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"abstract": "Coronavirus 2019 (COVID-19) infection causes excessive cytokine response and a decrease in cellular immune response and this increases susceptibility to fungal co-infections. Mucormycosis is a rare, lifethreatening invasive fungal infection. In this report, two cases who developed rhino-orbito-cerebral mucormycosis shortly after having COVID-19 infection were presented. The first case was a 68-year old woman who admitted to our clinic with orbital cellulitis in her left eye and had a known diagnosis of asthma and rheumatoid arthritis. She was diagnosed with COVID-19 pneumonia 40 days ago, stayed in the intensive care unit for a long time, and received pulse steroid (1000 mg methylprednisolone), interleukin-1 (IL-1) inhibitor (anakinra) and broad-spectrum antibiotic treatments together with antiviral therapy during this period. The second case was a 63-year-old male patient with known diabetes mellitus, hypertension and retinitis pigmentosa, with a history of hospitalization in the intensive care unit due to COVID-19 pneumonia 20 days ago and received pulse steroid therapy during this period. He admitted to our clinic with the complaints of droopy right eyelid, swelling, nausea and vomiting. In both cases, paranasal sinus tomography findings were consistent with invasive sinusitis. Functional endoscopic sinus surgery was performed immediately in less than 16 hours from the first admission in both cases. Histopathological examination of the both cases revealed results consistent with mucormycosis. Mucorales spp. was isolated in sinus tissue culture of the second case taken during the operation. Both of the patients received liposomal amphotericin B. First case died on the 19th day of the treatment. Second case was discharged with full recovery after nine weeks of treatment. The suppression of cellular immunity during the COVID-19 infection, and the use of steroids and interleukin inhibitors in the treatment of severe cases may increase secondary invasive fungal infections. Therefore, clinicians should more frequently consider possible fungal infections in patients with COVID-19.",
"affiliations": "Baskent University Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Adana, Turkey.;Baskent University Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Adana, Turkey.;Baskent University Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Adana, Turkey.;Baskent University Faculty of Medicine, Department of Otolaryngology, Adana, Turkey.;Baskent University Faculty of Medicine, Department of Opthtalmology, Adana, Turkey.;Baskent University Faculty of Medicine, Department of Pathology, Adana, Turkey.;Baskent University Faculty of Medicine, Department of Radiology, Adana, Turkey.;Baskent University Faculty of Medicine, Department of Medical Microbiology, Adana, Turkey.",
"authors": "Demiroğu|Yusuf Ziya|YZ|;Ödemiş|İlker|İ|;Oruç|Ebru|E|;Özer|Fulya|F|;Ulaş|Burak|B|;Canpolat|Emine Tuba|ET|;Yalçın|Çiğdem|Ç|;Öğüç Şanlı|Özlem|Ö|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Turkey",
"delete": false,
"doi": "10.5578/mb.20219719",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0374-9096",
"issue": "55(4)",
"journal": "Mikrobiyoloji bulteni",
"keywords": null,
"medline_ta": "Mikrobiyol Bul",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D000086382:COVID-19; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009916:Orbital Diseases; D000086402:SARS-CoV-2",
"nlm_unique_id": "7503830",
"other_id": null,
"pages": "673-682",
"pmc": null,
"pmid": "34666667",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two Case of Rhino-Orbito-Cerebral Mucormicosis Developed After COVID-19 Infection.",
"title_normalized": "two case of rhino orbito cerebral mucormicosis developed after covid 19 infection"
} | [
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"companynumb": "TR-PFIZER INC-202101604259",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstancename": "METHYLPREDNISOLONE ACETATE"
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"abstract": "This case report concentrates on the fatal consequences of the chronic aspects of neuroleptic malignant syndrome (NMS). It is a life-threatening side effect and has been identified since antipsychotics were developed. Efforts to highlight the propensity to develop NMS for those more sensitive to psychotropic medications have been infrequent. Ethnic groups, such as Asians and African Americans, seem to be at higher risk, and therefore clinicians must be hypervigilant of NMS with these groups. Strategies on how to keep a heightened level of awareness about the use of traditional antipsychotic medications with those at risk for NMS are discussed.",
"affiliations": "Dr. Buttar is with the Buffalo Psychiatric Center in Buffalo New York.;Dr. Buttar is with the Buffalo Psychiatric Center in Buffalo New York.;Dr. Buttar is with the Buffalo Psychiatric Center in Buffalo New York.",
"authors": "Buttar|Kulwant|K|;Trigoboff|Eileen|E|;Grace|Jeffery J|JJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2158-8333",
"issue": "17(10-12)",
"journal": "Innovations in clinical neuroscience",
"keywords": "Neuroleptic malignant syndrome; antipsychotic medications; chronic illness; creatine phosphokinase (CPK); psychiatric inpatients; risk",
"medline_ta": "Innov Clin Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101549695",
"other_id": null,
"pages": "35-37",
"pmc": null,
"pmid": "33898100",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "22732295;27423483;16255668;25438028;8731718;25387323;29061403;12006894;12760609",
"title": "Neuroleptic Malignant Syndrome: Can Be an Unrecognized Chronic Fatal Disease.",
"title_normalized": "neuroleptic malignant syndrome can be an unrecognized chronic fatal disease"
} | [
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"companynumb": "US-NOVARTISPH-NVSC2021US227711",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
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"drugadditional": "4",
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{
"abstract": "A 50-year-old man with a history of acromegaly was referred for preoperative cardiac evaluation preceding trans-sphenoidal resection of a pituitary macroadenoma. Dobutamine stress echocardiography was negative for myocardial ischaemia. Resting left ventricular (LV) LV ejection fraction (LVEF) was 64% and there was hypertrophy of ventricular septum (18 mm) without resting LV outflow tract obstruction. With 40 µg/kg/min of dobutamine, the LVEF became hyperdynamic at 80%, and there was a maximal instantaneous LV outflow tract gradient of 77 mm Hg. There was no delayed myocardial enhancement on cardiac MRI and the pattern of hypertrophy was concentric. Acromegaly-induced cardiomyopathy can mimic hypertrophic cardiomyopathy in the setting of dobutamine provocation. Because cardiomyopathy is an important cause of mortality in acromegaly, diagnosis and appropriate management are critical to improve survival.",
"affiliations": "Department of Cardiology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Endocrinology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Cardiology, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Abdelsalam|Mahmoud A|MA|;Nippoldt|Todd B|TB|;Geske|Jeffrey B|JB|",
"chemical_list": "D004280:Dobutamine",
"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": "D000172:Acromegaly; D009202:Cardiomyopathies; D004280:Dobutamine; D025401:Echocardiography, Stress; D006352:Heart Ventricles; D006801:Humans; D008297:Male; D008875:Middle Aged; D016277:Ventricular Function, Left; D014694:Ventricular Outflow Obstruction",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26961727",
"pubdate": "2016-03-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12501975;15531475;17220469;22572504;11081170;22878800;23226648;16230430;19725857;11886323;18445662;7641357;12034409;20413025;18490319;24070600;17854389;11028493",
"title": "Acromegaly-induced cardiomyopathy with dobutamine-induced outflow tract obstruction.",
"title_normalized": "acromegaly induced cardiomyopathy with dobutamine induced outflow tract obstruction"
} | [
{
"companynumb": "US-BAXTER-2016BAX019144",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXTROSE MONOHYDRATE\\DEXTROSE MONOHYDRATE\\DOBUTAMINE HYDROCHLORID... |
{
