolumab blocks the interactions between programmed cell death protein 1 and programmed death ligand 1 allowing for activation of a latent immune response against the malignancy. Ipilimumab binds to and blocks cytotoxic T-lymphocyte-associated protein 4, alleviating the negative regulation of T-cell activation that is mediated by that checkpoint. Combination therapy with nivolumab and ipilimumab is associated with longer overall survival at 5 years compared with nivolumab monotherapy. Solid organ transplant recipients have a significantly higher risk of malignancies compared with the general population. There is limited data surrounding the efficacy of combination immunotherapy in solid organ transplant recipients, as these patients were excluded from seminal trials due to risk of organ rejection.\n\nCase presentations\nHere we present four cases of combination immunotherapy in kidney transplant recipients. Three patients had metastatic melanoma, and one patient had metastatic cutaneous squamous cell carcinoma. Two patients had radiographic responses from immunotherapy, one patient had stable disease, and one patient had disease progression. Only one patient had biopsy-proven rejection. At last follow-up, three patients had functioning grafts, though one required hemodialysis after treatment, and one patient succumbed to disease, but graft function remained intact throughout her course.\n\nConclusions\nThese cases describe the use of ipilimumab and nivolumab combination immunotherapy for cutaneous malignancies in kidney transplant recipients. They highlight the potential to preserve kidney graft function while effectively treating the disease.\n\ntransplantation immunologyimmunotherapymelanomaspecial-featureunlocked\n==== Body\nBackground\nImmune checkpoint blockade has emerged as a standard treatment for melanoma,1–5 cutaneous squamous cell carcinoma (cSCC),6 and others.7 Ipilimumab binds cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), preventing normal ligand binding, thereby alleviating negative regulation of T-cell activation. Nivolumab, pembrolizumab, and cemiplimab interfere with a separate T-cell negative regulation pathway, by blocking the interactions between programmed cell death protein 1 (PD-1) on exhausted effector T cells and its ligands, PD-L1 and PD-L2.7 Blockade of CTLA-4 or PD-1/PD-L1 allows for activation of a latent immune response to cancer antigens, especially in highly immunogenic malignancies such as melanoma and cSCC. CheckMate 067 found greater 5-year survival in patients who received combination ipilimumab and nivolumab or nivolumab alone compared with ipilimumab alone (52%, 44%, and 22%, respectively).8 9 Currently, dual therapy is utilized in aggressive cases, although this has not been proven to improve survival. Higher power studies with longer follow-up may show a significant survival difference between combination ipilimumab and nivolumab versus nivolumab monotherapy.\n\nSolid organ transplant recipients (SOTR) have increased rates of cancer, which is the second leading cause of death in this population.10 11 This is attributed to long-term use of antirejection immunosuppressants causing impaired immune surveillance. SOTRs have a significantly higher incidence of cSCC12 (65-fold to 250-fold increased risk) and malignant melanoma13 (two-fold to eight-fold increased risk). Immunosuppressed patients are particularly vulnerable to developing highly aggressive cSCC. In kidney SOTRs, cSCC accounts for over 70% of all new malignancies, affecting over 50% of kidney transplant patients. Post-transplant cSCC occurs earlier and is more aggressive than in non-transplant cohorts, with 30% of cSCC recurring within 1 year and up to 8% of disease associated with metastasis.14–16 Median survival after diagnosis of metastasis is 3 years.16 17\n\nWhile multiple case reports and series of single agent checkpoint blockade in SOTRs exist,18 few cases treated with concurrent ipilimumab and anti-PD1 therapy have been reported.19–21 This patient exhibited partial response; however, graft rejection developed 21 days after treatment initiation.21 Here, we present four cases of metastatic cutaneous malignancy in the setting of kidney transplant treated with combination ipilimumab and nivolumab immunotherapy.\n\nCase 1\nA 67-year-old Caucasian man with a history of membranous nephropathy diagnosed in 1997, status post two living donor kidney transplants, developed metastatic melanoma following over 10 years of immunosuppression (online supplementary table 1). The first kidney transplant (2008–2016) was pre-emptive from a living unrelated donor, with T-cell depletional induction (thymoglobulin) and maintenance immunosuppression with tacrolimus (2 mg twice daily), mycophenolic acid (360 mg twice daily), and prednisone (5 mg four times a day). His first transplant course was complicated by invasive melanoma of the left scapular region in July 2015 (pT2a, N0), graft rejection treated with pulse steroids and intravenous immunoglobulin (IVIG), multiple invasive cutaneous SCCs and melanoma of the upper back in June 2016. The first graft failed due to chronic antibody-mediated rejection in October 2016. He underwent repeat kidney transplantation in November 2016 from his daughter, with non-depletional induction (basiliximab), and in July 2019 was diagnosed with metastatic melanoma following left axillary lymph node biopsy. Computed tomography (CT) and magnetic resonance imaging (MRI) showed liver, lung, and possible brain metastases (figure 1A). He was transitioned from tacrolimus to sirolimus (2 mg four times a day), and the sirolimus was ultimately discontinued in August 2019. Following comprehensive discussion of risk and benefits, the patient initiated standard dosing ipilimumab 3 mg/kg and nivolumab 1 mg/kg later that month given rapid progression and possible brain metastases, receiving two doses total. He subsequently developed septic shock and multiple organ failure, requiring initiation of hemodialysis. Restaging scans showed decreased size of melanoma in the liver, lungs, and spleen (figure 1B). Retrospective review of the images performed before and after combined checkpoint blockade with tumor measurements revealed a 40% response by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 criteria,22 consistent with a partial response to therapy. Mycophenolic acid was discontinued in 2017. Given the critical illness, he was transitioned to nivolumab monotherapy, initially 240 mg every 2 weeks and transitioned later to 480 mg every 4 weeks. Of note, the patient’s kidney function improved with supportive care, and he was taken off dialysis after approximately 1 month. Serum creatinine prior to initiation of immunotherapy was 0.79 mg/dL and has trended to 2.41 mg/dL as of December 2019 (figure 2). He remains on nivolumab with ongoing radiographic response over 6 months after initiating immunotherapy.\n\n10.1136/jitc-2020-000908.supp1Supplementary data \n\n Figure 1 Radiographic improvement in disease. (A) Case 1: baseline chest CT in July 2019 at initiation of ipilimumab and nivolumab showing lung metastases; left axillary lesion (red arrow) was further examined with ultrasound and found to be a benign seroma or hematoma post left axillary biopsy. (B) CT in October 2019 after two doses of ipilimumab and nivolumab showing improvement in the lung metastases. (C) Case 3: baseline CT in August 2019 (at initiation of ipilimumab and nivolumab). (D) Case 3: October 2019 (after three treatments with ipilimumab and nivolumab). (E) Case 3: February 2019 (4 months after last dose ipilimumab). The CT scan shows significant reduction in lung metastases at the end of treatment with continual improvement 4 months after completing treatment with immunotherapy. Arrows track the metastases in each of the scans.\n\nFigure 2 eGFR values over time after treatment with immunotherapy. Y label max is 60, indicates eGFR >60. (A) Case 1: metastatic melanoma diagnosed in July 2019. (B) Case 2: primary melanoma diagnosed in February 2018. (C) Case 3: metastatic cutaneous squamous cell carcinoma diagnosed in January 2019. (D) Case 4. primary melanoma diagnosed in December 2017. metastatic melanoma diagnosed in August 2019.\n\nCase 2\nA Caucasian woman in her early 40s underwent pre-emptive living unrelated kidney transplantation (four antigen mismatch) in 2017 due to primary focal segmental glomerulosclerosis (FSGS), for which she had been treated with immunosuppressive regimens including cyclophosphamide (2004), steroids, tacrolimus, cyclosporine A, mycophenolic acid, rituximab, and IVIG, with biweekly plasmapheresis from 2014. T-cell depletional induction therapy was with thymoglobulin. Maintenance immunosuppression included tacrolimus (1 mg four times a day), mycophenolic acid (360 mg four times a day), and prednisone (5 mg four times a day). Post-transplant, she received plasmapheresis and IVIG for biopsy-proven recurrent FSGS, though she never experienced biopsy-proven rejection. In February 2018, two synchronous primary non-ulcerated melanomas were diagnosed on her back (0.8 mm, 1.5 mm). She underwent wide local excision with 0.5 mm residual disease, no ulceration, and one mitosis/mm2. Sentinel lymph node biopsy was negative. Due to close surgical margins, she completed adjuvant radiation therapy to the left back and shoulder. She discontinued treatment with mycophenolic acid around this time.\n\nIn December 2018, MRI showed a gluteal lesion, and biopsy in January 2019 confirmed recurrent melanoma (BRAF wildtype, NRAS mutant). Staging studies revealed two areas of distant soft tissue melanoma recurrence on the back and buttocks, from different lymphatic beds. Following discussion between the patient’s oncologist and transplant physician, tacrolimus and plasmapheresis were discontinued in January 2019, resulting in single-agent maintenance immunosuppression with prednisone (5 mg four times a day). Given that surgery was felt unlikely to be curative, the patient received a single treatment with pembrolizumab 200 mg IV in February 2019. A rash developed 1 week following treatment initiation, and at 1 month, reported increased growth in the nodules on the back and buttocks. CT imaging confirmed disease progression. She experienced worsening proteinuria and refractory edema related to recurrent FSGS and began dialysis. Because of rapid disease progression following a single dose of pembrolizumab, she was switched to treatment with the oncolytic virus vaccine, talimogene laherparepvec, and combination ipilimumab 3 mg/kg and nivolumab 1 mg/kg in March 2019. Following one course of combination therapy, she was admitted for seizures and altered mental status and found to have new spine, lung, and brain metastases. She received stereotactic radiosurgery for the brain metastasis. She received single agent chemotherapy with paclitaxel in April 2019 and combination paclitaxel/carboplatin in May 2019. The patient was subsequently admitted to the hospital with shortness of breath and found to have a large malignant pleural effusion. Subsequent scans showed further disease progression, and, given the patient’s strong desire to continue on immunotherapy for melanoma, she was restarted on pembrolizumab 200 mg IV q3 weeks in May 2019. Review of the images performed before and after combined checkpoint blockade by RECIST V.1.1 criteria revealed 28% progression in target lesions as well as the development of multiple new metastases following therapy, consistent with progression of disease. She ultimately passed away in June 2019.\n\nCase 3\nA 58-year-old Caucasian man with a history of IgA nephropathy underwent kidney transplantation from deceased donors in 1996 and 2006. Maintenance regimen for the second kidney allograft consisted of tacrolimus (0.5 mg four times a day), sirolimus (1 mg every other day), and mycophenolate mofetil (500 mg twice daily). His post-transplant course was complicated by multiple melanoma and non-melanoma skin cancers, ultimately developing metastatic cSCC in late 2018. Positron emission tomography-computed tomography (PET-CT) in December 2018 revealed bilateral fludeoxyglucose (FDG)-avid neck nodes, a large skin lesion at the base of the left posterior neck, and a hypermetabolic right lower lung nodule suspicious for metastatic disease. He was treated with carboplatin plus cetuximab in January 2019, complicated by severe nausea and vomiting requiring hospitalization. Transition to single agent cetuximab caused significant fatigue, so single agent carboplatin was trialed in early March 2019. Palliative radiation therapy was administered to the shoulder. Staging scans showed stable disease after the two cycles of carboplatin-based therapy. After discussion with his transplant nephrologist, he began cemiplimab 350 mg IV every 3 weeks. He was continued on sirolimus (1 mg three times weekly) with monitoring by his transplant nephrologist. He underwent five cycles of treatment with cemiplimab which he tolerated well. However, restaging scans showed disease progression, with growth of the dominant right middle lobe mass as well as many newer, smaller pulmonary nodules. Further options were discussed, and a plan was made to start combination immunotherapy with ipilimumab 3 mg/kg and nivolumab 1 mg/kg in late July 2019. He took prednisone (5 mg four times a day) as prescribed by his transplant nephrologist to prevent graft failure.23 After three cycles of ipilimumab and nivolumab between July and September 2019, there was radiographic improvement and no evidence of toxicity (figure 1C–E). Review of the images at baseline and after combined checkpoint blockade demonstrated a 40% response by RECIST V.1.1 criteria consistent with a partial response. However, he was hospitalized for adverse effects including rash from September to October. The rash improved with systemic steroids. He has since been on observation with no further active therapy, with continued radiographic response 9 months following initiation of combination checkpoint blockade and with preserved kidney function.\n\nCase 4\nA Caucasian man in his late 50s with a history of end-stage kidney disease secondary to hypertension underwent his third kidney transplant from a living unrelated donor in November 2015. Induction regimen included thymoglobulin, and initial maintenance immunosuppression was with prednisone, tacrolimus, and mycophenolic acid. Due to development of multiple cSCCs, tacrolimus was switched to sirolimus in March 2016, and maintenance immusuppression included prednisone (5 mg four times a day), mycophenolic acid (360 mg twice daily), and sirolimus (2 mg alternating with 1 mg daily). In 2017, he was diagnosed with primary melanoma and underwent resection but developed metastatic disease of the cervical lymph nodes and liver in August 2019. Mycophenolic acid was discontinued in September 2019, and he continued prednisone (5 mg four times a day) and sirolimus (1 mg four times a day). He started combination immunotherapy (nivolumab and ipilimumab) in October 2019. Serum creatinine rose from a baseline of 1.1–1.3 to 1.84 mg/dL in mid-November 2019 at which time a kidney allograft biopsy was performed. Biopsy showed moderate interstitial inflammation and severe lymphocytic tubulitis with diffuse C4d positivity, consistent with mixed acute T-cell mediated and antibody-mediated rejection (figure 3). He was treated with 500 mg IV solumedrol daily for 3 days. No clinical evidence of progression at 2-month follow-up after initiation of combination checkpoint blockade; however, no postcheckpoint blockade imaging has been performed. His graft function has improved following treatment for immunotherapy-associated rejection, with serum creatinine decreasing from 1.84 mg/dL at the time of biopsy in November 2019 to 1.32 mg/dL in February 2020.\n\nFigure 3 Kidney allograft biopsy in case 4, after treatment with combination immunotherapy and decreased immunosuppression, showing moderate interstitial inflammation, severe lymphocytic tubulitis, peritubular capillaritis and diffuse C4d positivity, consistent with mixed acute T-cell mediated and antibody-mediated rejection. (A) Periodic acid Schiff stain. (B and C) Jones methenamine silver stain. (D) C4d indirect immunofluorescence stain.\n\nDiscussion and conclusions\nCheckpoint inhibitor use in SOTRs has been challenging due to risks of graft rejection following the release of inhibitory T-cell signals.24 The efficacy and toxicity of these agents is less well studied in this cohort, as the seminal trials leading to the approval of checkpoint inhibitors excluded SOTRs.25 Prospective studies evaluating the safety and efficacy of immune checkpoint blockade in SOTRs with cancer are ongoing, and a clinical trial was launched evaluating the use of tacrolimus, ipilimumab and nivolumab in kidney transplant recipients with malignancy that might benefit from immune checkpoint blockade. The published experience is currently limited to case series and retrospective cohort studies.7 18 21\n\nThree systematic reviews have examined the use of immunotherapies for malignancy in SOTRs.7 20 21 One review included 39 patients with kidney, hepatic, or cardiac allografts. The majority of patients had metastatic melanoma (62%); 16/39 patients (41%) had allograft rejection after initiation of checkpoint inhibitor therapy (48% kidney, 36% hepatic, 20% cardiac) with no difference between those receiving anti-PD1 monotherapy, anti-CTLA-4 monotherapy, or combination treatment. The median time to organ rejection was 21 days after treatment initiation.26 Another systematic review of 57 SOTRs treated with ipilimumab, nivolumab, or pembrolizumab found that 37% of patients experienced organ rejection and 14% died due to graft failure.7 This study included 32 kidney, 20 liver, and five heart allograft recipients with rejection rates of 13%, 7%, and 1%, respectively. The authors concluded that physicians should exercise caution when treating this population with checkpoint inhibitors. However, the most common cause of death was malignancy (64%) rather than graft rejection. In both reviews, the majority of patients received single agent immunotherapy with only one patient receiving combination therapy. More recently, a larger systematic review reported 83 SOTRs treated with immunotherapy (two-thirds anti-PD1/PDL1, 15.7% anti-CTLA-4, and 10.8% combination therapy either sequentially or simultaneously).20 This included 53 kidney, 24 liver, and six heart transplants with similar rejection rates across organs and checkpoint inhibitors. Time since transplantation of at least 8 years was associated with lower risk of graft rejection, and history of prior allograft rejection was associated with higher risk. Patients on no other immunosuppression besides corticosteroids at initiation of checkpoint inhibitor therapy had a higher risk of rejection. At the end of the study, 19.3% of patients were alive without cancer progression or allograft rejection. Kidney transplant populations were the only group where there was similar mortality in patients with and without rejection. This shows that checkpoint inhibitor therapy may be a better option in these patients where hemodialysis is a life-saving alternative in case of rejection.\n\nWe present four cases of metastatic cutaneous malignancies in kidney transplant recipients treated with combination immunotherapy. One patient passed away from progressive malignant disease. Two of the four patients have shown durable radiographic improvement in disease after treatment. The fourth showed rejection on kidney allograft biopsy following immunotherapy and reduction in immunosuppression, with stabilized kidney function after high dose steroid treatment and no clinical evidence of disease progression although radiographic follow-up was not performed.\n\nA recent paper found that combination immune checkpoint inhibitor therapy was associated with increased risk of immune-mediated acute kidney injury.27 In case 1, transient hemodialysis was required for septic shock and multiple organ failure, though it was unclear whether or not these events were related to the immunotherapy, and the patient has shown improved kidney function on single-agent nivolumab therapy. Though hemodialysis was initiated in case 2, it bears repeating that this was due to recurrent FSGS-related graft dysfunction which developed prior to treatment with ipilimumab and nivolumab and not due to graft rejection. The third patient has shown preserved kidney allograft function and remains on immunotherapy. This further supports the use of immunotherapy in patients with kidney transplantation versus other SOTRs, as graft loss can be medically managed, while heart or lung transplantation would be much more difficult to address.7 Though each patient presented here was advised that graft loss was a highly probable outcome under immunotherapy, they elected to undergo treatment, as metastatic disease was of primary concern, and hemodialysis was an acceptable outcome.\n\nImmunosuppressive regimens for prevention of kidney allograft rejection were comanaged with a kidney transplant physician in all cases. Previous studies have shown that frequency of allograft rejection varies based on the maintenance immunosuppressive regimen at the time of checkpoint inhibitor initiation.21 The systematic review from MD Anderson found that patients maintained on prednisone alone have higher risk of rejection (78%) versus those continuing calcineurin inhibitor therapy (11%), suggesting that aggressive reduction of maintenance immunosuppression increases rejection risk with checkpoint blockade.21 However, future studies are needed to determine the optimal immunosuppressive regimen to achieve a protective effect on graft function in the setting of blockade. Of our patients, one was initially treated with tacrolimus, then switched to sirolimus which was discontinued prior to checkpoint inhibitor therapy, leaving prednisone monotherapy for prevention of allograft rejection. The second patient was also treated with prednisone monotherapy for antirejection during immunotherapy, and the third and fourth patients continued treatment with sirolimus and prednisone during immune checkpoint blockade.\n\nThese cases add to the current literature describing ipilimumab and nivolumab combination immunotherapy for cutaneous malignancies in kidney transplant recipients. They highlight the possibility to preserve kidney graft function while improving outcomes from malignancy with combination immunotherapy.\n\nCorrection notice: This article has been corrected since it was published Online First to remove the incorrect trial registration number from abstract that was inserted by error.\n\nContributors: All authors contributed to this manuscript. MHT wrote the manuscript and prepared tables and figures. SMC helped with conception and interpretation of the work. She edited the manuscript. GD, SK, and LJG helped with editing and conceptualization of the manuscript. DMcD helped with editing of the manuscript and obtaining clinical images for figures. YS contributed to conceptualization and design of the manuscript as well as editing. RC conceptualized the project, helped with writing of the initial manuscript, making figures and tables, and editing the final draft.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.\n\nCompeting interests: RC is a consultant for Astra Zeneca, BMS, Castle Biosciences, Foundation Medicine, Immunocore, Incyte, Merck, Novartis, Roche, Compugen, I-Mab, PureTech Health, Sanofi Genzyme, and Sorrento Therapeutics. He is on advisory boards for Aura Biosciences, Chimeron, and Rgenix.\n\nPatient consent for publication: Not required.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: The authors confirm that the data supporting the findings of this study are available in the manuscript and supplementary table.\n==== Refs\nReferences\n1 Eggermont AMM , Chiarion-Sileni V , Grob J-J , et al \nProlonged survival in stage III melanoma with ipilimumab adjuvant therapy\n. N Engl J Med \n2016 ;375 :1845 –55\n. 10.1056/NEJMoa1611299 27717298 \n2 Larkin J , Chiarion-Sileni V , Gonzalez R , et al \nCombined nivolumab and ipilimumab or monotherapy in untreated melanoma\n. N Engl J Med \n2015 ;373 :23 –34\n. 10.1056/NEJMoa1504030 26027431 \n3 Weber J , Mandala M , Del Vecchio M , et al \nAdjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma\n. N Engl J Med \n2017 ;377 :1824 –35\n. 10.1056/NEJMoa1709030 28891423 \n4 Larkin J , Hodi FS , Wolchok JD \nCombined nivolumab and ipilimumab or monotherapy in untreated melanoma\n. N Engl J Med \n2015 ;373 :23 –34\n. 10.1056/NEJMoa1504030 26027431 \n5 Eggermont AMM , Blank CU , Mandala M , et al \nAdjuvant pembrolizumab versus placebo in resected stage III melanoma\n. N Engl J Med \n2018 ;378 :1789 –801\n. 10.1056/NEJMoa1802357 29658430 \n6 Migden MR , Rischin D , Schmults CD , et al \nPd-1 blockade with Cemiplimab in advanced cutaneous squamous-cell carcinoma\n. N Engl J Med \n2018 ;379 :341 –51\n. 10.1056/NEJMoa1805131 29863979 \n7 Fisher J , Zeitouni N , Fan W , et al \nImmune checkpoint inhibitor therapy in solid organ transplant recipients: a patient-centered systematic review\n. J Am Acad Dermatol \n2019 :S0190-9622(19)32317-5. 10.1016/j.jaad.2019.07.005 \n8 Wolchok JD , Chiarion-Sileni V , Gonzalez R , et al \nOverall survival with combined nivolumab and ipilimumab in advanced melanoma\n. N Engl J Med \n2017 ;377 :1345 –56\n. 10.1056/NEJMoa1709684 28889792 \n9 Larkin J , Chiarion-Sileni V , Gonzalez R , et al \nFive-Year survival with combined nivolumab and ipilimumab in advanced melanoma\n. N Engl J Med \n2019 ;381 :1535 –46\n. 10.1056/NEJMoa1910836 31562797 \n10 Engels EA , Pfeiffer RM , Fraumeni JF , et al \nSpectrum of cancer risk among US solid organ transplant recipients\n. JAMA \n2011 ;306 :1891 –901\n. 10.1001/jama.2011.1592 22045767 \n11 Acuna SA , Fernandes KA , Daly C , et al \nCancer mortality among recipients of solid-organ transplantation in Ontario, Canada\n. JAMA Oncol \n2016 ;2 :463 –9\n. 10.1001/jamaoncol.2015.5137 26746479 \n12 Krynitz B , Olsson H , Lundh Rozell B , et al \nRisk of basal cell carcinoma in Swedish organ transplant recipients: a population-based study\n. Br J Dermatol \n2016 ;174 :95 –103\n. 10.1111/bjd.14153 26333521 \n13 Fattouh K , Ducroux E , Decullier E , et al \nIncreasing incidence of melanoma after solid organ transplantation: a retrospective epidemiological study\n. Transpl Int \n2017 ;30 :1172 –80\n. 10.1111/tri.13011 28700114 \n14 Harwood CA , Mesher D , McGregor JM , et al \nA surveillance model for skin cancer in organ transplant recipients: a 22-year prospective study in an ethnically diverse population\n. Am J Transplant \n2013 ;13 :119 –29\n. 10.1111/j.1600-6143.2012.04292.x \n15 Buell JF , Hanaway MJ , Thomas M , et al \nSkin cancer following transplantation: the Israel Penn international transplant tumor registry experience\n. Transplant Proc \n2005 ;37 :962 –3\n. 10.1016/j.transproceed.2004.12.062 15848591 \n16 Wisgerhof HC , van der Geest LGM , de Fijter JW , et al \nIncidence of cancer in kidney-transplant recipients: a long-term cohort study in a single center\n. Cancer Epidemiol \n2011 ;35 :105 –11\n. 10.1016/j.canep.2010.07.002 20674538 \n17 Martinez J-C , Otley CC , Stasko T , et al \nDefining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study\n. Arch Dermatol \n2003 ;139 :301 –6\n. 10.1001/archderm.139.3.301 12622621 \n18 Chae YK , Galvez C , Anker JF , et al \nCancer immunotherapy in a neglected population: the current use and future of T-cell-mediated checkpoint inhibitors in organ transplant patients\n. Cancer Treat Rev \n2018 ;63 :116 –21\n. 10.1016/j.ctrv.2017.12.004 29276997 \n19 Miller DM , Faulkner-Jones BE , Stone JR , et al \nComplete pathologic response of metastatic cutaneous squamous cell carcinoma and allograft rejection after treatment with combination immune checkpoint blockade\n. JAAD Case Rep \n2017 ;3 :412 –5\n. 10.1016/j.jdcr.2017.06.005 28932782 \n20 d'Izarny-Gargas T , Durrbach A , Zaidan M \nEfficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: a systematic review\n. Am J Transplant \n2020 :15811. 10.1111/ajt.15811 \n21 Abdel-Wahab N , Safa H , Abudayyeh A , et al \nCheckpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature\n. J Immunother Cancer \n2019 ;7 :106 . 10.1186/s40425-019-0585-1 30992053 \n22 Eisenhauer EA , Therasse P , Bogaerts J , et al \nNew response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)\n. Eur J Cancer \n2009 ;45 :228 –47\n. 10.1016/j.ejca.2008.10.026 19097774 \n23 Barnett R , Barta VS , Jhaveri KD \nPreserved renal-allograft function and the PD-1 pathway inhibitor nivolumab\n. N Engl J Med \n2017 ;376 :191 –2\n. 10.1056/NEJMc1614298 28076715 \n24 Smedman TM , Line P-D , Guren TK , et al \nGraft rejection after immune checkpoint inhibitor therapy in solid organ transplant recipients\n. Acta Oncol \n2018 ;57 :1414 –8\n. 10.1080/0284186X.2018.1479069 29912605 \n25 Kittai AS , Oldham H , Cetnar J , et al \nImmune checkpoint inhibitors in organ transplant patients\n. J Immunother \n2017 ;40 :277 –81\n. 10.1097/CJI.0000000000000180 28719552 \n26 Perazella MA , Shirali AC \nImmune checkpoint inhibitor nephrotoxicity: what do we know and what should we do?\n\nKidney Int \n2020 ;97 :62 –74\n. 10.1016/j.kint.2019.07.022 31685311 \n27 Cortazar FB , Kibbelaar ZA , Glezerman IG , et al \nClinical features and outcomes of immune checkpoint inhibitor-associated AKI: a multicenter study\n. J Am Soc Nephrol \n2020 ;31 :435 –46\n. 10.1681/ASN.2019070676 31896554\n\n",
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"keywords": "immunotherapy; melanoma; transplantation immunology",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D005260:Female; D006084:Graft Rejection; D006801:Humans; D000074324:Ipilimumab; D016030:Kidney Transplantation; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D000077594:Nivolumab; D011379:Prognosis; D012878:Skin Neoplasms",
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"title": "Combination checkpoint blockade for metastatic cutaneous malignancies in kidney transplant recipients.",
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"abstract": "Strongyloides stercoralis (SS) is an intestinal nematode which infects a large proportion of tropical and subtropical populations. The endemic areas are southeast Asia, South America and sub-Saharan Africa. Infection is acquired when the worms penetrate the skin, pass via the blood stream to the lungs, ascend the respiratory tract, are swallowed and grow into adult worms in the mucosa of the small intestine. The eggs laid by the female release larvae which pass down the lumen and reach the soil via the feces. While passing down the intestinal tract, a few of the rhabditiform larvae may be transformed into infective filariform larvae which can penetrate the distal intestinal and anal mucosa, returning to the blood stream. This \"autoinfection\" cycle is unique to SS, and explains why the infection can be perpetuated without further exposure to exogenous, infective larvae and can persist decades after departure from endemic areas. A substantial proportion of those affected are asymptomatic, but overwhelming infection may occur in immunosuppressed patients. This \"hyperinfection\" state is characterized by severe gastrointestinal and respiratory tract involvement, along with skin rash, Gram-negative bacteremia and cerebral signs. While frequently fatal, it is curable when diagnosed and treated promptly. We present a 79-year-old woman with idiopathic polymyositis, who was immunosuppressed by prolonged corticosteroid treatment. Her illness was complicated by SS hyperinfection. Diagnosis was made from stool and bronchial smears. Treatment with thiabendazole was started early and within a week there was complete cure. This is the fourth reported case of SS hyperinfection treated in Israel.",
"affiliations": "Dept. of Medicine A, Laniado Hospital, Natanya.",
"authors": "Gelber|M|M|;Rodrig|J|J|",
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"mesh_terms": "D000368:Aged; D000818:Animals; D000969:Antinematodal Agents; D005243:Feces; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007814:Larva; D018512:Parasitemia; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D013827:Thiabendazole",
"nlm_unique_id": "0034351",
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"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Strongyloides stercoralis hyperinfection.",
"title_normalized": "strongyloides stercoralis hyperinfection"
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"abstract": "BACKGROUND\nGreat progress has recently been made in the treatment of metastatic renal cell carcinoma, including the introduction of nivolumab, an immune checkpoint inhibitor. Despite promising results, this treatment brings a completely new spectrum of adverse events, distinct from those experienced with small-molecule kinase inhibitors. Neurologic immune-related adverse events may be serious and potentially life-threatening complications requiring immediate immunosuppressive therapy. Only a few cases of immune-related encephalitis induced by checkpoint inhibitors have been described and the data regarding the management of this serious adverse event are limited.\n\n\nMETHODS\nWe report the case of a 63-year-old white man with metastatic renal cancer who developed severe chorea-like dyskinesia during nivolumab therapy. The findings on brain magnetic resonance imaging and flow cytometry of cerebrospinal fluid, and the positivity of anti-paraneoplastic antigen Ma2 immunoglobuline G class autoantibodies were consistent with a diagnosis of immune-related encephalitis. High-dose intravenous corticosteroid therapy was started immediately, with no signs of improvement, even when infliximab was added. Our patient refused further hospitalization and was discharged. Three weeks later, he presented with signs of severe urosepsis. Despite intensive treatment, he died 4 days after admission.\n\n\nCONCLUSIONS\nThe management of less frequent immune-related adverse events has not been fully established and more information is required to provide uniform recommendations. Immune-related encephalitis is a severe and potentially fatal complication requiring immediate hospital admission and extensive immunosuppressive therapy. The examination of cerebrospinal fluid for paraneoplastic antibodies, such as anti-N-methyl-D-aspartate receptor and anti-Ma2 antibodies, in order to distinguish autoimmune etiology from other possible causes is essential and highly recommended.",
"affiliations": "Department of Clinical Oncology and Radiotherapy, University Hospital in Hradec Králové, Sokolská 581, 50005, Hradec Králové, Czech Republic. kopecjin@fnhk.cz.;Department of Clinical Oncology and Radiotherapy, University Hospital in Hradec Králové, Sokolská 581, 50005, Hradec Králové, Czech Republic.;Department of Fingerland Pathology, University Hospital in Hradec Králové, Sokolská 581, 50005, Hradec Králové, Czech Republic.;Department of Psychiatry, University Hospital in Hradec Králové, Sokolská 581, 50005, Hradec Králové, Czech Republic.;Department of Radiology, University Hospital in Hradec Králové, Sokolská 581, 50005, Hradec Králové, Czech Republic.;Department of Clinical Oncology and Radiotherapy, University Hospital in Hradec Králové, Sokolská 581, 50005, Hradec Králové, Czech Republic.;Department of Clinical Oncology and Radiotherapy, University Hospital in Hradec Králové, Sokolská 581, 50005, Hradec Králové, Czech Republic.",
"authors": "Kopecký|Jindřich|J|http://orcid.org/0000-0002-4126-0410;Kubeček|Ondřej|O|;Geryk|Tomáš|T|;Slováčková|Birgita|B|;Hoffmann|Petr|P|;Žiaran|Miroslav|M|;Priester|Peter|P|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 178610.1186/s13256-018-1786-9Case ReportNivolumab induced encephalopathy in a man with metastatic renal cell cancer: a case report http://orcid.org/0000-0002-4126-0410Kopecký Jindřich 495832176kopecjin@fnhk.czjindrich.kopecky@fnhk.cz 1Kubeček Ondřej ondrej.kubecek@fnhk.cz 1Geryk Tomáš tomas.geryk@fnhk.cz 2Slováčková Birgita birgita.slovackova@fnhk.cz 3Hoffmann Petr petr.hoffmann@fnhk.cz 4Žiaran Miroslav miroslav.ziaran@fnhk.cz 1Priester Peter peter.priester@fnhk.cz 11 0000 0004 0609 2284grid.412539.8Department of Clinical Oncology and Radiotherapy, University Hospital in Hradec Králové, Sokolská 581, 50005 Hradec Králové, Czech Republic 2 0000 0004 0609 2284grid.412539.8Department of Fingerland Pathology, University Hospital in Hradec Králové, Sokolská 581, 50005 Hradec Králové, Czech Republic 3 0000 0004 0609 2284grid.412539.8Department of Psychiatry, University Hospital in Hradec Králové, Sokolská 581, 50005 Hradec Králové, Czech Republic 4 0000 0004 0609 2284grid.412539.8Department of Radiology, University Hospital in Hradec Králové, Sokolská 581, 50005 Hradec Králové, Czech Republic 15 9 2018 15 9 2018 2018 12 26216 3 2018 29 7 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\nGreat progress has recently been made in the treatment of metastatic renal cell carcinoma, including the introduction of nivolumab, an immune checkpoint inhibitor. Despite promising results, this treatment brings a completely new spectrum of adverse events, distinct from those experienced with small-molecule kinase inhibitors. Neurologic immune-related adverse events may be serious and potentially life-threatening complications requiring immediate immunosuppressive therapy. Only a few cases of immune-related encephalitis induced by checkpoint inhibitors have been described and the data regarding the management of this serious adverse event are limited.\n\nCase presentation\nWe report the case of a 63-year-old white man with metastatic renal cancer who developed severe chorea-like dyskinesia during nivolumab therapy. The findings on brain magnetic resonance imaging and flow cytometry of cerebrospinal fluid, and the positivity of anti-paraneoplastic antigen Ma2 immunoglobuline G class autoantibodies were consistent with a diagnosis of immune-related encephalitis. High-dose intravenous corticosteroid therapy was started immediately, with no signs of improvement, even when infliximab was added. Our patient refused further hospitalization and was discharged. Three weeks later, he presented with signs of severe urosepsis. Despite intensive treatment, he died 4 days after admission.\n\nConclusions\nThe management of less frequent immune-related adverse events has not been fully established and more information is required to provide uniform recommendations. Immune-related encephalitis is a severe and potentially fatal complication requiring immediate hospital admission and extensive immunosuppressive therapy. The examination of cerebrospinal fluid for paraneoplastic antibodies, such as anti-N-methyl-D-aspartate receptor and anti-Ma2 antibodies, in order to distinguish autoimmune etiology from other possible causes is essential and highly recommended.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13256-018-1786-9) contains supplementary material, which is available to authorized users.\n\nKeywords\nRenal cancerNivolumabEncephalitisImmune-related adverse eventCase reportUniverzita Karlova v Praze (CZ)SVV- 2016-260286http://dx.doi.org/10.13039/100007397Univerzita Karlova v PrazeQ40/06issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nGreat progress has recently been made in the treatment of metastatic renal cell carcinoma (mRCC). Currently available drugs include multikinase vascular endothelial growth factor (VEGF) inhibitors (sunitinib, sorafenib, pazopanib), cytokines (interferon α), and mammalian target of rapamycin (mTOR) inhibitors (temsirolimus, everolimus), with the recent additions of the MEK inhibitor cabozantinib and the immune checkpoint inhibitor nivolumab. Nivolumab is a fully human immunoglobuline (Ig) G4 antibody targeting programmed cell death-1 (PD-1) receptor, which achieves a durable objective response in many cancers including mRCC [1]. Nivolumab acts as a checkpoint inhibitor, preventing the PD-1 mediated transmission of inhibitory signals that would normally attenuate T cell activity. This consequently enables the immune system to regain or maintain its antitumor activity. The anti-PD-1 effect is achieved mainly in tumor tissue during the effector phase of the immune response. Nivolumab is administered intravenously at a dose of 3 mg/kg every 14 days.\n\nThe advent of immunotherapy with checkpoint inhibitors has resulted in a completely different spectrum of activity than that experienced with chemotherapy and small-molecule kinase inhibitors. Desired antitumor activity can be achieved in a considerable number of patients. However, stimulation of the immune system response may simultaneously induce symptoms resembling an autoimmune disorder. These adverse reactions are usually referred to as an immune-related adverse event (irAE) and may affect practically any organ or tissue in the human body. Although these adverse reactions are usually mild and easily manageable with appropriate treatment, severe complications with potentially fatal consequences may occur.\n\nWe report a case of a patient with mRCC who developed severe chorea-like dyskinesia during therapy with nivolumab. The aim of this case report was to present a rare neurological complication of nivolumab treatment and to emphasize the necessity of close collaboration among the physician, the patient, and the patient’s family as a prerequisite for a good clinical outcome.\n\nCase presentation\nA 63-year-old white man with no significant comorbidities was diagnosed as having mRCC affecting his right kidney with metastatic spread in the Th11 vertebra and multiple pulmonary sites (Figs. 1a–c, 2a). He underwent a cytoreductive nephrectomy in December 2015. A histological examination was consistent with clear cell carcinoma, predominantly grade 2–3 (focally grade 4) with small areas of sarcomatoid differentiation and necrosis. The tumor stage was assessed as pT1b pN1 cM1. He was sent to the Comprehensive Cancer Center of the University Hospital in Hradec Králové, where he started therapy with sunitinib (50 mg daily, 4 weeks on/2 weeks off schedule) in December 2015. Considering the bone metastases, treatment with denosumab was started simultaneously. Owing to poor tolerability (nausea, fatigue, and anorexia) of the treatment, the schedule was changed to 2 weeks on/1 week off. Due to progressive back pain, combined analgesic therapy with opiates was required (oxycodone, transdermal fentanyl patches). Disease progression was documented in his lungs and spine after 4 months on sunitinib in April 2016. His progressive back pain resulted in hospital admission to perform analgesic radiotherapy to the Th 9–12 area with a dose of 20 Gy in five fractions on 5 consecutive days. He developed diarrhea during the hospitalization. A possible infectious etiology was ruled out with microbiological stool examination, as well as examination for Clostridium difficile and its toxin, and he was started on symptomatic therapy with an antidiarrheal treatment (diphenoxylate hydrochloride 2.5 mg three times a day) and probiotics.Fig. 1 Frontal, sagittal, and axial computed tomography scan demonstrating a destructive mass affecting Th11body (see arrows) from April 2016 (a–c) and August 2016 (d–f)\n\nFig. 2 Axial contrast-enhanced computed tomography scans of the thorax showing tumor regression (see arrows) April 2016 (a) and August 2016 (b)\n\n\n\nAfter finishing radiotherapy, nivolumab therapy was started in May 2016 within an expanded access program at an absolute dose of 300 mg every 14 days. Both diarrhea and back pain were gradually resolving during treatment, enabling dose reduction of the opiates. Our patient completed a total of six doses of nivolumab with no laboratory or clinical signs of adverse effects.\n\nHowever, 14 days following the last dose of nivolumab, he reported a change in behavior and a history of uncontrollable movements. His family started to say that he was strange and restless. He personally felt very well when taking nivolumab and the pain was even improving. He was fully aware of the uncontrollable movements, and although he could think rationally, he was not able to influence or stop them.\n\nThere was no family history of neurological or mental illness, and he denied any head trauma or neurological disorders in the past. A physical neurological examination revealed no significant findings in his head and peripheral nerves, but there were mild generalized choreatic movements of his upper extremities and head. A psychiatrist described our patient as cooperative, with pronounced choreatic movements of the entire body. His behavior was described as social, without signs of hostility or aggression, and at a reasonable psychomotor tempo. His mood was described as mildly dysphoric in response to the current situation of somatic manifestations. Laboratory tests showed no marked abnormalities. The only medication he was on at that time was a transdermal fentanyl patch (100 mcg/hour changed every 3 days), and he intermittently used antidiarrheal medications (diphenoxylate hydrochloride 2.5 mg or probiotics based on Lactobacillus acidophilus metabolites); during the sunitinib treatment, he irregularly used metoclopramide 10 mg, but he denied any history of neuroleptic use. Because of a serious suspicion of a possible side effect associated with immunotherapy, he was admitted to our hospital on 11 August 2016. A general overview of the timeline of the case report is shown in an additional file (see Additional file 1).\n\nCT (computed tomography) of his chest, abdomen, and pelvis showed signs of tumor regression in his lungs and bones (Figs. 1d–f, 2b). CT of his brain ruled out brain lesions or infiltrative brain damage. Because of the deterioration of choreatic movements, a magnetic resonance imaging (MRI) of his brain was performed. There were no signs of any tumor lesion. However, the MRI revealed a symmetrical, pathologically increased signal within the basal ganglia consistent with possible inflammatory involvement of these structures (Fig. 3).Fig. 3 Susceptibility-weighted imaging magnetic resonance imaging of the brain showing (see arrows) an areaof inflammatory increased signal within the basal ganglia (August 2016)\n\n\n\nSerum laboratory tests for infection and autoimmune diseases were negative. A cerebrospinal fluid (CSF) examination yielded negative results for bacterial and viral involvement and for the presence of malignant cells. Specific neuroimmunological examination of the CSF showed only mild inflammatory changes without any evidence of tissue destruction and no signs of primary infectious etiology. Anti-paraneoplastic antigen Ma2 (anti-PNMA2) IgG class autoantibodies were the only positive findings. Flow cytometry of CSF demonstrated a majority of lymphocytes (approximately 61%); most of the lymphocyte population was represented by T cells (approximately 95%), with the dominant proportion being CD4+ helper T cells (Fig. 4).Fig. 4 Flow cytometry gating of cerebrospinal fluid. a Side scatter versus CD45 plot for identification of basic population of leucocytes. b Identification of T (CD3+) and B (CD19+) cells. c Identification of Th (helper) cells (CD4+) and d Tc (cytotoxic) cells (CD8+). SS side scatter\n\n\n\nAccording to the recommendations for the management of irAE, high-dose intravenously administered corticosteroid therapy was started: Solu-Medrol (methylprednisolone) 2 mg/kg per day. Trimethoprim/sulfamethoxazole was administered simultaneously to prevent possible infectious complications: 960 mg twice a day (BID) twice a week. Despite the high dose of intravenously administered corticosteroid therapy, there was further deterioration of choreiform movements. The choreiform, athetoid, and ballistic movements spread to his lower limbs and trunk. The choreiform movements were so intense that our patient was unable to rest or lie on a bed. Furthermore, he developed a paranoid hallucinatory syndrome with suicidal thoughts. He was started on antipsychotic therapy (clonazepam 2 mg per day, haloperidol 15 mg per day, olanzapine 20 mg per day) after consultation with a psychiatrist and a neurologist and he experienced partial improvement. Considering the lack of a significant effect of corticosteroid therapy, the administration of infliximab at a dose of 5 mg/kg was started. However, infliximab did not achieve any clinical effect.\n\nOur patient and his family insisted on discharge from our hospital. According to the conclusion of a psychiatric examination, he was pronounced capable of signing an against-medical-advice discharge form and was discharged on 23 August 2016. An early out-patient visit to administer a further dose of infliximab was scheduled, and he was duly informed about the importance of doing so. However, he did not come to visit and refused any further treatment despite the provided information about possible adverse consequences.\n\nHe was eventually admitted to the standard ward on 13 September 2016, presenting with a fever and soporific state (Glasgow Coma Scale 5) on admission. Because of urinary retention (initially 1000 ml) and elevated levels of C-reactive protein, we suspected urinary infection, and he was started on intravenously administered amoxicillin/clavulanic acid 3.6 g/day and intravenously administered hydration. No other laboratory abnormalities were found. He partially regained consciousness after 2 days of treatment, with clinical manifestations of aggression and choreiform movement as described above. Therefore, therapy with antipsychotics and corticosteroids was reintroduced. However, his condition started to deteriorate again, and he developed bronchopneumonia. His level of consciousness started to deteriorate again, and he died 4 days following admission.\n\nAn autopsy confirmed the histology of clear cell renal cancer with metastatic para-aortic lymph nodes and necrotic Th11 vertebra, probably due to necrotic metastasis rather than radiotherapy-induced focal necrosis. Considering the clinical suspicion of aseptic meningitis, his brain was extensively examined. Its weight was 1480 g, and there were no macroscopically notable findings. A histological examination revealed inconclusive areas, suggesting focal lymphocytic meningitis of the entire brain—the cerebrum, brainstem, and cervical spinal cord (Fig. 5a)—and multiple perivascular lymphocytic infiltrates, which were most prominent in the basal ganglia on both sides; these findings were consistent with the MRI examination (Fig. 6a). The perivascular infiltrates localized in the frontal lobe and basal ganglia were immunohistochemically analyzed for surface markers of CD4 and CD8 T cells (Figs. 5b, c and 6b, c). The ratio of CD4+/CD8+, which is typically 3:1 in aseptic meningitis, was unusually low (approximately 1:1) in both sections.Fig. 5 Histological samples of the brain (× 100 magnification). a Hematoxylin and eosin staining showing lymphocytic meningitis. b Immunohistochemical staining of affected brain tissue for CD4+ and c CD8+ markers\n\nFig. 6 Histological samples of the basal ganglia (× 100 magnification). a Hematoxylin and eosin staining of perivascular infiltration. b Immunohistochemical staining of perivascular area of basal ganglia for CD4+ and c CD8+ markers\n\n\n\nDiscussion\nImmunotherapy is a treatment modality that has experienced a renaissance in the treatment of solid tumors during the last decade. Despite numerous attempts to utilize the immune system to fight cancer, including the depletion of T-regulatory lymphocytes [2], and the use of cancer vaccines or cytokines [3], previous results have been unsatisfactory. However, the discovery and understanding of the function and regulatory role of several receptors and their ligands, that is, cytotoxic T-lymphocyte antigen-4 (CTLA-4), PD-1, and programmed death-ligand 1 (PD-L1) in T cell activation have encouraged the further development and clinical use of immunotherapy [4, 5]. Currently, we can affect these regulatory mechanisms with a new class of drugs called immune checkpoint inhibitors. There is a growing body of evidence that these drugs represent effective treatments with the possibility of achieving a durable response in a wide spectrum of solid tumors, including melanoma [6, 7], non-small cell lung cancer [8, 9], urothelial carcinoma [10, 11], and renal cell carcinoma (RCC) [1].\n\nThe pathogenesis of irAEs is closely related to immune regulation affecting the activity of cytotoxic T cells. The mechanism of action of checkpoint inhibitors is to disrupt an interaction between regulatory receptors and their ligands, which normally produce an inhibitory signal with subsequent attenuation of immune activity. If the binding of ligands to regulatory receptors is prevented, for example, by anti-PD-L1 or anti-PD-1 antibodies, the activated T cells can contribute to an antitumor response [12–14]. On the other hand, this leads to an imbalance and possible disruption of immunological tolerance, which might cause an uncontrolled immune response directed against self-tissue antigens. This may result in undesired inflammatory activity involving various organ systems, referred to as irAEs. The most commonly affected sites are the gastrointestinal tract, skin, and endocrine system, but any organ or system of the human body can be affected.\n\nIn our case the initial presentation of adverse symptoms related to nivolumab was poor but unusual with severe chorea-like dyskinesia symptoms. There is only sparse information in the literature about similar cases; that is why the diagnostic and therapeutic algorithm is more difficult than, for example, for immune-related pneumonitis. Our case shows and emphasizes the urgent need of up front resolute immunosuppressive therapy in cases of immune-related encephalitis. Based on our case we propose the paraneoplastic antigen Ma2 as a helpful biomarker in order to make a correct diagnosis and to distinguish immune-related encephalitis from other possible causes.\n\nAccording to the literature, irAEs affecting the central nervous system (CNS) induced by anti-PD-1 antibody treatment are rare [15]. The vast majority of observed irAEs affecting the CNS have been related to anti-CTLA-4 antibodies [16, 17]. Most cases of immune checkpoint inhibitor-related CNS toxicities were of lower grade, with only approximately 0.1–3% of all events being grade 3 or 4 [18]. There are a limited number of anecdotal reports regarding anti-PD-1 antibody-induced autoimmune CNS toxicities [19–21].\n\nImmune-mediated encephalitis can be difficult to distinguish from encephalitis related to other causes. It can produce a wide range of symptoms, including headache, fever, weakness, fatigue, impaired memory, hallucinations, and convulsions. The diagnosis is usually made per exclusionem (a diagnosis of exclusion). Immune-mediated encephalitis induced by checkpoint inhibitors usually arises at the very beginning of therapy [15, 19]. However, as we demonstrate here, it can occur at any time during therapy.\n\nThe ratio of CD4+/CD8+ T cells in aseptic meningitis is typically approximately 3:1 [22]; however, it was unusually low in our case (approximately 1:1). This result is probably because the PD-1 receptor is strongly expressed on CD8+ T cells [23], resulting in the proliferation of the CD8+ subpopulation. Another explanation is that the CD4+/CD8+ ratio naturally decreases during inflammation, so the result might be affected by the time of examination [24].\n\nThe exact mechanism of immune-mediated encephalitis remains unclear. It is believed that the majority of irAEs are caused predominantly by T cells, although some proportion of irAEs may be mediated by other immune cells. N-methyl-D-aspartate (NMDA) receptor antibodies seem to play an important role in the pathogenesis of immune-mediated encephalitis [25]. These antibodies have been found in patients who developed immune-mediated encephalitis related to immune checkpoint inhibitor therapy [19]. NMDA receptors are expressed on the surface of melanocytes and are coded by the gene GRIN2A, which tends to be highly mutated in patients with melanoma [26]. The formation of antibodies against aberrant NMDA receptors in melanoma is supposed to induce encephalitis, as these antibodies may cross-react with NMDA receptors in the brain [15]. This mechanism has not been observed in mRCC yet. Antibodies against the NMDA receptor were not present in our patient, suggesting that other mechanisms are probably involved in the pathogenesis of checkpoint inhibitor-induced immune encephalitis.\n\nAnti-Ma2-associated paraneoplastic neurological syndromes, such as brain encephalitis, usually present as isolated or combined limbic, diencephalic, or brainstem dysfunction [27, 28]. The presence of anti-Ma2 antibodies has been associated with neoplasms in approximately 96% of described cases [28], mainly cases of testicular cancer and small cell lung carcinoma. There is a growing body of evidence that anti-Ma2-associated encephalitis differs from typical paraneoplastic limbic or brainstem encephalitis and may therefore be unrecognized. The association of anti-Ma2 antibodies and mRCC has not been proven yet. However, the association between anti-Ma2 antibodies and immune encephalitis might be similar to that between anti-NMDA antibodies and melanoma. We cannot exclude the presence of anti-Ma2 antibodies prior to the start of checkpoint inhibitor therapy, but this finding undoubtedly contributed to the diagnosis of immune-mediated encephalitis in our patient.\n\nThe mainstay of the management of immune-mediated encephalitis is therapy with intravenously administered corticosteroids, similarly to that of other irAEs. However, therapy can be successful only if absolute compliance of the patient and his family can be guaranteed. The dose of corticosteroids depends on toxicity grade, ranging from 0.5 to 2 mg/kg per day [29]. The response to corticosteroid therapy in immune encephalitis seems to be slower and less pronounced than that in other irAEs. Therefore, higher initial doses of corticosteroids may be required. Alternatively, other immunosuppressive drugs such as infliximab can be used.\n\nIt must be emphasized that patients treated with intravenously administered corticosteroids are especially prone to infectious complications, and adequate care should be paid to this issue. The presented patient was administered trimethoprim/sulfamethoxazole as prevention against Pneumocystis pneumonia. Unfortunately, early signs of infection could not be recognized as he refused to remain in our hospital. It should therefore be recommended that patients with severe irAEs are treated in an in-patient setting in order to recognize early signs of infectious complications and start antibiotic treatment as soon as possible.\n\nUnfortunately, we were not able to convince either our patient or his family to comply, so there was no way to extend our therapy (for example, with intravenously administered immunoglobulins or plasmapheresis) to prevent his death.\n\nConclusions\nThe major problem with immune checkpoint inhibitors is the relatively short-term collective experience. Hence, there is an urgent need to extend physicians’ and patients’ knowledge of possible complications of this promising treatment modality. This is especially important for rare but potentially fatal complications. Therefore, it is of great importance to include this topic in multidisciplinary tumor board meetings. Considering the rarity of immune checkpoint inhibitor-related encephalitis, it is essential to report such cases and share experience regarding treatment approaches and diagnostic tools. Immune-related encephalitis is a severe and potentially fatal complication requiring immediate hospital admission and extensive immunosuppressive therapy. The examination of CSF for paraneoplastic antibodies such as anti-NMDA receptor and anti-Ma2 antibodies in order to distinguish autoimmune etiology from other possible causes is essential and highly recommended.\n\nAdditional file\n\nAdditional file 1. Timeline of the case report. (PDF 177 kb)\n\n \n\n\nAbbreviations\nanti-PNMA2Anti-paraneoplastic antigen Ma2\n\nBIDTwice a day\n\nCNSCentral nervous system\n\nCSFCerebrospinal fluid\n\nCTComputed tomography\n\nCTLA-4Cytotoxic T-lymphocyte antigen-4\n\nIgImmunoglobuline\n\nirAEImmune-related adverse event\n\nmRCCMetastatic renal cell carcinoma\n\nMRIMagnetic resonance imaging\n\nmTORMammalian target of rapamycin\n\nNMDAN-methyl-D-aspartate\n\nPD-1Programmed cell death-1\n\nPD-L1Programmed death-ligand 1\n\nRCCRenal cell carcinoma\n\nVEGFVascular endothelial growth factor\n\nFunding\nThe study was supported by the Charles University Faculty of Medicine in Hradec Králové grant (SVV- 2016-260286), UK Progres (Q40/06), to cover the fees linked with language corrections and proof reading of manuscript and further with article processing charges.\n\nAvailability of data and materials\nThe data acquired during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nJK analyzed and interpreted the patient data regarding the toxicity and was a major contributor in writing the manuscript. OK interpreted the patient data regarding the toxicity and was second major contributor in writing the manuscript. BS made substantial contributions to acquisition of data regarding the toxicity and revised manuscript critically. PH made substantial contributions to acquisition of data regarding the toxicity and revised manuscript critically. TG performed the histological examination of the kidney and brain tissue and contributed to manuscript with pathological report. MZ has been involved in drafting the manuscript, participated on interpretation of data, literature research. PP was involved in revising the draft critically for important intellectual content and participated on interpretation of data. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe patient signed written consent with treatment; all collected data were acquired during the standard diagnostic procedures following internal regulations of university hospital.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s wife 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\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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"issn_linking": "1752-1947",
"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "Case report; Encephalitis; Immune-related adverse event; Nivolumab; Renal cancer",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D002292:Carcinoma, Renal Cell; D004660:Encephalitis; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab",
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"pubdate": "2018-09-15",
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"title": "Nivolumab induced encephalopathy in a man with metastatic renal cell cancer: a case report.",
"title_normalized": "nivolumab induced encephalopathy in a man with metastatic renal cell cancer a case report"
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"abstract": "Agranulocytosis is a rare but dreaded side-effect of thiamazole. A 61-year-old woman presented at the emergency department with fever and dyspnoea. Because she had recently started therapy with thiamazole for hyperthyroidism, a case of agranulocytosis was feared. Laboratory findings did indeed reveal an absolute neutrophil count of zero. Broad-spectrum antibiotics were given immediately, granulocyte-colony stimulating factor was started and she was admitted to the ICU for supportive care. Unfortunately, she died a day after admission. In this case report, we wanted to place the focus on the importance of this severe side-effect. We emphasize the value of warning the patient, preferably in writing, about the risk of agranulocytosis. We also draw attention to the fact that every doctor must know about agranulocytosis. In this case, the patient consulted her family doctor because she had a sore throat and fever, but was admitted to the hospital only three days after the onset of the symptoms. We believe the risk of agranulocytosis should be understood by every doctor and that the publication of many cases such as this could help heighten general awareness of possibly fatal side-effects like agranulocytosis.",
"affiliations": "Tergooiziekenhuizen, Afd. Interne Geneeskunde, Hilversum, the Netherlands. k.bessembinders@jbz.nl",
"authors": "Bessembinders|Kirsten M|K|;Brinkers|J M Mariska|JM|;van der Linden|Paul D|PD|;van Keulen|Kris|K|;de Sonnaville|Jeroen J J|JJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D013956:Antithyroid Agents; D016179:Granulocyte Colony-Stimulating Factor; D008713:Methimazole",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "157(25)",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000380:Agranulocytosis; D000900:Anti-Bacterial Agents; D013956:Antithyroid Agents; D017809:Fatal Outcome; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D006980:Hyperthyroidism; D007958:Leukocyte Count; D008713:Methimazole; D008875:Middle Aged",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "A6351",
"pmc": null,
"pmid": "23777968",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute agranulocytosis from thiamazole: points for improvement in daily practice.",
"title_normalized": "acute agranulocytosis from thiamazole points for improvement in daily practice"
} | [
{
"companynumb": "PHHY2013NL087047",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": null,
... |
{
"abstract": "Neoadjuvant cisplatin-based chemotherapy (NAC; 70 mg/m2) is standard of care for muscle-invasive bladder carcinoma (MIBC). Many patients (pts) cannot receive cisplatin because of renal impairment, and administration of cisplatin 35 mg/m2 on day 1 + 8 or 1 + 2 (i.e., split schedule) is a commonly used alternative. In this retrospective analysis, we compared complete (pT0) and partial (<pT2) pathologic response rates between split schedule (SS) and conventional schedule (CS) pts, after 1:1 matching on chemotherapy regimen, number of cycles, tumor histology, and clinical stage. Eighty matched pts were identified. pT0 rates were 17.5% (95% confidence interval [CI], 7%-33%) and 32.5% (95% CI, 19%-49%) in SS and CS cisplatin pts, respectively (p = .21), corresponding to an odds ratio for pT0 of 0.45 (95% CI, 0.16-1.31) with SS cisplatin. Split schedule cisplatin was associated with numerically but not statistically significant lower pathologic response rates relative to full dose.",
"affiliations": "University of North Carolina Medical Center, Chapel Hill, North Carolina, USA.;University of Rochester Medical Center, Rochester, New York, USA.;Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;MD Anderson Cancer Center at Cooper, Camden, New Jersey, USA.;Langone Medical Center, New York University, New York City, New York, USA.;Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Florida Cancer Specialists and Research Institute, Sarasota, Florida, USA.;MD Anderson Cancer Center at Cooper, Camden, New Jersey, USA.;Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Department of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Department of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.;University of Rochester Medical Center, Rochester, New York, USA.;Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA ronac.mamtani@uphs.upenn.edu.",
"authors": "Osterman|Chelsea K|CK|;Babu|Dilip S|DS|;Geynisman|Daniel M|DM|;Lewis|Bianca|B|;Somer|Robert A|RA|;Balar|Arjun V|AV|;Zibelman|Matthew R|MR|;Guancial|Elizabeth A|EA|;Antinori|Gianna|G|;Yu|Shun|S|;Narayan|Vivek|V|;Guzzo|Thomas J|TJ|;Plimack|Elizabeth R|ER|;Vaughn|David J|DJ|;Fung|Chunkit|C|;Mamtani|Ronac|R|",
"chemical_list": "D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0561",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(5)",
"journal": "The oncologist",
"keywords": "Cisplatin; Muscle‐invasive bladder cancer; Neoadjuvant chemotherapy; Nephrotoxicity",
"medline_ta": "Oncologist",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002295:Carcinoma, Transitional Cell; D002945:Cisplatin; D015653:Cystectomy; D005260:Female; D006801:Humans; D007668:Kidney; D008297:Male; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D051437:Renal Insufficiency; D012189:Retrospective Studies; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "688-690",
"pmc": null,
"pmid": "30728277",
"pubdate": "2019-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "22741006;26184106;22595043;29742009;26001531;12944571;29576445",
"title": "Efficacy of Split Schedule Versus Conventional Schedule Neoadjuvant Cisplatin-Based Chemotherapy for Muscle-Invasive Bladder Cancer.",
"title_normalized": "efficacy of split schedule versus conventional schedule neoadjuvant cisplatin based chemotherapy for muscle invasive bladder cancer"
} | [
{
"companynumb": "US-JNJFOC-20190610300",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"drugadditional": "3",
... |
{
"abstract": "Acquired hemophilia A (AHA) is a severe bleeding disorder caused by inhibiting autoantibodies to coagulation factor VIII (FVIII). For hemostatic treatment, bypassing agents and human or porcine FVIII are currently standard of care. Emicizumab is a bispecific, FVIII-mimetic therapeutic antibody that reduced the annualized bleeding rates in congenital hemophiliacs. Here, we report on 6 male and 6 female patients with AHA treated with emicizumab (all data medians and interquartile range), age 74 (64-80) years, initial FVIII <1%; inhibitor titer 22.3 Bethesda units (BU)/mL (range, 3-2000). Eight patients had severe bleeding. Emicizumab was started, 3 mg/kg subcutaneously, weekly for 2 to 3 doses, followed by 1.5 mg/kg every 3 weeks to keep the lowest effective FVIII levels. For FVIII monitoring, chromogenic assays with human and bovine reagents were used. All patients received immunosuppression with steroids and/or rituximab. After the first dose of emicizumab, activated partial thromboplastin time normalized in 1 to 3 days, FVIII (human reagents) exceeded 10% after 11 (7.5-12) days. Hemostatic efficacy was obtained and bypassing therapy stopped after 1.5 (1-4) days. FVIII (bovine reagents) exceeded 50%, indicating complete remission after 115 (67-185) days, and emicizumab was stopped after 31 (15-79) days. A median of 5 injections (range, 3-9) were given. No patient died of bleeding or thromboembolism, and no breakthrough bleeding was observed after the first dose of emicizumab. In conclusion, emicizumab seems to be an effective hemostatic therapy for AHA, with the advantages of subcutaneous therapy, good hemostatic efficacy, early discharge, and reduction of immunosuppression and adverse events.",
"affiliations": "Division for Hematology and Hemostasis, Department of Medicine 1, and.;Division for Hematology and Hemostasis, Department of Medicine 1, and.;Coagulation Laboratory, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.;Coagulation Laboratory, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.;Division for Hematology and Hemostasis, Department of Medicine 1, and.;Division for Hematology and Hemostasis, Department of Medicine 1, and.",
"authors": "Knoebl|Paul|P|;Thaler|Johannes|J|;Jilma|Petra|P|;Quehenberger|Peter|P|;Gleixner|Karoline|K|;Sperr|Wolfgang R|WR|",
"chemical_list": "D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D006490:Hemostatics; D007166:Immunosuppressive Agents; C000608208:emicizumab; C078147:F8 protein, human; D005169:Factor VIII",
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2020006315",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "137(3)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000368:Aged; D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII; D005260:Female; D006467:Hemophilia A; D006490:Hemostatics; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "410-419",
"pmc": null,
"pmid": "32766881",
"pubdate": "2021-01-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Emicizumab for the treatment of acquired hemophilia A.",
"title_normalized": "emicizumab for the treatment of acquired hemophilia a"
} | [
{
"companynumb": "AT-TAKEDA-2021TJP037891",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ANTI-INHIBITOR COAGULANT COMPLEX"
},
"drugaddit... |
{
"abstract": "The prognosis of acute promyelocytic leukemia (APL) has become the most favorable among all acute myeloid leukemias, due to the efficacy of treatment with all-trans retinoic acid (ATRA). ATRA combined with anthracycline-based chemotherapy has significantly improved the long-term outcome for low-to-intermediate-risk APL patients; thus, the efficacy of maintenance therapy for patients achieving molecular complete remission (MCR) following consolidation therapy has become debatable. To evaluate the efficacy of maintenance therapy, we conducted a retrospective analysis of 11 consecutive patients with low-to-intermediate-risk APL who received induction and consolidation therapy with ATRA and anthracyclines according to the PETHEMA LPA protocols at our hospital between January, 2001 and March, 2013. All the patients achieved MCR following consolidation therapy. Of these patients, 7 were followed without maintenance therapy, including 2 patients who discontinued maintenance therapy within 2 months. With a median follow-up of 85 months, the overall survival for all the patients was 100%, while the disease-free survival estimate at 5 years with and without maintenance therapy was 100 and 85.7%, respectively; the difference was not statistically significant (P=0.45). Two patients treated with maintenance therapy later developed secondary primary malignancy. Thus, even without maintenance therapy, ATRA combined with anthracyclines exhibited significant efficacy in low-to-intermediate-risk APL patients, suggesting that maintenance therapy, which is associated with adverse events, may be dispensable for patients achieving MCR following adequate consolidation therapy.",
"affiliations": "Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.;Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.;Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.;Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.;Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.",
"authors": "Yamamoto|Masahide|M|;Okada|Keigo|K|;Akiyama|Hiroki|H|;Kurosu|Tetsuya|T|;Miura|Osamu|O|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2014.476",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "3(2)",
"journal": "Molecular and clinical oncology",
"keywords": "acute promyelocytic leukemia; all-trans retinoic acid; anthracycline; maintenance therapy; molecular remission",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "449-453",
"pmc": null,
"pmid": "25798284",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": "12393590;10556184;20393132;20018913;17374742;21385856;10438706;24528179;24692677;23208313;10942364;9321529;23841729",
"title": "Evaluation of the efficacy of maintenance therapy for low-to-intermediate-risk acute promyelocytic leukemia in molecular remission: A retrospective single-institution study.",
"title_normalized": "evaluation of the efficacy of maintenance therapy for low to intermediate risk acute promyelocytic leukemia in molecular remission a retrospective single institution study"
} | [
{
"companynumb": "JP-MYLANLABS-2015M1005052",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
... |
{
"abstract": "The results of treatment of acute lymphoblastic leukemia (ALL) from the low population countries are missing in the literature.\n\n\n\nWe retrospectively examined biological characteristics and survival of 90 patients with ALL.\n\n\n\nAt median follow-up 17 months, 52 men and 38 women were eligible for the analysis with median age 43 years (18-74). As for the risk stratification, 25.6% of patients were in standard risk, 46.7% in high risk and 27.8% in very high-risk group. Complete remission achieved 88.9% of patients. We observed 5.6% of induction deaths and 4.5% of resistant disease. 47.8% of the patients underwent allogeneic stem cell transplantation (alloSCT), 59% in the young adults (YA; < 40 years) and 40% in adult group (≥ 40 years). We noticed 32.6% relapses overall with median survival of relapsed patients 3.9 months. YA patients had longer survival than adults: 3-year overall survival (OS) 65.0% vs 30.2%; (HR = 0.36; 95% CI 0.2-0.64; P = .001) and event free survival (EFS) 51.5% vs 21.9%; (HR = 0.45; 95% CI 0.26-0.78; P = .005). There was significant difference in 3-year EFS between risk groups in YA patients 90.9%, 48.0%, 11.4%; (P = .001). OS after alloSCT individually for the YA was 62.6% and for adults 39.1%, hazard ratio (HR) = 0.49 (95% CI 0.20-1.21); (P = .095). We observed 14% early deaths, 25.6% late deaths and 3 relapses (7%) after allogeneic stem cell transplantation.\n\n\n\nOur data proved that even in a low population country similar result can be achieved as in larger ones while using well designed adapted protocols from leukemic study groups.",
"affiliations": "Department of Oncohematology, Faculty of Medicine Comenius University and National Cancer Institute, Bratislava, Slovakia. Electronic address: iveta.oravcova@nou.sk.;Department of Hematology and Transfusiology of University Hospital in Bratislava, Faculty of Medicine Comenius University and Faculty of Medicine Slovak Medical University, Bratislava, Slovakia.;Department of Oncohematology, Faculty of Medicine Comenius University and National Cancer Institute, Bratislava, Slovakia.;Department of Oncohematology, Faculty of Medicine Comenius University and National Cancer Institute, Bratislava, Slovakia.;Department of Oncohematology, Faculty of Medicine Comenius University and National Cancer Institute, Bratislava, Slovakia.;Department of Oncohematology, Faculty of Medicine Comenius University and National Cancer Institute, Bratislava, Slovakia.;Department of Hematology and Transfusiology of University Hospital in Bratislava, Faculty of Medicine Comenius University and Faculty of Medicine Slovak Medical University, Bratislava, Slovakia.;Department of Hematology and Transfusiology of University Hospital in Bratislava, Faculty of Medicine Comenius University and Faculty of Medicine Slovak Medical University, Bratislava, Slovakia.;Department of Hematology and Transfusiology of University Hospital in Bratislava, Faculty of Medicine Comenius University and Faculty of Medicine Slovak Medical University, Bratislava, Slovakia.;Department of Hematology and Transfusiology of University Hospital in Bratislava, Faculty of Medicine Comenius University and Faculty of Medicine Slovak Medical University, Bratislava, Slovakia.",
"authors": "Oravcova|Iveta|I|;Lukas|Jozef|J|;Cingelova|Silvia|S|;Demitrovicova|Ludmila|L|;Mikuskova|Eva|E|;Drgona|Lubos|L|;Sopko|Ladislav|L|;Galffy|Balazs|B|;Batorova|Angelika|A|;Mistrik|Martin|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2021.06.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "21(10)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Mortality; Ph-positivity; Remission; Survival; risk",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": null,
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e782-e791",
"pmc": null,
"pmid": "34275773",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of Adults and Young Adults with Acute Lymphoblastic Leukemia: Real Life Data from Two Centers in Slovakia.",
"title_normalized": "treatment of adults and young adults with acute lymphoblastic leukemia real life data from two centers in slovakia"
} | [
{
"companynumb": "SK-AMGEN-SVKSP2021187179",
"fulfillexpeditecriteria": "2",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BLINATUMOMAB"
},
"drugadditional": "4",
... |
{
"abstract": "A 16-year-old boy had a past medical history of primary hypogonadism, due to bilateral anorchia. He presented with gallstones located in the gallbladder and a mild dilatation of the intrahepatic biliary tree. The histology study reported cholesterol gallstones. The patient had been treated with testosterone replacement therapy since infancy. We suggest a possible correlation between testosterone replacement therapy and the presence of cholesterol gallstones.",
"affiliations": "Departamento de Radiología, ASST Santi Paolo e Carlo, Hospital San Carlo Borromeo, Milán, Italia. Electronic address: silvia.squarza@yahoo.it.;Departamento de Radiología, ASST Santi Paolo e Carlo, Hospital San Carlo Borromeo, Milán, Italia; Unidad de Radiología Intervencionista Hospital Galliera, Mura delle Cappuccine 14, Génova.;Departamento de Radiología, ASST Santi Paolo e Carlo, Hospital San Carlo Borromeo, Milán, Italia.;Departamento de Radiología, ASST Santi Paolo e Carlo, Hospital San Carlo Borromeo, Milán, Italia.",
"authors": "Squarza|S|S|;Rossi|U G|UG|;Torcia|P|P|;Cariati|M|M|",
"chemical_list": "D013739:Testosterone",
"country": "Mexico",
"delete": false,
"doi": "10.1016/j.rgmx.2017.09.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2255-534X",
"issue": "83(2)",
"journal": "Revista de gastroenterologia de Mexico (English)",
"keywords": "Cholesterol; Colesterol; Cálculos biliares; Gallbladder; Gallstones; Hipogonadismo primario; Primary hypogonadism; Terapia; Testosterona; Testosterone; Therapy; Vesícula biliar",
"medline_ta": "Rev Gastroenterol Mex (Engl Ed)",
"mesh_terms": "D000369:Aged, 80 and over; D005260:Female; D042882:Gallstones; D020249:Hormone Replacement Therapy; D006801:Humans; D007006:Hypogonadism; D013739:Testosterone; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101778603",
"other_id": null,
"pages": "205-207",
"pmc": null,
"pmid": "29656844",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Association between cholesterol gallstones and testosterone replacement therapy in a patient with primary hypogonadism.",
"title_normalized": "association between cholesterol gallstones and testosterone replacement therapy in a patient with primary hypogonadism"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1041019",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TESTOSTERONE"
},
"drugadditional": "3",
... |
{
"abstract": "A Meckel's diverticulum is an unusual site of gastrointestinal bleeding in adults. Bleeding often results from ulceration of ileal mucosa that lies adjacent to ectopic gastric mucosa. We report on a 27-yr-old man who bled from a Meckel's diverticulum after receiving oral ibuprofen, a nonsteroidal antiinflammatory drug. Examination of the resected diverticulum revealed fundal-type gastric mucosa with inflammation, submucosal hemorrhages, erosions and ulceration in the absence of Helicobacter pylori. The ileal mucosa was spared in this patient. These features suggest that oral ibuprofen caused damage to the ectopic gastric mucosa, precipitating significant hemorrhage. This is the first report in the English literature of such an occurrence.",
"affiliations": "Department of Medicine (Division of Gastroenterology), Baylor College of Medicine, Houston, Texas.",
"authors": "Mathur|S|S|;Verseman|S|S|;Estrada|R|R|;Hollinger|F B|FB|",
"chemical_list": "D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "87(10)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000328:Adult; D005753:Gastric Mucosa; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007052:Ibuprofen; D007413:Intestinal Mucosa; D008297:Male; D008467:Meckel Diverticulum",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1467-70",
"pmc": null,
"pmid": "1415106",
"pubdate": "1992-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bleeding from a Meckel's diverticulum after the use of ibuprofen.",
"title_normalized": "bleeding from a meckel s diverticulum after the use of ibuprofen"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2021-024833",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "The anticoagulation of biological heart valves remains a 'hot spot' of discussion in various domains due to the risk of developing valve thrombosis and arterial thromboembolism. The situation has always been controversial, especially during the early postoperative phase. The American College of Cardiology/ American Heart Association and European Society of Cardiology guidelines recommend the use of warfarin for the first three months after biological aortic valve replacement (BAVR), although the American College of Chest Physicians guidelines suggest that these recommendations are experience-based and that the risk/benefit is unclear. The aim of the present study was to compare the efficacy of aspirin and warfarin in patients after BAVR.\n\n\n\nA total of 863 patients who underwent BAVR between 2008 and 2015 was allocated to two groups. Each group was managed with a specific anticoagulation regimen, with 430 patients receiving warfarin during the first three postoperative months, and 433 receiving aspirin. The major study end points were bleeding, cerebral ischemic events, and survival.\n\n\n\nIn total, 10 and 15 postoperative cerebral ischemic events occurred between 24 h and three months after surgery in patients treated with aspirin and warfarin, respectively. After three months the incidence of cerebral ischemic events did not differ greatly between the two groups. The rate of major bleeding events and rates of stroke-free survival and overall survival were not statistically significant between the warfarin and aspirin groups.\n\n\n\nPlasma anticoagulation with warfarin during the early postoperative phase was shown statistically to be inferior to platelet aggregation inhibition by aspirin with regards to postoperative bleeding risk, cerebral ischemic events, and survival.",
"affiliations": "Department of Cardiac Surgery and Cardiology, Central Clinic of Bad Berka, Germany.;Department of Cardiac Surgery and Cardiology, Central Clinic of Bad Berka, Germany.;Department of Cardiac Surgery and Cardiology, Central Clinic of Bad Berka, Germany.;Department Anaesthesiology and Intensive Medicine, Central Clinic of Bad Berka, Germany.;Department Anaesthesiology and Intensive Medicine, Central Clinic of Bad Berka, Germany.;Department of Cardiac Surgery and Cardiology, Central Clinic of Bad Berka, Germany.;Department of Cardiac Surgery and Cardiology, Central Clinic of Bad Berka, Germany.",
"authors": "Owais|Tamer|T|;Rouman|Mina|M|;Breuer|Martin|M|;Hüter|Lars|L|;Fuchs|Jürgen|J|;Lauer|Bernward|B|;Kuntze|Thomas|T|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0966-8519",
"issue": "25(2)",
"journal": "The Journal of heart valve disease",
"keywords": null,
"medline_ta": "J Heart Valve Dis",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001021:Aortic Valve; D001241:Aspirin; D001705:Bioprosthesis; D001777:Blood Coagulation; D002545:Brain Ischemia; D005260:Female; D006349:Heart Valve Diseases; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006470:Hemorrhage; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D011474:Prosthesis Design; D012189:Retrospective Studies; D020521:Stroke; D013927:Thrombosis; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "9312096",
"other_id": null,
"pages": "139-144",
"pmc": null,
"pmid": "27989055",
"pubdate": "2016-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Anticoagulation After Biological Aortic Valve Replacement: Is There An Optimal Regimen?",
"title_normalized": "anticoagulation after biological aortic valve replacement is there an optimal regimen"
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"abstract": "BACKGROUND\nHypereosinophilia, defined by an absolute eosinophil count of more than 1500/mm3, is rarely observed in patients treated for cancer, and rarely imputable to anti-cancer agents. Drug-induced hypereosinophilia usually appears within a few weeks of the start of treatment and resolves after discontinuation of the medication. We report here a first case of hypereosinophilia with digestive allergic reaction imputable to docetaxel in a woman treated for breast cancer.\n\n\nMETHODS\nThis patient, with a history of childhood atopic dermatitis and asthma, underwent surgery for breast lobular carcinoma, followed with chemotherapy including 3 cycles of the FEC100 protocol and 3 cycles of docetaxel. Ten days after the second cycle of docetaxel, she had abdominal pain with diarrhea, which increased after the third cycle of docetaxel at the same dose. The blood eosinophil count increased up to 4685/mm(3) at day 92. All biological tests were normal, except elevated seric IgE. The systematic biopsies of the upper and lower digestive tract showed diffuse edema of the lamina propria, lymphocytic infiltrate and CD117-expressing cells both in the epithelium and in the lamina propria. Electron microscopy showed a large number of degranulating mast cells, while the number of tissue eosinophils was small. The blood eosinophil count decreased after day 96, three months after the last injection of docetaxel. After day 182, the hypereosinophilia and symptoms resolved. This spontaneous evolution, the history of atopic dermatitis and asthma, and the negativity of all biological tests performed led us to hypothesize a diagnosis of a systemic digestive Type 1 drug-induced hypersensitivity reaction. Using two validated pharmacovigilance scales, we found that docetaxel had the highest imputability score compared to the other drugs.\n\n\nCONCLUSIONS\nRecognition of allergic reactions imputable to docetaxel is important because it requires the drug to be discontinued. In the difficult setting of anti-cancer treatment, if reintroduction of the drug is needed, a close collaboration between oncologists, gastroenterologists and allergologists is required.",
"affiliations": "Centre Hospitalier de Marne-la-Vallée, Service d'Oncologie Médicale, Jossigny, F-77600, France. diaddin_h@hotmail.com.;U1165, Université Paris7, Inserm, Hôpital Saint-Louis, Paris, F-75010, France. christophe.leboeuf@gmail.com.;AP-HP-Hôpital Saint-Louis, Laboratoire de Pathologie, Paris, F-75010, France. cathy.pereira@aphp.fr.;AP-HP-Hôpital Saint-Louis, Pharmacie, Paris, F-75010, France. nathalie.jourdan@aphp.fr.;U1165, Université Paris7, Inserm, Hôpital Saint-Louis, Paris, F-75010, France. laurence.verneuil@gmail.com.;U1165, Université Paris7, Inserm, Hôpital Saint-Louis, Paris, F-75010, France. guilhem.bousquet@aphp.fr.;U1165, Université Paris7, Inserm, Hôpital Saint-Louis, Paris, F-75010, France. anne.janin1165@gmail.com.",
"authors": "Hamdan|Diaddin|D|;Leboeuf|Christophe|C|;Pereira|Cathy|C|;Jourdan|Nathalie|N|;Verneuil|Laurence|L|;Bousquet|Guilhem|G|;Janin|Anne|A|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel",
"country": "England",
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"doi": "10.1186/s12885-015-2008-0",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 200810.1186/s12885-015-2008-0Case ReportA digestive allergic reaction with hypereosinophilia imputable to docetaxel in a breast cancer patient: a case report Hamdan Diaddin diaddin_h@hotmail.com Leboeuf Christophe christophe.leboeuf@gmail.com Pereira Cathy cathy.pereira@aphp.fr Jourdan Nathalie nathalie.jourdan@aphp.fr Verneuil Laurence laurence.verneuil@gmail.com Bousquet Guilhem +(33)142385428guilhem.bousquet@aphp.fr Janin Anne +(33) 1 42 49 45 70anne.janin1165@gmail.com Centre Hospitalier de Marne-la-Vallée, Service d’Oncologie Médicale, Jossigny, F-77600 France U1165, Université Paris7, Inserm, Hôpital Saint-Louis, Paris, F-75010 France Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, F-75010 Paris, France AP-HP-Hôpital Saint-Louis, Laboratoire de Pathologie, Paris, F-75010 France AP-HP-Hôpital Saint-Louis, Pharmacie, Paris, F-75010 France Université de Caen Basse-Normandie, Medical School, Caen, F-14000 France AP-HP-Hôpital Avicenne, Service d’Oncologie Médicale, Bobigny, F-93008 France Université Paris 13, Leonard de Vinci, Villetaneuse, F-93430 France U1165, 1 avenue Vellefaux, Paris, F-75010 France 21 12 2015 21 12 2015 2015 15 9934 9 2015 14 12 2015 © Hamdan et al. 2015\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\nHypereosinophilia, defined by an absolute eosinophil count of more than 1500/mm3, is rarely observed in patients treated for cancer, and rarely imputable to anti-cancer agents. Drug-induced hypereosinophilia usually appears within a few weeks of the start of treatment and resolves after discontinuation of the medication.\n\nWe report here a first case of hypereosinophilia with digestive allergic reaction imputable to docetaxel in a woman treated for breast cancer.\n\nCase presentation\nThis patient, with a history of childhood atopic dermatitis and asthma, underwent surgery for breast lobular carcinoma, followed with chemotherapy including 3 cycles of the FEC100 protocol and 3 cycles of docetaxel. Ten days after the second cycle of docetaxel, she had abdominal pain with diarrhea, which increased after the third cycle of docetaxel at the same dose. The blood eosinophil count increased up to 4685/mm3 at day 92. All biological tests were normal, except elevated seric IgE. The systematic biopsies of the upper and lower digestive tract showed diffuse edema of the lamina propria, lymphocytic infiltrate and CD117-expressing cells both in the epithelium and in the lamina propria. Electron microscopy showed a large number of degranulating mast cells, while the number of tissue eosinophils was small.\n\nThe blood eosinophil count decreased after day 96, three months after the last injection of docetaxel. After day 182, the hypereosinophilia and symptoms resolved. This spontaneous evolution, the history of atopic dermatitis and asthma, and the negativity of all biological tests performed led us to hypothesize a diagnosis of a systemic digestive Type 1 drug-induced hypersensitivity reaction. Using two validated pharmacovigilance scales, we found that docetaxel had the highest imputability score compared to the other drugs.\n\nConclusion\nRecognition of allergic reactions imputable to docetaxel is important because it requires the drug to be discontinued. In the difficult setting of anti-cancer treatment, if reintroduction of the drug is needed, a close collaboration between oncologists, gastroenterologists and allergologists is required.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12885-015-2008-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nDocetaxelAllergic reactionHypereosinophiliaDigestive tractissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nHypereosinophilia, defined by an absolute eosinophil count of more than 1500/mm3, is rarely observed in patients treated for cancer [1]. The main drugs responsible for hyperesosinophilia are penicillins, cephalosporins, sulfas, quinolones, and non-steroid anti-inflammatory drugs [2], but hypereosinophilia is rarely imputable to anti-cancer agents (see Additional file 1: Methods M1 for details on search strategy, and Additional file 2: Table S1 for the results of the systematic literature search). Drug-induced blood hypereosinophilia usually appears within a 2 to 10 weeks of the start of treatment and resolves after discontinuation of the medication (Additional file 2: Table S1).\n\nBlood hypereosinophilia is associated with potentially lethal clinical complications, mainly cardiac, cutaneous, neurologic or pulmonary [3].\n\nWe report here a first case of hypereosinophilia with systemic digestive allergic reaction imputable to docetaxel in a woman treated for a localized breast cancer.\n\nCase presentation\nThis 40-years-old Caucasian woman, with a history of childhood atopic dermatitis and asthma, underwent surgery for breast lobular carcinoma of 30 mm, histological grade III, expressing estrogen and progesterone receptors, with no lymph node involvement. In accordance with French guidelines, she received post-surgery chemotherapy including 3 cycles of the FEC100 protocol – 5Fluoro-Uracile 500 mg/m2/cycle (Accord, France), epirubicin 100 mg/m2/cycle (Mylan, France) cyclophosphamid 500 mg/m2/cycle (Baxter, France) – and 3 cycles of docetaxel 100 mg/m2/cycle (Docetaxel Kabi © (ATC-Code L01CD02), Fresenius, France).\n\nTen days after the second cycle of docetaxel, she had abdominal pain with diarrhea (2–5 stools/day), which increased after the third cycle of docetaxel at the same dose. The eosinophil count was 2001/mm3 at day 60, and 4685/mm3 at day 92 (Fig. 1).Fig. 1 Event time-line and blood eosinophil count curve. C1, C2, C3: first, second and third cycles of docetaxel\n\n\n\nSystematic biological tests and digestive biopsies were performed at day 92. No parasitological, bacteriological, virological, immunological or hematological cause was found; only seric IgE were elevated (Additional file 3: Table S2). The systematic biopsies of the upper and lower digestive tract showed similarities in the gut and colonic biopsies. All four biopsies had diffuse edema of the lamina propria, lymphocytic infiltrate and CD117-expressing cells both in the epithelium and in the lamina propria (see Additional file 1: Methods and Fig. 2a). We used electron microscopy, and anti-tryptase and anti-eosinophil peroxidase antibodies to differentiate and count mast cells and eosinophils in the two compartments (see Additional file 1: Methods and Fig. 2b, c, and Tables 1, 2). The diagnosis of eosinophilic gastro-enteritis was excluded because of the small number of tissue eosinophils [4]. Electron microscopy showed a large number of degranulating mast cells. No sign of thrombosis, necrosis or vascular-wall damage was found.Fig. 2 Characterization of cell infiltrates in the epithelium and lamina propria of the duodenum. Duodenal biopsies with CD117-expressing cells (a), which include eosinophils expressing eosinophil peroxidase (EPO) and containing specific granules (b); and mast cells (M) expressing tryptase and located in the lamina propria and epithelium (arrows, c). Mast cells in the lamina propria coexpress tryptase and chymase (d). Mast cells in the epithelium (arrows) coexpress tryptase and carboxypeptidase A3 (e)\n\nTable 1 Inflammatory cell counts in gut and colon\n\nDigestive samples\tEpithelium\t\n\tLymphocytes\tMast cells\tEosinophils\t\nDuodenum\t10.2 ± 4.1\t4.4 ± 0.8\t2.4 ± 0.7\t\nJejunum\t12.4 ± 3.1\t2.3 ± 0.5\t1.2 ± 0.5\t\nRight colon\t7.8 ± 1.2\t2.5 ± 0.3\t0.4 ± 0.1\t\nLeft colon\t8.4 ± 0.9\t3.2 ± 1.1\t1.3 ± 0.4\t\nTable 2 Inflammatory cell counts in gut and colon\n\nDigestive samples\tLamina propria\t\n\tLymphocytes\tPlasma cells\tMast cells\tEosinophils\t\nDuodenum\t66.3 ± 9.2\t28.7 ± 5.1\t12.3 ± 2.1\t4.8 ± 0.9\t\nJejunum\t70.8 ± 10.1\t26.4 ± 4.5\t9.6 ± 2.5\t4.2 ± 1.1\t\nRight colon\t65.5 ± 7.5\t27.9 ± 5.3\t8.2 ± 1.6\t3.5 ± 0.6\t\nLeft colon\t58.0 ± 6.7\t24.3 ± 3.9\t9.5 ± 1.0\t2.0 ± 0.3\t\n\n\nThe blood eosinophil count decreased after day 96, three months after the last injection of docetaxel. Despite 4 months of hypereosinophilia, we did not detect cardiac, respiratory, liver or renal complications.\n\nAfter day 182, the hypereosinophilia and symptoms resolved. This spontaneous evolution, the history of atopic dermatitis and asthma, and the negativity of all biological tests performed led us to hypothesize a diagnosis of a drug-induced hypersensitivity reaction (HSR). Using two validated pharmacovigilance scales, we found that docetaxel had the highest imputability score compared to the other drugs (Additional file 4: Figure S1 and Table 3).Table 3 Drug imputability scores\n\n\tAdverse Drug Reaction probability scale a\n\tFrench imputability score b\n\t\nDrugs\tScore\tIS\tC\tS\tIntrinsic imputability\t\nDocetaxel\t7\t2\t3\t3\t16\t\nOndansetrone\t4\t2\t1\t2\t12\t\nDiosmectite\t−1\t2\t0\t1\t10\t\nParacetamol\t−1\t2\t0\t1\t10\t\nFluconazole\t−1\t2\t0\t1\t10\t\nRacecadotril\t−1\t2\t0\t1\t10\t\nMetoclopramide\t−1\t2\t0\t1\t10\t\nOmeprazole\t−1\t2\t0\t1\t10\t\nPhloroglucinol\t−1\t2\t0\t1\t10\t\nPrednisone\t−1\t2\t0\t1\t10\t\n\nIS Informativeness score, C chronology, S semiology\n\n\naNaranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45\n\n\nbArimone Y, Bidault I, Dutertre JP, et al. Updating the French method for the causality assessment of adverse drug reactions. Therapie 2013;68:69–76\n\n\n\nDocetaxel, a semi-synthetic taxoid that inhibits depolymerization of microtubules, is currently approved for the treatment of breast, lung and prostate cancers. The most frequent adverse effects of docetaxel are hematological (pancytopenia) and digestive. Diarrhea is reported in 30 to 60 % of patients (Additional file 5: Table S3), often associated with severe oral mucositis. These toxic lesions (Type A adverse drug reaction) are predictable, dose-dependent reactions linked to prolonged or daily exposure to the drug [5], whereas HSR under docetaxel treatment (Type B immunologically-mediated adverse drug reaction according to Gell-Coombs classification, ref [5]) is dose-independent [6]. Severe HSR to docetaxel is observed in 3 % to 7.7 % of patients (Additional file 3: Table S2, and Reference [7] for review). Lethal drug-induced HSR has been reported in 0.05 % of 36,983 pati ents [8].\n\nIn the case of our patient who developed diarrhea and severe hypereosinophilia after the second injection of docetaxel, the two available pharmacovigilance scales concluded to docetaxel imputability. Since our patient had neither pancytopenia nor oral mucositis, and since docetaxel had not been administered daily or for a prolonged period, we concluded that the diarrhea was not related to a classic digestive toxicity but to Type B immune-mediated adverse drug reaction. The digestive symptoms occurred after the second injection of docetaxel, and the blood hypereosinophilia after the third injection concomitantly with elevated seric IgE. The digestive biopsies showed that the whole digestive tract was involved, with edema, large numbers of mast cells, and few eosinophils. Under electron microscopy, both eosinophils and mast cells were degranulated. Overall, these findings are in favor of a systemic digestive Type 1 hypersensitivity reaction.\n\nUsing specific antibodies (see Additional file 1: Methods), we showed that mast cells and eosinophils were distributed within the epithelium and the lamina propria. In bronchial biopsies of mild to moderate TH2-high asthma associated with blood eosinophilia [9], intra-epithelial mast cells co-expressed tryptase and carboxypeptidase A3, whereas mast cells of the lamina propria co-expressed tryptase and chymase. We also found these differential enzymatic co-expressions in epithelial and lamina propria mast cells in the digestive biopsies of our patient (Fig. 2d, e). In asthmatic and atopic patients, a similar immunoreactivity for IL-3, IL-5 and GM-CSF has also been found in bronchial and gut mucosa [10].\n\nConclusion\nWe here report a case of severe HSR with hypereosinophilia imputable to docetaxel. While this condition is rare, it is important to recognize it, since it requires the drug to be discontinued. Since blood hypereosinophilia over 1500/μL and lasting more than 1 month entails a risk of major organ dysfunction [1, 11], including death through cardiac failure [12], therapy discontinuation can be recommended if these conditions are observed. In the field of adverse reactions to anti-cancer drugs, this is particularly relevant for docetaxel treatment, which can be prolonged for several months in case of good response for metastatic breast, lung or prostate cancers. If reintroduction of this anti-cancer agent is needed, a close collaboration between oncologists, gastroenterologists and allergologists is required.\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 of this journal.\n\nAdditional files\nAdditional file 1: Methods M1. (DOCX 18 kb)\n\nAdditional file 2: Table S1. Published cases of blood hypereosinophilia imputable to anti-cancer drugs. (DOCX 15 kb)\n\nAdditional file 3: Table S2. Laboratory tests (DOCX 18 kb)\n\nAdditional file 4: Figure S1. Drug intake between day 0 (D0) and D182. D0 is the time of the first injection of docetaxel and D182 the time when all drugs were stopped. For drugs administered continuously like omeprazole, the period of drug intake is symbolized by a straight line between the first day and the last day of treatment. (JPG 81 kb)\n\nAdditional file 5: Table S3. Adverse events in clinical trials using docetaxel monotherapy. (DOCX 16 kb)\n\n\n\nAbbreviations\nHSRhypersensitivity reaction\n\nAnne Janin and Guilhem Bousquet are co-senior authors\n\nCompeting interests\n\nThe authors do not have any conflict of interest\n\nAuthors’ contributions\n\nDH, GB and AJ conceived and designed the study; DH and GB collected clinical data. CP performed electron microscopy. CL performed immunostainings. DH, CL, NJ, GB and AJ did analysis and interpretation of data. DH, GB and AJ wrote the manuscript. LV made a critical revision of the manuscript. All authors read and approved the final version of the manuscript.\n\nAcknowledgements\nThis work was supported by University-Paris-Diderot, INSERM.\n\nWe thank Massimiliano Orri for the algorithm design of literature search. Ms Angela Swaine reviewed the English language.\n==== Refs\nReferences\n1. Helbig G Advances in the diagnosis and treatment of eosinophilia Curr Opin Hematol 2014 21 1 3 7 10.1097/MOH.0000000000000011 24322486 \n2. Nutman TB Evaluation and differential diagnosis of marked, persistent eosinophilia Immunol Allergy Clin North Am 2007 27 3 529 49 10.1016/j.iac.2007.07.008 17868863 \n3. Weller PF Bubley GJ The idiopathic hypereosinophilic syndrome Blood 1994 83 10 2759 79 8180373 \n4. Desreumaux P Bloget F Seguy D Capron M Cortot A Colombel JF Interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 in eosinophilic gastroenteritis Gastroenterology 1996 110 3 768 74 10.1053/gast.1996.v110.pm8608886 8608886 \n5. Rive CM Bourke J Phillips EJ Testing for drug hypersensitivity syndromes Clin Biochem Rev 2013 34 1 15 38 23592889 \n6. Pazdur R Newman RA Newman BM Fuentes A Benvenuto J Bready B Phase I trial of Taxotere: five-day schedule J Natl Cancer Inst 1992 84 23 1781 8 10.1093/jnci/84.23.1781 1359154 \n7. Picard M Castells MC Re-visiting hypersensitivity reactions to taxanes: a comprehensive review Clin Rev Allergy Immunol 2015 49 2 177 91 10.1007/s12016-014-8416-0 24740483 \n8. Kadoyama K Kuwahara A Yamamori M Brown JB Sakaeda T Okuno Y Hypersensitivity reactions to anticancer agents: data mining of the public version of the FDA adverse event reporting system, AERS J Exp Clin Cancer Res 2011 30 93 10.1186/1756-9966-30-93 21970649 \n9. Dougherty RH Sidhu SS Raman K Solon M Solberg OD Caughey GH Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma J Allergy Clin Immunol 2010 125 5 1046 53 e8 10.1016/j.jaci.2010.03.003 20451039 \n10. Wallaert B Desreumaux P Copin MC Tillie I Benard A Colombel JF Immunoreactivity for interleukin 3 and 5 and granulocyte/macrophage colony-stimulating factor of intestinal mucosa in bronchial asthma J Exp Med 1995 182 6 1897 904 10.1084/jem.182.6.1897 7500035 \n11. Valent P Klion AD Horny HP Roufosse F Gotlib J Weller PF Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes J Allergy Clin Immunol 2012 130 3 607 12 10.1016/j.jaci.2012.02.019 22460074 \n12. Sohn KH Song WJ Kim BK Kang MK Lee SY Suh JW Eosinophilic myocarditis: case series and literature review Asia Pacific Allergy 2015 5 2 123 7 10.5415/apallergy.2015.5.2.123 25938077\n\n",
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"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D000077143:Docetaxel; D004342:Drug Hypersensitivity; D004802:Eosinophilia; D005260:Female; D041981:Gastrointestinal Tract; D006801:Humans; D043823:Taxoids",
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"title": "A digestive allergic reaction with hypereosinophilia imputable to docetaxel in a breast cancer patient: a case report.",
"title_normalized": "a digestive allergic reaction with hypereosinophilia imputable to docetaxel in a breast cancer patient a case report"
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"abstract": "Double-hit lymphomas are rare tumors that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14; 18)(q32;q21)involving BCL2. We report a case of a 38-yearold woman with a 2-month history of abdominaldistention. 18F-FDG PET showed multiple positive systemic lymph nodes, positive peritoneum, and multiple positive intra-abdominal masses. Histopathology results of the cervical lymph node were compatible with double-hit follicular lymphoma(Grade 3A)because fluorescence in situ hybridization(FISH)demonstrated both MYC rearrangement and BCL2 gene fusion. She was initially started on R-CHOP(rituximab and doxorubicin, vincristine, cyclophosphamide, and prednisolone), but after one course the regimen was changed to dose-adjusted EPOCH-R(rituximab and doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisolone). However, she showed no response to this chemotherapy regimen or haploidentical stem cell transplantation. The treatment strategy included salvage chemothera- py. An autologous and/or allogeneic hematopoietic transplantation is important for non-responders to DA-EPOCH-R.",
"affiliations": "Dept. of Hematology, Osaka City General Hospital.",
"authors": "Horiuchi|Mirei|M|;Fuseya|Hoyuri|H|;Tsutsumi|Minako|M|;Hayashi|Yoshiki|Y|;Hagihara|Kiyoyuki|K|;Kanashima|Hiroshi|H|;Nakao|Takafumi|T|;Fukushima|Yuko|Y|;Inoue|Takeshi|T|;Yamane|Takahisa|T|",
"chemical_list": "C000595707:BCL2 protein, human; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc",
"country": "Japan",
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"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D014178:Translocation, Genetic",
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"title": "Double-Hit Follicular Lymphoma with BCL2 and MYC Translocations.",
"title_normalized": "double hit follicular lymphoma with bcl2 and myc translocations"
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"abstract": "To investigate the prevalence of retinal pathology in patients with a history of exposure to pentosan polysulfate sodium (PPS).\nPatients exposed to PPS and seen in the ophthalmology clinic at Northwestern University during 1/1/2002 to 1/1/2019 were identified from electronic health records (EHR) by an electronic data warehouse (EDW) search. Visual acuity (VA), reasons for clinic visit, ocular conditions, and duration of exposure to PPS were noted. Chart review was performed for fundus exam findings and ophthalmologic imaging, specifically fundus photography, fundus autofluorescence, and ocular coherence tomography (OCT) images. When OCT or fundus photography was available, studies were evaluated by two independent graders.\nA total of 131 patients who were exposed to PPS and seen at the Northwestern Ophthalmology clinic were identified in the EHR. Forty patients of 131 had imaging. Patients with imaging or fundus examination suspicious for PPS maculopathy were placed into the suspect group. Of the 40 patients that had imaging, 5 (12.5%) had features suspicious for PPS maculopathy. Of the remaining 91, 5 (5.4%) had macular pigmentary changes described on fundus exam. Among the 10 patients in the suspect group, the average duration of PPS use was 4.2 years (range 0.3-11.6 years, interquartile range 5.5 years) and the average cumulative dose was 380g (range 29-1092g, interquartile range 132g).\nA novel drug-induced maculopathy has been associated with PPS use with a distinct clinical constellation that can be accurately identified with multimodal imaging.",
"affiliations": "Department of Ophthalmology, Northwestern University, Chicago, IL, USA.;Department of Ophthalmology, Northwestern University, Chicago, IL, USA.;Department of Ophthalmology, Northwestern University, Chicago, IL, USA.;Department of Ophthalmology, Northwestern University, Chicago, IL, USA.",
"authors": "Kalbag|Neil S|NS|;Maganti|Nenita|N|;Lyon|Alice T|AT|;Mirza|Rukhsana G|RG|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OPTH.S285013",
"fulltext": "\n==== Front\nClin Ophthalmol\nClin Ophthalmol\nopth\nclinop\nClinical Ophthalmology (Auckland, N.Z.)\n1177-5467 1177-5483 Dove \n\n285013\n10.2147/OPTH.S285013\nOriginal Research\nMaculopathy Secondary to Pentosan Polysulfate Use: A Single-Center Experience\nKalbag et alKalbag et alKalbag Neil S 1 Maganti Nenita 1 Lyon Alice T 1 Mirza Rukhsana G 1 1 Department of Ophthalmology, Northwestern University, Chicago, IL, USA\nCorrespondence: Rukhsana G Mirza Department of Ophthalmology, Northwestern University, Chicago, IL, USA Email r-mirza@northwestern.edu\n11 2 2021 \n2021 \n15 513 519\n05 10 2020 13 1 2021 © 2021 Kalbag et al.2021Kalbag et al.This work is published and licensed by Dove Medical Press Limited. The 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Aim\nTo investigate the prevalence of retinal pathology in patients with a history of exposure to pentosan polysulfate sodium (PPS).\n\nMethods\nPatients exposed to PPS and seen in the ophthalmology clinic at Northwestern University during 1/1/2002 to 1/1/2019 were identified from electronic health records (EHR) by an electronic data warehouse (EDW) search. Visual acuity (VA), reasons for clinic visit, ocular conditions, and duration of exposure to PPS were noted. Chart review was performed for fundus exam findings and ophthalmologic imaging, specifically fundus photography, fundus autofluorescence, and ocular coherence tomography (OCT) images. When OCT or fundus photography was available, studies were evaluated by two independent graders.\n\nResults\nA total of 131 patients who were exposed to PPS and seen at the Northwestern Ophthalmology clinic were identified in the EHR. Forty patients of 131 had imaging. Patients with imaging or fundus examination suspicious for PPS maculopathy were placed into the suspect group. Of the 40 patients that had imaging, 5 (12.5%) had features suspicious for PPS maculopathy. Of the remaining 91, 5 (5.4%) had macular pigmentary changes described on fundus exam. Among the 10 patients in the suspect group, the average duration of PPS use was 4.2 years (range 0.3–11.6 years, interquartile range 5.5 years) and the average cumulative dose was 380g (range 29–1092g, interquartile range 132g).\n\nConclusion\nA novel drug-induced maculopathy has been associated with PPS use with a distinct clinical constellation that can be accurately identified with multimodal imaging.\n\nKeywords\ninterstitial cystitisICmaculopathypentosan polysulfate sodiumPPSNo financial support was received for this studyNo financial support was received for this study.\n==== Body\nIntroduction\nInterstitial cystitis (IC) or bladder pain syndrome is a chronic condition that causes pain or pressure in the bladder, predominantly in women.1 The pathophysiology of this disease is still unknown. In the US, 2.7–6.5% of the population is affected by IC.1 Antihistamines, tricyclic antidepressants, cyclosporine, bacille Calmette-Guérin, nitric oxide, and pentosane polysulfate (PPS) have all been used to treat IC.2 PPS is a sulfated polysaccharide, with a structure similar to heparin and glycosaminoglycan and is the only United States Food and Drug Administration (FDA)-approved drug for IC, typically dosed at 100mg three times per day.3 It works as a mucosal protecting agent in the bladder to provide symptomatic relief by binding to the uroepithelium and reducing permeability to decrease irritation from toxins.3\n\nLong-term studies on PPS report nausea, diarrhea, and headache as the common adverse effects.3 Pearce et al recently described a unique pigmentary maculopathy associated with chronic exposure to PPS in which toxic changes to the retina in 6 out of 38 patients studied at a single center were described.4 They noted changes in the retinal pigment epithelium including parafoveal pigmented deposits, paracentral atrophy, and hyperreflective lesions.4 Further studies have shown that key features of PPS-associated maculopathy include a hypoautofluorescent peripapillary halo on imaging and early involvement of the central macula.5 Prior to understanding the new maculopathy, several patients were diagnosed as having macular dystrophies and hereditary maculopathies.5 Prospective studies by Wang et al and Vora et al have reported the prevalence of PPS-associated maculopathy to be 20% and 23.1% respectively.6,7 Theorized mechanisms include the antagonism of the fibroblastic growth factor pathway in the retina by PPS, specifically in the retinal pigmental epithelium layer (RPE), PPS being directly toxic to the retina, or interaction between PPS and the glycosaminoglycans in the photoreceptor layer of the retina.8,9 Although PPS was approved by the FDA in 1996, it was only recently in June of 2020 that the FDA released an updated label to include retinal pigmentary changes as a warning and adverse effect of the drug.\n\nThis study reports retinal changes noted in patients on PPS, for any duration of the drug, at a tertiary-care center to add to the previously reported single-center case series. The current state of identification of this disease, steps to understand the association versus causation between PPS and pigmentary maculopathy, and changes to improve identification of this condition are also discussed.\n\nMethods\nA retrospective study was performed on patients from the Northwestern Medicine EPIC electronic health records (EHR) by using an Electronic Data Warehouse (EDW) search. The study cohort included patients aged 18–95 years who had been exposed to PPS and seen in the Northwestern ophthalmology clinic from January 1, 2002 to January 1, 2019. An EDW query was performed to obtain visual acuities, duration of drug, dose of drug, other health conditions, and demographics for patients in the study group. Patient charts were reviewed by study team members for fundus findings documented in the examination and ophthalmologic imaging, specifically multimodal imaging including fundus photography, fundus autofluorescence, and ocular coherence tomography (OCT) images. When imaging was available, the images were evaluated by at least two independent ophthalmologists. In cases where imaging was not available, patient charts were reviewed for fundus examinations with clinical documentation of macular pigmentary changes such as pigmentary clumping or mottling. Subjective complaints were not utilized to identify suspicious findings. Patients with fundus exam or imaging findings suspicious for PPS-associated maculopathy as described by Pearce et al were separated into the suspect group for further evaluation.\n\nThis study was approved by the Institutional Review Board of Northwestern University. All data accessed complied with relevant data protection and privacy regulations. Descriptive statistics were used to summarize patient demographics. Continuous measures were summarized with means and standard deviations (SD), and categorical measures were summarized with frequencies and percentages. SAS version 9.4 (SAS Institute, Cary, NC) was used for all statistical analyses.\n\nResults\nThe study cohort comprised a total of 262 eyes of 131 patients. One hundred and eleven (84.7%) patients were female, and the cohort’s average age was 59.5 (±16.1) years old (range: 21–90). Demographic data are shown in Table 1. Of the 131 patients, 40 patients (30.5%) had imaging while 91 (69.5%) did not. Of the 40 patients with imaging on file, 5 (12.5%) had findings suspicious for PPS-associated maculopathy and of the 91 patients without imaging, 82 patients had documented fundus examinations and 5 (6.1%) of such patients were noted to have macular pigmentary changes. The 5 patients with imaging findings suspicious for PPS maculopathy and the other 5 patients with macular pigmentary changes were separated into a suspect group.Table 1 Characteristics of Patients Taking Pentosan Polysulfate Sodium\n\n\tAll Patients\tPatients in Suspect Group\tPatients without Suspicious Features\t\n\tN\tMean\tSD\tN\tMean\tSD\tN\tMean\tSD\t\nAge (years)\t131\t59.5\t16.1\t10 (7.6%)\t67.3\t12.0\t121 (92.4%)\t58.5\t16.3\t\nGender\t\n Male\t20 (15.3%)\t\t\t2 (20%)\t20\t\t18 (14.9%)\t17.5\t\t\n Female\t111 (84.7%)\t\t\t8 (80%)\t80\t\t103 (85.1%)\t82.5\t\t\n\tRange (Interquartile Range)\tMean\tMedian\tRange (Interquartile Range)\tMean\tMedian\tRange (Interquartile Range)\tMean\tMedian\t\nVisual acuity logMAR\t0–1.6\t0.19\t0.1\t0–1.6\t0.19\t0.1\t0–1.6\t0.19\t0.1\t\nPPS duration (years)\t0.1–19.1 (5.3)\t3.7\t2.0\t0.3–11.6 (5.5)\t4.2\t3.0\t0.1–19.1 (5.3)\t3.6\t1.7\t\nCumulative dose (g)\t0.3–2086 (468.1)\t430.2\t272.7\t29–1092 (132)\t380\t319\t0.3–2086 (645.7)\t442\t188.1\t\n\n\n\nIndividual examination and imaging findings for the suspect group and their classification based on degree of suspicion as described in a recent paper by Hanif et al are shown in Table 2.10 Patients 8 and 9 had the most striking findings including pigmentary changes around the fovea (Figures 1 and 2) with both hyper- and hypoautofluorescent pigmentary changes associated with vitelliform/hyperreflective lesions on OCT. Patient 8 had multiple studies over a 5 year period documenting progression of RPE atrophy in the late stage of the disease. (Figure 3).Table 2 Clinical Findings in Patients Suspicious for PPS-Associated Maculopathy\n\nPatient #\tClinical Exam Findings\tImage Type and Findings\tCategory per Hanif et al\tReason for Examination\t\nPatient 1\tRPE mottling\tFundus photo; paracentral macular pigmented spots\t2\tGlaucoma suspect\t\nPatient 2\tMild RPE mottling\tOCT; retinal pigment epithelial mottling\t3\tDiabetic screening exam\t\nPatient 3\tRetinal pigment epithelial mottling\tOCT; retinal pigment epithelial mottling\t2\tOpen angle glaucoma\t\nPatient 4\tEarly age-related macular degeneration\tNo imaging available\t2\tNuclear cataract\t\nPatient 5\tNormal macula\tOCT; retinal pigment epithelial mottling and mild pigment clumping\t2\tNuclear cataract\t\nPatient 6\tParafoveal pale yellow spots\tNo imaging available\t2\tDry age-related macular degeneration\t\nPatient 7\tVery fine central drusen\tNo imaging available\t3\tPosterior vitreous detachment\t\nPatient 8\tMultiple drusen, pigmentary atrophy, pigment mottling\tFAF, OCT; Reticular hypo- and hyperautofluorescent spots, pigment mottling, large areas of confluent RPE atrophy, Focal RPE enlargement\t1\tDry age-related macular degeneration\t\nPatient 9\tMultiple drusen, pigment mottling\tFAF, OCT: Reticular hypo- and hyperautofluorescent spots, pigment mottling, subretinal hyperreflective deposits\t1\tPigmentary retinal dystrophy\t\nPatient 10\tDrusen, hard drusen, ERM, mild pigmentary change\tNo imaging available\t3\tDrusen\t\nAbbreviations: N/A, not available; OCT, ocular coherence tomography; FAF, fundus autofluorescence.\n\n\nFigure 1 (Patient 9) Fundus photography: Fundus autofluorescence at early stage of disease showing pigment mottling, reticular hypoautofluorescent and hyperautofluorescent spots, and focal areas of RPE enlargement.\n\nFigure 2 (Patient 8) OCT: Later stage of the disease shows large areas of confluent RPE atrophy.\n\nFigure 3 (Patient 8) Fundus autofluorescence at presentation and 4 years later, depicting the increase in areas of RPE atrophy.\n\n\n\nThe average logMAR visual acuity (VA) for all 131 patients was 0.19. The mean duration of PPS use and mean cumulative dose in the suspect group were 4.2 years and 380g respectively and in the non-suspect group were 3.6 years and 442g (Table 1). Common other diagnoses for which patients were seen in the ophthalmology clinic included ocular surface issues (blepharitis, dry eye syndrome, meibomian gland dysfunction) (n=37), cataract: pre- or post-op (n=30), glaucoma/ocular hypertension (n=7), diabetic retinopathy surveillance (n=6), uveitis (n=8), and other issues including posterior vitreous detachment, retinal tear, esotropia, and migraine (n=23).\n\nDiscussion\nOur study evaluated the prevalence of retinal pathology in a cohort of patients who had been exposed to PPS and examined in a tertiary care setting. Pearce et al described a potential association between chronic use of PPS and the development of a vision-threatening maculopathy,4 and Hanif et al recently reported a strong causal relationship between the two.4,9,10 An associated study with 35 patients noted that this maculopathy is associated with long-term exposure to PPS with a median of 15 years and a range of 3–22 years.10 Common symptoms of the maculopathy included difficulty reading, metamorphopsia, impaired dark adaptation, and nyctalopia.11 While several studies have shown the association of PPS to a maculopathy, some studies have discussed the possibility of IC causing the maculopathy itself.12,13\n\nGiven these findings, we conducted a retrospective chart review at our institution to look for evidence of retinal pathology in patients with PPS. Our suspect group was found to have been taking PPS for an average of 4.2 years and an average dosage 380g respectively while the non-suspect group took it for an average of 3.6 years at 442g. However, the median cumulative dosage for the non-suspect group was lower than that of the suspect group at 188.1g as opposed to 317g. This suggests that a majority of patients without pigmentary changes had lower exposure to the drug, with either a shorter duration and/or lower doses when compared to those in the suspect group.\n\nTwo patients from our cohort had fundus findings that were consistent with the maculopathy described by Pearce et al. However, it is of note that even patients with as little as 0.3 years on the drug had evidence of pigmentary changes documented in their chart. In our study cohort, age, gender, visual acuity, and duration of drug therapy were not found to be significant factors in the development of PPS-related maculopathy.\n\nAlthough this is a retrospective analysis, this emphasizes the need to start monitoring patients on PPS early on as well as documenting a baseline comprehensive eye exam to identify any changes that occur during the use of the drug. When pathology was noted, it was commonly diagnosed as age-related macular degeneration or pattern dystrophy. Such diagnoses were also noted in the prior study by Hanif et al.8 Imaging analyses reported by Hadad et al showed that all patients (n=17) using 100mg of PPS daily for at least 3 years had mottling changes of the retina on near-infrared imaging, 75% of patients showed a hypoautofluorescence defect in the macula similar to those reported by Pearce et al,4 and hyperreflectivity, thickening of the foci of the RPE, and a flying saucer macular sign were also noted on OCT imaging.14\n\nA recent prospective study by Wang et al found that patients with a cumulative dosage over 1500g had a significant risk of developing a PPS-associated maculopathy.6 They recommend baseline ophthalmological examinations with multimodal imaging of patients who are to receive PPS in a cumulative dose of about 500g. In our study cohort, Patient 9 was found to have prominent macular pigmentary findings that were consistent with the previously described PPS-associated maculopathy. However, this patient only had a cumulative dosage of 304.4g. Further study is needed to determine at what cumulative dosage patients become at risk for the development of PPS-associated macular changes.\n\nAdditionally, some patients in our suspect group were examined in the clinic post-drug cessation, so it is unclear at which point in their course of treatment pigmentary changes developed. A recent case study discussed the possibility of progressing maculopathy after discontinuation of the drug, where a 67-year-old woman with a history of PPS use for 18 years presented with worsening vision despite stopping the drug at the age of 62.15 Additionally, a retrospective study by Shah et al proposed that pigmentary changes can continue to develop for at least ten years after the cessation of PPS.16 Longitudinal study is required to understand the course of the PPS-associated maculopathy development.\n\nStrengths of our work include the fact that our study cohort includes all patients taking PPS seen at the Northwestern Ophthalmology clinic during our study period, not just those seen in by a retina specialist. This prevented potential bias towards the existence of retinal findings. We were able to establish a relationship between the drug and macular pathology, and confirm recent findings by other authors. Lastly, since it was a retrospective study, there was minimal selection or recall bias. There are limitations to our study. Given that it was a single center study, the number of patients included in the analysis were limited. Consequently, our non-suspect group does not serve strictly as a control group because patients in both the suspect and non-suspect group experienced ocular comorbidities. This is one likely explanation for the lack of difference in average visual acuity between the two groups. Additionally, dates of medication discontinuation may not always be entered into the appropriate sections of the EHR and patients occasionally discontinue their medications on their own. The last date of PPS use was missing in the EHR for 48% of our patients, who may or may not have discontinued the drug. This affected our analysis for the true duration and cumulative dosage of the drug. Because of the retrospective nature of this study, data was derived from the existing EHR. Consequently, not all patients in the cohort had imaging on file, likely because conditions for which they were seen in the ophthalmology clinic frequently did not warrant any multimodal or posterior segment imaging. Even when posterior segment examination was performed, mild findings of early stages of the retinopathy could be easily missed. Educating eye providers is critical in early identification of patients who are on the drug, improving detection of new changes that develop during therapy, and ensuring regular follow up. Further, patients should be counseled on the potential side effects of the drug along with a careful consideration of the risks and benefits prior to starting PPS therapy. Lyons et al also recommend prescribing the lowest dose and duration of the medication if the decision to start PPS is made.17\n\nOur study adds to the growing body of work that supports the presence of a distinct pigmentary maculopathy associated with chronic usage of PPS. Future study is warranted, and guidelines are in the process of being established for the screening for PPS-associated maculopathy. A prospective analysis employing baseline ophthalmologic exams, regular follow-up, along with multimodal imaging is important in understanding the course of the disease while patients are on the medication as well as after discontinuation.\n\nAcknowledgments\nSaena A. Sadiq, BS for her work which was critical in the revision of the manuscript, including additional literature review and incorporation of new findings into the manuscript, updating the tables, and reformatting the images.\n\nDisclosure\nThe authors have no proprietary or commercial interest in any of the materials discussed in this article and report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Berry \nSH , Elliott \nMN , Suttorp \nM , et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States\n. J Urol . 2011 ;186 (2 ):540 –544\n. doi:10.1016/j.juro.2011.03.132 21683389 \n2. Chancellor \nMB , Yoshimura \nN . Treatment of interstitial cystitis\n. Urology . 2004 ;63 (3 ):85 –92\n. doi:10.1016/j.urology.2003.10.034 15013658 \n3. Anderson \nVR , Perry \nCM . Pentosan polysulfate\n. Drugs . 2006 ;66 (6 ):821 –835\n. doi:10.2165/00003495-200666060-00006 16706553 \n4. Pearce \nWA , Chen \nR , Jain \nN . Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium\n. Ophthalmology . 2018 ;125 (11 ):1793 –1802\n. doi:10.1016/j.ophtha.2018.04.026 29801663 \n5. Barnes \nAC , Hanif \nAM , Jain \nN . Pentosan polysulfate maculopathy versus inherited macular dystrophies: comparative assessment with multimodal imaging\n. Ophthalmol Retina . 2020 ;4 (12 ):1196 –1201\n. doi:10.1016/j.oret.2020.05.008 32446908 \n6. Wang \nD , Au \nA , Gunnemann \nF , et al. Pentosan-associated maculopathy: prevalence, screening guidelines, and spectrum of findings based on prospective multimodal analysis\n. Can J Ophthalmol . 2020 ;55 (2 ):116 –125\n. doi:10.1016/j.jcjo.2019.12.001 31973791 \n7. Vora \nRA , Patel \nAP , Melles \nR . Prevalence of maculopathy associated with long-term pentosan polysulfate therapy\n. Ophthalmology . 2020 ;27 (6 ):835 –836\n. doi:10.1016/j.ophtha.2020.01.017 \n8. Greenlee \nT , Hom \nG , Conti \nT , Babiuch \nAS , Singh \nR . Re: pearce et al.: pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium (Ophthalmology. 2018; 125 (11):1793-1802)\n. Ophthalmology . 2019 ;126 (7 ):e51 . doi:10.1016/j.ophtha.2018.12.037 \n9. Hanif \nAM , Armenti \nST , Taylor \nSC , et al. Phenotypic spectrum of pentosan polysulfate sodium–associated maculopathy: a multicenter study\n. JAMA Ophthalmol . 2019 ;137 (11 ):1275 . doi:10.1001/jamaophthalmol.2019.3392 \n10. Hanif \nAM , Shah \nR , Yan \nJ , et al. Strength of association between pentosan polysulfate and a novel maculopathy\n. Ophthalmology . 2019 ;126 (10 ):1464 –1466\n. doi:10.1016/j.ophtha.2019.04.024 31004677 \n11. Mogica \nJAP , De \nEJB . Pentosan polysulfate maculopathy: what urologists should know in 2020\n. Urology . 2020 ;S0090-4295(20)31240-1.\n12. Ludwig \nCA , Vail \nD , Callaway \nNF , Pasricha \nMV , Moshfeghi \nDM . Pentosan polysulfate sodium exposure and drug-induced maculopathy in commercially insured patients in the United States\n. Ophthalmology . 2020 ;127 (4 ):535 –543\n. doi:10.1016/j.ophtha.2019.10.036 31899034 \n13. Jain \nN , Li \nAL , Yu \nY , VanderBeek \nBL . Association of macular disease with long-term use of pentosan polysulfate sodium: findings from a US cohort\n. B J Ophthalmol . 2020 ;104 (8 ):1093 –1097\n. doi:10.1136/bjophthalmol-2019-314765 \n14. Hadad \nA , Helmy \nO , Leeman \nS , Schaal \nS , Novel Multimethod \nA . A novel multimethod image analysis to quantify pentosan polysulfate sodium retinal toxicity\n. Ophthalmology . 2020 ;127 (3 ):429 –431\n. doi:10.1016/j.ophtha.2019.10.013 31757495 \n15. Huckfeldt \nRM , Vavvas \nDG . Progressive maculopathy after discontinuation of pentosan polysulfate sodium\n. Ophthalmic Surg Lasers Imaging Retina . 2019 ;50 (10 ):656 –659\n. doi:10.3928/23258160-20191009-10 31671200 \n16. Shah \nR , Simonett \nJM , Lyons \nRJ , Rao \nRC , Pennesi \nME , Jain \nN . Disease course in patients with pentosan polysulfate sodium-associated maculopathy after drug cessation\n. JAMA Ophthalmol . 2020 ;138 (8 ):894 –900\n. doi:10.1001/jamaophthalmol.2020.2349 32644147 \n17. Lyons \nRJ , Ahmad \nS , Ansari \nS , Foote \nJE , Jain \nN . Pentosan polysulfate-associated macular disease in patients with interstitial cystitis\n. Obstet Gynecol . 2020 ;135 (5 ):1091 –1094\n. doi:10.1097/AOG.0000000000003794 32282604\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "15()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "IC; PPS; interstitial cystitis; maculopathy; pentosan polysulfate sodium",
"medline_ta": "Clin Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101321512",
"other_id": null,
"pages": "513-519",
"pmc": null,
"pmid": "33603329",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "32282604;31671200;31899034;31004677;31229012;15013658;32644147;32085877;32446908;31973791;29801663;31694837;16706553;31486843;31757495;21683389",
"title": "Maculopathy Secondary to Pentosan Polysulfate Use: A Single-Center Experience.",
"title_normalized": "maculopathy secondary to pentosan polysulfate use a single center experience"
} | [
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"companynumb": "US-JNJFOC-20210221172",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "PENTOSAN POLYSULFATE SODIUM"
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{
"abstract": "OBJECTIVE\nThe purpose of this study was to determine the fertility rates following treatment by means of the BEACOPP regimen (regular and escalated) (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) as compared to the ABVD regimen (doxorubicin, vinblastine, dacarbazine, bleomycin) in Hodgkin lymphoma patients under the age of 40 at the time of treatment.\n\n\nMETHODS\nA questionnaire was sent to 180 Hodgkin lymphoma (HL) patients. The questionnaire was composed of questions concerning reproduction and also menopausal and aging symptoms in females and males. The analyses were made using data collected from 123 patients (76 females and 47 males) who returned the questionnaire. All of the patients were treated between 1999 and 2012.\n\n\nRESULTS\nIn comparing the ABVD and BEACOPP groups of female patients, the frequency of the therapy-induced amenorrhea and the restored menses following treatment were found to be significantly different statistically (p = 0.002 and p = 0.012, respectively). The secondary amenorrhea statistically appeared more often in the BEACOPP group (p = 0.003) while the cases of achieving pregnancy and having children after chemotherapy were not significantly different (p = 0.630, p = 0.070, respectively). In comparing the ABVD and BEACOPP treatments in male patients, the only significant difference was in the number of artificially inseminated or in vitro pregnancies achieved in the BEACOPP and escalated BEACOPP group, p = 0.008 and p = 0.002, respectively. In total, 45.2% of patients in the ABVD female group, 34.6% in the BEACOPP female group, 52.6% in the ABVD male group, and 33.3% in the male BEACOPP group, respectively, of patients attempting conception post-therapy, had children after chemotherapy.\n\n\nCONCLUSIONS\nBased on these high rates of childbirth following BEACOPP chemotherapy, we have concluded that intensified chemotherapy is not a definite predictor of reduced fertility in young HL patients.",
"affiliations": "Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000, Ljubljana, Slovenia.;Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia.;Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000, Ljubljana, Slovenia. bjezersek@onko-i.si.",
"authors": "Boltežar|Lučka|L|;Pintarić|Karlo|K|;Jezeršek Novaković|Barbara|B|",
"chemical_list": "D001761:Bleomycin; D011344:Procarbazine; D014750:Vincristine; D014747:Vinblastine; D005047:Etoposide; D003606:Dacarbazine; D004317:Doxorubicin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10815-015-0636-6",
"fulltext": "\n==== Front\nJ Assist Reprod GenetJ. Assist. Reprod. GenetJournal of Assisted Reproduction and Genetics1058-04681573-7330Springer US New York 63610.1007/s10815-015-0636-6Fertility PreservationFertility in young patients following treatment for Hodgkin’s lymphoma: a single center survey Boltežar Lučka Pintarić Karlo Jezeršek Novaković Barbara +38615879631bjezersek@onko-i.si Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia 17 12 2015 17 12 2015 3 2016 33 3 325 333 15 8 2015 8 12 2015 © The Author(s) 2015\nOpen Access This 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.Purpose\nThe purpose of this study was to determine the fertility rates following treatment by means of the BEACOPP regimen (regular and escalated) (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) as compared to the ABVD regimen (doxorubicin, vinblastine, dacarbazine, bleomycin) in Hodgkin lymphoma patients under the age of 40 at the time of treatment.\n\nMethods\nA questionnaire was sent to 180 Hodgkin lymphoma (HL) patients. The questionnaire was composed of questions concerning reproduction and also menopausal and aging symptoms in females and males. The analyses were made using data collected from 123 patients (76 females and 47 males) who returned the questionnaire. All of the patients were treated between 1999 and 2012.\n\nResults\nIn comparing the ABVD and BEACOPP groups of female patients, the frequency of the therapy-induced amenorrhea and the restored menses following treatment were found to be significantly different statistically (p = 0.002 and p = 0.012, respectively). The secondary amenorrhea statistically appeared more often in the BEACOPP group (p = 0.003) while the cases of achieving pregnancy and having children after chemotherapy were not significantly different (p = 0.630, p = 0.070, respectively). In comparing the ABVD and BEACOPP treatments in male patients, the only significant difference was in the number of artificially inseminated or in vitro pregnancies achieved in the BEACOPP and escalated BEACOPP group, p = 0.008 and p = 0.002, respectively. In total, 45.2 % of patients in the ABVD female group, 34.6 % in the BEACOPP female group, 52.6 % in the ABVD male group, and 33.3 % in the male BEACOPP group, respectively, of patients attempting conception post-therapy, had children after chemotherapy.\n\nConclusions\nBased on these high rates of childbirth following BEACOPP chemotherapy, we have concluded that intensified chemotherapy is not a definite predictor of reduced fertility in young HL patients.\n\nKeywords\nHodgkin lymphomaABVDBEACOPPSecondary amenorrheaFertility following treatmentMinistry of Science and Technology, SloveniaP3-0321issue-copyright-statement© Springer Science+Business Media New York 2016\n==== Body\nIntroduction\nHodgkin lymphoma (HL) is one of the most curable types of lymphoma [1]. Patients are usually young when treated with chemotherapy [2, 3], so being aware of the postliminary consequences of oncologic treatment is crucial. Chemotherapy has been linked to gonadal damage [2–5], with myeloablative therapy increasing the likelihood of childlessness [6]. A study by Meirow et al. on female reproductive organs showed that premature ovarian failure is more frequent in women over 30 years of age, and that this depends on the chemotherapeutic regimen and the particular dose of pelvic irradiation [3]. Especially toxic to the ovarian tissue are alkylating agents [2, 5, 7]. For male patients, Rueffer et al. demonstrated that 70 % of patients suffer from disease-related gonadal dysfunction and semen abnormality even before the initiation of treatment [8]. Today, semen analysis and cryoconservation prior to HL treatment is part of the standard procedure [4, 9].\n\nThere have been many studies dealing with fertility in patients following HL treatment performed to the present day [2, 4–6, 10–12]. The dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, where the alkylating agents are cyclophosphamide and procarbazine) regimen has been linked to a higher incidence of secondary amenorrhea than the ABVD regimen (doxorubicin, vinblastine, dacarbazine, and bleomycin, where an alkylating agent is dacarbazine); these two being the most frequently used regimens [3, 4, 13]. The latest largest study by Behringer et al. showed that hormone levels correlated with the intensity of chemotherapy as well as the fact that survivors (following BEACOPP treatment for advanced-stage disease) had the highest risk of symptomatic gonadal dysfunction [13].\n\nThe aim of this study was to determine whether the BEACOPP regimen (regular and escalated) compared to the ABVD regimen’s reportedly low fertility rates in Hodgkin lymphoma patients under the age of 40 at the time of treatment.\n\nPatients and methods\nPatients\nThe study population included 180 adult patients with HL, who received treatment at the Institute of Oncology in Ljubljana between 1999 and 2012 and were also under age of 40 at the time of treatment. All of these patients were treated with chemotherapy in form of the ABVD (mostly stages I and II) or BEACOPP regimen (mostly stages III or IV until 2011 with 4 cycles of escalated and 4 cycles of regular BEACOPP and, from 2012 on with 6 cycles of escalated BEACOPP). Patients with the nodular lymphocyte predominant type of HL, treated only with irradiation, were excluded from the evaluation as well as patients who received other treatment regimens, i.e., patients treated with pediatric protocols. Patients whose histological diagnosis was inconclusive were also excluded. Informed consent was obtained from all individual participants included in the study and the study was approved by the national ethical committee.\n\nQuestionnaire\nWe designed a questionnaire including questions about how many pregnancies patients had had before chemotherapy, how many children they had had before chemotherapy, whether or not their menstrual cycle was regular prior to treatment, and whether or not it returned after treatment. Questions concerning the number of children born and pregnancies achieved following treatment were also included, as were the questions regarding embryo/oocyte cryopreservation and in vitro fertilization. For females, the questionnaire, the Menopausal Rating Scale (MRS) [14, 15], was translated into Slovene language comprising the 11 complaints, but without scoring every complaint individually. Patients evaluated their total menopausal symptoms (hot flushes, sweating, unpleasant sensation of impulsive heart palpitations, sleeping disorders, a more depressed mood, irritability, exhaustion, bladder difficulties, vaginal dryness, muscle, and joint pain) with a score from 1 to 10. For males, questions dealing with children engendered before and after chemotherapy were the same. Our male patients were also asked to answer whether or not they had had sperm cryopreservation and whether they had used it for fertilization. The Aging Males’ Symptoms scale (AMS) [16] was also translated into Slovene language scoring the overall complaints on a scale from 1 to 10 (muscle and joint pain, hot flushes, sleeping disorders, excessive need to sleep, a more depressed mood, irritability, exhaustion, loss of physical strength, diminished hair growth, fewer morning erections, loss of sexual desire). The MRS and AMS part of the questionnaire were a subjective measure of patients’ symptoms.\n\nIn the questionnaire, questions regarding a partner’s fertility were not asked nor were questions about birth control. The male questionnaire comprised no questions including testosterone treatment of any kind. However, at the end of the questionnaire, all patients were encouraged to comment on any of the questions included as well as state whether they had had as many children as they had wanted as well as whether they were trying to have children post-treatment.\n\nDetermination of hormonal levels as well as gynecological examinations to evaluate patients’ fertility status was not a part of this study.\n\nPrior to sending out the questionnaire, each of the 180 patients included in the study population was called in order to obtain her/his consent for the questionnaire. After obtaining consent, the survey was mailed to their address. Four weeks later, the filled in questionnaires (signed and with informed consent) were included in a further analysis, while the non-responders were neither called nor resent the questionnaire. Patients were uncompensated for participation in the study.\n\nStatistics\nThe tests used for analyses included the chi-square, unpaired t test, Pearson’s correlation test, Mann-Whitney test, and the ANOVA test (for age correlation concerning the number of children born before and after treatment, three subgroups were made: 0—no children, 1—1 child, 2—two or more children). The p value <0.05 (two-sided) was considered to be statistically significant. The programs used included the SPSS Statistics (version 19.0, IBM SPSS Inc., USA) and the GraphPad Prism program (version 3.02, GraphPad Software, USA).\n\nResults\nPatients’ characteristics\nA total of 131 (72.78 %) of the 180 patients contacted returned a completed questionnaire. Eighty-two were female (85 % response rate), 49 were male (58 % response rate). Following the aforementioned exclusions, 123 questionnaires were analyzed. Patients were divided into two groups: one that received the ABVD treatment and the other that received the BEACOPP treatment, either regular or escalated. If the patient began with BEACOPP and was later treated with ABVD for whatever reason, he or she was assigned to the BEACOPP group. The BEACOPP group was further subdivided into escalated and normal dosing subgroups for the purpose of statistical analyses. All patients who received at least one cycle of escalated BEACOPP were included into the eBEACOPP subgroup.\n\nThere was no significant difference in the disease stage or treatment of those who returned the questionnaire and those who did not (p = 0.348 and p = 0.244, respectively). Patients answered the questionnaire between 2 and 16 years after treatment with a median of 9 years. The number of children patients had before the treatment had no influence on the selection of therapy regimen. None of the patients were prescribed gonadotropin-releasing hormone analogues during their treatment.\n\nFemale survivors\nIn the ABVD group, the median age at the time of treatment was 26 years (range 18–39) (Table 1). Two (4.3 %) patients had stage I of the disease, 39 (84.8 %) patients had stage II, one (2.2 %) patient had stage III, and four (8.7 %) patients had stage IV of the disease. Two (4.3 %) patients suffered from constitutional symptoms. Nine patients (19.6 %) had bulky disease and two (4.3 %) had extranodal involvement. Ninety-three point five percent of patients reported a regular menstrual cycle prior treatment. The median number of chemotherapy cycles received was 4 (range 2–8). One (2.2 %) patient had her pelvis irradiated with 23.4 Gy and underwent oocyte cryopreservation prior to treatment. Six patients (13.0 %) relapsed after first line treatment, five received salvage chemotherapy, and one underwent surgical removal of the involved lymph node. All but one, are at present in complete remission (CR).Table 1 Female patients’ characteristics\n\n\tABVD group\tBEACOPP group\t\np value\t\nNumber of patients\t46\t30 (19e/11b)\tNA\t\nMedian age in years at diagnosis (range)\t26 (range 18–39)\t26.5 (range 20–36)\t\np = 0.869\t\nStage of disease prior to treatment\t\n I\t2 (4.3 %)\t0 (0 %)\tNA\t\n II\t39 (84.8 %)\t10 (33.3 %)\tNA\t\n III\t1 (2.2 %)\t5 (16.7 %)\tNA\t\n IV\t4 (8.7 %)\t15 (50.0 %)\tNA\t\n A/B\t44 (95.7 %)/2 (4.3 %)\t21 (70.0 %)/9 (30.0 %)\t\np = 0.005\n\t\n X\t9 (19.6 %)\t9 (30.0 %)\t\np = 0.408\t\n E\t2 (4.3 %)\t7 (23.3 %)\t\np = 0.025\n\t\nMedian number of cycles (range)\t4 (range 2–8)\t8 (range 4–8)\tNA\t\nCR/PR after chemotherapy\t8 (17.4 %)/38 (82.6 %)\t12 (40.0 %)/18 (60.0 %)\t\np = 0.036\n\t\nIrradiation of the pelvis\t1 (2.2 %)\t0 (0 %)\t\np = 1.000\t\nNumber of patients receiving at least 1 cycle of eBEACOPP\t0 (0 %)\t19 (63.3 %)\tNA\t\nNumber of patients with children before treatment\t17 (37.0 %)\t16 (53.3 %)\t\np = 0.154\t\nRegular cycle before treatment\t43 (93.5 %)\t28 (93.3 %)\t\np = 1.000\t\nEmbryo/oocyte cryopreservation\t2 (4.3 %)\t0 (0 %)\t\np = 0.516\t\nTherapy-induced amenorrhea\t17 (37.0 %)\t23 (76.7 %)\t\np = 0.002\n\t\nRestored menses after treatment\t14 (82.4 %)\t10 (43.5 %)\t\np = 0.012\n\t\nSecondary amenorrheab\n\t3 (6.5 %)\t13 (43.3 %)\t\np = 0.003\n\t\nAll pregnancies after treatment/in vitro fertilizationa\n\t21/1 (4.8 %)\t10/0 (0 %)\t\np = 0.630\t\nNumber of patients attempting conception post-treatment\t42 (91.3 %)\t26 (86.7 %)\t\np = 0.879\t\nNumber of patients having children after treatmentc\n\t19 (45.2 %)\t9 (34.6 %)\t\np = 0.573\t\nMenopausal problems/mean score\t17 (37 %)/4.65\t17 (56.7 %)/6.05\t\np = 0.095\t\nItalic values indicate statistical significance\n\n\nA without constitutional symptoms, B with constitutional symptoms, X bulky disease, E extranodal involvement, CR complete remission, PR partial remission, NA not applicable, e escalated, b basal\n\n\naNumber of in vitro fertilized pregnancies among all pregnancies after chemotherapy\n\n\nbPercentage of all patients in ABVD and BEACOPP groups\n\n\ncPercentage of patients attempting conception post-treatment\n\n\n\nIn the BEACOPP group, the median age at the time of treatment was 26.5 years (range 20–36). Ten (33.3 %) patients had stage II of the disease, five (16.7 %) patients had stage III, and 15 (50.0 %) patients had stage IV of the disease. Nine (30.0 %) had constitutional symptoms and nine (30.0 %) had bulky disease. Seven (23.3 %) had an extranodal localization. Ninety-three point three percent of patients reported a regular menstrual cycle prior to treatment. The median number of chemotherapy cycles received was 8 (range 4–8). There was only one relapse (3.3 %) in this group (the patient in question was treated with salvage chemotherapy and is now in remission). The rest of the group achieved CR after first line treatment with chemotherapy or chemoradiotherapy. None of the patients received irradiation of the pelvis.\n\nA higher age in female patients correlated significantly with a higher number of children born before and a lower number of children born after treatment (p < 0.001, p = 0.032, respectively) (Table 2). There was no difference in age at the time they answered the questionnaire (p = 0.905). Regardless of the regimen used, a higher age at the time of treatment also correlated positively with therapy-induced amenorrhea as well as with the presence of menopausal symptoms and correlated negatively with pregnancies achieved after treatment as well as in the birth of children after therapy (p = 0.016, p < 0.001, p = 0.014, p = 0.010, respectively). A higher age at the time of treatment in the ABVD group correlated only with a higher number of children prior to the treatment (p = 0.002) and also with the presence of menopausal symptoms (p = 0.013). However, in the BEACOPP group, a higher age at the time of treatment significantly correlated with a higher number of children born before treatment (p < 0.001). A positive correlation was found with therapy-induced amenorrhea and with the presence of menopausal symptoms while a negative correlation was found with both the restored menses and with the birth of children after chemotherapy (p = 0.029, p = 0.015, p = 0.010, and p = 0.040, respectively). It did not correlate with the number of achieved pregnancies (p = 0.051) or with the severity of menopausal symptoms (p = 0.511). None of our patients had been fertilized with a donor egg cell, though one female was in the process of in vitro fertilization with a donor egg at the time of the questionnaire. Only one patient from the ABVD and one from the BEACOPP group reported difficulties in becoming pregnant before chemotherapy. They both bore one child following chemotherapy with one of them (ABVD) selecting the in vitro fertilization procedure.Table 2 Correlations and statistical significance among female patients\n\n\tAge at treatment\tAge at treatment (ABVD group)\tAge at treatment (BEACOPP group)\tABVD vs. BEACOPP\tABVD vs. eBEACOPP\tbBEACOPP vs. eBEACOPP\t\nNumber of children before treatment\t\np < 0.001\na\n\t\np = 0.002\na\n\t\np < 0.001\na\n\t\np = 0.297b\n\t\np = 0.027\nb\n\t\np = 0.168b\n\t\nTherapy-induced amenorrhea\t\np = 0.016\nc\n\t\np = 0.118c\n\t\np = 0.029\nc\n\t\np = 0.002\nd\n\t\np < 0.001\nd\n\t\np = 0.712d\n\t\nRestored menses after treatment\t\np = 0.062c\n\t\np = 0.348c\n\t\np = 0.010\nc\n\t\np = 0.012\nd\n\t\np = 0.032\nd\n\t\np = 1.000d\n\t\nSecondary amenorrhea\t\np = 0.062c\n\t\np = 0.348c\n\t\np = 0.010\nc\n\t\np = 0.003\nd\n\t\np = 0.494d\n\t\np = 1.000d\n\t\nPregnancies after therapy\t\np = 0.014\nc\n\t\np = 0.095c\n\t\np = 0.051c\n\t\np = 0.630d\n\t\np = 0.174d\n\t\np = 0.425d\n\t\nChildren after therapy (yes/no)\t\np = 0.010\nc\n\t\np = 0.079c\n\t\np = 0.040\nc\n\t\np = 0.070d\n\t\np = 0.155d\n\t\np = 0.225d\n\t\nNumber of children after therapy\t\np = 0.032\na\n\t\np = 0.191a\n\t\np = 0.124a\n\t\np = 0.297b\n\t\np = 0.122b\n\t\np = 0.205b\n\t\nMenopausal symptoms\t\np < 0.001\nc\n\t\np = 0.013\nc\n\t\np = 0.015\nc\n\t\np = 0.095d\n\t\np = 0.984d\n\t\np = 0.454d\n\t\nSeverity of symptoms\t\np = 0.665e\n\t\np = 0.983e\n\t\np = 0.511e\n\t\np = 0.657b\n\t\np = 0.766b\n\t\np = 0.836b\n\t\nItalic values indicate statistical significance\n\n\naANOVA test\n\n\nbMann-Whitney test\n\n\nc\nt test\n\n\ndChi-square\n\n\nePearson’s correlation\n\n\n\nThe severity of problems in achieving pregnancy before treatment did not differ among ABVD and BEACOPP groups nor did the embryo/oocyte cryopreservation (p = 1.000, data not shown and p = 0.516 (Table 1), respectively). Only four women in each treatment group reported that they had not tried to conceive a child after the treatment. The therapy-induced amenorrhea was significantly different statistically among the groups and so was the restored menses after treatment (p = 0.002 and p = 0.012, respectively, Tables 1 and 2). The value of the therapy-induced amenorrhea was only determined for women who had previously had regular cycles. There was no difference in amenorrhea and restored menses among women below and over 30 years of age in joined group analyses (p = 0.388). Statistically, secondary amenorrhea after treatment appeared significantly more often in the BEACOPP group (p = 0.003, Table 1 and 2) and was also more frequent in patients over 30 years of age (p = 0.008). It was defined as an absent (and not only irregular) cycle after treatment. Achieving pregnancy (conception) and having children after chemotherapy were non-significant variables between the two groups (p = 0.630, p = 0.070, respectively). Only one patient in the ABVD group reported a miscarriage, but had another child after treatment while others birthed live children. Also, no difference was found among the groups in regard to the presence of menopausal symptoms (p = 0.095) or severity of these symptoms (p = 0.657). In the BEACOPP subgroups, there was no significant difference in any of the aforementioned parameters (Table 2). When comparing the ABVD group and the escalated BEACOPP group, a statistically significant difference was discovered in the number of children born before treatment began (p = 0.027) (higher in the eBEACOPP group), in therapy-induced amenorrhea (p < 0.001) (more frequent in the eBEACOPP group), and so was the incidence of restored menses after treatment (p = 0.032) (less often in the eBEACOPP group). Other parameters were considered insignificant.\n\nMale survivors\nIn the ABVD group, the median age at the time of treatment was 28 (range 20–39) (Table 3). Four (14.8 %) patients had stage I and 23 (85.2 %) patients had stage II of the disease. Six (22.2 %) patients had bulky disease and 3 (11.1 %) suffered from constitutional symptoms. One (3.7 %) had extranodal involvement. The median number of chemotherapy cycles was 4 (range 1–6). Only three (11.1 %) patients had CR after first line chemotherapy, while 24 (88.9 %) patients needed additional radiotherapy. One (3.7 %) patient received irradiation of the scrotum with 24 Gy due to the involvement of regional lymph nodes while sperm cryoconservation was not done due to his age (38 years). Three (11.1 %) patients relapsed, two of them received salvage chemotherapy and are now in remission, the third declined chemotherapy and is still under observation without any further treatment. Thirteen (48.1 %) patients reported male aging symptoms. Six out of eight patients who declined sperm cryopreservation had already had children previously and were older than 35 years of age. Only in one patient, the usage of cryopreserved sperm was reported unsuccessful in terms of conception, other six utilizations were successful.Table 3 Male patients’ characteristics\n\n\tABVD group\tBEACOPP group\t\np value\t\nNumber of patients\t27\t20 (16e, 4b)\tNA\t\nMedian age in years at diagnosis (range)\t28 (range 20–39)\t25.5 (range 16–38)\t\np = 0.054\t\nStage of disease prior to treatment\t\n I\t4 (14.8 %)\t2a (10.0 %)\tNA\t\n II\t23 (85.2 %)\t1a (5.0 %)\tNA\t\n III\t0 (0 %)\t7 (35.0 %)\tNA\t\n IV\t0 (0 %)\t10 (50.0 %)\tNA\t\n A/B\t24 (88.9 %)/3 (11.1 %)\t11 (55.0 %)/9 (45.0 %)\t\np = 0.016\n\t\n X\t6 (22.2 %)\t9 (45.0 %)\t\np = 0.122\t\n E\t1 (3.7 %)\t2 (10.0 %)\t\np = 0.563\t\nMedian number of cycles (range)\t4 (1–6)\t8 (4–8)\tNA\t\nCR/PR after chemotherapy\t3 (11.1 %)/24 (88.9 %)\t11 (55.0 %)/9 (45.0 %)\t\np = 0.003\n\t\nIrradiation of the scrotum\t1 (3.7 %)\t0 (0 %)\t\np = 1.000\t\nNumber of patients receiving at least 1 cycle of eBEACOPP\t0 (0 %)\t16 (80.0 %)\tNA\t\nNumber of patients with children before treatment\t10 (37.0 %)\t8 (40.0 %)\t\np = 1.000\t\nSperm cryoconservation prior treatment\t19 (70.4 %)\t18 (90.0 %)\t\np = 0.154\t\nNumber of patients achieving pregnancy after therapy/in vitro fertilizationb\n\t10 (37.0 %)/1 (10.0 %)\t6 (30.0 %)/5 (83.3 %)\t\np = 0.753/p = 0.008\n\t\nNumber of patients attempting conception post-treatment\t19 (70.4 %)\t18 (90.0 %)\t\np = 0.154\t\nNumber of patients having children after therapyc\n\t10 (52.6 %)\t6 (33.3 %)\t\np = 0.554\t\nAging male symptoms/mean score\t13 (48.1 %)/4.60\t10 (50.0 %)/3.80\t\np = 1.000\t\nItalic values indicate statistical significance\n\n\nA without constitutional symptoms, B with constitutional symptoms, X bulky disease, E extranodal involvement, CR complete remission, PR partial remission, NA not applicable, e escalated, b basal\n\n\naAll patients with stage I and II in BEACOPP group were treated with regular-dose BEACOPP\n\n\nbNumber of artificially inseminated or in vitro fertilized pregnancies among achieved pregnancies after treatment\n\n\ncPercentage of patients attempting conception post-treatment\n\n\n\nIn the BEACOPP group, the median age at the time of treatment was 25.5 (range 16–38). Two (10.0 %) patients had stage I of the disease, one (5.0 %) patient had stage II, seven (35.0 %) patients had stage III, and ten (50.0 %) patients had stage IV of the disease. Nine (45.0 %) patients suffered from constitutional symptoms, nine (45.0 %) had bulky disease, and two (10.0 %) had extranodal involvement. The median number of chemotherapy cycles was 8 (range 4–8). None of the patients were irradiated in the scrotal area. Eleven (55.0 %) patients achieved CR after chemotherapy, nine (45.0 %) needed radiotherapy. One (5.0 %) patient relapsed and received salvage treatment and is now in CR. Ten (50 %) patients reported aging male symptoms.\n\nNone of the male participants specifically stated that they did not try to have children after chemotherapy with the exception of the ten (eight in the ABVD and two in the BEACOPP group) patients who refused the sperm cryopreservation. A higher age correlated negatively with sperm cryoconservation (Table 4) and with achieving pregnancy following chemotherapy and correlated positively with the number of children born before chemotherapy (p < 0.001, p < 0.001, p = 0.010, respectively). A higher age, however, did not correlate with the presence of aging male symptoms (p = 0.382), the severity of these problems (p = 0.200), with a higher number of in vitro fertilization procedures necessary to achieve pregnancy (p = 0.826) or with a lower number of children born following chemotherapy (p = 0.921). The BEACOPP group was significantly younger at the time they answered the questionnaire (p = 0.023, data not shown) but not at the time of diagnosis of HL (p = 0.054). In the ABVD group, a higher age correlated positively with the number of children born before chemotherapy (p < 0.001) and the presence of aging male symptoms (p = 0.028), while it correlated negatively with sperm cryoconservation (p < 0.001) and with achieving pregnancy after therapy (p = 0.043). However, it did not correlate with the severity of aging male symptoms (p = 0.806) or the number of children born after therapy (p = 0.129). In the BEACOPP group, a higher age correlated only with a higher number of children before treatment (p = 0.034) and none of the other parameters.Table 4 Correlations and statistical significance among male patients\n\n\tAge at treatment\tAge at treatment (ABVD group)\tAge at treatment (BEACOPP group)\tABVD vs. BEACOPP\tABVD vs. eBEACOPP\tBEACOPP vs. eBEACOPP\t\nNumber of children before treatment\t\np = 0.010\na\n\t\np < 0.001\na\n\t\np = 0.034\na\n\t\np = 0.594b\n\t\np = 0.782b\n\t\np = 0.475b\n\t\nSperm cryopreservation\t\np < 0.001\nc\n\t\np < 0.001\n\t/\t\np = 0.154d\n\t\np = 0.276d\n\t\np = 1.000d\n\t\nAchieving pregnancy after treatment\t\np < 0.001\nc\n\t\np = 0.043\nc\n\t\np = 0.185c\n\t\np = 0.753d\n\t\np = 0.512d\n\t\np = 0.549d\n\t\nIn vitro fertilization/artificial insemination\t\np = 0.826c\n\t/\t/\t\np = 0.008\nd\n\t\np = 0.002\nd\n\t\np = 0.333d\n\t\nNumber of children after therapy\t\np = 0.921a\n\tp = 0.129a\n\t/\t\np = 0.674b\n\t\np = 0.446b\n\t\np = 0.384b\n\t\nAging male symptoms\t\np = 0.382c\n\t\np = 0.028\nc\n\t\np = 0.386c\n\t\np = 1.000d\n\t\np = 1.000d\n\t\np = 1.410d\n\t\nSeverity of aging male symptoms\t\np = 0.200e\n\t\np = 0.806e\n\t\np = 0.126e\n\t\np = 0.426b\n\t\np = 0.432b\n\t\np = 0.937b\n\t\nItalic values indicate statistical significance\n\n\n/ statistical analyses could not be performed due to a small number of subjects in analyzed subgroup\n\n\naANOVA test\n\n\nbMann-Whitney test\n\n\nc\nt test\n\n\ndChi-square\n\n\nePearson’s correlation\n\n\n\nThere was no difference between the ABVD group and the BEACOPP group in case of sperm cryopreservation, achieving pregnancy post-treatment, the number of children after therapy or aging male symptoms and its severity (p = 0.154, p = 0.753, p = 0.674, p = 1.000 and p = 0.426, respectively). The only statistical significance discovered was in the frequency of cryopreserved sperm use for artificial insemination or in vitro fertilization for the achieved pregnancies when comparing the ABVD and BEACOPP group as well as the ABVD and the escalated BEACOPP group (p = 0.008, p = 0.002, respectively). The cryopreserved sperm was more frequently used for fertilization in the BEACOPP group with 83.3 % of patients requiring it. No other aforementioned parameters were significantly different between the two groups. No statistically significant difference was found in comparing the regular BEACOPP and the escalated BEACOPP groups.\n\nDiscussion\nFemale survivors\nThe patients’ age at the time of treatment correlated with the number of children the women had had before therapy in the joined group, as well as in both divided groups, which is representative of the reproductive age of the female population. Those aged between 25–29 and 30–35 years had the highest birth rates in Slovenia in 2013 [17]. Regardless of the regimen used, a higher age resulted in more therapy-induced amenorrhea and with the presence of menopausal symptoms. A higher age correlated negatively with pregnancy achieved after treatment, children born after therapy, and the number of children born after chemotherapy. In the BEACOPP group, a higher age positively correlated with therapy-induced amenorrhea and with definite secondary amenorrhea and correlated negatively with restored menses and with the number of children born after chemotherapy. With no difference in median age at the time of diagnosis between the two groups, we attributed this difference to the depleted number of follicles in older female patients and therefore increased susceptibility to the toxicities of chemotherapy [11]. For the same reason, we presume that age strongly correlated with menopausal symptoms. The BEACOPP regimen has often been linked to secondary amenorrhea [3, 4, 13] especially due to the alkylating agents used [4, 5] unlike ABVD [12, 13]. Behringer et al. strongly correlated the risk of amenorrhea in BEACOPP patients 4 years after chemotherapy to 30 years of age or above [13]. Our study showed the same and the secondary amenorrhea in the BEACOPP group was more frequent in those above 30 years of age, but this was not so in the ABVD group (p = 0.008, p = 0.537, respectively, data not shown). In their study, Behringer et al. also correlated 30-year-old BEACOPP patients with the severity of menopausal problems, which has not been proven in our study. Namely, in our study, the p value in the BEACOPP group was 0.724 and in the escalated BEACOPP group it was 0.442 (data not shown).\n\nStatistically, the therapy-induced amenorrhea was significantly different among the ABVD and BEACOPP groups (more frequent in the BEACOPP group) as was the restored menses following treatment (more frequent in the ABVD group). Forty-three percent of women in the BEACOPP group and 6.5 % in the ABVD group reported secondary amenorrhea, which is in accordance with the literature [13]. In the German Hodgkin Lymphoma Study Group, a study of secondary amenorrhea was reported in 51.4 % patients who received 8 cycle dosages for escalated BEACOPP [4], whereas in van der Kaaij’s premature ovarian failure study, 34 % of 202 women treated with alkylating chemotherapy and only 3 % of the 151 patients treated with nonalkylating chemotherapy developed premature ovarian failure [2]. Statistically, secondary amenorrhea was significantly different between the ABVD and BEACOPP groups, but not in the case of comparing ABVD to the escalated BEACOPP. This is fascinating as the escalated BEACOPP was expected to do more secondary gonadal damage than other regimens [4, 7, 18]. However, caution is required in such an interpretation as a rather small number of women were included in the basal BEACOPP and escalated BEACOPP group. Moreover, as in the questionnaire, we did not specifically ask whether women were taking oral contraceptives; this fact should also be considered while evaluating amenorrhea.\n\nWe found no difference in the pregnancy rate among the groups: 34.6 % of women in the BEACOPP group attempting conception post-treatment reported having children after therapy along with 45.2 % in the ABVD group, respectively, which is almost twice the number reported in Behringer’s study [13]. However, these numbers might have been even higher as a number of patients reported that they have not even tried to have children and therefore they cannot know whether they are infertile. Therefore, our results may perhaps be an underestimation of the actual fertility rate as our study only included a questionnaire without determining hormone levels, consequently, leaving the reduced ovarian reserve unmeasured. Furthermore, the extent of ovarian damage due to salvage therapy has not been separately evaluated in this study, hypothetically contributing additionally to lower observed pregnancy rates. Still, we feel obliged to report a successful conception and a birth of a healthy child following high-dose chemotherapy and autologous stem-cell transplantation in ABVD treated woman. Nevertheless, with no difference in the pregnancy rate following chemotherapy and in children born following therapy, we can conclude that the BEACOPP regimen is not as toxic as previously reported [4, 7, 13], which is also consistent with the Cochrane review of 2011 reporting no differences in fertility following treatment between the ABVD and escalated BEACOPP regimen [19]. Still, a concerning observation was that no women in the BEACOPP group underwent embryo/oocyte cryopreservation and only two (4.3 %) patients in the ABVD group did, which implies that each physician should be more aware of discussing the fertility preservation procedures with his patient prior to treatment. In the last 2 years, almost every young patient under the age of 40 is offered a cryopreservation procedure prior to treatment.\n\nMale survivors\nIn male patients, a higher age at the time of treatment correlated with the number of children born before chemotherapy in both regimens analyzed together and separately. Regardless of the regimen used, a higher age at the time of treatment also correlated with a less frequent sperm cryoconservation and a smaller probability of achieving pregnancy after chemotherapy in general. However, it is interesting that a higher age did not correlate with the presence of aging male symptoms or with the severity of these symptoms. The ABVD group was the only group where a higher age correlated with more frequent aging male symptoms with the median age at the time of treatment being 2.5 years more than in the BEACOPP group. Miwa et al. did not find a correlation between age and the aging male symptoms score; however, their study was conducted in ambulatory men and not on cancer patients undergoing treatment [20]. The presence and severity of aging male symptoms did not differ among group analyses, which is consistent with the Behringer’s study [13].\n\nHormone levels were not measured in our study along with the presence of pretreatment dysspermia as in other studies [13, 21]. Also, questions about steroid therapy after treatment were left out of the questionnaire. However, 52.6 % of men in the ABVD group attempting conception post-treatment and 33.3 % of men in the BEACOPP group reported having children after chemotherapy, 10 % with cryoconservated sperm in the ABVD group, and 83.3 % with cryoconservated sperm in the BEACOPP group, which could be attributed to the higher toxicity of the BEACOPP treatment. In Behringer’s study, only 12 % of patients treated with the BEACOPP regimen reported parenthood after 4 years; 10 % used their cryopreserved sperm [13]. Also, the number of sperm cryoconservation procedures was higher in our study with 70.4 % in ABVD and 90 % in BEACOPP group vs. 30 and 37 %, respectively, in Behringer’s study which could explain patients having more children after therapy in our study [13].\n\nThe only statistically significant parameter found was the frequency of cryoconserved sperm use for in vitro fertilization procedures between the ABVD group and the BEACOPP as well as in the ABVD and the escalated BEACOPP regimen. However, as previously mentioned, Rueffer demonstrated that 70 % of patients already suffered from semen abnormality before the initiation of anticancer treatment [8]. Also, the German Hodgkin Study Group reported 89 % of patients with azoospermia and 11 % with other forms of dysspermia after BEACOPP [21]. Since our study did not include the semen analyses and its evaluation before treatment, we cannot conclude whether or not the dysspermia (before or after treatment) was the cause for the statistical difference. Still, the significance in the usage of cryopreservated sperm (more often in the BEACOPP group) could be due to the toxicity of the BEACOPP regimen. However, the number of children born after chemotherapy did not differ between the two groups suggesting that our male patients were likely affected by the gonadotoxic BEACOPP, but were still able to achieve similar rates of parenthood as in the ABVD group by means of assisted reproduction. The stage of the disease prior to treatment, however, was significantly higher in the escalated BEACOPP group, which was the foundation for the selection of more aggressive treatments, but it could also mean that the disease was more systemic, affecting the spermatogenesis itself. Van der Kaaji et al. showed that in early stage HL (stages I and II), 41 % of patients have good quality sperm, 49 % intermediate, and 7 % of patients have poor quality sperm (according to the World Health Organisation classification) [22]. However, their patients did not receive the BEACOPP treatment. The outcome of the chemotherapy, on the other hand, was significantly better in the BEACOPP group than in the ABVD group, indicating a higher level of effectiveness in the BEACOPP regimen and implying the frequent dilemma of weighing a more effective chemotherapy option against reduced fertility afterwards. The other possible cause for a higher frequency of assisted reproduction procedures in the BEACOPP group could also be found in the men’s partners. In the questionnaire, it was not specifically noted whether the in vitro fertilization procedure was performed due to lower male reproductive capacities or female reproductive capacities.\n\nConclusion\nAlthough the expected frequency of secondary amenorrhea is high, we can also report a high percentage of pregnancies following treatment with the ABVD and BEACOPP regimens: 45.2 % in the ABVD group and 34.6 % in the BEACOPP group, respectively, of patients attempting conception post-therapy, in comparison with previous reports. High post-therapy fatherhood rates were also observed among male patients with 52.6 % of patients in the ABVD group of patients attempting conception post-therapy and 33.3 % patients in the BEACOPP group, respectively, producing children with a significantly more frequent usage of cryopreserved sperm in the BEACOPP group. Based on our findings, we can conclude that even intensified chemotherapy is not a definite predictor of infertility in young HL patients.\n\nAbbreviations\nAwithout constitutional symptoms\n\nABVD regimendoxorubicin, vinblastine, dacarbazine, and bleomycin\n\nAMSAging Males’ Symptoms scale\n\nANOVAanalysis of variance test\n\nBwith constitutional symptoms\n\nbBEACOPPbasal BEACOPP\n\nBEACOPP regimenbleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone\n\nCRcomplete remission\n\neBEACOPPescalated BEACOPP\n\nEextranodal involvement\n\nGygray\n\nHLHodgkin lymphoma\n\nMRSMenopause Rating Scale\n\nNAnot applicable\n\nPRpartial remission\n\nSPSSStatistical Package for Social Sciences\n\nXbulky disease\n\nCapsule\n\nBased on these high rates of childbirth following BEACOPP chemotherapy, we have concluded that intensified chemotherapy is not a definite predictor of reduced fertility in young HL patients.\n\nThis study was partially financed by the Ministry of Science and Technology, Slovenia, grant P3-0321.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no competing interests.\n\nInformed consent\nInformed consent was obtained from all individual participants included in the study.\n\nFunding\nThis study was partially funded by the grant P3-0321 of the Slovenian Ministry of Science and Technology.\n==== Refs\nReferences\n1. Borchmann P Engert A The past: what we have learned in the last decade Hematol Am Soc Hematol Educ Program 2010 2010 101 7 10.1182/asheducation-2010.1.101 \n2. van der Kaaij MA Heutte N Meijnders P Abeilard-Lemoisson E Spina M Moser EC Premature ovarian failure and fertility in long-term survivors of Hodgkin’s lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d’Etude des Lymphomes de l’Adulte Cohort Study J Clin Oncol 2012 30 291 9 10.1200/JCO.2011.37.1989 22184372 \n3. Meirow D Biederman H Anderson RA Wallace WH Toxicity of chemotherapy and radiation on female reproduction Clin Obstet Gynecol 2010 53 727 39 10.1097/GRF.0b013e3181f96b54 21048440 \n4. Behringer K Breuer K Reineke T May M Nogova L Klimm B Secondary amenorrhea after Hodgkin’s lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin’s Lymphoma Study Group J Clin Oncol 2005 23 7555 64 10.1200/JCO.2005.08.138 16234521 \n5. De Bruin ML Huisbrink J Hauptmann M Kuenen MA Ouwens GM van’t Veer MB Treatment-related risk factors for premature menopause following Hodgkin lymphoma Blood 2008 111 101 8 10.1182/blood-2007-05-090225 17890454 \n6. Greaves P Sarker SJ Chowdhury K Johnson R Matthews J Matthews R Fertility and sexual function in long-term survivors of haematological malignancy: using patient-reported outcome measures to assess a neglected area of need in the late effects clinic Br J Haematol 2014 164 526 35 10.1111/bjh.12651 24236665 \n7. Decanter C Morschhauser F Pigny P Lefebvre C Gallo C Dewailly D Anti-Müllerian hormone follow-up in young women treated by chemotherapy for lymphoma: preliminary results Reprod Biomed Online 2010 20 280 5 10.1016/j.rbmo.2009.11.010 20113967 \n8. Rueffer U Breuer K Josting A Lathan B Sieber M Manzke O Male gonadal dysfunction in patients with Hodgkin’s disease prior to treatment Ann Oncol 2001 12 1307 11 10.1023/A:1012464703805 11697845 \n9. Fitoussi F Eghbali H Tchen N Berjon JP Soubeyran P Hoerni B Semen analysis and cryoconservation before treatment in Hodgkin’s disease Ann Oncol 2000 11 679 84 10.1023/A:1008353728560 10942055 \n10. Biasoli I Falorio S Luminari S Spector N Federico M Fertility in female survivors of Hodgkin’s lymphoma Rev Bras Hematol Hemoter 2012 34 48 53 10.5581/1516-8484.20120014 23049384 \n11. Eeltink CM Incrocci L Witte BI Meurs S Visser O Huijgens P Fertility and sexual function in female Hodgkin lymphoma survivors of reproductive age J Clin Nurs 2013 22 3513 21 10.1111/jocn.12354 23808758 \n12. Hodgson DC Pintilie M Gitterman L Dewitt B Buckley CA Ahmed S Fertility among female hodgkin lymphoma survivors attempting pregnancy following ABVD chemotherapy Hematol Oncol 2007 25 11 5 10.1002/hon.802 17036376 \n13. Behringer K Mueller H Goergen H Thielen I Eibl AD Stumpf V Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials J Clin Oncol 2013 31 231 9 10.1200/JCO.2012.44.3721 23150709 \n14. Heinemann LAJ Potthoff P Schneider HPG International versions of the menopause rating scale (MRS) Health Qual Life Outcomes 2003 1 28 10.1186/1477-7525-1-28 12914663 \n15. Heinemann K Ruebig A Potthoff P Schneider HPG Strelow F Heinemann LAJ The Menopause Rating Scale (MRS) scale: a methodological review Health Qual Life Outcomes 2004 2 45 10.1186/1477-7525-2-45 15345062 \n16. Daig I Heinemann LA Kim S Leungwattanakij S Badia X Myon E The Ageing Males’ Symptoms (AMS) scale: review of its methodological characteristics Health Qual Life Outcomes 2003 1 77 10.1186/1477-7525-1-77 14675485 \n17. Demographic statistics according to female age and child gender for Slovene female population. In: Statistic Bureau, Republic of Slovenia. 2015. http://pxweb.stat.si/pxweb/Database/Dem_soc/05_prebivalstvo/30_Rodnost/05_05J10_rojeni_SL/05_05J10_rojeni_SL.asp. Accessed 22 July 2015.\n18. Franchi-Rezgui P Rousselot P Espié M Brière J Pierre Marolleau J Gisselbrecht C Fertility in young women after chemotherapy with alkylating agents for Hodgkin and non-Hodgkin lymphomas Hematol J 2003 4 116 20 10.1038/sj.thj.6200248 12750730 \n19. Bauer K Skoetz N Monsef I Engert A Brillant C Comparison of chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for patients with early unfavourable or advanced stage Hodgkin lymphoma Cochrane Database Syst Rev 2011 8 21833963 \n20. Miwa Y Kaneda T Yokoyama O Correlation between the Ageing Males’ Symptoms Scale and sex steroids, gonadotropins, dehydroepiandrosterone sulfate, and growth hormone levels in ambulatory men J Sex Med 2006 3 723 6 10.1111/j.1743-6109.2006.00277.x 16839329 \n21. Sieniawski M Reineke T Nogova L Josting A Pfistner B Diehl V Fertility in male patients with advanced Hodgkin lymphoma treated with BEACOPP: a report of the German Hodgkin Study Group (GHSG) Blood 2008 111 71 6 10.1182/blood-2007-02-073544 17890456 \n22. van der Kaaij MA Heutte N van Echten-Arends J Raemaekers JM Carde P Noordijk EM Sperm quality before treatment in patients with early stage Hodgkin’s lymphoma enrolled in EORTC-GELALymphoma Group trials Haematologica 2009 94 1691 7 10.3324/haematol.2009.009696 19850901\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1058-0468",