"abstract": "BACKGROUND Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is a variant of idiopathic multicentric Castleman disease. Adrenal hemorrhage has rarely been reported in TAFRO syndrome, and previous cases have mainly been Asian patients. This report is of two Caucasian patients with TAFRO syndrome presenting with acute adrenal insufficiency due to bilateral adrenal hemorrhage. CASE REPORT Case 1 was a 19-year-old Caucasian man with no significant past medical history who was admitted with acute abdominal pain, vomiting, anorexia, and moderate weight loss. Case 2 was a 31-year-old Caucasian woman with no past medical history who was admitted to hospital with fever, dyspnea, thoracic and abdominal pain, polyarthralgia, and hypotension. Both patients had splenomegaly, mild lymphadenopathy, thrombocytopenia, acute kidney injury, and myelofibrosis. In both cases, lymph node biopsy histology showed mixed-type idiopathic multicentric Castleman disease. In both patients, a diagnosis of TAFRO was made, and they developed bilateral adrenal hemorrhage with adrenal insufficiency. Case 1 was treated with high-dose steroids, followed by tocilizumab infusion. Due to persistent thrombocytopenia, second-line treatment commenced with rituximab, but the patient relapsed two months later. Tocilizumab treatment was recommenced, which was followed by an immuno-allergic adverse event. He then had a good response to sirolimus. Case 2 died nine months after diagnosis due to acute respiratory distress. CONCLUSIONS Two cases of TAFRO syndrome presented with acute adrenal insufficiency due to bilateral adrenal hemorrhage. The symptoms were only partially controlled with tocilizumab, rituximab, and tacrolimus. Adrenal hemorrhage may be a specific manifestation of TAFRO syndrome.",
"affiliations": "Department of Internal Medicine, Edouard Herriot Hospital, Lyon, France.;Department of Internal Medicine, Edouard Herriot Hospital, Lyon, France.;Department of Internal Medicine, Edouard Herriot Hospital, Lyon, France.;Department of Internal Medicine, Edouard Herriot Hospital, Lyon, France.;Department of Internal Medicine - Hematology, Saint-Louis Hospital, Paris, France.;Department of Internal Medicine, Edouard Herriot Hospital, Lyon, France.",
"authors": "Ducoux|Grégoire|G|;Guerber|Arthur|A|;Durel|Cécile-Audrey|CA|;Asli|Bouchra|B|;Fadlallah|Jehane|J|;Hot|Arnaud|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.919536",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32249274\n10.12659/AJCR.919536\n919536\nArticles\nThrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome with Bilateral Adrenal Hemorrhage in Two Caucasian Patients\nDucoux Grégoire *ABCDEF1 Guerber Arthur *ABCDEF1 Durel Cécile-Audrey ACDEF1 Asli Bouchra DE1 Fadlallah Jehane ABCDEFG2 Hot Arnaud DE1 \n1 Department of Internal Medicine, Edouard Herriot Hospital, Lyon, France\n\n2 Department of Internal Medicine – Hematology, Saint-Louis Hospital, Paris, France\nCorresponding Author: Grégoire Ducoux, e-mail: gregoire.ducoux@chu-lyon.frAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n* Grégoire Ducoux and Arthur Guerber contributed equally to this report\n\nConflict of interest: None declared\n\n\n2020 \n06 4 2020 \n21 e919536-1 e919536-7\n20 8 2019 02 1 2020 17 2 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Case series\n\nPatients: Male, 19-year-old • Female, 31-year-old\n\nFinal Diagnosis: TAFRO syndrome\n\nSymptoms: Fever • splenomegaly • lymphadenopathies\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Hematology\n\nObjective:\nUnusual clinical course\n\nBackground:\nThrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is a variant of idiopathic multicentric Castleman disease. Adrenal hemorrhage has rarely been reported in TAFRO syndrome, and previous cases have mainly been Asian patients. This report is of two Caucasian patients with TAFRO syndrome presenting with acute adrenal insufficiency due to bilateral adrenal hemorrhage.\n\nCase Reports:\nCase 1 was a 19-year-old Caucasian man with no significant past medical history who was admitted with acute abdominal pain, vomiting, anorexia, and moderate weight loss. Case 2 was a 31-year-old Caucasian woman with no past medical history who was admitted to hospital with fever, dyspnea, thoracic and abdominal pain, polyarthralgia, and hypotension. Both patients had splenomegaly, mild lymphadenopathy, thrombocytopenia, acute kidney injury, and myelofibrosis. In both cases, lymph node biopsy histology showed mixed-type idiopathic multicentric Castleman disease. In both patients, a diagnosis of TAFRO was made, and they developed bilateral adrenal hemorrhage with adrenal insufficiency. Case 1 was treated with high-dose steroids, followed by tocilizumab infusion. Due to persistent thrombocytopenia, second-line treatment commenced with rituximab, but the patient relapsed two months later. Tocilizumab treatment was recommenced, which was followed by an immuno-allergic adverse event. He then had a good response to sirolimus. Case 2 died nine months after diagnosis due to acute respiratory distress.\n\nConclusions:\nTwo cases of TAFRO syndrome presented with acute adrenal insufficiency due to bilateral adrenal hemorrhage. The symptoms were only partially controlled with tocilizumab, rituximab, and tacrolimus. Adrenal hemorrhage may be a specific manifestation of TAFRO syndrome.\n\nMeSH Keywords:\nAdrenal InsufficiencyEdemaGiant Lymph Node HyperplasiaPrimary MyelofibrosisRenal InsufficiencyThrombocytopenia\n==== Body\nBackground\nThrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is a variant of idiopathic multicentric Castleman disease [1]. In 2010, Takai et al. described TAFRO syndrome as a new variant of human Herpesvirus 8 (HHV8)-negative idiopathic multicentric Castleman disease in Asian patients. The clinical features initially described included thrombocytopenia, anasarca (edema, pleural effusion, and ascites), fever, renal dysfunction, reticulin myelofibrosis, and organomegaly (hepatosplenomegaly and lymphadenopathy) [2]. The lymph node histology in patients with TAFRO syndrome is characterized by hyalinization of lymphoid follicles, capillary proliferation, and increased numbers of plasma cells, consistent with mixed type idiopathic multi-centric Castleman disease [3]. A central role for interleukin-6 (IL-6) has been proposed for the pathogenesis of multicentric Castleman disease [4].\n\nDespite similar histopathology, TAFRO syndrome can be distinguished from multicentric Castleman disease by several clinical and histological findings. A normal immunoglobulin level, thrombocythemia (platelet count, <100×109/L), mild lymphadenopathy, with a lymph node diameter of ≤1.5 cm, hypoalbuminemia, and anasarca are more typical for TAFRO syndrome. Polyclonal hypergammaglobulinemia, thrombocytosis, and lymphadenopathy are characteristics of multicentric Castleman disease. A recently published retrospective study analyzed 220 patients from the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome database that included 87 patients with idiopathic multicentric Castleman disease, not otherwise specified (iMCD-NOS), 63 patients with TAFRO-iMCD, and 19 patients with TAFRO alone [5]. The findings showed that the outcome for patients with TAFRO was poor, with a five-year survival rate of 65% [5]. However, while the pathogenesis of HHV-8-associated multicentric Castleman disease is better understood, idiopathic multicentric Castleman disease and TAFRO syndrome remain to be determined.\n\nAdrenal involvement in multicentric Castleman disease has previously been described, and increased expression of IL-6 has been reported in these cases [6,7]. However, adrenal hemorrhage has only been reported in TAFRO syndrome in the idiopathic multicentric Castleman disease subtype. Also, the majority of reported cases were Asian patients, with few reported cases in Caucasians [8]. To our knowledge, hemorrhagic events in other organs during TAFRO syndrome had not been previously described. This report is of two Caucasian patients with TAFRO syndrome who presented with acute adrenal insufficiency due to bilateral adrenal hemorrhage.\n\nCase Reports\nCase 1\nA 19-year-old French Caucasian man with no significant past medical history was admitted to hospital with acute abdominal pain and vomiting associated with anorexia and moderate weight loss. Physical examination showed splenomegaly, normal arterial blood pressure, and no fever. Blood tests initially showed a high serum C-reactive protein (CRP) level (27 mg/dL), hyperfibrinogenemia (5 g/L), thrombocytopenia (platelet count, 114×109/L), lymphopenia (1×109/L), hypoalbuminemia (29 g/L), hyponatremia, and hyperkalemia. The prothrombin time (PT) was 12.5 s (normal range, 9–14 s), and the partial thromboplastin time (PTT) was 31 s (normal range, 27–40 s). Blood cultures were negative. The serum cortisol level was low, and the adrenocorticotrophic hormone (ACTH) level was increased, in keeping with a diagnosis of acute adrenal insufficiency. Replacement therapy with hydrocortisone and fludrocortisone began with an excellent clinical response within a few days.\n\nAn abdominal computed tomography (CT) scan showed bilateral adrenal hemorrhage associated with a mild celiac, mesenteric, and axillary lymphadenopathy. He did not have splenomegaly, and there were no pleural, pericardial, or abdominal effusions. Adrenal hemorrhage was confirmed by magnetic resonance imaging (MRI) (Figure 1). The QuantiFERON-TB Gold (QFT) test for Mycobacterium tuberculosis (Qiagen, Hilden, Germany) and viral detection by polymerase chain reaction (PCR) were negative. Serum anti-adrenal antibodies, antibodies to beta2-glycoprotein I (anti-beta2-GPI), anti-cardiolipin antibodies, and antinuclear antibodies were negative. The Dilute Russell’s viper venom time (dRVVT) test for lupus anticoagulant (LA) was negative at 12 weeks. Gamma globulins were within the normal range (<14 g/L).\n\nTwo weeks later, he developed fever (39°C), night sweats, limb edema, dyspnea, bilateral exudative pleural effusion, ascites, and purpura. All laboratory parameters worsened over time with normochromic anemia (6.3 g/dL), severe thrombocytopenia (platelet count, 26×109/L), high serum ferritin level (2294 µg/L), and hypoalbuminemia (23 g/L). Imaging by computed tomography (CT) showed anasarca, or generalized edema. A bone marrow biopsy showed grade 1 myelofibrosis. Right axillary and left inguinal lymph node biopsies were performed and showed histological changes of multicentric mixed-type Castleman disease, characterized by a hyaline vascular pattern (Figure 2), atrophic germinal centers (Figure 3) and mantle cell hyperplasia with polyclonal plasmacytosis (Figure 4). Immunohistochemistry staining for the latency-associated nuclear antigen (LANA-1) of human herpesvirus 8 (HHV-8) was negative. A slight increase in serum vascular endothelial growth factor (VEGF) was detected at 171 pg/mL (normal range, 0–115 pg/mL). He rapidly developed acute kidney injury with a rise in serum creatinine levels from 95 µmol/L at baseline to 155 µmol/L, without proteinuria or microscopic hematuria.\n\nBased on the clinical manifestations, biochemical laboratory findings, and histopathology, the patient was diagnosed with thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome, according to the 2015 diagnostic criteria [9]. He was treated with tocilizumab (8 mg/kg/15 days) and high-dose prednisone using 1 g for two days, followed by 1 mg/kg/day. A few days after starting tocilizumab treatment, his fever resolved, the CRP and creatinine levels decreased, but thrombocytopenia persisted, at <50×109/L. Treatment was suspended after three injections of tocilizumab because of severe hypotension. Second-line therapy with rituximab commenced using four once-weekly doses of 375 mg/m2. Two months later, the patient experienced disease relapse, with auto-immune hemolytic anemia (Hb, 3.9 g/dL), acute kidney injury, systemic inflammation, and anasarca, which was treated with tocilizumab. The patient developed a further immune drug-related reaction after the second infusion, and a third-line therapy with sirolimus began. Sirolimus treatment resulted in a hematologic response with the recovery of the platelet count to >100×109/L at six months after disease onset (Figure 5).\n\nCase 2\nA 31-year-old Caucasian woman with no significant past medical history was admitted to hospital with a fever of 39°C, dyspnea, thoracic and abdominal pain, polyarthralgia, and low blood pressure. Physical examination showed limb edema, pleuritis, mild lymphadenopathy, and bilaterally enlarged parotid glands. Blood tests showed an increased CRP level (11 mg/dL), normocytic anemia (Hb, 10 g/dL), thrombocytopenia (platelet count, 120×109/L), increased alkaline phosphatase (ALP) (142 g/L), hyponatremia, and hyperkalemia. Microbiology tests were negative. Thoracic and abdominal CT scans showed a large bilateral pleural effusion, mild ascites, mediastinal and subdiaphragmatic lymphadenopathy, mild hepatosplenomegaly, and bilateral adrenal hemorrhage, which supported the diagnosis of acute adrenal insufficiency. Pleural aspiration showed an exudative effusion containing neutrophils without bacterial growth. Because of respiratory failure and the worsening biochemical laboratory findings, she was admitted to the intensive care unit (ICU). Antinuclear antibodies (ANAs) were positive (1/1280) with a high titer of ANAs for Sjögren’s syndrome A (SSA) and SSB, a low titer of DNA antibodies, reduced levels of complement C3 and C4 factors, and a low titer of mixed type III cryoglobulins. Lupus anticoagulant, IgG anti-cardiolipin, and anti-beta2 glycoprotein 1 antibodies were initially positive. The partial thromboplastin time (PTT) was 31.6 s (normal range, 27–40 s), the prothrombin time (PT) was 13.6 s (normal range, 9–14 s), and the fibrinogen level was 7.14 g/L. She had moderate polyclonal hypergammaglobulinemia (15 g/L), and increased ferritin (2,000 μg/L), with a normal percentage of ferritin glycosylation.\n\nA preliminary diagnosis was made of systemic lupus erythematosus (SLE) with articular, pleural, and hematologic manifestations associated with antiphospholipid syndrome. She was initially treated with three daily doses of 500 mg of methylprednisolone, then 1 mg/kg/day of prednisone, with anticoagulant therapy. However, there was no clinical or biochemical improvement. She then developed progressive subacute renal dysfunction and required hemodialysis. There was no glomerular proteinuria or microscopic hematuria. The serum VEGF level was increased (500 pg/mL). However, antiphospholipid antibodies were negative, three months after her initial diagnosis. A bone marrow biopsy showed a grade 1 reticulin pattern indicating myelofibrosis. A computed tomography (CT) scan confirmed anasarca with mild generalized lymphadenopathy and organomegaly. Two lymph node biopsies were successively performed, which showed a polyclonal population of lymphoplasmacytic cells and vascular hyalinization consistent with the histological features of multicentric Castleman disease. The patient was diagnosed with TAFRO syndrome complicated by bilateral adrenal hemorrhage.\n\nThis patient had a minor salivary gland biopsy that showed lymphocytic sialadenitis (focus score ≥1). The diagnosis of Sjögren syndrome was also considered, as the diagnosis of SLE and antiphospholipid syndrome were excluded. She received second-line treatment with tocilizumab (8 mg/kg/15 days), but developed toxic epidermal necrolysis after the first infusion, and tocilizumab was withdrawn. Third-line therapy commenced with rituximab (375 mg/m2 by intravenous infusion) using a four doses per week regimen, which resulted in clinical improvement and a partial response with reduced fever and systemic inflammation, and increased platelet levels. Her anasarca and renal dysfunction persisted, and tacrolimus treatment was initiated. However, the patient died suddenly with acute respiratory distress from an unknown cause nine months after the diagnosis of TAFRO syndrome, and 15 days after the tacrolimus treatment.\n\nDiscussion\nThrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is a variant of idiopathic multicentric Castleman disease [9]. TAFRO syndrome is a systemic inflammatory disorder that is challenging to diagnose and treat. In 2015, Masaki et al. proposed a disease severity classification, diagnostic criteria, and recommendations for the treatment of TAFRO syndrome [9]. The two patients described in this report met all the major and minor diagnostic criteria for TAFRO syndrome [9]. The first case was a typical case of idiopathic multicentric Castleman disease or TAFRO subtype, without evidence of autoimmune diseases. The second case had clinical features of TAFRO syndrome and overlap with Sjögren syndrome, which is an association that has been previously described [10].\n\nAuto-antibodies, such as antinuclear or anti-SS-A antibodies have been described in Caucasian patients with TAFRO syndrome [9]. However, the criteria used to define a connective tissue disease are usually not found in these patients [8]. A definitive diagnosis of connective tissue disease would exclude TAFRO syndrome [9]. However, all the clinical, biochemical, and histological findings from the second case could not be explained only by a diagnosis of Sjögren syndrome. Severe thrombocytopenia, reticulin myelofibrosis, mild organomegaly, anasarca, and acute kidney injury were consistent with a diagnosis of TAFRO syndrome. The optimal therapeutic strategy for idiopathic multicentric Castleman disease with TAFRO syndrome has not been clearly defined. Treatment with steroids has been suggested as first-line therapy, but a lack of response is common. A significant improvement of the symptoms can be achieved using interleukin-6 (IL-6) blockade with tocilizumab or siltuximab [9,11,12]. Previously published studies have shown that rituximab can be effective in controlling idiopathic multicentric Castleman disease with TAFRO syndrome [13,14].\n\nThe therapeutic use of inhibitors of mammalian target of rapamycin (mTOR), such as sirolimus, are a promising new approach for treating refractory idiopathic multicentric Castleman disease. A recent study analyzed the potential targeting pathways in three patients with multicentric Castleman disease with TAFRO syndrome refractory to IL-6 blockade. All the patients received sirolimus, and a clinical response included reduced T-cell activation and reduced levels of VEGF-A in all patients [15]. The two patients described in this report initially presented with acute adrenal insufficiency due to bilateral adrenal hemorrhage. The symptoms of TAFRO syndrome developed a few days for the first patient, and concomitantly for the second patient.