"issue": "33(3)",
"journal": "Journal of assisted reproduction and genetics",
"keywords": "ABVD; BEACOPP; Fertility following treatment; Hodgkin lymphoma; Secondary amenorrhea",
"medline_ta": "J Assist Reprod Genet",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000568:Amenorrhea; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D005298:Fertility; D059247:Fertility Preservation; D005500:Follow-Up Studies; D006689:Hodgkin Disease; D006801:Humans; D007247:Infertility, Female; D007248:Infertility, Male; D008297:Male; D011247:Pregnancy; D011344:Procarbazine; D011795:Surveys and Questionnaires; D014747:Vinblastine; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "9206495",
"other_id": null,
"pages": "325-333",
"pmc": null,
"pmid": "26678493",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17036376;24236665;21239778;23808758;21048440;16839329;12914663;15345062;17890456;12750730;16234521;21833963;10942055;20113967;23150709;11697845;19850901;22184372;23049384;17890454;14675485",
"title": "Fertility in young patients following treatment for Hodgkin's lymphoma: a single center survey.",
"title_normalized": "fertility in young patients following treatment for hodgkin s lymphoma a single center survey"
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{
"companynumb": "SI-BAYER-2016-053266",
"fulfillexpeditecriteria": "1",
"occurcountry": "SI",
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"activesubstance": {
"activesubstancename": "VINBLASTINE"
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... |
{
"abstract": "Extra-nodal natural killer/T cell lymphoma (ENKTL) is rare in elderly patients, and its clinical course is unclear. The efficacy and tolerability of non-anthracycline-based treatments as a standard regimen in elderly patients have not been fully investigated. This study assessed the impact of aging on clinical outcomes and treatment tolerability. We retrospectively analyzed 51 patients aged ≥60 years who were diagnosed with ENKTL from January 1998 to December 2012. We defined new treatments as non-anthracycline regimens (etoposide, ifosfamide, mesna, cisplatin, and dexamethasone (VIPD); etoposide, ifosfamide, mesna, dexamethasone, and L-asparaginase (VIDL); methotrexate, leucovorin, etoposide, ifosfamide, mesna, dexamethasone, and L-asparaginase (MIDLE); ifosfamide, methotrexate, etoposide, and prednisolone (IMVP16/PD); or methotrexate, leucovorin, etoposide, ifosfamide, mesna, dexamethasone, and L-asparaginase (SMILE), with or without radiation therapy). The median age was 66 years (60-83 years). Twenty patients were diagnosed at advanced stage, and 18 had poor performance status. The overall survival and progression-free survival were 6.7 and 5.2 months, respectively. Clinical outcomes of patients with early disease were superior to those of patients with advanced disease. Among patients who received new treatments, concurrent chemoradiation therapy (CCRT) for localized disease was tolerable, although 37.5 % of patients with advanced disease who received SMILE discontinued chemotherapy due to intolerability. Elderly patients with ENKTL have poor prognostic factors compared to younger patients. In particular, patients with advanced disease have extremely poor prognosis due to inability to tolerate treatment and rapid progression of disease.",
"affiliations": "Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.;Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea. wskimsmc@skku.edu.",
"authors": "Kim|Sung Min|SM|;Park|Silvia|S|;Oh|Dong Ryul|DR|;Ahn|Yong Chan|YC|;Ko|Young Hyeh|YH|;Kim|Seok Jin|SJ|;Kim|Won Seog|WS|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-015-2581-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "95(4)",
"journal": "Annals of hematology",
"keywords": "Concurrent chemoradiation therapy; Elderly patients; L-Asparaginase; NK/T cell lymphoma; Tolerability; Treatment completion",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D005260:Female; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "581-91",
"pmc": null,
"pmid": "26729202",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extra-nodal natural killer/T cell lymphoma in elderly patients: the impact of aging on clinical outcomes and treatment tolerability.",
"title_normalized": "extra nodal natural killer t cell lymphoma in elderly patients the impact of aging on clinical outcomes and treatment tolerability"
} | [
{
"companynumb": "KR-BAXTER-2016BAX045555",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Cerebral venous and sinus thrombosis is a rare cerebrovascular disorder, which seldom represents a complication of acute promyelocytic leukemia (APL). As a part of the coagulopathy of APL, thrombosis is a less recognized and underestimated life-threatening manifestation and is overshadowed by the more obvious bleeding complications. Here, we described a 28-year-old woman with APL who developed massive thrombosis of the cerebral sinuses while on induction treatment with all-trans retinoic acid. On the basis of this report, the potential pathogenic mechanisms and the diagnosis based on magnetic resonance imaging (MRI) combined with magnetic resonance venogram (MRV) are discussed. Early anticoagulant therapy contributed to the progressive dissolution of the thrombosis, as documented by MRI, with the complete disappearance of neurological signs without sequelae. Given the increasing recognition of thromboembolic events in APL, the use of prophylactic anticoagulation during induction therapy may need to be redefined.",
"affiliations": "aDepartment of Hematology, Shanghai No.6 People's Hospital affiliated to Shanghai Jiaotong University bHematology Section, Shanghai Yangpu District Central Hospital, Shanghai, PR China *Lu-xi Song and Hong-yu Lu contributed equally to the writing of this article and share first authorship.",
"authors": "Song|Lu-xi|LX|;Lu|Hong-yu|HY|;Chang|Chun-kang|CK|;Li|Xiao|X|;Zhang|Zhen|Z|",
"chemical_list": "D000925:Anticoagulants; D000970:Antineoplastic Agents; D014212:Tretinoin",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "25(7)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D012851:Sinus Thrombosis, Intracranial; D014212:Tretinoin",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "773-6",
"pmc": null,
"pmid": "24717424",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cerebral venous and sinus thrombosis in a patient with acute promyelocytic leukemia during all-trans retinoic acid induction treatment.",
"title_normalized": "cerebral venous and sinus thrombosis in a patient with acute promyelocytic leukemia during all trans retinoic acid induction treatment"
} | [
{
"companynumb": "CN-BAUSCH-BL-2015-013927",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": ... |
{
"abstract": "We report a case series of buprenorphine-related respiratory and neurological depression in opioid-naïve elderly hospitalised patients who received buprenorphine for acute pain management at our institution over a 24-month period. All six patients had risk factors for respiratory depression such as advanced age, concurrent comorbidities, or the ingestion of other potential central nervous system depressants. All patients required escalation of management with additional monitoring, with some transferred to a high dependency or intensive care unit. Five patients had attempted naloxone reversal with varying results. Our cases highlight the fact that while buprenorphine has been demonstrated to have a ceiling effect in relation to respiratory depression in healthy volunteers, it remains an important side-effect and may result in significant respiratory depression in patients with reduced respiratory or neurological reserve. Difficulties with buprenorphine's reversal using naloxone are described. We recommend additional caution when considering buprenorphine for acute pain management in elderly opioid-naïve patients, especially if they have comorbidities or are taking other central nervous system depressants. When buprenorphine is used in patients with risk factors, we recommend additional monitoring and education about potential adverse respiratory effects and their management.",
"affiliations": "Intensivist, Sir Charles Gairdner Hospital, Perth, Western Australia.;Associate Professor, Intensive Care, Sir Charles Gairdner Hospital, Perth, Western Australia.;Anaesthetic consultant, Director of Acute Pain Service, Anaesthesia, Sir Charles Gairdner Hospital, Perth, Western Australia.",
"authors": "Richards|S|S|;Torre|L|L|;Lawther|B|B|",
"chemical_list": "D000701:Analgesics, Opioid; D009270:Naloxone; D002047:Buprenorphine",
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X1704500217",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0310-057X",
"issue": "45(2)",
"journal": "Anaesthesia and intensive care",
"keywords": "buprenorphine, respiratory depression, pain management, naloxone, risk factors",
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D002047:Buprenorphine; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D009270:Naloxone; D012131:Respiratory Insufficiency",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "256-261",
"pmc": null,
"pmid": "28267949",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Buprenorphine-related complications in elderly hospitalised patients: a case series.",
"title_normalized": "buprenorphine related complications in elderly hospitalised patients a case series"
} | [
{
"companynumb": "AU-LANNETT COMPANY, INC.-AU-2017LAN000805",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
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"abstract": "Hepatic dysfunction, in the absence of liver metastases, occurs in 10-15% of renal cell carcinoma (RCC) patients, while immune hepatitis due to anti-CTLA4 and anti-PD1 administration affects about 3-9% and 0.7-1.8% of treated patients, respectively. Liver toxicity following combination therapy (anti-CTLA4 and anti-PD1) is seen in 29% of patients overall and grade 3-4 toxicity in 14% of patients. Stauffer's syndrome is a rare para-neoplastic phenomenon associated with RCC and characterized by abnormal liver function tests, hepato-splenomegaly and histological changes consistent with non-specific hepatitis. We describe a case of RCC treated with anti-CTLA4 and anti-PD1 therapy resulting in immediate liver toxicity and death after 2 months of progressive hepatic impairment. We hypothesize that high IL-6 levels due to Stauffer's syndrome might have contributed to immune-related hepatic failure.\nConsider Stauffer's syndrome in patients who develop liver toxicity unresponsive to immunotherapy.Evaluate IL-6 as high levels are seen in Stauffer's syndrome patients undergoing immunotherapy.Consider taking a liver biopsy to assess the severity of liver injury.",
"affiliations": "Medical Oncology, St. Croce & Carle University Teaching Hospital, Cuneo, Italy.;Medical Oncology, St. Croce & Carle University Teaching Hospital, Cuneo, Italy.;Medical Oncology, St. Croce & Carle University Teaching Hospital, Cuneo, Italy.;Medical Oncology, St. Croce & Carle University Teaching Hospital, Cuneo, Italy.;Medical Oncology, St. Croce & Carle University Teaching Hospital, Cuneo, Italy.;Medical Oncology, IRCCS Candiolo, Turin, Italy.;Medical Oncology, St. Croce & Carle University Teaching Hospital, Cuneo, Italy.",
"authors": "Denaro|Nerina|N|;Garrone|Ornella|O|;Occelli|Marcella|M|;Fea|Elena|E|;Granetto|Cristina|C|;Merlano|Marco Carlo|MC|;Numico|Gianmauro|G|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2021_002639",
"fulltext": "\n==== Front\nEur J Case Rep Intern Med\nEuropean Journal of Case Reports in Internal Medicine\n2284-2594\nSMC Media Srl\n\n34268267\n10.12890/2021_002639\n2639-1-23195-1-10-20210616\nArticles\nUnusual Fatal Outcome Following Administration of a Combination of anti-PD1 and anti-CTLA4 in Metastatic Renal Cell Carcinoma: Liver Toxicity Case Report and a Literature Review\nDenaro Nerina 1\nGarrone Ornella 1\nOccelli Marcella 1\nFea Elena 1\nGranetto Cristina 1\nMerlano Marco Carlo 23\nNumico Gianmauro 1\n1 Medical Oncology, St. Croce & Carle University Teaching Hospital, Cuneo, Italy\n2 Medical Oncology, IRCCS Candiolo, Turin, Italy\n3 ARCO Foundation, Cuneo, Italy\n2021\n17 6 2021\n8 6 00263913 5 2021\n20 5 2021\n© EFIM 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This article is licensed under a Commons Attribution Non-Commercial 4.0 License\nHepatic dysfunction, in the absence of liver metastases, occurs in 10–15% of renal cell carcinoma (RCC) patients, while immune hepatitis due to anti-CTLA4 and anti-PD1 administration affects about 3–9% and 0.7–1.8% of treated patients, respectively. Liver toxicity following combination therapy (anti-CTLA4 and anti-PD1) is seen in 29% of patients overall and grade 3–4 toxicity in 14% of patients.\n\nStauffer’s syndrome is a rare para-neoplastic phenomenon associated with RCC and characterized by abnormal liver function tests, hepato-splenomegaly and histological changes consistent with non-specific hepatitis. We describe a case of RCC treated with anti-CTLA4 and anti-PD1 therapy resulting in immediate liver toxicity and death after 2 months of progressive hepatic impairment. We hypothesize that high IL-6 levels due to Stauffer’s syndrome might have contributed to immune-related hepatic failure.\n\nLEARNING POINTS\n\nConsider Stauffer’s syndrome in patients who develop liver toxicity unresponsive to immunotherapy.\n\nEvaluate IL-6 as high levels are seen in Stauffer’s syndrome patients undergoing immunotherapy.\n\nConsider taking a liver biopsy to assess the severity of liver injury.\n\nHepatitis\nhepatic failure\nimmunotherapy\nrenal carcinoma\n==== Body\nCASE DESCRIPTION\n\nIn June 2019, a 56-year-old woman without a relevant medical history underwent right renal tumourectomy. Histology findings demonstrated clear cell renal cell carcinoma (RCC), sarcomatoid type, grade 4 (Fuhrman), free margins, pT1b Nx M0. On 26 July after a multidisciplinary team discussion (MTD), follow-up with chest and abdominal CT scans within 1 month was scheduled.\n\nIn August 2019, the patient was admitted to the emergency department for neurological symptoms. A brain CT scan showed a left frontal lesion. She was admitted to the neurology department and started steroid treatment. A whole-body CT scan confirmed progressive disease with mediastinal node involvement and two enlarged abdominal nodes (one perirenal and one close to the right iliac vessels).\n\nSteroid therapy during hospitalization resulted in improvement.\n\nIn August 2019, the MTD advised radical single brain metastasis excision followed by systemic therapy. The patient underwent brain surgery. Histology showed epithelial neoplasia with clear cell aspects and large necrotic areas, immuno-morphologically consistent with secondary RCC.\n\nIn October 2019, the patient started combination immunotherapy with ipilimumab and nivolumab. After 1 week, liver toxicity was reported (grade 2 on aspartate aminotransferase (AST) and alanine transaminase (ALT), and grade 3 on total bilirubin (TB) and direct bilirubin (DB)). The patient then underwent a liver ultrasound (Fig. 1) which was negative for metastasis. She was started on oral prednisone 25 mg (1 capsule) three times a day.\n\nOn 4 November, due to progressive liver impairment, the patient started methylprednisolone at 2 mg/kg. Alternative causes for the liver impairment were investigated and excluded. Tests for hepatitis A, B and C infection, cytomegalovirus and immune hepatitis were performed and resulted negative.\n\nBudd–Chiari syndrome was excluded because neither imaging or coagulation status were suggestive for the disease.\n\nBlood analysis demonstrated worsening liver toxicity. We considered the liver failure was due to immune-related toxicity and increased the steroid dose. The patient was admitted to the oncology ward to start intravenous high-dose steroids according to international guideline [1–3]. The patient’s medication included 2 mg/kg methylprednisolone (daily dose 80 mg×2), euthyrox 125 μg, levetiracetam 500 mg×2, furosemide 20 mg × 2, omeprazole 20 mg ×2 in the evening, delorazepam 8 mg in the evening, and cetirizine 10 mg (1 capsule)×2. The blood results during treatment are given in Table 1.\n\nIn November 2019, the patient underwent an abdominal CT scan (Fig. 2A) which showed a slightly enlarged liver without focal lesions. Liver enzymes continued to increase without impairment in coagulation function. The patient maintained a fair general condition until the beginning of December 2019.\n\nAt the end of November, the patient started mycophenolate 100 mg twice daily and underwent liver ultrasound plus-guided biopsy (Fig. 3). Liver enzyme trends are shown in Fig. 4. The histology report noted hepatic tissue with cytoplasmic and intracanalicular cholestasis, sinusoid ectasia and histiocytosis, tissue macrophage or dendritic cell aggregation, and microfoci of liver necrosis in single or a few cells.\n\nThere was no evidence of endotheliosis.\n\nOn 11 December, the patient started the third-line immunosuppressive therapy with tacrolimus 2 mg daily. On 17 December, she underwent an abdominal CT scan (Fig. 2B) which showed progressive disease but no liver involvement. The patient’s condition deteriorated and she died on 27 December. Her relatives did not consent to an autopsy.\n\nDISCUSSION\n\nImmunotherapy is an important treatment for cancer. However, its use is associated with a spectrum of adverse effects (immune-related adverse events, irAEs) related to the drugs’ mechanisms of action. The adverse effects most commonly affect the skin, gastrointestinal tract, lungs and endocrine glands. Hepatic irAEs are uncommon and little is known about their pathogenesis and management as they are quite rare, at least with monotherapy. Recently, a pooled analysis in melanoma patients showed that immune hepatitis due to anti-CTLA4 and anti-PD1 treatment affects about 3–9% and 0.7–1.8% of patients, respectively, and causes grade 3–4 hepatic toxicity in up to 14% of patients [1]. Currently, guidelines recommend high-dose steroids (from 1 to 2 mg/kg/day) for grade 3–4 or persistent grade 2 hepatitis (more than 1–2 weeks). If there is no response to corticosteroids within 2–3 days, mycophenolate should be considered [2–4].\n\nZarrabi et al. reported a case of RCC in which hyper-bilirubinaemia was unrelated to irAEs but correlated with Stauffer’s syndrome and benefited from renal surgery [5]. Stauffer’s syndrome is characterized by cholestatic liver dysfunction in the absence of underlying hepatobiliary disease (elevated TB, DB and alkaline phosphatase). It is estimated that hepatic dysfunction, in the absence of liver metastases, occurs in 10–15% of RCC cases, but it is difficult to estimate the incidence of Stauffer’s syndrome as the literature is mainly confined to case reports [6]. Stauffer’s syndrome is associated with an unfavourable prognosis [7]. In 2018, having considered knowledge accumulated since 1961 when the syndrome was first described, Fontes-Sousa et al. proposed the use of a broader designation, that is ‘paraneoplastic intrahepatic cholestasis’, and new diagnostic criteria, which are given in Table 2 [6].\n\nTo our knowledge, this is the first report of grade 5 hepatic toxicity following administration of a combination of anti-PD1 and anti-CTLA4 in a patient with possible latent Stauffer’s syndrome. In our patient, Stauffer’s syndrome was not described at the onset of RCC; however, after the first dose of combination immunotherapy, she developed hepatic toxicity refractory to immunosuppressive therapy. We hypothesize that a variant of Stauffer’s syndrome may have caused the clinical features and that immunotherapy worsened the hepatic failure. In our patient both endotheliosis and histiocytosis was described on liver histology without liver metastasis or hepatitis. Current available guidelines for irAEs were followed. Of note, Fontes-Sousa et al. in their review did not find that immunotherapy affected hepatic symptoms in Stauffer’s syndrome [6].\n\nIn retrospect, we should have measured IL-6 levels in our patient, because we later hypothesized that IL-6 might have had a role in the pathophysiology of checkpoint inhibitor-associated hepatotoxicity and Stauffer’s syndrome. The central role of IL-6 in Stauffer’s syndrome pathogenesis and in immunotherapy responses supports this conclusion.\n\nThe case report confirms the role of liver biopsy in reaching the diagnosis and evaluating the severity of liver injury as well as establishing the absence of metastases or underlying liver disease, and demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment. Our patient received higher-dose but ultimately useless steroid treatment and was refractory to all hepatitis treatment administered. Also, our patient did not have predictors of immune events, according to the Kartolo et al. classification, except for use of anti-CTLA4 inhibitors [7]. We should have considered earlier the possibility of a cause other than immunotoxicity and we recommend a liver biopsy should be taken earlier (within 2 weeks). A flow chart for the management of hepatic failure after the administration of combination therapy is provided in Table 3.\n\nFigure 1 Ultrasound scan on 31 October 2019\n\nFigure 2 CT scans on 11 November 2019 (A), 17 December 2019 (B) and 23 December 2019 (C)\n\nFigure 3 Ultrasound scan on 27 November 2019\n\nFigure 4 Liver enzyme trends.\n\nALT, alanine transaminase (U/l); BIL, bilirubin (mg/dl); GGT, gamma-glutamyl transpeptidase (U/l)\n\nTable 1 Blood test results Normal ranges: alanine transaminase (ALT) to 49 U/l; alkaline phosphatase (ALP) 38–126 U/l; aspartate aminotransferase (AST) to 34 U/l; bilirubin, total (BIL) 0.3–1.2 mg/dl; creatinine (CREA) 0.4–1.10 mg/dl; gamma-glutamyl transpeptidase (GGT) to 49 U/l; haemoglobin (HB) 12–16 g/dl; platelets (PLT) 150–400,000/μl; urea (UREA) 9.0–23.0 mg/dl; white blood cells (WBC) 4–10×103/μl. INR, international normalized ratio.\n\n\tPLT (/μl)\tWBC (×103/μl)\tHB (g/dl)\tUREA (mg/dl)\tCREA (mg/dl)\tINR\tAST (U/l)\tALT (U/l)\tGGT (U/l)\tBIL (mg/dl)\tALP (U/l)\t\n16/06/2019\t248\t6.2\t9\t\t\t\t\t\t\t\t\t\n05/11/2019\t183\t15.6\t11.1\t\t\t1.02\t\t\t\t\t\t\n07/11/2019\t\t\t\t\t\t\t1142\t765\t1359\t8.8\t\t\n09/11/2019\t\t\t\t\t\t\t1069\t558\t1448\t9.7\t\t\n13/11/2019\t\t\t\t\t\t\t1220\t541\t1852\t14.6\t\t\n18/11/2019\t195\t3.19\t9.1\t18\t0.52\t1.05\t1150\t491\t\t16.1\t\t\n22/11/2019\t185\t9.87\t9.0\t17\t0.43\t1.13\t992\t311\t2620\t17.1\t450\t\n03/12/2019\t147\t5.87\t8.8\t\t\t1.03\t847\t356\t2827\t21\t\t\n06/12/2019\t\t\t\t\t\t1.08\t775\t296\t2773\t24\t\t\n12/12/2019\t94\t4.22\t8.1\t\t0.35\t\t751\t352\t2774\t28\t\t\n14/12/2019\t93\t5.16\t8.3\t\t\t1.16\t\t\t\t\t\t\n16/12/2019\t167\t6.75\t8.5\t\t0.61\t1.10\t613\t254\t1924\t24.1\t725\t\n18/12/2019\t146\t5.9\t9.3\t31\t0.4\t1.05\t439\t167\t1658\t22.8\t718\t\n20/12/2019\t92\t8.3\t7.6\t\t\t1.05\t451\t247\t2048\t21\t\t\n24/12/2019\t97\t7.09\t8.9\t\t\t1\t606\t432\t1778\t28.1\t\t\n25/12/2019\t68\t5.75\t7.9\t49\t0.6\t\t\t\t\t\t\t\n26/12/2019\t52\t4.91\t10.3\t\t\t\t\t\t\t\t\t\n\nTable 2 Stauffer’s syndrome and intrahepatic cholestasis paraneoplastic criteria\n\nCriterion\tFeatures\t\n1\tHistologically proven diagnosis of malignancy, most notably renal cell carcinoma\t\n2\tMandatory liver dysfunction or cholestasis, including prolonged thrombin time; jaundice, pruritus or urinary hyperpigmentation may be present\t\n3\tNo evidence or suspicion of liver metastasis or mass effect on liver or biliary ducts, such as direct tumour or nodal disease with hepatic invasion or compression\t\n4\tHepatosplenomegaly may be present\t\n5\tThe alterations are reversible in nature, and expected to normalize in the weeks to months after treatment of the primary tumour\t\n6\tIn the metastasized setting (excluding liver), the alterations may be reversible with systemic therapy\t\n7\tOther causes of intrahepatic cholestasis should be excluded. Liver biopsy may be necessary for accurate differential diagnosis\t\n\nTable 3 Proposed liver evaluation in renal cell carcinoma treated with combination immunotherapy\n\nCriterion\tFeatures\t\n1\tScreening for viral, bacterial and drug-related causes of hepatitis\t\n2\tSteroid administration according current immune-related adverse event (irAE) guidelines\t\n3\tLiver biopsy\t\n4\tIL-6 test (differential diagnosis of Stauffer’s syndrome and prognosticator)\t\n5\tConsider surgery or other targeted therapy if immunosuppressive therapy fails (including mycophenolate and plasma exchange)\t\n\nConflicts of Interests: ND, OG, MO, EF, CG and GN declare there are no conflicts of interest; MCM has worked as a consultant for MSD, Bristol-Myers Squibb and Merck.\n\nEthics’ Approval: Ethics approval for use of the combination of anti-PD1 and anti-CTLA4 was obtained.\n==== Refs\nREFERENCES\n\n1 Sznol M Ferrucci PF Hogg D Atkins MB Wolter P Guidoboni M Pooled analysis safety profile of nivolumab and ipilimumab combination therapy in patients with advanced melanoma J Clin Oncol 2017 35 34 3815 3822 28915085\n2 Trinh S Le A Gowani S La-Beck N Management of immune-related adverse events associated with immune checkpoint inhibitor therapy: a minireview of current clinical guidelines Asia Pac J Oncol Nurs 2019 6 2 154 160 30931360\n3 Brahmer JR Lacchetti C Thompson JA Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline summary J Oncol Pract 2018 14 4 247 249 29517954\n4 De Martin E Michot JM Papouin B Champiat S Mateus C Lambotte O Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors J Hepatol 2018 68 6 1181 1190 10.1016/j.jhep.2018.01.033 29427729\n5 Zarrabi K Masic S Schaefer C Bartel MJ Kutikov A Zibelman M Neoadjuvant checkpoint inhibition in renal cell carcinoma associated Stauffer’s syndrome Urol Case Rep 2020 29 101077 31853444\n6 Fontes-Sousa M Magalhães H da Silva FC Maurício MJ Stauffer’s syndrome: a comprehensive review and proposed updated diagnostic criteria Urol Oncol 2018 36 7 321 326 10.1016/j.urolonc.2018.01.019 29657090\n7 Kartolo A Sattar J Sahai V Baetz T Lakoff JM Predictors of immunotherapy-induced immune-related adverse events Curr Oncol 2018 25 5 e403 e410 10.3747/co.25.4047 30464691\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "8(7)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Hepatitis; hepatic failure; immunotherapy; renal carcinoma",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "002639",
"pmc": null,
"pmid": "34268267",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "29517954;28915085;29657090;29427729;31853444;30464691;30931360",
"title": "Unusual Fatal Outcome Following Administration of a Combination of anti-PD1 and anti-CTLA4 in Metastatic Renal Cell Carcinoma: Liver Toxicity Case Report and a Literature Review.",
"title_normalized": "unusual fatal outcome following administration of a combination of anti pd1 and anti ctla4 in metastatic renal cell carcinoma liver toxicity case report and a literature review"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-324267",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
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"abstract": "Coronavirus disease 2019 (COVID-19), mediated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with flu-like illness and severe pneumonia with acute respiratory distress syndrome (ARDS). Immunocompromised patients merit particular attention as altered host immunity may influence both disease severity and duration of viral shedding as is described with several other ribonucleic acid respiratory viruses. Yet immunocompromised status alone, in the absence of other comorbidities, may not necessarily predict severe illness presentations and poorer clinical outcomes as indicated by recent reports of COVID-19-infected solid organ transplant recipients and people living with human immunodeficiency virus (HIV). Such patients may even be spared the robust inflammatory response that precipitates ARDS associated with COVID-19, complicating the management of iatrogenic immunosuppression in this setting. We present a case of an orthotopic liver transplant recipient with well-controlled HIV who successfully recovered from a mild, flu-like illness attributed to SARS-CoV-2.",
"affiliations": "Department of Infectious Disease, Respiratory Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Department of Infectious Disease, Respiratory Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Department of Infectious Disease, Respiratory Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Department of Gastroenterology and Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Department of Gastroenterology and Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.",
"authors": "Modi|Anita R|AR|https://orcid.org/0000-0002-1252-734X;Koval|Christine E|CE|https://orcid.org/0000-0002-8196-2601;Taege|Alan J|AJ|;Modaresi Esfeh|Jamak|J|;Eghtesad|Bijan|B|;Narayanan Menon|K V|KV|;Quintini|Cristiano|C|;Miller|Charles|C|",
"chemical_list": "D019380:Anti-HIV Agents; D007166:Immunosuppressive Agents; D006886:Hydroxychloroquine; D011241:Prednisone",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13351",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "COVID-19; HIV; hydroxychloroquine; immunocompromised; orthotopic liver transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D000086382:COVID-19; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006084:Graft Rejection; D015658:HIV Infections; D006801:Humans; D006886:Hydroxychloroquine; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D011241:Prednisone; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13351",
"pmc": null,
"pmid": "32500666",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "32091533;12859532;31978945;32150618;21083386;32329975;31986264;32379955;32278366;32362390;30817023;32330343;32205204;32304642;32500666;32090448;25716741",
"title": "Coronavirus disease 2019 in an orthotopic liver transplant recipient living with human immunodeficiency virus.",
"title_normalized": "coronavirus disease 2019 in an orthotopic liver transplant recipient living with human immunodeficiency virus"
} | [
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-254443",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "PREDNISONE"
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"abstract": "Kaposi sarcoma is a vascular tumor related to herpesvirus-8 and is promoted by immunosuppression. For the last 15 years, human immunodeficiency virus (HIV) patients have had access to organ transplantation. The dual immunosuppression of HIV and immunosuppressive treatments might increase the risk and severity of Kaposi sarcoma.\n\n\n\nWe conducted a multicentric retrospective study by collecting cases from French databases and society members of transplanted patients, among which 7 HIV-infected patients who subsequently developed Kaposi sarcoma were included.\n\n\n\nIn the CRISTAL database (114 511 patients) and the DIVAT (Données Informatisées et VAlidées en Transplantation) database (19 077 patients), the prevalence of Kaposi sarcoma was 0.18% and 0.46%, respectively, in transplanted patients; these values compare with 0.66% and 0.50%, respectively, in transplanted patients with HIV. The median time from HIV infection to Kaposi sarcoma was 20 years. Kaposi sarcoma occurred during the first year after transplantation in most cases, whereas HIV viral load was undetectable. Only 2 patients had visceral involvement. Five patients were treated with conversion of calcineurin inhibitor to mammalian target of rapamycin inhibitor, and 5 patients were managed by decreasing immunosuppressive therapies. At 1 year, 4 patients had a complete response, and 3 had a partial response.\n\n\n\nIn our study, Kaposi sarcoma in transplanted patients with HIV did not show any aggressive features and was treated with the usual posttransplant Kaposi sarcoma management protocol.",
"affiliations": "APHP Department of Dermatology, Saint Louis Hospital, Paris, France.;APHP Department of Dermatology, Saint Louis Hospital, Paris, France.;Paris Diderot University, Sorbonne Paris Cité, France.;Paris Diderot University, Sorbonne Paris Cité, France.;Department of Nephrology, Dupuytren Hospital, Limoges, France.;UPMC, Department of Urology, Nephrology and Transplantation, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.;Department of Dermatology, Edouard Herriot Hospital, Lyon, France.;Department of Hepatology and Gastrology, Paul Brousse Hospital, Villejuif, France.;Biomedicine Agency. Saint-Denis La Plaine, France.;UPMC, Unit of Dermatology, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.;APHP Department of Dermatology, Saint Louis Hospital, Paris, France.",
"authors": "Charpentier|Chloé|C|;Delyon|Julie|J|;Glotz|Denis|D|;Peraldi|Marie-Noelle|MN|;Rerolle|Jean-Philippe|JP|;Barrou|Benoît|B|;Ducroux|Emilie|E|;Coilly|Audrey|A|;Legeai|Camille|C|;Barete|Stéphane|S|;Lebbé|Céleste|C|",
"chemical_list": "D019380:Anti-HIV Agents; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000002468",
"fulltext": null,
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"issn_linking": "0041-1337",
"issue": "103(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D016208:Databases, Factual; D005260:Female; D005602:France; D015658:HIV Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D012514:Sarcoma, Kaposi; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "e22-e28",
"pmc": null,
"pmid": "30273235",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016454:Review",
"references": null,
"title": "Kaposi Sarcoma in HIV-positive Solid-Organ Transplant Recipients: A French Multicentric National Study and Literature Review.",
"title_normalized": "kaposi sarcoma in hiv positive solid organ transplant recipients a french multicentric national study and literature review"
} | [
{
"companynumb": "FR-TEVA-2019-FR-1010501",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Despite the widespread prevalence of hyponatremia and its deleterious effects on patients, it is often overlooked and consequently undertreated. This set of four cases provides practical advice on how to identify, diagnose, and treat patients with syndrome of inappropriate antidiuretic hormone (SIADH). The first steps that a physician should take when diagnosing a patient with hyponatremia are to assess the severity of neurological symptoms, and check the patient's volemic status in order to determine whether emergency treatment with hypertonic saline is indicated. Laboratory tests are necessary for the diagnosis of SIADH, but, in severe, symptomatic cases of hyponatremia, patients need treatment before the results of laboratory tests can be obtained. In this series, Case 1 demonstrates how awareness of hyponatremia led to early diagnosis and treatment. Case 2 demonstrates how multiple causes of hyponatremia can be diagnosed and managed sequentially. Case 3 illustrates how a patient with severe symptoms should be treated while waiting for laboratory test results to confirm diagnosis. Case 4 examines how the priorities of a patient should inform the management of their chronic SIADH, using palliative care of a patient with small-cell lung cancer as an example. There are several factors that clinicians should consider when making treatment decisions, including signs and symptoms, risks and benefits of different treatments, psychosocial factors, and the patient's wishes. All the available treatment options have a place in the management of patients with SIADH, and a physician should individualize decisions based on a patient's needs and priorities.",
"affiliations": "Endocrine Unit, Department of Experimental and Biomedical Sciences \"Mario Serio\", Center for Research, Transfer and Higher Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies, University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy. alessandro.peri@unifi.it.;Department of Respiratory Diseases, Ev. Lungenklinik Berlin, Universitätsmedizin Charite, Lindenberger Weg 27, 13125, Berlin, Germany.;Clinica di Oncologia Medica, A.O.U. Ospedali Riuniti di Ancona, Università Politecnica delle Marche, Ancona, Italy.;Department of Endocrinology, Metabolism and Nutrition, Instituto de Investigación Sanitaria San Carlos (IdISSC) Hospital Clínico San Carlos, Madrid, Spain.",
"authors": "Peri|Alessandro|A|;Grohé|Christian|C|;Berardi|Rossana|R|;Runkle|Isabelle|I|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-016-0936-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-008X",
"issue": "55(1)",
"journal": "Endocrine",
"keywords": "Diagnosis; Hyponatremia; Management; Syndrome of inappropriate antidiuretic hormone secretion",
"medline_ta": "Endocrine",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003937:Diagnosis, Differential; D019468:Disease Management; D005260:Female; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D008297:Male",
"nlm_unique_id": "9434444",
"other_id": null,
"pages": "311-319",
"pmc": null,
"pmid": "27025948",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25905459;20946646;20935451;16141458;24809970;23558469;24074529;22469248;10768609;20185637;2913218;7054549;16843082;16737547;25671764;16517805;24367479;10024938;26584969;16886968;21130960;26195098;26070626;22618570;15540881;20609688;20142578;26036812;10816188;17105757",
"title": "SIADH: differential diagnosis and clinical management.",
"title_normalized": "siadh differential diagnosis and clinical management"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1010595",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAROXETINE"
},
"drugadditional": "1",
... |
{
"abstract": "The aim of this study was to define the incidence of left ventricular thrombus (LVT) and its predictors in the contemporary era of primary percutaneous intervention (pPCI) and contrast echocardiography. We retrospectively analyzed 1,059 patients presenting with ST-elevation myocardial infarction (STEMI) to our tertiary cardiac center and treated with pPCI. Preprocedural pharmacology and procedural technique (including access route, the use of drug-eluting stents, and thrombectomy) were at the operators' discretion. Transthoracic echocardiography was performed before discharge; echo contrast agent was used when appropriate. LVT was detected in 42 subjects (4%). There were no significant differences in baseline demographics or pre-PCI clinical features between the 2 groups. Post-treatment, mean ejection fraction (EF) in patients with LVT was 35±8.4% and in those without LVT was 47±10%, p<0.001. Thirty-seven patients (88%) in the LVT group presented with an anterior STEMI versus 471 patients (42%) in the without LVT group (p<0.001). Apical akinesis was noted in all patients with LVT irrespective of the principal location of the MI. Multivariate analysis predictors of LVT were reduced EF, anterior site of MI, and the use of platelet glycoprotein IIb/IIIa inhibitors. After diagnosis of LVT, patients were treated with warfarin for 3 to 6 months. No significant difference in mortality was detectable at discharge between the 2 groups. In conclusion, in the contemporary era of pPCI, the incidence of LVT in patients with STEMI is significantly lower than that of the previous (thrombolysis) literature. The early presence of LVT is more likely in patients with anterior STEMI (involving the apex) and reduced EF.",
"affiliations": "Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom.;Department of Public Health Sciences and NIHR BRC, Guy's and St Thomas' NHS Trust, King's College London, London, United Kingdom.;Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom.;Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom.;Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom.;Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom.;Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom.;Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom.;Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom.;Department of Cardiology, King's College Hospital, Denmark Hill, London, United Kingdom. Electronic address: philip.maccarthy@nhs.net.",
"authors": "Gianstefani|Silvia|S|;Douiri|Abdel|A|;Delithanasis|Ioannis|I|;Rogers|Toby|T|;Sen|Arup|A|;Kalra|Sundeep|S|;Charangwa|Langton|L|;Reiken|Joseph|J|;Monaghan|Mark|M|;MacCarthy|Philip|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9149",
"issue": "113(7)",
"journal": "The American journal of cardiology",
"keywords": null,
"medline_ta": "Am J Cardiol",
"mesh_terms": "D017023:Coronary Angiography; D017548:Echocardiography, Transesophageal; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases; D006352:Heart Ventricles; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D011379:Prognosis; D012189:Retrospective Studies; D013927:Thrombosis; D013997:Time Factors; D006113:United Kingdom",
"nlm_unique_id": "0207277",
"other_id": null,
"pages": "1111-6",
"pmc": null,
"pmid": "24485697",
"pubdate": "2014-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence and predictors of early left ventricular thrombus after ST-elevation myocardial infarction in the contemporary era of primary percutaneous coronary intervention.",
"title_normalized": "incidence and predictors of early left ventricular thrombus after st elevation myocardial infarction in the contemporary era of primary percutaneous coronary intervention"
} | [
{
"companynumb": "GB-JNJFOC-20150213943",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ABCIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "MYC and BCL2 translocations in B-cell lymphomas are defined as \"double-hit\" associated with poor prognosis in adult patients. Such double-hit events are extremely rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), especially in pediatric patients or young adults. This study is to investigate the clinical manifestation of de novo MYCyBCL2 double-hit BCP-ALL in young patients. Two pediatric and one young adult patients were identified after a retrospective data review and all without previous history of lymphoma. There were two females and one male aged 15, 18, and 24, respectively. All patients had an unremarkable medical history before presenting with extensive bone marrow and central nervous system involvement at diagnosis. Flow cytometry immunophenotypic analysis showed an immature B-cell immunophenotype (CD10+, CD19+, TdT+, surface Ig-) and immunohistochemistry showed high expression of MYC and BCL2 in all cases. All patients showed complex karyotypes associated with 8q24 abnormalities in the form of t(8;9)(q24;p13) or t(8;14)(q24;q32) and t(14;18)(q32;q21) and fluorescence in situ hybridization confirmed MYC and BCL2 rearrangements. Two patients died of refractory disease or disease progression 7 and 13 months after initial diagnosis, respectively, and the third patient was treated with protocol AALL0232 under the Children's Oncology Group study, achieved complete remission and remained in remission for 53 months at last follow-up. Our study showed that De novo MYCyBCL2 double-hit BCP-ALL is a rare disease that also occurs in pediatric and young adult patients and associated with complex karyotypes and poor prognosis. Younger patients may benefit from intensified chemotherapy.",
"affiliations": "a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;c Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;d Department of Pathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.;a Department of Hematopathology , The University of Texas MD Anderson Cancer Center , Houston , Texas , USA.",
"authors": "Liu|Wei|W|;Hu|Shimin|S|;Konopleva|Marina|M|;Khoury|Joseph D|JD|;Kalhor|Neda|N|;Tang|Guilin|G|;Bueso-Ramos|Carlos E|CE|;Jorgensen|Jeffrey L|JL|;Lin|Pei|P|;Medeiros|L Jeffrey|LJ|;Lu|Xinyan|X|",
"chemical_list": "C000595707:BCL2 protein, human; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc",
"country": "England",
"delete": false,
"doi": "10.3109/08880018.2015.1087611",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "32(8)",
"journal": "Pediatric hematology and oncology",
"keywords": "B-cell precursor acute lymphoblastic leukemia (BCP-ALL); BCL2; Cytogenetic; MYC; double-hit",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002877:Chromosomes, Human; D005260:Female; D006801:Humans; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012189:Retrospective Studies; D014178:Translocation, Genetic",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "535-47",
"pmc": null,
"pmid": "26558423",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "De Novo MYC and BCL2 Double-hit B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) in Pediatric and Young Adult Patients Associated With Poor Prognosis.",
"title_normalized": "de novo myc and bcl2 double hit b cell precursor acute lymphoblastic leukemia bcp all in pediatric and young adult patients associated with poor prognosis"
} | [
{
"companynumb": "PHHY2016US001230",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "AVIATOR, a phase 2 clinical trial, evaluated ritonavir-boosted paritaprevir (a protease inhibitor), ombitasvir (an NS5A inhibitor), and dasabuvir (a nonnucleoside polymerase inhibitor) (the three-drug [3D] regimen) with or without ribavirin (RBV) for 8, 12, or 24 weeks in 406 HCV genotype 1 (GT1)-infected patients. The rate of sustained virologic response 24 weeks after treatment ranged from 88% to 100% across the arms of the 3D regimen with or without RBV; 20 GT1a-infected patients and 1 GT1b-infected patient experienced virologic failure (5.2%). Baseline resistance-conferring variants in NS3 were rare. M28V in GT1a and Y93H in GT1b were the most prevalent preexisting variants in NS5A, and C316N in GT1b and S556G in both GT1a and GT1b were the most prevalent variants in NS5B. Interestingly, all the GT1a sequences encoding M28V in NS5A were from the United States, while GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. Variants preexisting at baseline had no significant impact on treatment outcome. The most prevalent treatment-emergent resistance-associated variants (RAVs) in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The single GT1b-infected patient experiencing virologic failure had no RAVs in any target. A paritaprevir-ritonavir dose of 150/100 mg was more efficacious in suppressing R155K in NS3 than a 100/100-mg dose. In patients who failed after receiving 12 or more weeks of treatment, RAVs were selected in all 3 targets, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. Results from this study guided the selection of the optimal treatment regimen, treatment duration, and paritaprevir dose for further development of the 3D regimen. (This study has been registered at ClinicalTrials.gov under registration number NCT01464827.).",
"affiliations": "Research and Development, AbbVie Inc., North Chicago, Illinois, USA preethi.krishnan@abbvie.com.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.;Research and Development, AbbVie Inc., North Chicago, Illinois, USA.",
"authors": "Krishnan|Preethi|P|;Tripathi|Rakesh|R|;Schnell|Gretja|G|;Reisch|Thomas|T|;Beyer|Jill|J|;Irvin|Michelle|M|;Xie|Wangang|W|;Larsen|Lois|L|;Cohen|Daniel|D|;Podsadecki|Thomas|T|;Pilot-Matias|Tami|T|;Collins|Christine|C|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.00998-15",
"fulltext": "\n==== Front\nAntimicrob Agents ChemotherAntimicrob. Agents ChemotheraacaacAACAntimicrobial Agents and Chemotherapy0066-48041098-6596American Society for Microbiology 1752 N St., N.W., Washington, DC 2610071100998-1510.1128/AAC.00998-15Antiviral AgentsResistance Analysis of Baseline and Treatment-Emergent Variants in Hepatitis C Virus Genotype 1 in the AVIATOR Study with Paritaprevir-Ritonavir, Ombitasvir, and Dasabuvir Resistance Analysis of HCV Genotype 1 in AVIATOR StudyKrishnan et al.Krishnan Preethi Tripathi Rakesh Schnell Gretja Reisch Thomas Beyer Jill Irvin Michelle Xie Wangang Larsen Lois Cohen Daniel Podsadecki Thomas Pilot-Matias Tami Collins Christine Research and Development, AbbVie Inc., North Chicago, Illinois, USAAddress correspondence to Preethi Krishnan, preethi.krishnan@abbvie.com.Citation Krishnan P, Tripathi R, Schnell G, Reisch T, Beyer J, Irvin M, Xie W, Larsen L, Cohen D, Podsadecki T, Pilot-Matias T, Collins C. 2015. Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir. Antimicrob Agents Chemother 59:5445–5454. doi:10.1128/AAC.00998-15.\n\n22 6 2015 14 8 2015 9 2015 14 8 2015 59 9 5445 5454 26 4 2015 21 5 2015 16 6 2015 Copyright © 2015, Krishnan et al.2015Krishnan et al.This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.AVIATOR, a phase 2 clinical trial, evaluated ritonavir-boosted paritaprevir (a protease inhibitor), ombitasvir (an NS5A inhibitor), and dasabuvir (a nonnucleoside polymerase inhibitor) (the three-drug [3D] regimen) with or without ribavirin (RBV) for 8, 12, or 24 weeks in 406 HCV genotype 1 (GT1)-infected patients. The rate of sustained virologic response 24 weeks after treatment ranged from 88% to 100% across the arms of the 3D regimen with or without RBV; 20 GT1a-infected patients and 1 GT1b-infected patient experienced virologic failure (5.2%). Baseline resistance-conferring variants in NS3 were rare. M28V in GT1a and Y93H in GT1b were the most prevalent preexisting variants in NS5A, and C316N in GT1b and S556G in both GT1a and GT1b were the most prevalent variants in NS5B. Interestingly, all the GT1a sequences encoding M28V in NS5A were from the United States, while GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. Variants preexisting at baseline had no significant impact on treatment outcome. The most prevalent treatment-emergent resistance-associated variants (RAVs) in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The single GT1b-infected patient experiencing virologic failure had no RAVs in any target. A paritaprevir-ritonavir dose of 150/100 mg was more efficacious in suppressing R155K in NS3 than a 100/100-mg dose. In patients who failed after receiving 12 or more weeks of treatment, RAVs were selected in all 3 targets, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. Results from this study guided the selection of the optimal treatment regimen, treatment duration, and paritaprevir dose for further development of the 3D regimen. (This study has been registered at ClinicalTrials.gov under registration number NCT01464827.)\n==== Body\nINTRODUCTION\nHepatitis C virus (HCV) is an enveloped, single-stranded, positive-sense RNA virus in the Flaviviridae family that infects approximately 130 million to 150 million people worldwide (1, 2). Seven distinct HCV genotypes and 67 subtypes have been characterized (3). The level of nucleotide sequence diversity between genotypes is 30 to 35% and that between subtypes is 20 to 25% (4), leading to HCV genotype- and subtype-dependent variability in the treatment response to individual direct-acting antiviral agents (DAAs) (5–7). The RNA-dependent RNA polymerase of HCV is intrinsically error prone, and its lack of a proofreading function results in the introduction of approximately 1 nucleotide change per genome per replication cycle, leading to the presence of preexisting drug-resistant variants and their expansion under selective pressure (8). Understanding treatment-emergent resistance-associated variants (RAVs) as well as the impact of preexisting variants on treatment outcome in patients failing treatment with DAA therapy is important for the assessment of treatment and retreatment options.\n\nIn the AVIATOR phase 2b clinical study (study M11-652; ClinicalTrials.gov number NCT01464827), several combinations of three HCV DAAs with distinct mechanisms of action were evaluated (9). Paritaprevir (formerly ABT-450, identified by AbbVie and Enanta) is an inhibitor of the HCV NS3/4A protease and is coadministered with the pharmacokinetic enhancer ritonavir (paritaprevir/r). Amino acid variants conferring resistance to paritaprevir were detected in NS3 at position 155, 156, or 168 in vitro or following monotherapy in HCV genotype 1 (GT1)-infected subjects (10). Ombitasvir (formerly ABT-267) is an HCV NS5A inhibitor. NS5A variants conferring resistance to ombitasvir were selected in vitro or following monotherapy in GT1-infected subjects at amino acid position 28, 30, 31, 58, or 93 (11). Dasabuvir (formerly ABT-333) is a palm I site nonnucleoside HCV RNA-dependent RNA polymerase inhibitor. Variants conferring resistance to dasabuvir were selected in NS5B at amino acid position 316, 414, 448, 556, or 559 in vitro or following monotherapy in GT1-infected subjects (12, 13).\n\nAVIATOR was an open-label study with 14 treatment arms that enrolled 571 GT1-infected patients without cirrhosis who were treatment naive or prior null responders to pegylated interferon and ribavirin (RBV). Patients were randomly assigned to one of several two-drug (2D) or three-drug (3D) regimens of paritaprevir/r combined with ombitasvir or dasabuvir, or both, for 8, 12, or 24 weeks (9). All treatment arms except one also included RBV. The rate of sustained virologic response 24 weeks after treatment (SVR24) ranged from 83% to 100% across the treatment arms, with optimal SVR24 rates being in the arms that contained a 3D rather than a 2D regimen (9). Among the treatment-naive patients who received a 3D regimen with RBV (with paritaprevir administered at 150 mg with 100 mg of ritonavir), SVR24 rates ranged from 88% to 97% among those who received 8 and 12 weeks of therapy; extending treatment to 24 weeks offered no further benefit (9). Across the study, the most frequent adverse events were fatigue, headache, nausea, and insomnia, and 1% of the patients discontinued treatment due to adverse events (9).\n\nThe objective of this analysis was to provide a comprehensive evaluation of viral resistance in patients in the AVIATOR study who received the 3D regimen with or without RBV (Table 1). This subpopulation included 406 treatment-naive or prior null-responder patients receiving 8, 12, or 24 weeks of therapy in 10 treatment arms (9). The overall SVR24 rate in the treatment-naive patients was 87.5% (189/216) for the GT1a-infected patients and 98% (100/102) for the GT1b-infected patients. The SVR24 rate in the prior null responders was 93% (51/55) for the GT1a-infected patients and 97% (32/33) for the GT1b-infected patients. Twenty-one patients (20 infected with GT1a and 1 infected with GT1b) experienced virologic failure (VF), due to on-treatment breakthrough or posttreatment relapse. Thirteen patients did not achieve an SVR24 for nonvirologic reasons, e.g., early discontinuations or missing viral load data at 24 weeks posttreatment. The results of the analysis of viral resistance in patients in the AVIATOR study who received a 2D regimen with RBV are presented in the supplemental material.\n\nTABLE 1 Study design and treatment outcome of the AVIATOR 3D regimen with and without RBV\n\nStudy population and arm\tInclusion of RBV with 3Da regimen\tDuration (wk) of treatment\tParitaprevir dose (mg)b\t% SVR24c\tNo. of patients experiencing VFd\t\nBreakthrough\tRelapse\t\nGT1a\tGT1b\tGT1a\tGT1b\tGT1a\tGT1b\t\nTreatment naive\t\t\t\t\t\t\t\t\t\t\n A\t+\t8\t150\t83.9 (47/56)\t95.8 (23/24)\t\t\t9\t1\t\n E\t−\t12\t150\t82.7 (43/52)\t100 (25/25)\t1\t\t4\t\t\n F\t+\t12\t100\t96.3 (26/27)\t100 (12/12)\t\t\t\t\t\n G\t+\t12\t150\t92.6 (25/27)\t100 (13/13)\t\t\t1\t\t\n H\t+\t24\t100\t92.6 (25/27)\t92.3 (12/13)\t\t\t1\t\t\n I\t+\t24\t150\t85.2 (23/27)\t100 (12/12)\t\t\t\t\t\nTreatment-experienced null responders\t\t\t\t\t\t\t\t\t\t\n K\t+\t12\t100\t86.7 (13/15)\t100 (8/8)\t2\t\t\t\t\n L\t+\t12\t150\t92.3 (12/13)\t100 (9/9)\t1\t\t\t\t\n M\t+\t24\t100\t92.9 (13/14)\t88.9 (8/9)\t1\t\t\t\t\n N\t+\t24\t150\t100 (13/13)\t100 (7/7)\t\t\t\t\t\na The 3D regimen consisted of paritaprevir/r, ombitasvir, and dasabuvir.\n\nb The daily dose of paritaprevir (plus 100 mg of ritonavir) in each arm is indicated; ombitasvir was included at 25 mg once daily, dasabuvir was included at 400 mg twice daily, and RBV was included at 1,000 mg if the body was less than 75 kg or 1,200 mg if the body weight was 75 kg or more.\n\nc Data in parentheses represent the number of patients achieving SVR24/total number of patients in the treatment arm.\n\nd Patients not achieving SVR24 for nonvirologic reasons, e.g., early discontinuations and missing SVR24 data, were not considered VFs.\n\nIn the resistance analyses of the AVIATOR study, the prevalence of baseline variants at resistance-associated amino acid positions in NS3, NS5A, and NS5B and their impact on treatment outcome (SVR24) were evaluated. Treatment-emergent RAVs in the 21 patients who experienced VF and 2 of the patients who did not achieve SVR24 for nonvirologic reasons and for whom posttreatment samples were available were assessed.\n\nMATERIALS AND METHODS\nClinical study design.\nThe AVIATOR study (Clinical.Trials.gov number NCT01464827) was a randomized, open-label, phase 2b study with 14 treatment arms that examined the safety and efficacy of combinations of paritaprevir/r, ombitasvir, dasabuvir, and RBV in patients with HCV GT1 infection. Details of the study and randomization procedure were previously described (9). Paritaprevir was administered once daily at a dose of 100 mg, 150 mg, or 200 mg with 100 mg of ritonavir. Ombitasvir was dosed at 25 mg once daily, and dasabuvir was dosed at 400 mg twice daily. The daily dose of RBV was 1,000 mg (divided into doses of 400 mg and 600 mg) if the body weight was less than 75 kg or 1,200 mg (600 mg twice daily) if the body weight was 75 kg or more. The treatment duration was 8, 12, or 24 weeks. Ten of the treatment arms included the 3D regimen with paritaprevir doses of 100 mg or 150 mg, as shown in Table 1. Four of the treatment arms included the 2D regimen with paritaprevir (100 mg, 150 mg, or 200 mg) dosed with either ombitasvir or dasabuvir plus RBV (see Table S1 in the supplemental material). The primary efficacy endpoint was SVR24 (which was considered an HCV RNA level below the lower limit of quantitation [25 IU/ml] at 24 weeks posttreatment).\n\nAll of the patients provided written informed consent. The study was performed in accordance with good clinical practice guidelines and the principles of the Declaration of Helsinki, and the study protocol was approved by the relevant institutional review boards and regulatory agencies.\n\nSample processing.\nThe subtype-specific primers for reverse transcription-PCR (RT-PCR), nested PCR, and sequencing were designed based on the alignments of GT1a or GT1b sequences in the European HCV database (14) in conserved regions specific to the gene of interest, with nucleotide degeneracies incorporated at positions where significant variability existed among the HCV sequences for the subtype. HCV RNA was purified from 550 μl of plasma samples using an Abbott m2000 instrument (Abbott Molecular, Des Plaines, IL) and eluted in a volume of 70 μl. The target genes, the NS3/4A, NS5A, and NS5B genes, were each amplified from 20 μl of the purified HCV RNA by RT-PCR using a SuperScript III one-step RT-PCR system with Platinum Taq high-fidelity DNA polymerase (Invitrogen, Carlsbad, CA), followed by nested PCR using primers appropriate for subtype 1a or 1b samples. Only samples with HCV RNA levels of ≥1,000 IU/ml were amplified in order to reduce the chance of oversampling bias. For patients who did not achieve SVR24, the sample with an HCV RNA level of ≥1,000 IU/ml obtained the closest in time after VF or treatment discontinuation was utilized. In this study, no patient samples were excluded due to a low viral titer. For samples with HCV RNA levels of ≤50,000 IU/ml, the RT-PCR was carried out in triplicate, and the products were pooled prior to their use as a template for nested PCR.\n\nPopulation sequencing of NS3/4A, NS5A, and NS5B was conducted on the nested PCR products using gene- and subtype-specific primers. For clonal sequencing, the nested gel-purified NS3 or NS5A PCR products were cloned into the pJET1.2/blunt cloning vector using a CloneJET PCR cloning kit (Fermentas, Glen Burnie, MD), while NS5B was cloned into the GT1a or GT1b replicon shuttle vector cassette as described previously (10, 11, 13, 15, 16). Plasmid DNA was isolated from an average of 81 individual colonies per sample (range, 52 to 95), and the target gene was sequenced. At least two sequencing reads were performed in each direction across each target, providing a minimum of four sequencing reads.\n\nSequence analyses.\nAnalyses for (i) the prevalence of variants at resistance-associated amino acid positions in NS3, NS5A, and NS5B at baseline, (ii) the impact of baseline HCV variants on treatment response (SVR24) using the chi-square test, and (iii) treatment-emergent RAVs were performed using SAS (version 9.3) software (SAS Institute, Inc., Cary, NC) under a UNIX operating system. On the basis of the results of in vitro studies with HCV subgenomic replicons and phase 2a clinical studies in HCV-infected patients, the following were identified to be signature resistance-associated amino acid positions in the baseline sequence analysis: 36, 56, 155, 156, and 168 in NS3 in GT1a and 155, 156, and 168 in NS3 in GT1b for paritaprevir; 28, 30, 31, 32, 58, and 93 in NS5A in GT1a and 28, 29, 30, 31, 32, 58, and 93 in NS5A in GT1b for ombitasvir; and 316, 414, 446, 448, 451, 553, 554, 555, 556, 558, 559, and 561 in NS5B in GT1a and 316, 368, 411, 414, 445, 448, 553, 556, 558, and 559 in NS5B in GT1b for dasabuvir (10–13). Although variants at amino acid residue 80 in NS3 are not associated with resistance to paritaprevir (10), position 80 was included in the GT1a analysis due to its impact on the NS3 protease inhibitor simeprevir (5, 7). Clonal sequencing validation experiments had previously established that variants identified in a single clone by clonal sequencing were not reproducibly detected in replicate experiments (P. Krishnan, unpublished data). Therefore, RAVs by clonal sequencing were defined as variants observed in 2 or more clones from a sample obtained at a baseline or postbaseline time point relative to the appropriate reference sequence GT1a strain H77 (GenBank accession number NC004102) or GT1b strain Con1 (GenBank accession number AJ238799).\n\nAntiviral activity against a panel of resistant variants.\nThe methods for measuring the effects of individual amino acid variants on the activity of an inhibitor in HCV replicon cell culture assays were described previously (17). Variants in NS3, NS5A, or NS5B were each introduced into the GT1a strain H77 replicon using a Change-IT multiple-mutation site-directed mutagenesis kit (Affymetrix, Santa Clara, CA). After the presence of the variant(s) was confirmed by sequence analysis, the plasmid was linearized and a TranscriptAid T7 high-yield transcription kit (Fermentas, Glen Burnie, MD) was used to transcribe the HCV genomic RNA from the plasmid. In a transient-transfection assay, the replicon RNA containing the variant was transfected via electroporation into a Huh-7 cell line (16). The luciferase activity in the cells was measured using a Victor II luminometer (Perkin-Elmer, Waltham, MA). The 50% effective concentration was calculated using nonlinear regression curve fitting to the 4-parameter logistic equation and GraphPad Prism (version 4) software.\n\nCompounds.\nParitaprevir [(2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamidehydrate], ombitasvir [dimethyl ([(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate hydrate], and dasabuvir (sodium N-{6-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl]naphthalen-2-yl} methanesulfonamide) were synthesized at AbbVie, and their structures have been previously disclosed (10, 13, 18).\n\nPhylogenetic analysis of baseline sequences.\nThe population DNA sequences from baseline samples were included in the phylogenetic analyses to determine the genetic relatedness of the DAA target sequences according to geographic region: the United States or the European Union. One sample each from Canada and Australia was included in the analysis. Sequences encompassing nucleotides 1 to 1080 in NS3, 1 to 645 in NS5A, and 898 to 1773 in NS5B were aligned using the MAFFT method (19), and phylogenetic trees were constructed using the neighbor-joining tree-building method (20) with the HKY85 nucleotide substitution model (21). The reliability of the tree topology was examined using 1,000 bootstrapping replicates to generate a consensus tree with a 50% threshold cutoff for each phylogenetic analysis. Nucleotide sequence alignments and phylogenetic trees were generated using the Geneious (22) and MEGA (version 5) (23) software packages.\n\nRESULTS\nBaseline analyses.\nThe baseline amino acid variants at positions associated with resistance to NS3, NS5A, or NS5B inhibitors in GT1a and GT1b are shown in Tables 2 and 3, respectively.\n\nTABLE 2 Prevalence of baseline polymorphisms in GT1a-infected patients\n\nTarget and variant\t%a\t\nNS3 (nb = 230)\t\t\n V36A\t0.9\t\n V36L\t1.3\t\n V36M\t0.9\t\n Q80K\t41\t\n Q80L\t2.2\t\n D168A\t0.4\t\nNS5 (n = 235)\t\t\n M28T\t0.4\t\n M28V\t6.0\t\n L31M\t0.4\t\n L31V\t0.4\t\n Q30H\t2.1\t\n Q30R\t1.3\t\n H58C\t0.4\t\n H58P\t1.7\t\n H58Q\t0.9\t\n H58R\t1.3\t\n H58Y\t0.4\t\n Y93C\t0.4\t\n Y93H\t1.3\t\n Y93N\t0.4\t\nNS5B (n = 258)\t\t\n C316Y\t0.8\t\n M414T\t0.4\t\n A553G\t0.4\t\n S556G\t3.1\t\n S556N\t0.4\t\n S556R\t0.4\t\na Percentage of patients with the baseline polymorphism relative to the GT1a strain H77 reference sequence.\n\nb n, number of samples sequenced for that target.\n\nTABLE 3 Prevalence of baseline polymorphisms in GT1b-infected patients\n\nTarget and variant\t%a\t\nNS3 (nb = 119), nonec\t\t\nNS5A (n = 130)\t\t\n R30Q\t8.5\t\n L31I\t2.3\t\n L31M\t6.2\t\n P58A\t0.8\t\n P58L\t0.8\t\n P58R\t0.8\t\n P58S\t3.8\t\n P58T\t2.4\t\n Y93H\t5.4\t\nNS5B (n = 125)\t\t\n C316H\t0.8\t\n C316K\t0.8\t\n C316N\t18.4\t\n C316W\t0.8\t\n S368A\t0.8\t\n M414L\t0.8\t\n C445F\t1.6\t\n S556G\t16.0\t\na Percentage of patients with the baseline polymorphism relative to the GT1b strain Con1 reference sequence.\n\nb n, number of samples sequenced for that target.\n\nc None, baseline polymorphisms were not detected at resistance-associated amino acid positions.\n\nBaseline polymorphisms in NS3 in GT1a at amino acid position V36, Q80, or D168 were detected in 45% (104/230) of the sequences. Variants at amino acid position 36 or 168 were rarely observed at the baseline. Polymorphisms at amino acid position 80, predominantly Q80K, were frequently observed but conferred ≤3-fold resistance to paritaprevir (10). Baseline polymorphisms at resistance-associated amino acid positions were not observed in the 119 NS3 sequences from GT1b-infected patients.\n\nBaseline polymorphisms in NS5A in GT1a at amino acid position M28, Q30, L31, H58, or Y93 were detected in 15% (35/235) of the sequences. M28V, which confers 58-fold resistance to ombitasvir in the GT1a replicon (11), was the most prevalent variant in GT1a. Baseline polymorphisms at amino acid position L28, R30, L31, P58, or Y93 in NS5A were detected in 25% (32/130) of the sequences in GT1b. Y93H, which confers 77-fold resistance to ombitasvir in the GT1b replicon (11), was the predominant resistance-conferring GT1b variant.\n\nBaseline polymorphisms in NS5B in GT1a at amino acid position C316, M414, A553, or S556 were detected in 5% (13/258) of the sequences. S556G, which confers 30-fold resistance to dasabuvir (13), was the most prevalent variant in GT1a. Baseline polymorphisms amino acid position C316, S368, M414, C445, or S556 were detected in 28% (35/125) of the sequences in GT1b. The combination of variants C316N plus S556G, which confers 38-fold resistance to dasabuvir (13), was observed in 10.4% (13/125) of the samples.\n\nBy population sequencing analysis, none of the patients had baseline RAVs in all 3 targets, and only 2 patients (1 GT1a-infected patient and 1 GT1b-infected patient) had RAVs in NS5A as well as NS5B.\n\nAssociation between baseline polymorphisms and treatment outcome.\nThe most prevalent amino acid variants in GT1a-infected patients at baseline were Q80K in NS3, M28V in NS5A, and S556G in NS5B; of these, Q80K confers minimal resistance (10). Other variants conferring high-level resistance to components of the 3D regimen, observed in a minority of GT1a-infected patients, were D168A in NS3, Q30R, L31V, or Y93C/H/N in NS5A, and C316Y in NS5B (10, 11, 13). Although the number of patients with baseline variants other than Q80K was small, there was no difference in SVR24 rates among GT1a-infected patients with any of these variants at the baseline from those among patients with the reference amino acid residue at the corresponding position (Table 4).\n\nTABLE 4 Observed SVR24 rate in the presence of baseline variants\n\nGT1a target\tVariant\t% SVR24a\tP valueb\t\nWith variant\tWithout variant\t\nNS3\tQ80K\t88 (78/89)\t94 (122/130)\t0.14\t\n\tD168A\t0 (0/1)\t92 (200/218)\t0.087\t\nNS5A\tM28T/V\t86 (12/14)\t92 (192/209)\t0.339\t\n\tQ30R\t100 (3/3)\t91 (201/220)\t1.0\t\n\tL31V\t100 (1/1)\t91 (203/222)\t1.0\t\n\tY93C/N/H\t80 (4/5)\t92 (200/218)\t0.362\t\nNS5B\tS556G\t100 (7/7)\t92 (220/239)\t1.0\t\n\tC316Y\t50 (1/2)\t93 (226/244)\t0.149\t\na Data in parentheses represent the number of patients achieving SVR24/total number of patients who had a sequence available. Patients not achieving SVR24 for nonvirologic reasons, e.g., early discontinuations and missing SVR24 data, were excluded from this analysis.\n\nb P values were determined by the chi-square test.\n\nTreatment-emergent variants in patients not achieving SVR24.\nOf the 406 treatment-naive or prior null-responder patients receiving 8, 12, or 24 weeks of therapy with the 3D regimen, 21 patients experienced VF. Of these 21 patients, 5 experienced on-treatment breakthroughs and 16 were posttreatment relapsers (Table 1). Ten of the 21 patients, including the single GT1b-infected patient who experienced a posttreatment relapse, were in the 8-week arm of the study. The baseline variants and treatment-emergent RAVs identified by clonal sequencing in at least 2 clones (detection limit, 5 to 10%) in the patients experiencing VF are listed in Table 5.\n\nTABLE 5 RAVs relative to reference sequence in NS3, NS5A, and NS5B at time of VFa\n\nStudy population and arm\tGT\tVF type\tVariant(s)\t\nNS3\tNS5A\tNS5B\t\nBaseline\tTime of VF\tBaseline\tTime of VF\tBaseline\tTime of VF\t\nTreatment naive\t\t\t\t\t\t\t\t\t\n A\t1a\tRelapse at PTW 2\tNoneb\tNone\tM28V\tM28V\tNone\tNone\t\n A\t1a\tRelapse at PTW 4\tD168A/D\tD168A\tnone\tQ30R\tS556G/S\tS556G\t\n A\t1a\tRelapse at PTW 4\tNone\tNone\tNone\tNone\tNone\tNone\t\n A\t1a\tRelapse at PTW 4\tNone\tNone\tNone\tNone\tNone\tNone\t\n A\t1a\tRelapse at PTW 8\tNone\tNone\tL31L/M\tNone\tS556G/S\tNone\t\n A\t1a\tRelapse at PTW 2\tNone\tNone\tNone\tM28T + H58P\tS556G/S\tNone\t\n A\t1a\tRelapse at PTW 4\tNone\tNone\tNone\tNone\tNone\tNone\t\n A\t1a\tRelapse at PTW 4\tNone\tNone\tNone\tNone\tNone\tNone\t\n A\t1a\tRelapse at PTW 24\tNone\tD168V\tNone\tQ30R\tNone\tS556G\t\n A\t1b\tRelapse at PTW 4\tNone\tNone\tNone\tNone\tNone\tNone\t\n E\t1a\tRelapse at PTW 8\tNone\tD168V\tY93N/S/Y\tY93N\tNone\tNone\t\n E\t1a\tBreakthrough at wk 12\tNone\tY56H + D168Y, D168Y\tNone\tM28V + Q30K\tNone\tS556G\t\n E\t1a\tRelapse at PTW 8\tNone\tD168V\tY93N/Y\tY93N\tNone\tM414T, S556G\t\n E\t1a\tRelapse at PTW 12\tNone\tD168V\tNone\tQ30R\tC316Y, S556G/S\tC316Y + S556G\t\n E\t1a\tRelapse at PTW 2\tNone\tD168V\tNone\tQ30R\tNone\tS556G\t\n G\t1a\tRelapse at PTW 2\tNone\tR155K, D168V\tM28M/V\tM28T\tNone\tG554S, S556G\t\n H\t1a\tRelapse at PTW 48\tNone\tNone\tNone\tNone\tNone\tNone\t\nTreatment-experienced null responders\t\t\t\t\t\t\t\t\t\n K\t1a\tBreakthrough at wk 8\tNone\tV36M + R155K, R155K\tNone\tM28T, Q30R\tNone\tD559G\t\n K\t1a\tBreakthrough at wk 6\tNone\tD168V\tQ30Q/R\tQ30R\tNone\tA553T\t\n L\t1a\tBreakthrough at wk 12\tNone\tD168Y\tNone\tQ30R\tNone\tS556G\t\n M\t1a\tBreakthrough at wk 16\tNone\tV36A/M + R155K\tNone\tQ30R\tM414I/M\tG558R\t\nTreatment naive\t\t\t\t\t\t\t\t\t\n I\t1a\tD/C\tNone\tNone\tM28V\tM28V\tNone\tS556G\t\n I\t1a\tD/C\tNone\tNone\tNone\tNone\tNone\tNone\t\na GT, genotype; D/C, premature study drug discontinuation; PTW, posttreatment week; VF, virologic failure; +, linked variants; slashes, mixture of variants.\n\nb None, variants at resistance-associated amino acid positions were not detected by clonal sequencing.\n\nOf the 20 GT1a-infected VF patients, 12 had RAVs in NS3 at the time of VF. Seven patients from the 8-week treatment arm had no RAVs in NS3 at the time of failure, nor did one patient who was treated for 24 weeks and subsequently relapsed at posttreatment week 48. Among the other patients, the treatment-emergent RAV D168V was detected in 7 patients, D168Y alone or in combination with Y56H was detected in 2 patients, and R155K alone or in combination with V36A/M was detected in 3 patients. D168A was identified at baseline and at the time of failure in 1 patient. Of note, 2 of the 3 patients with treatment-emergent R155K received a regimen including paritaprevir at the lower dose of 100 mg.\n\nFourteen of the 20 GT1a-infected patients had RAVs in NS5A at the time of VF. The 6 patients with no RAVs in NS5A at the time of failure included 5 from the 8-week treatment arm, as well as the patient described above who relapsed at posttreatment week 48. Among the other patients, treatment-emergent NS5A variants M28V plus Q30K were detected in 1 patient, M28T was detected in 3 patients, and Q30R was detected in 7 patients. Four of the 6 patients with preexisting NS5A variants at baseline also had the same variant at the time of failure.\n\nEleven of the 20 GT1a-infected patients had RAVs in NS5B at the time of VF. Nine of these patients had no RAVs in NS5B at the time of failure, including 7 patients treated for 8 weeks, 1 patient treated for 12 weeks without RBV, and the patient described above who relapsed at posttreatment week 48. Treatment-emergent NS5B RAVs M414T, G554S, A553T, G558R, and D559G were each observed in 1 patient, and S556G was detected in 6 patients. Two of the 5 patients with preexisting NS5B variants at baseline had the same variant at the time of failure.\n\nOne GT1b-infected patient in the 8-week treatment arm experienced VF; this patient did not have any RAVs at baseline or at the time of VF in any of the three targets.\n\nAmong the 20 GT1a-infected patients with VF, treatment-emergent RAVs were detected in all 3 targets in 7 patients, in NS3 and NS5A in 1 patient, in NS3 and NS5B in 2 patients, and in only NS5A in 2 patients. One GT1a-infected patient had a preexisting NS5A variant but no treatment-emergent variants, and 7 GT1a-infected patients (including 6 in the 8-week treatment arm) had no RAVs in any target. The resistance profile was similar among patients experiencing on-treatment breakthrough and those who relapsed posttreatment.\n\nAmong the 13 patients not achieving SVR24 for nonvirologic reasons, 6 had missing data at the SVR24 time point. Postbaseline samples with HCV RNA levels of ≥1,000 IU/ml were available for 2 of the 13 patients (Table 5). Neither patient had treatment-emergent RAVs in NS3 or NS5A, and 1 had S556G in NS5B.\n\nActivity of paritaprevir, ombitasvir, and dasabuvir against variants in GT1a H77 replicons.\nThe activity of paritaprevir, ombitasvir, and dasabuvir against variants observed in GT1a-infected patients experiencing VF was evaluated in the GT1a H77 replicon (Table 6). NS3 variants R155K and D168A conferred lower levels of resistance to paritaprevir than the D168V and D168Y variants. The combination of these variants with either V36M or Y56H conferred an additional 2-fold resistance to paritaprevir. The lower level of resistance conferred by R155K supports the observation that this variant appeared to be suppressed with higher doses of paritaprevir. NS5A variants L31M and H58P did not confer resistance to ombitasvir, and M28V conferred moderate levels of resistance, while M28T, Q30R, and Y93N each conferred at least 800-fold resistance to ombitasvir. Consistent with the phenotype, L31M was not enriched in the patient treated for 8 weeks who had a 31L/M mixture at baseline, and M28V was rarely detected as a treatment-emergent variant in patients experiencing VF. NS5B variants M414I/T and S556G conferred lower levels of resistance to dasabuvir than the C316Y, G554S, and A553T variants. Consistent with the phenotype, M414I was not enriched at the time of failure in the patient randomized to 24 weeks of treatment who had a mixture of 414I/M at baseline.\n\nTABLE 6 Activity of paritaprevir, ombitasvir, and dasabuvir against variants in GT1a H77 replicon\n\nNS3\tNS5A\tNS5B\t\nVariant\tFold resistance to paritaprevir\tVariant\tFold resistance to ombitasvir\tVariant\tFold resistance to dasabuvir\t\nV36A\t3\tM28T\t8,965\tC316Y\t1,472\t\nV36M\t2\tM28V\t58\tM414I\t8\t\nY56H\t3\tQ30R\t800\tM414T\t32\t\nR155K\t37\tL31M\t2\tA553T\t152\t\nD168A\t50\tH58P\t0.5\tG554S\t198\t\nD168V\t96\tY93N\t66,740\tS556G\t30\t\nD168Y\t219\t\t\tG558R\tNDa\t\nV36M + R155K\t79\t\t\tD559G\tND\t\nY56H + D168Y\t451\t\t\t\t\t\na ND, fold resistance could not be determined due to the low replication capacity of the variant.\n\nGeographic and phylogenetic analysis of baseline sequences.\nPhylogenetic analyses were conducted using baseline sequences from GT1a- and GT1b-infected patients to determine the genetic relatedness of the DAA target sequences according to geographic region. The analysis of NS3 in GT1a included 229 baseline sequences and 3 reference sequences. The geographic distribution of GT1a NS3 sequences included in the analysis was 83% (190/229) from the United States, 16% (37/229) from the European Union, and 1 sequence each from Canada and Australia. Four major phylogenetic groups are depicted in Fig. 1. The GT1b strain Con1 and GT1c strain HC-G9 reference sequences each sorted as separate groups, and GT1a baseline sequences from the AVIATOR study sorted into 2 distinct clades, with the GT1a H77 reference sequence sorting to clade 1. Both GT1a clades included sequences from the United States and the European Union. Clade 1 included 61% (140/229) of the GT1a baseline sequences, including 7 subgroups comprising 23 sequences. Clade 2 included 39% (89/229) of the GT1a baseline sequences, including 2 subgroups comprising 4 sequences. Baseline sequences from the United States clustered predominantly into clade 1 (68%, 129/190 sequences), while baseline sequences from the European Union clustered predominantly into clade 2 (73%, 27/37 sequences).\n\nFIG 1 Geographic distribution of HCV NS3 nucleotide sequences. The NS3 neighbor-joining phylogenetic tree is displayed in a circular format. The reliability of the tree topology was examined using 1,000 bootstrapping replicates, and bootstrap values of ≥50 are listed at appropriate nodes in the tree. The genetic distance scale bar indicates the number of nucleotide substitutions per site between sequences. Rest of world, 1 sequence each from Canada and Australia.\n\nPhylogenetic analyses of NS5B GT1a baseline sequences also revealed a similar conservation of the 2 GT1a clades (data not shown). Phylogenetic analyses of NS5A in GT1a and NS3, NS5B, and NS5A baseline sequences in GT1b each revealed one major cluster of sequences, and specific clustering according to geographic region was not seen (data not shown).\n\nSome of the polymorphisms in NS3, NS5A, and NS5B showed specific geographic distribution (Table 7).The majority of the GT1a sequences with Q80K in NS3 sorted into clade 1 (98%, 93/95), with the overall prevalence of Q80K being 66.4% in this clade. The prevalence of Q80K was 46.8% (89/190) in the United States, whereas it was 13.5% (5/37) in the European Union. All of the GT1a-infected patients with M28V in NS5A were from the United States. C316N and S556G in NS5B in GT1b were predominant among sequences from the European Union. Other variants were observed in sequences from the United States as well as the European Union, as shown in Table 7.\n\nTABLE 7 Distribution of prevalent baseline variants by geographic region\n\nTarget, GT\tVariant\tPhylogenetic cluster\t%a\t\nUnited States\tEuropean Union\t\nNS3, GT1a\tQ80K\tClade 1 (n = 140)\t67.4 (87/129)\t50 (5/10)\t\n\t\tClade 2 (n = 89)\t3.3 (2/61)\t0 (0/27)\t\n\t\tTotal\t46.8 (89/190)\t13.5 (5/37)\t\nNS5A, GT1a\tM28V\t\t7 (14/191)\t0 (0/42)\t\nNS5B, GT1a\tS556G\tClade 1\t2.9 (4/139)\t6.2 (1/16)\t\n\t\tClade 2\t3.1 (2/65)\t2.8 (1/36)\t\n\t\tTotal\t2.9 (6/204)\t3.9 (2/52)\t\nNS5A, GT1b\tY93H\t\t2.9 (2/68)\t8.2 (5/61)\t\nNS5B, GT1b\tC316N\t\t4.6 (3/65)\t32 (19/59)\t\n\tS556G\t\t6.2 (4/65)\t25 (15/59)\t\na The percentage of patients within each geographic region with the variant. Values in parentheses represent the number of patients with the variant/number of available sequences in the geographic region for each target.\n\nDISCUSSION\nThe phase 2b AVIATOR trial assessed 2D or 3D combination regimens in 571 treatment-naive and treatment-experienced patients for 8, 12, and 24 weeks. On the basis of the differential SVR24 rates observed in this trial (9), a 3D regimen with and without RBV was selected for further clinical development. Among the 406 subjects across the various arms in the AVIATOR study administered the 3D regimen with or without RBV, there were low rates of discontinuation due to adverse events, and SVR24 rates ranged from 88% to 100% (9). There were 21 virologic failures, of which 10 were in the 8-week arm of the study.\n\nIn the AVIATOR trial, the prevalence of baseline RAVs varied by drug target, HCV subtype, and geographic region. The presence of RAVs in NS3 at baseline was rare in either subtype. M28V in GT1a and Y93H in GT1b were the most prevalent baseline RAVs in NS5A, while S556G in NS5B was the most prevalent baseline RAV in both GT1 subtypes. There was not a significant difference in SVR24 rates in patients with any preexisting RAV at baseline compared to patients without the RAV, suggesting that either the drug levels or the nonoverlapping resistance profiles of the drugs in the 3D regimen reduce the impact of baseline resistance on treatment response.\n\nAmong the 21 patients who experienced VF, the majority of those who received 12 weeks or more of treatment showed the emergence of RAVs across all 3 targets. The most prevalent treatment-emergent RAVs in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. Consistent with the lower levels of resistance conferred by M28V in NS5A to ombitasvir in the GT1a H77 replicon, this variant, which had a 6% baseline prevalence, did not impact treatment outcome and was rarely treatment emergent in virologic failures. The paucity of RAVs at the time of failure among samples from patients who relapsed after 8 weeks of treatment, as detected by clonal sequencing (detection limit, 5 to 10%), suggested that for those patients the duration of treatment was insufficient to fully suppress the wild-type virus population. Virologic failure was rarely seen in patients with GT1b, and the single GT1b-infected patient experiencing VF in the 8-week arm of the study had no RAVs at the time of failure.\n\nAmong the 165 patients receiving a 2D regimen with RBV, 17 experienced VF, all with GT1a infection (see Table S1 in the supplemental material). The pattern of treatment-emergent RAVs in these patients was similar to that observed with the 3D regimen (see Table S2 in the supplemental material).\n\nThe AVIATOR trial also helped to establish the optimal dosage of paritaprevir. Although comparable efficacies were seen with all doses of paritaprevir/r studied, the infrequent emergence of R155K in patients with VF at a dose of 150/100 mg suggests that this dose was more efficacious at suppressing this variant, which confers 37-fold resistance, than the 100/100-mg dose; hence, in the phase 3 development program, paritaprevir/r was dosed at 150/100 mg.\n\nThe persistence of treatment-emergent RAVs is currently being followed to posttreatment week 48 among patients treated with paritaprevir/r-, ombitasvir-, and dasabuvir-based regimens in a pooled analysis of phase 2 and 3 clinical studies and in a 3-year follow-up study that enrolled a subset of subjects from the phase 2 and 3 clinical studies. Resistance analyses with other combination DAA regimens generally suggest that NS5A variants are persistent, while NS3 variants generally decay through posttreatment week 48 (24).\n\nGiven the heterogeneity of the HCV genome, phylogenetic analyses were conducted on NS3, NS5A, and NS5B baseline sequences from patients infected with GT1a and GT1b to compare the genetic relatedness of the sequences according to geographic region. Analysis of NS3 and NS5B revealed conservation of 2 major clusters of HCV GT1a sequences. Clade 1 contained a larger proportion of sequences from the United States and clade 2 contained a larger proportion of sequences from the European Union for both targets. NS3 and NS5B sequences from the United States or the European Union did not form specific subgroup clusters in either clade, suggesting similar genetic relatedness between sequences from the United States and the European Union within each clade of the phylogenetic analysis. A similar divergence of GT1a isolates into 2 distinct clades was described by Pickett et al., using full-genome sequencing data (25). The clustering of GT1a isolates was not attributed to geography or time of isolation, but a number of clade-informative sites were identified within the NS3 protease, NS5A domains 2 and 3, and NS5B (25), which is consistent with our observations. The inclusion of only domain 1 of NS5A in our phylogenetic analysis may account for the observed lack of clustering of GT1a NS5A sequences into separate clades.\n\nIn this study, all GT1a sequences encoding M28V in NS5A were from the United States, and GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. As Q80K in GT1a NS3 impacts treatment outcome with the NS3 protease inhibitor simeprevir (5, 7), the prevalence of this polymorphism was evaluated in this study. The majority of sequences encoding Q80K in NS3 (98%) were found within one GT1a cluster. A phylogenetic analysis of GT1a sequences by geographic region and time of sample collection by McCloskey et al. indicated that the majority of the Q80K-carrying sequences (96%) have descended from a single substitution event that occurred over 50 years ago in the United States (26). This evolutionary history may account for the geographic differences in Q80K prevalence. In this study, Q80K was observed at a prevalence of 46.8% among sequences from the United States and at a prevalence of 13.5% among the sequences from the European Union.\n\nIn conclusion, while RAVs in NS5A and NS5B were observed at baseline, they did not appear to affect treatment response, suggesting that this multitargeted HCV GT1 antiviral regimen affords a high barrier to resistance. Overall VF rates were low at 5.2%. RAVs were typically selected in all 3 targets in patients who failed after receiving 12 or more weeks of treatment, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. The results from the AVIATOR study were used to determine the optimal treatment regimen, duration, and paritaprevir dose for further development of paritaprevir/r, ombitasvir, and dasabuvir in treatment-naive and treatment-experienced patients with chronic HCV GT1 infection, including those with compensated cirrhosis (27–31).\n\nSupplementary Material\nSupplemental material\n Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.00998-15.\n\nACKNOWLEDGMENTS\nWe thank the trial participants, investigators, and coordinators who made this study possible. We thank Barbara McGovern for critical review of the manuscript.\n\nDesign, study conduct, and financial support for this study were provided by AbbVie. AbbVie participated in the interpretation of the data, review, and approval of the publication. We are all employees of AbbVie and may own AbbVie stock.\n==== Refs\nREFERENCES\n1. Lavanchy D \n2011 \nEvolving epidemiology of hepatitis C virus . Clin Microbiol Infect \n17 :107 –115 . doi:10.1111/j.1469-0691.2010.03432.x .21091831 \n2. Mohd Hanafiah K , Groeger J , Flaxman AD , Wiersma ST \n2013 \nGlobal epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence . Hepatology \n57 :1333 –1342 . doi:10.1002/hep.26141 .23172780 \n3. Smith DB , Bukh J , Kuiken C , Muerhoff AS , Rice CM , Stapleton JT , Simmonds P \n2014 \nExpanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource . Hepatology \n59 :318 –327 . doi:10.1002/hep.26744 .24115039 \n4. Simmonds P \n2004 \nGenetic diversity and evolution of hepatitis C virus—15 years on . 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"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0066-4804",