\n\nThere have been three previously published cases of bilateral adrenal hemorrhage associated with TAFRO syndrome, which supports the possibility that adrenal hemorrhage may be a specific manifestation of TAFRO syndrome [16–18]. To our knowledge, there have been no previously reported cases of other subtypes of Castleman disease associated with adrenal hemorrhage. Nara et al. reported a case of a 48-year-old Japanese man with a two-month history of general fatigue with a diagnosis of TAFRO syndrome and adrenal hemorrhage [16]. Crump et al. reported a case of idiopathic multicentric Castleman disease associated with adrenal hemorrhage and acute adrenal insufficiency, 15 years before the first description of TAFRO syndrome [17]. In this previously published case report, the patient had an atypical presentation for idiopathic multicentric Castleman disease because of thrombocytopenia and myelofibrosis on bone marrow biopsy [17]. Currently, this patient would meet the diagnostic criteria of TAFRO syndrome and was probably the first description of this association [17]. A previous case reported by Fumiko and al. in 2017 was of a 48-year-old Japanese man who fulfilled all the diagnostic criteria for TAFRO syndrome with adrenal insufficiency due to bilateral adrenal hemorrhage on computed tomography (CT) scan, without evidence of antiphospholipid syndrome [18].\n\nAntiphospholipid syndrome can be associated with unilateral or bilateral adrenal hemorrhage and is sometimes associated with Castleman disease [19,20]. Antiphospholipid antibodies were initially positive in the two patients presented in this report but were negative 12 weeks later. Also, the two patients did not experience episodes of thrombosis during follow-up, which excluded the diagnosis of antiphospholipid syndrome. Antiphospholipid antibodies were also negative in the three previously published cases of TAFRO syndrome associated with adrenal hemorrhage. Therefore, antiphospholipid syndrome does not seem to be the mechanism of adrenal hemorrhage in TAFRO syndrome. Adrenal involvement without hemorrhage has previously been reported in Castleman disease [6,7]. In these cases, Castleman disease presented as an adrenal mass without adrenal insufficiency [6,7].\n\nThe mechanisms involved in the development of adrenal hemorrhage are not well understood, but several theories have been proposed. An increase in levels of ACTH induced by stress leads to increased blood flow to the adrenal glands, which can lead to hemorrhage from the capillaries at the cortico-medullary junction due to the fragility of the capillary plexus [21]. Patients with TAFRO syndrome might experience ACTH release as a cellular stress response. Experimental studies have shown that IL-6 has a role in the activation of the hypothalamic-pituitary-adrenal axis in humans is a nonspecific stress-induced defense mechanism involving the innate immune system [22]. Mastorakos et al. showed a trophic effect of IL-6 on the adrenal gland in patients treated with a parenteral form of IL-6 [22]. However, evidence for the potential effect of IL-6 on adrenal hemorrhage is weak. Also, adrenal hemorrhage has not previously been described in association with high Il-6 levels, including inflammatory diseases or hemophagocytic lymphohistiocytosis, and inflammatory cytokines are also involved in TAFRO syndrome. A catecholamine surge from the adrenal gland may promote vasoconstriction and platelet aggregation, which may induce vasospasm and hemorrhage of the fragile adrenal capillary vessels. Fujiwara et al. identified a hypercoagulation state in TAFRO syndrome, but catecholamine levels were not studied [11]. Finally, profound thrombocytopenia as a common manifestation of TAFRO syndrome that may lead to adrenal hemorrhage.\n\nConclusions\nThis report described two patients with thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome associated with bilateral adrenal hemorrhage with acute adrenal insufficiency. TAFRO) syndrome is recognized to be a variant of idiopathic multicentric Castleman disease. These two cases are distinctive in that they occurred in Caucasian patients, rather than previously described Asian patients. Although adrenal hemorrhage remains to be incorporated in the diagnostic criteria of TAFRO, adrenal insufficiency is now well described. These reports highlight that the presence of adrenal hemorrhage should be sought in the presence of abdominal pain in TAFRO syndrome with abdominal imaging and biochemical investigations. Adrenal hemorrhage in TAFRO syndrome may occur due to the hypercoagulation state and thrombocytopenia, but these predisposing factors require further investigation. As these cases have shown, adrenal hemorrhage may be a specific manifestation of TAFRO syndrome.\n\nConflict of interest\n\nNone.\n\nFigure 1. Case 1. Magnetic resonance imaging (MRI) of the adrenal gland with thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome, associated with adrenal hemorrhage and insufficiency. The adrenal gland axial volume acceleration-flexible (LAVA-Flex) magnetic resonance imaging (MRI) (blue arrow). The coronal T2-weighted sequence (yellow arrow) shows bilateral adrenal masses with a fluid collection (hemorrhage) and a hyperintense T1-weighted non-enhancing lesion, typical for adrenal hemorrhage.\n\nFigure 2. Case 1. Photomicrograph of the histology of the lymph node biopsy in a case of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome associated with adrenal hemorrhage and insufficiency. Lymph node histology shows a mixed subtype Castleman disease showing an onion skin pattern of fibrosis around an atrophic germinal center with prominent vascularity. The bar represents 60 μm. Hematoxylin and eosin (H&E).\n\nFigure 3. Case 1. Photomicrograph of the immunohistochemistry for CD23 in the lymph node biopsy in a case of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome associated with adrenal hemorrhage and insufficiency. Immunohistochemistry with a primary monoclonal antibody to CD23 for dendritic cells shows atrophic and concentric follicular dendritic cells distributed in the germinal center, which a histological pattern found in idiopathic multicentric Castleman disease. The bar represents 60 μm.\n\nFigure 4. Case 1. Photomicrograph of the immunohistochemistry for CD138 in the lymph node biopsy in a case of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome, associated with adrenal hemorrhage and insufficiency. Immunohistochemistry with a primary monoclonal antibody to CD138 (syndecan-1) shows lymph node infiltration by plasma cells. The bar represents 160 μm.\n\nFigure 5. Case 1. The clinical course in a patient with thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome associated with adrenal hemorrhage and insufficiency. The clinical course in a 19-year-old Caucasian man included fever, platelet count, C-reactive protein (CRP), and creatinine levels. A partial response was obtained with tocilizumab injection. The patient was treated with high-dose steroids, followed by tocilizumab infusion. Due to persistent thrombocytopenia, second-line treatment commenced with rituximab, but the patient relapsed two months later. Tocilizumab treatment was recommenced, which was followed by an immuno-allergic adverse event. The patient then had a good response to sirolimus.\n==== Refs\nReferences:\n1. Sakashita K Murata K Takamori M TAFRO syndrome: Current perspectives J Blood Med 2018 9 15 23 29403325 \n2. Takai K Nikkuni K Shibuya H Hashidate H [Thrombocytopenia with mild bone marrow fibrosis accompanied by fever, pleural effusion, ascites and hepatosplenomegaly] Rinsho Ketsueki 2010 51 320 25 [in Japanese] 20534952 \n3. Fajgenbaum DC Uldrick TS Bagg A International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease Blood 2017 129 1646 57 28087540 \n4. Wang H-W Pittaluga S Jaffe ES Multicentric Castleman disease: Where are we now? Semin Diagn Pathol 2016 33 294 306 27296355 \n5. Fujimoto S Sakai T Kawabata H Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease? Am J Hematol 2019 [Epub ahead of print] \n6. Müssig K Horger M Wehrmann M Adrenal Castleman’s disease Ann Hematol 2007 86 63 65 17039362 \n7. Santomauro M Choe C Heimbigner J Castleman’s disease in the left suprarenal region, mimicking an adrenal neoplasm Urology 2011 78 319 21316092 \n8. Louis C Vijgen S Samii K TAFRO syndrome in caucasians: A case report and review of the literature Front Med (Lausanne) 2017 4 149 29018798 \n9. Masaki Y Kawabata H Takai K Proposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, 2015 version Int J Hematol 2016 103 686 92 27084250 \n10. Fujimoto S Kawabata H Kurose N Sjögren’s syndrome manifesting as clinicopathological features of TAFRO syndrome: A case report Medicine 2017 96 e9220 29390349 \n11. Fujiwara S Mochinaga H Nakata H Successful treatment of TAFRO syndrome, a variant type of multicentric Castleman disease with thrombotic microangiopathy, with anti-IL-6 receptor antibody and steroids Int J Hematol 2016 103 718 23 26980221 \n12. Sakai K Maeda T Kuriyama A TAFRO syndrome successfully treated with tocilizumab: A case report and systematic review Mod Rheumatol 2018 28 564 69 26886414 \n13. Jain P Verstovsek S Loghavi S Durable remission with rituximab in a patient with an unusual variant of Castleman’s disease with myelofibrosis – TAFRO syndrome Am J Hematol 2015 90 1091 92 25808231 \n14. Hiramatsu S Ohmura K Tsuji H Successful treatment by rituximab in a patient with TAFRO syndrome with cardiomyopathy Nihon Rinsho Meneki Gakkai Kaishi 2016 39 64 71 27181237 \n15. Fajgenbaum DC Langan R-A Japp AS Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade – refractory idiopathic multicentric Castleman disease J Clin Invest 2019 129 4451 63 \n16. Nara M Komatsuda A Itoh F Two cases of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome with high serum procalcitonin levels, including the first case complicated with adrenal hemorrhaging Intern Med 2017 56 1247 52 28502946 \n17. Crump JA Beard ME Angus HB Acute adrenal insufficiency: A new presentation of Castleman’s disease J Intern Med 1995 238 81 84 7608651 \n18. Ito F Kameoka Y Nara M [TAFRO Syndrome with Bilateral Adrenal Hemorrhage] Nippon Naika Gakkai Zasshi 2017 106 288 94 [in Japanese] 30182658 \n19. Isilak Z Uzun M Incedayi M Coronary pseudoaneurysm and superior vena cava occlusion in a young patient with multicentric Castleman’s disease and antiphospholipid antibody positivity Eur J Echocardiogr 2011 12 E35 21729930 \n20. Jakubíková M Piťha J Latta J Myasthenia gravis, Castleman disease, pemphigus, and anti-phospholipid syndrome Muscle Nerve 2013 47 447 51 23386221 \n21. Vella A Nippoldt TB Morris JC Adrenal hemorrhage: A 25-year experience at the Mayo Clinic Mayo Clin Proc 2001 76 161 68 11213304 \n22. Mastorakos G Chrousos GP Weber JS Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans J Clin Endocrinol Metab 1993 77 1690 94 8263159\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000307:Adrenal Gland Diseases; D005871:Castleman Disease; D017809:Fatal Outcome; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e919536",
"pmc": null,
"pmid": "32249274",
"pubdate": "2020-04-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31408438;27181237;27084250;28087540;20534952;31222819;29390349;23386221;21316092;26886414;27296355;30182658;7608651;26980221;25808231;17039362;11213304;29018798;29403325;21729930;8263159;28502946",
"title": "Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome with Bilateral Adrenal Hemorrhage in Two Caucasian Patients.",
"title_normalized": "thrombocytopenia anasarca fever reticulin fibrosis renal failure and organomegaly tafro syndrome with bilateral adrenal hemorrhage in two caucasian patients"
} | [
{
"companynumb": "FR-PBT-000041",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"drugadmi... |
{
"abstract": "We report a 21-year-old man with bipolar disorder who was on a stable dose of escitalopram and risperidone. Tramadol and cough syrup (dextromethorphan) were added for his recent attack of upper respiratory tract infection. However, he developed various neurological symptoms. Haloperidol and ondansetron were added after hospitalisation. However, his condition deteriorated. A diagnosis of serotonin syndrome (SS) was made, and cyproheptadine was started. Cyproheptadine provided relief in most of the symptoms within 48 hours except for the presence of fever and rigidity. The addition of bromocriptine provided a complete resolution of the symptoms. We considered the presence of both SS and neuroleptic malignant syndrome (NMS) in this case. There are four similar cases in the literature. We discussed a diagnostic and therapeutic approach for patients who are on both serotonergic agents and neuroleptics and develop SS-like or NMS-like clinical features.",
"affiliations": "Neurolgy, SBKSMI&RC, Sumandeep Vidyapeeth University, Vadodara, Gujarat, India drprakashs@yahoo.co.in.;Department of Medicine, Smt BK Shah Medical Institute and Research Centre, Waghodia, Gujarat, India.;Neurolgy, Smt BK Shah Medical Institute and Research Centre, Waghodia, Gujarat, India.",
"authors": "Prakash|Sanjay|S|http://orcid.org/0000-0001-7322-904X;Lodha|Deepali|D|;Rawat|Kalu Singh|KS|",
"chemical_list": "D014150:Antipsychotic Agents; D006220:Haloperidol; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-241578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "drugs: psychiatry; neurology (drugs and medicines); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D006220:Haloperidol; D006801:Humans; D008297:Male; D009459:Neuroleptic Malignant Syndrome; D018967:Risperidone; D020230:Serotonin Syndrome; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34400419",
"pubdate": "2021-08-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Coexistence of serotonin syndrome and neuroleptic malignant syndrome: does it exist?",
"title_normalized": "coexistence of serotonin syndrome and neuroleptic malignant syndrome does it exist"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2021-21711",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
},
"drug... |
{
"abstract": "Childhood tuberculous meningitis is associated with serious long-term sequelae, including mental retardation, behavior disturbances, and motor handicap. Brain damage in tuberculous meningitis results from a cytokine-mediated inflammatory response, which causes vasculitis and obstructive hydrocephalus. Thalidomide, a potent tumor necrosis factor alpha inhibitor, was well tolerated and possibly showed some clinical benefit in children with tuberculous meningitis during a pilot study. The purpose of the present study was to assess the effect of adjunctive thalidomide in addition to standard antituberculosis and corticosteroid therapy on the outcome of tuberculous meningitis. Thalidomide (24 mg/kg/day orally) or placebo was administered in a double-blind randomized fashion for 1 month to patients with stage 2 or 3 tuberculous meningitis. The study was terminated early because all adverse events and deaths occurred in one arm of the study (thalidomide group). Thirty of the 47 children enrolled received adjunctive thalidomide, of whom 6 (20%) developed a skin rash, 8 (26%) hepatitis, and 2 (6%) neutropenia or thrombocytopenia. Four deaths (13%) occurred in patients with very severe neurologic compromise at baseline; two deaths were associated with a rash. Motor outcome after 6 months of antituberculosis therapy was similar in the two groups, even though the thalidomide group showed greater neurologic compromise on admission. In addition, the mean IQ of the two treatment groups did not differ significantly (mean IQ thalidomide group 57.8 versus mean IQ control group 67.5; P = .16). These results do not support the use of adjunctive high-dose thalidomide therapy in the treatment of tuberculous meningitis.",
"affiliations": "Department of Pediatrics and Child Health, Tygerberg Children's Hospital, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa. jfs@sun.ac.za",
"authors": "Schoeman|Johan F|JF|;Springer|Priscilla|P|;van Rensburg|Anita Janse|AJ|;Swanevelder|Sonja|S|;Hanekom|Willem A|WA|;Haslett|Patrick A J|PA|;Kaplan|Gilla|G|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D016207:Cytokines; D007166:Immunosuppressive Agents; D013792:Thalidomide",
"country": "United States",
"delete": false,
"doi": "10.1177/088307380401900402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "19(4)",
"journal": "Journal of child neurology",
"keywords": null,
"medline_ta": "J Child Neurol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003128:Coma; D016207:Cytokines; D004311:Double-Blind Method; D005076:Exanthema; D006505:Hepatitis; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D007360:Intelligence; D010291:Paresis; D013019:South Africa; D018709:Statistics, Nonparametric; D013792:Thalidomide; D016896:Treatment Outcome; D014390:Tuberculosis, Meningeal",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "250-7",
"pmc": null,
"pmid": "15163089",
"pubdate": "2004-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study.",
"title_normalized": "adjunctive thalidomide therapy for childhood tuberculous meningitis results of a randomized study"
} | [
{
"companynumb": "ZA-CELGENE-ZAF-2015023033",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe a case of bilateral, asymmetrical outer macular atrophy in a patient with pulmonary hypertension treated with long-term sildenafil (Revatio).\n\n\nMETHODS\nCase report with fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, and fluorescein angiography imaging.\n\n\nRESULTS\nA 32-year-old African American woman with a history of primary pulmonary hypertension and 5-year history of oral sildenafil (Revatio) use presented with decreasing central vision in her left eye. She reported a decline in central vision in the left eye that started 1 month after treatment initiation and progressed until discontinuation 5 years later. Visual acuity was 20/20 in the right eye and 20/100 in the left eye. Fundus photography revealed retinal pigment epithelial mottling and atrophy in the right eye and parafoveal retinal pigment epithelial mottling and atrophy in a ring-like configuration of the left eye. Optical coherence tomography demonstrated outer retinal irregularity in the right eye and disrupted outer retina involving the external limiting membrane, inner segment/outer segment junction, and the retinal pigment epithelium in the left eye; no choroidal thickening was observed. Fundus autofluorescence showed mild hypoautofluorescence in the foveal center with an irregular autofluorescence pattern in the parafovea of the left eye. Fluorescein angiography revealed capillary dropout with pinpoint hyperfluorescence and leakage in the far periphery bilaterally. A window defect was also observed in the foveal center of the left eye.\n\n\nCONCLUSIONS\nSildenafil and other PDE5 inhibitors have been associated with several ocular side effects. However, this is the first report in the literature of outer macular atrophy in a patient with pulmonary hypertension and long-term use of oral sildenafil. All patients with long-term use of sildenafil should be educated on the risk of potential visual adverse effects.",