"issue": "59(9)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": null,
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D015081:2-Naphthylamine; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D005838:Genotype; D016174:Hepacivirus; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D011392:Proline; D019438:Ritonavir; D013449:Sulfonamides; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "5445-54",
"pmc": null,
"pmid": "26100711",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15483230;25534735;3447015;16189112;17142229;16914212;17604129;19378139;21091831;20565573;21546353;25389307;3934395;22543367;23431163;23172780;23607594;23504694;24115039;24428468;24400777;24720679;24720703;24725237;24795200;24818763;24907224;25451053;25451055",
"title": "Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir.",
"title_normalized": "resistance analysis of baseline and treatment emergent variants in hepatitis c virus genotype 1 in the aviator study with paritaprevir ritonavir ombitasvir and dasabuvir"
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"companynumb": "US-CIPLA LTD.-2015US07164",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DASABUVIR"
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{
"abstract": "A 12-month-old (former 24 week gestational age), 8.7 kg male was hospitalized after an uneventful colostomy reversal. In the postoperative unit, the patient unintentionally received 1000 mg IV (114.9 mg/kg) acetaminophen instead of the intended 100 mg IV. Serial acetaminophen concentrations were drawn. The patient received IV Nacetylcysteine and ultimately had no adverse outcomes.\nThis case report adds to the existing literature regarding toxicokinetics of IV APAP in infants. Our patient had a calculated ke of 0.263 h-1, correlating with a half-life of 2.63 hours. Based on current available data, the half-life of IV APAP in infants varies (2.6 to 4.9 hours). The reason for this variation is unknown and further research is needed in this area.",
"affiliations": "Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, 12297NYU Grossman School of Medicine, New York, NY, USA.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, 12297NYU Grossman School of Medicine, New York, NY, USA.;Department of Pediatrics, Maria Fareri Children's Hospital, 497001Westchester Medical Center Health Network, Valhalla, NY, USA.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, 12297NYU Grossman School of Medicine, New York, NY, USA.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, 12297NYU Grossman School of Medicine, New York, NY, USA.",
"authors": "Trebach|Joshua|J|https://orcid.org/0000-0002-8322-2500;Mahonski|Sarah G|SG|https://orcid.org/0000-0002-3575-780X;Melchert|Kristina|K|https://orcid.org/0000-0001-9999-5762;Howland|Mary Ann|MA|;Chiang|William K|WK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/08971900211021286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": null,
"journal": "Journal of pharmacy practice",
"keywords": "acetaminophen; medication safety; pediatrics",
"medline_ta": "J Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "8971900211021286",
"pmc": null,
"pmid": "34080465",
"pubdate": "2021-06-03",
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"abstract": "Lung cancer prognosis has improved in the last decade, including in patients with brain metastasis. However, few of these patients who receive corticosteroids have a primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP). We report the case of an 80-year-old man diagnosed with non-small cell lung cancer and concomitant symptomatic brain metastases, treated with 50 mg/day of prednisolone without any prophylaxis, who presented an acute PJP. After 72 hours of unsuccessful treatment of PJP, the patient died. In our review of this case and the existing literature, we emphasise the importance of a wide use of prophylaxis for PJP, especially in advanced lung cancer treated with corticosteroid therapy. We discuss this issue and report current evidence for primary prophylaxis by trimethoprim-sulfamethoxazole.",
"affiliations": "Infectious Diseases and Intensive Care Unit, CHU Rennes, Rennes, France.;Department of Respiratory Medicine, Centre Hospitalier Universitaire de Rennes, Rennes, France.;Infectious Diseases and Intensive Care Unit, CHU Rennes, Rennes, France.;Department of Respiratory Medicine, Centre Hospitalier Universitaire de Rennes, Rennes, France charles.ricordel@chu-rennes.fr.",
"authors": "Luque Paz|David|D|;Jouneau|Stephane|S|;Tattevin|Pierre|P|;Ricordel|Charles|C|http://orcid.org/0000-0001-6160-2732",
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"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbcr-2019-232895\n10.1136/bcr-2019-232895\nCase Report\n1506\n1333\n291\n508\n523\nPneumocystis in metastatic lung cancer, a pragmatic approach in support of prophylaxis\nLuque Paz David 1\nJouneau Stephane 2\nTattevin Pierre 1\nhttp://orcid.org/0000-0001-6160-2732\nRicordel Charles 2\n1 Infectious Diseases and Intensive Care Unit, CHU Rennes, Rennes, France\n2 Department of Respiratory Medicine, Centre Hospitalier Universitaire de Rennes, Rennes, France\nCorrespondence to Dr Charles Ricordel; charles.ricordel@chu-rennes.fr\n2021\n28 6 2021\n28 6 2021\n14 6 e23289507 5 2021\n© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nLung cancer prognosis has improved in the last decade, including in patients with brain metastasis. However, few of these patients who receive corticosteroids have a primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP). We report the case of an 80-year-old man diagnosed with non-small cell lung cancer and concomitant symptomatic brain metastases, treated with 50 mg/day of prednisolone without any prophylaxis, who presented an acute PJP. After 72 hours of unsuccessful treatment of PJP, the patient died. In our review of this case and the existing literature, we emphasise the importance of a wide use of prophylaxis for PJP, especially in advanced lung cancer treated with corticosteroid therapy. We discuss this issue and report current evidence for primary prophylaxis by trimethoprim–sulfamethoxazole.\n\nlung cancer (oncology)\npneumonia (respiratory medicine)\nspecial-featureunlocked\n==== Body\nBackground\n\nHuman pneumocystosis is a fungal infection caused by Pneumocystis jirovecii, a cosmopolitan and opportunistic ubiquitous fungus. P. jirovecii pneumonia (PJP) is potentially lethal, developing mainly in the lungs of profoundly immunocompromised patients. HIV infection, organ transplants and haematological malignancies are well-defined risk factors.1 2\n\nA review of the literature provided arguments to consider a pathophysiological association between P. jirovecii and the use of corticosteroids, and American Thoracic Society (ATS) guidelines recommend prophylaxis when prednisone doses exceed 20 mg/day for longer than 1 month.3\n\nWe present a case of a lethal PJP in a patient with metastatic lung cancer who received corticosteroids without prophylaxis.\n\nCase presentation\n\nIn August 2015, an 83-year-old HIV-negative, non-smoker Caucasian man was diagnosed with T3N2M0 small cell lung carcinoma. He went into complete remission after six cycles of carboplatin/etoposide and thoracic radiation (30 Gy with daily fractions of 3 Gy).\n\nIn December 2016, a stage I (pT1N0M0) right lower lobe lung adenocarcinoma was discovered and treated with lobectomy. The tumour had no EGFR, BRAF or KRAS mutation and no ALK, ROS1, RET rearrangement; only a copy number variation of MET gene (two to three copies). In April 2017, a neurological impairment revealed a frontal brain metastasis. The patient was treated with radiotherapy associated with methylprednisolone initially at 100 mg/day and then reduced to 50 mg/day.\n\nIn June 2017, he presented dry cough and shortness of breath associated with self-reported fever. Two days after the first symptoms, he was admitted to hospital. At admission, he had fever (38.2°C), blood pressure was 108/61 mm Hg, regular pulse of 79 bpm, respiration of 18 cycles/min, and 95% SpO2 with 2 L/min of oxygen supplementation. There was no recent chemotherapy, and no immunosuppressive treatment other than corticosteroids.\n\nInvestigations\n\nBlood laboratory tests revealed no cytopenia: haemoglobin concentration 129 g/L, platelet count 244 000×10ˆ9/L, white cell count 6400/mm3, including neutrophil count 3900/mm3. There was no renal dysfunction with an estimated glomerular filtration rate of >60 mL/min. Chest CT scan showed bilateral excavated nodules evoking lung abscesses, associated with diffuse bilateral ground-glass opacities (figure 1). A bronchoalveolar lavage (BAL) was immediately performed with good tolerance, for bacteriological and mycological analyses. Blood culture and serum galactomannan antigen were negative.\n\nFigure 1 Chest CT scan with bilateral excavated nodules evoking lung abscesses, associated with diffuse bilateral ground-glass opacities.\n\nDifferential diagnosis\n\nA posteriori, BAL results revealed the presence of P. jiroveci (with Gomori-Grocott staining, indirect immunofluorescence and positive Pneumocystis PCR at the 21st cycle of amplification), as well as a few colonies of Aspergillus fumigatus in culture, Actinomyces odontolyticus (105 UFC/mL) in culture and Nocardia nova susceptible to trimethoprim–sulfamethoxazole (TMP–SMX).4\n\nTo explain the acute respiratory failure, we discarded the role of A. odontolyticus, which is probably a contamination during the BAL procedure. Images of lung abscesses are compatible with N. nova, but nocardiosis would not explain the rapid clinical degradation. A. fumigatus could be implicated in respiratory failure, but the patient had no neutropenia and a negative A. fumigatus PCR in BAL, making the possibility of rapidly lethal invasive aspergillosis less likely.\n\nThe association of diffuse bilateral ground-glass opacities, very low cycle threshold value of Pneumocystis PCR in BAL, a positive direct examination and a deep hypoxaemia progressing into severe acute respiratory failure are solid arguments to attribute the death of the patient to a PJP, rather than other coinfections.\n\nTreatment\n\nFirst, the patient was treated with ceftriaxone and rovamycin as recommended for community-acquired pneumonia with comorbidities and severity criteria. After the chest CT, intravenous voriconazole and TMP–SMX treatment was started. Corticosteroids were maintained as adjuvant therapy of hypoxaemic PJP.\n\nOutcome and follow-up\n\nHis clinical situation worsened on a respiratory level with increasing oxygen needs. Despite 48 hours of probabilistic treatment, his respiratory failure became critical. On arterial blood gas, he presented an extremely severe hypoxaemia despite oxygen supply (flow rate 15 L/min) with a PaO2 measured at 39 mm Hg. The patient died on day 3.\n\nDiscussion\n\nIn patients with lung cancer, especially with brain metastasis, corticosteroids are commonly prescribed. Life expectancy is limited to a few months or years in most cases, and physicians do not prescribe chemoprophylaxis against Pneumocystis spp. A retrospective study showed that fewer patients with solid tumours (3.9%) received prophylaxis compared with patients with haematological malignancies (63.6%).5\n\nLung cancer is at low risk of PJP (<25 cases/100 000 patient-year) like other solid tumours, excluding central nervous system cancer.6 But for patients having solid cancer and being treated by corticosteroids, the incidence of PJP rises to 1.3%.7 Furthermore, PJP is usually more abrupt and fulminant8 among patients with neoplastic disease, and its mortality rate is much higher, approaching 50%,7 9 and a significant risk factor of mortality with an OR=2.66. In different studies, 55%–87% of patients with PJP had previously used corticosteroids, and 18%–31% had a solid tumour.9 10 The most important predisposing factor for developing PJP is the use of steroids, even at a low dose (equivalent to ≥20 mg/day prednisone for ≥1 month).11 12 ATS guidelines recommend prophylaxis when prednisone doses exceed 20 mg/day for longer than 1 month.\n\nRecent guidelines13 and two general reviews14 15 recommend prophylaxis for patients with solid cancer receiving prolonged, high-dose corticosteroid treatment (16–25 mg of prednisolone/day or ≥4 mg dexamethasone daily for ≥4 weeks) regardless of the stage of malignancy.\n\nConcerning the toxicity of TMP–SMX, 85% of the patients do not experience any toxic effects.16 So, when steroids are prescribed for a patient with cancer, especially in metastatic diseases, we prioritise a pragmatic attitude: start a prophylaxis if survival exceeds 3 months.\n\nLearning points\n\nCorticosteroids are a major risk factor of Pneumocystis jirovecii pneumonia (PJP), adding to the risk of PJP in lung cancer.\n\nGuidelines recommend PJP prophylaxis by trimethoprim–sulfamethoxazole (TMP–SMX) when dose >20 mg/day.\n\nSide effects occur in 15% of cases, and discontinuation of the prophylaxis is required in 3% of patients treated.\n\nOur pragmatic proposal: start a primary prophylaxis if survival exceeds 3 months, and eventually discuss alternatives in case of TMP–SMX intolerance.\n\nEthics statements\n\nPatient consent for publication\n\nNext of kin consent obtained.\n\nContributors: DLP and PT contributed to conception and design of the manuscript. PT and SJ were responsible for the literature review. DLP was responsible for clinical data collection. DLP and CR were responsible for figures. All authors were responsible for manuscript editing and final approval of the article. CR takes responsibility for the paper as a whole.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer-reviewed.\n==== Refs\nReferences\n\n1 Radhi S, Alexander T, Ukwu M, et al . Outcome of HIV-associated Pneumocystis pneumonia in hospitalized patients from 2000 through 2003. BMC Infect Dis 2008;8 :118. 10.1186/1471-2334-8-118 18796158\n2 Maertens J, Cesaro S, Maschmeyer G, et al . ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother 2016;71 :2397–404. 10.1093/jac/dkw157 27550992\n3 Limper AH, Knox KS, Sarosi GA, et al . An official American thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183 :96–128. 10.1164/rccm.2008-740ST 21193785\n4 Schlaberg R, Fisher MA, Hanson KE. Susceptibility profiles of Nocardia isolates based on current taxonomy. Antimicrob Agents Chemother 2014;58 :795–800. 10.1128/AAC.01531-13 24247124\n5 Worth LJ, Dooley MJ, Seymour JF, et al . An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer Hospital. Br J Cancer 2005;92 :867–72. 10.1038/sj.bjc.6602412 15726101\n6 Fillatre P, Decaux O, Jouneau S, et al . Incidence of Pneumocystis jiroveci pneumonia among groups at risk in HIV-negative patients. Am J Med 2014;127 :1242.e11–17. 10.1016/j.amjmed.2014.07.010\n7 Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc 1996;71 :5–13. 10.4065/71.1.5 8538233\n8 Gripaldo R, Lippmann ML. Pneumocystis pneumonia in HIV-negative patients: a review of the literature. Clin Pulmonary Med 2012;19 :5–13. 10.1097/CPM.0b013e31823e2401\n9 Sepkowitz KA, Brown AE, Telzak EE, et al . Pneumocystis carinii pneumonia among patients without AIDS at a cancer Hospital. JAMA 1992;267 :832–7. 10.1001/jama.1992.03480060078034 1732656\n10 Roblot F, Godet C, Le Moal G, et al . Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis 2002;21 :523–31. 10.1007/s10096-002-0758-5 12172743\n11 Schoovaerts K, Dirix L, Rutten A, et al . Pneumocystis jiroveci pneumonia (PJP) in non-HIV immunocompromised individuals. Acta Clin Belg 2017;72 :413–6. 10.1080/17843286.2017.1305136 28346081\n12 Barbounis V. Should patients with malignancy receive chemoprophylaxis against Pneumocystis jirovecii pneumonia? Nat Clin Pract Oncol 2005;2 :490–1. 10.1038/ncponc0299 16205763\n13 Cooley L, Dendle C, Wolf J, et al . Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J 2014;44 :1350–63. 10.1111/imj.12599 25482745\n14 Rouyer M, Stoclin A, Blanc F-X. [Pneumocystis pneumonia in HIV-negative adults]. Rev Mal Respir 2015;32 :985–90. 10.1016/j.rmr.2015.06.007 26572261\n15 Roux A, Gonzalez F, Roux M, et al . Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. Med Mal Infect 2014;44 :185–98. 10.1016/j.medmal.2014.01.007 24630595\n16 Green H, Paul M, Vidal L, et al . Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc 2007;82 :1052–9. 10.4065/82.9.1052 17803871\n\n",
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"title": "Pneumocystis in metastatic lung cancer, a pragmatic approach in support of prophylaxis.",
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"abstract": "BACKGROUND\nTizanidine (Zanaflex) is a centrally acting imidazoline muscle relaxant that is structurally similar to clonidine (α(2)-adrenergic agonist) but not to other myorelaxants such as baclofen or benzodiazepines. Interestingly, cardiac arrhythmias and QT interval prolongation have been reported with tizanidine.\n\n\nOBJECTIVE\nTo evaluate the effects of tizanidine on cardiac ventricular repolarization.\n\n\nMETHODS\n(1) Whole-cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to tizanidine 0.1-100 µmol/L (n = 29 cells, total) to assess drug effect on the rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectifier potassium current. (2) Langendorff retroperfusion experiments: isolated hearts from male Hartley guinea pigs (n = 6) were exposed to tizanidine 1 µmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). (3) In vivo wireless cardiac telemetry experiments: guinea pigs (n = 6) implanted with radio transmitters were injected a single intraperitoneal (ip) dose of tizanidine 0.25 mg/kg and 24 hours electrocardiography (ECG) recordings were made.\n\n\nRESULTS\n(1) Patch-clamp experiments revealed an estimated IC(50) for tizanidine on I(Kr) above 100 µmol/L. Moreover, tizanidine 1 µmol/L had hardly any effect on I(Ks) (5.23% ± 4.54% inhibition, n = 5 cells). (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, tizanidine 1 µmol/L prolonged MAPD(90) by 8.22 ± 2.03 (6.7%) and 11.70 ± 3.08 ms (8.5%), respectively (both P < .05 vs baseline). (3) Tizanidine 0.25 mg/kg ip caused a maximal 11.93 ± 1.49 ms prolongation of corrected QT interval (QTc), 90 minutes after injection.\n\n\nCONCLUSIONS\nTizanidine prolongs the QT interval by blocking I(Kr). Patients could be at risk of cardiac proarrhythmia during impaired drug elimination, such as in case of CYP1A2 inhibition during drug interactions.",
"affiliations": "Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC Canada.",
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"title": "Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr.",
"title_normalized": "tizanidine zanaflex a muscle relaxant that may prolong the qt interval by blocking ikr"
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"abstract": "BACKGROUND\nSpontaneous esophageal rupture, also known as Boerhaave syndrome, is a very serious life-threatening benign disease of the gastrointestinal tract. It is typically caused by vomiting after heavy eating and drinking. However, in our patient, because of a combination of hypopharyngeal cancer with stenosis and chemoradiotherapy (CRT), which caused chemotherapy-induced vomiting, radiotherapy-induced edema, relaxation failure, and delayed reflexes; resistance to the release of increased pressure due to vomiting was exacerbated, thus leading to Boerhaave syndrome. To the best of our knowledge, this is the first report of a patient with esophageal rupture occurring during CRT for hypopharyngeal cancer with stenosis.\n\n\nMETHODS\nA 66-year-old man with a sore throat was referred to our hospital. He was found to have stage IVA hypopharyngeal cancer, cT2N2bM0, and underwent radical concurrent CRT consisting of weekly cisplatin (30 mg/m2) and radiation (70 Gy/35fr), for larynx preservation. On day 27 of treatment, he vomited, which was followed by severe left chest pain radiating to the back and the upper abdomen. Enhanced computed tomography (CT) revealed extensive mediastinal emphysema and a small amount of left pleural effusion. Esophagography revealed extravasation into the left thoracic cavity, and the patient was diagnosed with an intrathoracic rupture type of Boerhaave syndrome. He underwent emergency left thoracotomy 21 h after the onset. The ruptured esophageal wall was primarily repaired by closure with two-layer suturing and covered by a pedicled omentum. A jejunostomy tube was placed for postoperative enteral nutrition. On postoperative day (POD) 16, the patient was transferred to head and neck surgery to finish CRT and was discharged on POD 56. He has survived without relapse for 11 months after surgery.\n\n\nCONCLUSIONS\nPatients with head and neck cancer are at risk for developing Boerhaave syndrome during CRT. In addition, since such patients often are in poor overall condition because of immunosuppression and protracted wound healing, Boerhaave syndrome can rapidly lead to severe life-threatening infections such as empyema and mediastinitis. Therefore, awareness of this condition is important so that appropriate treatment can rapidly be implemented to increase the likelihood of a good outcome.",
"affiliations": "Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. h-tanaka@aichi-cc.jp.;Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Department of Head and Neck Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Department of Head and Neck Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Department of Head and Neck Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.",
"authors": "Tanaka|Hideharu|H|http://orcid.org/0000-0003-2573-2497;Uemura|Norihisa|N|;Nishikawa|Daisuke|D|;Oguri|Keisuke|K|;Abe|Tetsuya|T|;Higaki|Eiji|E|;Hosoi|Takahiro|T|;An|Byonggu|B|;Hasegawa|Yasuhisa|Y|;Shimizu|Yasuhiro|Y|",
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"fulltext": "\n==== Front\nSurg Case RepSurg Case RepSurgical Case Reports2198-7793Springer Berlin Heidelberg Berlin/Heidelberg 46210.1186/s40792-018-0462-zCase ReportBoerhaave syndrome due to hypopharyngeal stenosis associated with chemoradiotherapy for hypopharyngeal cancer: a case report http://orcid.org/0000-0003-2573-2497Tanaka Hideharu h-tanaka@aichi-cc.jp 1Uemura Norihisa nuemura@aichi-cc.jp 1Nishikawa Daisuke dsknishi@aichi-cc.jp 2Oguri Keisuke koguri@aichi-cc.jp 2Abe Tetsuya tabe@aichi-cc.jp 1Higaki Eiji ehigaki@aichi-cc.jp 1Hosoi Takahiro thosoi@aichi-cc.jp 1An Byonggu anbyongu@aichi-cc.jp 1Hasegawa Yasuhisa hasegawa@aichi-cc.jp 2Shimizu Yasuhiro yashimizu@aichi-cc.jp 11 0000 0001 0722 8444grid.410800.dDepartment of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681 Japan 2 0000 0001 0722 8444grid.410800.dDepartment of Head and Neck Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681 Japan 8 6 2018 8 6 2018 12 2018 4 5426 2 2018 31 5 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.Background\nSpontaneous esophageal rupture, also known as Boerhaave syndrome, is a very serious life-threatening benign disease of the gastrointestinal tract. It is typically caused by vomiting after heavy eating and drinking. However, in our patient, because of a combination of hypopharyngeal cancer with stenosis and chemoradiotherapy (CRT), which caused chemotherapy-induced vomiting, radiotherapy-induced edema, relaxation failure, and delayed reflexes; resistance to the release of increased pressure due to vomiting was exacerbated, thus leading to Boerhaave syndrome. To the best of our knowledge, this is the first report of a patient with esophageal rupture occurring during CRT for hypopharyngeal cancer with stenosis.\n\nCase presentation\nA 66-year-old man with a sore throat was referred to our hospital. He was found to have stage IVA hypopharyngeal cancer, cT2N2bM0, and underwent radical concurrent CRT consisting of weekly cisplatin (30 mg/m2) and radiation (70 Gy/35fr), for larynx preservation. On day 27 of treatment, he vomited, which was followed by severe left chest pain radiating to the back and the upper abdomen. Enhanced computed tomography (CT) revealed extensive mediastinal emphysema and a small amount of left pleural effusion. Esophagography revealed extravasation into the left thoracic cavity, and the patient was diagnosed with an intrathoracic rupture type of Boerhaave syndrome. He underwent emergency left thoracotomy 21 h after the onset. The ruptured esophageal wall was primarily repaired by closure with two-layer suturing and covered by a pedicled omentum. A jejunostomy tube was placed for postoperative enteral nutrition. On postoperative day (POD) 16, the patient was transferred to head and neck surgery to finish CRT and was discharged on POD 56. He has survived without relapse for 11 months after surgery.\n\nConclusion\nPatients with head and neck cancer are at risk for developing Boerhaave syndrome during CRT. In addition, since such patients often are in poor overall condition because of immunosuppression and protracted wound healing, Boerhaave syndrome can rapidly lead to severe life-threatening infections such as empyema and mediastinitis. Therefore, awareness of this condition is important so that appropriate treatment can rapidly be implemented to increase the likelihood of a good outcome.\n\nKeywords\nBoerhaave syndromeSpontaneous esophageal ruptureEsophageal perforationChemoradiotherapyHypopharyngeal cancerissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nSpontaneous esophageal rupture leading to full-thickness transmural rupture of a normal esophagus, also known as Boerhaave syndrome, is an emergency. Although it is typically caused by vomiting after heavy eating and drinking [1], Boerhaave syndrome can be caused by chemotherapy-induced vomiting. Furthermore, as in the case of advanced hypopharyngeal cancer with stenosis involving the oropharynx, vomiting-induced elevated pressure might not be relieved through the oropharynx, which therefore results in rapidly increased intraesophageal pressure. The recent organ-preserving treatment for pharyngeal cancer is aggressive concurrent chemoradiotherapy (CRT), which has obtained high rates of organ preservation [2]. However, some patients are adversely affected by the side effects of chemoradiotherapy, which include mucositis, dysphagia, and nausea and vomiting [3]. Here, we report a patient with hypopharyngeal cancer with stenosis, who developed esophageal rupture during CRT.\n\nCase presentation\nA 66-year-old man with sore throat was referred to our hospital. He was diagnosed with stage IVA hypopharyngeal cancer, cT2N2bM0, based on the classification of the 8th edition of the Union for International Cancer Control. He underwent radical concurrent CRT that consisted of weekly cisplatin (30 mg/m2) and radiation (70 Gy/35fr) for larynx preservation (Fig. 1a). He received antiemetic therapy along with CRT to prevent chemotherapy-induced nausea and vomiting. Because of dysphagia and prolonged nausea due to the radiotherapy, a nasogastric tube was inserted on day 23 of CRT. Enteral nutrition was administered by intermittent injection three times a day, and the nasogastric tube was clamped overnight after the last daily administration of enteral nutrition. On the evening of day 27, the patient vomited, which was followed by severe left chest pain radiating to the back and the upper abdomen. During the vomiting episode, the nasogastric tube was unintentionally removed along with vomitus. A physical exam was negative for rebound tenderness in the abdomen; the symptoms were relieved by analgesics; and the patient was observed overnight. His symptoms returned in the morning, and his temperature was 38.2 °C. Laboratory testing showed an intense inflammatory response (CRP 8.02 mg/dL). Contrast-enhanced computed tomography (CT) revealed extensive mediastinal emphysema extending from the neck to the gastric cardia, a small amount of left pleural effusion, and no pneumothorax (Fig. 1b, c). Boerhaave syndrome was suspected at this point in the patient’s clinical course. Since his general status and vital signs were stable, he underwent esophagography to confirm the diagnosis and aid in treatment planning. Since reinsertion of a nasogastric tube was difficult, the esophagogram was obtained after the patient ingested contrast medium orally while being observed for aspiration. The esophagogram revealed extravasation of contrast from the lower esophageal wall into the left thoracic cavity (Fig. 2), which was diagnosed as an intrathoracic rupture type of Boerhaave syndrome.Fig. 1 a Enhanced CT on sagittal section demonstrates stenosis caused by hypopharyngeal cancer involving the oropharnx (arrowhead, hypopharyngeal cancer). b, c Enhanced CT demonstrates extensive mediastinal emphysema, which ranged from the neck to the gastric cardia, and a small amount of left pleural effusion\n\nFig. 2 An esophagogram shows extravasation of contrast from the lower esophageal wall into the left thoracic cavity (arrowhead, extravasation of contrast)\n\n\n\nHe underwent emergency left thoracotomy in the right lateral decubitus position approximately 21 h from the onset. In preparation for left thoracotomy, surgery was first performed with the patient in the right half-lateral decubitus position. The left plural cavity contained contaminated pleural effusate, and a small rupture site was found in the left thoracic cavity. We dissected the lower lung ligament along the descending aorta, opened the mediastinal space for drainage, and identified the wall of the esophagus. Via the thoracotomy incision, we found a rupture site on the wall of the lower esophagus above the diaphragm (Fig. 3). The position of the patient was then changed for laparotomy by rotating the surgical bed. Subsequently, while exploring via a laparotomy midline incision in the upper abdomen, we found a 4-cm-long rupture site on the left side of the lower esophagus that extended to the gastroesophageal junction (Fig. 3b). The ruptured esophageal wall was primarily repaired by closure with two-layer suturing and covered by pedicled omentum that was elevated through the esophageal hiatus (Fig. 3c). A jejunostomy tube was placed for postoperative enteral nutrition, and the mediastinal and thoracic space were irrigated with saline and drained.Fig. 3 Surgical findings. a Via the thoracotomy incision, a rupture site is seen on the wall of the lower esophagus above the diaphragm. b Via a laparotomy midline incision in the upper abdomen, a 4-cm-long rupture is seen on the left side of the lower esophagus, and the rupture extends to the gastroesophageal junction. c Via the left thoracotomy, the ruptured esophageal wall was primarily repaired by closure with two-layer suturing and covered by pedicled omentum which was elevated thorough the esophageal hiatus (black dotted line, pedicled omentum)\n\n\n\nImmediately after the operation, the patient was placed on enteral nutrition therapy and a course of antibiotics. The drain was changed for the remaining mediastinal abscess on postoperative day (POD) 10; otherwise, the postoperative course was uneventful. On POD 16, the patient was transferred to head and neck surgery to finish CRT and was discharged on POD 56. He has survived without relapse for 10 months after surgery.\n\nDiscussion\nSpontaneous esophageal rupture, also known as Boerhaave syndrome, is a very serious life-threatening benign disease of the gastrointestinal tract. The rupture is caused by a sudden increase in intraesophageal pressure, leading to a full-thickness transmural rupture of the normal esophagus. Vomiting is the most frequent cause of Boerhaave syndrome; 70% of patients are reported to have developed Boerhaave syndrome from vomiting after heavy eating and drinking [1]. However, Boerhaave syndrome has been reported in various patients, including those with gastrointestinal stenosis, ileus, vomiting during pretreatment for an endoscopic examination, and vomiting after general anesthesia [4–6]. Thus, Boerhaave syndrome can occur irrespective of the cause of vomiting. The signs and symptoms of Boerhaave syndrome that are typically seen after heavy alcohol use occur in a sequence of events that include severe vomiting, mild hematemesis, and substernal chest pain [1]. Left pleuritic chest pain may radiate to the epigastrium, substernal area, or back. This characteristic medical history is the key to the diagnosis of Boerhaave syndrome, which should be the first suspected possible diagnosis. Moreover, imaging is very important for the diagnosis. The typical findings of chest radiography and CT are subcutaneous emphysema, mediastinal emphysema, and pleural effusion [1]. A definitive diagnosis can be obtained by esophagography, which aids in identifying the site and type of rupture, which include intrathoracic and rupture localized to the mediastinum. Studies have reported that 84% of ruptures were located in the left wall of the lower third of the esophagus, a site that is anatomically vulnerable [7]. Based on a patient’s general condition and type of esophageal rupture, the treatment approach can be either surgical or conservative. Surgical treatment is commonly used for intrathoracic rupture [8]. The principle of surgical treatment is primary suture repair of the rupture and adequate drainage of the mediastinum and thoracic cavity [9]. If the esophagus is seriously damaged by severe mediastinitis so that a suture repair cannot be performed, placement of a T-tube, oversewing of adjacent tissue such as a pedicled omentum, or esophagectomy that includes the rupture site and second-stage reconstruction, are often performed [7]. Conservative treatment has been reported for patients with mild symptoms, without severe infection, and with the rupture localized to the mediastinal space, with the esophagus completely draining through the rupture site [10]. If after conservative treatment the patient’s condition deteriorates, surgical treatment must be performed immediately. Delayed diagnosis and treatment can rapidly lead to severe life-threatening infections such as empyema and mediastinitis, and multiple organ failure. Therefore, especially in patients who are undergoing CRT for tumors, the rapid diagnosis and appropriate treatment of Boerhaave syndrome are extremely important for avoiding sepsis and a lethal outcome [1, 7]. Although the mortality rates of patients with Boerhaave syndrome previously ranged from 30 to 40%, improvements in the postoperative management of patients treated for Boerhaave syndrome, which include the administration of nutritional therapy, have recently led to better outcomes, with mortality rates ranging from 3.7 to 7.9% [1, 7, 11].\n\nWith the inclusion of our case, three cases of Boerhaave syndrome during CRT for hypopharyngeal cancer have been reported (Table 1) [6, 12]. In all three cases, chemotherapy-induced vomiting triggered Boerhaave syndrome. In our case, the causes of Boerhaave syndrome are thought to include not only chemotherapy-induced vomiting but also pharyngeal stenosis associated with the tumor, radiotherapy-induced edema, and relaxation failure. That is, elevated pressure due to vomiting was directly focused on the lower esophagus, leading to esophageal rupture. Kiyuna et al. reported that CRT for pharyngeal cancer can lead to serious problems such as dysphagia. The pathogenesis of dysphagia has been reported to include mucositis, pharyngeal edema, stenosis due to scarring, attenuation of pharyngeal contraction due to fibrosis, relaxation failure, and delayed reflexes [3].Table 1 Previously reported cases of Boerhaave syndrome during CRT\n\nNo.\tAuthor\tYear\tAge\tSex\tDays from CRT to onset\tRupture site\tRupture type\tHours from onset to treatment\tTreatment\tOutcome\t\n1\tOkumura\t2014\t61\tM\t19\tLeft side of the lower esophagus\tIntrathoracic\t19\tSurgical (primary suture and covered by omentum)\tPostoperative death (24 POD)\t\n2\tFurukawa\t2015\t58\tM\t8\tLeft side of the lower esophagus\tMediastinal\t8\tConservative (endoscopic stent replacement)\tSurvive (12 months)\t\n3\tOur case\t2017\t66\tM\t28\tLeft side of the lower esophagus\tIntrathoracic\t21\tSurgical (primary suture and covered by omentum)\tSurvive (11 months)\t\n\n\nRegarding the two other reported cases, although the patient reported by Okumura et al. had hypopharyngeal cancer without stenosis, chronic, severe radiotherapy-induced mucositis in addition to vomiting was associated with the development of Boerhaave syndrome. Furukawa et al. reported that the effect of radiotherapy on their patient with Boerhaave syndrome was unclear; it occurred in association with circumferential esophageal cancer in the mid thorax instead of in association with hypopharyngeal cancer.\n\nIn all three cases, treatment was initiated within 24 h after onset. However, Okumura et al. reported that the general condition of their patient worsened because of failed suture repair, and the patient died after surgery. The authors thought that the patient was in poor overall condition because of the tumor and CRT, and was also immunocompromised with protracted wound healing. Kiyuna et al. reported that patients with a tumor who undergo CRT often have poor overall condition because of immunosuppression and protracted wound healing [3]. Such patients who develop Boerhaave syndrome are probably at greater risk of dying than patients with normal immune status. The initiation of enteral nutrition during the early postoperative period is recommended, especially for patients treated for conditions such as Boerhaave syndrome that manifest as acute abdomen, because enteral nutrition maintains the functions of the immune system in the intestinal tract and prevents atrophy of the intestinal mucosa [13]. Moreover, the rate of postoperative infectious complications in patients undergoing enteral nutrition is lower than that of patients undergoing intravenous nutrition [14]. Therefore, enteral nutrition therapy for our patient was started immediately after surgery to prevent further decline in his immune status.\n\nPhysicians should be aware of Boerhaave syndrome when caring for patients with head and neck cancer who may have pharyngeal stenosis due to the tumor or radiotherapy, and who undergo chemotherapy that might cause vomiting. In addition, since patients undergoing CRT are often in poor overall condition, Boerhaave syndrome must be diagnosed early and treated promptly.\n\nConclusions\nWe encountered a patient who developed Boerhaave syndrome during CRT for hypopharyngeal cancer, and we successfully diagnosed the syndrome and performed surgery during the early stage of the syndrome. Patients with head and neck cancer are at risk for developing Boerhaave syndrome during CRT, because of the combination of hypopharyngeal cancer with stenosis and CRT, which leads to chemotherapy-induced vomiting, radiotherapy-induced edema, relaxation failure, and delayed reflexes. Therefore, awareness of this condition is important so that appropriate treatment can rapidly be implemented to increase the likelihood of a good outcome.\n\nAbbreviations\nCRTChemoradiotherapy\n\nCTComputed tomography\n\nPODPostoperative day\n\nAcknowledgements\nThe authors thank Helen Londe, MD, Board-Certified Editor in the Life Sciences (BELS.org), of JAM Post Inc. for editing the draft of this manuscript.\n\nFunding\nThis report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAuthors’ contributions\nNU, TH, and HO performed the operation. HT, NU, DN, and KO managed the postoperative course. HT and NU wrote the manuscript. All the authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nInformed consent was obtained from the patient and his family for publication of this case report.\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. Curci JJ Horman MJ Boerhaave’s syndrome: the importance of early diagnosis and treatment Ann Surg 1976 183 401 408 10.1097/00000658-197604000-00013 1267496 \n2. Forastiere AA Goepfert H Maor M Pajak TF Weber R Morrison W Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer N Engl J Med 2003 349 2091 2098 10.1056/NEJMoa031317 14645636 \n3. Kiyuna A Hasegawa M Higa A Shinhama A Suzuki M Swallowing function before and after concurrent chemoradiotherapy for pharyngeal cancer J Jpn Bronchoesophagol Soc 2010 61 291 298 10.2468/jbes.61.291 \n4. Maeda C Kuwabara S Katayanagi N Kameyama H Takushi Y Yokoyama N Esophageal perforation after ingestion of polyethylene glycol for colonoscopy preparation Niigata Med J 2009 12 363 367 \n5. Atallah FN Riu BM Nguyen LB Seguin PO Fourcade OA Boerhaave’s syndrome after postoperative vomiting Anesth Analg 2004 98 4 1164 1166 10.1213/01.ANE.0000101981.85523.82 15041618 \n6. Furukawa T Iwae S Hirayama Y Yonezawa K Morita N A case of Boerhaave’s syndrome during concurrent chemoradiotherapy for head and neck cancer J Jpn Bronchoesophagel Soc 2014 65 44 49 10.2468/jbes.65.44 \n7. Chino O Makuuchi H Ozawa S Shimada H Nishi T Yamamoto S Clinical study on the treatment and strategy for spontaneous esophageal rupture J Abdom Emerg Med 2015 35 831 840 \n8. Matsutani T Nomura T Hagiwara N Makino H Maruyama H Miyashita M A study on cases of esophageal rupture and perforation J Abdom Emerg Med 2015 35 61 65 \n9. Kawabe T Sato T Rino Y Hayashi T Yamada T Yamamoto N A spontaneous rupture of the esophagus treated with primary closure under thoracoscopic surgery Japanese Soc Gastroenterol Surg 2015 48 186 191 10.5833/jjgs.2014.0136 \n10. Cameron JL Kieffer RF Hendrix TR Mehigan DG Baker RR Selective nonoperative management of contained intrathoracic esophageal disruptions Ann Thorac Surg 1979 27 404 10.1016/S0003-4975(10)63335-8 110275 \n11. Mekata E Kawaguchi A Naito H Hanasawa K Tani T Tsutamoto Y A case of spontaneous esophageal rupture associated with liver cirrhosis J Jpn Surgical Asssociation 2003 64 2134 2138 10.3919/jjsa.64.2134 \n12. Okumura H Uchikado Y Omoto I Osako Y Ishigami S Natsugoe S Successful management of vomiting-induced esophageal perforation using a removable self-expanding metal stent during therapy for esophageal cancer—report of a case J Jpn Surgical Assoc 2015 76 2946 2950 10.3919/jjsa.76.2946 \n13. McClave SA Martindale RG Vanek VW McCarthy M Roberts P Taylor B Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN) JPEN P Parenter Enteral Nutr 2009 33 277 316 10.1177/0148607109335234 \n14. Moore FA Feliciano DV Andrassy RJ McArdle AH Booth FV Morgenstein-Wagner TB Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a meta-analysis Ann Surg 1992 216 172 183 10.1097/00000658-199208000-00008 1386982\n\n",
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"title": "Boerhaave syndrome due to hypopharyngeal stenosis associated with chemoradiotherapy for hypopharyngeal cancer: a case report.",
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"abstract": "BACKGROUND\nCurrently, AIDS is the worldwide leading cause of death among 15- to 59-year-old individuals. This trend has had particularly harsh social and economic consequences in sub-Saharan Africa, where more than half of global AIDS deaths take place. In the United States, an estimated 1.2 million people are infected with HIV. In 2012, a worldwide estimate of 1.7 million deaths due to AIDS-related causes was reported.About 10% to 12% of all AIDS patients will develop intracranial tumors. Differential diagnosis should rule out brain tumors such as central nervous system lymphoma and gliomas, as well as infectious processes such as toxoplasmosis, tuberculosis, and cryptococcosis.\n\n\nMETHODS\nA 27-year-old homosexual man was referred to our care center after 2 months of disabling left frontal headache. Upon AIDS diagnosis, the patient was given abacavir (ABC), lamivudine (3TC), and efavirenz (EFV), but he discontinued the treatment after 9 months and failed to attend follow-up appointments. Three years later, the patient returned to the hospital and received ABC, 3TC, and lopinavir/ritonavir (LPV/r). On admission, computed tomographic scan reported multiple contrast-enhancing lesions compatible with meningiomas. The patient underwent uncomplicated surgical resection of the frontal basal lesion originating in the left olfactory bulb. No new neurological deficits were reported during the postoperative stay.\n\n\nCONCLUSIONS\nAccording to a literature revision, it is likely that associated meningiomas are more aggressive in AIDS patients. Severe immunosuppression and the HIV-Tat protein may be involved in the pathogenesis of tumoral growth.",
"affiliations": "Departments of *Neurology †Neuroinfectology, National Institute of Neurology and Neurosurgery Manuel Velasco Suárez ‡Department of Neurology, 1st Faculty of Medicine, Charles University §General University Hospital, Prague, Czech Republic.",
"authors": "Romero|César F|CF|;Soto-Hernández|José L|JL|;Bonnet|Cecilia|C|;Cárdenas|Graciela|G|",
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"abstract": "BACKGROUND\nThis study analysed subsequent pregnancy outcome in patients treated for persistent gestational trophoblastic tumour (GTT).\n\n\nMETHODS\nBetween 1974 and 1999, a total of 378 patients with GTT (83 patients with high-risk and 295 patients with low-risk GTT) were treated at Chiba University Hospital, Japan. Of these 378 patients, 363 (96.0%) achieved primary remission and 315 survivors have been followed at our hospital.\n\n\nRESULTS\nTo date, 129 patients have had 243 subsequent conceptions. While pregnancy outcome was comparable with that of the general Japanese population, the incidence of repeat molar pregnancy (2.1%) was approximately seven times higher than that of the general population. During the mandatory HCG follow-up period of 1 year, 15 patients conceived within 6 months of completion of chemotherapy. The incidence of spontaneous abortion in these 15 patients was significantly higher than that in patients who conceived after a waiting period of >6 months (P = 0.0053).\n\n\nCONCLUSIONS\nPatients treated for GTT may anticipate a normal future reproductive outcome, although it would be better to avoid pregnancy for at least 6 months after completion of chemotherapy.",
"affiliations": "Department of Obstetrics and Gynecology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. matsui.heyte@cnc1.wakwak.com",
"authors": "Matsui|Hideo|H|;Iitsuka|Yoshinori|Y|;Suzuka|Kiyomi|K|;Yamazawa|Koji|K|;Seki|Katsuyoshi|K|;Sekiya|Souei|S|",
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"abstract": "Diffuse hepatic hemangiomas are a challenging disease that can be life threatening. We present the case of an infant with diffuse hepatic hemangiomas who failed first-line therapies but later responded to sirolimus and high-dose propranolol.",
"affiliations": "Baylor Scott & White, Marble Falls, Texas.;Dell Children's Medical Center, Austin, Texas.;Dell Children's Medical Center, Austin, Texas.",
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"abstract": "A 70-year-old woman with liver cirrhosis caused by primary biliary cirrhosis and rheumatoid arthritis was found to have multiple pulmonary nodular shadows in the right middle and lower lung fields on chest radiography. The multiple pulmonary nodules and masses rapidly increased over 2 months. Trichosporon mycotoxinivorans and Cryptococcus neoformans were identified in brushing specimens, bronchial lavage, and transbronchial lung biopsy specimens. The patient was diagnosed as having a co-infection of the lung with T. mycotoxinivorans and C. neoformans, and was treated with fluconazole. Although the pulmonary shadows were under control with treatment, she died 5 months later due to liver failure. We report herein a rare case of co-infection of the lung with T. mycotoxinivorans and C. neoformans.",
"affiliations": "Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: sadamatsu2hiro9@yahoo.co.jp.;Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: takahak@cc.saga-u.ac.jp.;Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: si3222@cc.saga-u.ac.jp.;Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: m02023so@jichi.ac.jp.;Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: st8753@cc.saga-u.ac.jp.;Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: d4208@cc.saga-u.ac.jp.;Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: nakamurt@cc.saga-u.ac.jp.;Division of Haematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: sueokan@cc.saga-u.ac.jp.",
"authors": "Sadamatsu|Hironori|H|;Takahashi|Koichiro|K|;Tashiro|Hiroki|H|;Ogusu|Shinsuke|S|;Haraguchi|Tetsuro|T|;Nakashima|Chiho|C|;Nakamura|Tomomi|T|;Sueoka-Aragane|Naoko|N|",
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"keywords": "Cryptococcus neoformans; Immunocompromised host; Trichosporon mycotoxinivorans",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D001706:Biopsy; D001992:Bronchoalveolar Lavage Fluid; D060085:Coinfection; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D017809:Fatal Outcome; D005260:Female; D015725:Fluconazole; D006801:Humans; D008168:Lung; D008172:Lung Diseases, Fungal; D011859:Radiography; D016896:Treatment Outcome; D014250:Trichosporon; D060586:Trichosporonosis",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "838-842",
"pmc": null,
"pmid": "32249160",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A rare case of Trichosporon mycotoxinivorans and Cryptococcus neoformans co-infection in lung.",
"title_normalized": "a rare case of trichosporon mycotoxinivorans and cryptococcus neoformans co infection in lung"
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"abstract": "We report several cases in which pediatric patients at our institution have elevated lidocaine levels in toxicology screens after subcutaneous injection of lidocaine using a needle-free device. The purpose of this article is to report 4 cases in which pediatric patients have elevated lidocaine levels in toxicology screens after J-Tip administration. In particular, the article highlights 2 cases in which children younger than 3 years had lidocaine levels in the toxic range. Although the literature has reported the device to be effective with no significant untoward effects in children as young as 3 years, it seems that no information is available for children younger than 3 years. From a quality assurance/safety perspective, a summary is provided as our institutional response to concerns raised over what is typically thought to be a benign and beneficial intervention in children.",
"affiliations": "From the *Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital; †Harvard Medical School; and Departments of ‡Emergency Medicine, and §Pediatrics, Massachusetts General Hospital, Boston, MA.",
"authors": "Gulur|Padma|P|;Cohen|Ari R|AR|;Watt|Lisa|L|;Lau|Mary E|ME|;El Saleeby|Chadi|C|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000178",
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"issn_linking": "0749-5161",
"issue": "30(11)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000779:Anesthetics, Local; D002675:Child, Preschool; D004867:Equipment Design; D005260:Female; D006801:Humans; D007223:Infant; D007279:Injections, Subcutaneous; D008012:Lidocaine; D008297:Male; D009339:Needles",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "829-31",
"pmc": null,
"pmid": "25198765",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Elevated lidocaine serum concentration after subcutaneous lidocaine administration using a needle-free device in pediatric patients.",
"title_normalized": "elevated lidocaine serum concentration after subcutaneous lidocaine administration using a needle free device in pediatric patients"
} | [
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"companynumb": "US-APOTEX-2015AP015585",
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"occurcountry": "US",
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"activesubstancename": "CLONAZEPAM"
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"abstract": "OBJECTIVE\nGiven that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan-bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2-5), overall CINV CR (days 1-5), and QoL, fatigue, and toxicity.\n\n\nMETHODS\nA two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL-DEX. Validated surveys assessed fatigue and QoL.\n\n\nRESULTS\nA total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL-DEX dose administrations 1-3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade ≥3 PAL-DEX treatment-related toxicities.\n\n\nCONCLUSIONS\nData suggest that PAL-DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma.",
"affiliations": "The Preston Robert Tisch Brain Tumor Center at Duke, South Hospital, Duke University Medical Center; Department of Neurosurgery, Duke University Health System; Duke University School of Nursing.;The Preston Robert Tisch Brain Tumor Center at Duke, South Hospital, Duke University Medical Center; Department of Neurosurgery, Duke University Health System.;The Preston Robert Tisch Brain Tumor Center at Duke, South Hospital, Duke University Medical Center; Department of Neurology.;Department of Biostatistics and Bioinformatics, Duke University Health System, Durham, NC.;Department of Biostatistics and Bioinformatics, Duke University Health System, Durham, NC.;Department of Biostatistics and Bioinformatics, Duke University Health System, Durham, NC.;The Preston Robert Tisch Brain Tumor Center at Duke, South Hospital, Duke University Medical Center; Department of Neurology.;Saint Francis Cancer Center, Hartford, CT, USA.;The Preston Robert Tisch Brain Tumor Center at Duke, South Hospital, Duke University Medical Center; Department of Neurosurgery, Duke University Health System.",
"authors": "Affronti|Mary Lou|ML|;Woodring|Sarah|S|;Peters|Katherine B|KB|;Herndon|James E|JE|;McSherry|Frances|F|;Healy|Patrick N|PN|;Desjardins|Annick|A|;Vredenburgh|James J|JJ|;Friedman|Henry S|HS|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/TCRM.S122480",
"fulltext": "\n==== Front\nTher Clin Risk ManagTher Clin Risk ManagTherapeutics and Clinical Risk ManagementTherapeutics and Clinical Risk Management1176-63361178-203XDove Medical Press 10.2147/TCRM.S122480tcrm-13-033Original ResearchA Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab Affronti Mary Lou 123Woodring Sarah 12Peters Katherine B 14Herndon James E II5McSherry Frances 5Healy Patrick N 5Desjardins Annick 14Vredenburgh James J 6Friedman Henry S 121 The Preston Robert Tisch Brain Tumor Center at Duke, South Hospital, Duke University Medical Center2 Department of Neurosurgery, Duke University Health System3 Duke University School of Nursing4 Department of Neurology5 Department of Biostatistics and Bioinformatics, Duke University Health System, Durham, NC6 Saint Francis Cancer Center, Hartford, CT, USACorrespondence: Mary Lou Affronti, Preston Robert Tisch Brain Tumor Center at Duke, Room 047, Baker House, South Hospital, Trent Drive, Duke University Medical Center, Durham, NC 27710, USA, Tel +1 919 684 5301, Fax +1 919 681 1697, Email affro002@mc.duke.edu2017 23 12 2016 13 33 40 © 2017 Affronti et al. This work is published and licensed by Dove Medical Press Limited2017The 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.Purpose\nGiven that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan–bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2–5), overall CINV CR (days 1–5), and QoL, fatigue, and toxicity.\n\nMaterials and methods\nA two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL–DEX. Validated surveys assessed fatigue and QoL.\n\nResults\nA total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL–DEX dose administrations 1–3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade ≥3 PAL–DEX treatment-related toxicities.\n\nConclusion\nData suggest that PAL–DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma.\n\nKeywords\nchemotherapynauseachemotherapy-induced nausea and vomitingantiemetic guidelinesevidence-based practiceglioma\n==== Body\nIntroduction\nChemotherapy-induced nausea and vomiting (CINV) continues to be one of the most debilitating side effects of cancer therapy, despite dramatic advances in antiemetics.1,2 Although effective evidence-based guidelines are available, CINV prevention in cancer patients receiving antineoplastic therapy remains suboptimal, because providers often do not adhere to practice guidelines.3 Available antiemetics can prevent up to 90% of CINV, but 60%–80% of patients continue to experience NV, which negatively impacts quality of life (QoL).4–8\n\nCINV can be classified as acute CINV (NV occurring within 24 hours postchemotherapy), and delayed CINV (NV occurring ≥24–120 hours postchemotherapy). Short-acting 5-hydroxytryptamine 3 (5-HT3)-receptor antagonists (RAs), the most frequently used antiemetics, are effective in preventing acute CINV, but less effective in ameliorating delayed CINV.4,9–11 Providers underestimate the incidence of delayed CINV, resulting in inadequate management of overall CINV.4,5,12\n\nPublished meta-analyses demonstrate that the second-generation long-acting 5-HT3-RA single-dose palonosetron (PAL; Eisai Inc, Woodcliff Lake, NJ, USA) or equivalent multidose ramosetron with higher serotonin selectivity is superior to first-generation 5-HT3-RAs in preventing both acute and delayed CINV.13–16 Unique advantages of PAL over older 5-HT3-RAs include longer half-life, higher 5-HT3-receptor binding, and ability to inhibit cross talk between 5-HT3 and neurokinin 1-signaling pathways.17–20 Patients receiving PAL with moderately emetic chemotherapy (MEC) have similar minor toxicities and fewer acute and delayed NV episodes than patients receiving short-acting 5-HT3-RAs.14\n\nThe emetogenicity of chemotherapy regimens varies. MEC causes CINV in >30% of patients; highly emetic agents can cause CINV in >90% of patients. Current National Comprehensive Cancer Network and American Society of Clinical Oncology antiemetic guidelines for patients receiving MEC regimens recommend combining PAL (“preferred” 5-HT3-RA) with dexamethasone (DEX) to prevent both acute and delayed CINV.21,22 These guidelines are supported by meta-analyses of high-level evidence. However, patients with malignant glioma (MG) were excluded from these larger studies, due to brain pathology, seizure potential, and glioma–drug interactions. For MG patients with CINV, PAL plus DEX antiemetic guidelines are supported only by small studies.23 Neurokinin 1-RAs are often avoided in MG patients, because they interact with certain medications (eg, DEX, enzyme-inducing antiepileptic drugs [EIAEDs]) used in this population.23,24\n\nGiven the poor prognosis of recurrent MG (median survival is 3–9 months), improving health-related QoL through symptom management is an important goal. Once-a-week PAL dosing is expected to increase antiemetic efficacy in MG patients, whose antiemetic compliance is often compromised by memory deficits. Older 5HT3-RA antiemetics are less expensive, but this benefit is offset by PAL’s ability to reduce the risk of extreme CINV events (eg, rehospitalizations due to dehydration), thus substantially reducing overall costs and staff time required to manage delayed CINV.25 The majority of patients receiving PAL have higher functionality with no significant impact on QoL compared to patients treated with older 5HT3-RAs.26\n\nStudy objective\nIrinotecan in combination with bevacizumab (BEV) is an effective MEC regimen for MG, but is associated with a low CINV complete response (CR) of 55% with ondansetron. Therefore, a single-arm Phase II trial was conducted to determine the efficacy of intravenous PAL (0.25 mg) plus DEX (10 mg) in MG patients receiving biweekly irinotecan–BEV treatment. The primary end point was the proportion of patients achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2–5), overall CINV CR (days 1–5), QoL, fatigue, and toxicity.\n\nMaterials and methods\nStudy design\nIn several Phase II glioma studies of irinotecan–BEV conducted in the authors’ institution (Duke-Institutional Review Board Pro00002273), patients were treated with ondansetron (first-generation 5HT3-RA) for CINV prevention. Approximately 55%–60% of patients experienced no emetic episode and needed no rescue medications.24 A pilot survey suggested that 60% of patients experience no emetic episode on ondansetron; however, most of these patients were on a significant amount of oral DEX (an antiemetic), which probably added to the overall CR rate.24 Therefore, 55% was used as the acute and overall CR rate for historical control patients on ondansetron plus DEX.\n\nTo assess efficacy of PAL treatment in this study, a two-phase design27 was planned. If the true acute CINV CR rate for patients receiving PAL plus DEX is ≤55%, there would be little interest in adopting this regimen as standard treatment in patients receiving chemotherapy for MG. However, if the true CINV CR rate is ≥65%, use of this regimen in MG patients merits further exploration. Therefore, in this study, there was interest in differentiating between acute CINV CR rates of 55% and 65%. The variable to be tested was proportion <0.55 versus proportion >0.65, where “proportion” represents the proportion of patients who do not experience CINV during the first 24 hours of chemotherapy treatment and do not need rescue medication.\n\nIt was anticipated that 80 patients would be accrued during the first stage of the study, after which one of three actions would be taken. If <44 patients had an acute CINV CR, accrual would be terminated and the treatment rejected as ineffective in preventing CINV in MG patients. If ≥53 patients had an acute CINV CR, accrual would be terminated and the effectiveness of the regimen in treating MG patients would be accepted. Otherwise, an additional 80 patients would be accrued to the study.\n\nEligibility criteria\nPatients aged ≥18 years with histologically confirmed malignant (or progressive low-grade) glioma who were scheduled to receive multidose irinotecan–BEV every 2 weeks for one 6-week cycle were eligible for the study. Study inclusion criteria were: 1) interval of >6 weeks from surgery and >4 weeks from radiotherapy, 2) Karnofsky Performance Scale score ≥60%, 3) stable dose of steroids 1 week prior to entry, 4) adequate blood count and renal and hepatic function, and electrolytes within normal limits, 5) no evidence of central nervous system hemorrhage on baseline magnetic resonance imaging or computed tomography, and 6) agreement by sexually active patients to use contraceptive measures for the duration of treatment. Exclusion criteria were: 1) received any intravenous drug with potential antiemetic effect within 24 hours before the start of the study, 2) any vomiting, retching, or National Cancer Institute common toxicity criteria grade 2–4 nausea during 24 hours preceding chemotherapy, 3) received PAL <14 days prior to study enrollment, 4) comedication (other than corticosteroids for cerebral swelling) interfering with study results, and 5) homozygosity of the *28 polymorphism of the UGT1A1 gene (refers specifically to TA7, not TA6). The protocol for this study was approved by the Duke University Health System Institutional Review Board, and each patient signed informed consent.\n\nTreatment plan\nPatients received intravenous PAL 0.25 mg and DEX 10 mg (hereafter PAL–DEX) 30 minutes prior to the MEC regimen of irinotecan in combination with BEV 5–10 mg/kg. Patients received standard diarrhea prophylaxis (loperamide/atropine). This MEC regimen was delivered every other week, for a total of three doses in a 6-week cycle (Table 1). The irinotecan dose was 340 mg/m2 for patients taking EIAEDs, such as phenytoin, carbamazepine, and phenobarbital. Patients taking non-EIAEDs and those taking no AEDs received irinotecan at 125 mg/m2. Irinotecan dose was reduced by 25% if a patient experienced grade 3 or 4 gastrointestinal or hematological toxicity; patients were taken off the study if they experienced grade 3 or 4 toxicity at the reduced dose.\n\nCINV assessment\nThe objective of this study was to assess the efficacy of PAL–DEX in preventing CINV in glioma patients receiving an MEC regimen combining irinotecan and BEV (hereafter irinotecan–BEV). CINV was assessed by reviewing patient diaries, which were used to record nausea, vomiting, or rescue medication taken during the 5 days after each of the three PAL–DEX doses.\n\nThe primary end point for this assessment was the proportion of patients with an acute CINV CR, defined as no emetic episode and no antiemetic rescue medication during the first 24 hours after chemotherapy administration, determined from reports in patient diaries. Delayed CINV CR and overall CINV CR rates – defined respectively as the proportions of patients achieving CR during the delayed (>24–120 hours) and the overall (0–120 hours) periods following chemotherapy administration – were calculated in secondary analyses. Acute, delayed, and overall CR rates were also calculated separately for chemotherapy-induced vomiting (CIV CR; defined as having no vomiting episodes) and for CIN (CIN CR, defined as having no nausea episodes).\n\nToxicity and QoL assessment\nToxicity grading was conducted using the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 3.0,28 and the frequency of patients experiencing adverse events was summarized using the maximum grade of each type of toxicity experienced. A survey including three validated, reliable measures of CINV-related QoL outcomes29 was administered to each patient at baseline, day 1 (acute CINV), and days 2–5 (delayed CINV) of each dose (Table 1). The survey, which took 10–15 minutes to complete, included the Modified Functional Living Index–emesis (M-FLIE),30,31 Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F),32 and Martin et al’s NV-5 instruments.33 The M-FLIE measures functional impact of nausea (nine items) and vomiting (nine items) on daily life; total scores range from 18 to 126, and higher scores indicate better QoL.30,31,34 The 13-item FACIT-F assesses the impact of fatigue on QoL; total scores range from 0 to 52, higher values indicate better QoL, and a ±3-point change in score from baseline is considered clinically meaningful.32 The NV-5 includes separate modules for nausea and vomiting/retching. Patients rate the impact of each symptom in five QoL domains, and summed ratings within each module are converted to a standardized 0–100 scale, with 0 indicating no symptom impact on any QoL domain and high scores indicating severe symptom impact on multiple domains.33\n\nTo assess CINV effects on QoL (M-FLIE) and fatigue (FACIT-F), change scores were calculated for baseline vs day 1 (acute), baseline vs average score for days 2–5 (delayed), and baseline vs average score for days 1–5 (overall). Effects of nausea and vomiting on QoL were assessed separately by determining the percentage of patients with a standardized score of 0 on each NV-5 module for day 1 (acute) and days 2–5 (delayed) after each PAL–DEX dose.\n\nResults\nPatient characteristics\nAfter enrollment of 63 patients, the study was ended early due to low accrual rate. Patient characteristics are summarized in Table 2. Mean age was 53.2 (standard deviation: 13.1, range: 28–75) years, 67% were males, and 92% were Whites. Seventy percent were diagnosed with glioblastoma (World Health Organization grade IV), 52% had Karnofsky Performance Scale score ≥90%, 27% were taking EIAEDs, and 36.5% used oral steroids. Of note, there were no statistical differences in CINV CR rates by baseline steroid use.\n\nCINV risk factors\nThe majority of patients in this study had at least one risk factor for CINV: 51% reported prior chemotherapy, and 62% reported never using alcohol. With respect to other risk factors, 33% were females, 41% were aged <50 years, 49% had a prior history of CINV, 13% had a prior history of motion sickness, and 14% had prior history of morning sickness.\n\nCINV complete response\nA total of 52 patients were evaluable for the primary outcome of acute CINV CR (percentage of patients with no vomiting or antiemetic rescue by dose); their CINV CR rates are summarized in Tables 3 and 4. For MEC and PAL–DEX dose administrations 1–3 (hereafter referred to as doses 1–3), acute CINV CR rates were 62%, 68%, and 70%, respectively, delayed CINV CR rates were 62%, 66%, and 70%, respectively, and overall CINV CR rates were 47%, 57%, and 62%, respectively (Table 3).\n\nTable 3 also presents acute, delayed, and overall CR rates for CIV (percentage of patients with no vomiting event) and CIN (percentage of patients reporting no nausea) for each dose. Acute CR rates for doses 1–3 were higher for CIV (89%, 91%, and 89%, respectively) than CIN (60%, 66%, and 59%, respectively). Delayed and overall CR rates were also higher for CIV than CIN. Overall CINV CR rates pooled across all three doses were 59% for acute, 51% for delayed, and 38% for overall response (Table 4).\n\nToxicity\nOverall, patients tolerated PAL well: 12% experienced mild-to-moderate PAL-related toxicities (mild headache 2%, diarrhea 5%, constipation 5%), and there were no grade ≥3 PAL-related toxicities. The vast majority of reported adverse events were attributable to the chemotherapy regimen or the underlying disease, and not to PAL: 41% (27 of 63) of patients experienced a grade ≥3 non-PAL-related adverse event. Four patients were hospitalized (three with infections, one with grade 4 fatigue due to grade 3 diarrhea), and one hospitalized patient died due to Klebsiella pneumonia.\n\nHealth-related quality of life and fatigue\nMean scores on the M-FLIE and FACIT-F during the 5 days following dose 1 are shown in Tables 5 and 6. M-FLIE scores were eleven points below baseline on day 1 after dosing (indicating some worsening in daily functioning due to CINV during the acute phase), and showed improvement in the delayed phase, with scores returning to near-baseline levels by day 5 (Table 5). M-FLIE scores after doses 2 and 3 (not presented) followed similar patterns. Mean FACIT-F scores dropped 5.6 points on day 1 after dosing (indicating a clinically meaningful increase in fatigue during the acute phase, as per Cella et al),32 but showed partial recovery during days 2–5 (Table 6). FACIT-Fatigue results were similar after doses 2 and 3 (not presented). NV-5 data for dose 1 (Table 7) indicated that 37% of patients reported that nausea reduced QoL on day 1 (38% during days 2–5), but only 12% reported that retching/vomiting reduced QoL on day 1 (13% during days 2–5); results were similar for doses 2 and 3.\n\nDiscussion\nIndividuals with malignant primary brain tumors are often excluded from antiemetic clinical trials, due to brain pathology, steroid use, and potential for drug interactions with standard glioma medications. Therefore, the generalizability of robust trial results to this patient population remains limited. To date, one small (33-patient) Phase II trial has documented that the guideline antiemetic PAL is effective in nonrecurrent patients receiving adjuvant temozolomide therapy.23 Acute, delayed, and overall CINV CR rates were 88%, 91%, and 88%, respectively, in newly diagnosed glioma patients receiving standard multidose temozolomide (150–200 mg/m2/day) for 5 days; grade 1–2 headache (21%) was the most frequent adverse event.23\n\nThe paucity of evidence-based antiemetic literature in the recurrent glioma patient population is complicated by low provider adherence to prescribing guideline antiemetics to prevent CINV. Implementing a combination intervention (educational in-service, standardized guideline antiemetic order sets) and audit-feedback system significantly increased prescription of PAL–DEX guideline antiemetics (from 58% baseline to sustained 90%), resulting in significant improvement of both acute (75%) and delayed (84%) CINV CR rates while maintaining QoL.35 One goal of this Phase II trial was thus to add to the guideline CINV literature by determining the efficacy of treating MG patients receiving MEC with intravenous PAL (0.25 mg)–DEX (10 mg).\n\nThe majority of glioma patients enrolled had two major CINV risk factors: prior treatment with chemotherapy (51%), and no history of alcohol use (62%). CINV CR rates were higher than the historical 55% control rate for multidose cycles: acute CR rates were 62%, 68%, and 70%, and delayed CR rates of 62%, 66%, and 70% for doses 1–3, respectively.\n\nAcute and delayed vomiting CR rates (89%–91% and 84%–89%, respectively) were significantly higher than nausea CR rates (59%–66% and 55%–59%, respectively), supporting the contention that nausea and vomiting are separate phenomena and should be treated differently. More patients reported impact of nausea (35%) than vomiting (13%) on QoL overall.3 Nausea, which has been associated with anorexia, may be better controlled by medication classes other than antiemetics or nonpharmacological interventions. Patients who reported nausea did not consistently use rescue antiemetics, emphasizing that nausea is subjectively measured and a separate phenomenon than vomiting. Historically, the literature has combined the constructs of nausea and vomiting into one end point. Future trial designs should separate the two symptoms, because current guideline antiemetics may not effectively ameliorate nausea.\n\nWhile these results are clinically significant and meaningful, this study was terminated early due to low accrual rates, and did not have the opportunity to reach predefined statistical thresholds for evaluation of treatment effectiveness. The low accrual rate was a direct result of rapidly changing treatment regimens and the lack of effective standardized therapy for patients with recurrent MGs. Although attempts to increase accrual were made by including patients receiving additional moderately emetic irinotecan-treatment combinations, most patients were treated with other available (targeted) therapies during the study enrollment period, which decreased accrual rates. Nevertheless, irinotecan and BEV remain two of the primary US Food and Drug Administration-approved drugs for recurrent glioma treatment, and supportive-care data for this regimen are essential. Therefore, despite its premature termination, the descriptive results of this study have important clinical implications for the recurrent glioma population.\n\nThe PAL–DEX regimen was well tolerated: few patients experienced PAL–DEX-related adverse events (12%). Few patients experienced the expected side effects (mild headache 2%, diarrhea 5%, constipation 5%). There were no reported grade 3 toxicities related to the biweekly PAL–DEX antiemetic regimen. More importantly, despite the well-documented association of 5-HT3-RAs with prolonged QT intervals, there were no cardiac toxicities with this regimen.\n\nBecause most guidelines are based on research utilizing single-dose chemotherapy regimens, there are no clear current guidelines for CINV management in patients receiving multiple-dose regimens. In this study, overall CR rates for multiple doses decreased over time. Overall CR rate for all three doses over a 6-week period was only 38% (Table 4), a suboptimal outcome, although overall CR rates over multiple doses were not an end point in this study. One contributing factor to reduction in CR rates over time was patient dropout due to progressive disease (not CINV), which reduced subject numbers and decreased the precision of estimates. Although patient dropout remains a challenge in research on patients receiving multidose chemotherapy, preventing CINV in this population should be a primary focus of future NV research.\n\nLimitations\nLimitations of this study included a nonrandomized design and lack of a control group. Due to rapidly changing treatment options for patients with recurrent glioma, for whom there was no consensus standardized treatment, accrual was incomplete, and study results were thus inconclusive within the framework of the original statistical design. Additionally, overall CR rates after doses 2 and 3 should be cautiously interpreted, because fewer patient surveys were completed and returned (primarily due to disease progression). If patients who dropped out experienced more or less CINV than those who completed the study, response bias could be an additional limitation.\n\nConclusion\nThe magnitude of response observed in the Phase II trial is consistent with the current evidence-based guideline literature, which identifies PAL plus DEX as an effective, well-tolerated antiemetic regimen for glioma patients receiving MEC. Antiemetic research on recurrent glioma patients receiving multidose, nonstandardized regimens is challenging. However, the data reported here support recommendations that additional PAL research should be conducted using alternative trial designs to accommodate small patient numbers, and Phase III randomized trials should be initiated when a standard regimen for recurrent glioma is established.\n\nAcknowledgments\nThis work was supported by Eisai Inc (Duke Institutional Review Board Protocol number Pro00002273). The authors thank Elizabeth Flint and Wendy Gentry for their contributions in editing and the patients and staff at Preston Robert Tisch Brain Tumor Center, Duke Cancer Institute.\n\nDisclosure\n\nMLA and KBP have received research funding from Eisai. KBP also received research funding from Agios, Genentech, Merck, and VBL. MLA has participated as an advisory board member for Eisai and NEPA. KBP has participated as an advisory board member for Novocure and Agios. AD has participated as an advisory board member for Genentech/Roche, Cavion, Novella, EMD Serono, and PTC Therapeutics. HSF has participated as an advisory board member for Tactical Therapeutics. HSF has served as an advisor/speaker/consultant for Genentech. AD has stock/ownership interest with IST GmbH. AD and HSF hold letters of patent for oncolytic poliovirus human tumors. The other authors report no conflicts of interest in this work.\n\nTable 1 Study schema for biweekly (every 2 weeks) administration of chemotherapy over a 6-week cycle\n\nDay\t−14 to 1\t1\t2\t3\t4\t5\t15\t\nScreening*\tX\t\t\t\t\t\t\t\nNCI toxicity\tX\tX\tX\tX\tX\tX\t\t\nNCI toxicity telephone assessment\t\t\t\t\t\t\tX\t\nOsoba NV-5 modules\tX\tX\tX\tX\tX\tX\t\t\nM-FLIE\tX\tX\tX\tX\tX\tX\t\t\nFACIT-F\tX\tX\tX\tX\tX\tX\t\t\nPAL 0.25 mg IV\t\tX\t\t\t\t\t\t\nDEX 10 mg IV\t\tX\t\t\t\t\t\t\nIrinotecan\t\tX\t\t\t\t\t\t\nBevacizumab\t\tX\t\t\t\t\t\t\nNote:\n\n* Screening (baseline) criteria only completed once at the beginning of the 6-week cycle.\n\nAbbreviations: NCI, National Cancer Institute; M-FLIE, Modified Functional Living Index—emesis; FACIT-F, Functional Assessment of Chronic Illness Therapy-fatigue; PAL, palonosetron; DEX, dexamethasone.\n\nTable 2 Characteristics of patients in the study (n=63)\n\nPatient characteristics\n(continuous variables)\tMean (SD)\tRange\n(min–max)\t\nAge (years)\t53.2 (13.1)\t28–75\t\nSteroid dose at baseline (mg)\t5.3 (4.4)\t0.9–16\t\n\n\t\nPatient characteristics\n(categorical variables)\tn\t%\t\n\n\t\nSex\t\t\t\n Female\t21\t33.3\t\n Male\t42\t66.7\t\nRace/ethnicity\t\t\t\n White\t58\t92.1\t\n Black/African-American\t3\t4.8\t\n Asian\t1\t1.6\t\n White, Hispanic\t1\t1.6\t\nInitial diagnosis\t\t\t\n GBM\t44\t69.9\t\n AA\t9\t14.7\t\n AO\t6\t9.5\t\n Mixed glioma\t2\t3.2\t\n Well-differentiated infiltrated glioma\t2\t3.2\t\n Pleomorphic xanthoastrocytoma with anaplastic features\t1\t1.6\t\nKPS score\t\t\t\n ≥90%\t33\t52.3\t\n <90%\t30\t47.7\t\nAED status\t\t\t\n EIAED taken\t17\t27.0\t\n Non-EIAED taken\t26\t41.3\t\n No AED taken\t20\t31.7\t\nSteroid use at baseline\t\t\t\n Yes\t23\t36.5\t\n No\t40\t63.5\t\nAbbreviations: SD, standard deviation; GBM, glioblastoma multiforme; AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; KPS, Karnofsky Performance Scale; AED, antiepileptic drug; EIAED, enzyme-inducing AED.\n\nTable 3 CINV complete response rates (acute, delayed, and overall), by dose\n\nTime point\tDose 1 (week 1; n=53)\n\tDose 2 (week 3; n=44)\n\tDose 3 (week 5; n=37)\n\t\nn\tPercentage\n(95% CI)\tn\tPercentage\n(95% CI)\tn\tPercentage\n(95% CI)\t\nComplete response rate (CINV): percentage of patients with no vomiting and no antiemetic rescue by dose\t\n Acute (day 1)\t32a\t62 (47, 75)\t30\t68 (52, 81)\t26\t70 (53, 84)\t\n Delayed (days 2–5)\t33\t62 (48, 75)\t29\t66 (50, 80)\t26\t70 (53, 84)\t\n Overall (days 1–5)\t25\t47 (33, 61)\t25\t57 (41, 72)\t23\t62 (45, 78)\t\nVomiting response rate (CIV): percentage of patients with no vomiting event by dose\t\n Acute (day 1)\t46a\t89 (77, 96)\t40\t91 (78, 97)\t33\t89 (75, 97)\t\n Delayed (days 2–5)\t46a\t89 (77, 96)\t38a\t88 (75, 96)\t31\t84 (68, 94)\t\n Overall (days 1–5)\t42\t79 (66, 89)\t36a\t84 (69, 93)\t28\t76 (59, 88)\t\nNausea response rate (CIN): percentage of patients with no nausea reported by dose\t\n Acute (day 1)\t31a\t60 (45, 73)\t29\t66 (50, 80)\t22\t59 (42, 75)\t\n Delayed (days 2–5)\t29\t55 (40, 68)\t26\t59 (43, 74)\t21\t57 (39, 73)\t\n Overall (days 1–5)\t28\t53 (39, 67)\t25\t57 (41, 72)\t19\t51 (34, 68)\t\nNote:\n\na One patient missing a response, so denominator one less than reported in the total for the week.\n\nAbbreviations: CINV, chemotherapy-induced nausea and vomiting; CI, confidence interval; CIV, chemotherapy-induced vomiting; CIN, chemotherapy-induced nausea.\n\nTable 4 Overall CINV CR rates (across all doses over 6 weeks)a\n\nOverall (across all 3 doses over 6 weeks)\n\t\nTime point\tTotal\tCR (n)\tCR (%)\t95% CI\t\nAcute response (day 1)\t37\t22\t59\t42, 75\t\nDelayed response (days 2–5)\t37\t19\t51\t34, 68\t\nOverall response (days 1–5)\t37\t14\t38\t22, 55\t\nNote:\n\na Includes only patients with no missing CINV data for all doses over 3 weeks.\n\nAbbreviations: CINV, chemotherapy-induced nausea and vomiting; CR, complete response; CI, confidence interval.\n\nTable 5 M-FLIE: mean change in total score from baseline after dose 1\n\nTime point\tn\tTotal M-FLIE score\n\tChange from baseline\n(day X – baseline)\n\t\nMean\t95% CI\tMean\t95% CI\t\nBaseline\t52\t123\t119, 126\t–\t–\t\n Day 1\t49\t112\t105, 120\t−11.0\t−17, −3.9\t\n Day 2\t51\t114\t106, 121\t−10.0\t−17, −3.5\t\n Day 3\t51\t119\t115, 123\t−4.8\t−8.9, −0.8\t\n Day 4\t51\t121\t116, 125\t−3.6\t−7.9, 0.8\t\n Day 5\t51\t122\t119, 125\t−2.0\t−5.6, 1.7\t\nBaseline\t52\t123\t119, 126\t–\t–\t\n Acute (day 1)\t49\t112\t105, 120\t−11.0\t−17, −3.9\t\n Delayed (days 2–5)\t51\t119\t115, 123\t−5.2\t−9.1, −1.4\t\nOverall (days 1–5)\t52\t117\t112, 121\t−6.1\t−10, −2.0\t\nNote: Higher scores indicate better quality of life.\n\nAbbreviations: M-FLIE, Modified Functional Living Index–emesis; CI, confidence interval.\n\nTable 6 FACIT-F: Mean change in total score from baseline after dose 1\n\nTime point\tn\tTotal FACIT score\n\tChange from baseline (day X – baseline)\n\t\nMean\t95% CI\tMean\t95% CI\t\nBaseline\t48\t37.0\t34.2, 39.9\t–\t–\t\n Day 1\t46\t31.3\t27.6, 34.9\t−5.6\t−8.8, −2.4\t\n Day 2\t45\t32.8\t28.8, 34.9\t−4.2\t−7.3, −1.1\t\n Day 3\t47\t34.5\t31.0, 38.0\t−2.7\t−5.6, 0.1\t\n Day 4\t47\t34.8\t31.4, 38.1\t−2.5\t−5.4, 0.4\t\n Day 5\t47\t35.1\t31.6, 38.6\t−2.2\t−5.1, 0.8\t\nBaseline\t48\t37.0\t34.2, 39.9\t–\t–\t\n Acute (day 1)\t46\t31.3\t27.6, 34.9\t−5.6\t−8.8, −2.4\t\n Delayed (days 2–5)\t47\t34.4\t31.0, 37.7\t−2.9\t−5.5, 0.2\t\nOverall (days 1–5)\t48\t33.5\t30.3, 36.8\t−3.5\t−6.1, −0.9\t\nNote: Higher scores indicate better quality of life.\n\nAbbreviations: FACIT-F, Functional Assessment of Chronic Illness Therapy-fatigue; CI, confidence interval.\n\nTable 7 Impact of CINV on HR-QoL in malignant glioma patients, based on standardized scores from the NV-5 nausea and vomiting/retching modules\n\nDose\tAcute impact of CINV (day 1): patients with a maximum standardized score of zeroa\n\tDelayed impact of CINV (days 2–5): patients with a maximum standardized score of zeroa for the entire period\n\t\nn (%)\tn (%)\t\nNV-5 nausea module\t\t\t\n Dose 1 (n=52)\t33 (63)\t32 (62)\t\n Dose 2 (n=44)\t31 (70)\t25 (57)\t\n Dose 3 (n=37)\t22 (59)\t22 (59)\t\nNV-5 vomiting/retching module\t\t\t\n Dose 1 (n=52)\t46 (88)\t45 (87)\t\n Dose 2 (n=44)\t40 (91)\t37 (84)\t\n Dose 3 (n=37)\t31 (84)\t31 (84)\t\nNotes:\n\na In each NV-5 module, patients with a maximum standardized score of 0 were those who reported no impact of a chemotherapy-induced symptom (either nausea or vomiting/retching) on QoL during the acute (day 1) or delayed (days 2–5) phase. All other patients reported that the symptom had a negative impact on their QoL during the same phase.\n\nAbbreviations: CINV, chemotherapy-induced nausea and vomiting; HR-QoL, health-related quality of life.\n==== Refs\nReferences\n1 Sun CC Bodurka DC Weaver CB Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer Support Care Cancer 2005 13 4 219 227 15538640 \n2 Poli-Bigelli S Rodrigues-Pereira J Carides AD Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting: results from a randomized, double-blind, placebo-controlled trial in Latin America Cancer 2003 97 12 3090 3098 12784346 \n3 Navari RM Aapro M Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting N Engl J Med 2016 374 14 1356 1367 27050207 \n4 Hesketh PJ Chemotherapy-induced nausea and vomiting N Engl J Med 2008 358 23 2482 2494 18525044 \n5 Hawkins R Grunberg S Chemotherapy-induced nausea and vomiting: challenges and opportunities for improved patient outcomes Clin J Oncol Nurs 2009 13 1 54 64 19193549 \n6 Chung SK Ahn MJ Yoo JY Implementation of best practice for chemotherapy-induced nausea and vomiting in an acute care setting Int J Evid Based Healthc 2011 9 1 32 38 21332661 \n7 Grunberg SM Deuson RR Mavros P Incidence of chemotherapy-induced nausea and emesis after modern antiemetics Cancer 2004 100 10 2261 2268 15139073 \n8 Boccia RV Chemotherapy-induced nausea and vomiting: identifying and addressing unmet needs J Clin Outcomes Manag 2013 20 8 377 384 \n9 Gralla RJ Osoba D Kris MG Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines J Clin Oncol 1999 17 9 2971 2994 10561376 \n10 Kris MG Hesketh PJ Herrstedt J Consensus proposals for the prevention of acute and delayed vomiting and nausea following high-emetic-risk chemotherapy Support Care Cancer 2005 13 2 85 96 15565277 \n11 Herrstedt J Rapoport B Warr D Acute emesis: moderately emetogenic chemotherapy Support Care Cancer 2011 19 Suppl 1 S15 S23 20680356 \n12 Wickham R Best practice management of CINV in oncology patients: II. Antiemetic guidelines and rationale for use J Support Oncol 2010 8 2 Suppl 1 10 15 20629453 \n13 Likun Z Xiang J Yi B Xin D Tao ZL A systematic review and meta-analysis of intravenous palonosetron in the prevention of chemotherapy-induced nausea and vomiting in adults Oncologist 2011 16 2 207 216 21282670 \n14 Botrel TE Clark OA Clark L Paladini L Faleiros E Pegoretti B Efficacy of palonosetron (PAL) compared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systematic review and meta-analysis Support Care Cancer 2011 19 6 823 832 20495832 \n15 Schwartzberg L Barbour SY Morrow GR Ballinari G Thorn MD Cox D Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting (CINV) Support Care Cancer 2014 22 2 469 477 24141698 \n16 Kim JS Kim JY Lee SJ Multicenter nonrandomized trial of ramosetron versus palonosetron in controlling chemotherapy-induced nausea and vomiting for colorectal cancer Ann Surg Treat Res 2014 87 1 9 13 25025021 \n17 Navari RM Palonosetron: a second generation 5-hydroxytryptamine 3 receptor antagonist Expert Opin Drug Metab Toxicol 2009 5 12 1577 1586 19929251 \n18 Rojas C Stathis M Thomas AG Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor Anesth Analg 2008 107 2 469 478 18633025 \n19 Rojas C Li Y Zhang J The antiemetic 5-HT3 receptor antagonist palonosetron inhibits substance P-mediated responses in vitro and in vivo J Pharmacol Exp Ther 2010 335 2 362 368 20724484 \n20 Rojas C Thomas AG Alt J Palonosetron triggers 5-HT3 receptor internalization and causes prolonged inhibition of receptor function Eur J Pharmacol 2010 626 2–3 193 199 19836386 \n21 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Antiemesis Version 1 Fort Washington (PA) NCCN 2015 \n22 Basch E Prestrud AA Hesketh PJ Kris MG Somerfield MR Lyman GH Antiemetic use in oncology: updated guideline recommendations from ASCO Am Soc Clin Oncol Educ Book 2012 532 540 24451791 \n23 Rozzi A Nardoni C Corona M Palonosetron for the prevention of chemotherapy-induced nausea and vomiting in glioblastoma patients treated with temozolomide: a phase II study Support Care Cancer 2011 19 5 697 701 20467757 \n24 Affronti ML Brickhouse A Marcello J A phase II single arm trial of palonosetron (PALO) for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in malignant glioma (MG) patients receiving irinotecan in combination with bevacizumab Neuro Oncol 2009 11 5 656 \n25 Feinberg B Gilmore J Haislip S Impact of initiating antiemetic prophylaxis with palonosetron versus ondansetron on risk of uncontrolled chemotherapy-induced nausea and vomiting in patients with lung cancer receiving multi-day chemotherapy Support Care Cancer 2012 20 3 615 623 21761096 \n26 Decker GM DeMeyer ES Kisko DL Measuring the maintenance of daily life activities using the functional living index-emesis (FLIE) in patients receiving moderately emetogenic chemotherapy J Support Oncol 2006 4 1 35 41 52 16444851 \n27 O’Brien PC Fleming TR A multiple testing procedure for clinical trials Biometrics 1979 35 3 549 556 497341 \n28 Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Bethesda (MD) CTEP 2006 \n29 Brearley SG Clements CV Molassiotis A A review of patient self-report tools for chemotherapy-induced nausea and vomiting Support Care Cancer 2008 16 11 1213 1229 18551323 \n30 Martin AR Pearson JD Cai B Elmer M Horgan K Lindley C Assessing the impact of chemotherapy-induced nausea and vomiting on patients’ daily lives: a modified version of the Functional Living Index-Emesis (FLIE) with 5-day recall Support Care Cancer 2003 11 8 522 527 12827483 \n31 Martin AR Carides AD Pearson JD Functional relevance of antiemetic control: experience using the FLIE questionnaire in a randomised study of the NK-1 antagonist aprepitant Eur J Cancer 2003 39 10 1395 1401 12826042 \n32 Cella D Eton DT Lai JS Peterman AH Merkel DE Combining anchor and distribution-based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales J Pain Symptom Manage 2002 24 6 547 561 12551804 \n33 Martin CG Rubenstein EB Elting LS Kim YJ Osoba D Measuring chemotherapy-induced nausea and emesis Cancer 2003 98 3 645 655 12879484 \n34 Ballatori E Roila F Impact of nausea and vomiting on quality of life in cancer patients during chemotherapy Health Qual Life Outcomes 2003 1 46 14521717 \n35 Affronti ML Schneider SM Herndon JE 2nd Schlundt S Friedman HS Adherence to antiemetic guidelines in patients with malignant glioma: a quality improvement project to translate evidence into practice Support Care Cancer 2014 22 7 1897 1905 24570103\n\n",