"affiliations": "*Baylor College of Medicine, Houston, Texas; and †Cullen Eye Institute, Baylor College of Medicine-Department of Ophthalmology, Houston, Texas.",
"authors": "Sajjad|Ahmar|A|;Weng|Christina Y|CY|",
"chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000355",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "11(4)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000328:Adult; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D008266:Macula Lutea; D058986:Phosphodiesterase 5 Inhibitors; D012162:Retinal Degeneration; D000068677:Sildenafil Citrate; D015354:Vision, Low",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "325-328",
"pmc": null,
"pmid": "27355186",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "VISION LOSS IN A PATIENT WITH PRIMARY PULMONARY HYPERTENSION AND LONG-TERM USE OF SILDENAFIL.",
"title_normalized": "vision loss in a patient with primary pulmonary hypertension and long term use of sildenafil"
} | [
{
"companynumb": "US-PFIZER INC-2017409701",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMBRISENTAN"
},
"drugadditional": null,
... |
{
"abstract": "Intravenous injection of drugs is associated with a host of medical complications, notably soft-tissue infections. On the contrary, intra-arterial injections of drugs have also been reported, largely restricted to inadvertent injections. Here we describe a patient who engaged in repeated intra-arterial injections of heroin when she exhausted most of her venous access, and presented acutely with a radial artery occlusion requiring thrombolytic therapy. Clinicians should have a high index of suspicion for intra-arterial injection in injection drug users who present with limb pain, ischemia, and motor/sensory deficits. Given the reluctance patients may have in discussing their injection practices, clinicians should proactively discuss and counsel patients about safe injection practices and the dangers of intra-arterial injections.",
"affiliations": "Brigham and Women's Hospital (JS); Harvard Medical School (JS, ESV); and Harvard Longwood Psychiatry Residency Training Program (ESV), Boston, MA.",
"authors": "Suzuki|Joji|J|;Valenti|Erin S|ES|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "11(1)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000328:Adult; D001157:Arterial Occlusive Diseases; D005260:Female; D006556:Heroin Dependence; D006801:Humans; D007269:Injections, Intra-Arterial; D017534:Radial Artery; D015912:Thrombolytic Therapy",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "77-79",
"pmc": null,
"pmid": "28027191",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intentional Intra-arterial Injection of Heroin: A Case Report.",
"title_normalized": "intentional intra arterial injection of heroin a case report"
} | [
{
"companynumb": "US-INDIVIOR LIMITED-INDV-100739-2017",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
},
"drugadditional"... |
{
"abstract": "Secondary leukemia following chemotherapy or radiotherapy for mediastinal germ cell tumors in a well-described entity. It also may occur in patients with testicular germ cell tumors. We report a case of secondary leukemia occurring in a 31-year-old man who received ultra high-dose chemotherapy with peripheral blood stem cell autotransplantation (PBSCT) for a refractory testicular cancer (pathology; Seminoma, Embryonal carcinoma, Yolk sac tumor, Choriocarcinoma) with IIIB2 under Japanese classification, poor-risk group under Indiana classification. The initial levels of serum LDH, AFP and beta-HCG were high at 959 IU/l, 1,452 ng/ml and 800 ng/ml. He received total 11 cycles of systemic chemotherapy (2 cycles of PVB regimen, 4 cycles of PEB regimen, 3 cycles of VIP regimen and 2 cycles of ultra high-dose chemotherapy with PBSCT for pulmonary and para-aortic lymph node metastasis following his initial orchiectomy. The total amount of etoposide (VP-16), cisplatin (CDDP), carboplatin (CBDCA) and ifosfamide (IFM), this patient received was 7,225 mg/m2, 1,510 mg/m2 1,750 mg/m2, and 50.5 g. He has survived with CR of disease. Severe and persistent pancytopenia developed 25 months after his initial orchiectomy. Bone marrow examination showed AML (M2 with eosinophilia) under French-America-British (FAB) classification. Therefore, he was diagnosed as secondary leukemia following high-dose chemotherapy. He received total 6 cycles of systematic chemotherapy for the secondary leukemia in the internal department. He is planing to have bone marrow transplantation. To our knowledge, this is the first reported case in the literature relevant to secondary leukemia following ultra high-dose chemotherapy with PBSCT in testicular tumor in Japan.",
"affiliations": "Department of Urology, Kinki University School of Medicine.",
"authors": "Matsumoto|S|S|;Matsuda|H|H|;Uejima|S|S|;Kurita|T|T|",
"chemical_list": "D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin",
"country": "Japan",
"delete": false,
"doi": "10.5980/jpnjurol1989.91.687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5287",
"issue": "91(10-11)",
"journal": "Nihon Hinyokika Gakkai zasshi. The japanese journal of urology",
"keywords": null,
"medline_ta": "Nihon Hinyokika Gakkai Zasshi",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D018236:Carcinoma, Embryonal; D002822:Choriocarcinoma; D002945:Cisplatin; D003131:Combined Modality Therapy; D005047:Etoposide; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia; D008297:Male; D016609:Neoplasms, Second Primary; D018239:Seminoma; D013736:Testicular Neoplasms; D014182:Transplantation, Autologous",
"nlm_unique_id": "2984841R",
"other_id": null,
"pages": "687-91",
"pmc": null,
"pmid": "11109821",
"pubdate": "2000",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Secondary leukemia following ultra high-dose chemotherapy with peripheral blood stem cell autotransplantation for refractory testicular cancer.",
"title_normalized": "secondary leukemia following ultra high dose chemotherapy with peripheral blood stem cell autotransplantation for refractory testicular cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2016447488",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo determine the maximum tolerated dose of oblimersen, an antisense oligonucleotide directed to the Bcl-2 mRNA, in combination with cisplatin and 5-flourouracil in patients with advanced gastric and esophageal carcinoma.\n\n\nMETHODS\nPatients were treated with escalating doses of oblimersen administered by continuous intravenous infusion (CIVI) days 1 to 7, CIVI 5-fluorouracil (5-FU) days 4 to 7, and cisplatin on day 4 every 3 weeks.\n\n\nRESULTS\nFifteen patients received a total of 49 courses of oblimersen at doses of 3, 5, or 7 mg/kg/d given as a 7 day CIVI in combination with 4 or 5 day CIVI of 5-FU (1000 or 750 mg/m2/d) plus intravenous cisplatin (100 or 75 mg/m2 over 2 hours). The recommended phase II dose of oblimersen was 5 mg/kg/d in combination with 5-FU (750 mg/m2/d for 4 days) and cisplatin (75 mg/m). The most common grade 3 to 4 adverse events that occurred in at least 10% of patients at all dose levels included neutropenia (33%), hypokalemia (27%), infection (20%), and mucositis, fatigue, dizziness, thrombosis, and dehydration (in 13% for each category).\n\n\nCONCLUSIONS\nThe combination of oblimersen with 5-FU and cisplatin chemotherapy is feasible in patients with advanced upper gastrointestinal cancer, with antitumor activity observed in gastric carcinoma.",
"affiliations": "Department of Oncology, Montefiore-Einstein Cancer Center, New York Cancer Consortium Coordinating Center, Bronx, New York 10461, USA.",
"authors": "Raab|Rachel|R|;Sparano|Joseph A|JA|;Ocean|Allyson J|AJ|;Christos|Paul|P|;Ramirez|Mark|M|;Vinciguerra|Vincent|V|;Kaubisch|Andreas|A|",
"chemical_list": "D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; C408162:oblimersen; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0b013e3181a31ad0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "33(1)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D004359:Drug Therapy, Combination; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D016376:Oligonucleotides, Antisense; D010865:Pilot Projects; D011379:Prognosis; D013274:Stomach Neoplasms; D015996:Survival Rate; D013873:Thionucleotides; D016896:Treatment Outcome",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "61-5",
"pmc": null,
"pmid": "19738454",
"pubdate": "2010-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "17664468;18483366;15277270;12056703;11073801;15217967;8186165;15897586;17237035;14519654;9093725;11895895;11685732;12529680;15476281;12162702;12822513;16782930;10739650;16322117;16239906;16966688;7776992;17664467;16195754;18172173;11751483;15020613;7533517;18281659;9626464;10655437",
"title": "A phase I trial of oblimersen sodium in combination with cisplatin and 5-fluorouracil in patients with advanced esophageal, gastroesophageal junction, and gastric carcinoma.",
"title_normalized": "a phase i trial of oblimersen sodium in combination with cisplatin and 5 fluorouracil in patients with advanced esophageal gastroesophageal junction and gastric carcinoma"
} | [
{
"companynumb": "US-MYLANLABS-2017M1007778",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "We present the case of a male patient not vaccinated against hepatitis B virus (HBV) and with reactivity to a surface antibody who, after immunosuppression for a multiple myeloma, had HBV reactivation. Pharmacological HBV suppression was tried, but viremia could not be suppressed. Production-detection core mutations or immunity issues can explain this clinical phenomenon.",
"affiliations": "Infectious Diseases Department, Hospital São João, Porto, Portugal Faculty of Medicine of University of Porto, Porto, Portugal pintoandre@gmail.com.;Haematology Department, Hospital São João, Porto, Portugal.;Faculty of Medicine of University of Porto, Porto, Portugal Blood Bank and Transfusion Medicine Department, Hospital São João, Porto, Portugal.;Infectious Diseases Department, Hospital São João, Porto, Portugal Faculty of Medicine of University of Porto, Porto, Portugal.;Infectious Diseases Department, Hospital São João, Porto, Portugal Faculty of Medicine of University of Porto, Porto, Portugal.",
"authors": "Silva-Pinto|André|A|;Andrade|Joaquim|J|;Araújo|Fernando|F|;Santos|Lurdes|L|;Sarmento|António|A|",
"chemical_list": "D000998:Antiviral Agents; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; C413685:entecavir; D006147:Guanine",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.03546-14",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "53(4)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000998:Antiviral Agents; D006147:Guanine; D018380:Hematopoietic Stem Cell Transplantation; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006515:Hepatitis B virus; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "1434-5",
"pmc": null,
"pmid": "25631798",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24976703;24016646;23893811;22436845",
"title": "Reactivation of hepatitis B virus without core antibody.",
"title_normalized": "reactivation of hepatitis b virus without core antibody"
} | [
{
"companynumb": "PT-CELGENE-PRT-2015041635",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
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"drugadditional": null,
... |
{
"abstract": "We present a case of a 27-year-old woman in whom idiopathic hypersomnolence was diagnosed in adolescence with adequate symptomatic control on daily dosage of 250 mg of modafinil. She maintained this dosage throughout her pregnancy and during the peripartum period, but did not breastfeed her newborn because of a lack of information on the transmission of modafinil in human breast milk. Samples of her breast milk were obtained at various times over a 24-hour period and analyzed using liquid chromatography mass spectrometry. The relative infant dose was calculated to be 5.3%, below the threshold of concern for drug passage via breast milk. This is the first reported case of modafinil transfer into human breast milk. Given the drug's use in a variety of sleep disorders, the results of this case can be used to advise breastfeeding mothers prescribed modafinil.",
"affiliations": "Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts.;Texas Tech University Health Sciences Center School of Medicine, Amarillo, Texas.;Department of Pediatrics, Texas Tech University Health Sciences Center, Amarillo, Texas.;Department of Pediatrics, Texas Tech University Health Sciences Center, Amarillo, Texas.;Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, Amarillo, Texas.;Department of Pediatrics, Texas Tech University Health Sciences Center, Amarillo, Texas.",
"authors": "Aurora|Sanjay|S|;Aurora|Nadia|N|;Datta|Palika|P|;Rewers-Felkins|Kathleen|K|;Baker|Teresa|T|;Hale|Thomas W|TW|",
"chemical_list": "D000077408:Modafinil",
"country": "United States",
"delete": false,
"doi": "10.5664/jcsm.7546",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "14(12)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "armodafinil; human breast milk; idiopathic hypersomnia; modafinil",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D000328:Adult; D002853:Chromatography, Liquid; D006970:Disorders of Excessive Somnolence; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007774:Lactation; D013058:Mass Spectrometry; D008895:Milk, Human; D000077408:Modafinil; D011247:Pregnancy",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "2087-2089",
"pmc": null,
"pmid": "30518447",
"pubdate": "2018-12-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1524962;26599679;19300566;25196321;20465024;25367475;23560595;19293415",
"title": "Evaluating Transfer of Modafinil Into Human Milk During Lactation: A Case Report.",
"title_normalized": "evaluating transfer of modafinil into human milk during lactation a case report"
} | [
{
"companynumb": "US-TEVA-2019-US-1004333",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARMODAFINIL"
},
"drugadditional": "3",
... |
{
"abstract": "The contiguous gene deletion syndrome of congenital adrenal hyperplasia and Ehlers-Danlos syndrome, named CAH-X, is a rare entity that occurs because of a deletion of a chromosomal area containing 2 neighboring genes, TNXB and CYP21A. Here, we describe a patient from a consanguineous family in which coincidentally MEN-1 syndrome is associated with CAH-X, causing particular challenges explaining the phenotypic features of the patient. A 33-year-old man with salt-wasting congenital adrenal hyperplasia and classic-like Ehlers-Danlos syndrome presented with an adrenal crisis with a history of recurrent hypoglycemia, abdominal pain, and vomiting. He was found to have primary hyperparathyroidism, hyperprolactinemia, and pancreatic neuroendocrine tumors, as well as primary hypogonadism, large adrenal myelolipomas, and low bone mineral density. A bladder diverticulum was incidentally found. Genetic analysis revealed a heterozygous previously well-described MEN1 mutation (c.784-9G > A), a homozygous complete deletion of CYP21A2 (c.1-?_1488+? del), as well as a large deletion of the neighboring TNXB gene (c.11381-?_11524+?). The deletion includes the complete CYP21A2 gene and exons 35 through 44 of the TNXB gene. CGH array found 12% homozygosity over the whole genome. This rare case illustrates a complex clinical scenario with some initial diagnostic challenges.",
"affiliations": "Division of Endocrinology, Diabetes, and Metabolism. The Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Endocrinology, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE.;Department of Endocrinology, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE.;Pathology and Laboratory Medicine Institute, Cleveland Clinic Abu Dhabi and National Reference Laboratory, Abu Dhabi, UAE.;Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.;Division of Endocrinology, Diabetes, and Metabolism. The Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Chen Cardenas|Stanley M|SM|0000-0001-7719-4729;El-Kaissi|Samer|S|;Jarad|Ola|O|;Liaqat|Muneezeh|M|;Korbonits|Márta|M|0000-0002-4101-9432;Hamrahian|Amir H|AH|0000-0001-8832-9385",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1210/jendso/bvaa077",
"fulltext": "\n==== Front\nJ Endocr Soc\nJ Endocr Soc\njes\nJournal of the Endocrine Society\n2472-1972 Oxford University Press US \n\n32715272\n10.1210/jendso/bvaa077\nbvaa077\nCase Reports\nAcademicSubjects/MED00250\nUnusual Combination of MEN-1 and the Contiguous Gene Deletion Syndrome of CAH and Ehlers-Danlos Syndrome (CAH-X)\nhttp://orcid.org/0000-0001-7719-4729Chen Cardenas Stanley M 1 El-Kaissi Samer 2 Jarad Ola 2 Liaqat Muneezeh 3 http://orcid.org/0000-0002-4101-9432Korbonits Márta 4m.korbonits@qmul.ac.uk http://orcid.org/0000-0001-8832-9385Hamrahian Amir H 1ahamrah1@jhmi.edu 1 \nDivision of Endocrinology, Diabetes, and Metabolism. The Johns Hopkins University School of Medicine, Baltimore, Maryland\n2 \nDepartment of Endocrinology, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE\n3 \nPathology and Laboratory Medicine Institute, Cleveland Clinic Abu Dhabi and National Reference Laboratory, Abu Dhabi, UAE\n4 \nDepartment of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK\nCorrespondence: Amir H. Hamrahian, MD, Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Suite 333, Baltimore, MD 21217. E-mail: ahamrah1@jhmi.edu; Márta Korbonits, Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London. E-mail: m.korbonits@qmul.ac.uk.\n01 8 2020 \n27 6 2020 \n27 6 2020 \n4 8 bvaa07709 4 2020 04 6 2020 20 7 2020 © Endocrine Society 2020.