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"issue": "13()",
"journal": "Therapeutics and clinical risk management",
"keywords": "antiemetic guidelines; chemotherapy; chemotherapy-induced nausea and vomiting; evidence-based practice; glioma; nausea",
"medline_ta": "Ther Clin Risk Manag",
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"pages": "33-40",
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"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "12879484;20495832;497341;21282670;10561376;12551804;20724484;24570103;24451791;15139073;19836386;25025021;20467757;24141698;27050207;18525044;21332661;14521717;12826042;16444851;20629453;15538640;18633025;18551323;20680356;12784346;12827483;15565277;21761096;19193549;19929251",
"title": "A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab.",
"title_normalized": "a phase ii single arm trial of palonosetron for the prevention of acute and delayed chemotherapy induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab"
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"abstract": "Within the last decade, there has been a sharp global rise in the number of young people identifying as transgender. More recently, there appears to be an increase in the numbers of young people detransitioning or returning to identifying with their natal sex after pursuing medical transition. A case is presented of a young woman who pursued a gender transition and returned to identifying as female after almost two years on testosterone. The author considers and critiques the affirmative model of care for gender dysphoric youth in light of this case.",
"affiliations": "Philadelphia, USA.",
"authors": "Marchiano|Lisa|L|0000-0003-2398-5650",
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"doi": "10.1111/1468-5922.12711",
"fulltext": "\n==== Front\nJ Anal Psychol\nJ Anal Psychol\n10.1111/(ISSN)1468-5922\nJOAP\nThe Journal of Analytical Psychology\n0021-8774\n1468-5922\nJohn Wiley and Sons Inc. Hoboken\n\n34758129\n10.1111/1468-5922.12711\nJOAP12711\nJAP-2019-Nov-OA-030.R1\nOriginal Article\nOriginal Articles\nGender detransition: a case study\nGender detransition: a case study\nLisa Marchiano\nMarchiano Lisa https://orcid.org/0000-0003-2398-5650\n1 timetodream14@gmail.com\n\n1 Philadelphia USA\n10 11 2021\n9 2021\n66 4 10.1111/joap.v66.4 813832\n19 1 2021\n17 11 2019\n22 6 2021\n© 2021 The Authors. Journal of Analytical Psychology published by John Wiley & Sons Ltd on behalf of The Society of Analytical Psychology.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nWithin the last decade, there has been a sharp global rise in the number of young people identifying as transgender. More recently, there appears to be an increase in the numbers of young people detransitioning or returning to identifying with their natal sex after pursuing medical transition. A case is presented of a young woman who pursued a gender transition and returned to identifying as female after almost two years on testosterone. The author considers and critiques the affirmative model of care for gender dysphoric youth in light of this case.\n\nDans les dix dernières années, on a vu un accroissement considérable du nombre de jeunes personnes qui s’identifient transgenre. Plus récemment, il semble qu’il y ait un accroissement du nombre de jeunes personnes qui reviennent en arrière par une détransition, ou qui reviennent à s’identifier à leur sexe de naissance après avoir souhaité une transition médicale. L’article présente le cas d’une jeune femme qui est entrée dans le processus de transition de genre et qui est ensuite revenue à une identification en tant femme, après presque deux années sous testostérone. A la lumière de ce cas, l’auteur examine et critique le modèle de soin qui va dans le sens d’affirmer la dysphorie de genre chez de jeunes personnes.\n\nInnerhalb des letzten Jahrzehnts hat die Zahl der jungen Menschen, die sich als transgender identifizieren, weltweit stark zugenommen. In jüngerer Zeit scheint es einen Anstieg der Zahl junger Menschen zu geben, die sich nach einer medizinischen Umwandlung wieder mit ihrem Geburtsgeschlecht identifizieren. Es wird ein Fall einer jungen Frau vorgestellt, die eine Geschlechtsumwandlung anstrebte und sich nach fast zwei Jahren mit Testosterongaben wieder als weiblich identifizierte. Der Autor betrachtet und kritisiert das affirmative Modell der Betreuung geschlechtsbezüglich dysphorischer Jugendlicher im Lichte dieses Falls.\n\nDurante l'ultima decade c’è stato un netto incremento del numero dei giovani che si sono identificati come transgender. Più recentemente, sembra ci sia un aumento nel numero dei giovani che de‐transitano o ritornano ad identificarsi con il loro sesso originario dopo aver fatto una transizione medica. Viene presentato il caso di una giovane donna che si è sottoposta ad una transizione ed è poi tornata ad identificarsi come femmina dopo circa due anni di testosterone. L’Autrice considera e critica il modello di cura affermativo in relazione alla disforia di genere nel caso clinico di una giovane.\n\nЗа последнее десятилетие мы стали свидетелями резкого увеличения числа молодых людей, которые идентифицируют себя как трансгендеров. Однако недавно наметилась обратная тенденция: де‐переход или возвращение к идентификации cо cвоим биологическим полом после медицинского вмешательства. Представлен случай молодой женщины, которая предприняла попытку смены пола, а затем вернулась к идентификации себя как женщины после двух лет приема тестостерона. В свете этого случая автор критически рассматривает аффирмативную модель помощи гендерно‐дисфоричным молодым людям\n\nEn la última década, ha habido un crecimiento global agudo de jóvenes que se han identificado como transgénero. Más recientemente, pareciera haber un incremento en el número de jóvenes de‐transicionando o retornando a la identificación con su género natal luego de haber realizado una transición médica. Se presenta el caso de una joven mujer quien prosiguió una transición de género y retornó a identificarse como de género femenino, casi dos años después de haber tomado testosterona. La autora considera y critica, a la luz de este caso, el modelo afirmativo de cuidado para la disforia de género en las y los jóvenes.\n\n去跨性别化:个案研究\n\n在过去十年间, 全球跨性别青年的数量剧增。近期, 去除跨性别或是在追逐医学跨性别的个体重返对自身生理性别的认同的年轻人数量也在增加。文章呈现了一个个案, 关于一位女性曾经追求性别转换, 但在使用睾丸酮差不多两年后, 又重返女性化性别的认同。作者透过这个案例论述了对性别焦虑的年轻人的性别平权护理模型。\n\nadolescence\naffirmative care\ndetransition\ngender\ngender dysphoria (GD)\ntransgender\ntransgenre\ndétransition\nsoins trans‐affirmatifs\nadolescence\ndysphorie de genre\ngenre\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:20.07.2022\nMarchiano, L. (2021) Gender detransition: a case study. J Anal Psychol, 66 : 813–832. 10.1111/1468-5922.12711.34758129\n==== Body\npmcIntroduction\n\nIn the past decade, there have been significant changes in the demographics of those presenting with gender dysphoria. The number of adolescents seeking treatment for gender dysphoria has been rising since 2004, with sharp increases noted especially over the last decade. In the words of one researcher, ‘the increase in the number of adolescents referred to specialized gender identity clinics/programs has become an international phenomenon, observed all across North America, Europe, Scandinavia, and elsewhere’ (Zucker 2019, p. 1). In the last 10 years gender clinics in the U.K. have seen a 4,400% increase in teen girls seeking treatment for gender dysphoria (Rayner 2018). Also notable is that the sex ratio of those seeking services has flipped. Prior to about 2006, most adolescents presenting with gender dysphoria were natal males (Aitken et al. 2015). In subsequent years, natal females have made up the majority of referrals, with the ratio of natal female to natal male as high as 7.58 to 1, according to one calculation (Zucker 2019). Over the past 10 to 15 years, treatment for these adolescents has also undergone substantial change, for example, the use of gonadotropin releasing hormone agonists (GnRH agonists) to suppress puberty (de Vries et al. 2014) followed by cross sex hormones and later surgery: double mastectomies are being performed on trans boys as young as 13 years‐of‐age (Olson‐Kennedy et al. 2018).\n\nRecent clinical guidelines from the World Professional Association for Transgender Health (WPATH) and the Pediatric Endocrine Society have relaxed their eligibility criteria for treatments (Coleman et al. 2012; Hembree et al. 2017). In addition, the informed consent model of care has become widespread (Ashley 2019). For example, in the United States those over 18 years‐of‐age can access cross sex hormones at one of Planned Parenthood’s informed consent clinics without input from a mental health clinician. Finally, the gender affirmative model of care has become increasingly accepted as the dominant model of care in the treatment of children and adolescents (Ashley 2020). Together with the rise of teens seeking to change gender, the number of young people detransitioning (reaffirming their natal sex) also appears to be increasing. Detransitioners are now sharing their stories online and entering therapy. Though there is still little research on this population, discussions of individual cases are available (Withers 2015, 2020; Levine 2017; D’Angelo 2020; Korpaisarn & Modzelewski 2019; Turban & Keuroghlian 2018; Marchiano 2017). Detransition has also begun receiving increased attention in the clinical literature (Butler & Hutchinson 2020, Expósito‐Campos 2021, Entwistle 2021, Guerra et al. 2020).\n\nI feel that the rising rates of transition and detransition call for a depth understanding; this cultural phenomenon has life‐long physical and psychological effects on teens and young adults. The case of a young woman in my practice who detransitioned illustrates the complex psychological dynamics underlying the quest for gender change. This young person began to identify as trans in her teens, took testosterone for almost two years in order to acquire a masculine appearance and later reaffirmed her identity as female. Although a single case cannot represent the full range of issues involved in gender detransition, her story depicts the implications of unaddressed psychological complexities in gender transition.\n\nCase history: Maya\n\nA young woman whom I will call Maya was referred to me by someone aware of my experience with gender dysphoria in young people. Maya was quickly open to a connection and we began once‐weekly treatment. A petite young woman, Maya presented in a typical, if casual manner, and usually wore jeans and a T‐shirt to our sessions. Maya’s parents were educated professionals. According to Maya, it was a standing joke in her home that her mother was not cut out for motherhood. She precipitously ended her maternity leave just two weeks after Maya’s birth to return to her demanding job, sending for an aunt to come and take care of the baby.\n\nMaya’s aunt lived close by and Maya remembers her as warm and loving. Maya loved her traditional cooking and often slept with her because she was afraid to sleep alone. Both parents were absorbed in their careers and Maya’s memories of them are few except for the stilted family meals her mother scheduled a couple of times during the week. Mother did take an interest in Maya’s clothing and dance lessons, but it was her aunt who provided daily care. Maya remembers her father as sometimes warm and playful and other times angrily explosive. He and Maya’s aunt did not get along, and she voiced her criticism of him to Maya.\n\nWhen Maya was nine, her aunt suddenly died. Maya was not allowed to attend the funeral as her parents felt that it was better if Maya didn’t ‘dwell on the loss’ and they encouraged her to ‘move on’. A succession of au pairs and babysitters quickly replaced Maya’s aunt and life went on ‘as usual’. Maya managed to maintain a strong connection to her dance squad peers until age 12 but had difficulty with the transition to middle school and the pubertal changes which caused significant breast development. She dropped out of dance and began dieting. Mother, who was slender and small‐boned was ‘concerned’ about Maya’s rounding body and encouraged dieting. Maya discovered she could binge and purge. She also began to struggle in school and was diagnosed with ADHD. She was assigned to some remedial classes and acquired a reputation as a ‘problem student’ despite her obvious intelligence. Deficits in parental attention and the loss of her aunt were augmented by these physical and school changes which together with the absence of emotional support at home left her feeling outcast and unworthy. Maya isolated and spent more and more time online.\n\nMaya’s time on social media fed a rumination about identity. When she shared with some of her online friends that she wondered whether she might be trans because she felt uncomfortable in her body, her friends on social media were quick to affirm and celebrate her. Maya cut her hair boyishly short and began wearing oversized jeans and sweatshirts. In her online life – which felt more real and rewarding than her ‘real’ life – Maya adopted a male name. At 14 years‐of‐age, Maya announced to her mother that she was trans and wanted to see a gender therapist and begin hormone therapy. Although mother was at first dismissive, she eventually accompanied her daughter to the school psychologist. Even Maya was surprised by how quickly the psychologist confirmed her trans identity, agreed with the name change and encouraged her parents to affirm Maya’s identity as male and support medical transition. Her parents, however, would not approve this treatment. The psychologist concurred with Maya that mother’s reluctance to approve hormone treatment was harmful. However, at age 18, when Maya no longer needed parental permission, she visited an informed consent clinic and was given a prescription for testosterone after a 30‐minute meeting with a physician’s assistant.\n\nMaya’s parents were preoccupied with work and Maya was left to navigate this tumultuous time mostly on her own. Maternal attention often came as criticism of Maya’s refusal to conform to expectations about appearance and traditional femininity as mother placed a high value on cultural norms for feminine beauty: her figure, make‐up, fashionable clothes and heels. Mother had taken pride in the elaborate outfits required for Maya’s childhood dance performances; ‘she liked to dress me up’, Maya recalled. Mother found Maya’s masculine presentation enraging, no longer being the adorable daughter who could serve as a narcissistic extension. Maya’s father attempted to be more tolerant of Maya’s gender struggles, but his efforts were sporadic and undermined by his occasional rages. Maya recalls that their relationship during her teen years was characterized by alternating currents of distance and conflict. This pattern intensified during her period of trans identification.\n\nWhen Maya began taking testosterone it initially made her euphoric, however overall she found the 20 months of treatment difficult and disorienting. She became easily enraged and isolated herself in her room to shield herself from experiences that would provoke and overwhelm her. She lost contact with friends, rarely attended class and, preoccupied with matters other than academics, her grades were poor. Though she presented and often passed as male, she was small and slight and so people usually treated her as a much younger boy. When Maya was assigned a single room in an all‐male dormitory, she felt very vulnerable among the bigger men and showered late at night to avoid them. She dropped out of college at the end of her first year.\n\nMaya’s mental health had deteriorated, possibly due in part to testosterone. Although there is little research about the effects of testosterone in natal females, Maya feels that the hormone destabilized her emotionally. She recalls being an ‘anxious, angry mess’ and experienced intense self‐destructive moods. She was hospitalized twice, once for suicidal intent and once because depression rendered her unable to bathe or care for herself. A few months after her last hospitalization, Maya stopped taking testosterone because she suspected that the hormone was contributing to her worsening mental health. Shortly after that, she began the process of re‐identifying as female, and six months later, Maya entered therapy with me due to continued struggles with depression, anxiety and disordered eating.\n\nDiscussion\n\nAt first, I didn’t know what to make of Maya. She swung back and forth between self‐states and narratives. Some weeks, she was full of passionate energy about a new project, feeling expansive and optimistic. Other weeks, she was overwhelmed with emotions and spoke in a pressured and hyperbolic manner. For the first several months of treatment, she brought a new, overwhelming problem to every other session. One week, she was insistent that her ADHD would forever prevent her from attending community college, another week, she would be paralyzed by indecision over whether or not to move to another city. She continued to struggle with bulimia. Sometimes she expressed confidence that things were getting better, other times she confessed to bingeing and purging nearly every day. Despite occasional bright moods, emptiness and sadness underlay most of her experiences. Maya didn’t know who she was and neither did I.\n\nIn trying to formulate an understanding of Maya and her suffering, I would catch hold of a narrative thread, only to have it ripped out in a subsequent session. We couldn’t settle on anything cohesive that might contain, much less organize, Maya’s chaotic emotional life and missing sense of identity. Maya’s inability to symbolize her experience provoked a concretizing countertransference. I found myself wanting to contain her pain by locating it within a single explanatory narrative that we could then neatly ‘conquer’ with appropriate treatment. Was the main issue the eating disorder? Then it might be addressed by a referral to a specialized treatment centre. Or was her ADHD the main cause of her confusion and disorientation? Then maybe she could be helped by a coach who could teach her appropriate skills. The impulse to contain by diagnosing and treating Maya’s distress arose from a sense of disorientation and inadequacy that was alive in the field between us. Maya sometimes felt as though she were ‘too much’ for me and I worried that I wasn’t enough for her. This led me to look for a solution ‘out there’, beyond the bounds of our relationship. I frequently felt overwhelmed and pulled to offer concrete suggestions in a desperate attempt to relieve distress and create a sense of order. I wondered if this echoed the dynamic between Maya and the school psychologist who had so quickly affirmed her trans identity. In both cases, ‘the emphasis … was on doing something, fixing targeted symptoms’, in the words of Laurel Silber (2019, p. 138).\n\nUnmetabolized grief\n\nAfter about six months, Maya off‐handedly referenced the loss of her aunt. I was surprised to learn of this significant rupture, and in such a casual manner, and reflected this to her. This began a period of our work in which we explored this important early relationship. In the analytic container, Maya was able to recall many details of the relationship that she hadn’t remembered for years. Importantly, Maya had few memories of her aunt’s death, and almost no access to any feelings around this event until we began to explore it together. She was surprised by the strength of her emotion as she recalled her aunt’s loving presence. When she died, the secure base of love and care that she had provided was gone overnight. Maya was alone with only babysitters to ‘mind’ her. Without any way to integrate this significant trauma into consciousness, the pain, grief, fear, and confusion Maya felt went into her body, for it had nowhere else to go. Relational psychotherapist Laurel Silber speaks of ‘disarticulated grief’ and explores the ways in which such grief may manifest as gender dysphoria. In examining attachment ruptures, she writes: The co‐creation of nonmentalizable states of mind, or the shared dissociation, serves to reduce the threat of loss of connection to attachment figure(s), lonely as that may be. To protect from thinking, disavowed affects can move within the concrete realm of the body and find expression in unsymbolized felt experience …. Disavowed affects find hosts: one of them, located in gender.\n\n(Silber 2019, p. 136)\n\nMaya’s adolescent gender dysphoria may therefore have been, at least in part, her psyche’s way of giving expression to split‐off and unformulated grief related to significant attachment ruptures, especially the loss of her aunt and possibly also the significant rupture that occurred at two weeks of age when her mother abruptly went back to work This latter loss was not something that we focused on explicitly, perhaps because it was so deeply unconscious that we both ‘forgot’ it. The loss of her aunt was more available to us in our work, but the earlier loss of her mother percolated beneath this, remaining unthinkable.\n\nAustralian psychoanalyst Roberto D’Angelo (2020) has written about a case of a young woman with significant trauma who transitioned in adolescence. During the analysis, she realized that her transition had been an attempt to dissociate from painful affects. ‘While medical/surgical transition seemed life‐saving at the time, it also drained Josh’s pain of any meaning, history and signification, simply encasing it in the body’ (p. 17). In such a case, transition may reinforce the reductive notion that psychic pain is located in the body and can be gotten rid of by ‘fixing’ the body. As one detransitioned woman who had a mastectomy at 23 years‐of‐age noted, ‘it felt like I had asked a doctor to just cut off one of my fingers because I thought that finger was where the depression was stored’ (personal correspondence).\n\nThe body\n\nJung noted the way in which the body can become a receptacle for split‐off and denied contents. He noted that ‘the body is often the personification of the shadow of the ego. Sometimes it forms a skeleton in a cupboard and everybody wants to get rid of it’ (1950, para. 40). Jung’s prescient awareness of the modern desire to escape or alter the body as a way of avoiding contact with reviled, instinctual parts of ourselves may be relevant in cases where there is somatized distress such as eating disorders, cutting or gender dysphoria.\n\nMaya’s eating disorder and subsequent trans identification seem likely to have been part of an effort to relegate intolerable affect to the body. Pursuing transformation through disordered eating and then gender transition had the effect of concretizing her emotional losses. Displacing painful losses onto her body seemed to allow Maya to avoid her intolerable grief and gain the illusion of control. Transition into the masculine may have been an attempt to compensate for an unbearably vulnerable aspect of her wounded feminine self. Clinicians at the Tavistock Gender Identity Development Service in the U.K. have noted this defensive dynamic among young people who desisted from a trans identity without pursuing medical intervention. One such young person felt that ‘her (female) self had carried these painful experiences which needed to be got rid of; she reflected, “I felt that I had always wanted to put that poor girl in a box and put the lid on top”’ (Clarke & Spiliadis 2019, p. 347).\n\nThe mother complex\n\nThroughout our work, Maya’s narrative about her mother shifted dramatically from week to week. Sometimes Maya extolled her mother’s extensive professional successes or expressed gratitude for material support, equating it with maternal care. She would describe mother’s strength and resilience as if it were a heritable quality that she could someday claim for herself. At other times, Maya was filled with explosive rage at her mother. She avoided visiting her mother for months at a time and sometimes blocked her phone calls and texts. During these phases Maya seemed to inflate her mother’s negative qualities, as if only intensified experience could have any hope of impact. But when the COVID‐19 lockdown disrupted aspects of Maya’s life, she turned to her parents, especially her mother, for emotional and material support. She began visiting her parents weekly and took a job as a receptionist at her mother’s firm. This increased contact drew her closer to her family and painful truths became unavoidable.\n\nMaya became more distraught than I had yet seen her. Without at first knowing why, she became mired in self‐loathing. Suicidal feelings frequently overtook her and bulimia aggressively reasserted itself. I shared my impression with her that her worsening distress was a result of confronting the reality of her relationship with her mother. Daily contact with her mother for the first time in years meant that Maya had to come to terms with her mother’s relational unavailability. Maya also began to explore her relationship with her deceased aunt, seeking photographs and speaking to extended family members about the person who had been so important to her. She also reconnected with an older family friend who was able to confirm and add to Maya’s impressions about the quality of her early relationship with her mother. She validated Maya’s experience of her mother’s critical, cool and disinterested nature, and recalled that after Maya’s aunt’s death, Maya was sometimes sent to her house for the weekend. Maya would cry when it was time to leave and would beg this kindly friend not to make her go. ‘Your house feels like home and mine doesn’t’, she would say. However, this friend was able to hold the dual truths of Maya’s mother’s complex nature, the lack of maternal warmth and her positive qualities of intelligence, energy, will and achievement. Maya, in turn, slowly began to integrate split images of her mother – and herself.\n\nMaya’s early attachment experiences included the secure base that her aunt had provided. I believe this allowed her to establish trust in our relationship. Alongside the experiences of confusion and disorientation in which we sometimes found ourselves, I was aware very early on of a positive transference and countertransference. I liked Maya very much and recognized that I held the positive mother for her in our work. I found Maya charming, intelligent and funny. She could make me break out into a hearty laugh – and I noticed her watching me laugh, a tentative but delighted smile on her face. I imagined it must have felt wonderful to see me mirroring and enjoying her. Over time, our connection solidified. I became less anxious in the face of her distress and she became able to use our sessions to discharge overwhelming affects in a way that made her feel more settled and contained. During one discussion about managing a difficult and expensive situation without parental help, I commented that this was the kind of thing with which many parents would help a young adult child. Maya looked at me and asked, ‘Could you adopt me?’ I heard the poignant question behind her humorous query. Maya had been looking for a good mother her whole life – first in her aunt, then in the family friend, and now in me. Though the question elicited a twinge of anxiety on my part due to the implied transgression of therapeutic boundaries and the possibility of excessive dependence, the ‘good mother’ was generally a congruent place for me in our work. I felt very warm toward Maya and enjoyed my role as her ‘adoptive’ mother.\n\nConfronting regressive tendencies\n\nMaya began to see that internal factors repeatedly lured her into hoping that ‘this time’ things would be different with her mother. She had ‘relentless hope’ that she would find the mother for whom she had been yearning. This dynamic came to light in the following dream: I’m at my parent’s house and it’s very late at night, so I decide to sleep there. I am so tired I can barely drag myself upstairs to my room. It feels almost as if I have been drugged. I have to push past a mountain of boxes piled outside my room. As soon as my head hits the pillow, I’m out, but only for a second, because my mom is there and she is shaking me awake. I’m begging her to let me sleep. She’s really strange and creepy. Her voice is excited but breathy and threatening. Her eyes are wide and glazed over. Her body language is weird and exaggerated. I don’t remember what she is saying but it is demeaning and aggressive. I start pleading with her to stop. She’s almost acting as if she is possessed. I’m telling her how much I need her love, how I’ve always admired her and wanted to be like her. Then I realize something – I think she is drunk. ‘Are you drunk?’ I ask. Her demeanour changes immediately. Instead of seeming drunk or high, she becomes intense, predatory and sinister. She looks at me and I am terrified. I regret asking her if she was drunk. She grabs my arm and I try to pull away but her grip is so strong, I feel as though she is going to break my bones. I’m begging her to stop. She brings my arm to her mouth and takes a huge, grizzly, excruciating bite out of my flesh.\n\nWe agreed that the dream showed Maya’s tendency to fantasize about her relationship with her mother by crawling back into a childlike, unconscious state. The dream illustrated that surrendering to this regressive attitude led to meeting her mother complex in its worst and most devouring form. Paradoxically, the negative mother complex in this dream also wants her to wake up, perhaps to confront the reality of the relationship.\n\nEnvy and competitiveness\n\nAs we spent more time discussing Maya’s relationship with her mother, it felt like we had broken through a somewhat histrionic defensive layer and dropped into more authentic affect. Maya spoke more about her mother’s critiques of her adolescent body and the diets she prescribed. She talked about her mother’s disregard for her academic struggles and disdain for her subsequent lack of career achievement. One week, Maya expressed feelings of distress over her inability to decorate her new apartment. Although her mother had recently stepped in to ‘help’, Maya felt shamed. This led Maya to realize that her mother’s unspoken message was that while she excelled at many things, especially successful womanhood, Maya did not. Maya felt she had flunked weight, appearance, academics, and now aesthetics; she would never match her mother. Maya began to discover that her desire to transition was in part an angry and rebellious response to her mother. She had sought instead to identify with her father, but he also was treated with disdain, so Maya felt as if she was in a no‐win situation. As we explored themes of envy and competition it became clear that Maya was never to surpass or challenge her mother; we understood that her poor school performance and male presentation actually ‘meant’ that Maya was following the unconscious rules of the family.\n\nSplit‐off aggression\n\nDuring our discussions of envy and the taboo against surpassing her mother, I referenced ‘Snow White’ and, to my surprise, Maya was unfamiliar with the story. Snow White’s envious queen mother cannot tolerate a challenge to her beauty and therefore wishes to kill the daughter blooming into womanhood. Snow White’s innocence complex is so strong that she is unable to see through the queen’s repeated efforts to trick and kill her. Because she is not able to access her aggression, she is easily seduced by the queen into compliance. Maya’s dream of her mother biting into her flesh perhaps shows the extent to which this aggression was split‐off and held by the negative mother, Maya being unable at that point to consciously own it. Maya, like Snow White, must now take a bite of the apple and metabolize some of her mother’s poison before she can wake up and differentiate from her mother.\n\nMaya was captivated by the tale of the vulnerable maiden who was able to grow into her aggressive capacity. Maya’s nightmare and the fairy‐tale image of metabolizing poison took hold quickly: she discovered that she could anonymously troll her mother on social media and fire her up over pet political topics. It gave Maya devilish pleasure to see her mother lose her cool. On dark days when she was feeling suicidal this activity fueled Maya with a sense of agency and forward momentum. I felt this use of trickster aggression gave Maya a toe‐hold of power in the relationship with her mother. Overall, I felt that this was a positive development that could mature into claiming her authority overtly in time.\n\nSacrificing emotional reality\n\nAccording to Ronald Fairbairn (1943), the traumatized child introjects an idealized parent and a persecutory or absent parent and relates to them out of two corresponding self‐states. For Maya, relating to the idealized mother offered the illusory promise of love and care, but required her to sacrifice relational truth. Maya recalls trying to tell other adults about her mother’s indifference and coldness and always being reassured that her mother loved her. This dynamic now became visible in her adult relationship with her mother. When she looked forward to a weekend get‐together with mother, Maya began to see that she was silencing an awareness of reality: the meeting would be hurtful or disappointing, and it would end with a confirmation of her mother’s inaccessibility. This is the bargain she had made repeatedly in the past – that her own emotional truth would be sacrificed in exchange for the hope of maternal love and attention. We came to see a similar dynamic in her identification of herself as ‘trans’: Maya had sacrificed her female ‘identity’ in exchange for belonging and connection in the trans community.\n\nAs the dynamics with her mother came into focus, we had a clearer understanding of the defensive function of Maya’s trans identity which seemed to serve several unconscious goals. Rejecting her femaleness offered Maya a way of rejecting her mother and asserting her independence and defiance of her mother’s expectations. This allowed Maya to disavow her desire to be like her mother (which included identifying as ‘female’) and be loved and admired by her while also allowing her to be the obedient child by abiding by the unwritten rule that she must never surpass her mother. It was a way to opt out of her mother’s paradigm of feminine attractiveness, and it gave Maya a way to identify with the aggressor by acting out her rage towards her own body. Just as her mother imposed restrictive dieting regimes on Maya’s growing body to change it and make it conform to her arbitrary expectations, Maya imposed testosterone and binding her breasts to change her body and make it conform to her arbitrary expectations. Identifying as trans also shifted the power dynamic in Maya’s relationship with her mother, allowing her to claim some aggression and authority. When Maya tried to speak about her difficulties with her mother as a child, her concerns were often dismissed or minimized. Now, as the righteous, beleaguered victim of her mother’s intolerance and lack of care, adults and peers agreed loudly that Maya’s mother was deficient. As a trans man, Maya’s complaints about her mother were valorized.\n\nGender affirmative approach\n\nWhen Maya sought therapy from the school psychologist, it seems that she was treated according to the gender affirmative model of care. The therapist affirmed Maya in her belief and wish to identify as trans and confirmed her belief that she needed to transition socially and medically. The gender affirmative model of care was first developed in the U.S. and has become the dominant way of working with trans identified teens in many contexts in the U.S. and elsewhere. Psychologist Diane Ehrensaft defines the gender affirmative model as: a method of therapeutic care that includes allowing children to speak for themselves about their self‐experienced gender identity and expressions and providing support for them to evolve into their authentic gender selves, no matter at what age. Interventions include social transition from one gender to another and/or evolving gender nonconforming expressions and presentations, as well as later gender‐affirming medical interventions (puberty blockers, cross‐sex hormones, surgeries).\n\n(Ehrensaft 2017, p. 62)\n\nTo facilitate this process, the therapist ‘assesses a child’s gender status’ using assessment instruments, observation, play, interviewing, dialogue, or projective measures. Diane Ehrensaft sums up the gender affirmative approach in the following manner: ‘When it comes to knowing a child’s gender, it is not for us to tell, but for the children to say’ (ibid., p. 63).\n\nThe affirmative model takes at face value a child or teen’s declaration about feelings and thoughts related to gender. It encourages parents, schools, and other authorities in a child’s life to accept those claims. Though this approach has gained widespread acceptance, I feel that it has significant shortcomings. For example, it may foreclose thinking about a young person’s development by conflating gender dysphoria with trans identification, and it may concretize an adolescent’s desire to transition without extended exploration and assessment. Because the basic premise of the model is that gender is something ‘for the children to say’, unconscious relational, systemic, archetypal and social factors may be denied relevance and exploration (Evans 2020).\n\nMaya came to see me after she had decided to dis‐identify from her trans identification and to re‐identity as female. After getting to know Maya I formed the view that her trans identification was an attempt to adapt to a complex array of interrelated factors: her social environment at school and online; the dynamic between herself and her parents; her rejection of her body inculcated in part by her mother’s insistence on thinness and dieting; and her unmetabolized grief about the loss of a primary attachment figure early in life. In Maya’s case, I understand that affirmative treatment addressed the superficial distress only and seemed to leave little room to explore other factors. It was only after Maya decided to detransition that psychological work in these important areas could occur.\n\nThe gender affirmative model of care may leave some or all of these psychological factors unaddressed because one of its basic tenets is that the role of the therapist is to affirm – or confirm – what the patient ‘knows’ (Spiliadis 2019). I believe that this principle is in direct opposition to usual and best psychotherapeutic practice: the role of the therapist is to open space for exploration, for nuanced thinking and expanded and deepened self‐understanding. For Maya, the affirmative approach appears to have supported a narrow and superficial understanding of the presenting problem. According to Maya’s report of this therapeutic encounter, she was encouraged to believe that physical interventions might resolve her conflicting feelings about herself, thereby substituting the possibility of legitimate and potentially transformative ‘suffering’ for a concretized solution that, in my opinion, promoted dissociation from the body.\n\nI have a number of concerns regarding the gender affirmative model of care. It is my view that this model rests on a false premise and encourages the patient to make critical health decisions, including surgical interventions, based on beliefs rather than ‘facts’. Gender identity is not a well‐defined concept and lacks empirical validity. Although there have been efforts to identify biomarkers that might correlate with gender dysphoria, no robust evidence has been found. The U.K.’s Gender Identity Development Service, for example, has noted the chromosomal normality of their patients (Butler et al. 2018).\n\nGender affirmative clinicians themselves acknowledge the lack of material basis for gender identity. According to advocates of the affirmative approach, ‘we understand gender identity, both its match and its mismatch with assigned natal sex, as primarily informed by a child’s cognitions and emotions, rather than by genitalia and observable external sex characteristics’ (Hidalgo et al. 2013, p. 286). The affirmative approach, then, affirms ‘self‐experienced gender identity’ (Ehrensaft 2017, p. 62) and treats as ‘fact’ a child or young person’s thoughts and feelings about themselves even when those thoughts and feelings do not align with the material reality of the body (Hidalgo et al. 2013, p. 286). I believe that without a basis in biological reality, ‘gender identity’ takes on the significance of an essence, something akin to a soul. The term ‘gender identity’, refers to a person’s inner sense of being a male, female or something else. Whether we believe in the existence of an immortal soul or find it a worthy metaphor for describing experience, we recognize the value of the concept. As a metaphor, the notion of gender identity invites questions about our nature, our relationship with culture, and our relationship with the inner ‘other’. It may be the best possible way to express an ineffable truth, but we do not treat ‘soul’ as an empirical fact. When gender identity is taken as empirical fact, the metaphor becomes concretized and we lose the ability to relate to our inner world in a symbolic way. When metaphors are made literal, the literal body becomes a vehicle for metaphoric expression (Bret Alderman, personal communication).\n\nWe can validate a young person’s discomfort with restrictive gender roles. We can celebrate her desire to flout conventional gender norms and to wear clothes or hairstyles that defy gendered expectations. We can affirm and normalize feelings of same‐sex attraction and help her to come to terms with these in a society where homosexuality is not always accepted. We can validate a young person’s distress about the perceived mismatch between her self‐perception and her body. We can affirm the importance of these feelings and the distress that they cause. And we can respect her need to live in the opposite‐sex role as a potential way to manage this distress. However, in my experience, I believe that the gender affirmative model of care perhaps too often confirms prematurely a patient’s belief and forecloses the opportunity for thinking symbolically about this distressing experience. In this case, are we colluding with an avoidance of reality?\n\nComing to terms with reality\n\nJung stressed that adequate adaptation requires that an individual be able to ‘grow in the soil in which it is planted’ before individuation can proceed (1971, para. 761). Adaptation requires confrontation and acceptance of the realities in which we find ourselves. In adolescence, one confronts the end of childhood and begins to meet the demands of the external world. Jung recognized that engaging reality on its own terms was an integral part of this passage: For most people it is the demands of life which harshly put an end to the dream of childhood. If the individual is sufficiently well prepared, transition to a profession or career can take place smoothly. But if he clings to illusions that are contrary to reality, then problems will surely arise.\n\n(Jung 1960, para. 761)\n\nLivia, a 23‐year‐old detransitioned woman who had a mastectomy and hysterectomy when she was 20 and 21 respectively spoke at the Detransition Advocacy Network event in Manchester, U.K. in 2019. She emphasized the role of reality in her transition and detransition: It’s really hard to focus on one thing but the word that’s stuck in my mind the most is ‘reality.’ I feel like for me transition was a way to get out of my reality as a homosexual woman ….\n\nWhen we started this conversation the word that was important to me was ‘reality’. And reality to me is that… a hysterectomy and removal of your ovaries doesn’t make you any less female. So, it doesn’t make any sense to me why this is called transition or a sex change because it’s not it’s castration. And now that I am trying to care for my health as much as possible, I spend a lot of time on hysterectomy support sites and message boards for women – for women because only women get hysterectomies, and only women deal with the consequences of a hysterectomy.\n\n(Livia 2019)\n\nAffirmative care for teens may inadvertently reify ‘defenses against reality’ (Lemma 2016, p. 366). Life’s task – as well as the task of analysis – is to come to terms with that which cannot be changed and to mourn this so that we may move forward. The reality of our bodies insists on being confronted and accepted in adolescence. This task can be particularly challenging for adolescent females. Social and medical transition undertaken without adequate understanding may facilitate a ‘bypassing of a mourning process about that which cannot be changed’ (ibid., p. 369).\n\nComing to terms with bodily reality is a major task in adolescence. It is the time when we learn what our adult body will look like. How tall will I be? How will I look? Will I tend to put on weight easily? The inexorable reality of our bodies is, for many of us, the first demand to face limitations, a painful prerequisite for coming into existence in three‐dimensional space and time. Jung understood the great importance of coming to terms with reality – and the reality of our bodies – as regards individuation: If you were a spirit you could be anywhere, but the damnable fact is that you are rooted just here, and you cannot jump out of your skin; you have definite necessities. You cannot get away from the fact of your sex, for instance, or of the colour of your eyes, or the health or the sickness of your body, your physical endurance. Those are definite facts which make you an individual, a self that is just yourself and nobody else. If you were a spirit you could exchange your form every minute for another one, but being in the body you are caught; therefore, the body is such an awkward thing: it is a definite nuisance. All people who claim to be spiritual try to get away from the fact of the body; they want to destroy it in order to be something imaginary, but they never will be that, because the body denies them; the body says otherwise. They think they can live without sex or feeding, without the ordinary human conditions; and it is a mistake, a lie, and the body denies their convictions.\n\n(Jung 1988, pp. 63‐64).\n\nAgonists that suppress the release of natural hormones, cross‐sex hormones that create opposite‐sex characteristics, and surgery that removes body parts or creates facsimiles of them can be seen as Promethean efforts to subdue biological reality. We defy the body at a cost. As Jung says, we must acknowledge the realities of embodiment.\n\nReality and trauma\n\nPsychological trauma warps our sense of reality, rendering us unable to trust our senses. Helping an analysand to reclaim her relationship with reality can be an important aspect of trauma work. Maya’s grief over the loss of her aunt was denied and she was encouraged to ‘move on’, as though that relationship were insignificant. The reality of her relationship with her parents had also not been mirrored back to her. This rupture in her sense of reality made it difficult for her to make meaning out of her situation and contributed to poor affect regulation as she was always confused about the nature and location of the problem. When Maya detransitioned and reaffirmed her female identity and accepted her biological reality, her distress decreased, and she felt somewhat more contained. As she reconnected with reality in her relationships, her sense of coherence and psychic equilibrium increased. Even though reality was distressing, having a firm grasp on her emotional truth gave her greater resilience.\n\nThe case of Maya illustrates the extent to which her presenting problem was a metaphor for unresolved grief and deficient parenting which was later exacerbated by both peer and, in my opinion, professional wounding. The purpose of psychological treatment is to bring unconscious issues to consciousness, thereby recovering and reconnecting affect, cognition and reality. Depth psychology posits the active presence of unconscious compensation and symbolization processes. We owe it to young people to explore multiple facets of any individual’s expressed desire to transition. For some people, living life in the opposite sex role – even to the point of undergoing physical transition – may be what the psyche requires of them. We help our patients best by affirming the significance of their experience but without explicitly endorsing a specific course of action.\n\nThe mythos of gender identity\n\nIf, as I do, we think of a belief in gender identity as a kind of neurotic fantasy, ‘we might also imagine a hidden treasure within it, something potentially curative and redemptive’ (Alderman 2016, p. 58). What is this symptom trying to cure or compensate in the collective? My view is that the affirmative model of care concretizes psychic pain, locates it in the body, and seeks biomedical treatments for it. Paradoxically, it also offers a compensatory belief in a disembodied, ineffable essence. In a BBC documentary, transgender psychotherapist Herschel Russell relates the story of a mum who asked her eight‐year‐old gender diverse child how he knew he was really a boy. According to Russell, the child responded, ‘I know way down deep where the music plays’ (Conroy 2017). With the continued decline of traditional religious beliefs, are we unconsciously seeking a new way to conceptualize spirit, and does gender as a mysterious, disembodied imperative offer this? The mythos that informs affirmative care paradoxically allows us to see ourselves as beings with an existence that transcends our mere corporeal form. Jung famously remarked that ‘the gods have become diseases’ (1967, para. 54). I have wondered if gender identity theory may be an unconscious attempt to find the divine hidden within the disease. We are perhaps being asked to find a new a connection with that which is nonrational and transcends materiality. If this is the corrective offered by gender identity theory, we would do well to allow ourselves to be informed by this impulse while also maintaining contact with embodied reality.\n\nAcknowledgment\n\nI would like to thank my patient ‘Maya’ for her permission to write about our work together.\n==== Refs\nReferences\n\nAitken, M. , Steensma, T.D. , Blanchard, R. , VanderLaan, D.P. , Wood, H. , Fuentes, A. , Spegg, C. , Wasserman, L. , Ames, M. , Fitzsimmons, C.L. , Leef, J.H. , Lishak, V. , Reim, E. , Takagi, A. , Vinik, J. , Wreford, J. , Cohen‐Kettenis, P.T. , de Vries, A.L.C. , Kreukels, B.P.C. & Zucker, K.J. (2015). ‘Evidence for an altered sex ratio in clinic‐referred adolescents with gender dysphoria’. The Journal of Sexual Medicine, 12 , 3 , 756–63.25612159\nAlderman, B. (2016). Symptom, Symbol and the Other of Language: a Jungian Interpretation of the Linguistic Turn. Oxon. & N.Y.: Routledge.\nAshley, F. (2019). ‘Thinking an ethics of gender exploration: against delaying transition for transgender and gender creative youth’. Clinical Child Psychology and Psychiatry, 24 , 2 , 223–36.30968720\nAshley, F. (2020). ‘Homophobia, conversion therapy, and care models for trans youth: defending the gender‐affirmative approach’. Journal of LGBT Youth, 17 , 4 , 361–83.\nButler, C. & Hutchinson, A. (2020). ‘Debate: the pressing need for research and services for gender desisters/detransitioners’. Child and Adolescent Mental Health, 25 ,1 , 45–47.32285632\nButler, G. , Graaf, N.D. , Wren, B. & Carmichael, P. (2018). ‘Assessment and support of children and adolescents with gender dysphoria’. Archives of Disease in Childhood, 103 , 631–36.29650510\nClarke, A.C. & Spiliadis, A. (2019). ‘“Taking the lid off the box”: the value of extended clinical assessment for adolescents presenting with gender identity difficulties’. Clinical Child Psychology and Psychiatry , 24 , 2 , 338–52.30722669\nColeman, E. , Bockting, W. , Botzer, M. , Cohen‐Kettenis, P. , DeCuypere, G. , Feldman, J. , Fraser, L. , Green, J. , Knudson, G. , Meyer, W.J. , Monstrey, S. , Adler, R.K. , Brown, G.R. , Devor, A.H. , Ehrbar, R. , Ettner, R. , Eyler, E. , Garofalo, R. , Karasic, D.H. , Lev, A.I. , Mayer, G. , Meyer‐Bahlburg, H. , Hall, B.P. , Pfaefflin, F. , Rachlin, K. , Robinson, B. , Schechter, L.S. , Tangpricha, V. , van Trotsenburg, M. , Vitale, A. , Winter, S. , Whittle, S. , Wylie, K.R. & Zucker, K. (2012). ‘Standards of care for the health of transsexual, transgender, and gender‐nonconforming people’, Version 7. International Journal of Transgenderism, 13 , 4 , 165–232.\nConroy, J. (Producer and Director). (2017). Transgender Kids: Who Knows Best? [Television show]. Retrieved from https://www.dailymotion.com/video/x58s24i\nde Vries, A.L.C. , Mcguire, J.K. , Steensma, T.D. , Wagenaar, E.C.F. , Doreleijers, T.A.H. & Cohen‐Kettenis, P.T. (2014). ‘Young adult psychological outcome after puberty suppression and gender reassignment’. Pediatrics, 134 , 4 , 696–704.25201798\nD’Angelo, R. (2020). ‘The man I am trying to be is not me’. The International Journal of Psychoanalysis, 101 , 5 , 951–70.33952136\nEhrensaft, D. (2017). ‘Gender nonconforming youth: current perspectives’. Adolescent Health, Medicine and Therapeutics, 8 , 57–67.28579848\nEntwistle, K. (2021). ‘Debate: Reality check – detransitioners’ testimonies require us to rethink gender dysphoria’. Child and Adolescent Mental Health, 26 , 1 , 15–16.32406585\nEvans, M. (2020). ‘Freedom to think: the need for thorough assessment and treatment of gender dysphoric children’. Bulletin of the Royal College of Psychiatrists, 21 July 2020, 1–5.\nExpósito‐Campos, P. (2021). ‘A typology of gender detransition and its implications for healthcare providers’. Journal of Sex & Marital Therapy, 47 , 1–11.32706310\nFairbairn, W.R.D. (1943). ‘The repression and the return of bad objects (with special reference to the “war neuroses”)’. British Journal of Medical Psychology, 19 , 3–4 , 327–41.\nGuerra, M.P. , Balaguer, M.G. , Porras, M.G. , Murillo, F.H. , Izquierdo, E.S. & Ariño, C.M. (2020). ‘Transexualidad: transiciones, detransiciones y arrepentimientos en España’. Endocrinología, Diabetes y Nutrición, 67 , 9 , 562–67.32591293\nHembree, W.C. , Cohen‐Kettenis, P.T. , Gooren, L. , Hannema, S.E. , Meyer, W.J. , Murad, M. , Rosenthal, S.M. , Safer, J.D. , Tangpricha, V. & T'sjoen, G.G. (2017). ‘Endocrine treatment of gender‐dysphoric/gender‐incongruent persons: an Endocrine Society Clinical Practice Guideline’. Endocrine Practice, 23 , 12 , 1. Retrieved from 10.4158/1934-2403-23.12.1437\nHidalgo, M.A. , Ehrensaft, D. , Tishelman, A.C. , Clark, L.F. , Garofalo, R. , Rosenthal, S.M. , Spack, N.P. & Olson, J. (2013). ‘The gender affirmative model: what we know and what we aim to learn’. Human Development, 56 , 5 , 285–90.\nJung, C.G. (1950). The Symbolic Life. CW 18.\nJung, C.G. (1960). The Structure and Dynamics of the Psyche. CW 8.\nJung, C.G. (1967). Alchemical Studies. CW 13.\nJung, C.G. (1971). Psychological Types. CW 6.\nJung, C.G. (1988). Nietzsche’s Zarathustra, Notes of the Seminars Given in 1934–1939, Vol. 1 . Princeton, NJ: Princeton University Press.\nKorpaisarn, S. & Modzelewski, K. (2019). ‘MON‐195 Trans‐transgender female: gender identity reversal following irreversible gender affirming surgeries’. Journal of the Endocrine Society , 3 , Supplement 1 . Retrieved from https://academic.oup.com/jes/article/3/Supplement_1/MON‐195/5483989\nLemma, A. (2016). ‘Present without past: the disruption of temporal integration in a case of transsexuality’.Psychoanalytic Inquiry , 36 , 5 , 360–70.\nLevine, S.B. (2017). ‘Transitioning back to maleness’. Archives of Sexual Behavior , 47 , 4 , 1295–1300.29264844\nLivia (2019). Detransition Advocacy Network event transcript. Retrieved from: https://www.youtube.com/watch?v=stBt7_NTT3o&t=1291s\nMarchiano, L. (2017). ‘Outbreak: on transgender teens and psychic epidemics’. Psychological Perspectives , 60 , 3 , 345–66.\nOlson‐Kennedy, J. , Warus, J. , Okonta, V. , Belzer, M. & Clark, L.F. (2018). ‘Chest reconstruction and chest dysphoria in transmasculine minors and young adults’. JAMA Pediatrics, 172 , 5 , 431.29507933\nRayner, G. (2018). ‘Minister orders inquiry into 4,000 per cent rise in children wanting to change sex’. The Telegraph. Retrieved from https://www.telegraph.co.uk/politics/2018/09/16/minister‐orders‐inquiry‐4000‐per‐cent‐rise‐children‐wanting/\nSilber, L.M. (2019). ‘Locating ruptures encrypted in gender: developmental and clinical considerations’. Journal of Infant, Child and Adolescent Psychotherapy, 18 , 2 , 134–54.\nSpiliadis, A. (2019). ‘Towards a gender exploratory model: slowing things down, opening things up and exploring identity development’. Metalogos Systemic Therapy Journal, 35 , 1–9.\nTurban, J. & Keuroghlian, A.S. (2018). ‘Dynamic gender presentations: understanding transition and “de‐transition” among transgender youth’. Journal of the American Academy of Child & Adolescent Psychiatry, 57 , 7 , 451–53.29960687\nWithers, R. (2015). ‘The seventh penis: towards effective psychoanalytic work with pre‐surgical transsexuals’. Journal of Analytical Psychology , 60 , 3 , 390–412.25989331\nWithers, R. (2020). ‘Transgender medicalization and the attempt to evade psychological distress’. Journal of Analytical Psychology, 65 , 5 , 865–89.33202051\nZucker, K.J. (2019). ‘Adolescents with gender dysphoria: reflections on some contemporary clinical and research issues’. Archives of Sexual Behavior, 48 , 7 , 1983–92.31321594\n\n",
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"keywords": "Adoleszenz; Geschlecht; Geschlechtsdysphorie (GD); Rückumwandlung; adolescence; adolescencia; adolescenza; affirmative Betreuung; affirmative care; cuidado afirmativo; cura affermativa; de-transición; detransition; detransizione; disforia de género (GD); disforia di genere (DG); dysphorie de genre; détransition; gender; gender dysphoria (GD); genere; genre; género; soins trans-affirmatifs; transgender; transgenre; transgénero; аффирмативная помощь; гендер; гендерная дисфория; обратный переход; трансгендер; 去跨性别; 性别; 性别平权护理; 性别焦虑; 跨性别; 青少年",
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"title": "Gender detransition: a case study.",
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"abstract": "To describe the experience with Anterior Nucleus of the Thalamus-Deep Brain Stimulation (ANT-DBS) for the treatment of epilepsy at a Canadian Center.\n\n\n\nAll patients who underwent ANT-DBS implantation between 2013 (first patient implanted at our center) and 2020 were included. These patients had therapy-resistant epilepsy (TRE), were not candidates for resective surgery, and failed vagus nerve stimulation (VNS) treatment. Baseline of monthly seizure frequency was calculated within 3 months prior to VNS placement. Monthly seizure frequency was assessed at different points along the timeline: 3 months before ANT-DBS implantation as well as 3, 6, 12, 24, 36, 48, 60, and 72 months after ANT-DBS device placement. At each time point, seizure frequency was compared to baseline.\n\n\n\nSix patients were implanted with ANT-DBS. Three (50%) patients had multifocal epilepsy, one (16.6%) had focal epilepsy, and two (33.4%) had combined generalized and focal epilepsy. Two patients with multifocal epilepsy experienced a seizure reduction >50% in the long-term follow-up. Three (50%) patients did not showed improvement: two with combined generalized and focal epilepsy and one with focal epilepsy. There were not surgical or device-related side effects. Two (33.3%) patients presented mild and transient headaches as a stimulation-related side effect.\n\n\n\nANT-DBS is an effective and safe treatment for focal TRE. Our experience suggests that patients with multifocal epilepsy due to regional lesion may benefit from ANT-DBS the most. Further investigations are required to determine optimal parameters of stimulation.",
"affiliations": "Epilepsy Program, Department of Clinical Neurological Sciences, Schulich School of Medicine, Western University, London, Ontario, Canada.;Epilepsy Program, Department of Clinical Neurological Sciences, Schulich School of Medicine, Western University, London, Ontario, Canada.;Epilepsy Program, Department of Clinical Neurological Sciences, Schulich School of Medicine, Western University, London, Ontario, Canada.;Epilepsy Program, Department of Clinical Neurological Sciences, Schulich School of Medicine, Western University, London, Ontario, Canada.;Epilepsy Program, Department of Clinical Neurological Sciences, Schulich School of Medicine, Western University, London, Ontario, Canada.",
"authors": "Herrera|Manuel L|ML|;Suller-Marti|Ana|A|;Parrent|Andrew|A|;MacDougall|Keith|K|;Burneo|Jorge G|JG|0000-0002-3644-2826",
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"country": "England",
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"doi": "10.1017/cjn.2020.230",
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"issue": "48(4)",
"journal": "The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques",
"keywords": "Deep brain stimulation; Epilepsy; Epilepsy surgery; Thalamus",
"medline_ta": "Can J Neurol Sci",
"mesh_terms": "D020643:Anterior Thalamic Nuclei; D002170:Canada; D046690:Deep Brain Stimulation; D004827:Epilepsy; D006801:Humans; D016896:Treatment Outcome; D055536:Vagus Nerve Stimulation",
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"title": "Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy: A Canadian Experience.",
"title_normalized": "stimulation of the anterior nucleus of the thalamus for epilepsy a canadian experience"
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"abstract": "Preinjury antiplatelet agent (APA) use in trauma patients can increase traumatic hemorrhage and worsen outcomes. Thromboelastography with platelet mapping (TEGPM) has characterized platelet function via arachidonic acid (AA) and adenosine diphosphate (ADP) inhibition in nontrauma settings, but limited data exist in the acute trauma population.\n\n\n\nA prospective observational study of adult trauma patients with suspected preinjury APA use who received TEGPM testing from 2017 to 2020 was performed. Patients on anticoagulants were excluded. Patients were grouped according to preinjury APA regimen: 81 mg or 325 mg of aspirin daily, 81 mg of aspirin and 75 mg of clopidrogrel daily, 75 mg of clopidrogrel daily, or no antiplatelet. Ability of TEGPM to detect APA use was assessed using predictive statistics and area under receiver operating characteristic curves (AUROCs).\n\n\n\nA total of 824 patients were included with most patients taking 81 mg of aspirin (n = 558). Patients on no antiplatelet were younger and had higher baseline platelet counts, while patients on 75 mg of clopidrogrel were more likely to be admitted after ground level fall. All other baseline characteristics were balanced. Admission TEG values were similar between groups. Median AA inhibition was higher in patients on aspirin containing regimens (p < 0.0001). Median ADP inhibition was higher in patients on clopidogrel containing regimens and those taking 325 mg of aspirin (p < 0.0001). Arachidonic acid inhibition accurately detected preinjury APA use and aspirin use (AUROC, 0.89 and 0.84, respectively); however, ADP inhibition performed poorly (AUROC, 0.58). Neither AA nor ADP inhibition was able to discern specific APA regimens or rule out APA use entirely.\n\n\n\nHigh AA inhibition accurately detects preinjury APA use in trauma patients. High ADP inhibition after trauma is common, limiting its utility to accurately identify preinjury APA use. Further study is needed to identify assays that can reliably detect and further characterize preinjury APA use in trauma populations.\n\n\n\nDiagnostic test, level II.",
"affiliations": "From the Department of Pharmacy (C.A.B., H.J.O., G.J.R.), and Department of Surgery (E.N.D., A.G., M.S.), Oregon Health & Science University, Portland, Oregon.",
"authors": "Barton|Cassie A|CA|;Oetken|Heath J|HJ|;Roberti|Gregory J|GJ|;Dewey|Elizabeth N|EN|;Goodman|Andrew|A|;Schreiber|Martin|M|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D004294:Domperidone; C010894:clopimozide; D001241:Aspirin",
"country": "United States",
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"title": "Thromboelastography with platelet mapping: Limited predictive ability in detecting preinjury antiplatelet agent use.",
"title_normalized": "thromboelastography with platelet mapping limited predictive ability in detecting preinjury antiplatelet agent use"
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"abstract": "Our goal was to provide comprehensive data on the effectiveness of ketamine in refractory status epilepticus (RSE) and to describe the potential consequences of long-term ketamine infusion. Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, blocks excitatory pathways contributing to ongoing seizure. While ketamine use is standard in anaesthetic induction, no definitive protocol exists for its use in RSE, and little is known about its adverse effects in long-term, high-dose administration. We present two cases of RSE that responded rapidly to ketamine infusion, both with fatal outcomes secondary to metabolic acidosis and cardiovascular collapse. We performed a systematic review of the application and consequences of ketamine use in RSE. PubMed, Ovid, MEDLINE and PMC were searched for articles describing ketamine treatment for RSE according to a predetermined search strategy and inclusion criteria. The systematic review revealed wide discrepancies in ketamine dosing (infusion maintenance dose range 0.0075-10.5 mg/kg/hour), but good outcomes in medically managed RSE (75% of studies reported moderate or complete seizure control in adults, 62.5% in paediatrics). Additionally, literature review elucidated a potentially causal relationship between prolonged ketamine infusion and both cardiovascular and metabolic dysregulation. Ketamine is effective in RSE by antagonising excitotoxic NMDA receptors. However, there is high variability in ketamine dosing and scarce data on its safety in long-term infusion. Metabolic acidosis and haemodynamic instability associated with the use of long-term, high-dose ketamine infusions must be of concern to clinicians administering ketamine to critically ill patients.",
"affiliations": "NYU Langone Health.;Professor, Departments of Medicine, Anesthesiology, Neurology and Neurosurgery, NYU School of Medicine, New York, NY, USA.",
"authors": "Golub|D|D|;Yanai|A|A|;Darzi|K|K|;Papadopoulos|J|J|;Kaufman|B|B|",
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"keywords": "ketamine, midazolam, status epilepticus, seizures, acidosis, haemodynamics",
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"mesh_terms": "D000138:Acidosis; D000328:Adult; D004569:Electroencephalography; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine; D008297:Male; D012769:Shock; D013226:Status Epilepticus",
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"title": "Potential consequences of high-dose infusion of ketamine for refractory status epilepticus: case reports and systematic literature review.",
"title_normalized": "potential consequences of high dose infusion of ketamine for refractory status epilepticus case reports and systematic literature review"
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... |
{
"abstract": "BACKGROUND\nStevens-Johnson syndrome and toxic epidermal necrolysis are severe mucocutaneous adverse drug reactions characterized by extensive epidermal detachment. The mortality rates have been reported to vary between 1% and 5% for Stevens-Johnson syndrome and 25% and 35% for patients with toxic epidermal necrolysis. Studies have shown that early recognition and prompt withdrawal of the causative agent leads to increased patient survival.\n\n\nMETHODS\nA retrospective chart review was conducted on 64 patients admitted to Vancouver General Hospital with a diagnosis of Stevens-Johnson syndrome or toxic epidermal necrolysis from 2001 to 2011. The aim of this study was to identify the medications most often implicated in triggering Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as to delineate the timeline of identification and removal of these triggers.\n\n\nRESULTS\nA trigger was identified in 75% of cases. Allopurinol was the single most common offending agent (20% of cases). Anticonvulsants and antibiotics were common triggers. The offending agent was often removed at time of hospital admission/diagnosis but not at onset of symptoms. A history of prior culprit drug exposure with previous mucocutaneous adverse reaction was noted in 19% of cases with identified triggers. Asians and Native North Americans had a higher mortality than whites, and Asians more frequently had allopurinol as a trigger.\n\n\nCONCLUSIONS\nThe onset and high mortality rate of Stevens-Johnson syndrome/toxic epidermal necrolysis may be related to unawareness of the early signs and symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis, the common drug triggers that cause it, and what investigations (human leukocyte antigen typing in Asians) can be done to prevent it.",
"affiliations": "Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada.;Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada; Division of Dermatology, Department of Medicine, Queen's University, Kingston, Ont, Canada.;Division of Plastic Surgery, University of British Columbia, Vancouver, Canada.;Division of Plastic Surgery, University of British Columbia, Vancouver, Canada.;Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada; Child and Family Research Institute, University of British Columbia, Vancouver, Canada. Electronic address: dutz@interchange.ubc.ca.",
"authors": "Miliszewski|Monica A|MA|;Kirchhof|Mark G|MG|;Sikora|Sheena|S|;Papp|Anthony|A|;Dutz|Jan P|JP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D006074:Gout Suppressants; D006680:HLA Antigens; D000493:Allopurinol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjmed.2016.03.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9343",
"issue": "129(11)",
"journal": "The American journal of medicine",
"keywords": "Allopurinol; Drug reactions; HLA testing; Phenytoin; Stevens-Johnson syndrome; Sulfamethoxazole-trimethoprim; Toxic epidermal necrolysis",
"medline_ta": "Am J Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000493:Allopurinol; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D044466:Asians; D001955:British Columbia; D005260:Female; D006074:Gout Suppressants; D006680:HLA Antigens; D006801:Humans; D007198:Indians, North American; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013262:Stevens-Johnson Syndrome; D044465:Whites",
"nlm_unique_id": "0267200",
"other_id": null,
"pages": "1221-1225",
"pmc": null,
"pmid": "27086495",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: An Analysis of Triggers and Implications for Improving Prevention.",
"title_normalized": "stevens johnson syndrome and toxic epidermal necrolysis an analysis of triggers and implications for improving prevention"
} | [
{
"companynumb": "CA-ROCHE-1895292",
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"occurcountry": "CA",
"patient": {
"drug": [
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"actiondrug": "5",
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"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
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{
"abstract": "OBJECTIVE\nThe appearance of antitumor necrosis factor drugs (ATDs) has been a major advance in the management of these patients. However, due to the immunosuppressive effect of these therapies, side effects that require treatment discontinuations can appear. The purpose of this study was to evaluate the frequency of ATD discontinuation due to adverse drug effects (ADEs) and the influence of different factors such as diagnosis, ATD prescribed and concomitant disease-modifying antirheumatic drugs (DMARDs).\n\n\nMETHODS\nObservational study from a prospective cohort conducted in a tertiary hospital (1350 beds) in Spain. Data were obtained from the database of the Rheumatology Outpatient Unit of the hospital and patients' clinical files. Included patients had a diagnosis of RA or peripheral or axial SpA (ankylosing spondylitis, psoriatic SpA, non-radiographic SpA, SpA associated with inflammatory bowel disease or reactive arthritis) treated between November 2000 and March 2014 with infliximab (IFX), etanercept (ETN) or adalimumab (ADA).\n\n\nCONCLUSIONS\nStudy cohort included 531 rheumatic patients (282 patients with RA, 53·1%, and 249 patients with SpA, 46·9%). ATDs were discontinued in 62 cases (11·7%) because of ADEs, mainly inmunogenicity and infections (mainly due to infusion reactions, 58·1%, and infections, 19·3%). ATD discontinuation was higher in the group of RA patients compared with SpA (44/282 (15·6%) in RA vs. 18/249 (7·23%) in SpA). The appearance of ADEs that led to drop out was more frequent in patients under IFX therapy (45 (18·6%) with IFX vs. 12 (7·59%) with ETN and 5 (3·81%) with ADA). We observed a significantly increased risk of ADEs when patients received IFX than when ETN or ADA were used (P < 0·001); 444 patients (83·6%) received DMARDs in combination with ATDs. The risk of ATD withdrawal was significantly higher in patients treated with leflunomide as compared to those who do not (OR = 1·984, P < 0·05).\n\n\nCONCLUSIONS\nDiscontinuation of ATD due to ADEs is relatively frequent and it depends on the diagnosis and ATD administered. The risk of treatment discontinuation is higher in patients diagnosed with RA vs. SpA or treated with IFX (rather than with ETN or ADA). The addition of DMARDs to ATDs increased the frequency of treatment discontinuation, up to three concomitant medications. Leflunomide in combination with an ATD significantly increased the probability of treatment discontinuation due to adverse reactions.",
"affiliations": "Pharmacy, La Paz University Hospital, Madrid, Spain.;Pharmacy, La Paz University Hospital, Madrid, Spain.;Rheumatology, La Paz University Hospital, Madrid, Spain.;Pharmacy, La Paz University Hospital, Madrid, Spain.;Pharmacy, La Paz University Hospital, Madrid, Spain.;Rheumatology, La Paz University Hospital, Madrid, Spain.;Pharmacy, La Paz University Hospital, Madrid, Spain.",
"authors": "Varela|H|H|;Villamañán|E|E|;Plasencia|C|C|;Romero|J A|JA|;Ruano|M|M|;Balsa|A|A|;Herrero|A|A|",
"chemical_list": "D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12393",
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"issn_linking": "0269-4727",
"issue": "41(3)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "adverse drug events; antitumor necrosis factor; therapy withdrawal",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D018501:Antirheumatic Agents; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012216:Rheumatic Diseases; D013030:Spain; D062606:Tertiary Care Centers; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "306-9",
"pmc": null,
"pmid": "27191537",
"pubdate": "2016-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Safety of antitumour necrosis factor treatments in chronic rheumatic diseases: therapy discontinuations related to side effects.",
"title_normalized": "safety of antitumour necrosis factor treatments in chronic rheumatic diseases therapy discontinuations related to side effects"
} | [
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"companynumb": "ES-JNJFOC-20160521972",
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"activesubstance": {
"activesubstancename": "METHOTREXATE"
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{
"abstract": "In the UK 127,000 people are diagnosed with Parkinson's disease, many of whom are frequently admited to hospital. However, Parkinson's disease is not usually the primary cause of admission. Emergency department (ED) nurses must be aware of the medication needs of people with Parkinson's disease and how these can be met in emergency setings to ensure the stability of their condition and to prevent the development of neuroleptic malignant syndrome, a potentially fatal condition caused by abrupt omission of Parkinson's medication. This article highlights the importance of ensuring that patients with Parkinson's disease continue their medication regimen while in an ED, even if they are temporarily unable to swallow, and uses a case study to illustrate various ways of achieving this.",
"affiliations": "Torbay Hospital, Torbay and South Devon NHS Foundation Trust, Torquay, England.",
"authors": "Queen|Vicky|V|",
"chemical_list": "D000978:Antiparkinson Agents",
"country": "England",
"delete": false,
"doi": "10.7748/en.2017.e1696",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1354-5752",
"issue": "25(5)",
"journal": "Emergency nurse : the journal of the RCN Accident and Emergency Nursing Association",
"keywords": "Parkinson’s disease; Parkinson’s disease emergency; Parkinson’s disease nursing; emergency nurse; hypotension; nasogastric tube; neuroleptic malignant syndrome; transdermal patch",
"medline_ta": "Emerg Nurse",
"mesh_terms": "D000368:Aged; D000978:Antiparkinson Agents; D016529:Emergency Nursing; D004636:Emergency Service, Hospital; D006801:Humans; D008297:Male; D009459:Neuroleptic Malignant Syndrome; D010300:Parkinson Disease; D006113:United Kingdom",
"nlm_unique_id": "9208913",
"other_id": null,
"pages": "34-39",
"pmc": null,
"pmid": "29115757",
"pubdate": "2017-09-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Parkinson's disease: nursing care in emergency settings.",
"title_normalized": "parkinson s disease nursing care in emergency settings"
} | [
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"companynumb": "GB-TEVA-2019-GB-1087157",
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "BENSERAZIDE HYDROCHLORIDE\\LEVODOPA"
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"drugad... |
{
"abstract": "Varicella zoster virus (VZV) has been increasingly linked with encephalitis and atypical presentations in immunosuppressed patients. We present a patient with history of immunosuppressant intake for polymyositis who initially presented with throbbing frontal headache that raised the suspicion of migraine. She did not respond to anti-migraine medication and later developed stimulus induced myoclonus. She then had significant neurological decline and eventually became encephalopathic. Her initial imaging of brain was unremarkable which warranted further investigations. She was then diagnosed to be VZV positive in the cerebrospinal fluid (CSF) sample that confirmed VZV encephalitis. She responded well to IV Acyclovir treatment and her neurological function improved significantly. In this case, there was delay in diagnosis of VZV in the setting of immunosuppression and non-specific clinical presentation. Therefore, we encourage to strongly consider early VZV diagnostic work up and treatment in immunocompromised patients who can present with non-specific symptoms without a typical cutaneous rash.",
"affiliations": "Division of Neurology, Detroit Medical Center, 4201 St. Antoine street, Detroit, MI 48201, United States of America.;Division of Neurology, Children's Hospital of Michigan, 4201 St. Antoine street, Detroit, MI 48201, United States of America.;Division of Neurology, Detroit Medical Center, 4201 St. Antoine street, Detroit, MI 48201, United States of America.;Division of Neurology, Detroit Medical Center, 4201 St. Antoine street, Detroit, MI 48201, United States of America.;Division of Neurology, Detroit Medical Center, 4201 St. Antoine street, Detroit, MI 48201, United States of America.;Division of Neurology, Detroit Medical Center, 4201 St. Antoine street, Detroit, MI 48201, United States of America.",
"authors": "Sriwastava|Shitiz|S|;Kanna|Anila|A|;Basha|Omar|O|;Xu|Jian|J|;Yarraguntla|Kalyan|K|;George|Edwin|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ensci.2019.100205",
"fulltext": "\n==== Front\neNeurologicalScieNeurologicalScieNeurologicalSci2405-6502Elsevier S2405-6502(19)30029-210.1016/j.ensci.2019.100205100205Case ReportVaricella zoster encephalitis in an immunocompromised patient presented with migraine type headache: A case report Sriwastava Shitiz ssriwast@med.wayne.edusks00002@hsc.wvu.educd⁎Kanna Anila akanna@dmc.orgabdBasha Omar obasha@med.wayne.educdXu Jian jian.xu@wayne.educdYarraguntla Kalyan kyarragu@med.wayne.educdGeorge Edwin egeorge@med.wayne.educd1a Division of Neurology, Children's Hospital of Michigan, 4201 St. Antoine street, Detroit, MI 48201, United States of Americab Carman and Ann Adams Department of Pediatrics Children's Hospital of Michigan, 4201 St. Antoine street, Detroit, MI 48201, United States of Americac Division of Neurology, Detroit Medical Center, 4201 St. Antoine street, Detroit, MI 48201, United States of Americad Wayne State University School of Medicine, 4201 St. Antoine street, Detroit, MI 48201, United States of America⁎ Corresponding author at: Wayne state university, Detroit Medical Center, 4201 St. Antoine street, UHC 8A, Detroit, MI 48201, United States of America. ssriwast@med.wayne.edusks00002@hsc.wvu.edu1 These authors contributed equally to the manuscript.\n\n22 8 2019 9 2019 22 8 2019 16 10020529 5 2019 14 8 2019 19 8 2019 © 2019 The Authors. Published by Elsevier B.V.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Varicella zoster virus (VZV) has been increasingly linked with encephalitis and atypical presentations in immunosuppressed patients. We present a patient with history of immunosuppressant intake for polymyositis who initially presented with throbbing frontal headache that raised the suspicion of migraine. She did not respond to anti-migraine medication and later developed stimulus induced myoclonus. She then had significant neurological decline and eventually became encephalopathic. Her initial imaging of brain was unremarkable which warranted further investigations. She was then diagnosed to be VZV positive in the cerebrospinal fluid (CSF) sample that confirmed VZV encephalitis. She responded well to IV Acyclovir treatment and her neurological function improved significantly. In this case, there was delay in diagnosis of VZV in the setting of immunosuppression and non-specific clinical presentation. Therefore, we encourage to strongly consider early VZV diagnostic work up and treatment in immunocompromised patients who can present with non-specific symptoms without a typical cutaneous rash.\n\nHighlights\n• VZV encephalitis can be differential diagnoses of immunocompromised patients in absence of cutaneous lesions. If untreated it can be uniformly fatal.\n\n• Newly onset headache that mimics status migraine in immunocompromised status raises red flag for VZV encephalitis.\n\n\n\nKeywords\nVZVEncephalitisPolymyositisImmunocompromised\n==== Body\n1 Introduction\nEncephalitis is an uncommon complication of varicella zoster virus (VZV) infection in immunocompetent population. However, immunocompromised patients, individuals with autoimmune diseases and patients on immunosuppression have increased vulnerability to VZV dissemination, thus increasing morbidity and mortality [1,2].\n\nIt has been reported that VZV is not only associated with dermatomyositis (DM) and polymyositis (PM) but also increases the risk [3]. The factors determining VZV infection are old age, female gender, history of trauma to already affected dermatome, immunologic response and interleukin 10 gene polymorphism [4,5].\n\nClinical features may be atypical and skin lesions may be frequently be absent masking the varicella diagnosis in immunocompromised patients [4]. Instead these patients may present with neurological complications such as meningoencephalitis, cerebellitis, myelopathy, zoster paresis, vasculopathy, leukoencephalopathy, dorsal root or cranial nerve ganglionitis, postherpetic neuralgia, polyradiculoneuritis, ventriculitis and necrozting angiitis and cause fatal outcome if overlooked [6].\n\nDiagnosis is usually delayed due these atypical presentations and initial focus on nonspecific investigative results. It is still not a routine practice to investigate for varicella in immunocompromised encephalopathic patients during initial investigations. Frequently, the patient's clinical symptoms are initially attributed to other etiologies and the therapeutic window of opportunity is lost before the definitive diagnosis can be established. At our medical center, we treated a patient with suspicion of encephalitis based on clinical features and CSF (cerebrospinal fluid) findings supported the diagnosis of VZV which led to timely intervention [2].\n\n2 Case\nA 60-year-old African American female who has been treated for polymyositis was admitted recently for management of vulvar abscess.\n\nThe patient had vulvar abscess incision and drainage surgery performed under intradermal bupivacaine. She developed non-radiating throbbing frontal headaches and occasional occipital headaches of 8/10 severity the night prior to surgery. The associated symptoms included nausea, vomiting, photophobia but no phonophobia.\n\nShe had no prior history of severe headache or migraine. Her past medical history included hypertension, type II diabetes, interstitial lung disease secondary to polymyositis, pulmonary hypertension, non-ischemic cardiomyopathy status post ICD placement, paroxysmal chronic Atrial fibrillation, chronic kidney disease (CKD) stage III and chronic anemia.\n\nComputer tomography (CT) scan of head was unremarkable. Magnetic resonance imaging (MRI) could not be done because her implantable cardioverter defibrillator was not MRI compatible.\n\nShe was treated with Toradol, Compazine and Benadryl for possible migraine that didn't resolve completely.\n\nFollowing the surgery, she developed multiple repetitive jerking movements from third day onward. These jerking movements were induced by physical stimuli and lasted for a few minutes each. Her mentation worsened over the next few days which raised the concern for encephalopathy. There were no medications administered perioperatively which could be associated with myoclonus. She was diagnosed with encephalitis induced myoclonus with superimposed renal failure which was well controlled after starting Acyclovir.\n\nOn the physical exam, her Glasgow coma scale score was 3. Her gaze was deviated upwards. Pupils were round and symmetrically reactive to light. She was intubated with absent cough or gag reflex. When the patient was physically stimulated, irregular myoclonic jerking activity was observed in all extremities that lasted for about one minute.\n\nThere were antigravity movements in her extremities. Kernig and Brudzinski sign were not present but concern was the new onset of headache with worsening in setting of immunocompromised status.\n\nElectroencephalogram (EEG) showed generalized slowing with triphasic waves that is consistent with metabolic/hypoxic encephalopathy. She was started on Depakote to control stimulus induced myoclonus. Given the chronic history of steroid use and CellCept for polymyositis, and presence of altered mentation along with aforementioned symptoms, lumbar puncture (LP) was performed to evaluate for underlying meningitis/encephalitis. CSF VZV polymerase chain reaction returned positive.\n\nCSF analysis revealed glucose of 120 mg/dL, protein of 179 mg/dL, nucleated cells of 85/cumm (Neutrophils 0%, Lymphocyte 83%, Monocyte 17%). CSF culture showed no organisms growth. Serum glucose level was 115 mg/dL. Based on CSF findings and clinical signs, VZV encephalitis was diagnosed and Acyclovir was prescribed for twenty-one days.\n\nThe frequency of myoclonic jerks decreased after starting Acyclovir. Her mentation improved gradually and she was extubated. She was alert and oriented to person, place, and time. Speech was fluent but slow. Comprehension and higher cognitive functions were intact. Her myoclonic jerks improved but she had some residual motor deficits. At discharge, patient was sent to long term facility.\n\n3 Discussion\nVZV encephalitis is an uncommon complication of immunosuppressive treatment with mean annual incidence of 3 cases per 100,000 inhabitants [7]. Delayed diagnosis and treatment of VZV encephalitis in patients who presented with non-specific symptoms in the absence of skin lesions can have grave outcomes. Previous episodes of shingles in an immunosuppressed patient with encephalopathy should raise the alarm of VZV encephalitis [8]. However, this part of history can go overlooked or missed during history collection in the absence of current skin lesions. The lack of evidence of such episodes should not eliminate this diagnosis of VZV encephalitis from the initial differential. In our case the patient presented with typical migraine type of headache followed by myoclonic jerks. Even though the patient was immunocompromised, VZV was not suspected initially because of the atypical presentation. The diagnosis and treatment were delayed until the patient became encephalopathic. We propose that migraine or other forms of headaches in an immunocompromised patient in the absence of typical cutaneous zoster lesions should alert the physician of VZV CNS infection to avoid delay in diagnosis. VZV encephalitis should therefore be considered in immunosuppressed patients presenting with headache, seizure, myoclonic jerks and encephalopathy.\n\n4 Conclusion\nVZV encephalitis should be included in initial list of differential diagnoses of immunocompromised patients with altered mentation, absence of cutaneous zoster lesions and unremarkable brain imaging to avoid delay in diagnosis. It might also be beneficial to screen for immunization status and administer vaccine in patients with PM or DM like our case, prior to commencing immunosuppression.\n\nIn the medical community there is still a lag in starting patients on appropriate empiric treatment until confirmation with a positive result (s) that would lead us to appropriate management. We should consider including VZV encephalitis in the differential diagnosis for all CNS manifestations in immunocompromised patients to avoid the delay in the diagnosis and early treatment.\n\nNewly onset severe headache that mimics status migraine in the setting of immunocompromised status raises a red flag for VZV encephalitis. Untreated VZV encephalitis is uniformly fatal unless early treatment with acyclovir is initiated before extensive CNS tissue destruction ensues. We recommend that any immunocompromised patient with progressive encephalopathy be started on empiric treatment with acyclovir, particularly if there is an antecedent history of cutaneous zoster, until the diagnosis can be confirmed or ruled out by a definitive test for VZV.\n\nAuthor contributions\nDrafting the manuscript: Shitiz Sriwastava, Anila Kanna, MD.\n\nOmar Basha MD Jian Xu, MD, PhD, Kalyan Yarraguntla MD.\n\nEditing and Final Draft: Edwin George, MD, PhD.\n\nConflict of interest\nThere is no conflict of interest for the submitted case report.\n==== Refs\nReferences\n1 Saylor D. Thakur K. Venkatesan A. Acute encephalitis in the immunocompromised individual Curr. Opin. Infect. Dis. 28 4 2015 330 336 26098507 \n2 Hackett C.B. Varicella-zoster virus immunity in dermatological patients on systemic immunosuppressant treatment Br. J. Dermatol. 164 6 2011 1387 1389 21410679 \n3 Marie I. Infectious complications in polymyositis and dermatomyositis: a series of 279 patients Semin. Arthritis Rheum. 41 1 2011 48 60 21047670 \n4 Lewis D.J. Schlichte M.J. Dao H. Jr. Atypical disseminated herpes zoster: management guidelines in immunocompromised patients Cutis 100 5 2017 (p. 321;324;330) \n5 Zerboni L. Molecular mechanisms of varicella zoster virus pathogenesis Nat. Rev. Microbiol. 12 3 2014 197 210 24509782 \n6 Wiegering V. Varicella-zoster virus infections in immunocompromised patients - a single centre 6-years analysis BMC Pediatr. 11 2011 31 21569228 \n7 Arruti M. Incidence of varicella zoster virus infections of the central nervous system in the elderly: a large tertiary hospital-based series (2007-2014) J. Neuro-Oncol. 23 3 2017 451 459 \n8 Espiritu R. Rich M. Herpes zoster encephalitis Infect. Dis. Clin. Pract. 15 4 2007 284 288\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2405-6502",
"issue": "16()",
"journal": "eNeurologicalSci",
"keywords": "Encephalitis; Immunocompromised; Polymyositis; VZV",
"medline_ta": "eNeurologicalSci",
"mesh_terms": null,
"nlm_unique_id": "101667077",
"other_id": null,
"pages": "100205",
"pmc": null,
"pmid": "31497657",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "21047670;21410679;21569228;24509782;26098507;28224485;29232422",
"title": "Varicella zoster encephalitis in an immunocompromised patient presented with migraine type headache: A case report.",
"title_normalized": "varicella zoster encephalitis in an immunocompromised patient presented with migraine type headache a case report"
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"activesubstancename": "MYCOPHENOLATE MOFETIL\\MYCOPHENOLATE MOFETIL HYDROCHLORIDE"
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{
"abstract": "Clindamycin is a bacteriostatic lincosamide antibiotic with a broad spectrum. Side effects include nausea, vomiting, diarrhea, and metallic taste; however, hepatotoxicity is rare. The incidence is unknown. It is characterized by increases in aspartate and alanine transaminases. There may be no symptoms and the treatment is to stop the administration of clindamycin. We have described a 62-year-old African American female medicated with acetaminophen and clindamycin who had initially presented to the dental clinic for the evaluation of gum pain following tooth extraction. She had significantly increased levels of liver transaminases, which trended downwards on quitting the medication.",
"affiliations": "School of Public Health, University of Texas, 1200 Pressler Street, Houston, TX 77030, USA.;Department of Medicine, Saint Joseph Regional Medical Center, 5215 Holy Cross Parkway, Mishawaka, IN 46545, USA.",
"authors": "Okudo|Jerome|J|0000-0002-2183-7024;Anusim|Nwabundo|N|",
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"issue": "2016()",
"journal": "Case reports in hepatology",
"keywords": null,
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"nlm_unique_id": "101622103",
"other_id": null,
"pages": "2724738",
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"pmid": "27462474",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "21544079;4432865;24552865;27366152;8053440;17451560;20564754;22346533;26517184;17014577;877644;17879418;20107858;19624990;21642826;26486111;20170750",
"title": "Hepatotoxicity due to Clindamycin in Combination with Acetaminophen in a 62-Year-Old African American Female: A Case Report and Review of the Literature.",
"title_normalized": "hepatotoxicity due to clindamycin in combination with acetaminophen in a 62 year old african american female a case report and review of the literature"
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{
"abstract": "An elderly woman developed a high serum digoxin concentration resulting in toxicity when alprazolam was added to her digoxin therapy. The reduced renal clearance of digoxin is postulated as the mechanism for this interaction.",
"affiliations": null,
"authors": "Tollefson|G|G|;Lesar|T|T|;Grothe|D|D|;Garvey|M|M|",
"chemical_list": "D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D004077:Digoxin; D000525:Alprazolam",
"country": "United States",
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"issue": "141(12)",
"journal": "The American journal of psychiatry",
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"mesh_terms": "D000368:Aged; D000525:Alprazolam; D014151:Anti-Anxiety Agents; D001145:Arrhythmias, Cardiac; D001569:Benzodiazepines; D004077:Digoxin; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007700:Kinetics",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "1612-3",
"pmc": null,
"pmid": "6150651",
"pubdate": "1984-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Alprazolam-related digoxin toxicity.",
"title_normalized": "alprazolam related digoxin toxicity"
} | [
{
"companynumb": "US-PFIZER INC-2013171426",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nThis study aimed to determine the maximum tolerated dose and the recommended dose of combining S-1 with gemcitabine and cisplatin for advanced biliary tract adenocarcinoma first-line therapy.\n\n\nMETHODS\nChemotherapy-naive patients with histologically or cytologically proven unresectable or metastatic biliary tract adenocarcinoma were enrolled. Patients with advanced biliary tract adenocarcinoma received gemcitabine and cisplatin intravenously on Days 1 and 8 and S-1 orally twice daily from Days 1 to 14. Cycles were repeated every 21 days until disease progression. Patients were scheduled to receive gemcitabine (mg/m(2)/week), cisplatin (mg/m(2)/week) and S-1 (mg/m(2)/day) at four dose levels: 800/25/40 (level 0), 1000/25/40 (level 1), 1000/25/60 (level 2) and 1000/25/80 (level 3). Level 1 was chosen as the starting dose. For cases where recommended dose could not be determined within the triweekly schedule, we prepared a biweekly schedule to find recommended dose.\n\n\nRESULTS\nSeventeen patients with advanced biliary tract adenocarcinoma were treated across three dose levels. Maximum tolerated dose and recommended dose were defined as level 0. Dose-limiting toxicities included a Grade 3 maculopapular rash, Grade 4 thrombocytopenia and consecutive administration skips of gemcitabine and cisplatin on Day 8. Five partial responses were observed.\n\n\nCONCLUSIONS\nThis triweekly triplet regimen was well tolerated and showed promising antitumor activity in patients with advanced biliary tract adenocarcinoma. We recommend level 0, gemcitabine at 800 mg/m(2)/week, cisplatin at 25 mg/m(2)/week and S-1 at 40 mg/m(2)/day during a 21-day cycle, in further studies with this schedule.",
"affiliations": "Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo cmorizan@ncc.go.jp.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo.",
"authors": "Shoji|Hirokazu|H|;Morizane|Chigusa|C|;Sakamoto|Yasunari|Y|;Kondo|Shunsuke|S|;Ueno|Hideki|H|;Takahashi|Hideki|H|;Ohno|Izumi|I|;Shimizu|Satoshi|S|;Mitsunaga|Shuichi|S|;Ikeda|Masafumi|M|;Okusaka|Takuji|T|",
"chemical_list": "D004338:Drug Combinations; D003841:Deoxycytidine; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C056507:gemcitabine; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyv179",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "46(2)",
"journal": "Japanese journal of clinical oncology",
"keywords": "S-1; advanced biliary tract cancer; cisplatin; gemcitabine",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001661:Biliary Tract Neoplasms; D002945:Cisplatin; D003841:Deoxycytidine; D018450:Disease Progression; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010094:Oxonic Acid; D005641:Tegafur; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "132-7",
"pmc": null,
"pmid": "26685318",
"pubdate": "2016-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I clinical trial of oral administration of S-1 in combination with intravenous gemcitabine and cisplatin in patients with advanced biliary tract cancer.",
"title_normalized": "phase i clinical trial of oral administration of s 1 in combination with intravenous gemcitabine and cisplatin in patients with advanced biliary tract cancer"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1021363",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drugadditio... |
{
"abstract": "We present the case of a female, aged 22 years, with a long history of recalcitrant pustular psoriasis and psoriatic arthritis, treated with ustekinumab during pregnancy. The result of treatment was an uncomplicated pregnancy with delivery, at term, of a healthy boy. To our knowledge, this is the first reported use of ustekinumab in a human during pregnancy. Following a description of the case, we discuss the characteristics of ustekinumab and review the known information from human case reports, case series, and animal studies regarding the use of TNF-a inhibitors and ustekinumab during pregnancy. We also provide a short discussion of administration of ustekinumab during the time period when a mother is nursing and the potential for complications to infants in this setting.",
"affiliations": "University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.",
"authors": "Andrulonis|Ryan|R|;Ferris|Laura Korb|LK|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; D000069549:Ustekinumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "11(10)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D011565:Psoriasis; D047929:Term Birth; D000069549:Ustekinumab; D055815:Young Adult",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "1240",
"pmc": null,
"pmid": "23134993",
"pubdate": "2012-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of severe psoriasis with ustekinumab during pregnancy.",
"title_normalized": "treatment of severe psoriasis with ustekinumab during pregnancy"
} | [
{
"companynumb": "US-JNJFOC-20121107337",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Background:Cardiac conduction abnormalities are reported after ingestion of a toxic dose of carbamazepine. Case presentation:We describe the case of a four-year-old child with carbamazepine acute poisoning who developed reversible synoatrial block along with neurological toxic signs, despite a serum level of carbamazepine close to the upper limit of the therapeutic range. Discussion:Although carbamazepine-induced sinoatrial block has been reported in the literature even at therapeutic doses in adult patients, our personal research has not identified any record of this cardiac conduction abnormality in acute carbamazepine poisoning at pediatric age. Conclusion:The electrocardiogram is indispensable in the assessment and monitoring of pediatric cases with acute poisoning with carbamazepine.",
"affiliations": "\"Grigore Alexandrescu\" Emergency Children's Hospital, Bucharest, Romania.;\"Grigore Alexandrescu\" Emergency Children's Hospital, Bucharest, Romania.",
"authors": "Vivisenco|Cristina Iolanda|CI|;Ulmeanu|Coriolan Emil|CE|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.26574/maedica.2019.14.2.165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1841-9038",
"issue": "14(2)",
"journal": "Maedica",
"keywords": null,
"medline_ta": "Maedica (Bucur)",
"mesh_terms": null,
"nlm_unique_id": "101526930",
"other_id": null,
"pages": "165-168",
"pmc": null,
"pmid": "31523299",
"pubdate": "2019-06",
"publication_types": "D016421:Editorial",
"references": "10866337;11146615;12475188;1640302;16835785;17724878;2269999;3585400;7741340;8215250;9853982",
"title": "Rare Conduction Abnormality in a Four-year-old Child with Carbamazepine Acute Poisoning.",
"title_normalized": "rare conduction abnormality in a four year old child with carbamazepine acute poisoning"
} | [
{
"companynumb": "RO-VALIDUS PHARMACEUTICALS LLC-RO-2019VAL000558",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drug... |
{
"abstract": "Treatment of paroxetine-induced penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) by Low-power Laser Irradiation (LPLI) is unknown in medical literature. The aim of the current article is to report partial efficacy of LPLI for paroxetine-induced persistent penile anesthesia. We report on a male patient who presented with a history of reversible loss of smell, taste and skin sensitivity occurring within a week after start of 20mg/day paroxetine-hemihydrate for a depressive period. Concurrently, patient suffered from penile anesthesia, scrotum hypesthesia, anejaculation and erectile difficulties with normal sexual desire. During 2.5 years of paroxetine treatment and throughout 2 years after paroxetine discontinuation, genital and sexual complaints persisted. Penile anesthesia was treated by LPLI with single and multi diode pulsed laser probes. After 20 LPLI-treatment sessions of 15min each, patient reported partial return of penile touch and temperature sensation. Clinical improvement of glans penis sensitivity was reported to 20% and 40%, compared to pre-paroxetine treatment penile sensitivity during erect and flaccid states, respectively. However, anejaculation and erectile difficulties remained unchanged. Briefly, in the current patient with early onset of PSSD, LPLI treatment reduced paroxetine-induced penile anesthesia. It is hypothesized that SSRI treatment induces disturbances of transient receptor potential (TRP) ion channels of mechano-, thermo- and chemosensitive nerve endings and receptors resulting in the penile anesthesia in PSSD. It is further hypothesized that there are two types of PSSD, one of which occurs soon after the start of SSRI treatment.",
"affiliations": "Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of BetaSciences, Utrecht University, Universiteitslaan 99, 3584 CG Utrecht, The Netherlands; Private Practice Psychiatry and Neurosexology, Amstelveen, The Netherlands. Electronic address: md@waldinger.demon.nl.;Medisch Centrum Buitenveldert, Amsterdam, The Netherlands.;Department of Internal Medicine and Endocrinology, Reinier de Graaf Groep of Hospitals, Delft-Voorburg, The Netherlands.;Department of Neuroscience, Section Anatomy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.",
"authors": "Waldinger|Marcel D|MD|;van Coevorden|Ruben S|RS|;Schweitzer|Dave H|DH|;Georgiadis|Janniko|J|",
"chemical_list": "D050051:Transient Receptor Potential Channels; D017374:Paroxetine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0014-2999",
"issue": "753()",
"journal": "European journal of pharmacology",
"keywords": "Low-power laser irradiation; Paroxetine; Penile anesthesia; Post SSRI sexual dysfunction; TRPV1; Transient receptor potential",
"medline_ta": "Eur J Pharmacol",
"mesh_terms": "D000328:Adult; D006801:Humans; D028022:Low-Level Light Therapy; D008297:Male; D017374:Paroxetine; D010413:Penis; D012735:Sexual Dysfunction, Physiological; D050051:Transient Receptor Potential Channels",
"nlm_unique_id": "1254354",
"other_id": null,
"pages": "263-8",
"pmc": null,
"pmid": "25483212",
"pubdate": "2015-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) responds to low-power laser irradiation: a case study and hypothesis about the role of transient receptor potential (TRP) ion channels.",
"title_normalized": "penile anesthesia in post ssri sexual dysfunction pssd responds to low power laser irradiation a case study and hypothesis about the role of transient receptor potential trp ion channels"
} | [
{
"companynumb": "NL-MYLANLABS-2015M1013052",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAROXETINE\\PAROXETINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "A 67-year-old man with significant smoking history presented with fever, unintentional weight loss, night sweats, productive cough, and progressive dyspnea. Multiple respiratory specimens grew Mycobacterium branderi. Computed tomography scanning of the chest revealed a cavitary right upper lung lesion. Bronchoscopy and thoracoscopic biopsy were negative for malignancy but showed necrotizing granulomatous inflammation, which was culture negative. Due to clinical and radiologic progression despite therapy with clarithromycin, ethambutol and moxifloxacin, the lesion was surgically resected and the patient's symptoms resolved. Mycobacteria were seen in histopathology but did not grow from resected tissue. The patient received an additional 6 months of medical therapy and remains asymptomatic 1 month after completing antimicrobials. Cases of M. branderi causing human infection are very rarely reported. This is a novel case of multi-drug resistant M. branderi pulmonary infection in an apparently immunocompetent patient, progressive despite medical therapy and requiring surgical resection for definitive management.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address: sturvey@ualberta.ca.;The Division of Diagnostic and Applied Microbiology, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada; The Provincial Laboratory for Public Health (Microbiology), Edmonton, Alberta, Canada. Electronic address: Greg.Tyrrell@albertahealthservices.ca.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address: chernand@ualberta.ca.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address: dkabbani@ualberta.ca.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address: karen.doucette@ualberta.ca.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Electronic address: cerveraa@ualberta.ca.",
"authors": "Turvey|Shannon L|SL|;Tyrrell|Gregory J|GJ|;Hernandez|Cristina|C|;Kabbani|Dima|D|;Doucette|Karen|K|;Cervera|Carlos|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004977:Ethambutol; D017291:Clarithromycin",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2017.03.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "58()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Mycobacterium branderi; Non-tuberculous mycobacteria; multi-drug resistant mycobacteria",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001999:Bronchoscopy; D017291:Clarithromycin; D004977:Ethambutol; D006801:Humans; D008297:Male; D009161:Mycobacterium; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "65-67",
"pmc": null,
"pmid": "28268125",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Mycobacterium branderi infection: Case report and literature review of an unusual and difficult-to-treat non-tuberculous mycobacterium.",
"title_normalized": "mycobacterium branderi infection case report and literature review of an unusual and difficult to treat non tuberculous mycobacterium"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2017US-136482",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"dr... |
{
"abstract": "Stroke occurs due to the interruption of blood flow to the brain and it is divided into ischemic and hemorrhagic. In the ischemic strokes, while the most commonly affected vessel is median cerebral artery (MCA), it is particularly affected bilateral posterior cerebral artery (PCA) is very rare condition. In this study, a case of sudden loss of vision and bilateral occipital infarct associated with bilateral vertebral system pathology and methylene tetrahydrofolate reductase (MTHFR) gene mutation were reported. A 62-year-old man was admitted with sudden loss of vision complaint starting 10 h before applying to emergency department. The patient was oriented and cooperative. On neurological examination, there was complete loss of vision in the right eye and only a response to light in the left eye. On the brain computerized tomography (CT), ischemic lesions were observed in the bilateral occipital areas and on magnetic resonance imaging (MRI), there were foci showing diffusion limitation in cortico-subcortical areas of bilateral parieto-occipital region. On the detailed examination at the clinic, MTHFR (a1298c) gene mutation was detected. Bilateral occipital infarction is rare and its diagnosis can be difficult because of its atypical symptoms. Therefore, occipital infarction should be suspected when the only sign is isolated vision loss in patients with risk factor for thromboembolism in their history and detailed visual-neurological examination of these patients should be performed.",
"affiliations": "Bulent Ecevit University, Faculty of Medicine, Emergency Medicine Department, Zonguldak, Turkey.;Bulent Ecevit University, Faculty of Medicine, Emergency Medicine Department, Zonguldak, Turkey.;Bulent Ecevit University, Faculty of Medicine, Emergency Medicine Department, Zonguldak, Turkey.;Bulent Ecevit University, Faculty of Medicine, Emergency Medicine Department, Zonguldak, Turkey.",
"authors": "Tanrikulu|Ceren Sen|CS|;Hocagil|Hilal|H|;Kaya|Ural|U|;Hocagil|Abdullah Cuneyt|AC|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.tjem.2014.12.001",
"fulltext": "\n==== Front\nTurk J Emerg MedTurk J Emerg MedTurkish Journal of Emergency Medicine2452-2473Elsevier S2452-2473(16)00011-X10.1016/j.tjem.2014.12.001Case ReportAcute bilateral vision loss in emergency department: A case report Tanrikulu Ceren sen cerensen81@hotmail.com∗Hocagil Hilal Kaya Ural Hocagil Abdullah Cuneyt Bulent Ecevit University, Faculty of Medicine, Emergency Medicine Department, Zonguldak, Turkey∗ Corresponding author. Tel.: +90 0505 887 1387. cerensen81@hotmail.com10 3 2016 3 2016 10 3 2016 16 1 38 40 2 11 2014 15 12 2014 24 12 2014 Copyright © 2016 The Emergency Medicine Association of Turkey. Production and hosting by Elsevier B.V. on behalf of the Owner.2016The Emergency Medicine Association of TurkeyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Stroke occurs due to the interruption of blood flow to the brain and it is divided into ischemic and hemorrhagic. In the ischemic strokes, while the most commonly affected vessel is median cerebral artery (MCA), it is particularly affected bilateral posterior cerebral artery (PCA) is very rare condition. In this study, a case of sudden loss of vision and bilateral occipital infarct associated with bilateral vertebral system pathology and methylene tetrahydrofolate reductase (MTHFR) gene mutation were reported. A 62-year-old man was admitted with sudden loss of vision complaint starting 10 h before applying to emergency department. The patient was oriented and cooperative. On neurological examination, there was complete loss of vision in the right eye and only a response to light in the left eye. On the brain computerized tomography (CT), ischemic lesions were observed in the bilateral occipital areas and on magnetic resonance imaging (MRI), there were foci showing diffusion limitation in cortico-subcortical areas of bilateral parieto-occipital region. On the detailed examination at the clinic, MTHFR (a1298c) gene mutation was detected. Bilateral occipital infarction is rare and its diagnosis can be difficult because of its atypical symptoms. Therefore, occipital infarction should be suspected when the only sign is isolated vision loss in patients with risk factor for thromboembolism in their history and detailed visual-neurological examination of these patients should be performed.\n\nKeywords\nMTHFROccipital infarctusVisual loss\n==== Body\n1 Introduction\nStroke occurs due to interruption of blood flow to the brain and it is the third most common cause of deaths. Stroke is one of the major causes of morbidity and loss of labor.1, 2 Basically, stroke is classified as ischemic and hemorrhagic stroke. Ischemic strokes constitute the majority of cases. In the etiology of ischemic stroke, thromboembolic events often take place. The most important factors that increase susceptibility to thromboembolism are malignancies, trauma and gene mutations. In ischemic stroke, while the most commonly affected vessel is middle cerebral artery, particularly bilateral PCA involvement is a very rare condition. Clinical process may vary depending on the affected vessel. In patients with posterior cerebral artery infarct, as occipital lobe which contains the primary visual cortex is usually affected, patients may present with visual impairment only.1 In patients admitted with isolated visual symptoms to emergency department, diagnosis can be delayed or the patient may be misdiagnosed unless a careful physical examination is performed. In this study, bilateral occipital infarct associated with MTHFR gene mutation is presented in a patient that was admitted with bilateral visual field defect to our emergency department.\n\n2 Case report\nA 62-year-old man admitted to emergency clinic with sudden loss of vision complaint starting 10 h ago. The patient did not have any complaints other than minimal headache. The patient was oriented and cooperative and there was no comorbid disease in medical history. Arterial blood pressure was 170/90 mmHg, pulse was 80 rpm, respiratory rate was 14 bpm, temperature was 36.6 °C, and oxygen saturation was 98%. On neurological examination, there was complete loss of vision in the right eye and only a slight light reflex. Pupils were bilaterally isochoric and light reflex was bilaterally positive. The patient's eye movements, fundoscopic examination, cranial nerve examination and other neurological examination findings were normal. There was no motor and sensorial deficit and facial asymmetry. But, cerebellar examination (dysdiadochokinesis, finger-to-nose test, heel-to-shin test, cerebellar ataxia) of patient could not be performed due to bilateral visual loss. On patient's laboratory, complete blood count, renal-liver function test, electrolytes, cardiac enzymes were normal. Electrocardiogram was normal sinus rhythm. Unenhanced brain CT scan was performed on the patient on presentation, and ischemic lesions were observed in the bilateral occipital areas (Fig. 1). On MRI, the foci showing diffusion limitation in cortico-subcortical areas of bilateral parieto-occipita region and cerebellar hemisphere were seen (Fig. 2). Antiplatelet agent aspirin and unfractioned heparin were given to the patient during the treatment in the emergency department. The patient was consulted to the neurologist with the preliminary diagnosis of ischemic stroke, and the patient was hospitalized. During the detailed examination at the clinic, on the MRI angiography, moderate to severe stenosis at the level output of internal cerebral artery and hypoplasia of the right vertebral artery were detected, and MTHFR (a1298c) gene mutation was detected. Anticoagulant therapy was given to the patient during the hospitalization period. The patient who had neither any improvement in vision nor any new onset pathology was discharged.\n\n3 Discussion\nStroke is a common disease in the community and is one of the major causes of mortality and morbidity. Stroke induced bilateral occipital infarct is a rare condition and its diagnosis may be difficult due to atypical symptoms. In this study, a case of bilateral occipital infarct associated with bilateral vertebral system pathology and MTHFR gene mutation were discussed with literature.\n\nAge is an important risk factor for stroke and the incidence of the stroke increases with age.3 Yoneda et al4 have found that the mean age was 70 ± 11. Similarly, Reganon et al5 have found that the mean age was 65.3 ± 8.2. Our case was 62 years old male and these demographic features were consistent with the literature.\n\nThe etiology of stroke is basically divided into two: ischemic and hemorrhagic. 87% of cases are ischemic stroke. 10% of hemorrhagic strokes are intracerebral hemorrhage, 3% are nontraumatic subarachnoid hemorrhage.1 Common causes of ischemic stroke are thrombotic events (atherosclerosis, vasculitis, hypercoagulation status), embolic events (septic embolism, fat embolism and cardiac tumors), and hypoperfusion (causes of systemic hypotension).1 Hypercoagulable states may be acquired or inherited. One of the acquired hypercoagulable states is MTHFR gene mutation which appears frequently in recent years. The MTHFR gene mutation leading to vascular thrombosis is rare and thrombosis occurs especially in patient with homozygous mutations.6 In our case, type 1 gene MTHFR a1298c mutation with ischemic stroke was present.\n\nIn ischemic stroke, the most commonly affected vessel is MCA. Other vessels such as PCA, anterior cerebral artery (ACA) and vertebra-basillary artery (VBA) are more rarely affected.1 PCA obstructing embolism generally arises from internal cerebral artery (ICA). Clinical presentation varies according to the region of the brain damage. The clinical picture such as facial weakness, motor deficits in limb can be obvious, but the symptoms might be obscure such as dizziness. Although patients with PCA infarction usually suffer from unilateral headache, clinical signs are visual defects with contralateral homonymous hemianopia and unilateral cortical blindness.7\n\nTherefore, in bilateral visual defect, if eye and pupil examinations are normal “cortical blindness” that is the partial or complete loss of vision in the normal-appearing eye and occurs due to damaged visual field in the occipital cortex of the brain should be considered.8 There were similar findings in our patient.1 In a comprehensive study conducted Geddes et al9 found that the rates of right and left visual field defects associated with stroke are 0.5% and 0.7%, respectively. In other study10 carried out with 474 patients (402 patients with ischemic stroke and 72 patients with hemorrhagic stroke) with stroke diagnosed at the end of an observation period of over 9 years, it was found that the most common complaints among patients was weakness (80%), hemianopia (14.6%) and diplopia (5.5%). Among the causes of cerebral blindness, other than occipital infarction, there are traumas of occipital region, migraine, occipital seizures, invasive cardiac procedures, and the preeclampsia.11\n\nEarly diagnosis is very important in all kinds of ischemia. In the emergency department, non-contrast brain CT is the most appropriate tests terms of accessibility and cost. MRI is more preferable if diffusion weighted MRI is easily accessible and the lesion is presumed to be in the posterior fossa.12 On CT of our patient, ischemic lesions were observed in the bilateral occipital area because our patient was admitted after 10 h from onset of symptoms. On the MRI angiography, moderate to severe stenosis at the level output of internal cerebral artery and hypoplasia of the right vertebral artery were detected, and homozygous MTHFR (a1298c) gene mutation was detected.\n\nThrombolytic therapy administered during first 3 h provides significant clinical improvement in patients with acute ischemic stroke. Therefore, early application and diagnosis is very important for initiation of thrombolytic therapy at the appropriate time. However, studies indicated that up to 21–48% of patients are admitted to emergency department in the first 3 h. In patients with stroke, the period between detection of visual field defects and to confirm the diagnosis is quite long. Therefore, in this group of patients, early detection of visual field defects is very important because long-term functional outcomes of these patients are worse than other stroke patients.13 Thrombolytic therapy was not given to our patient because of late admission to the emergency department.\n\nCauses of late presentation of patients are inability to recognize of the symptoms of cerebrovascular event (SVE) by patients, ignoring symptoms, and status can't be determined due to unconsciousness induced SVE.14 The causes of admission of our patient after about 10 h from the onset of his complaints were transportation difficulties and hope that his complaints will be resolved.\n\nAs a result, stroke patients who present to the emergency department with a loss of vision and who have risk factors for thromboembolism should be evaluated more carefully and detailed neurological and visual examination should be performed. Because early diagnosis and treatment are important factors in terms of mortality and morbidity. Even if the only sign is isolated loss of vision, in addition to ocular problems occipital infarction should be considered.\n\nConflict of interest\nThe authors declare that there is no potential conflict of interest.\n\nPeer review under responsibility of The Emergency Medicine Association of Turkey.\n\nFig. 1 The foci showing diffusion limitation on brain CT.\n\nFig. 2 Density reduction on brain MRI.\n==== Refs\nReferences\n1 Go S. Worman D.J. Stroke, transient ischemic attack, and cervical artery dissection Tintinalli J.E. Stapczynski J.S. A Comprehensive Study Guide 7th ed. 2010 McGraw-Hill New York, NY 1382 1390 \n2 Lopez A.D. Mathers C.D. Ezzati M. Jamison D.T. Murray C.J. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data Lancet 367 2006 1747 1757 16731270 \n3 Oguzhan C. Beyin damar hastalıklarında tanımlar, sınıflama, epidemiyoloji ve risk faktorleri Oge A.E. Noroloji 2004 Nobel Tıp Kitapevleri İstanbul 193 194 \n4 Yoneda Y. Okuda S. Hamada R. Hospital cost of ischemic stroke and intracerebral hemorrhage in Japanese stroke centers Health Policy 73 2005 202 211 15978963 \n5 Reganon E. Vila V. Martínez-Sales V. Association between inflammation and hemostatic markers in atherothrombotic stroke Thromb Res 112 2003 217 221 14987914 \n6 Cinemre H. Bilir C. Akdemir N. Isolated renal vein thrombosis associated with MTHFR-1298 and PAI-1 4G gene mutations Clin Appl Thromb Hemost 16 2010 708 710 19825918 \n7 Brandt T. Steinke W. Thie A. Pessin M.S. Caplan L.R. Posterior cerebral artery territory infarcts: clinical features, infarct topography, causes and outcome. Multicenter results and a review of the literature Cerebrovasc Dis 10 2000 170 182 10773642 \n8 Evereklioglu C. Hepsen I.F. Cortical blindness Turkiye Klinikleri J Ophthalmol 8 1999 219 224 \n9 Geddes J.M. Fear J. Tennant A. Pickering A. Hillman M. Chamberlain M.A. Prevalence of self reported stroke in a population in northern England J Epidemiol Community Health 50 1996 140 143 8762377 \n10 Rathore S.S. Hinn A.R. Cooper L.S. Tyroler H.A. Rosamond W.D. Characterization of incident stroke signs and symptoms: findings from the atherosclerosis risk in communities study Stroke 33 2002 2718 2721 12411667 \n11 Chang Khai Meng Subrayan Visvaraja Kumar Patel Dinesh Bilateral occipital infarction: an uncommon cause of bilateral visual loss J Emerg Med 44 2013 668 669 23312775 \n12 Hjort N. Butcher K. Davis S.M. Magnetic resonance imaging criteria for thrombolysis in acute cerebral infarct Stroke 36 2005 388 397 15618445 \n13 Zhang X. Kedar S. Lynn M.J. Newman N.J. Biousse V. Homonymous hemianopias: clinical-anatomic correlations in 904 cases Neurology 66 2006 906 910 16567710 \n14 Ringleb P.A. Bousser M.G. Ford G. Guidelines for management of ischaemic stroke and transient ischaemic attack Cerebrovasc Dis 25 2008 457 507 18477843\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2452-2473",
"issue": "16(1)",
"journal": "Turkish journal of emergency medicine",
"keywords": "MTHFR; Occipital infarctus; Visual loss",
"medline_ta": "Turk J Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101681782",
"other_id": null,
"pages": "38-40",
"pmc": null,
"pmid": "27239639",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports",
"references": "19825918;15978963;16567710;8762377;15618445;10773642;16731270;12411667;23312775;14987914;18477843",
"title": "Acute bilateral vision loss in emergency department: A case report.",
"title_normalized": "acute bilateral vision loss in emergency department a case report"
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"abstract": "Bone metastases (BMs) are a negative prognostic factor in patients with non-small cell lung cancer (NSCLC). Although immune-checkpoint inhibitors (ICIs) have dramatically changed the therapeutic landscape of NSCLC, little information is available on BMs from NSCLC treated with ICIs alone or in association with bone-targeted therapy (BTT) such as zoledronate or denosumab.\n\n\n\nFrom 2014 to 2020, 111 of the 142 patients with BMs secondary to NSCLC extrapolated from the prospective multicenter Italian BM Database were eligible for analysis. Information on blood count, comorbidities, and toxicity was retrospectively collected. The neutrophil-to-lymphocyte ratio (NLR) pre- and post-treatment was calculated. Survival was analyzed using the Kaplan-Meier method, with statistical significance of survival differences assessed using the log-rank test.\n\n\n\nMedian age was 66 (range, 42-84) years. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 0-1 in 79/111 patients. The majority of patients (89.2%) had adenocarcinoma histology. At a median follow-up of 47.4 months, median progression-free (mPFS) and overall survival (mOS) was 4.9 (95%CI, 2.8-10.0) and 11.9 (95%CI, 8.2-14.4) months, respectively. Forty-six (43.4%) patients with BM NSCLC underwent first- or further-line therapy with ICIs: 28 (60.8%) received nivolumab, 9 (19.6%) pembrolizumab, and 9 (19.6%) atezolizumab. Of the 46 patients treated with ICIs, 30 (65.2%) underwent BTT: 24 (80.0%) with zoledronate and 6 (20.0%) with denosumab. The ICI-alone group had an mOS of 15.8 months [95%CI, 8.2-not evaluable (NE)] vs. 21.8 months (95%CI, 14.5-not evaluable) for the ICI plus BTT group and 7.5 (95%CI, 6.1-10.9) months for the group receiving other treatments (p < 0.001). NLR ≤5 had a positive impact on OS.\n\n\n\nBTT appears to have a synergistic effect when used in combination with ICIs, improving patient survival.",
"affiliations": "Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.;Medical Oncology Unit, Policlinico Hospital of Bari Department of Biomedical Sciences and Human Oncology University of Bari \"A. Moro\", Bari, Italy.;Division of Medical Oncology, Ramazzini Hospital, Carpi, Italy.;IRCCS National Cancer Institute (INT), Milan, Italy.;UOC di Oncologia Medica Ospedale Sacro cuore di Gesù, Gallipoli, Italy.;Oncology Unit, Infermi Hospital, Rimini, Italy.;San Camillo De Lellis Hospital, ASL Rieti, Rieti, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.;Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\", Meldola, Italy.",
"authors": "Bongiovanni|Alberto|A|;Foca|Flavia|F|;Menis|Jessica|J|;Stucci|Stefania Luigia|SL|;Artioli|Fabrizio|F|;Guadalupi|Valentina|V|;Forcignanò|Maria Rosachiara|MR|;Fantini|Manuela|M|;Recine|Federica|F|;Mercatali|Laura|L|;Spadazzi|Chiara|C|;Burgio|Marco Angelo|MA|;Fausti|Valentina|V|;Miserocchi|Anna|A|;Ibrahim|Toni|T|",
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"doi": "10.3389/fimmu.2021.697298",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.697298\nImmunology\nOriginal Research\nImmune Checkpoint Inhibitors With or Without Bone-Targeted Therapy in NSCLC Patients With Bone Metastases and Prognostic Significance of Neutrophil-to-Lymphocyte Ratio\nBongiovanni Alberto 1 *\n\nFoca Flavia 2\nMenis Jessica 3 4 5\n\nStucci Stefania Luigia 6\n\nArtioli Fabrizio 7\nGuadalupi Valentina 8\nForcignanò Maria Rosachiara 9\nFantini Manuela 10\nRecine Federica 11\n\nMercatali Laura 1\n\nSpadazzi Chiara 1\nBurgio Marco Angelo 12\nFausti Valentina 1\n\nMiserocchi Anna 2\nIbrahim Toni 1\n\n1 Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\n2 Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\n3 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy\n4 Medical Oncology Department, Istituto Oncologico Veneto IRCCS, Padova, Italy\n5 Medical Oncology, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata (AOUI) di Verona, Verona, Italy\n6 Medical Oncology Unit, Policlinico Hospital of Bari Department of Biomedical Sciences and Human Oncology University of Bari “A. Moro”, Bari, Italy\n7 Division of Medical Oncology, Ramazzini Hospital, Carpi, Italy\n8 IRCCS National Cancer Institute (INT), Milan, Italy\n9 UOC di Oncologia Medica Ospedale Sacro cuore di Gesù, Gallipoli, Italy\n10 Oncology Unit, Infermi Hospital, Rimini, Italy\n11 San Camillo De Lellis Hospital, ASL Rieti, Rieti, Italy\n12 Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy\nEdited by: Hubing Shi, Sichuan University, China\n\nReviewed by: Francesca Colonese, San Gerardo Hospital, Italy; Daniele Santini, Campus Bio-Medico University, Italy\n\n*Correspondence: Alberto Bongiovanni, alberto.bongiovanni@irst.emr.it\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n10 11 2021\n2021\n12 69729819 4 2021\n08 10 2021\nCopyright © 2021 Bongiovanni, Foca, Menis, Stucci, Artioli, Guadalupi, Forcignanò, Fantini, Recine, Mercatali, Spadazzi, Burgio, Fausti, Miserocchi and Ibrahim\n2021\nBongiovanni, Foca, Menis, Stucci, Artioli, Guadalupi, Forcignanò, Fantini, Recine, Mercatali, Spadazzi, Burgio, Fausti, Miserocchi and Ibrahim\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nIntroduction\n\nBone metastases (BMs) are a negative prognostic factor in patients with non-small cell lung cancer (NSCLC). Although immune-checkpoint inhibitors (ICIs) have dramatically changed the therapeutic landscape of NSCLC, little information is available on BMs from NSCLC treated with ICIs alone or in association with bone-targeted therapy (BTT) such as zoledronate or denosumab.\n\nMethods\n\nFrom 2014 to 2020, 111 of the 142 patients with BMs secondary to NSCLC extrapolated from the prospective multicenter Italian BM Database were eligible for analysis. Information on blood count, comorbidities, and toxicity was retrospectively collected. The neutrophil-to-lymphocyte ratio (NLR) pre- and post-treatment was calculated. Survival was analyzed using the Kaplan–Meier method, with statistical significance of survival differences assessed using the log-rank test.\n\nResults\n\nMedian age was 66 (range, 42–84) years. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 0–1 in 79/111 patients. The majority of patients (89.2%) had adenocarcinoma histology. At a median follow-up of 47.4 months, median progression-free (mPFS) and overall survival (mOS) was 4.9 (95%CI, 2.8–10.0) and 11.9 (95%CI, 8.2–14.4) months, respectively. Forty-six (43.4%) patients with BM NSCLC underwent first- or further-line therapy with ICIs: 28 (60.8%) received nivolumab, 9 (19.6%) pembrolizumab, and 9 (19.6%) atezolizumab. Of the 46 patients treated with ICIs, 30 (65.2%) underwent BTT: 24 (80.0%) with zoledronate and 6 (20.0%) with denosumab. The ICI-alone group had an mOS of 15.8 months [95%CI, 8.2–not evaluable (NE)] vs. 21.8 months (95%CI, 14.5–not evaluable) for the ICI plus BTT group and 7.5 (95%CI, 6.1–10.9) months for the group receiving other treatments (p < 0.001). NLR ≤5 had a positive impact on OS.\n\nConclusion\n\nBTT appears to have a synergistic effect when used in combination with ICIs, improving patient survival.\n\nimmune checkpoint inhibitors\nNSCLC\nbone metastases\nzoledronate\ndenosumab\nlung cancer\n==== Body\npmcIntroduction\n\nLung cancer remains, independently of gender, one of the leading causes of cancer death worldwide (1). Despite the therapeutic breakthrough following the development of molecular-targeted therapies and immune checkpoint inhibitors (ICIs), the prognosis of patients with metastatic disease, albeit highly variable, remains poor (2). Previous studies and routine clinical practice have confirmed that ICIs show good tolerance and clinical efficacy in patients with advanced or recurrent non-small cell lung cancer (NSCLC) in both first- and further-line settings (3–9). Nevertheless, the effect on specific subgroups warrants further investigation.\n\nThe bone is one of the most common sites of metastasis in NSCLC, with 30–66% of patients developing bone metastases (BMs) during the course of their disease (10). BMs usually appear as mainly lytic, mainly osteoblastic, or mixed lesions and are excluded from Response Evaluation Criteria in Solid Tumors (RECIST) because they are difficult to measure (11). For this reason, in 2004, Hamaoka et al. developed the MD Anderson response classification criteria (MDA criteria), which are specific for the assessment of BMs (12, 13).\n\nRecently, a negative effect of BMs was seen in large populations of NSCLC patients treated with nivolumab, independently of the presence of brain or liver metastases or of poor Performance Status (PS) (14, 15). One explanation for this may be related to the immunosuppressive status of the tumor microenvironment (TME), which, in some patients, cannot be effectively reversed after ICI therapy (16).\n\nIn a preclinical breast cancer mouse model, a combination of anti-PD-1 antibody plus zoledronic acid induced a better antitumor response than untreated controls or single-agent treatment, without significant toxicity (17). The RANKL/RANK signaling pathway also appears to modulate the immune microenvironment and enhance the efficacy of anti-CTLA-4 and anti-PD-1 monoclonal antibodies against solid tumors. This positive synergistic effect has also been suggested in real-world studies on patients with metastatic melanoma and NSCLC (18, 19).\n\nIn addition to PD‐L1 expression, tumor mutational burden, and mismatch repair deficiency or microsatellite instability, several other potential biomarkers have been investigated or are currently under evaluation (20). Despite the large-scale use of immunotherapy in early and advanced NSCLC, there are still no validated or reliable predictive biomarkers of response or resistance to immunological agents (2).\n\nAlthough some authors have reported a predictive and prognostic role of the neutrophil-to-lymphocyte ratio (NLR) in patients with advanced NSCLC undergoing different systemic treatments, its role in NCSLC patients with BMs has yet to be clarified (21–26).\n\nGiven the above premises, we decided to investigate the efficacy and safety of ICIs in NSCLC patients with BMs treated with zoledronate or denosumab, usually referred to as bone-targeted therapy (BTT). We also explored the relationship between bone response and tumor control in patients treated with ICIs and evaluated the potential predictive and prognostic role of NLR in this population.\n\nMaterial and Methods\n\nStudy Design, Patients, and Treatment\n\nThe present analysis was performed on information extrapolated from our Bone Metastasis Database (BMDB) and from retrospectively collected data. The Italian BMDB was a prospective, observational multicenter project designed to collect data on BMs from solid tumors. Details on the project and its main inclusion and exclusion criteria have been described elsewhere (27).\n\nBriefly, we extrapolated data on patients aged ≥18 years, with a histological or cytological diagnosis of NSCLC, treated for advanced disease, and with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS). Patients included in the analysis had received at least one dose of ICIs as first- or further-line treatment. Blood count, comorbidities, presence of brain metastases, and safety information were retrospectively collected. NLR was calculated by dividing neutrophils and lymphocytes measured in peripheral blood. We recorded the NLR before ICI +/− BTT treatment and at response. This study was conducted in accordance with the International Conference of Harmonization Guidelines for Clinical Practice and the principles laid down in the 1964 Declaration of Helsinki. The protocol was approved by the Institutional Review Board of each participating center. All patients provided written informed consent.\n\nOutcome Measures\n\nTumor response was assessed using RECIST criteria version 1.1 (28). Investigator-assessed progression-free survival (PFS) and overall survival (OS) were evaluated. OS was calculated for all patients as the time between the fist diagnosis of BM and the date of death or date of last follow-up visit. PFS was calculated for the subgroup of patients undergoing ICI +/− BTT as the time from the start of treatment until the first documented evidence of progressive disease (PD) or death, whichever occurred first. Patients were monitored for adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. MDA criteria were used to evaluate bone response (12, 29). A multidisciplinary group dedicated to bone evaluation was involved to better clarify the bone response (30).\n\nStatistical Analysis\n\nObjective response rate (ORR), PFS, OS, and safety were assessed. Reverse Kaplan–Meier method was used to estimate median follow-up. Efficacy and safety analyses were conducted on all patients who received at least one ICI dose. The chi-square test was used to evaluate the association between patient characteristics and ORR. PFS and OS were estimated using the Kaplan–Meier method, and 95% confidence intervals (95%CIs) were reported. Differences between survival curves were evaluated with the log-rank test. The Wilcoxon signed-rank test was used to compare pre- and post-treatment NLR values.\n\nResults\n\nPatient Characteristics\n\nFrom January 2014 to December 2020, 142 patients with BMs were selected from the lung cancer cohort of our BMDB, and 111 (78.2%) were eligible for analysis. Median age was 66 years (range, 42–84). Forty-six (43.4%) of the 111 patients had been treated with an ICI, 28 (60.8%) with nivolumab, 9 (19.6%) with pembrolizumab, and 9 (19.6%) with atezolizumab ( Figure 1 ). Thirty-five patients only had one comorbidity (cardiovascular), while 44 patients had more than one comorbidity ( Table 1 and Supplementary Table S1 ).\n\nFigure 1 Flow chart of patient selection.\n\nTable 1 Demographics and clinical characteristics of NSCLC patients (n = 111).\n\n\tPatients (n = 111)\t\nMedian age, years, at diagnosis of first bone metastasis (range)\t66 (42–84)\t\n\tNo. (%)\t\nAge (years) at diagnosis of primary bone metastasis\t\t\n ≤65\t47 (42.3)\t\n >65\t64 (57.7)\t\nGender\t\t\n Male\t70 (63.1)\t\n Female\t41 (36.9)\t\nECOG PS at diagnosis of first bone metastasis\t\t\n 0\t26 (30.6)\t\n 1\t53 (62.4)\t\n ≥2\t6 (7.0)\t\n Unknown\t26\t\nHistology\t\t\n Adenocarcinoma\t99 (89.2)\t\n Squamous carcinoma\t9 (8.1)\t\n Large-cell carcinoma\t1 (0.9)\t\n Adenosquamous carcinoma\t1 (0.9)\t\n Undifferentiated\t1 (0.9)\t\nGrading (G)\t\t\n 1\t2 (4.1)\t\n 2\t13 (26.5)\t\n 3\t32 (65.3)\t\n 4\t2 (4.1)\t\n Unknown\t62\t\nPresence of visceral metastasis\t\t\n Yes\t91 (82.0)\t\n No\t20 (18.0)\t\nPresence of brain metastasis\t\t\n Yes\t18 (22.0)\t\n No\t64 (78.0)\t\n Unknown\t29\t\nPresence of comorbidity\t\t\n Cardiovascular\t35 (42.2)\t\n Cardiovascular + other*\t10 (12.0)\t\n Other§\t5 (6.0)\t\n None\t33 (39.8)\t\n Unknown\t28\t\n*Cardiovascular + other: 4 cardiovascular + diabetes; 1 cardiovascular + diabetes + renal impairment + other; 1 cardcardiovascular + diabetes + other; 2 cardiovascular + renal impairment; 2 cardiovascular + other.\n\n§Other: 2 diabetes, 1 renal impairment; 1 other, 1 diabetes + renal impairment.\n\nTwenty (18.0%) patients only had BMs. Of those with both BMs and visceral metastases (n = 91, 81.9%), 18 (22.0%) also had brain lesions. The majority of patients had mainly osteolytic BMs (n = 77, 77.0%), 6 (6.0%) had mainly osteoblastic BMs, and 17 (17.0%) had mixed BMs. This information was not available for 11 patients. Fifty-four (48.7%) patients had multiple (>6) bone metastases, 33 (29.7%) had two to six BMs, and 24 (21.6%) had only one BM. Only five patients (11.6%) received bone radiotherapy ( Supplementary Table S2 ).\n\nWe also recorded information on the molecular profile of tumors. Epidermal growth factor receptor (EGFR) mutation was present in 12 (12.5%) cases and wild type in 84 (87.5%). c-Ros oncogene 1 (ROS1) was rearranged in 3 (5.9%) patients and wild type in 48 (94.1%). Anaplastic lymphoma kinase (ALK) translocation was detected in 4 (5.6%) of the 67 patients in which it was evaluated. Ten (28.6%) of the 35 patients analyzed for KRAS (Kirsten rat sarcoma viral oncogene homolog) showed a mutation ( Table 2 ).\n\nTable 2 Biological characteristics of NSCLC patients (n = 111).\n\n\tNo. (%)\t\nEGFR\t\t\n Mutated\t12 (12.5)\t\n Wild type\t84 (87.5)\t\n Not evaluated\t12\t\n Unknown\t3\t\nALK\t\t\n Translocated\t4 (5.6)\t\n Wild type\t67 (94.4)\t\n Not evaluated\t26\t\n Unknown\t14\t\nROS1\t\t\n Rearranged\t3 (5.9)\t\n Wild type\t48 (94.1)\t\n Not evaluated\t30\t\n Unknown\t30\t\nKRAS\t\t\n Mutated\t10 (28.6)\t\n Wild type\t25 (71.4)\t\n Not evaluated\t48\t\n Unknown\t28\t\nPDL1 (1)\t\t\n <50%\t29 (76.3)\t\n ≥50%\t9 (23.7)\t\n Unknown\t73\t\nPDL1 (2)\t\t\n <1%\t14 (36.8)\t\n ≥1%\t24 (63.2)\t\n Unknown\t73\t\nEGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ROS1, c-ros oncogene 1; KRAS, Kirsten rat sarcoma viral oncogene homolog; PDL1, programmed death-ligand 1.\n\nPatient Outcome\n\nAt a median follow-up of 41.4 months, the median OS (mOS) of the entire population was 11.9 months (95%CI, 8.2–14.4). Of the 46 patient treated with ICIs, 30 (65.2%) underwent BTT, 24 (80.0%) with zoledronate, and 6 (20.0%) with denosumab. In all patients treated with ICI +/− BTT, the median PFS (mPFS) and mOS were 4.9 (95%CI, 2.8–10.0) and 19.2 (95%CI, 13.6–36.8) months, respectively.\n\nNo differences were seen according to the RECIST 1.1 criteria response in the two groups ( Supplementary Table S2 ).\n\nWith regard to bone response evaluated using MD Anderson criteria, 10 (43.5%) patients obtained a partial response (PR) following ICIs plus BTT, while only 2 (16.7%) obtained the same response when treated with ICIs alone. In the latter group, stable disease (SD) as a response was more frequent than in the combination group (p = 0.042) ( Supplementary Table S3 ).\n\nPatients treated with ICIs plus BTT had an mOS of 21.8 months (95%CI, 14.5–NE) and a 24-month OS rate of 45.7% (95%CI, 26.5–62.9); those undergoing ICIs alone showed an mOS of 15.8 months (95%CI, 8.2–NE) and a 24-month OS of 30.8% (95%CI, 9.9–54.8); and the group receiving other treatments had an mOS of 7.5 months (95%CI, 6.1–10.9) and a 24-month OS of 12.2% (95%CI, 5.4–21.9). This difference was statistically significant (p < 0.001) ( Figure 2 ).\n\nFigure 2 OS by treatment.\n\nThere was no difference in PFS between patients treated or not with BTT, although those receiving denosumab (n = 6) had a better mPFS (15.9 months; 95%CI, 5.1–not estimable) than patients treated with ICIs alone or with zoledronate (p = 0.068).\n\nPrognostic and Predictive Factors Evaluation\n\nThere were no differences in PFS and OS in relation to the number of BMs, type of BM, presence of visceral metastases, and age ( Figure 3 ). ECOG PS had an impact on OS but not on PFS ( Supplementary Table S5 ). No differences in PFS and OS were seen in relation to PDL1 status and tumor molecular profile, with the exception of KRAS mutations; patients with KRAS-mutated disease had an mOS of 8 months (95%CI, 4.3–8.2–NE) compared to 38.8 months (95%CI, 13.9–NE) for those with KRAS wild-type tumors ( Figure 4 and Tables 3 , 4 ).\n\nFigure 3 PFS by treatment.\n\nFigure 4 OS by KRAS status.\n\nTable 3 Univariable analysis of overall survival.\n\n\tNo. patients\tNo. events\tMedian OS(95%CI)\t12-month OS(95%CI)\t24-month OS (95%CI)\tp-valuelog-rank test\t\nOverall no. patients\t111\t88\t11.9 (8.2–14.4)\t49.7 (40.0–58.7)\t24.0 (16.3–32.6)\t–\t\nAge, years, at first diagnosis of BM\t\t\t\t\t\t\t\n <65\t47\t36\t13.9 (8.0–18.6)\t56.4 (40.8–69.3)\t29.1 (16.7–42.8)\t0.235\t\n ≥65\t64\t52\t10.3 (6.9–13.6)\t45.0 (32.5–56.7)\t20.4 (11.2–31.6)\t\nGender\t\t\t\t\t\t\t\n Male\t70\t54\t12.4 (8.0–15.4)\t50.9 (38.5–61.9)\t21.6 (12.6–32.2)\t0.842\t\n Female\t41\t34\t11.9 (5.8–15.8)\t47.7 (31.7–62.1)\t28.4 (15.2–43.1)\t\nECOG at first diagnosis of BM\t\t\t\t\t\t\t\n 0\t26\t14\t32.9 (12.8–NE)\t76.9 (55.7–88.9)\t57.2 (36.1–73.6)\t0.002\t\n 1\t53\t42\t12.6 (7.2–15.4)\t53.6 (39.1–66.0)\t20.6 (10.4–33.1)\t\n ≥2\t6\t6\t5.6 (3.9–NE)\t16.7 (0.7–51.7)\t0\t\nTreatment\t\t\t\t\t\t\t\n ICI alone\t16\t11\t15.8 (8.2–NE)\t63.0 (38.3–84.9)\t30.8 (9.9–54.8)\t<0.001\t\n ICI+Deno/Zol\t30\t17\t21.8 (14.5–NE)\t79.5 (59.9–90.2)\t45.7 (26.5–62.9)\t\n No ICI\t60\t55\t7.5 (6.1–10.9)\t33.1 (21.5–45.1)\t12.2 (5.4–21.9)\t\nVisceral metastasis\t\t\t\t\t\t\t\n No\t20\t16\t14.9 (5.8–27.6)\t53.6 (29.6–72.6)\t37.5 (16.9–58.2)\t0.413\t\n Yes\t91\t72\t11.9 (8.2–13.8)\t48.9 (38.1–58.7)\t20.9 (13.0–30.2)\t\nNo. BMs\t\t\t\t\t\t\t\n 1\t24\t19\t15.4 (7.5–19.4)\t59.9 (36.9–76.8)\t23.0 (8.4–41.8)\t0.761\t\n 2–6\t33\t26\t9.8 (6.5–13.8)\t48.5 (30.8–64.0)\t25.9 (12.4–41.7)\t\n >6\t54\t43\t10.9 (6.7–15.8)\t46.1 (32.4–58.7)\t23.1 (12.5–35.6)\t\nType of bone lesion\t\t\t\t\t\t\t\n Osteoblastic\t6\t6\t14.9 (1.6–NE)\t66.7 (19.5–90.4)\t–\t0.386\t\n Lytic\t77\t57\t11.5 (8.2–15.8)\t49.6 (37.8–60.3)\t29.6 (19.6–40.3)\t\n Mixed\t17\t15\t9.8 (5.4–15.4)\t47.1 (22.9–67.9)\t17.7 (4.3–38.3)\t\nEGFR status\t\t\t\t\t\t\t\n Mutated\t12\t10\t12.2 (5.6–NE)\t58.3 (27.0–80.1)\t25.0 (6.0–50.5)\t0.937\t\n Wild type\t84\t65\t12.6 (8.0–14.9)\t50.3 (39.0–60.5)\t25.4 (16.3–35.4)\t\nALK status\t\t\t\t\t\t\t\n Translocated\t4\t2\t–\t–\t–\t–\t\n Wild type\t67\t52\t12.7 (8.2–14.9)\t54.3 (41.5–65.4)\t26.5 (16.3–37.9)\t\nROS1 status\t\t\t\t\t\t\t\n Rearranged\t3\t2\t–\t–\t–\t\t\n Wild type\t48\t32\t13.9 (11.5–22.8)\t63.6 (48.1–75.6)\t35.8 (22.1–49.8)\t\nKRAS status\t\t\t\t\t\t\t\n Mutant\t10\t8\t8.0 (3.1–15.8)\t23.3 (3.6–52.9)\t11.7 (0.6–40.1)\t0.005\t\n Wild type\t25\t15\t36.8 (13.9–NE)\t80.0 (58.4–91.2)\t52.0 (31.3–69.2)\t\nPDL1 (1)\t\t\t\t\t\t\t\n <50%\t29\t19\t15.7 (12.6–48.6)\t78.8 (58.7–89.8)\t37.7 (19.9–55.4)\t0.995\t\n ≥50%\t9\t4\t13.9 (5.4–NE)\t63.5 (23.8–86.6)\t47.6 (12.3–76.9)\t\nPDL1 (2)\t\t\t\t\t\t\t\n <1%\t14\t8\t15.8 (13.6–NE)\t100.0\t42.8 (17.7–66.0)\t0.275\t\n ≥1%\t24\t15\t12.8 (8.2–NE)\t59.4 (36.3–76.5)\t38.2 (17.7–58.5)\t\nMutational status (1)\t\t\t\t\t\t\t\n EGFR mutated\t12\t10\t12.2 (5.6–NE)\t58.3 (27.0–80.0)\t25.0 (6.0–50.5)\t0.114\t\n ALK translocated\t4\t2\t–\t\t\t\n KRAS mutated\t10\t8\t8.0 (4.3–15.8)\t23.3 (3.6–52.9)\t11.7 (0.6–40.0)\t\n ROS1 rearranged\t3\t2\t–\t\t\t\n EGFR, ALK, KRAS and ROS1 wild type\t14\t10\t14.7 (9.6–NE)\t71.4 (40.6–88.2)\t42.9 (17.7–66.0)\t\nMutational status (2)\t\t\t\t\t\t\t\n EGFR mutated or ALK translocated or ROS1 rearranged\t19\t14\t17.4 (9.7–48.6)\t73.7 (47.9–88.1)\t36.8 (16.5–57.5)\t0.778\t\n None\t36\t24\t14.5 (9.6–27.2)\t62.5 (44.2–76.3)\t37.3 (21.1–53.4)\t\t\nPFS, progression-free survival; 95%CI, 95% confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BM, bone metastasis; ICI, immune checkpoint inhibitor; Deno, denosumab; Zol, zoledronate; NE, not estimable; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ROS1, c-ros oncogene 1; KRAS, Kirsten rat sarcoma viral oncogene homolog; PDL1, programmed death-ligand 1.\n\nTable 4 Univariable analysis of progression-free survival.\n\n\tNo. patients\tNo. events\tMedian PFS (95%CI)\t6-month PFS (95%CI)\t12-month PFS (95%CI)\tp-valuelog-rank test\t\nOverall no. patients\t46\t30\t4.9 (2.8–10.0)\t47.4 (29.9–61.4)\t29.9 (15.5–45.6)\t–\t\nAge, years, at first diagnosis of BM\t\t\t\t\t\t\t\n <65\t18\t11\t6.4 (2.0–11.9)\t57.1 (28.4–77.9)\t11.4 (0.7–39.0)\t0.698\t\n ≥65\t28\t19\t4.6 (2.2–15.9)\t40.6 (21.1–59.3)\t36.1 (17.6–55.0)\t\nGender\t\t\t\t\t\t\t\n Male\t35\t23\t4.9 (2.2–10.0)\t47.3 (28.3–64.2)\t25.8 (10.9–34.7)\t0.451\t\n Female\t11\t7\t5.1 (2.0–38.1)\t44.4 (13.6–71.9)\t44.4 (13.6–71.9)\t\nECOG PS at first diagnosis of BM\t\t\t\t\t\t\t\n 0\t15\t9\t7.2 (2.1–NE)\t54.5 (22.9–77.9)\t21.8 (3.5–50.1)\t0.955\t\n 1\t29\t21\t4.9 (1.9–13.3)\t43.5 (24.5–61.1)\t33.8 (16.3–52.3)\t\n ≥2\t2\t0\t–\t–\t–\t\nTreatment\t\t\t\t\t\t\t\n Only ICIs\t16\t10\t3.9 (1.9–6.4)\t26.7 (5.1–55.6)\t–\t0.068\t\n ICI+Deno\t6\t4\t15.9 (5.1–NE)\t83.3 (27.3–97.5)\t66.7 (19.5–90.4)\t\n ICI+Zol\t24\t16\t2.7 (1.8–13.3)\t45.0 (23.1–65.7)\t32.1 (12.8–53.4)\t\nPresence of visceral metastasis\t\t\t\t\t\t\t\n No\t7\t2\t–\t–\t–\t–\t\n Yes\t39\t28\t4.6 (2.2–9.3)\t43.6 (26.7–59.3)\t29.1 (14.4–45.5)\t\nNo. BMs\t\t\t\t\t\t\t\n 1\t11\t8\t4.3 (1.7–16.1)\t50.0 (18.4–75.3)\t25.0 (4.1–54.9)\t0.343\t\n 2–6\t15\t8\t4.9 (2.4–NE)\t45.5 (16.7–70.7)\t36.4 (11.2–62.7)\t\n >6\t20\t14\t5.1 (2.2–13.3)\t45.4 (20.9–67.2)\t27.2 (7.4–52.1)\t\nType of bone lesion\t\t\t\t\t\t\t\n Osteoblastic\t1\t0\t–\t–\t–\t–\t\n Lytic\t38\t24\t6.4 (3.6–11.9)\t51.9 (33.3–67.7)\t31.9 (15.8–49.4)\t\n Mixed\t6\t5\t1.8 (1.7–NE)\t20.0 (0.8–58.2)\t20.0 (0.8–58.2)\t\n Unknown\t1\t1\t–\t–\t–\t\t\nEGFR status\t\t\t\t\t\t\t\n Mutant\t1\t0\t–\t–\t–\t–\t\n Wild–type\t38\t24\t5.1 (2.2–11.9)\t47.8 (29.5–64.0)\t31.9 (15.8–49.2)\t\nALK status\t\t\t\t\t\t\t\n Translocated\t0\t–\t–\t–\t–\t–\t\n Wild type\t35\t22\t4.9 (2.4–9.3)\t44.7 (26.5–62.2)\t29.8 (13.1–48.6)\t\nROS1 status\t\t\t\t\t\t\t\n Rearranged\t1\t–\t–\t–\t–\t–\t\n Wild–type\t30\t20\t5.1 (2.7–13.3)\t48.1 (27.7–65.9)\t32.1 (14.1–51.7)\t\nKRAS status\t\t\t\t\t\t\t\n Mutant\t8\t3\t4.9 (1.7–NE)\t44.4 (6.6–78.5)\t44.4 (6.6–78.5)\t0.565\t\n Wild-type\t13\t11\t7.2 (2.4–11.9)\t61.5 (30.8–81.8)\t20.5 (33.3–47.8)\t\nPDL1 (1)\t\t\t\t\t\t\t\n <50%\t23\t15\t4.4 (2.2–7.2)\t37.1 (16.3–58.2)\t14.9 (2.6–36.8)\t0.810\t\n ≥50%\t7\t6\t5.1 (1.7–NE)\t42.8 (9.8–73.4)\t42.8 (9.8–73.4)\t\nPDL1 (2)\t\t\t\t\t\t\t\n <1%\t12\t8\t4.6 (1.6–9.3)\t50.0 (18.4–75.3)\t12.5 (0.7–41.8)\t0.941\t\n ≥1%\t18\t13\t4.3 (2.2–13.3)\t30.9 (10.5–54.3)\t30.9 (10.5–54.3)\t\t\nPFS, progression-free survival; 95%CI, 95% confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; BM, bone metastasis; ICI, immune checkpoint inhibitor; Deno, denosumab; Zol, zoledronate; NE, not estimable; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ROS1, c-ros oncogene 1; KRAS, Kirsten rat sarcoma viral oncogene homolog; PDL1, programmed death-ligand 1.\n\nThe mean NLR value in patients treated with ICI +/− BTT was 4.08 [standard deviation (SD), 1.83]. A statistically significant difference in OS was observed according to the basal value of NLR ( Figure 5A ). In particular, patients treated with ICIs alone or ICIs + BTT and with an NLR ≤5 had a better mOS (21.8 months; 95%CI, 15.4–NE) than those with an NLR >5 (14.5 months; 95%CI, 5.6–32.9). This difference was significant (p = 0.042) ( Supplementary Table S6 ). There was also a positive trend for PFS, with an mPFS of 9.3 months (95%CI, 3.3–25.4) in the former group and 2.0 months (95%CI, 1.7–13.2) in the latter group ( Figure 5B ) (p = 0.086). However, patients who obtained PR or SD on ICIs +/− BTT showed a decrease in NLR with respect to NLR at best response [basal NLR value, 3.52 (SD, 1.56) vs. best response, 2.78 (SD, 1.64)] (p = 0.030) ( Supplementary Figure S1 ). Conversely, NLR increased in patients progressing after ICIs +/− BTT [mean basal NLR value, 3.65 (SD, 1.42) vs. 5.18 at progression (SD, 2.79)] (p = 0.027).\n\nFigure 5 (A) OS and (B) PFS by NLR values.\n\nSafety\n\nPatients treated with ICIs had mild and reversible toxicities ( Table 5 ). In the combination group, six cases of grade (G)1 hypocalcemia, three cases of G1 renal toxicity, and one case of osteonecrosis of the jaw were reported. One case of G2 renal creatinine increase was recorded in the ICI-alone group. There were few cases of G3 toxicities (arthralgia, increased amylase and lipase, and dermatitis) related to ICI therapy, all of which were successfully resolved. The safety profile was consistent with literature data.\n\nTable 5 Toxicities recorded in both ICI and ICI+BTT treatments.\n\nToxicity\tGrade\tTotal No. (%)\t\n1No. (%)\t2No. (%)\t3No. (%)\t\nArthralgia\t1 (2.2)\t0 (0.0)\t1 (2.2)\t2 (4.3)\t\nAsthenia\t2 (4.3)\t0 (0.0)\t1 (2.2)\t3 (6.5)\t\nDermatitis\t0 (0.0)\t0 (0.0)\t1 (2.2)\t1 (2.2)\t\nDiarrhea\t2 (4.3)\t1 (2.2)\t0 (0.0)\t3 (6.5)\t\nDypnea\t0 (0.0)\t1 (2.2)\t0 (0.0)\t1 (2.2)\t\nInfection\t0 (0.0)\t1 (2.2)\t0 (0.0)\t1 (2.2)\t\nCreatinine increase\t5 (10.9)\t1 (2.2)\t0 (0.0)\t6 (13.0)\t\nHyperamylasemia\t1 (2.2)\t0 (0.0)\t1 (2.2)\t2 (4.3)\t\nHypertransaminasemia\t2 (4.3)\t0 (0.0)\t1 (2.2)\t3 (6.5)\t\nHypophosphatemia\t0 (0.0)\t1 (2.2)\t0 (0.0)\t1 (2.2)\t\nHypothyroidism\t1 (2.2)\t0 (0.0)\t0 (0.0)\t1 (2.2)\t\nNeuropathy\t0 (0.0)\t1 (2.2)\t0 (0.0)\t1 (2.2)\t\nNeutropenia\t0 (0.0)\t1 (2.2)\t0 (0.0)\t1 (2.2)\t\nPneumonitis\t0 (0.0)\t2 (4.3)\t0 (0.0)\t2 (4.3)\t\nSkin rash\t1 (2.2)\t1 (2.2)\t0 (0.0)\t2 (4.3)\t\nLipase increase\t1 (2.2)\t0 (0.0)\t1 (2.2)\t2 (4.3)\t\nSepsis\t0 (0.0)\t0 (0.0)\t1 (2.2)\t1 (2.2)\t\nSkin toxicity\t0 (0.0)\t0 (0.0)\t1 (2.2)\t1 (2.2)\t\n\nDiscussion\n\nICIs have dramatically changed the treatment of patients with NSCLC (2). However their immune-mediated antitumor activity is dependent on several complex mechanisms, also involving the microenvironment. In BMs, the microenvironment is represented by a particular landscape characterized by reciprocal interactions between cancer cells, local stromal cells, immune cells, and several other factors such as osteoclasts (members of the mononuclear-macrophage family) and cytokines (31).\n\nThe results from two large phase III studies, CheckMate 227 and CheckMate 057, not only suggested that bone involvement may be a negative prognostic factor in patients with metastatic NSCLC, but also that the presence of BMs could be predictive of a poor response to ICIs (32, 33). However, none of the randomized trials on immunotherapy, including CheckMate 227, stratified patients on the basis of the site of metastasis, thus precluding any definitive conclusions from being drawn (34).\n\nIn our study, the poor outcome of NSCLC patients with bone metastases was confirmed in patients treated or not with ICIs, the latter showing an mOS of 7.8 months.\n\nThis interest in defining the role of immunotherapy on the basis of the site of metastasis and, in particular, the bone (10–12) prompted us to explore this area using data extrapolated from the Italian BMDB. A strong point in our favor is that the characteristics, outcome, and safety data of the patients who received ICIs are consistent with literature data (35), thanks to the multicenter nature of our BMDB, the largest of its kind in Italy.\n\nA recent study stressed the concept of the negative modulation of the immune response by BMs in NSCLC (15). However, data on the concomitant use of BTTs were not collected. The hypothesis of the potential immunomodulatory effect of BTTs such as denosumab and zoledronate has been gaining ground worldwide over the past two decades.\n\nThere is evidence from preclinical research into prostate cancer and breast cancer mouse models of the immunomodulatory effect of zoledronate and of its enhancement of the antitumor efficacy of the PD-1 blockade (17). Nitrogen-containing bisphosphonates (N-BPs) such as zoledronate inhibit farnesyl pyrophosphate synthesis in the mevalonate pathway, leading to increased levels of isopentenyl pyrophosphate in tumor cells, which renders them targets of Vγ9Vδ2 T cells, and thus contributing to innate immunity (36).\n\nAlthough denosumab added to chemotherapy did not modify OS with respect to CT alone in the phase III SPLENDOUR trial, we observed that both zoledronate and denosumab improved ICI efficacy with respect to ICI alone, with a sustained OS and an increased bone response rate evaluated by MD Anderson criteria. Conversely, consistent with data from clinical trials on ICIs, PFS in our patients was not improved (19, 37).\n\nAnother point to be explored is that bone response seems to be correlated to medical therapy due to the low rate of patients treated with radiotherapy.\n\nBearing in mind the caveat of the limited number of patients involved in our study, we nonetheless observed that denosumab worked rapidly, whereas zoledronate exerted its action after at least 6 months, which fits in with the known slow effect of this drug on bone homeostasis (38). These data strongly suggest that targeting the microenvironment to improve the efficacy of immunotherapy is a strategy worth considering. Another important indication comes from the NLR evaluated in our population. In patients with BMs from NSCLC receiving ICIs, an NLR cutoff ≤5 showed prognostic significance. Furthermore, this value changed in conjunction with a change in sensitivity to therapy, increasing in the event of disease progression or decreasing when response occurred (35).\n\nOur study has a number of limitations, mainly that of limited sample size and the retrospective nature of the analysis (of note, the BMDA was prospectively built). Moreover, PD-L1 expression was not available for all patients. Despite these weaknesses, our data support the hypothesis that BTTs increase the activity of ICIs and reverse the negative impact of BMs on patient outcome. Larger prospective datasets or prospective randomized clinical trials are needed to provide more solid evidence of BTT potential.\n\nThere are still several open questions to be answered in the area of NSCLC, in particular how to overcome primary and acquired resistance to immunotherapy. This is often related to the status of the host’s immune homeostasis and involves myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and T-regulatory cells, all of which play immune-suppressive roles. The use of zoledronate or denosumab in combination with ICIs could represent a potentially useful strategy to modulate the microenvironment and, consequently, the immune response.\n\nConclusions\n\nOur data suggest that BTT could potentially increase the efficacy of immunotherapy in NSCLC patients with BMs. Prospective trials are warranted to further investigate this finding.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThis study was reviewed and approved by the IRCCS IRST Ethics Committee (number of approval 1783/2014 of 20/03/2014). The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nAB and TI conceived the idea for and designed the study. AB, JM, SS, FA, FR, VG, MRF, MB, and MF enrolled patients. FF performed the statistical analyses. VF, LM, and CS carried out the literature review. AB drafted the manuscript. All authors critically reviewed the manuscript, providing important feedback, and all read and approved the final version for submission.\n\nConflict of Interest\n\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\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.697298/full#supplementary-material\n\nSupplementary Figure 1 Differences between pre-treatment NLR values and NLR values (A) at disease progression (p-value from Wilcoxon signed-rank test: 0.027) and (B) at response (p-value from Wilcoxon signed-rank test: 0.030).\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Malvezzi M Bertuccio P Rosso T Rota M Levi F La Vecchia C . European Cancer Mortality Predictions for the Year 2015: Does Lung Cancer Have the Highest Death Rate in EU Women? Ann Oncol (2015) 26 (4 ):779–86. doi: 10.1093/annonc/mdv001\n2 Zappa C Mousa SA . Non-Small Cell Lung Cancer: Current Treatment and Future Advances. Transl Lung Cancer Res (2016) 5 (3 ):288–300. doi: 10.21037/tlcr.2016.06.07 27413711\n3 Reck M Rodríguez-Abreu D Robinson AG Hui R Csőszi T Fülöp A . Pembrolizumab Versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med (2016) 375 (19 ):1823–33. doi: 10.1056/NEJMoa1606774\n4 Gandhi L Rodríguez-Abreu D Gadgeel S Esteban E Felip E De Angelis F . Pembrolizumab Plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med (2018) 378 (22 ):2078–92. doi: 10.1056/NEJMoa1801005\n5 Socinski MA Jotte RM Cappuzzo F Orlandi F Stroyakovskiy D Nogami N . Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med (2018) 378 (24 ):2288–301. doi: 10.1056/NEJMoa1716948\n6 Herbst RS Baas P Kim DW Felip E Pérez-Gracia JL Han JY . Pembrolizumab Versus Docetaxel for Previously Treated, PD-L1-Positive, Advanced Non-Small-Cell Lung Cancer (KEYNOTE-010): A Randomised Controlled Trial. Lancet (2016) 387 (10027 ):1540–50. doi: 10.1016/S0140-6736(15)01281-7\n7 Rittmeyer A Barlesi F Waterkamp D Park K Ciardiello F von Pawel J . Atezolizumab Versus Docetaxel in Patients With Previously Treated Non-Small-Cell Lung Cancer (OAK): A Phase 3, Open-Label, Multicentre Randomised Controlled Trial. Lancet (2017) 389 (10066 ):255–65. doi: 10.1016/S0140-6736(16)32517-X\n8 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE . Nivolumab Versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med (2015) 373 (17 ):1627–39. doi: 10.1056/NEJMoa1507643\n9 Brahmer J Reckamp KL Baas P Crinò L Eberhardt WE Poddubskaya E . Nivolumab Versus Docetaxel in Advanced Squamous-Cell non-Small-Cell Lung Cancer. N Engl J Med (2015) 373 (2 ):123–35. doi: 10.1056/NEJMoa1504627\n10 Kuchuk M Addison CL Clemons M Kuchuk I Wheatley-Price P . Incidence and Consequences of Bone Metastases in Lung Cancer Patients. J Bone Oncol (2013) 2 (1 ):22–9. doi: 10.1016/j.jbo.2012.12.004\n11 Santini D Barni S Intagliata S Falcone A Ferraù F Galetta D . Natural History of Non-Small-Cell Lung Cancer With Bone Metastases. Sci Rep (2015) 5 :18670. doi: 10.1038/srep18670 26690845\n12 Hamaoka T Costelloe CM Madewell JE Liu P Berry DA Islam R . Tumour Response Interpretation With New Tumour Response Criteria vs the World Health Organisation Criteria in Patients With Bone-Only Metastatic Breast Cancer. Br J Cancer (2010) 102 (4 ):651–7. doi: 10.1038/sj.bjc.6605546\n13 Costelloe CM Chuang HH Madewell JE Ueno NT . Cancer Response Criteria and Bone Metastases: RECIST 1.1, MDA and PERCIST. J Cancer (2010) 1 :80–92. doi: 10.7150/jca.1.80 20842228\n14 da Silva LM da Silva GT Bergmann A Costa GJ Zamboni MM Santos Thuler LC . Impact of Different Patterns of Metastasis in Non-Small-Cell Lung Cancer Patients. Future Oncol (2021) 17 (7 ):775–82. doi: 10.2217/fon-2020-0587\n15 Landi L D’Incà F Gelibter A Chiari R Grossi F Delmonte A . Bone Metastases and Immunotherapy in Patients With Advanced Non-Small-Cell Lung Cancer. J Immunother Cancer (2019) 7 (1 ):316. doi: 10.1186/s40425-019-0793-8 31752994\n16 Sterling JA Edwards JR Martin TJ Mundy GR . Advances in the Biology of Bone Metastasis: How the Skeleton Affects Tumor Behavior. Bone (2011) 48 (1 ):6–15. doi: 10.1016/j.bone.2010.07.015 20643235\n17 Li Y Du Y Sun T Xue H Jin Z Tian J . PD-1 Blockade in Combination With Zoledronic Acid to Enhance the Antitumor Efficacy in the Breast Cancer Mouse Model. BMC Cancer (2018) 18 (1 ):669. doi: 10.1186/s12885-018-4412-8 29921237\n18 Simatou A Sarantis P Koustas E Papavassiliou AG Karamouzis MV . The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer With Immune Checkpoint Inhibitors and Anti-RANKL. Int J Mol Sci (2020) 21 (20 ):7570. doi: 10.3390/ijms21207570\n19 Liede A Hernandez RK Wade SW Bo R Nussbaum NC Ahern E . An Observational Study of Concomitant Immunotherapies and Denosumab in Patients With Advanced Melanoma or Lung Cancer. Oncoimmunology (2018) 7 (12 ):e1480301. doi: 10.1080/2162402X.2018.1480301 30524886\n20 Havel JJ Chowell D Chan TA . The Evolving Landscape of Biomarkers for Checkpoint Inhibitor Immunotherapy. Nat Rev Cancer (2019) 19 (3 ):133–50. doi: 10.1038/s41568-019-0116-x\n21 Ishihara M Ochiai R Haruyama T Sakamoto T Tanzawa S Honda T . Pretreatment Neutrophil-to-Lymphocyte Ratio Predicts Treatment Efficacy and Prognosis of Cytotoxic Anticancer Drugs, Molecular Targeted Drugs, and Immune Checkpoint Inhibitors in Patients With Advanced non-Small Cell Lung Cancer. Transl Lung Cancer Res (2021) 10 (1 ):221–32. doi: 10.21037/tlcr-20-777\n22 Ksienski D Wai ES Alex D Croteau NS Freeman AT Chan A . Prognostic Significance of the Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio for Advanced Non-Small Cell Lung Cancer Patients With High PD-L1 Tumor Expression Receiving Pembrolizumab. Transl Lung Cancer Res (2021) 10 (1 ):355–67. doi: 10.21037/tlcr-20-541\n23 Bongiovanni A Foca F Fantini M Forcignanò MR Artioli F Berardi R . First Prospective Data on Breast Cancer Patients From the Multicentre Italian Bone Metastasis Database. Sci Rep (2021) 11 (1 ):4329. doi: 10.1038/s41598-021-83749-1 33619285\n24 Petrova MP Eneva MI Arabadjiev JI Conev NV Dimitrova EG Koynov KD . Neutrophil to Lymphocyte Ratio as a Potential Predictive Marker for Treatment With Pembrolizumab as a Second Line Treatment in Patients With Non-Small Cell Lung Cancer. Biosci Trends (2020) 14 (1 ):48–55. doi: 10.5582/bst.2019.01279 32023563\n25 Giustini N Bazhenova L . Recognizing Prognostic and Predictive Biomarkers in the Treatment of Non-Small Cell Lung Cancer (NSCLC) With Immune Checkpoint Inhibitors (Icis). Lung Cancer (Auckl) (2021) 12 :21–34. doi: 10.2147/LCTT.S235102 33790679\n26 Fukui T Okuma Y Nakahara Y Otani S Igawa S Katagiri M . Activity of Nivolumab and Utility of Neutrophil-to-Lymphocyte Ratio as a Predictive Biomarker for Advanced Non-Small-Cell Lung Cancer: A Prospective Observational Study. Clin Lung Cancer (2019) 20 (3 ):208–14.e2. doi: 10.1016/j.cllc.2018.04.021 29803573\n27 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R . New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1). Eur J Cancer (2009) 45 (2 ):228–47. doi: 10.1016/j.ejca.2008.10.026\n28 U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (V4.03: June 14, 2010). Available at: https://www.eortc.be/services/doc/ctc/ctcae_4.03_2010-06-14_quickreference_5x7.pdf.\n29 Ibrahim T Mercatali L Amadori D . Bone and Cancer: The Osteoncology. Clin Cases Miner Bone Metab (2013) 10 (2 ):121–3.\n30 Bongiovanni A Recine F Fausti V Foca F Casadei R Falasconi MC . Ten-Year Experience of the Multidisciplinary Osteoncology Center. Support Care Cancer (2019) 27 (9 ):3395–402. doi: 10.1007/s00520-019-4635-5\n31 Hellmann MD Ciuleanu TE Pluzanski A Lee JS Otterson GA Audigier-Valette C . Nivolumab Plus Ipilimumab in Lung Cancer With a High Tumor Mutational Burden. N Engl J Med (2018) 378 (22 ):2093–104. doi: 10.1056/NEJMoa1801946\n32 Peters S Cappuzzo F Horn L Paz-Ares L Borghaei H Barlesi F . OA03.05 Analysis of Early Survival in Patients With Advanced non-Squamous NSCLC Treated With Nivolumab vs Docetaxel in Checkmate 057. J Thor Oncol (2017) 12 (1 ):S253. doi: 10.1016/j.jtho.2016.11.241\n33 Yang K Li J Bai C Sun Z Zhao L . Efficacy of Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer Patients With Different Metastatic Sites: A Systematic Review and Meta-Analysis. Front Oncol (2020) 10 :2020.01098. doi: 10.3389/fonc.2020.01098\n34 Hsu ML Naidoo J . Principles of Immunotherapy in Non-Small Cell Lung Cancer. Thorac Surg Clin (2020) 30 (2 ):187–98. doi: 10.1016/j.thorsurg.2020.01.009\n35 Silva-Santos B Serre K Norell H . γδ T Cells in Cancer. Nat Rev Immunol (2015) 15 (11 ):683–91. doi: 10.1038/nri3904\n36 Peters S Danson S Hasan B Dafni U Reinmuth N Majem M . A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial. J Thorac Oncol (2020) 15 (10 ):1647–56. doi: 10.1016/j.jtho.2020.06.011\n37 Daubiné F Le Gall C Gasser J Green J . Antitumor Effects of Clinical Dosing Regimens of Bisphosphonates in Experimental Breast Cancer Bone Metastasis. J Natl Cancer Inst (2007) 99 (4 ):322–30. doi: 10.1093/jnci/djk054\n38 Dalle Carbonare L Zanatta M Gasparetto A Valenti MT Clézardin P . Safety and Tolerability of Zoledronic Acid and Other Bisphosphonates in Osteoporosis Management. Drug Healthc Patient Saf (2010) 2 :121–37. doi: 10.2147/DHPS.S6285\n\n",
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"abstract": "We present a patient who, over the course of 35 years, presented with repeated episodes of ileus and melena and was misdiagnosed several times, leading to several surgeries. Macroscopic and microscopic features of his resected intestine were compatible with cryptogenic multifocal ulcerous stenosis enteritis (CMUSE), but additional angioectatic lesions were also noted. The patient responded dramatically to hormonal therapy consisting of ethinylestradiol and norethisterone. To our knowledge, this is the first reported case of CMUSE that has shown response to hormonal therapy. We suggest that this is a variant of CMUSE in which vasculopathy plays a role in the pathogenesis.",
"affiliations": "Department of Gastroenterology and Hepatobiliary Sciences, Siksha O. Anusandhan University Institute of Medical Sciences and SUM Hospital, Bhubaneswar, India.;Department of Gastroenterology and Hepatobiliary Sciences, Siksha O. Anusandhan University Institute of Medical Sciences and SUM Hospital, Bhubaneswar, India.;Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, India.;Department of Gastroenterology and Hepatobiliary Sciences, Siksha O. Anusandhan University Institute of Medical Sciences and SUM Hospital, Bhubaneswar, India.",
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"fulltext": "\n==== Front\nACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2017.4410.14309/crj.2017.44Case ReportSmall BowelCryptogenic Multifocal Ulcerous Stenosing Enteritis (CMUSE): A Tale of Three Decades Singh et alCryptogenic Multifocal Ulcerous Stenosing EnteritisSingh Ayaskanta MBBS, MD, DM1Sahu Manoj Kumar MBBS, MD, DM1Panigrahi Manas Kumar MBBS, MD, DM2Misra Debasis MBBS, MD, DM11 Department of Gastroenterology and Hepatobiliary Sciences, Siksha O. Anusandhan University Institute of Medical Sciences and SUM Hospital, Bhubaneswar, India2 Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, IndiaCorrespondence: Ayaskanta Singh, Department of Gastroenterology, IMS and SUM Hospital, Bhubaneswar, India (ayaskant1ce@gmail.com).2017 15 3 2017 4 e4420 11 2016 2 2 2017 Copyright © Singh et al.2017This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/We present a patient who, over the course of 35 years, presented with repeated episodes of ileus and melena and was misdiagnosed several times, leading to several surgeries. Macroscopic and microscopic features of his resected intestine were compatible with cryptogenic multifocal ulcerous stenosis enteritis (CMUSE), but additional angioectatic lesions were also noted. The patient responded dramatically to hormonal therapy consisting of ethinylestradiol and norethisterone. To our knowledge, this is the first reported case of CMUSE that has shown response to hormonal therapy. We suggest that this is a variant of CMUSE in which vasculopathy plays a role in the pathogenesis.\n==== Body\nIntroduction\nCryptogenic multifocal ulcerous stenosing enteritis (CMUSE) affects the small bowel exclusively and is characterized by repeated bouts of small bowel obstruction due to strictures and gastrointestinal bleeds (GIBs) due to superficial ulcerations.1 Chronic nonspecific ulcers of the small intestine (CNSU) is a term recognized by Japanese gastroenterologists that describes a similar disease entity.2 It is an extremely rare and underdiagnosed disease. CMUSE is frequently misdiagnosed with other diseases involving the small bowel, especially Crohn’s disease.3 Diagnosis is established by pathological evaluation after surgery or by double-balloon enteroscopy or capsule endoscopy.\n\nCase Report\nAs a teenager in 1982, our patient, now 52 years old, presented with intermittent colicky pain, constipation, and abdominal distension. He also had intermittent bouts of melena, during which his hemoglobin dropped to ∼6 g/dL, requiring multiple blood transfusions. There was no history of any nonsteroidal anti-inflammatory drug (NSAID) intake. Multiple gastroduodenoscopies revealed duodenal ulcers, for which proton pump inhibitors were prescribed on regular basis.\n\nThese symptoms persisted for 7 years, but during an episode of small bowel obstruction and GIB he underwent a laparotomy at a local hospital where jejunal ulcerations were identified and resection anastomosis was done. Biopsy of the resected specimen showed nonspecific ulcers. After surgery, however, there was no symptomatic relief. He was extensively evaluated during this period. Gastroduodenoscopy, colonoscopy, abdominal computed tomography, and Meckel’s scans were all normal.\n\nFor the next 10 years, the patient underwent several abdominal surgeries with no clinical improvement. He consulted several gastroenterologists. Barium studies revealed small bowel strictures and ulcerations. Small bowel tuberculosis (TB) was suspected, and antitubercular drugs were given empirically. As the patient didn’t respond, Crohn’s disease became the leading diagnosis. He received corticosteroids, mesalamine, and azathioprine for a prolonged period. His small bowel symptoms didn’t improve, but he developed complications of steroids such as cataracts and uncontrolled diabetes. He also developed features of chronic diarrhea and hypoproteinemia.\n\nCapsule endoscopy showed a stricture along with superficial ulceration of the mucosa in the mid-jejunal area (Figure 1). The capsule became lodged in the stricture and was retrieved using an enteroscope. Diagnostic laparotomy, adhesiolysis, on-table enteroscopy, and resection anastomosis of distal ileal segment were performed in 2005.The resected ileal segment showed multiple, superficial, circular and linear ulcers and sharply demarcated ulcers with normal surrounding mucosa. The microscopy showed nonspecific ulcerations and a few angioectasia (Figure 2). The ectasias on pathology did not show any evidence of obliteration or hypertrophy, which is inconsistent with diagnoses of Crohn’s disease or TB.\n\nFigure 1 Capsule endoscopy showing superficial jejunal ulcer with stricture.\n\nFigure 2 Histology showing superficial mucosal ulcerations, inflammatory infiltrates, and angioectasia (arrow).\n\nThus, from the clinical features, endoscopic pictures, and biopsy evaluation, a diagnosis of CMUSE was made. The patient was kept on a nonresidual diet, medium chain triglycerides, high protein, and dietary supplementations. His obstructive symptoms improved and hypoproteinemia was corrected. Periodic GIBs persisted, however, for which he received blood transfusions as before. Five years later, hormonal therapy consisting of ethinyl estradiol and norethisterone successfully addressed his angioectasias stopped his GIBs. For the past 7 years he has been on hormonal therapy and a nonresidual diet, and he is symptom-free. As a complication of hormonal therapy, however, he developed gynecomastia and loss in libido, so the therapy was stopped. The melena reappeared, and the hormonal therapy resumed.\n\nDiscussion\nExclusive small bowel disease always poses a diagnostic dilemma as most of the small intestine is not easily assessable. Enteroscopy and capsule endoscopy are uncovering new specific diseases, many of which had been traditionally characterized as Crohn’s disease or intestinal TB or NSAIDS enteropathy. CMUSE was first described in 1964.1 Clinico-pathological features of CMUSE have been summarized as unexplained small intestinal strictures found in adolescent and middle-aged subjects, superficial ulceration of the mucosa and submucosa, chronic or relapsing clinical course, a lack of biological signs of systemic inflammatory reaction, and beneficial effect of systemic glucocorticosteroids.\n\nJapanese gastroenterologists, however, who prefer the term CNSU, believe that these patients do not respond to steroid therapy.2 This is an extremely rare condition, with approximately 40 cases compatible with CMUSE published worldwide.2,4-5 Only 12 cases of CMUSE were reported in France between 1965 and 1993.3 Most of the reported cases have a very prolonged disease course interspersed with relapses and remission, and most of the patients undergo multiple surgeries. Matsumoto et al.2 reported a single case of CMUSE followed for 40 years since 1963, and that patient underwent several resections of the small bowel.\n\nOur patient meets the diagnostic criteria for CMUSE/CNSU, but he is unique, however, because of the presence of angioectasia in the histological specimen of the small bowel.6 Some suggestions indicate that this disease is a type of atypical “vasculitis,” although many have refuted this hypothesis.3 Complement (C2) deficiency has been associated with systemic vasculitis and CMUSE.7 The genetic basis of the disease was evaluated in a pair of affected siblings, and mutation in the cytosolic phospholipase A2 gene was recognized.8 Despite these evidences, the exact pathogenesis is still unclear. We suggest that this patient may represent a variant of CMUSE where vascular lesions (angioectasia) play a role and these patients may respond to hormonal therapy. To our knowledge, this is the first reported case where hormonal therapy has been tried and has been successful in decreasing gastrointestinal blood loss and controlling disease morbidity. The treatment of CMUSE remains symptomatic. Enteral and parenteral nutrition along with iron supplementation have been tried before and are transiently effective.9 Our patient responded to nonresidual diet and medium chain triglycerides. The response to corticosteroids is disappointing, and most patients undergo multiple surgeries. In one case, anti–tumor necrosis factor therapy (infliximab) was successful in inducing remission in a steroid-refractory case of CMUSE.10\n\nIn conclusion, not all cases of small bowel disease are Crohn’s disease, TB, or NSAID enteropathy. Although CMUSE is a rare clinical entity, more extensive imaging of the small bowel provided by double-balloon enteroscopy and capsule endoscopy may increase detection and diagnosis. Better understanding regarding the underlying pathology may help identify and treat this condition.\n\nDisclosures\nAuthor contributions: A. Singh collected the data, and wrote and edited the manuscript. MK Sahu collected the data, wrote and edited the manuscript, and is the article guarantor. MK Panigrahi wrote the manuscript and reviewed the literature. D. Misra edited the manuscript.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1 Debray C , Besancon F , Hardouin JP , Martin E , Marche C , Khoury K \n[Cryptogenetic plurifocal ulcerative stenosing enteritis.] . Arch Mal Appar Dig Mal Nutr . 1964 ;53 :193 –206 .14140712 \n2 Matsumoto T , Iida M , Matsui T , Yao T \nChronic nonspecific multiple ulcers of the small intestine: A proposal of the entity from Japanese gastroenterologists to Western enteroscopists . Gastrointest Endosc . 2007 ;66 (3 Suppl ):S99 –S107 .17709045 \n3 Perlemuter G , Guillevin L , Legman P , Weiss L , Couturier D , Chaussade S \nCryptogenetic multifocal ulcerous stenosing enteritis: An atypical type of vasculitis or a disease mimicking vasculitis . Gut . 2001 ;48 :333 –8 .11171822 \n4 Spencer H , Kitsanta P , Riley S \nCryptogenic multifocal ulcerous stenosing enteritis . J R Soc Med . 2004 ;97 :538 –40 .15520150 \n5 Fraile G , Norman F , Reguero ME , Defargues V , Redondo C \nCryptogenic multifocal ulcerous stenosing enteritis (CMUSE) in a man with a diagnosis of X-linked reticulate pigmentary disorder(PDR) . Scand J Gastroenterol . 2008 ;43 :506 –10 .18365917 \n6 Yao T , Iida M , Matsumoto T. \nChronic hemorrhagic ulcers of the small intestine or chronic nonspecific multiple ulcers of the small intestine . In: Yao T , Iida M , editors. Diseases of the small intestine . Tokyo : Igaku-Shoin ; 2004 :176 –86 .\n7 Perlemuter G , Chaussade S , Soubrane O , et al \nMultifocal stenosing ulcerations of the small intestine revealing vasculitis associated with C2 deficiency . Gastroenterology . 1996 ;110 (5 ):1628 –32 .8613071 \n8 Brooke MA , Longhurst HJ , Plagnol V , et al \nCryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α . Gut . 2014 ;63 (1 ):96 –104 .23268370 \n9 Kohoutová D , Bártová J , Tachecí I , Rejchrt S , Repák R , Kopáčová M , Bureš J \nCryptogenic multifocal ulcerous stenosing enteritis: A review of the literature . Gastroenterol Res Pract . 2013 ;2013 :918031 .24369459 \n10 De Schepper H , Macken E , Van Marck V , Spinhoven M , Pelckmans P , Moreels T \nInfliximab induces remission in cryptogenic multifocal ulcerous stenosing enteritis: First case . World J Gastroenterol . 2013 ;19 (10 ):1661 –4 .23539523\n\n",
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"abstract": "BACKGROUND\nHistologic transformation (HT) of indolent non-Hodgkin lymphomas is an event that results in considerable morbidity and mortality. The introduction of chemoimmunotherapy regimens has resulted in an improvement in the management of this disease, and consolidation of responses with autologous stem cell transplantation appears efficacious. Many patients are not eligible for high-dose therapy, however. Radioimmunotherapy (RIT) has demonstrated single-agent efficacy in HT and can be used safely as consolidation after chemoimmunotherapy. For these reasons, RIT consolidation after chemoimmunotherapy induction has been our standard treatment approach at the University of Rochester for patients with HT who were ineligible for autologous stem cell transplantation.\n\n\nMETHODS\nA retrospective cohort study was performed to describe the clinical outcomes of these patients. Twenty-one patients were identified who received RIT consolidation. The Kaplan-Meier method was used to estimate the distributions of overall survival and progression-free survival. Comparisons were made between patients with pathologic HT and the combination of clinical HT and composite lymphoma using the log-rank test to compare survival curves.\n\n\nRESULTS\nThe median overall survival of the cohort was 84 months, and progression-free survival was 38 months. The major toxicity was myelosuppression, and 2 deaths were attributed to therapy. One case of therapy-related acute myeloid leukemia was noted.\n\n\nCONCLUSIONS\nIn a population of patients ineligible for high-dose therapy with autologous stem cell support, consolidation of response to chemoimmunotherapy with RIT was well tolerated and should be considered in patients with disease responsive to induction therapy.",
"affiliations": "Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY. Electronic address: patrick_reagan@urmc.rochester.edu.;Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY.;Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY.;Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY.;Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY.;Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY.;Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY.",
"authors": "Reagan|Patrick M|PM|;Baran|Andrea|A|;Kelly|Jennifer L|JL|;Barr|Paul M|PM|;Casulo|Carla|C|;Chengazi|Vaseem U|VU|;Friedberg|Jonathan W|JW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "16(6)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "(131)I-tositumomab; (90)Y-ibritumomab tiuxetan; indolent lymphoma; radioimmunoconjugate; transformed lymphoma",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002423:Cause of Death; D002471:Cell Transformation, Neoplastic; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D016499:Radioimmunotherapy; D019233:Retreatment; D012189:Retrospective Studies; D016019:Survival Analysis",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "322-328.e2",
"pmc": null,
"pmid": "27130328",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Consolidative Radioimmunotherapy After Chemoimmunotherapy in Patients With Histologic Transformation of Indolent Non-Hodgkin Lymphoma.",
"title_normalized": "consolidative radioimmunotherapy after chemoimmunotherapy in patients with histologic transformation of indolent non hodgkin lymphoma"
} | [
{
"companynumb": "US-PFIZER INC-2017080988",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMisoprostol is a synthetic analog of prostaglandin-E1 and it is the most widely used drug for the medical management of incomplete abortion. Acute Coronary Syndrome (ACS) rarely occurs in perimenopausal women, in addition, its presentation is atypical, so the disease is not always recognized.\n\n\nMETHODS\nWe describe a case of 39-year-old woman with no major underlying cardiovascular risk factors, who developed an episode of ACS following the administration of two doses of misoprostol. After the discontinuation of misoprostol treatment, there was a complete resolution of patient's symptoms. The case draws attention to a rare side effect of a commonly used drug and alerts the clinicians to be cautious in those patients having baseline risk factors which make the patient more susceptible to such serious adverse drug effect.",
"affiliations": "Department of Basic Medical Sciences, Prince Sultan Military College of Health Sciences, King Fahd Military Medical Complex, Dhahran, Saudi Arabia.;Department of Pharmacy, Aga Khan University Hospital, Karachi, Pakistan.;Pharmaceutical Care Department, King Abdul-Aziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia.",
"authors": "Mazhar|Faizan|F|;Sultana|Jabeen|J|;Akram|Shahzad|S|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D016595:Misoprostol",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886312666171122100929",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "13(1)",
"journal": "Current drug safety",
"keywords": "Acute coronary syndrome; TV-USG.; adverse drug effect; misoprostol; premenopausal women; prostaglandins",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000027:Abortion, Incomplete; D054058:Acute Coronary Syndrome; D000328:Adult; D005260:Female; D006801:Humans; D016595:Misoprostol; D017697:Premenopause",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "65-68",
"pmc": null,
"pmid": "29173181",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Misoprostol-induced Acute Coronary Syndrome in a Premenopausal Woman: A Case Report with Literature Review.",
"title_normalized": "misoprostol induced acute coronary syndrome in a premenopausal woman a case report with literature review"
} | [
{
"companynumb": "SA-PFIZER INC-2017524999",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nViral populations are complex, dynamic, and fast evolving. The evolution of groups of closely related viruses in a competitive environment is termed quasispecies. To fully understand the role that quasispecies play in viral evolution, characterizing the trajectories of viral genotypes in an evolving population is the key. In particular, long-range haplotype information for thousands of individual viruses is critical; yet generating this information is non-trivial. Popular deep sequencing methods generate relatively short reads that do not preserve linkage information, while third generation sequencing methods have higher error rates that make detection of low frequency mutations a bioinformatics challenge. Here we applied BAsE-Seq, an Illumina-based single-virion sequencing technology, to eight samples from four chronic hepatitis B (CHB) patients - once before antiviral treatment and once after viral rebound due to resistance.\n\n\nRESULTS\nWith single-virion sequencing, we obtained 248-8796 single-virion sequences per sample, which allowed us to find evidence for both hard and soft selective sweeps. We were able to reconstruct population demographic history that was independently verified by clinically collected data. We further verified four of the samples independently through PacBio SMRT and Illumina Pooled deep sequencing.\n\n\nCONCLUSIONS\nOverall, we showed that single-virion sequencing yields insight into viral evolution and population dynamics in an efficient and high throughput manner. We believe that single-virion sequencing is widely applicable to the study of viral evolution in the context of drug resistance and host adaptation, allows differentiation between soft or hard selective sweeps, and may be useful in the reconstruction of intra-host viral population demographic history.",
"affiliations": "Genome Institute of Singapore, Singapore, 138672, Singapore. yuanzhu26@gmail.com.;Genome Institute of Singapore, Singapore, 138672, Singapore.;Genome Institute of Singapore, Singapore, 138672, Singapore.;Genome Institute of Singapore, Singapore, 138672, Singapore.;Institute of Molecular and Cell Biology, Singapore, 138673, Singapore.;Institute of Molecular and Cell Biology, Singapore, 138673, Singapore.;Genome Institute of Singapore, Singapore, 138672, Singapore.;Genome Institute of Singapore, Singapore, 138672, Singapore.;London School of Hygiene and Tropical Medicine, London, UK.;National University Hospital, Singapore, 119074, Singapore.;Genome Institute of Singapore, Singapore, 138672, Singapore.;Institute of Molecular and Cell Biology, Singapore, 138673, Singapore.;Genome Institute of Singapore, Singapore, 138672, Singapore.",
"authors": "Zhu|Yuan O|YO|;Aw|Pauline P K|PPK|;de Sessions|Paola Florez|PF|;Hong|Shuzhen|S|;See|Lee Xian|LX|;Hong|Lewis Z|LZ|;Wilm|Andreas|A|;Li|Chen Hao|CH|;Hue|Stephane|S|;Lim|Seng Gee|SG|;Nagarajan|Niranjan|N|;Burkholder|William F|WF|;Hibberd|Martin|M|",
"chemical_list": "D019259:Lamivudine",
"country": "England",
"delete": false,
"doi": "10.1186/s12864-017-4217-1",
"fulltext": "\n==== Front\nBMC GenomicsBMC GenomicsBMC Genomics1471-2164BioMed Central London 421710.1186/s12864-017-4217-1Research ArticleSingle-virion sequencing of lamivudine-treated HBV populations reveal population evolution dynamics and demographic history Zhu Yuan O. yuanzhu26@gmail.com 1Aw Pauline P. K. awp@gis.a-star.edu.sg 1de Sessions Paola Florez desessions@gis.a-star.edu.sg 1Hong Shuzhen shuzhenhong@hotmail.com 1See Lee Xian lixian6@gmail.com 2Hong Lewis Z. zuocheng.lewis.hong@merck.com 2Wilm Andreas wilma@gis.a-star.edu.sg 1Li Chen Hao lich@gis.a-star.edu.sg 1Hue Stephane stephane.hue@lshtm.ac.uk 3Lim Seng Gee mdclimsg@nus.edu.sg 4Nagarajan Niranjan nagarajann@gis.a-star.edu.sg 1Burkholder William F. wfburkholder@gmail.com 2Hibberd Martin Martin.Hibberd@lshtm.ac.uk 131 0000 0004 0620 715Xgrid.418377.eGenome Institute of Singapore, Singapore, 138672 Singapore 2 grid.418812.6Institute of Molecular and Cell Biology, Singapore, 138673 Singapore 3 0000 0004 0425 469Xgrid.8991.9London School of Hygiene and Tropical Medicine, London, UK 4 0000 0004 0621 9599grid.412106.0National University Hospital, Singapore, 119074 Singapore 27 10 2017 27 10 2017 2017 18 8298 5 2017 16 10 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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\nViral populations are complex, dynamic, and fast evolving. The evolution of groups of closely related viruses in a competitive environment is termed quasispecies. To fully understand the role that quasispecies play in viral evolution, characterizing the trajectories of viral genotypes in an evolving population is the key. In particular, long-range haplotype information for thousands of individual viruses is critical; yet generating this information is non-trivial. Popular deep sequencing methods generate relatively short reads that do not preserve linkage information, while third generation sequencing methods have higher error rates that make detection of low frequency mutations a bioinformatics challenge. Here we applied BAsE-Seq, an Illumina-based single-virion sequencing technology, to eight samples from four chronic hepatitis B (CHB) patients – once before antiviral treatment and once after viral rebound due to resistance.\n\nResults\nWith single-virion sequencing, we obtained 248–8796 single-virion sequences per sample, which allowed us to find evidence for both hard and soft selective sweeps. We were able to reconstruct population demographic history that was independently verified by clinically collected data. We further verified four of the samples independently through PacBio SMRT and Illumina Pooled deep sequencing.\n\nConclusions\nOverall, we showed that single-virion sequencing yields insight into viral evolution and population dynamics in an efficient and high throughput manner. We believe that single-virion sequencing is widely applicable to the study of viral evolution in the context of drug resistance and host adaptation, allows differentiation between soft or hard selective sweeps, and may be useful in the reconstruction of intra-host viral population demographic history.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12864-017-4217-1) contains supplementary material, which is available to authorized users.\n\nKeywords\nSingle-virion sequencingViral evolutionAdaptation regimeDrug resistanceChronic hepatitis BPopulation demographic historyBayesian MCMCAgency of Science, Technology and ResearchJCO CDA 13302FG059JCO DP 1334k00082Nagarajan Niranjan http://dx.doi.org/10.13039/501100001349National Medical Research CouncilNMRC/TCR/014-NUHS/2015Lim Seng Gee issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nViral intra-host evolution is a critical obstacle in the treatment of chronic infectious diseases. It is the root cause of viral host immune escape and drug resistance, and consequently a major impediment in disease cure and eradication [1, 2]. The hepatitis B virus (HBV) is a prime example. HBV is a small, circular DNA virus. The HBV polymerase is error prone, with an estimated error every 105 to 107 bases [3]. When coupled with a large viral load (often between ~103 copies/ml to 107 copies/ml of serum), this can give rise to substantial viral diversity in active infections [4]. In other words, a sufficiently large viral population can potentially carry, or produce within a short period of time, all possible mutations, thus providing a genetic reservoir for rapid viral response and adaptation [5–10]. Practically, the accumulation of viral mutations is indicative of chronic disease progression and severity [11–13]. Mutations that quickly become predominant in the population are also indicators for how the viruses might be circumventing host response and treatment that enable fresh approaches for drug development research [14].\n\nHBV viral populations, specifically those in chronic infections, can be extremely diverse genetically. Part of the reason is due to high mutation rates leading to the presence of quasispecies [15–20]. Another contributing factor may also stem from genetic repositories in the form of stable covalently closed circular DNA (cccDNA) in infected hepatocytes. Identifying medically important mutations in such populations can become complicated. First, consensus sequence changes occur relatively slowly. For HBV, the mean number of nucleotide substitutions is only estimated at between 1.5 × 10−5 to 7.9 × 10−5 nucleotide substitutions per site per year [19]. The study of consensus sequences alone may not reveal underlying quasispecies dynamics, which may be much more rapid as the population constantly explores possible genotypes [20]. Second, these hidden quasispecies dynamics may be important in understanding the key indicators of viral fitness. Human host immune response, host genetics, treatment regimes, and finally the viral genotype itself likely interact in a complex fashion that exerts multiple, possibly contradictory selective forces on the virus that ultimately culminates in clinical outcome. Identifying the relevant subpopulation of viruses that are reacting to selective pressures of interest, whether it is nucleoside analogues, interferon treatments, or a change in host immune response can reveal important viral indicators for disease progression.\n\nIn order to leverage the recent advancements in next generation sequencing (NGS) technology, we explored single-virion sequencing as an option for characterizing quasispecies diversity in active infections. Deep population sequencing is routinely used to identify polymorphisms, including extremely rare alleles [21–26]. However, without linkage information, it remains difficult to describe quasispecies based on allele frequencies alone. A large number of complete genomes from a single viral population must be sequenced to be confident of full quasispecies diversity. Traditionally, such studies require viruses to be individually cloned and sequenced – a rather tedious process requiring a large amount of work and precious source material [19, 27]. However, the complexity and importance of quasispecies has never been clearer [28], and there are two recent next NGS technologies that can be applied to single-virion sequencing in a high-throughput manner, promising up to thousands of viral sequences from every chronic hepatitis B (CHB) patient sample. BAsE-Seq is an Illumina-based method that makes use of random 20mer barcodes to tag every single viral genome with a unique sequence. The barcoded genomes are then amplified as a single amplicon for library construction [29]. Reads from BAsE-Seq libraries can be reassembled into individual viral genomes in silico post sequencing, effectively constructing thousands of viral genomes with full haplotype information. An alternative approach uses single molecule real time sequencing technology (SMRT) on the Pacific Biosciences platform (PacBio) to produce long reads for individual molecules (up to 60 kb). While single pass sequencing error rates are high, the relatively small 3 kb HBV genomes can be read up to dozens of times by the same polymerase, sharply lowering error rates and yielding highly accurate genome sequences, with the additional benefit of not requiring a reference genome [30].\n\nWe aimed to apply these single-virion sequencing methods in a manner tailored to characterizing viral population diversity, quasispecies structure, and population evolution. More specifically, we aimed to discover additional information on viral evolutionary dynamics not visible to regular deep sequencing. We picked a relatively well-understood model – that of HBV resistance to the antiviral drug Lamivudine - where the most common resistance alleles are well characterized [31], and obtained two serum samples from each of four CHB patients who were treated with and subsequently developed resistance to Lamivudine. We searched for resistance mutations in each of the patients and tried to reveal additional quasispecies dynamics using single-virion sequencing. We found that single-virion sequencing reveals vital information about viral population heterogeneity and fluctuations in population composition during viral evolution.\n\nMethods\nSample identification and collection in the clinic\nBoth clonal lab strains and patient samples were used in this study. Plasmids with clonal HBV sequences (referred to as Clone-1 and Clone-2 in the text) were constructed and processed as previously detailed in [28] and sequenced as controls. Patient samples were recruited to test single-virion sequencing on biological populations as well as to describe any additional information that can be gained through haplotype sequencing. Only patients who gained resistance to Lamivudine with serum samples of suitably high viral load (>103 viral copy number/ml) both pre-treatment and post-resistance were considered. As per standard clinical practice, patients who stop responding to anti-viral treatment were tested for resistance mutations through capillary sequencing. For these patients, viral DNA was extracted from 200 μl of serum using the Qiagen Blood mini kit, and the extracted HBV genome was PCR amplified using the Dynazyme DNA polymerase and the primers [Fwd (5′-G[T/C]GTAGACTCGTGGTGGACTTCTCTC-3′).\n\nRev. (5′-TGACA[T/A/G/C]ACTTTCCAATCA AT-3′)]. The amplified 650 bp fragment was purified by gel electrophoresis and extraction, followed by direct sequencing on an ABI 3730XL DNA Analyzers (SI Table 1). 4 patients with gains of resistance mutations totaling 8 time points had serum samples pulled from the database for sequencing.Table 1 Patient sample nomenclature and viral copy number\n\nSample ID\tPatient\tDate\tViral Copies/ul\tSingle-virion Sequences\tNucleotide Diversity ∏\t\n1.1\t1\t15th Nov 94\t378,500\t1717†, 1635*\t0.0012/base\t\n1.2\t1\t3rd Jul 99\t52,270\t3331†, 2514*\t0.0024/base\t\n2.1\t2\t22nd May 95\t239,750\t391†, 1330*\t0.0032/base\t\n2.2\t2\t29th Aug 97\t44,687\t3747†, 2504*\t0.0013/base\t\n7.1\t7\t19th May 95\t69,180\t2647†\n\t0.0022/base\t\n7.2\t7\t11th Apr 00\t48,083\t789†\n\t0.0016/base\t\n11.1\t11\t19th Jun 95\t208,275\t2754†\n\t0.0211/base\t\n11.2\t11\t3rd Nov 98\t466,200\t248†\n\t0.0052/base\t\n\n†-total number of single-virion sequences obtained from a BAsE-Seq library. *-total number of single-virion sequences obtained from a PacBio library. Nucleotide diversity Π, the arithmetic mean between all pairwise differences between viral sequences within each viral population, were calculated from BAsE-Seq single-virion sequences for the entire amplified genomic sequence of 3175 bases (3215 minus the 40 bases that were not amplified)\n\n\n\n\nBarcode-directed assembly for extra-long sequences (BAsE-Seq)\nBAsE-Seq was carried out on all samples. They were: Clone-1, Clone-2, Patient 1 timepoints 1.1 and 1.2, Patient 2 timepoints 2.1 and 2.2, Patient 7 timepoints 7.1 and 7.2, and Patient 11 timepoints 11.1 and 11.2. Library preparation was carried out according to the protocol as described in [28]. Briefly, a total of 106 HBV genomes were subjected to a 2-cycle PCR that assigned unique barcodes to each strand of the HBV genome. Two rounds of PCR were carried out to amplify the product, using HBV specific primers (5′-GCTCTTCTTTTTCACCTCTGCCTAATCA-3′ and 5′-GCTCTTCAAAAAGTTGCATGGTGCTGG-3′), taking care to stay within the exponential amplification regime during each round of PCR to minimize the generation of chimeric PCR products [28]. Specifically, a two-stage PCR protocol was employed such that reactions were stopped in the log-linear phase. The final amplicon spans 3175 bp. Samples were exonuclease- digested to generate a pool of nested deletions fragments, which were end-repaired and circularized. Circular products were fragmented and tagged with the Illumina adaptors followed by 14 cycles of PCR to incorporate primers for sequencing. The resulting 2 × 101 bp reads were trimmed for adaptor sequences and base quality with Trimmomatic [32]. A subset of 10,000 read pairs was first BWA-MEM (v 0.7.10) mapped to 8 known HBV genotypes A-H one at a time [33, 34]. All reads were then BWA-MEM mapped to the genotype reference with the lowest number of mismatches. At this point, mapped reads with identical barcodes, signifying their origin from the same viral molecule, are sorted into individual folders for further processing. For each barcode, aligned reads were duplicate-marked, realigned, and recalibrated with GATK v2.7 [35]. Finally, SNVs were called with LoFreq v2.1.2 [36] and incorporated into the final sequences for each barcode (Additional file 1: Figure S4, S5, S8). Full-length viral sequences that passed all quality filters went on to be part of the population analysis [SI]. Maximum Likelihood phylogenies were built from the top 100 sequences with the highest coverage for easier visual interpretation using FastTree v2.1.8 [37, 38]. PHYLIP Neighbor Joining trees were constructed [39] from the full set of viral sequences obtained [SI]. All trees presented were drawn with iTOL [40, 41]. For further details about the pipeline including all processing and error filters refer to [SI].\n\nPooled deep sequencing (Illumina)\nPooled deep sequencing was carried out on Clone-1, Clone-2, Patient 1 timepoints 1.1 and 1.2, and Patient 2 timepoints 2.1 and 2.2. Insufficient DNA remained from Patients 7 and patient 11 after BAsE-Seq sequencing, and these four samples had to be excluded from Pooled deep sequencing. For a detailed protocol of sample library preparation, refer to [31]. Briefly, 106 HBV viral genomes were PCR amplified using the same primers as in BAsE-Seq that cover all but the first 40 bp of the 3215 bp genome. 2–3 μg of PCR product for each viral DNA sample was sheared to achieve a fragment size range between 100 and 300 bp. Library preparation was performed using the Qiagen GeneRead DNA Library I Kit according to manufacturer instructions. After end-repair, A-tailing, and adapter ligation, ligated products in the 200–400 bp range were gel-extracted, and subjected to 14 PCR cycles to incorporate multiplexing indices. The final product was quantified and run on a Illumina HiSeq 2000 instrument. Resulting Illumina 2 × 101 bp reads were trimmed by base quality with Trimmomatic and mapped to the concatenated HBV pan-genome consisting of all 8 major genotypes A-H with BWA-MEM (Additional file 1: Figure S1, Table S2). All concordantly mapped read pairs were duplicate-marked, realigned, and recalibrated with GATK 2.7. SNVs present in the pool were called based on comparison with the best match genotype sequence using LoFreq 2.1.2.\n\nPacBio library construction and analysis\nPacBio SMRT sequencing was later carried out on Clone-1, Clone-2, Patient 1 timepoints 1.1 and 1.2, and Patient 2 timepoints 2.1 and 2,2. Insufficient DNA remained from Patients 7 and patient 11 after BAsE-Seq sequencing, and these four samples had to be excluded from PacBio library construction. 106 HBV viral genomes were PCR amplified using the same primers as mentioned above under Pooled Deep Sequencing and BAsE-Seq. 2–3 μg of PCR product was used for PacBio library construction following the 2 kb Template Preparation and Sequencing protocol. Library products were quantified on Agilent 2100 Bioanalyzer, and run on a PacBio instrument with V6 chemistry. PacBio raw reads were first processed with the SMRT Portal analysis programs. To focus on full length functional viruses, circular consensus sequences (CCS) from each library were called with a cutoff of at least 10× subreads within a polymerase read and a minimum subread length of 2500 bp using the RS_ReadsOfInsert application (Additional file 1: Figure 2a, b). CCSs were multiple-sequence aligned against all 8 genotypes with MUSCLE [42]. Bases within the CCS reads with quality scores <75 were masked as Ns to filter out false positives (Additional file 1: Figure. 2c), and the resulting (nearly) full-length viral sequences were BWA-SW mapped as extremely long reads to the concatenated HBV pan-genome consisting of all 8 major genotypes A-H (Additional file 1: Figure 3). (Although a reference panel is not necessary for PacBio long reads, it was included in the analysis here for direct comparison between outputs from the platforms.) Segregating sites within the viral populations were called with LoFreq 2.1.2 with primer regions masked. Maximum Likelihood phylogenies were built from the highest quality 100 CCs sequences of the correct length (3175 bp) using FastTree v2.1.8. Neighbor Joining trees were constructed from the full set of viral sequences obtained using PHYLIP [SI]. All trees presented were drawn with iTOL. For a detailed protocol regarding PacBio read processing and error filters refer to [SI].\n\nReconstruction of demographic history by BEAST\nA Bayesian Markov Chain Monte Carlo (MCMC) approach was implemented using BEAST v1.8.4 [43] on all sets of 4 patient samples in order to estimate demographic and evolutionary parameters, using the Bayesian skyline plot as a coalescent prior. Unique single-virion sequences constructed from BAsE-Seq libraries often carried missing information due to uneven coverage. Because an excess of ‘N’s can overwhelm the true signal, only the top 100 sequences with the highest overall coverage were used for BEAST analysis. A final fragment of 3134 coding bases was used for demographic history reconstruction. Samples prior to Lamivudine treatment were defined as sequences collected on day 0 and samples post drug resistance annotated as sequences collected n days after. We employed the GTR + Γ4 unlinked codon model of nucleotide substitution and a strict molecular clock. The MCMC chain length was set to 1E9 to 2E9 generations, depending on the patient sample in question, with sampling of every 1E4th. Convergence of the estimates was considered satisfactory when the effective sample size (ESS), calculated in Tracer v1.6, was >200 for all parameters. The first 10% of the estimates was discarded as burn-in. Where necessary, multiple runs were merged using LogCombiner as part of the BEAST package. Run results were analyzed and skyline plots, showing changes in effective population time over time, generated with Tracer v1.6 [44].\n\nResults\nSingle-virion sequencing platform error-rates\nThe three platforms - Pooled Deep sequencing, BAsE-Seq, and PacBio - were tested on two HBV clones with known sequences [28] for pipeline construction and optimization. The data available from each platform is represented in (Fig. 1). Pipelines tailored to each platform were then applied to viral populations from two patients (P1 and P2) to gauge single-virion sequencing performance and throughput on clinical samples [SI]. We began the study with BAsE-Seq, and added PacBio sequencing libraries as the technology became more accessible. We sequenced lab clones with know sequences and estimated the error rates of both methods by summarizing the frequency of base differences in sequenced haplotypes. The base error rates of BAsE-Seq and PacBio libraries were between 0.02–0.3 and 0.2–1.3 per kb of single-virion sequence respectively, and the error rates for small indels in BAsE-Seq and PacBio reads were <0.02/kb and 2.9–3.4/kb respectively. PacBio sequencing is known to have higher error rates in homopolymer runs [45]. We tried to further reduce PacBio error rates through careful selection of PCR polymerase [Additional file 1: Figure S2a-b] and CCS quality filters [Additional file 1: Figure S2c], but still faced multiple sequence alignment issues that gave false positive single nucleotide variants (SNVs) [Additional file 1: Figure S3]. As PacBio errors are random and thus low in frequency when consolidated across all reads, we bypassed this issue by mapping CCs reads to a reference sequence [Additional file 1 Figure S6–S7, S9–S13], and only considering these positions in our population analysis. Because PacBio is a reference independent sequencing technology, it is also possible to map reads to a de novo reference sequence generated from the run. Here, we elected for a common reference sequence across all samples for ease of comparison across BAsE-Seq, PacBio, and Pooled deep sequencing data. A more detailed explanation of all work conducted in this comparison exercise is available in Additional file 1.Fig. 1 Graphical representation of sequence reads obtained from BAsE-Seq, PacBio, and Pooled Deep sequencing. X-axis: Genome position. Y-axis: Relative coverage. Each dot represents coverage at a single base position. From left to right: Pooled deep sequencing short reads give uneven genomic coverage. BAsE-Seq reconstitutes single-virion sequences by mapping barcoded short reads to a reference, thus matching exact reference length but may have missing information spread throughout depending on local coverage as shown by dips in the coverage plot. PacBio circular consensus reads (CCSs) can vary in length, but will not necessarily require a reference for construction. A library of 3 kb amplicons will cover the entire genome evenly as shown. Dip in coverage around 1.5 kb is due to a deletion in the sample\n\n\n\n\nClassic resistance mutations observed\nSerum samples were taken from each patient twice for viral DNA library construction - once before they were treated with Lamivudine (labeled as P1.1, P2.1, P7.1, P11.1) and once after viral loads rebounded to detectable levels (labeled as P1.2, P2.2, P7.2, P11.2) (Table 1).\n\nThe four libraries from patients P1 and P2 were sequenced on Pooled Deep sequencing, BAsE-Seq, and PacBio platforms. The remaining four libraries from patients P7 and P11 were sequenced and analyzed only by BAsE-Seq due to limited patient serum availability.\n\nViral genotype composition in each sample was estimated from the percentage of reads mapping to each genotype reference in the pan-genome panel. Three out of four patients carried Genotype B viruses. The only exception was P11, who carried a mixed Genotype B and Genotype C infection prior to drug treatment, but only Genotype C viruses post Lamivudine resistance (Fig. 2). Illumina short reads tend to mis-map in regions where sequence divergence is ~3% between the references used, an issue absent in BAsE-Seq and PacBio long reads [Additional file 1 Figure S4]. Therefore, genotype identification in Illumina libraries must take into account evenness of coverage across the references, or number of mismatches in mapped reads, in addition to absolute percentage of reads mapped.Fig. 2 Genotype composition (Y-axis) of samples sequenced (X-axis) as reported by BWA-SW coverage across 8 reference genotype sequences. Samples are organized from left to right in order of P1.1, P1.2, P2.1, P2.2, P7.1, P7.2, P11.1, and P11.2, where P1.1 and P1.2 are two time points from the same patient P1, before and after drug resistance respectively. Wherever data from multiple technologies are available, order follows Pooled deep sequencing, BAsE-Seq, and lastly PacBio\n\n\n\n\nLamivudine resistance is achieved through mutations in the reverse transcriptase (RT) domain of the polymerase gene in HBV [46–48]. Two resistance phenotypes made up of three amino acid changes, M204I and L180 M + M204 V, are the most commonly observed. They confer similarly high resistance and only require one to two nucleotide changes [49]. Both of these resistant genotypes were found, and together explained resistance in all four patients (Table 2). The discrepancy in allele frequencies between the platforms may have been due to sampling error of low viral load samples.Table 2 The frequencies of detected resistance alleles in each of the 4 patients after drug resistance. None of these mutations were observed (below detection limit) in the populations prior to development of resistance\n\n#\tMutation\tPooled Deep Seq\tBAsE-Seq\tPacBio\t\nP1\tM204 V\nL180 M\nM204I\t0.525\n0.560\n0.457\t0.711\n0.752\n0.251\t0.567\n0.611\n0.358\t\nP2\tM204I\t0.978\t0.882\t0.990\t\nP7\tM204 V\nL180 M\t\t0.870\n0.946\t\t\nP11\tM204I\nL180 M\t\t0.948\n0.679\t\t\n\n\n\nWhile P2 (M204I) and P7 (M204 V+ L180 M) carried single resistance phenotypes, P1 carried both M204I and M204 V+ L180 M. The genotypes are not mutually exclusive and all three of the point mutations were found in the same patient at significant frequencies (Figs. 3, 4). P11 was nearly fixed for M204I, but also carried L180 M at a high frequency.Fig. 3 Change in allele frequencies of variable sites in P1 and P2 after drug treatment (detection limit >0.01). Left panels shows the delta change in allele frequencies of segregating sites (Y-axis) across the genome (X-axis) in patient 1 on all 3 sequencing platforms. Right panels show the corresponding data for patient 2. All non-synonymous changes were colored in red, synonymous changes in green\n\n\nFig. 4 Change in allele frequencies of variable sites in P7 and P11 after drug treatment (detection limit >0.01). Panels show the delta change in allele frequencies of segregating sites (Y-axis) across the genome (X-axis) from BAsE-Seq libraries. All non-synonymous changes were colored in red, synonymous changes in green\n\n\n\n\nDiscussion\nViral Quasispecies reveal both hard and soft selective sweeps\nSingle-virion haplotypes should yield deeper insights into how these resistance genotypes evolved. Here, we asked if we could identify whether resistance mutations came from a single source and quickly swept to high frequency (hard sweep), or multiple sources that then grew in frequency independently (soft sweep) [50–53]. Note that this question is extremely difficult to address without long-range haplotype information. Hard sweeps are likely to happen with lower mutation rate or extremely strong selection, where adaptive mutations occur one at a time and immediately outcompete other genotypes within the population. Soft sweeps tend to dominate if mutation rates are higher, selection is milder, population is large [54], and multiple lineages carrying advantageous mutations may be present at a time, all increasing in frequency due to the consequent selective advantage [55, 56]. While HBV is a DNA virus that mutates relatively slowly as compared to RNA viruses, it is also true that Lamivudine exerts a strong selective pressure against viral replication. We also asked if we could identify whether resistance alleles were from de novo mutations or from existing low frequency variants. Adaptation from de novo mutation is usually defined as serial fixation of novel alleles, with just one adaptive allele rising to fixation at a time, whereas adaptation from standing variation often also carries with it multiple pre-existing mutations linked to the advantageous allele [57–60]. Which model is more relevant is partly determined by population diversity and the presence of pre-existing drug resistant strains. A clonal viral infection, such as a recent or mono-strain infection seeded by very few drug-naïve virions is less likely to carry pre-existing resistance alleles as compared to a mixed infection or a long-term infection that has had time to diversify within the patient. There is also the possibility that a large, highly mutable viral population could theoretically carry all possible mutations in its quasispecies mutant pool at any point in time. Determining the correct model for HBV population evolution will be important for describing and modeling adaptation.\n\nWe made use of nearly full genome haplotype information from BAsE-Seq to characterize viral population quasi-species composition before and after drug treatment (Additional file 2). PacBio trees for P1 and P2 are available in SI. Phylogenetic trees built from viral haplotypes revealed three different patterns in how these patients gained viral resistance (Additional file 3).\n\nTwo patients, P2 and P7, had trees that showed clear mono-clonal gains of resistance, suggestive of hard sweeps (Fig. 5a,b, Additional file 1 Figure S14–S15). Allele frequency changes showed clusters of SNVs that increased in allele frequency together (11 SNVs in P2 spanning the entire 3.2 kb sequenced region [Fig. 3] and 6 SNVs in P7 spanning 2 kb–2.8 kb [Fig. 4]). Haplotype information confirmed that these were linked SNVs on the same haplotype. 9/11 SNVs in the P2 cluster were within the RT domain of the polymerase gene, and 7/11 SNVs were non-synonymous mutations within a 750 bp window. All six SNVs in the P7 cluster were within the RT domain of the polymerase gene, and three were non-synonymous mutations within a 150 bp window. These two sweeps with numerous SNVs linked to the resistance allele would support a model of evolution from standing variation. However, these exact combinations of SNVs were not found in the treatment naïve timepoints for either patient. The closest haplotypes found pre-treatment shared just 6/11 SNVs for P2 and 2/6 SNVs for P7. Haplotype analysis of linked SNVs in PacBio sequences for P2 showed the same pattern (Fig. 3).Fig. 5 BAsE-Seq approximately maximum-likelihood trees of viral sequences from P2 (a), P7 (b), P1 (c), and P11 (d). Tip label colors indicate if the viral sequence came from before (black) or after (orange) drug resistance. 100 sub-sampled sequences from each timepoint are used, color-coded by their branch labels. Bootstrap values are reflected in branch color, ranging between 0 (red) to 1 (green). Blue arrows indicate emergence of resistance mutations. For a full phylogeny of all sequences, refer to (Additional file 1 Figures 14–17)\n\n\n\n\nWe suggest three possible explanations for this linkage. First, there could be a detection limit for extremely rare haplotypes in the pre-treatment timepoints. We may simply have failed to sequence them. Second, because our samples came from patient blood samples, latent viral reservoirs outside of the blood stream could be contributing to the viral population. Perhaps even reshuffling viral haplotypes through recombination. Again, they would be missed by serum samples. Finally, the resistance mutation could have occurred later during the treatment regime by chance, and happened to rise on the background of a viral sequence that already accumulated multiple nucleotide differences from the population consensus. There was in fact a two to three fold difference in nucleotide diversity across the eight patient samples (Table 1), suggesting a range of quasispecies complexity across patients, which may affect observed evolutionary dynamics.\n\nThe two remaining patients, P1 and P11, had trees showing at least two independent instances of gain of resistance, in other words soft sweeps (Fig. 5c,d, SI Additional file 1 Figure S16–S17). P1 was highly clonal with just 6 sites shifting in frequency over time (Fig. 3), and independently gained M204I and L180 M + M204 V on two haplotypes. Again, this was seen in the PacBio library as well (Fig. 3). P11 carried the most diverse population out of all four patients, starting as a mixed population of 26% Genotype B and 74% Genotype C (Fig. 2). The same resistance allele M204I evolved twice on Genotype C sequences but none on Genotype B sequences, resulting in a resistant viral population that was 100% Genotype C. One lineage further gained the L180 M mutation, although it is unclear whether that conferred additional resistance on a M204I background.\n\nReconstructing demographic history\nThe BEAST analysis for P11 showed effective samples sizes (ESS) of >500, indicating convergence. Sequences came from day −1233 (sample before Lamivudine treatment) and day 0 (sample taken after viral resistance and consequently viral load rebound) [SI Table 3]. Reconstructed demographic history showed an initial exponential growth phase post infection, followed by a plateau. A sharp dip in effective viral population size (Ne) then occurred sometime between −1350 to −750 days prior to day 0. From actual patient viral load information, the population crash post drug treatment occurred right after the sample was take on day −1233. There was also a sharp increase in median Ne about 150 days prior to day 0 in the skyline plot, which matched clinical data almost perfectly (Fig. 6). Although the two major changes in population size were well identified, a smaller increase in the viral population size around day −700 was not, possibly indicating some limitations when reconstructing smaller scale changes in population demography, or that these viruses did not contribute to the effective population size. Due to the smaller nucleotide diversity present in the other patient samples (Table 1), runs for P1, P2 and P7 did not coalesce at 1E9 replications (Additional file 1 Figure S18–S20).Fig. 6 Overlay of BEAST reconstructed demographic history and clinical records of patient viral load (serum) for patient 11. X-axis – Timeline represented in days, going forward in time from left to right. Green arrows point out the two timepoints that were used for single-virion sequencing. Y-axis labeled “Viral load” – corresponding to red line tracing all available records of patient viral load (log10 scale) over time. Y-axis labeled “BEAST Ne” - Effective population size over time as simulated by BEAST (log10 scale) shown by black line (plotted values are local medians, with 95% highest probability density (HPD) confidence interval colored in blue)\n\n\n\n\nConclusions\nHaplotype information is vital for revealing hidden population dynamics invisible in standard deep sequencing data. While single-virion sequencing remains technically challenging, we employed two complementary single-virion sequencing platforms to reveal – and cross-validate - such information. We can tell, from nucleotide diversity calculations, the heterogeneity of a population. We can estimate, using up to thousands of single-virion haplotypes, the relative proportions of genotypes and quasispecies present in an infection. We can determine if resistance evolved from a single source, or multiple times independently. Using samples taken at different timepoints, we can begin to explore whether evolution occurs from standing variation or de novo mutations, and how that is linked to quasispecies complexity. While lamivudine resistance is a relatively simple adaptive process with very specific alleles conferring fitness gains, this work shows the potential of applying single-virion sequencing to complex events such as viral response to immune enhancement or viral dynamics during an active HBV flare. It may also be valuable in the study of difficult topics such as cccDNA stability, viral recombination, and viral reservoirs. Single-virion sequencing is therefore a powerful tool for understanding the role of viruses across disease stages of clinical importance.\n\nAdditional files\n\nAdditional file 1: A supplementary materials file provides additional technical details and figures deemed unnecessary for the main text, including BEAST results for all patient samples. (PDF 2754 kb)\n\n \nAdditional file 2: Supplementary_genomes.fasta. High quality single virion sequences Single-virion sequences that were reconstructed with BAsE-Seq and used in FastTree phylogeny analysis for all 4 patients. (FASTA 1289 kb)\n\n \nAdditional file 3: Supplementary_FastTrees.txt. Newick format phylogenetic trees. FastTree output in Newick format for all 4 patients (TXT 16 kb)\n\n \n\n\nAbbreviations\nBAsE-SeqBarcode-directed Assembly for Extra-long Sequences\n\ncccDNAcovalently close circular DNA\n\nCCscircular consensus sequence\n\nCHBchronic hepatitis B\n\nESSeffective sample size\n\nHBVhepatitis B virus\n\nMCMCMarkov chain Monte Carlo\n\nNGSnext generation sequencing\n\nSMRTSingle Molecule, Real-Time\n\nSNVsingle nucleotide variant.\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12864-017-4217-1) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nWe thank Wendy Soon, Gary Chen and the entire Next Generation Sequencing Platform team at the Genome Institute of Singapore for their support and expertise. We thank Siddarth Signh and the Pacific Biosciences support team for their expertise and invaluable advice and feedback.\n\nConsent for publication\n\n(Not applicable).\n\nFunding\nThe work presented here was funded by the Agency of Science, Technology and Research (A*STAR) and the grant JCO CDA 13302FG059. YOZ, PA, PFS, SGL, and MH were also funded by the grant titled Eradication of HBV TCR Program: NMRC/TCR/014-NUHS/2015. NN and WFB were also funded by the grant JCO DP 1334 k00082.\n\nAvailability of data and materials\nRaw sequencing reads from all libraries were deposited and publicly available on the NCBI SRA database under BioProject PRJNA407696. Scripts used in the BAsE-Seq pipeline are available on Github at https://github.com/OliviaZhu26/Single_virion_seq. 100 high quality single virion sequences from each patient, and the phylogenetic trees built from them using FastTree, are included in Additional file 1.\n\nAuthors’ contributions\nLZH, NN, WFB and MH conceived and designed the experiments. SGL procured the samples. PPKA, PFS, SZH, and LXS constructed the libraries. YOZ, AW, CHL, SH, and MH conducted the analyses. YOZ, PFS, LZH, AW, SH, NN, WFB, and MH drafted and edited the manuscript. All authors have read and approved the final version of this manuscript.\n\nAuthors’ information\nSZH is currently affiliated with Chugai Pharmabody Research Pte Ltd., Singapore 138,623. LZH is currently affiliated with Translational Biomarkers, Merck Research Laboratories, MSD, Singapore 138,665.\n\nEthics approval and consent to participate\nAll patients provided written informed consent according to the Declaration of Helsinki, and all study protocols were approved by the Domain Specific Review Board (DSRB), National Healthcare Group (NHG), Singapore.\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. Hughes D Andersson DI Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms Nat Rev Genet 2015 16 8 459 471 10.1038/nrg3922 26149714 \n2. Presloid JB Novella IS RNA viruses and RNAi: Quasispecies implications for viral escape Viruses 2015 7 6 3226 3240 10.3390/v7062768 26102581 \n3. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2164",
"issue": "18(1)",
"journal": "BMC genomics",
"keywords": "Adaptation regime; Bayesian MCMC; Chronic hepatitis B; Drug resistance; Population demographic history; Single-virion sequencing; Viral evolution",
"medline_ta": "BMC Genomics",
"mesh_terms": "D000483:Alleles; D019943:Amino Acid Substitution; D019295:Computational Biology; D058893:DNA Barcoding, Taxonomic; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005787:Gene Frequency; D016679:Genome, Viral; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D019259:Lamivudine; D009154:Mutation; D014771:Virion",
"nlm_unique_id": "100965258",
"other_id": null,
"pages": "829",
"pmc": null,
"pmid": "29078745",
"pubdate": "2017-10-27",
"publication_types": "D016428:Journal Article",
"references": "10384235;10640544;20224823;15302222;17854598;16378967;7612225;15716498;25406369;21440005;16520336;25658544;26202119;11157004;23242209;9126786;26755866;22757653;17913933;20644199;24695404;26647737;26648309;25382636;17041211;20080505;11512520;15034147;26102581;24075201;19304333;10880498;22688811;15249682;25824477;19377059;26101252;16941700;8013910;23066108;21470960;16306618;24696338;23023011;19451168;4942363;23718773;17996036;20585547;26309637;26617593;17050570;19301976;1743491;26149714;8795155",
"title": "Single-virion sequencing of lamivudine-treated HBV populations reveal population evolution dynamics and demographic history.",
"title_normalized": "single virion sequencing of lamivudine treated hbv populations reveal population evolution dynamics and demographic history"
} | [
{
"companynumb": "SG-VIIV HEALTHCARE LIMITED-SG2017GSK194691",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugaddition... |
{
"abstract": "Vascular endothelial growth factor (VEGF) inhibitors have produced demonstrable but limited benefit for various cancers. One mechanism of resistance includes revascularization, secondary to upregulation of alternative pro-angiogenic platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Nintedanib is an oral, triple kinase inhibitor that blocks these pathways and may improve anti-tumor activity by overcoming resistance to anti-VEGF therapies. The primary objective of this first in-human study was to evaluate the safety and tolerability of nintedanib in combination with bevacizumab.\n\n\n\nPatients were treated with escalating doses of nintedanib (150 mg or 200 mg oral twice daily) and bevacizumab (15 mg/kg once intravenously every 3 weeks) until disease progression or unacceptable toxicity using standard 3 + 3 phase 1 design. Plasma levels of angiogenic biomarkers were correlated with clinical outcomes.\n\n\n\nEighteen patients with advanced tumors [lung (n = 9), colon (n = 8), and cervical (n = 1)] previously treated with at least two lines of chemotherapy including bevacizumab (n = 9, 50%) were enrolled. The highest dose of nintedanib was 200 mg twice a day with no observed dose-limiting toxicities (DLT). Common adverse events (AE) were fatigue (grade 1-3) and diarrhea (grade 1-2). Durable clinical response was observed in 55% patients pretreated with bevacizumab (1 complete and 4 stable response). Better disease control was correlated with higher than median baseline values for VEFGR2 and E-selectin, and lower levels for SDF-1α.\n\n\n\nNintedanib was well-tolerated with bevacizumab with no DLT. Significant clinical activity was observed, including in bevacizumab-pretreated patients, suggesting nintedanib can overcome bevacizumab resistance.",
"affiliations": "University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA.;University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA.;University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA.;University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA.;University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA.;University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA.;University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA.;University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA.;University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, USA. pacorobertuab@cs.com.",
"authors": "Paluri|Ravi|R|;Madan|Ankit|A|;Li|Peng|P|;Jones|Benjamin|B|;Saleh|Mansoor|M|;Jerome|Mary|M|;Miley|Deborah|D|;Keef|Jennifer|J|;Robert|Francisco|F|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C530716:nintedanib",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-018-3761-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "83(3)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Bevacizumab; Metastasis; Nintedanib; Solid tumors; Vascular endothelial growth factors",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms; D047428:Protein Kinase Inhibitors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "551-559",
"pmc": null,
"pmid": "30603797",
"pubdate": "2019-03",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17442997;27987591;18650835;15863032;22759480;20688946;18559524;28285686;20028771;24411639;21204634;18316578;18421054;23729403;23008289;15175435;21859991;14657001;15294883;20008624",
"title": "Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.",
"title_normalized": "phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors"
} | [
{
"companynumb": "US-ROCHE-2248635",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "In December 2019, numerous coronavirus disease 2019 (COVID-19) cases were reported in Wuhan, China, which has since spread throughout the world. However, its impact on rheumatoid arthritis (RA) patients is unknown. Herein, we report a case of COVID-19 pneumonia in a 61-year-old female RA patient who was receiving conventional disease-modifying antirheumatic drugs (cDMARDs). The patient presented with a 4-day history of myalgia and febrile sensation. COVID-19 was confirmed by real-time polymerase chain reaction (PCR). Chest X-ray showed increased opacity on the right lower lung area, and C-reactive protein level was slightly elevated. The patient was treated with antiviral agents (lopinavir/ritonavir), and treatment with cDMARDs was discontinued except hydroxychloroquine. Her symptoms and laboratory results gradually improved. Three weeks later, real-time PCR for COVID-19 showed negative conversion, and the patient was discharged without any complications.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwan-doro, Dong-gu, Ulsan, 44033, South Korea.;Division of Rheumatology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwan-doro, Dong-gu, Ulsan, 44033, South Korea.;Division of Rheumatology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwan-doro, Dong-gu, Ulsan, 44033, South Korea.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea.;Division of Rheumatology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea.;Division of Rheumatology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, South Korea.;Division of Rheumatology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwan-doro, Dong-gu, Ulsan, 44033, South Korea. dlaengh@hanmail.net.",
"authors": "Song|Jehun|J|;Kang|Seongmin|S|;Choi|Seung Won|SW|0000-0001-5767-221X;Seo|Kwang Won|KW|0000-0003-0504-6924;Lee|Sunggun|S|0000-0003-3640-9185;So|Min Wook|MW|0000-0001-5027-0410;Lim|Doo-Ho|DH|0000-0002-8012-7364",
"chemical_list": "D018501:Antirheumatic Agents; D004338:Drug Combinations; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D006886:Hydroxychloroquine; D019438:Ritonavir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-020-04584-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "40(6)",
"journal": "Rheumatology international",
"keywords": "COVID-19; Coronavirus; Disease-modifying antirheumatic drugs; Pneumonia; Rheumatoid arthritis",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D000086382:COVID-19; D002681:China; D018352:Coronavirus Infections; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D016867:Immunocompromised Host; D061466:Lopinavir; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D060888:Real-Time Polymerase Chain Reaction; D019438:Ritonavir; D016896:Treatment Outcome",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "991-995",
"pmc": null,
"pmid": "32314010",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32037389;32125362;22925480;21180599;32091533;30917856;32192578;10922071;15494274;19843413;25608756;32150618;32109013;28422773;23192911;32056407;29029272;29161116;21800117",
"title": "Coronavirus Disease 19 (COVID-19) complicated with pneumonia in a patient with rheumatoid arthritis receiving conventional disease-modifying antirheumatic drugs.",
"title_normalized": "coronavirus disease 19 covid 19 complicated with pneumonia in a patient with rheumatoid arthritis receiving conventional disease modifying antirheumatic drugs"
} | [
{
"companynumb": "KR-PFIZER INC-2020202544",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "Severe thrombocytopenia poses a high risk for bleeding thus representing a relative contraindication for anticoagulation and therefore extracorporeal membrane oxygenation (ECMO). We herein report on a series of immunocompromised patients with severe thrombocytopenia undergoing long-term ECMO without systemic anticoagulation. We retrospectively identified seven adult patients with anticoagulation withdrawal for ≥3 days (range 5-317) during venovenous ECMO therapy due to thrombocytopenia < 50 G/L treated in a university-affiliated hospital from January 2013 to April 2017. All ECMO systems used were heparin coated. Overall, 530 ECMO days were observed, 404 (76%) of them without systemic anticoagulation. Platelet count during ECMO treatment was 24 G/L (median, range 1-138), ECMO duration was 35 days (5-317), and ECMO was run without any anticoagulation for 20 days (5-317). Altogether, five clotting events were seen leading to oxygenator exchanges. Bleeding was common including one fatal intracerebral hemorrhage. Altogether, 29 platelet concentrates per patient (7-207) were administered, which correspond to 0.8 per day (0.6-1.3). One patient survived ICU and hospital. In patients with thrombocytopenia, ECMO can be run without anticoagulation even for considerably long periods of time. Bleeding remains common, while clotting events seem to be rare. However, prognosis of this patient population undergoing ECMO support seems grim.",
"affiliations": "Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, General Hospital of Vienna, Vienna, Austria.;Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, General Hospital of Vienna, Vienna, Austria.;Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, General Hospital of Vienna, Vienna, Austria.;Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, General Hospital of Vienna, Vienna, Austria.;Department of Clinical Pharmacology, Medical University of Vienna, General Hospital of Vienna, Vienna, Austria.;Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, General Hospital of Vienna, Vienna, Austria.",
"authors": "Hermann|Alexander|A|https://orcid.org/0000-0001-6103-7884;Schellongowski|Peter|P|;Bojic|Andja|A|;Robak|Oliver|O|;Buchtele|Nina|N|;Staudinger|Thomas|T|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1111/aor.13514",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-564X",
"issue": "43(11)",
"journal": "Artificial organs",
"keywords": "anticoagulation withdrawal; extracorporeal life support; extracorporeal membrane oxygenation; thrombocytopenia; venovenous",
"medline_ta": "Artif Organs",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D012189:Retrospective Studies; D013921:Thrombocytopenia",
"nlm_unique_id": "7802778",
"other_id": null,
"pages": "1077-1084",
"pmc": null,
"pmid": "31188474",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ECMO without anticoagulation in patients with disease-related severe thrombocytopenia: Feasible but futile?",
"title_normalized": "ecmo without anticoagulation in patients with disease related severe thrombocytopenia feasible but futile"
} | [
{
"companynumb": "AT-FRESENIUS KABI-FK201913634",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "OBJECTIVE\nTo evaluate local and systemic safety of suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) injections in subjects with non-infectious uveitis (NIU).\n\n\nMETHODS\nOpen-label, prospective multicentre safety study.\n\n\nMETHODS\nThirty-eight subjects with NIU, with and without macular oedema (MO).\n\n\nMETHODS\nTreatment consisted of two suprachoroidal injections of CLS-TA 4 mg, 12 weeks apart. Best-corrected visual acuity (BCVA), adverse event (AE) assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks. Blood samples were analysed for plasma triamcinolone acetonide (TA) concentrations.\n\n\nMETHODS\nThe main outcome measure was frequency of AEs. Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal central subfield thickness (CST).\n\n\nRESULTS\nBased on a CST of >300 µm, 20 out of 38 subjects had MO at baseline. Mean intraocular pressure (IOP) was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye. A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related. No serious ocular AEs in the study eye occurred in the study. Quantifiable post-injection TA plasma concentration was <1 ng/mL. Efficacy parameters showed improvement over the 24-week study period.\n\n\nCONCLUSIONS\nSuprachoroidally administered CLS-TA was safe and well tolerated over the 24-week, open-label study in NIU subjects with and without MO.",
"affiliations": "Retina Consultants of Texas, Houston, Texas, USA crhmd@houstonretina.com.;Midwest Eye Institute, Indianapolis, Indiana, USA.;Retinal Consultants of Arizona, Phoenix, Arizona, USA.;Retina Vitreous Associates, Los Angeles, California, USA.;Texas Retina Associates, Dallas, Texas, USA.;Northern California Retina Vitreous Associates, Mountain View, California, USA.;Ophthalmic Consultants of Boston, Boston, Massachusetts, USA.;Ophthalmology, Emory Eye Center, Atlanta, Georgia, USA.;Clearside Biomedical Inc, Alpharetta, Georgia, USA.;Clearside Biomedical Inc, Alpharetta, Georgia, USA.",
"authors": "Henry|Christopher Ryan|CR|http://orcid.org/0000-0003-4011-3758;Shah|Milan|M|;Barakat|Mark R|MR|;Dayani|Pouya|P|;Wang|Robert C|RC|;Khurana|Rahul N|RN|http://orcid.org/0000-0001-5198-1353;Rifkin|Lana|L|;Yeh|Steven|S|;Hall|Colette|C|;Ciulla|Thomas|T|http://orcid.org/0000-0001-5557-6777",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bjophthalmol-2020-318019",
"fulltext": "\n==== Front\nBr J Ophthalmol\nBr J Ophthalmol\nbjophthalmol\nbjo\nThe British Journal of Ophthalmology\n0007-1161\n1468-2079\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n33547034\nbjophthalmol-2020-318019\n10.1136/bjophthalmol-2020-318019\nClinical Science\n1506\nSuprachoroidal CLS-TA for non-infectious uveitis: an open-label, safety trial (AZALEA)\nhttp://orcid.org/0000-0003-4011-3758\nHenry Christopher Ryan 12\nShah Milan 3\nBarakat Mark R 4\nDayani Pouya 5\nWang Robert C 6\nhttp://orcid.org/0000-0001-5198-1353\nKhurana Rahul N 78\nRifkin Lana 9\nYeh Steven 10\nHall Colette 11\nhttp://orcid.org/0000-0001-5557-6777\nCiulla Thomas 1112\n1 Retina Consultants of Texas, Houston, Texas, USA\n2 Ophthalmology, Houston Methodist Hospital, Houston, Texas, USA\n3 Midwest Eye Institute, Indianapolis, Indiana, USA\n4 Retinal Consultants of Arizona, Phoenix, Arizona, USA\n5 Retina Vitreous Associates, Los Angeles, California, USA\n6 Texas Retina Associates, Dallas, Texas, USA\n7 Northern California Retina Vitreous Associates, Mountain View, California, USA\n8 Ophthalmology, University of California, San Francisco, California, USA\n9 Ophthalmic Consultants of Boston, Boston, Massachusetts, USA\n10 Ophthalmology, Emory Eye Center, Atlanta, Georgia, USA\n11 Clearside Biomedical Inc, Alpharetta, Georgia, USA\n12 Retina Service, Midwest Eye Institute, Indianapolis, Indiana, USA\nCorrespondence to Dr Christopher Ryan Henry, Retina Consultants of Texas, Houston, TX 77079, USA; crhmd@houstonretina.com\n6 2022\n5 2 2021\n106 6 802806\n07 10 2020\n19 12 2020\n11 1 2021\n© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2022\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nPurpose\n\nTo evaluate local and systemic safety of suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) injections in subjects with non-infectious uveitis (NIU).\n\nDesign\n\nOpen-label, prospective multicentre safety study.\n\nParticipants\n\nThirty-eight subjects with NIU, with and without macular oedema (MO).\n\nMethods\n\nTreatment consisted of two suprachoroidal injections of CLS-TA 4 mg, 12 weeks apart. Best-corrected visual acuity (BCVA), adverse event (AE) assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks. Blood samples were analysed for plasma triamcinolone acetonide (TA) concentrations.\n\nMain outcome measures\n\nThe main outcome measure was frequency of AEs. Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal central subfield thickness (CST).\n\nResults\n\nBased on a CST of >300 µm, 20 out of 38 subjects had MO at baseline. Mean intraocular pressure (IOP) was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye. A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related. No serious ocular AEs in the study eye occurred in the study. Quantifiable post-injection TA plasma concentration was <1 ng/mL. Efficacy parameters showed improvement over the 24-week study period.\n\nConclusions\n\nSuprachoroidally administered CLS-TA was safe and well tolerated over the 24-week, open-label study in NIU subjects with and without MO.\n\ndrugs\ninflammation\nintraocular pressure\nretina\nspecial-featureunlocked\n==== Body\npmcUveitis is a group of inflammatory ocular diseases that is responsible for 5%–20% of cases of legal blindness in the USA and Europe and up to 25% of cases of blindness in the developing world. Uveitis frequently occurs between the ages of 20 and 60, affecting patients during their most productive earning years.1 2 While some uveitis cases are infectious in origin, non-infectious uveitis (NIU) comprises up to 90% of cases, affecting nearly 300 000 adults and 22 000 children in the USA.2\n\nThe primary goals of NIU treatment are to control inflammation, preserve vision and minimise risk of treatment-related sequelae. Corticosteroids have remained a mainstay of treatment for NIU but are associated with significant limitations. Topical steroid drops have limited intraocular penetration and are used most frequently in anterior uveitis. Periocular or intravitreal steroids, including intravitreal corticosteroid implants, are often used for non-infectious intermediate, posterior and panuveitis, but are associated with relatively high rates of cataract and intraocular pressure (IOP) elevations. Systemic corticosteroids, used long term, have well-established systemic side effects, including weight gain, hypertension, hyperglycaemia, osteoporosis and psychiatric disturbances. For these reasons, guidelines and recommendations by expert panels have advised using steroid-sparing immunomodulatory therapy for chronic or severe NIU when long-term treatment with systemic corticosteroids would otherwise be necessary. These immunosuppressive agents carry their own set of systemic risks, such as haematotoxicity, liver/kidney injury and an increased incidence of certain malignancies.\n\nSuprachoroidal (SC) administration of an investigational corticosteroid formulation (triamcinolone acetonide injectable suspension (CLS-TA)) via a microinjector is a minimally invasive, alternative therapeutic approach to macular oedema (MO) associated with NIU.3 In preclinical studies, SC CLS-TA demonstrated improved bioavailability to the posterior segment and reduced exposure of anterior segment structures. Proof of concept of the efficacy and safety of SC triamcinolone acetonide (TA) treatment for posterior uveitis was established in a porcine animal model.4 Human clinical trials validated the utility of this approach, culminating in the successful phase III PEACHTREE trial using SC CLS-TA to treat MO associated with NIU. MO is the leading cause of uveitic vision loss for which there is no specific approved treatment.3 PEACHTREE demonstrated clinically meaningful ≥15 ETDRS letter gain for nearly half of the subjects treated, marked reduction of central subfield thickness (CST), and clinically and statistically significant resolution of anterior and posterior segment inflammation in approximately 70% of subjects. Furthermore, CLS-TA had a favourable adverse event (AE) profile, inclusive of events related to IOP increase and cataracts.\n\nHerein, we report results of a companion study (AZALEA) designed to assess the safety of 4 mg of CLS-TA administered via SC injection for the treatment of subjects with NIU, both with and without the presence of MO. This study provides new information regarding the use of CLS-TA in NIU subjects without MO, while corroborating PEACHTREE results in NIU subjects with MO, and also reporting systemic pharmacokinetic (PK) outcomes for the first time.\n\nMethods\n\nStudy participants\n\nInstitutional Review Board approval was obtained for this study (ClinicalTrials.gov identifier NCT03097315), which adhered to the tenets of the Declaration of Helsinki. Subjects ≥18 years of age were eligible if they had a diagnosis of active or inactive NIU of any aetiology in any anatomic location and an ETDRS best-corrected visual acuity (BCVA) score of ≥5 letters in the study eye. Subjects were excluded if they had any active ocular disease other than uveitis or infection in the study eye; IOP>22 mm Hg; severe or uncontrolled glaucoma; or recent use of topical, intraocular or periocular steroids. Systemic corticosteroids at doses of ≤20 mg/day for oral prednisone (or equivalent for other corticosteroids) as well as non-steroidal anti-inflammatory drugs and/or systemic immunomodulatory therapies at stable doses for the previous two or more weeks were permissible. In subjects with IOP ≤22 mm Hg, use of up to two IOP-lowering medications was allowed. All subjects provided informed consent for the study and separately for PK sampling.\n\nStudy design\n\nThis open-label, prospective multicentre safety study was conducted at 11 sites in the USA from April 2017 to January 2018. Subject eligibility was established up to 30 days prior to baseline (day 0). If both eyes met the study criteria, the right eye was designated the study eye.\n\nEligible subjects returned to the clinic for treatment at day 0; screening and treatment could occur on the same day. Qualified subjects received a single unilateral SC injection of CLS-TA, 4 mg (0.1 mL of 40 mg/mL), at day 0 and at week 12. SC injection was administered via a proprietary microinjector (Clearside Biomedical, Alpharetta, Georgia, USA) with a 900 or 1100 µm needle length, approximately 4 mm posterior from the limbus, in the temporal hemisphere.\n\nFollow-up visits, consisting of AE assessment, BCVA, slit lamp examination, IOP measurement, indirect ophthalmoscopy and spectral-domain optical coherence tomography (SD-OCT), were conducted every 4 weeks up to 24 weeks for a total of 8 visits. Subjects providing consent for PK analysis had blood samples collected at day 0, week 4, week 12 and week 24. On day 0 and week 12, the blood samples were obtained prior to CLS-TA injection administration.\n\nBeginning at week 4, a rescue treatment could be introduced if any of the following criteria were met in the study eye: (1) decrease of 10 or more ETDRS BCVA letters read from baseline; (2) increase in CST of ≥100 µm or 20%, whichever was lower, from baseline; (3) a ≥1.5 step increase from baseline in the level of inflammation (eg, anterior chamber (AC) cells, AC flare or vitreous haze) or an increase from 3+ to 4+; (4) decrease of 10 or more ETDRS BCVA letters read compared with the best ETDRS BCVA data observed during the study, along with an increase in other signs or complications associated with uveitis; or (5) the uveitic complications in the study eye had not improved and the condition needed to be addressed according to the investigator’s medical judgement.\n\nSafety endpoints\n\nThe main safety outcome assessed was the incidence of treatment-emergent AEs (TEAEs) and serious AEs (SAEs) in the safety population. Additional safety outcomes included frequency of vision loss in the study eye, elevated IOP, frequency and severity of cataract formation, and plasma TA concentrations post-treatment.\n\nVisual and anatomical outcomes\n\nEfficacy measures included change in grade from baseline of AC cells, AC flare and vitreous haze as measured by Standardization of Uveitis Nomenclature (SUN) working group criteria5 at each visit; mean change from baseline in ETDRS BCVA; mean change from baseline in CST assessed by spectral-domain optical coherence tomography; the percentage of subjects with a decrease in systemic concomitant uveitis medications; and the percentage of subjects in whom any additional therapy was initiated to manage uveitis.\n\nStatistical analysis\n\nStatistical analyses were descriptive in nature. Continuous variables were summarised by descriptive statistics, and categorical variables were summarised by counts and percentages. The safety population included all subjects who entered this study and were administered at least 1 dose of CLS-TA. All safety analyses were performed for the safety population. The intent-to-treat (ITT) population included all subjects eligible to be treated with CLS-TA who did not fail screening. Values for missing data were imputed using the method of last observation carried forward. Subjects given additional treatment for uveitis had all data following the administration of additional treatment set to missing and imputed using the Last Observation Carried Forward (LOCF) method. The ITT population was used for efficacy assessments. The PK population included all subjects who were administered at least 1 dose of CLS-TA and provided a blood sample for the measurement of TA concentrations. Analyses were conducted on all samples collected during the study. A sample size of 35 subjects would provide approximately 80% probability of detecting at least one subject with an IOP >30 mm Hg over the 24-week follow-up period if the true incidence is 5% based on a binomial distribution.\n\nResults\n\nForty-three subjects consented to screening, and 38 enrolled in the study, comprising the ITT population. The same 38 subjects received at least 1 dose of CLS-TA and were therefore included in the safety population. Thus, the safety population and ITT population were identical. Six subjects had significant protocol deviations, leaving 32 subjects in the per-protocol population. Four were related to the injection procedure, and two were schedule-related deviations per the protocol; 37 subjects completed the study. Subjects were predominantly female and white (table 1). Uveitis was bilateral in 81.6% of cases. The most common anatomical classification was intermediate uveitis, followed by anterior uveitis, and then posterior and panuveitis (table 1), and 20 out of 38 subjects had MO based on a CST of >300 µm.\n\nTable 1 Subject and disease characteristics (safety population)\n\nSubject characteristic\tSafety population (N=38)\t\nAge at screening (years)\t\t\nMean (SD)\t52.4 (15.80)\t\nMin, Max\t22, 77\t\nSex, n (%)\t\t\nMale\t13 (34.2%)\t\nFemale\t25 (65.8%)\t\nRace/Ethnicity, n (%)\t\t\nWhite—not Hispanic or Latino\t26 (68.4%)\t\nBlack/African American—not Hispanic or Latino\t7 (18.4%)\t\nWhite—Hispanic or Latino\t5 (13.2%)\t\nDisease characteristic (N=38)\tStudy eye*\tFellow eye†\t\nUveitis type, n (%)\t\t\t\nAnterior uveitis\t12 (31.6%)\t10 (26.3%)\t\nIntermediate uveitis\t15 (39.5%)\t12 (31.6%)\t\nPosterior uveitis\t10 (26.3%)\t8 (21.1%)\t\nPanuveitis\t10 (26.3%)\t7 (18.4%)\t\nUveitis onset, n (%)\t\t\t\nSudden\t16 (42.1%)\t4 (10.5%)\t\nInsidious\t20 (52.6%)\t10 (26.5%)\t\nUveitis duration, n (%)\t\t\t\nLimited (≤3 months duration)\t5 (13.2%)\t3 (7.9%)\t\nPersistent (>3 months duration)\t31 (81.6%)\t11 (28.9%)\t\nUveitis course, n (%)\t\t\t\nAcute\t1 (2.6%)\t1 (2.6%)\t\nRecurrent\t11 (28.9%)\t1 (2.6%)\t\nChronic\t24 (63.2%)\t12 (31.6%)\t\nAetiology of uveitis, n (%)\t\t\t\nIdiopathic or not specified\t21 (55.3%)\t15 (39.5%)\t\nSarcoidosis\t8 (21.1%)\t8 (21.1%)\t\nHLA-B27 related\t3 (7.9%)\t2 (5.3%)\t\nReactive arthritis\t2 (5.3%)\t2 (5.3%)\t\nVogt-Koyanagi-Harada syndrome\t1 (2.6%)\t1 (2.6%)\t\nBirdshot retinochoroidopathy\t3 (7.9%)\t3 (7.9%)\t\n*Two study eyes were not assessed for disease characteristics.\n\n†Thirty-one out of 38 fellow eyes were diagnosed with uveitis.\n\nA total of six subjects were receiving one or more systemic corticosteroids or immunosuppressants at baseline, and six subjects were receiving inhaled or nasal corticosteroids. Systemic medications included adalimumab (n=3), methotrexate (n=2), mycophenolate mofetil (n=1), prednisone (n=4), rituximab (n=1), secukinumab (n=1) and vedolizumab (n=1). Each of these patients remained on at least one systemic medication for the duration of the study. A total of seven subjects were receiving IOP-lowering medication(s) in their study eye at baseline. Topical IOP-lowering medications included brimonidine (n=3), dorzolamide (n=2), timolol (n=1), combination brimonidine/timolol (n=1), combination brinzolamide/brimonidine (n=1) and combination dorzolamide/timolol (n=2). All patients remained on at least one medication for the duration of the study. No patients were on systemic IOP-lowering medications.\n\nSafety\n\nTreatment with CLS-TA was well tolerated over 24 weeks. Eye pain at the time of the injection procedure was reported in three (7.9%) subjects. Study eye TEAEs from AZALEA are summarised in table 2.\n\nTable 2 Ocular adverse events\n\nStudy eye, n (%)\tCLS-TA 4.0 mg\n(N=38)\t\nTotal number of ocular adverse events\t41\t\nNumber of patients with ≥1 ocular AE\t19 (50.0)\t\nTreatment-related ocular AEs\t7 (18.4)\t\nSerious ocular AEs\t0\t\nTreatment-related serious AEs\t0\t\nTEAEs leading to study drug discontinuation\t0\t\nAdverse events\t\t\n Cataract*\t4 (10.5)\t\n Cystoid macular oedema\t0\t\n Endophthalmitis\t0\t\n Eye pain†: time of procedure\t3 (7.9)\t\n Eye pain†: any time post procedure\t1 (2.6)\t\n Elevated IOP‡: time of procedure\t1 (2.6)\t\n Elevated IOP‡: pertaining to corticosteroid§\t5 (13.2)\t\n Retinal detachment\t0\t\n Suprachoroidal haemorrhage\t0\t\n Worsening of uveitis\t1 (2.6)\t\n Vitreous detachment\t1 (2.6)\t\n*Cataract includes the medDRA preferred terms (a) cataract, (b) cataract subcapsular and (c) cataract nuclear.\n\n†‘Eye pain’ includes the preferred terms (a) eye pain and (b) injection site pain.\n\n‡‘Elevated IOP’ includes the preferred terms (a) IOP increased and (b) ocular hypertension.\n\n§Includes all events of elevated IOP that did not occur on the day of the procedure.\n\nAE, adverse event; CLS-TA, investigational triamcinolone acetonide injectable suspension; IOP, intraocular pressure.\n\nThere were no TEAEs leading to study discontinuation or death, and no SAEs involving the study eye. Seven subjects (18.4%) experienced a TEAE that was considered by the investigator to be related to the study drug. One subject (2.6%) had a TEAE immediately following the injection procedure at baseline and five (13.2%) subjects had a TEAE associated with the corticosteroid. At the conclusion of the study, all causally related events were resolved, except one event of increased IOP, two events of ocular hypertension and one event of posterior subcapsular cataract. MedDRA preferred terms ‘IOP increased’ and ‘ocular hypertension’ were grouped together under ‘Elevated IOP’ in table 2.\n\nWith respect to IOP, mean values were 13.3 mm Hg at baseline to 15.2 mm Hg at week 24 in the study eye (figure 1). A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had an IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Four subjects were treated with one additional IOP-lowering medication and three subjects were treated with two additional IOP-lowering medications. Of the seven subjects receiving IOP-lowering medications at baseline, three subjects experienced a sponsor-defined IOP event (eg, an increase from baseline >10 mm Hg), and two of the three were treated with additional topical IOP-lowering medications. No subjects discontinued the study because of elevated IOP or required surgery related to elevated IOP.\n\nFigure 1 Mean (SEM) intraocular pressure. CLS-TA, investigational triamcinolone acetonide injectable suspension; IOP, intraocular pressure.\n\nThe formation or worsening of cataracts occurred in four (10.5%) subjects, one of which was considered to be treatment-related. No cases of cataract were related to the injection procedure itself; furthermore, penetration of the sclera to the lens would not be possible based on the length of the microneedle. Investigator descriptions of cataract progression included worsening of posterior subcapsular cataract, worsening of nuclear sclerosis, trace nuclear sclerosis and worsening of cataract. No patients required cataract surgery. Of note, two of these subjects developed cataracts, in the fellow eye, either concurrently or subsequently, during the trial. No patients experienced endophthalmitis or suprachoroidal haemorrhage.\n\nThirty-seven of 38 subjects contributed at least 1 PK sample for analysis and were included in the PK population. Analyses were conducted on all 91 samples collected during the study. Thirty-eight of 91 samples had no quantifiable TA levels, or <10.00 pg/mL (below the limit of quantitation (BLQ)) TA plasma concentration values. The quantifiable TA plasma concentration values for post-injection samples were all lower than 1 ng/mL and were no higher than those observed with intravitreal injected TA as reported in the product label.\n\nVision and anatomical outcomes\n\nFigure 2 summarises the effect of CLS-TA on the grading of AC cells, AC flare and vitreous haze in study eyes of the ITT population. The number of subjects with AC cell grade of 0 improved from 17 (44.7%) at baseline to 31 (81.6%) at week 24. Over the same timeframe, the number of subjects with AC flare grade of 0 improved from 27 (71.1%) at baseline to 34 (89.5%) at week 24. The number of subjects with a vitreous haze grade of 0 improved from 17 (44.7%) at baseline to 34 (89.5%) at week 24. Per predefined criteria, four subjects received rescue therapy including nepafenac, triamcinolone acetonide, aflibercept, prednisolone or prednisolone acetate. No subjects had a decrease in systemic concomitant uveitis medications during the study.\n\nFigure 2 Percentage of subjects with resolution of anterior chamber cells, anterior chamber flare and vitreous haze (safety population). CLS-TA, investigational triamcinolone acetonide injectable suspension\n\nAt baseline, the mean BCVA in the study eye was 68.9 (SD 19.07) for the ITT population. The mean BCVA improved at all post-baseline visits, measuring 75.0 (SD 16.93) at week 8 and 75.9 (SD 15.82) at week 24. In subjects with a baseline BCVA of ≤80 letters (27 subjects), 17 subjects (63.0%) had a gain of at least 5 letters at visit 8 (week 24).\n\nMO was not required for inclusion in this trial. At baseline, the mean CST in the study eye was 335.9 µm (SD 85.00) in the ITT population. At all post-baseline visits, mean CST improved, and at week 24, mean CST was 284.0 µm (SD 76.44), a decrease of 15%. Excess retinal thickness, an estimate of the amount of edematous tissue in the retina, was defined as the observed thickness minus a ‘normal’ subfield thickness of 300 µm. At baseline, 20 subjects in the ITT population had excess retinal thickness >300 µm in the study eye. Over time, between 70% and 85% of subjects with MO at baseline experienced a decrease in excess retinal thickness of 20% or more compared with baseline. CST results are summarised in figure 3.\n\nFigure 3 Mean (SEM) change from central subfield retinal thickness (intent-to-treat population).\n\nDiscussion\n\nThe goal of suprachoroidal delivery of corticosteroid is to provide a targeted therapy compartmentalised for safety and with the potential for prolonged PK for durability. AZALEA corroborates and augments the successful phase III PEACHTREE trial using SC CLS-TA for MO associated with NIU, assessing CLS-TA in NIU subjects both with and without MO, as well as reporting systemic PK outcomes for the first time. In preclinical studies involving a rabbit model, TA concentrations in plasma peaked 1 day after bilateral CLS-TA injection (4 mg/0.1 mL), with mean maximal serum concentrations of 12 ng/mL. Plasma TA concentrations were still quantifiable at very low levels in individual animals 60 days after each injection, and were undetectable in most animals 90 days after each injection. In this open-label trial, after treatment with 4 mg CLS-TA, quantifiable TA plasma concentration was <1 ng/mL in all samples and therapy was well tolerated over 24 weeks. There were no TEAEs leading to study discontinuation or death, and no ocular SAEs. Of note, this novel delivery method showed AEs related to pain which was similar to the previous PEACHTREE study3 and compared favourably with intravitreal injection of other corticosteroids.6\n\nAlthough the primary objective of this study was to assess safety of SC CLS-TA in NIU, visual and anatomical outcomes were also explored. Overall, all efficacy parameters showed improvement over the 24-week AZALEA study, with the majority of subjects demonstrating improvement in the signs of inflammation (AC cells, flare and vitreous haze). The majority of patients did not require rescue therapy, similar to the PEACHTREE trial.\n\nBCVA and CST showed modest improvement in this trial. Unlike the PEACHTREE trial, AZALEA had broader inclusion criteria and allowed subjects with active and inactive NIU to participate regardless of the presence of MO. The lack of MO among AZALEA subjects is consistent with better baseline mean BCVA and CST than in PEACHTREE subjects, potentially creating a relative ceiling effect for improvement in AZALEA compared with PEACHTREE.\n\nThe AZALEA study has several limitations, including the small number of subjects, the open-label study design and the lack of a control group. Nevertheless, CLS-TA shows meaningful promise, noted from preclinical testing through clinical studies, including AZALEA. In preclinical studies, suprachoroidal injection of TA demonstrated favourable ocular distribution with greater concentrations in the chorioretinal tissues than anterior tissues, along with prolonged therapeutic tissue levels. Also, preclinical uveitis models demonstrated the potential benefits of targeted delivery to affected tissue, as suprachoroidal injection of TA was as effective as intravitreal injection of TA at 1/10th the dose. This prolonged targeted compartmentalisation and preclinical efficacy correlated to results from AZALEA and its companion study, PEACHTREE, demonstrating clinically meaningful efficacy and safety manifested by both low IOP and cataract adverse events. In the future, CLS-TA may represent an additional promising local corticosteroid option for NIU.\n\nData availability statement\n\nNo data are available. Additional context can be found in the PEACHTREE manuscript (https://pubmed.ncbi.nlm.nih.gov/32173113/).\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nTwitter: @ThomasCiullaMD\n\nPresented at: Data from this manuscript were presented at the American Uveitis Society, held January 2019, in Park City, Utah, USA, the American Society of Retina Specialists (ASRS), held in July 2019, in Chicago, Illinois, USA, the Retina World Congress, held in March 2019, in Fort Lauderdale, Florida, USA, and the Macula Society, held in February 2019, in Bonita Springs, Florida, USA.\n\nCorrection notice: This article has been corrected since it was published online. An error was introduced during the production process in the results section of the abstract. In the Abstract results, first sentence: ‘Based on a CST of ≥300 µm, 20 out of 38 subjects had MO at baseline.’ has been changed to: ‘Based on a CST of >300 µm, 20 out of 38 subjects had MO at baseline.’ Further, in the Abstract results, fourth sentence: ‘Cataract formation AEs were reported in four study eyes; two of which were deemed treatment-related.’ should be: ‘Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related.’\n\nContributors: All coauthors contributed to the data acquisition and/or research execution, data analysis and/or interpretation, and manuscript preparation.\n\nFunding: This study was funded by Clearside Biomedical (Alpharetta, Georgia, USA). The sponsor participated in the design of the study, conducting the study, data collection, data management, data analysis, interpretation of the data, preparation and review of the manuscript.\n\nCompeting interests: CRH reports receiving consulting fees from Clearside Biomedical and Bausch & Lomb. MS reports receiving grant support from Clearside Biomedical. MRB reports receiving consulting fees from Allegro, Allergan, Alimera, Bausch & Lomb, Genentech, Novartis and Regenxbio. RNK reports receiving consulting fees from Allergan, Clearside Biomedical, Genentech and Regeneron. He also reports receiving grant support from Allergan, Chengdu Kanghong, Clearside Biomedical, Roche and Santen. LR reports receiving consulting fees from Bausch & Lomb. SY reports receiving consulting fees from Clearside Biomedical and Santen. He also reports receiving grant funding from Clearside Biomedical. CH and TC are employees of Clearside Biomedical.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Suttorp-Schulten MS , Rothova A . The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol 1996;80 :844–8. 10.1136/bjo.80.9.844 8962842\n2 Thorne JE , Suhler E , Skup M , et al . Prevalence of noninfectious uveitis in the United States: a Claims-Based analysis. JAMA Ophthalmol 2016;134 :1237–45. 10.1001/jamaophthalmol.2016.3229 27608193\n3 Yeh S , Khurana RN , Shah M , et al . Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial. Ophthalmology 2020;127 :948–55. 10.1016/j.ophtha.2020.01.006 32173113\n4 Gilger BC , Abarca EM , Salmon JH , et al . Treatment of acute posterior uveitis in a porcine model by injection of triamcinolone acetonide into the suprachoroidal space using microneedles. Invest Ophthalmol Vis Sci 2013;54 :2483–92. 10.1167/iovs.13-11747 23532526\n5 Jabs DA , Nussenblatt RB , Rosenbaum JT , et al . Standardization of uveitis nomenclature for reporting clinical data. results of the first International workshop. Am J Ophthalmol 2005;140 :509–16. 10.1016/j.ajo.2005.03.057 16196117\n6 Lowder C , Belfort R , Lightman S , et al . Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129 :545–53. 10.1001/archophthalmol.2010.339 21220619\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0007-1161",
"issue": null,
"journal": "The British journal of ophthalmology",
"keywords": "drugs; inflammation; intraocular pressure; retina",
"medline_ta": "Br J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "0421041",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33547034",
"pubdate": "2021-02-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Suprachoroidal CLS-TA for non-infectious uveitis: an open-label, safety trial (AZALEA).",
"title_normalized": "suprachoroidal cls ta for non infectious uveitis an open label safety trial azalea"
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-06104",
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"activesubstancename": "TRIAMCINOLONE ACETONIDE"
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"abstract": "BACKGROUND\nAdenoid cystic carcinoma (ACC) of the head and neck is a rare malignancy of the salivary glands that accounts for approximately 10% of salivary gland carcinoma. Despite aggressive local therapy, local recurrence and distant metastases occur frequently. Response rates (RR) to potential curative and palliative chemotherapy are limited, so new strategies are needed.\n\n\nMETHODS\nWe describe five case reports of patients with unresectable locally advanced or metastatic ACC of the head and neck who have been treated with sorafenib, a multi-tyrosine kinase inhibitor (mTKI).\n\n\nRESULTS\nIn this case series, we found that three out of five patients treated with sorafenib survived, respectively, 16, 35 and 35 months. Two patients showed a partial response (PR) and one patient had a prolonged stable disease (SD) for almost three years. Grade 3 adverse events (AE) occur under sorafenib so adequate toxicity management is essential. This retrospective case series hints towards the possibility of clinical benefit for treating ACC patients with sorafenib. Efficacy of sorafenib should be studied in a prospective-randomized clinical trial which is a challenging task due to the rarity of the disease.",
"affiliations": "Department of Medical Oncology, AZ Damiaan , Oostende, Belgium.;Department of Medical Oncology, UZ Gent , Ghent, Belgium.;Department of Medical Oncology, UZ Gent , Ghent, Belgium.;Department of Medical Oncology, AZ Damiaan , Oostende, Belgium.;Department of Head and Neck Surgery, UZ Gent , Ghent, Belgium.;Department of Radiotherapy, UZ Gent , Ghent, Belgium.;Department of Medical Oncology, UZ Gent , Ghent, Belgium.",
"authors": "Couvreur|Karen|K|;Celine|Jacobs|J|https://orcid.org/0000-0001-5286-3519;Marlies|Bock|B|https://orcid.org/0000-0001-9439-9881;Randal|D'Hondt|D|;Philippe|Deron|D|https://orcid.org/0000-0003-1703-4410;Frederic|Duprez|D|https://orcid.org/0000-0002-7633-1960;Sylvie|Rottey|R|https://orcid.org/0000-0003-2060-3725",
"chemical_list": "D000970:Antineoplastic Agents; D000077157:Sorafenib",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2019.1633490",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "75(5)",
"journal": "Acta clinica Belgica",
"keywords": "Adenoid cystic carcinoma; Sorafenib; salivary gland carcinoma; targeted therapy; tyrosine kinase inhibitor",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001859:Bone Neoplasms; D003528:Carcinoma, Adenoid Cystic; D005221:Fatigue; D005260:Female; D060831:Hand-Foot Syndrome; D006801:Humans; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D052016:Mucositis; D009364:Neoplasm Recurrence, Local; D010496:Pericardium; D010997:Pleural Neoplasms; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D012468:Salivary Gland Neoplasms; D000077157:Sorafenib",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "362-369",
"pmc": null,
"pmid": "31232197",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and toxicity of sorafenib in patients with adenoid cystic carcinoma of the head and neck: a case series of five patients.",
"title_normalized": "efficacy and toxicity of sorafenib in patients with adenoid cystic carcinoma of the head and neck a case series of five patients"
} | [
{
"companynumb": "BE-ACCORD-225273",
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"activesubstancename": "CISPLATIN"
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"drugadditional": null,
"druga... |
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"abstract": "The authors of Freedom study enrolling primary osteoporosis patients argued that the anti-fracture effect of denosmab is not dependent on baseline estimated glomerular filtration rate(eGFR)by showing the non-significant interaction term between treatment and CKD stage. However, given disproportionate numbers of patients in each subgroup(4069, 2817, and only 73 patients, in CKD stage 2, 3, and, 4, respectively), this study seems to lack the statistical power to reach a definite conclusion on the effect modification by CKD stage. Truly, the serum concentration of infused denosmab in patients with CKD stage 4 is equivalent to that in patients without CKD, the risk of developing life-threatening or prolonged hypocalcemia is huge even under active vitamin D therapy in this population. In hemodialysis patients, this drug is relatively safer because each dialysis session delivers calcium into the circulation 3 times a week. However, even with concomitant administration of massive active vitamin D, the increase of intact PTH levels greater than 1000 pg/mL by this agent is not rare. In other words, this drug worsens secondary hyperparathyroidism. Moreover, reportedly, calcium and active vitamin D administered to avoid hypocalcemia can lead to ectopic calcification especially under the low bone turnover induced by this agent. In fact, transient hypercalcemia often follows hypocalcemia by the inevitable calcium supplementation.",
"affiliations": "Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Japan.;Internal Medicine, Kisei Hospital, Japan.",
"authors": "Hamano|Takayuki|T|;Nakano|Chikako|C|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab; D002118:Calcium",
"country": "Japan",
"delete": false,
"doi": "CliCa160913091317",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0917-5857",
"issue": "26(9)",
"journal": "Clinical calcium",
"keywords": null,
"medline_ta": "Clin Calcium",
"mesh_terms": "D050071:Bone Density Conservation Agents; D002118:Calcium; D012080:Chronic Kidney Disease-Mineral and Bone Disorder; D000069448:Denosumab; D050723:Fractures, Bone; D006801:Humans; D006996:Hypocalcemia; D006435:Renal Dialysis; D012307:Risk Factors",
"nlm_unique_id": "9433326",
"other_id": null,
"pages": "1309-17",
"pmc": null,
"pmid": "27561346",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Is denosmab really effective and safe in the care of CKD-MBD?.",
"title_normalized": "is denosmab really effective and safe in the care of ckd mbd"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2014069868",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "FEBUXOSTAT"
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{
"abstract": "Lenalidomide plus dexamethasone is effective and well tolerated in relapsed/refractory multiple myeloma (RRMM). In this observational, noninterventional European post-authorization safety study, the safety profile of lenalidomide plus dexamethasone was investigated and compared with that of other agents in the treatment of RRMM in a real-world setting.\n\n\n\nPatients had received ≥ 1 prior antimyeloma therapy; prior lenalidomide was excluded. Treatment was per investigator's routine practice. Adverse events were analyzed by incidence rates per 100 person-years to account for differences in observation length and treatment duration.\n\n\n\nIn total, 2150 patients initiated lenalidomide, and 1479 initiated any other antimyeloma therapy, predominately bortezomib (80.3%), which was primarily administered intravenously (74.3%). The incidence rate of neuropathy was lower with lenalidomide (10.5) than with bortezomib (78.9) or thalidomide (38.7). Lenalidomide also had a lower incidence rate of infections (68.7) versus bortezomib (95.9) and thalidomide (76.0). Conversely, the incidence rate of neutropenia was higher with lenalidomide (38.0) than with bortezomib (18.2) or thalidomide (25.7). The incidence rates of thrombocytopenia were 24.4, 40.4, and 14.4 with lenalidomide, bortezomib, and thalidomide, respectively.\n\n\n\nNo new safety signals for lenalidomide were identified in this study, which is the largest prospective real-world European study of lenalidomide in patients with RRMM to date. These results confirm that the safety profile of lenalidomide plus dexamethasone in RRMM in a real-world setting is comparable to that reported in clinical trials.",
"affiliations": "Department of Hematology, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy. Electronic address: gamberi.barbara@asmn.re.it.;Centre Hospitalier Régional Universitaire, Hôpital Auguste Morvan, Brest, France.;Hemotherapy Service, Hospital Universitario de Canarias, Tenerife, Spain.;Department of Medicine, Azienda Ospedale Università di Padova, Padova, Italy.;Department of Haematology, Manchester Royal Infirmary, Manchester, United Kingdom.;Department of Clinic Subjects, University Hospital Ostrava and Faculty of Medicine Ostrava, Ostrava, Czech Republic.;Department of Hematology, Centre Hospitalier Universitaire de Liège, Liège, Belgium.;National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.;Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.;Uddevalla Hospital, NU Hospital Group, Uddavella, Sweden.;Instituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina, Universidade de Lisboa and Instiuto Português de Oncologia, Francisco Gentil, Lisboa, Portugal.;Department of Haematology, Midland Regional Hospital, Tullamore, Ireland.;Department of Internal Medicine, Turku University Hospital, Turku, Finland.;Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland.;Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland.;Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland.;Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland.;Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland.;Department of Internal Medicine III, Charité Campus Benjamin Franklin, Berlin, Germany.",
"authors": "Gamberi|Barbara|B|;Berthou|Christian|C|;Hernandez|Miguel|M|;Semenzato|Gianpietro|G|;Tholouli|Eleni|E|;Hájek|Roman|R|;Caers|Jo|J|;Dimopoulos|Meletios|M|;Minnema|Monique C|MC|;Andreasson|Bjorn|B|;Parreira|Joana|J|;Crotty|Gerard|G|;Remes|Kari|K|;Kueenburg|Elisabeth|E|;Rosettani|Barbara|B|;Di Micco|Antonia|A|;Peters|Sarah|S|;Bacon|Pamela|P|;Blau|Igor Wolfgang|IW|",
"chemical_list": "D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2020.05.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "20(10)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Adverse events of special interest; Immunomodulatory; Incidence rate; Prospective; Real-world",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005060:Europe; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011446:Prospective Studies",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e629-e644",
"pmc": null,
"pmid": "32605897",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Noninterventional, Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide.",
"title_normalized": "a noninterventional observational european post authorization safety study of patients with relapsed refractory multiple myeloma treated with lenalidomide"
} | [
{
"companynumb": "IT-TAKEDA-2020TUS046452",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "Secondary acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS) are known to develop in patients previously treated with different chemotherapeutic regimens. Nonrandom chromosomal abnormalities have been demonstrated in these therapy-related myeloid disorders which often evolve into refractory AML. The prognosis of these patients with conventional chemotherapy has been dismal and only allogeneic bone marrow transplantation offers a potential cure. We describe two patients who developed MDS after chemo/radiotherapy and had a spontaneous recovery. One patient was treated with MOPP-ABVD hybrid therapy for Hodgkin's disease, developed pancytopenia, marrow hypoplasia and dyserythropoiesis associated with monosomy 7. The other was treated with a combination of chemotherapy including VP-16 for Ewing's sarcoma, developed thrombocytopenia, marrow hypoplasia and dyserythropoiesis associated with an 11q23 translocation. Both patients received rhG-CSF after their cycles of chemotherapy and were considered for a bone marrow transplant. Marrow aspirates at frequent intervals showed gradual disappearance of the abnormal clone with parallel normalization of the peripheral count. In both patients G-CSF might have played a role in the development of the abnormal clone. We suggest that patients with therapy-related MDS without excess of blasts could be closely monitored for karyotypic and hematological improvement rather than transplanted immediately.",
"affiliations": null,
"authors": "Laver|J H|JH|;Yusuf|U|U|;Cantu|E S|ES|;Barredo|J C|JC|;Holt|L B|LB|;Abboud|M R|MR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2400576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "11(3)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002880:Chromosomes, Human, Pair 11; D002897:Chromosomes, Human, Pair 7; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009006:Monosomy; D009190:Myelodysplastic Syndromes; D016609:Neoplasms, Second Primary; D014178:Translocation, Genetic",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "448-50",
"pmc": null,
"pmid": "9067588",
"pubdate": "1997-03",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Transient therapy-related myelodysplastic syndrome associated with monosomy 7 and 11q23 translocation.",
"title_normalized": "transient therapy related myelodysplastic syndrome associated with monosomy 7 and 11q23 translocation"
} | [
{
"companynumb": "US-PFIZER INC-2018149574",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MECHLORETHAMINE OXIDE HYDROCHLORIDE"
},
"druga... |
{
"abstract": "Dexmedetomidine is a highly selective α-2 agonist which has recently revolutionized our anesthesia and intensive care practice. An obstetric patient presented for emergency cesarean delivery under general anesthesia, with pre-eclampsia and postpartum hemorrhage. In carefully selected cases with refractory hypertension and postpartum hemorrhage, dexmedetomidine can be used for improving overall patient outcome. It was beneficial in controlling both the blood pressure and uterine bleeding during cesarean section in our patient.",
"affiliations": "Bhagwan Mahavir Hospital, Rajiv Gandhi Cancer Institute and Research Centre, Delhi Government Health Services, New Delhi, Índia. Electronic address: uma1708@gmail.com.",
"authors": "Hariharan|Uma|U|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D020927:Dexmedetomidine",
"country": "Brazil",
"delete": false,
"doi": "10.1016/j.bjan.2015.09.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-7094",
"issue": "67(5)",
"journal": "Revista brasileira de anestesiologia",
"keywords": "Anestesia obstétrica; Cesariana de emergência; Dexmedetomidina; Dexmedetomidine; Emergency cesarean section; Hemorragia pós‐parto; Hipertensão induzida pela gravidez; Obstetric anesthesia; Post‐partum hemorrhage; Pregnancy‐induced hypertension",
"medline_ta": "Rev Bras Anestesiol",
"mesh_terms": "D000328:Adult; D018712:Analgesics, Non-Narcotic; D000773:Anesthesia, Obstetrical; D002585:Cesarean Section; D020927:Dexmedetomidine; D004638:Emergency Treatment; D005260:Female; D006801:Humans; D046110:Hypertension, Pregnancy-Induced; D006473:Postpartum Hemorrhage; D011247:Pregnancy",
"nlm_unique_id": "0401316",
"other_id": null,
"pages": "538-540",
"pmc": null,
"pmid": "28535940",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Postpartum hemorrhage and pregnancy induced hypertension during emergency lower segment cesarean section: dexmedetomidine to our rescue.",
"title_normalized": "postpartum hemorrhage and pregnancy induced hypertension during emergency lower segment cesarean section dexmedetomidine to our rescue"
} | [
{
"companynumb": "IN-BAXTER-2017BAX024598",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ISOFLURANE"
},
"drugadditional": null,
... |
{
"abstract": "To describe the clinical manifestations of presumed gadolinium toxicity in patients with normal renal function.\n\n\n\nParticipants were recruited from two online gadolinium toxicity support groups. The survey was anonymous and individuals were instructed to respond to the survey only if they had evidence of normal renal function, evidence of gadolinium in their system beyond 30days of this MRI, and no pre-existent clinical symptoms and/or signs of this type.\n\n\n\n42 subjects responded to the survey (age: 28-69, mean 49.1±22.4years). The most common findings were: central pain (n=15), peripheral pain (n=26), headache (n=28), and bone pain (n=26). Only subjects with distal leg and arm distribution described skin thickening (n=22). Clouded mentation and headache were the symptoms described as persistent beyond 3months in 29 subjects. Residual disease was present in all patients. Twenty-eight patients described symptoms following administration of one brand of Gadolinium-Based Contrast Agent (GBCA), 21 after a single GBCA administration and 7 after multiple GBCA administrations, including: gadopentetate dimeglumine, n=9; gadodiamide, n=4; gadoversetamide, n=4; gadobenate dimeglumine, n=4; gadobutrol, n=1; gadoteridol, n=2; and unknown, n=4.\n\n\n\nGadolinium toxicity appears to arise following GBCA administration, which appears to contain clinical features seen in Nephrogenic Systemic Fibrosis, but also features not observed in that condition.",
"affiliations": "Department of Radiology, University of North Carolina, Chapel Hill, NC, USA. Electronic address: richsem@med.unc.edu.;Department of Radiology, University of North Carolina, Chapel Hill, NC, USA; Department of Radiology, Centro Hospitalar Lisboa Central, Lisbon, Portugal.;Department of Radiology, University of North Carolina, Chapel Hill, NC, USA.;Department of Radiology, University of North Carolina, Chapel Hill, NC, USA; Department of Radiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Radiology, University of North Carolina, Chapel Hill, NC, USA.;Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.;Department of Radiology, University of North Carolina, Chapel Hill, NC, USA; Department of Radiology, Hospital Garcia de Orta, Almada, Portugal.",
"authors": "Semelka|Richard C|RC|;Ramalho|Joana|J|;Vakharia|Ami|A|;AlObaidy|Mamdoh|M|;Burke|Lauren M|LM|;Jay|Michael|M|;Ramalho|Miguel|M|",
"chemical_list": "D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C062402:gadoteridol; C064572:gadobenic acid; C090600:gadobutrol; D008536:Meglumine; C064925:gadodiamide; D005682:Gadolinium; D019786:Gadolinium DTPA; C112666:gadoversetamide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mri.2016.07.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-725X",
"issue": "34(10)",
"journal": "Magnetic resonance imaging",
"keywords": "Gadolinium based contrast agents; Gadolinium deposition disease; Gadolinium toxicity; NSF; Survey",
"medline_ta": "Magn Reson Imaging",
"mesh_terms": "D000328:Adult; D000368:Aged; D003287:Contrast Media; D005260:Female; D005682:Gadolinium; D019786:Gadolinium DTPA; D006571:Heterocyclic Compounds; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008536:Meglumine; D008875:Middle Aged; D009942:Organometallic Compounds; D010146:Pain; D011446:Prospective Studies",
"nlm_unique_id": "8214883",
"other_id": null,
"pages": "1383-1390",
"pmc": null,
"pmid": "27530966",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Gadolinium deposition disease: Initial description of a disease that has been around for a while.",
"title_normalized": "gadolinium deposition disease initial description of a disease that has been around for a while"
} | [
{
"companynumb": "US-BRACCO-013883",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOTERIDOL"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nThe objective of this study is to describe the clinical use and safety profile of low-dose ketamine (LDK) (0.1-0.3 mg/kg) for pain management in the emergency department (ED).\n\n\nMETHODS\nThis was a retrospective case series of consecutive patients given LDK for pain at a single urban ED between 2012 and 2013. Using a standardized data abstraction form, 2 physicians reviewed patient records to determine demographics, indication, dose, route, disposition, and occurrence of adverse events. Adverse events were categorized as minor (emesis, psychomimetic or dysphoric reaction, and transient hypoxia) and serious (apnea, laryngospasm, hypertensive emergency, and cardiac arrest). Additional parameters measured were heart rate and systolic blood pressure.\n\n\nRESULTS\nFive hundred thirty patients received LDK in the ED over a 2-year period. Indications for LDK were diverse. Median patient age was 41 years, 55% were women, and 63% were discharged. Route of administration was intravenous in 93% and intramuscular in 7%. Most patients (92%) received a dose of 10 to 15 mg. Comorbid diseases included hypertension (26%), psychiatric disorder (12%), obstructive airway disease (11%), and coronary artery disease (4%). There was no significant change in heart rate or systolic blood pressure. Thirty patients (6%) met our criteria for adverse events. Eighteen patients (3.5%) experienced psychomimetic or dysphoric reactions. Seven patients (1.5%) developed transient hypoxia. Five patients (1%) had emesis. There were no cases of serious adverse events. Agreement between abstractors was almost perfect.\n\n\nCONCLUSIONS\nUse of LDK as an analgesic in a diverse ED patient population appears to be safe and feasible for the treatment of many types of pain.",
"affiliations": "Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland CA. Electronic address: terryahern@gmail.com.;Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland CA; Department of Emergency Medicine, University of California, San Francisco, San Francisco CA.;Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland CA.;Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland CA.;Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland CA; Department of Emergency Medicine, University of California, San Francisco, San Francisco CA.;Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland CA; Department of Emergency Medicine, University of California, San Francisco, San Francisco CA.",
"authors": "Ahern|Terence L|TL|;Herring|Andrew A|AA|;Anderson|Erik S|ES|;Madia|Virat A|VA|;Fahimi|Jahan|J|;Frazee|Bradley W|BW|",
"chemical_list": "D000700:Analgesics; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "33(2)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D059787:Acute Pain; D000328:Adult; D000368:Aged; D000700:Analgesics; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007649:Ketamine; D008297:Male; D008875:Middle Aged; D059408:Pain Management; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "197-201",
"pmc": null,
"pmid": "25488336",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED.",
"title_normalized": "the first 500 initial experience with widespread use of low dose ketamine for acute pain management in the ed"
} | [
{
"companynumb": "US-MYLANLABS-2015M1030191",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Many patients with inborn errors of metabolism, due to early diagnosis and improved management, are living longer with less disease burden. Several are now having families of their own. This poses challenges both for the metabolic control of the mother and potential secondary effects on the fetus, as well as the risk of inheriting the inborn error. Classical homocystinuria (HCU, OMIM 236200) is a rare multisystem condition with intellectual, skeletal, ocular, and thromboembolic complications. Ireland has included HCU in the National Newborn Bloodspot Screening Program since 1971. The European network and registry for homocystinurias and methylation defects (E-HOD) guidelines outline the requirements for management and monitoring of this condition and associated complications. Pregnancy alone has many potential complications. When combined with an underlying condition such as HCU, which is prothrombotic and requires a highly medicalized diet, there are significantly increased risks to both mother and baby. Colleagues previously published an Irish case of maternal HCU with successful pregnancy outcome. We add five pregnancies to two women with classical HCU to the literature. We use these to highlight the importance of careful metabolic control and managing the predictable HCU associated risks during pregnancy and the postpartum period. Our cases demonstrate the potential for healthy pregnancies in HCU and that this is best achieved with a motivated clinical team and good patient engagement. Only small numbers of pregnancies in HCU have been reported and we are still learning best practice, but proactive management is essential, as in any inborn error of metabolism.",
"affiliations": "Paediatric Metabolic Department, Royal Belfast Hospital for Sick Children Belfast UK.;National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street Dublin Ireland.;Paediatric Haematology, Children's Health Ireland at Temple Street Dublin Ireland.;Department of Pediatrics, Tawam Hospital Al Ain United Arab Emirates.;National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street Dublin Ireland.;National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street Dublin Ireland.",
"authors": "Hart|Caroline|C|;McNulty|Jenny|J|;Cotter|Melanie|M|;Al Jasmi|Fatima|F|;Crushell|Ellen|E|;Monavari|Ahmad Ardeshir|AA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jmd2.12233",
"fulltext": "\n==== Front\nJIMD Rep\nJIMD Rep\n10.1002/(ISSN)2192-8312\nJMD2\nJIMD Reports\n2192-8304\n2192-8312\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n10.1002/jmd2.12233\nJMD212233\nCase Report\nCase Reports\nThe challenges of pregnancy management in pyridoxine nonresponsive homocystinuria: The Irish experience\nHart et al.\nHart Caroline 1 caroline.hart@belfasttrust.hscni.net\n\nMcNulty Jenny 2\nCotter Melanie 3\nAl Jasmi Fatima 4\nCrushell Ellen 2 5\nMonavari Ahmad Ardeshir 2 5\n1 Paediatric Metabolic Department, Royal Belfast Hospital for Sick Children Belfast UK\n2 National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street Dublin Ireland\n3 Paediatric Haematology, Children's Health Ireland at Temple Street Dublin Ireland\n4 Department of Pediatrics, Tawam Hospital Al Ain United Arab Emirates\n5 University College Dublin Dublin Ireland\n* Correspondence\nCaroline Hart, Paediatric Metabolic Medicine, Royal Belfast Hospital for Sick Children, 180 Falls Road, Belfast BT12 6BE.\nEmail: caroline.hart@belfasttrust.hscni.net\n\n09 6 2021\n9 2021\n61 1 10.1002/jmd2.v61.1 3441\n12 5 2021\n01 2 2021\n17 5 2021\n© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nMany patients with inborn errors of metabolism, due to early diagnosis and improved management, are living longer with less disease burden. Several are now having families of their own. This poses challenges both for the metabolic control of the mother and potential secondary effects on the fetus, as well as the risk of inheriting the inborn error. Classical homocystinuria (HCU, OMIM 236200) is a rare multisystem condition with intellectual, skeletal, ocular, and thromboembolic complications. Ireland has included HCU in the National Newborn Bloodspot Screening Program since 1971. The European network and registry for homocystinurias and methylation defects (E‐HOD) guidelines outline the requirements for management and monitoring of this condition and associated complications. Pregnancy alone has many potential complications. When combined with an underlying condition such as HCU, which is prothrombotic and requires a highly medicalized diet, there are significantly increased risks to both mother and baby. Colleagues previously published an Irish case of maternal HCU with successful pregnancy outcome. We add five pregnancies to two women with classical HCU to the literature. We use these to highlight the importance of careful metabolic control and managing the predictable HCU associated risks during pregnancy and the postpartum period. Our cases demonstrate the potential for healthy pregnancies in HCU and that this is best achieved with a motivated clinical team and good patient engagement. Only small numbers of pregnancies in HCU have been reported and we are still learning best practice, but proactive management is essential, as in any inborn error of metabolism.\n\npyridoxine nonresponsive homocystinuria\npregnancy in inborn errors of metabolism\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:02.09.2021\nHartC, McNultyJ, CotterM, Al JasmiF, CrushellE, MonavariAA. The challenges of pregnancy management in pyridoxine nonresponsive homocystinuria: The Irish experience. JIMD Reports. 2021;61 (1 ):34–41. 10.1002/jmd2.12233\n\nCommunicating Editor: Piero Rinaldo\n==== Body\npmc1 INTRODUCTION\n\nMany patients with inborn errors of metabolism, due to early diagnosis and improved management, are living longer with less disease burden. Several are now having families of their own. This poses challenges both for the metabolic control of the mother and potential secondary effects on the fetus, as well as the risk of inheriting the inborn error.\n\nClassical homocystinuria (HCU, OMIM 236200), caused by a deficiency of cystathionine β‐synthase (CBS) in the metabolism of methionine, is a rare multisystem condition. Complications include intellectual impairment, skeletal disease (osteoporosis), ocular disorders (severe myopia and lens dislocation) as well as vascular (an increased risk of venous and arterial thromboembolic events) disease. The international prevalence of HCU varies with a clinically detected cases occurring in 0.82 per 100 000 and cases detected via newborn screening occurring on 1.09 per 100 000.1 In Ireland, the incidence is significantly higher, occurring in approximately 1 in 64 900 births, roughly equating to one baby being diagnosed with HCU via newborn screening annually.2 Ireland has included HCU in the National Newborn Bloodspot Screening Program (NNBSP) since 1971 and identified patients are treated at the National Centre for Inherited Metabolic Disorders (NCIMD) at Children's Health Ireland (CHI) at Temple Street. Careful adherence to a regimen of a strict diet with reduced natural methionine (a prescribed number of methionine exchanges where 1 exchange is equivalent to 1 g of natural protein and 25 mg methionine is used at NCIMD), methionine free amino acid mixture/supplements, low protein foods and medication is required to achieve good control and avoid or minimize complications. The European network and registry for homocystinurias and methylation defects (E‐HOD) guidelines3 outline the requirements for management and monitoring, including for complications. At the NCIMD, we have traditionally used free homocysteine (fHcy), the nonprotein bound fraction,4 for monitoring biochemical control and have more recently added total homocysteine (they). With consistent maintenance of fHcy <11 μmoL/L, equating to a tHcy <120 μmoL/L,3 our patients have not encountered complications.2 Pregnancy has many potential complications and combined with an underlying condition such as HCU, which is prothrombotic and requires a highly medicalized diet, there are significantly increased risks to both mother and baby. Previously Yap and Levy have documented pregnancy outcomes in HCU and to this we add five pregnancies to two women with classical pyridoxine nonresponsive HCU.5, 6, 7\n\n1.1 Patient A\n\nOur first patient is a nonconsanguineous Irish woman who was diagnosed via the NNBSP with pyridoxine nonresponsive HCU. Later genetic testing demonstrated homozygosity for the classical HCU mutation in the CBS gene, c.919G > A (p.Gly307Ser). A standard HCU diet, vitamins B6, B12, folic acid and monitoring was initiated in the neonatal period and in infancy and childhood good compliance was achieved with satisfactory biochemical control. However, adolescence proved more challenging with variable attendance at clinic and engagement with the diet, therapeutic monitoring, and medication. This required a period of increased frequency of outpatient review and intensive education and therapeutic management, including the addition of betaine to increase the methionine tolerance. Following these measures satisfactory biochemical control was achieved intermittently. She completed third level education and was in full‐time employment.\n\nPatient A developed osteoporosis of the lumbar spine and neck of femur demonstrated on dual energy X‐ray absorptiometry (DEXA) scans with a wrist fracture, which occurred following a simple fall at 18 years old. She was intermittently vitamin B12 deficient requiring parenteral supplementation. At 24 years of age, she experienced bilateral lens dislocations and cataract formation. Lens replacements were scheduled, but these were deferred as she became pregnant with her first child at 28 years old. A clear baseline methionine tolerance was difficult to establish due to longstanding challenges with dietary adherence (see Supplementary Table 1 for full dietary and biochemistry details during pregnancy). Her prescribed daily folate (5 mg) was regularly taken but her pyridoxine (100 mg) and oral B12 were not, as the patient found these difficult to tolerate. Initially, she was commenced on aspirin, but this was changed to low‐molecular weight heparin (LYMPH), which was continued until 6 weeks postpartum. Vitamin B12 injections were administered, along with re‐instatement of pyridoxine and increase in folate to 10 mg per day. During the pregnancy, there was improvement in engagement with more frequent clinic visits and a significant increase in contact with the dietetic team. However, dietary control remained challenging despite initial progress, with variable methionine exchanges being taken and low amino acid mixture/supplement intake even after a variety of options were trialed. Consistent medication tolerance also proved difficult. Overall, tHcy levels were satisfactory (see Graph 1) and the maximum number of methionine exchanges tolerated was 25 (equating to 25 g of daily natural protein and 8.11 mg/kg/day of methionine), from a baseline of approximately 12 (prepregnancy weight not available for mg/kg/day calculation). All antenatal scans were normal and there was close communication with the obstetric team. A healthy baby boy was delivered without complication and high‐risk newborn screening for HCU was negative. The patient remained well post‐delivery and continued LMWH for 6 weeks postpartum, although issues with therapeutic compliance later re‐emerged. Eye surgery was carried out the following year.\n\nGRAPH 1 Total homocysteine level and methionine tolerance for patient A, pregnancy 1\n\nThe patient became pregnant again the next year and was reviewed within the first few weeks when it was noted that tHcy levels were high (193 μmoL/L) and she was taking excessive dietary methionine but compliance with her amino acid mixture/supplement had improved. LMWH was commenced and HCU medications including pyridoxine and B12 were reintroduced, although tolerance varied throughout the pregnancy. Most tHcy and fHcy levels were within the target range and regular levels were supplied (see Graph 2). The maximum methionine exchanges reached in this pregnancy was 29 (equivalent to 29 g/day natural protein and approximately 10.82 mg/kg/day methionine) and a healthy baby boy was delivered at term, again screening negative for HCU. Unfortunately, the baby became unwell with a febrile illness unrelated to maternal HCU at 2 weeks of age and required hospital admission. During this time, the patient discontinued her postpartum LMWH just after 2 weeks, and subsequently she developed a pulmonary embolus (PE) at 11 weeks postpartum. No tHcy or fHcy levels are available from this time.\n\nGRAPH 2 Total homocysteine levels and methionine intake for patient A in pregnancy 2\n\nThe patient was treated acutely and made a full recovery following the PE but was advised that future pregnancies would carry a significant thrombotic risk. Following a subsequent posterior sagittal sinus thrombosis at 37 years and she is now on warfarin. Both children remain healthy.\n\n1.2 Patient B\n\nOur second patient, a nonconsanguineous Irish woman, was also diagnosed with classical HCU through NNBSP, which was later genetically confirmed with homozygous c.919G > A (p.Gly307Ser) mutations in the CBS gene. She was on a protein restricted diet with amino acid mixture/supplements from diagnosis. Throughout childhood and adolescence, she exhibited good dietary and medication compliance with satisfactory biochemical control. There had never been any developmental concerns and she achieved third level education, going on to work in information technology with frequent long‐distance business travel. During her early years, she experienced significant myopia, although there was a family history of the same, had normal bone mineral density into adulthood and did not experience any thromboembolic events.\n\nPrepregnancy planning with the hematology team determined LMWH from the date of a confirmed pregnancy would be appropriate. Prepregnancy natural protein tolerance was 9‐12 methionine exchanges (9‐12 g of natural protein), approximating to 225‐300 mg methionine per day (no weight available for mg/kg/day calculations). She attended outpatient review at the start of the second month of her first pregnancy at 32 years of age, having already been commenced on LMWH by her GP. Her pyridoxine dose was revised to 100 mg per day (previously 400 mg), she was already taking folic acid 800 μg per day and was on a pregnancy multivitamin which was then discontinued (as sufficient vitamins were supplied by amino acid mixture/supplement). Her LMWH was increased to 40 mg once daily by hematology service at 6 weeks gestation. Dietary compliance was good with satisfactory tHcy and fHcy levels and synthetic amino acid mixture/supplement provision of just under 1 g/kg/day protein equivalent. Unfortunately, the patient suffered a first trimester miscarriage but did not require surgical intervention.\n\nA few months later the patient returned to clinic at 9 weeks gestation in her second pregnancy. She was well at this time with good metabolic control (see Graph 3). Again, LMWH had been commenced by her GP and she was linked in with obstetric services abroad due to her employment. At this time, she remained on folate 800 μg per day and pyridoxine 100 mg per day alongside her amino acid mixture/supplement. A second outpatient review took place at 16 weeks gestation and no acute issues were raised. A plan was provided for the local obstetric team to commence IV fluids during delivery and avoid nitric oxide for any required anesthesia. Metabolic control was ensured through on‐going biochemical monitoring of fHcy in Dublin and tHcy in a metabolic center close to where she was living and working abroad, alongside dietetic input and clinical metabolic assessments. The maximum natural methionine exchanges achieved during the pregnancy was 23 (23 g of natural protein), approximating to 8.27 mg/kg/day methionine (see supplementary Table 2). A healthy baby girl was delivered normally at term and was successfully breastfed.\n\nGRAPH 3 Total homocysteine levels and methionine intake for patient B, pregnancy 2. NB no prepregnancy weight available for baseline calculations but ranged from 9 to 12 methionine exchanges per day prepregnancy to a maximum of 23 per day, then back to 12 postpartum when breastfeeding\n\nAt the next outpatient review the following year the patient was 18 weeks pregnant, having had a normal antenatal scan and been commenced on LMWH by obstetrics at her local center abroad. Her medications and amino acid mixture/supplements were unchanged from her previous pregnancy. Again, good compliance and metabolic control was achieved throughout this pregnancy (see Graph 4) and a healthy term baby boy was delivered without complication. The patient continued on LMWH for a number of weeks postpartum for each pregnancy and neither infant was diagnosed with HCU. She successfully breastfed both babies and therefore required higher natural protein, and therefore methionine, intake during this period. Following cessation of breastfeeding, the patient returned to her baseline methionine tolerance. See supplementary Table 2 for a full summary of methionine intake and available biochemistry during pregnancy.\n\nGRAPH 4 Total homocysteine levels and methionine intake for patient B, pregnancy 3\n\n2 DISCUSSION\n\nPrevious reports of pregnancy in HCU have described various management approaches. In 2001, Yap and colleagues described the case of an Irish patient with pyridoxine unresponsive HCU with successful maternal and infant outcomes.5 That patient more than doubled their methionine tolerance during the pregnancy and achieved fair biochemical control, which had been previously suboptimal. Their case emphasized the importance of close monitoring and active measure to prevent thromboembolic complications.5\n\nThe largest cohort of pregnancies in HCU was reported by Mudd and colleagues, although the majority of these were in pyridoxine responsive women.7 They described 11 pregnancies in classical HCU, 8 of which resulted in live born infants and they noted the various, mainly postpartum maternal complications in all categories of HCU.7 In 2002, Levy and colleagues described their experience with 12 successful pregnancies (plus two early miscarriages) in 11 women, five of whom were pyridoxine nonresponsive.6 Their study showed infrequent pregnancy complications, but the dietary and medical management was quite varied, and the majority did not receive anticoagulation. They suggested that the high plasma Hcy levels seen in the postpartum period may be reflected by a particularly increased thrombotic risk.6 Vilaseca et al reported their experience with a woman with pyridoxine nonresponsive HCU who had three pregnancies with two healthy children and one miscarriage.8 Much like one of our cases, this woman had multiple baseline complications including eye and bone disease but unlike our cohort this patient was diagnosed late at 1 year of age with ectopia lentis. Although the importance of anticoagulation was emphasized in this case report, a combination of acetylsalicylic acid (aspirin) and heparin was used instead of LMWH.8 A more recent case report in 2006 also highlights the importance of anticoagulation, using first aspirin and then LMWH, and akin to patient A, their patient achieved good biochemical control despite prenatal poor control.9\n\nThe E‐HOD guidelines specifically recommend the use of LMWH during the third trimester, and perhaps throughout pregnancy, up until at least 6 weeks postpartum.3 They also go on to state that in the presence of additional thrombosis risk factors women should have LMWH prescribed for the whole pregnancy. E‐HOD noted that LMWH was the most widely used method of anticoagulation but that others were in use.3 Indeed, there is much experience with anticoagulation in obstetric practice. The Royal College of Obstetricians and Gynaecologists (RCOG) guideline on this issue stratifies women into at risk categories for venous thromboembolism (VTE) and uses this to determine how long to employ anticoagulation.10 Their anticoagulant of choice is LMWH and their standard duration of treatment in the postnatal period is 6 weeks, even in the case of prior VTE at which point those patients would re‐establish their maintenance treatment.10 It is logical therefore that the same practice be applied to HCU patients postpartum, although perhaps if there were issues with biochemical control and elevated fHcy or tHcy levels persist there could be merit in adapting this on a case by case basis and advice from hematology colleagues would be beneficial. This again is in line with the RCOG guideline, stating to use LMWH in high risk groups “for up to 6 weeks or until the additional risk factor/s is/are no longer present.”10 In patient A's case where VTE occurred at 11 weeks postpartum, there was early discontinuation of LMWH and it is unclear how strict their biochemical control was during this period, although we know baseline control was sub‐optimal. Therefore, it would be difficult to strongly recommend adaptations to the current guidance on the postpartum duration of LMWH in this high‐risk group based on this single case. However, our case highlights the need for close biochemical monitoring in the postpartum period until at least the end of the 6‐week window of increase VTE risk and if biochemical stability it not reached the possibility of extending LMWH treatment should be discussed with hematology. Also of note, both our patients received LMWH from early pregnancy based on hematology advice and this has also been a practice reported previously9 though current guidelines suggest only consideration of this.3 Based on our experience, we would recommend LMWH therapy from pregnancy confirmation and early hematology input. In addition to the use of LMWH, from our experience, we recommend ensuring adequate hydration during labor by pre‐emptively commencing IV fluids with the aim of reducing the risk of thrombosis, much like the E‐HOD guidance for the management of undercurrent illness and surgery.3 Modifying this risk are of importance to both mother and infant.\n\nIt is worth noting that there is no evidence to suggest an increased risk of miscarriage in HCU.3 This is despite it inferring a risk of VTE and that prothrombotic conditions tend to heighten the risk of pregnancy loss. In our case series, and those quoted above, early miscarriage was a feature, although this is likely to be reflective of the background population risk.\n\nBoth of our patients demonstrated an increased methionine, and therefore natural protein, intake and reduced tHcy during the third trimester, although the trend is less clear for patient B due to split site monitoring. This is a phenomenon reported previously5, 9 and is similar to the increased phenylalanine tolerance experienced by mother's with PKU in the later stages of pregnancy also.\n\nAs HCU control is reliant on adherence to a strict medicalized diet, deficiencies in nutrition of the mother and therefore the unborn infant could occur if dietary control is not adhered to. This relates not just too natural protein intake, the number of methionine exchanges taken but also ensuring appropriate vitamin, and mineral supplementation is achieved. Amino acid mixtures/supplements are fortified to meet dietary requirements and consistent tolerance of these is needed as well as considering the specific micronutrient needs of the expectant mother.\n\nThe cases presented here highlight the importance of careful metabolic control and managing the risks associated with HCU during pregnancy and the postpartum period. Both of our patients demonstrate the potential for healthy pregnancies in this condition and that this is best achieved with a motivated clinical team and an engaged patient. With such small numbers of pregnancies in HCU, we are still learning best practice and pre‐emptive management is essential, as in any inborn error of metabolism, with particular consideration needed in three phases: preconception, pregnancy, and the postpartum period.11\n\n2.1 Learning points\n\nPrevious reports have shown that in the Irish newborn screened adult patients with pyridoxine nonresponsive HCU, most have no or only minor complications of HCU and are leading healthy lives.\n\nChallenges with metabolic control can still arise at any stage in this condition and require a multidisciplinary approach with patient engagement.\n\nWhen considering pregnancy in HCU early consultation with hematology services and close communication with the obstetric team is important, so that clear plans can be established to minimize thromboembolic risk.\n\nPregnancy poses increased risk to women with HCU and pre‐emptive management is crucial to prevent harm to both mother and baby, with a particular focus required on nutrition and the risk of thromboembolism.\n\nCONFLICT OF INTEREST\n\nThe authors declare no conflicts of interest.\n\nINFORMED CONSENT\n\nAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study. Written informed consent was obtained from the patients included in this article and their identifying information is not included in this article.\n\nANIMAL RIGHTS\n\nThis article does not contain any studies with human or animal subjects performed by any if the authors.\n\nAUTHOR CONTRIBUTIONS\n\nCaroline Hart drafted the article, reviewed the literature and revised the manuscript, also acting as guarantor. Jenny McNulty critically reviewed the article and provided a dietetic perspective. Melanie Cotter reviewed the article and provided hematological advice. Fatima Al Jasmi revised the article content, as did Ellen Crushell. Ahmad Ardeshir Monavari created the article concept and critically appraised each draft.\n\nSupporting information\n\nSupplementary Table 1 Dietary management and biochemistry results for Patient A\n\nSupplementary Table 2: Dietary management and biochemistry results for Patient B\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nThe authors wish to acknowledge all the staff involved in patient care at the National Centre for Inherited Metabolic Disorders, the Department of Metabolic Disorders laboratory and the National Newborn Bloodspot Screening laboratory at Children's Health Ireland at Temple Street, Dublin. Professor Philip Mayne, Dr. Ingrid Borovickova, Dr. Jennifer Brady, Patricia Fitzsimons, Loretta O'Grady and all the laboratory Staff. Special thanks to Dr. Eileen Naughten, our consultant colleagues present and past Dr. Joanne Hughes, Prof. Ina Knerr, Prof. Eileen Treacy, Dr. Sufin Yap. The authors would like to extend our thanks to all our colleagues in our centre: Metabolic Dietitians Anne Clark, Fiona Boyle, Maria Irranca and all the Metabolic Dietitians; Metabolic Nurses, particularly Maria O'Regan, Celine Stenson; Psychologist Yvonne Rogers and Researcher Meabh O'Shea and the dedicated multidisciplinary team.\n==== Refs\nREFERENCES\n\n1 MoorthieS, CameronL, SagooGS, BonhamJR, BurtonH. Systematic review and meta‐analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis. 2014;37 :889‐898.25022222\n2 YapS, NaughtenE. Homocystinuria due to cystathionine beta‐synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis. 1998;21 :738‐747.9819703\n3 MorrisAAM, KozichV, SantraS, et al. Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency. J Inherit Metab Dis. 2017;40 :49‐74.27778219\n4 YapS, BoersGHJ, WilckenB, et al. Vascular outcome in patients with homocystinuria due to B‐synthase deficiency treated chronically; a multicentre observational study. Arterioscler Thromb Vasc Biol. 2001;21 :2080‐2085.11742888\n5 YapS, Barry‐KinsellaC, NaughtenER. Maternal pyridoxine non‐responsive homocystinuria: the role of dietary treatment and anticoagulation. BJOG. 2001;108 :425‐428.11305553\n6 LevyHL, VargaJE, WaisbrenSE, et al. Reproductive fitness in maternal homocystinuria due to cystathioine beta‐synthase deficiency. J Inherit Metab Dis. 2003;25 :299‐314.\n7 MuddSH, LevyHL, KrausJP. Disorders of transsulfuration. In: ScriverCR, BeaudetAL, SlyWS, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw‐Hill; 2001:2027‐2028.\n8 VilasecaMA, CuarteroML, Martinez de SalinasM, et al. Two successful pregnancies in pyridoxine‐nonresponsive homocystinuria. J Inherit Metab Dis. 2004;27 :775‐777.15617186\n9 PierreG, GissenP, ChakrapaniA, McDonaldA, PreeceMA, WrightJ. Successful treatment of pyridoxine‐unresponsive homocystinuria with betaine in pregnancy. J Inherit Metab Dis. 2006;29 :688‐689.16972179\n10 Royal College of Obstetricians and Gynaecologists . Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium. Green‐top Guideline No. 37a 2015. https://www.rcog.org.uk/globalassets/documents/guidelines/gtg‐37a.pdf (accessed May 2020).\n11 LeePJ. Pregnancy issues in inherited metabolic disorders. J Inherit Metab Dis. 2006;29 :311‐316.16763893\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2192-8304",
"issue": "61(1)",
"journal": "JIMD reports",
"keywords": "pregnancy in inborn errors of metabolism; pyridoxine nonresponsive homocystinuria",
"medline_ta": "JIMD Rep",
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"title": "The challenges of pregnancy management in pyridoxine nonresponsive homocystinuria: The Irish experience.",
"title_normalized": "the challenges of pregnancy management in pyridoxine nonresponsive homocystinuria the irish experience"
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"abstract": "To report the clinical findings of a patient who presented with an atypical bilateral fungal retinitis that was established by retinochoroidal biopsy.\nCase report.\nA 56-year-old systemically healthy man presented with progressive visual loss in his left eye for 3 weeks. Visual acuity was 20/40 in the left eye, and 20/20 in the right eye and fundus examination showed macular retinal pigmented epithelium changes in his left eye. Over the following four months, his lesions progressed to serpiginous-like widespread retinal pigmented epithelium atrophy and his visual acuity decreased to 20/100, but no signs of ocular inflammation were found. Treatment with oral corticoids, valganciclovir and trimethoprim/sulfamethoxazole showed no efficacy. Blood analysis and cultures, laboratory investigations, and imaging tests were carried out looking for infectious and inflammatory diseases, but all tests were negative. Two months later, the patient presented with the same kind of lesions in the other eye (right eye), so he was subjected to retinochoroidal biopsy. Histopathological examination of specimen revealed the presence of intraretinal and choroidal fungal hyphae. Oral voriconazole was initiated achieving clinical remission, but no visual improvement was obtained. The source of the infection remains unknown since all tests results were negative. However, his profession as brewmaster might be related to the origin of the infection.\nDiagnosis of intraocular fungal infection can be challenging. Retinochoroidal biopsy may be useful to establish the diagnosis in those atypical cases with nonrevealing workup and inflammation localized to the retina.",
"affiliations": "Instituto Universitario Oftalmológico Fernández-Vega, Fundación de Investigación Oftalmológica Fernández-Vega and Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain.;Instituto Universitario Oftalmológico Fernández-Vega, Fundación de Investigación Oftalmológica Fernández-Vega and Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain.;Instituto Universitario Oftalmológico Fernández-Vega, Fundación de Investigación Oftalmológica Fernández-Vega and Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain.;Instituto Universitario Oftalmológico Fernández-Vega, Fundación de Investigación Oftalmológica Fernández-Vega and Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain.;Instituto Universitario Oftalmológico Fernández-Vega, Fundación de Investigación Oftalmológica Fernández-Vega and Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain.",
"authors": "Fernández-Vega González|Alvaro|A|https://orcid.org/0000-0002-9104-7917;Fernández-Vega González|Carlos|C|;Fernández-Vega Sanz|Beatriz|B|;Peláez|María Teresa|MT|;Merayo-Lloves|Jesús|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1120672120908726",
"fulltext": null,
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"issn_linking": "1120-6721",
"issue": "31(3)",
"journal": "European journal of ophthalmology",
"keywords": "Fungal retinitis; Saccharomyces cerevisiae; bilateral retinitis; fungal chorioretinitis; ocular fungal infection; retinochoroidal biopsy; serpiginous-like retinitis",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D002829:Choroid; D005654:Fundus Oculi; D006801:Humans; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D012160:Retina; D014792:Visual Acuity",
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"pages": "NP50-NP56",
"pmc": null,
"pmid": "32106701",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral fungal infection inducing a serpiginous-like picture.",
"title_normalized": "bilateral fungal infection inducing a serpiginous like picture"
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"abstract": "A 24-year-old woman with Marfan syndrome was scheduled for cesarean section in order to avoid progression of heart failure due to severe mitral regurgitation and aortic dissection during labor. Cesarean section was performed under general anesthesia using remifentanil. Anesthesia was induced and maintained with remifentanil (0.1-0.3 μg x kg(-1) x min(-1)) and continuous administration of propofol (target-controlled infusion, 2-3 ng x ml(-1)). The trachea was intubated without a significant hemodynamic change. The patient's systolic blood pressure was maintained between 90 and 120 mmHg during surgery. Intraoperatively, we conducted a transesophageal echocardiography examination, and no remarkable change was seen in the severity of mitral regurgitation and the size of an ascending aorta. An infant was delivered 6 minutes after anesthesia induction. The Apgar scores were 4 at 1 min, 5 at 5 min and 8 at 10 min. Postoperative course was uneventful. We conclude that remifentanil can be used successfully to manage cesarean section of a parturient with Marfan syndrome associated with heart failure due to severe mitral regurgitation under general anesthesia.",
"affiliations": null,
"authors": "Fujita|Masahide|M|;Satsumae|Tsuyoshi|T|;Tanaka|Makoto|M|",
"chemical_list": "D000701:Analgesics, Opioid; D010880:Piperidines; D000077208:Remifentanil",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0021-4892",
"issue": "65(5)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000701:Analgesics, Opioid; D000768:Anesthesia, General; D000773:Anesthesia, Obstetrical; D002585:Cesarean Section; D005260:Female; D006333:Heart Failure; D006439:Hemodynamics; D006801:Humans; D007231:Infant, Newborn; D008382:Marfan Syndrome; D008944:Mitral Valve Insufficiency; D010880:Piperidines; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D000077208:Remifentanil; D055815:Young Adult",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "530-4",
"pmc": null,
"pmid": "27319100",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "General Anesthesia Using Remifentanil for Cesarean Section in a Parturient with Marfan Syndrome Associated with Heart Failure due to Severe Mitral Regurgitation.",
"title_normalized": "general anesthesia using remifentanil for cesarean section in a parturient with marfan syndrome associated with heart failure due to severe mitral regurgitation"
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"companynumb": "JP-VALIDUS PHARMACEUTICALS LLC-JP-2016VAL002075",
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"activesubstancename": "REMIFENTANIL"
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"abstract": "Out of seven venomous land snake species of Sri Lanka, hump-nosed pit viper (Hypnale spp.) causes the commonest venomous snakebites. It is widely distributed all over the country except in the peninsula of Jaffna. The genus has three species naming H. hypnale, H. zara and H. nepa. They frequently cause local envenoming and rarely cause coagulopathy and acute kidney injury. Systemic bleeding is the most trivial complication associated with coagulopathy caused by these snakes and pulmonary haemorrhages are one of them which are rarely reported. Antivenoms are currently not available for genus Hypnale bites in Sri Lanka. We describe a fatal case of pulmonary haemorrhage caused by a proven hump-nosed viper (Hypnale hypnale) bite associated with other systemic bleeding manifestations and thrombotic microangiopathy. This is the first known case of pulmonary and intracranial haemorrhages caused by hump-nosed viper bite.",
"affiliations": "Intensive Care Unit, Teaching Hospital, Ratnapura, Sri Lanka; Department of Veterinary Pathobiology, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Sri Lanka; Postgraduate Institute of Medicine (Clinical Pharmacology and Therapeutics), University of Colombo, Sri Lanka. Electronic address: namalrath10@yahoo.com.;Medical Unit, Teaching Hospital, Ratnapura, Sri Lanka.;Department of Medicine, Faculty of Medicine, University of Peradeniya, Sri Lanka.",
"authors": "Rathnayaka|R M M K Namal|RMMKN|;Ranathunga|P E A Nishanthi|PEAN|;Kularatne|S A M|SAM|",
"chemical_list": "D003435:Crotalid Venoms",
"country": "England",
"delete": false,
"doi": "10.1016/j.toxicon.2019.09.009",
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"issn_linking": "0041-0101",
"issue": "170()",
"journal": "Toxicon : official journal of the International Society on Toxinology",
"keywords": "Hump-nosed viper; Hypnale hypnale; Pulmonary haemorrhage; Snakebites; Sri Lanka; Systemic bleeding; Thrombotic microangiopathy",
"medline_ta": "Toxicon",
"mesh_terms": "D000368:Aged; D000818:Animals; D003435:Crotalid Venoms; D000073562:Crotalinae; D017809:Fatal Outcome; D006470:Hemorrhage; D006801:Humans; D008171:Lung Diseases; D008297:Male; D012909:Snake Bites; D013188:Sri Lanka",
"nlm_unique_id": "1307333",
"other_id": null,
"pages": "21-28",
"pmc": null,
"pmid": "31513811",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Systemic bleeding including pulmonary haemorrhage following hump-nosed pit viper (Hypnale hypnale) envenoming: A case report from Sri Lanka.",
"title_normalized": "systemic bleeding including pulmonary haemorrhage following hump nosed pit viper hypnale hypnale envenoming a case report from sri lanka"
} | [
{
"companynumb": "LK-MYLANLABS-2019M1099954",
"fulfillexpeditecriteria": "1",
"occurcountry": "LK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "Kaposiform hemangioendothelioma (KHE) is an infiltrative vascular tumor that classically presents in infancy. Management typically focuses on treating Kasabach-Merritt phenomenon (KMP), a disorder of severe and at times life-threatening platelet trapping. However, the morbidity of KHE extends beyond KMP. The infiltrative nature of the tumor can lead to long-term disability and often makes complete surgical resection impossible. We report the case of a 10-year-old boy with a KHE of his right distal thigh who was unable to walk without assistance due to fibrotic change and right knee contracture. He had no laboratory evidence of KMP at the time of representation. Rapamycin was started in hopes of reducing the tumor burden. Within 2 months of therapy, fibrotic areas softened, his contracture nearly resolved, and there was marked improvement in his mobility. Rapamycin has been previously reported to be effective in managing cases of KHE complicated by KMP. Our report emphasizes the role for rapamycin in the treatment of KHE in the absence of KMP through the inhibition of vasculogenesis and fibrotic pathways.",
"affiliations": "Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.;Department of Radiology, University of California, San Francisco, San Francisco, California.;Department of Radiology, University of California, San Francisco, San Francisco, California.;Department of Dermatology, University of California, San Francisco, San Francisco, California.;Department of Dermatology, University of California, San Francisco, San Francisco, California.",
"authors": "Oza|Vikash S|VS|;Mamlouk|Mark D|MD|;Hess|Christopher P|CP|;Mathes|Erin F|EF|;Frieden|Ilona J|IJ|",
"chemical_list": "D007166:Immunosuppressive Agents; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12787",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "33(2)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002648:Child; D006390:Hemangioendothelioma; D006801:Humans; D007166:Immunosuppressive Agents; D059885:Kasabach-Merritt Syndrome; D008297:Male; D012514:Sarcoma, Kaposi; D020123:Sirolimus",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e88-92",
"pmc": null,
"pmid": "26864138",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Role of Sirolimus in Advanced Kaposiform Hemangioendothelioma.",
"title_normalized": "role of sirolimus in advanced kaposiform hemangioendothelioma"
} | [
{
"companynumb": "PHHY2017US102422",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nPemphigus vegetans is a rare variant of pemphigus vulgaris, accounting for 1-2% of all pemphigus diseases. Systemic corticosteroids are the therapy of first choice in combination with immunosuppressants as steroid-sparing agents.\n\n\nOBJECTIVE\nTo highlight the exceptional but successful use of minocycline/nicotinamide monotherapy in pemphigus vegetans.\n\n\nMETHODS\nA review of the literature to date about pemphigus vegetans with special emphasis on therapy was performed. Due to its rarity, multiple anecdotal reports without long-term follow-up are available and prospective controlled trials are lacking. Only one retrospective study from Tunisia includes 17 patients with pemphigus vegetans.\n\n\nRESULTS\nWe present a 76-year-old woman with pemphigus vegetans achieving complete response to a minocycline/nicotinamide monotherapy at onset and at relapse of the disease. Treatment has been discontinued after repeated direct immunofluorescence (DIF) of previously affected normal skin and anti-desmoglein 3 antibodies had become negative. In addition, DIF of previously involved oral mucosa was negative. During long-term follow-up clinical remission has been maintained for more than 5 years. Up to now, negative results of serial performed indirect immunofluorescence and desmoglein ELISA testing also predict immunological remission.\n\n\nCONCLUSIONS\nIn our patient and in a case with oesophageal involvement, published more than 20 years ago, clearly the benefit of minocycline/nicotinamide monotherapy was demonstrated. We propose to consider minocycline/nicotinamide as first-line monotherapy in pemphigus vegetans, especially in elderly patients with comorbidities and contraindications to standard therapy, as it avoids the toxicities of systemic corticosteroids and immunosuppressants.",
"affiliations": "Department of Dermatology, University of Muenster, Muenster, Germany.;Department of Dermatology, University of Muenster, Muenster, Germany.;Department of Dermatology, University of Muenster, Muenster, Germany.;Department of Dermatology, University of Muenster, Muenster, Germany.;Department of Dermatology, University of Muenster, Muenster, Germany.;Department of Dermatology, University of Muenster, Muenster, Germany.",
"authors": "von Köckritz|A|A|;Ständer|S|S|;Zeidler|C|C|;Metze|D|D|;Luger|T|T|;Bonsmann|G|G|",
"chemical_list": "D009536:Niacinamide; D008911:Minocycline",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.13779",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "31(1)",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008911:Minocycline; D009536:Niacinamide; D010392:Pemphigus",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "85-88",
"pmc": null,
"pmid": "27600093",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful monotherapy of pemphigus vegetans with minocycline and nicotinamide.",
"title_normalized": "successful monotherapy of pemphigus vegetans with minocycline and nicotinamide"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-294241",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIACINAMIDE"
},
"dru... |
{
"abstract": "Cervical interlaminar epidural steroid injections (ESIs) are commonly performed as one part of a multi-modal analgesic regimen in the management of upper extremity radicular pain. Spinal epidural hematoma (SEH) is a rare complication with a reported incidence ranging from 1.38 in 10,000 to 1 in 190,000 epidurals. Current American Society of Regional Anesthesia (ASRA), American Society of Interventional Pain Physicians (ASIPP), and the International Spine Intervention Society (ISIS) recommendations are that non-steroidal anti-inflammatory drugs (NSAIDs) do not need to be withheld prior to epidural anesthesia. We report a case wherein intramuscular ketorolac and oral fluoxetine contributed to a SEH and tetraplegia following a cervical interlaminar (ESI). A 66 year-old woman with chronic renal insufficiency and neck pain radiating into her right upper extremity presented for evaluation and was deemed an appropriate CESI candidate. Cervical magnetic resonance imaging (MRI) revealed multi-level neuroforaminal stenosis and degenerative intervertebral discs. Utilizing a loss of resistance to saline technique, an 18-gauge Tuohy-type needle entered the epidural space at C6-7. After negative aspiration, 4 mL of saline with 80 mg of methyl-prednisolone was injected. Immediately thereafter, the patient reported significant spasmodic-type localized neck pain with no neurologic status changes. A decision was made to administer 30 mg intramuscular ketorolac as treatment for the spasmodic-type pain. En route home, she developed a sudden onset of acute tetraplegia. She was brought to the emergency department for evaluation including platelet and coagulation studies which were normal. MRI demonstrated an epidural hematoma extending from C5 to T7. She underwent a bilateral C5-T6 laminectomy with epidural hematoma evacuation and was discharged to an acute inpatient rehabilitation hospital. Chronic renal insufficiency, spinal stenosis, female gender, and increasing age have been identified as risk factors for SEH following epidural anesthesia. In the present case, it is postulated that after the spinal vascular system was penetrated, hemostasis was compromised by the combined antiplatelet effects of ketorolac, fluoxetine, fish oil, and vitamin E. Although generally well tolerated, the role of ketorolac, a potent anti-platelet medication used for pain relief in the peri-neuraxial intervention period, should be seriously scrutinized when other analgesic options are readily available. Although the increased risk of bleeding for the alternative medications are minimal, they are nevertheless well documented. Additionally, their additive impairment on hemostasis has not been well characterized. Withholding NSAIDs, fluoxetine, fish oil, and vitamin E in the peri-procedural period is relatively low risk and should be considered for all patients with multiple risk factors for SEH.",
"affiliations": "The Rehabilitation Institute of Chicago, Department of Physical Medicine and Rehabilitation, Chicago, IL.",
"authors": "Chien|George C Chang|GC|;McCormick|Zack|Z|;Araujo|Marco|M|;Candido|Kenneth D|KD|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D018687:Antidepressive Agents, Second-Generation; D013256:Steroids; D005473:Fluoxetine; D020910:Ketorolac",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-3159",
"issue": "17(3)",
"journal": "Pain physician",
"keywords": null,
"medline_ta": "Pain Physician",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018687:Antidepressive Agents, Second-Generation; D019299:Decompression, Surgical; D005260:Female; D005473:Fluoxetine; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D007268:Injections, Epidural; D020910:Ketorolac; D019547:Neck Pain; D010146:Pain; D011782:Quadriplegia; D051436:Renal Insufficiency, Chronic; D013256:Steroids",
"nlm_unique_id": "100954394",
"other_id": null,
"pages": "E385-95",
"pmc": null,
"pmid": "24850120",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The potential contributing effect of ketorolac and fluoxetine to a spinal epidural hematoma following a cervical interlaminar epidural steroid injection: a case report and narrative review.",
"title_normalized": "the potential contributing effect of ketorolac and fluoxetine to a spinal epidural hematoma following a cervical interlaminar epidural steroid injection a case report and narrative review"
} | [
{
"companynumb": "US-ACTAVIS-2015-13900",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FISH OIL"
},
"drugadditional": null,
"d... |
{
"abstract": "Vitiligo is an acquired idiopathic pigmentary skin disorder characterized by the development of white macules and patches due to the loss of functioning melanocytes. In this report, we describe a case of a patient with a longstanding history of dermatitis herpetiformis (DH) and celiac disease that developed rapidly progressing, biopsy-confirmed generalized vitiligo after 11 months of treatment with anti-inflammatory medication sulfasalazine, prescribed for the patient's DH. To the best of our knowledge, this is the first case report which has demonstrated the possible biochemical pathways, triggered by sulfasalazine, in the development of vitiligo.",
"affiliations": "Department of Dermatology, VA Boston Healthcare System, Boston, Massachusetts.;Department of Dermatology, VA Boston Healthcare System, Boston, Massachusetts.",
"authors": "Turkowski|Yana|Y|0000-0003-1349-5279;Konnikov|Nellie|N|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D012460:Sulfasalazine",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.13007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "32(5)",
"journal": "Dermatologic therapy",
"keywords": "celiac disease; dermatitis herpetiformis; generalized vitiligo; sulfasalazine",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001706:Biopsy; D002446:Celiac Disease; D003874:Dermatitis Herpetiformis; D006801:Humans; D008297:Male; D008875:Middle Aged; D012867:Skin; D012460:Sulfasalazine; D014820:Vitiligo",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e13007",
"pmc": null,
"pmid": "31237078",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sulfasalazine-induced generalized vitiligo in a patient with dermatitis herpetiformis and celiac disease.",
"title_normalized": "sulfasalazine induced generalized vitiligo in a patient with dermatitis herpetiformis and celiac disease"
} | [
{
"companynumb": "US-TEVA-2019-US-1142723",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 36-year-old HIV-positive man presented with symptoms of redness, blurred vision and foreign body sensation in his right eye for 3 months. The slit lamp examination revealed deep stromal infiltration with a feathery margin in an otherwise minimal anterior chamber reaction. A corneal scraping was negative. Confocal microscopy demonstrated an abnormal large hyper-reflective oval shape in the corneal stroma. Corneal infiltration did not show improvement after topical, intrastromal and intracameral antifungal treatment. Therapeutic penetrating keratoplasty was performed to eradicate the infection. Corneal button culture and histopathological results confirmed the diagnosis of Penicillium marneffei keratitis. No recurrent infection occurred after corneal transplantation. This appears to be the first report of P. marneffei keratitis in an HIV-infected patient. Although it is an uncommon condition, it should be one of the differential diagnoses in an HIV-infected patient presenting with keratitis.",
"affiliations": "Faculty of Medicine, Department of Ophthalmology, Srinagarind Hospital, Khon Kaen University, Moung, Thailand.;Department of Ophthalmology, Khon Kaen University, Khon Kaen, Thailand.;Department of Ophthalmology, Khon Kaen University, Khon Kaen, Thailand.",
"authors": "Anutarapongpan|Orapin|O|;Thanathanee|Onsiri|O|;Suwan-Apichon|Olan|O|",
"chemical_list": "D000935:Antifungal Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D000935:Antifungal Agents; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D015821:Eye Infections, Fungal; D006801:Humans; D007634:Keratitis; D008297:Male; D018613:Microscopy, Confocal; D010407:Penicillium",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27535731",
"pubdate": "2016-08-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "12355698;10420689;15824799;25177564;11853604;11444343;11579873;7983569;27236644;3936534;791355;10832689;3501559;8534648;11023963;4668484;21836342;11520759;16633023;12785170;12701872;8971625;7927819;1708747;20697003;8285625;15487911;12387776;11285665;10448232;3317183",
"title": "Penicillium keratitis in a HIV-infected patient.",
"title_normalized": "penicillium keratitis in a hiv infected patient"
} | [
{
"companynumb": "TH-JNJFOC-20160915824",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETOCONAZOLE"
},
"drugadditional": "3",
... |
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