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nThe contiguous gene deletion syndrome of congenital adrenal hyperplasia and Ehlers-Danlos syndrome, named CAH-X, is a rare entity that occurs because of a deletion of a chromosomal area containing 2 neighboring genes, TNXB and CYP21A. Here, we describe a patient from a consanguineous family in which coincidentally MEN-1 syndrome is associated with CAH-X, causing particular challenges explaining the phenotypic features of the patient. A 33-year-old man with salt-wasting congenital adrenal hyperplasia and classic-like Ehlers-Danlos syndrome presented with an adrenal crisis with a history of recurrent hypoglycemia, abdominal pain, and vomiting. He was found to have primary hyperparathyroidism, hyperprolactinemia, and pancreatic neuroendocrine tumors, as well as primary hypogonadism, large adrenal myelolipomas, and low bone mineral density. A bladder diverticulum was incidentally found. Genetic analysis revealed a heterozygous previously well-described MEN1 mutation (c.784-9G > A), a homozygous complete deletion of CYP21A2 (c.1-?_1488+? del), as well as a large deletion of the neighboring TNXB gene (c.11381-?_11524+?). The deletion includes the complete CYP21A2 gene and exons 35 through 44 of the TNXB gene. CGH array found 12% homozygosity over the whole genome. This rare case illustrates a complex clinical scenario with some initial diagnostic challenges.\n\ncongenital adrenal hyperplasiaEhlers-Danlos syndromecontiguous gene deletion syndromemultiple endocrine neoplasia type 1adrenal myelolipomaneuroendocrine tumor\n==== Body\nSalt-wasting congenital adrenal hyperplasia (CAH) and classic-like Ehlers-Danlos syndrome (EDS) were initially linked more than 20 years ago [1]. The gene leading to this form of EDS is TNXB (OMIM 600985), coding for Tenascin-X (TN-X), a protein involved in the stabilization of collagen fibers. Classic-like EDS is phenotypically similar to classic EDS, except for the absence of the characteristic scarring. It is caused by a different gene, and usually the full syndrome occurs when both alleles are affected. Clinical symptoms, such as velvety skin, joint hypermobility, cardiac valve abnormalities, among others, can be detected even when 1 allele is affected [2]. CYP21A2 (OMIM 201910), the gene mutated in salt-wasting CAH resulting from 21-hydroxylase deficiency, and TNXB, are both located close to each other on the short arm of chromosome 6, within the HLA locus. This region is particularly susceptible to recombination abnormalities resulting from the highly homologous nearby CYP21A1P and TNXA pseudogenes. Abnormal recombination can lead to larger deletions, resulting in contiguous gene deletion syndrome involving CYP21A2, TNXB, and its corresponding pseudogenes CYP21A1P and TNXA [3], named CAH-X. Here, we report a case that had a complex clinical presentation of the contiguous gene deletion syndrome of CAH-X and the multiple endocrine neoplasia type 1 (MEN-1) syndrome, a combination that has not been previously reported in the literature. Interestingly, in trying to find an association between these 2 syndromes, we found that both CAH-X and MEN-1 can disrupt the TGF-β signaling pathway, however in different ways [4, 5].\n\nCase Presentation\nA 33-year-old man with a history of learning disability, salt-wasting CAH, and MEN-1 syndrome resulting from a heterozygous hotspot MEN1 mutation c.784-9G > A (rs794728625) presented with recurrent hypoglycemia, abdominal pain, and vomiting for 6 weeks. His physical examination was significant for short stature 135 cm (4 ft, 5 in.), wrinkled forehead, teeth malocclusion, mild prognathism, short fingers and toes, hyperextensible and loose joints, and soft and velvety skin (Fig. 1A-D). His parents were first cousins. His father died at age 56 from liver cancer. Of his 10 full siblings, 2 had MEN-1, but none were known to have CAH. The proband had adrenal insufficiency since birth secondary to CAH, but was poorly compliant with glucocorticoid replacement. He had low cortisol and undetectable aldosterone levels at baseline and during the ACTH stimulation test, along with elevated 17-hydroxyprogesterone and ACTH levels (Table 1). He had primary hyperparathyroidism, hyperprolactinemia with no visible lesion on pituitary magnetic resonance imaging (Fig. 2A-B), and a normal IGF-1 (Table 2). Additionally, he had primary hypogonadism with small, soft testicles of 8 to 10 mL bilaterally, a 1.6-cm enhancing pancreatic mass, and replacement of the normal adrenal tissue with large bilateral (left 5.7 × 10.6 cm and right 8.5 × 3.7 cm) lipomatous lesions resembling myelolipomas (Fig. 2C-D). A dual-energy X-ray absorptiometry scan reported Z-scores consistent with low bone mineral density for his age (lumbar spine, –2.9, femoral neck, –1.8,and distal on-third forearm, –1.7). A bladder diverticulum, typical of EDS, was incidentally found (Fig. 2E). An echocardiogram revealed mild left atrial dilation and mild mitral valve regurgitation. He had an elevated proinsulin level with inappropriately normal insulin and C peptide in the setting of hypoglycemia of 47 mg/dL, consistent with endogenous hyperinsulinemia (Table 2). Chromogranin A and gastrin were elevated (while using pantoprazole 40 mg daily), whereas glucagon level was normal. Endoscopy revealed extensive duodenal and lower esophageal ulceration suggestive of Zollinger-Ellison syndrome.\n\nFigure 1. Clinical features, (A) short stature 135 cm (4 ft, 5 in.) compared with his brother; (B) wrinkled forehead, prognathism, jaw malocclusion; (C) short fingers, and (D) hyperextensible and loose joints.\n\nTable 1. Cortisol, 17 OH Progesterone, and Aldosterone Levels During Synacthen Stimulation Test\n\nHormone\tReference Range\tBaseline\t60 Min\t\n\nCortisol\na\n\t64-536 nmol/L\t22\t23\t\n\n17-Hydroxyprogesterone\na\n\t0.8-6.0 nmol/L\t10.2\t20.5\t\n\nAldosterone\na\n\t0-832 pmol/L\t<28\t<28\t\n\naHydrocortisone was held for 24 hours before the test.\n\nFigure 2. T1 post-contrast pituitary magnetic resonance imaging scan. (A) Coronal view and (B) sagittal view showing a normal-appearing pituitary gland with a prominent infundibulum, but no mass. Computed tomography of the abdomen with (C) transverse and (D, E) coronal view showing bilateral enlargement of the adrenal glands because of adrenal myelolipomas (C-D, arrows, 5.7 × 10.6 cm on the left and an 8.5 × 3.7 cm on the right). (C, arrowhead) A 1.6-cm enhancing pancreatic mass and (E, arrow) bladder diverticulum.\n\nTable 2. Hormonal Evaluation\n\nHormone\tPatient Result\tReference Range\t\n\nPlasma renin activity\n\t14.1\t0.167-5.380 ng/mL/hr \t\n\nACTH\n\t27.8 (4:32 pm) 220.7 (11:07 am)\t1.6-13.9 pmol/L\t\n\nDHEA-S\n\t0.1\t3.7-12.8 µmol/L\t\n\nTestosterone\n\t155 (8:51 am)\t348-1197 ng/dL\t\n\nFree testosterone\n\t4 (8:51 am)\t90-87 pmol/L\t\n\nLH\n\t16.1\t1.7-8.6 IU/L\t\n\nFSH\n\t20.5\t1.5-12.4 mIU/mL\t\n\nNormetanephrine\n\t0.14\t0-0.79 nmol/L\t\n\nMetanephrine\n\t0.09\t0-0.31 nmol/L\t\n\nGastrin\na\n\t307\t0-55 pmol/L\t\n\nGlucagon\na\n\t127\t50-150 ng/L\t\n\nPancreatic polypeptide\n\t343\t0-100 pmol/L\t\n\nSomatostatin\n\t39\t<30 pg/mL\t\n\nVasointestinal peptide\n\t16\t0-17 pmol/L\t\n\nChromogranin A\n\t33\t0-5 nmol/L\t\n\nGlucose\na\n\t47\t70-100 mg/dL\t\n\nC-peptide\na\n\t0.68\t0.37-1.47 nmol/L\t\n\nInsulin\na\n\t7.76\t2.6-24.9 U/mL\t\n\nProinsulin\na\n\t46.1\t0-10.0 pmol/L\t\n\nCalcium\n\t2.75\t2.15-2.55 nmol/L\t\n\nPTH\n\t11.4\t1.6-6.9 pmol/L\t\n\nIGF -1\n\t115\t82-242 ng/mL\t\n\nGH\n\t2.8\t0-10 µg/L\t\n\nProlactin\n\t88.4\t4-15.2 ng/mL\t\n\naPrepancreatic surgery.\n\nThe CAH genetic test revealed a homozygous complete deletion of CYP21A2 (c.1-?_1488+? del) as well as a large deletion of the neighboring TNXB gene (c.11381-?_11524+?). The deletion included the complete CYP21A2 gene and exons 35 through 44 of the TNXB gene. Because of the consanguinity and learning disability, a chromosomal microarray analysis was performed using the Cytoscan HD platform (Affymetrix) containing 2 699 550 markers distributed along the whole genome. This found 12% of the genome being homozygous but no obvious regions explaining the learning disability.\n\nHe underwent distal pancreatectomy and endoscopic duodenal tumor resection. Histopathological examination of the pancreatic specimen revealed 6 neuroendocrine tumors, from 0.5 to 1.8 cm in size. The neoplasms formed small nests, trabeculae, and glands composed of monomorphic cells with finely granular eosinophilic cytoplasm, round nuclei and coarsely clumped “salt and pepper” chromatin (Fig. 3A and C). The mitotic activity ranged from 0 to 1/10 high power field. Lymphovascular invasion was present. All the tumors were positive for chromogranin A. Three tumors showed cytoplasmic insulin positivity in the majority of cells, associated with very few cells staining for somatostatin and glucagon, most likely representing residual normal islet cells rather than secretion of multiple hormones by the tumor. One of the tumors stained only for glucagon (Fig. 3D), and 2 tumors did not stain with any of the 4 hormones insulin, glucagon, somatostatin, or gastrin. The distal pancreatectomy tumor was staged as pT1[m6]NX. The nonneoplastic pancreas showed a range of abnormalities, including islet cell hyperplasia, dysplastic islets, microadenomatosis, rare ductulo-insular complexes, and peliosis in islets (Fig. 3E and F). The duodenal biopsies and endoscopic resection showed multiple tumor nodules, the largest, 0.7 cm in size.\n\nFigure 3. (A) NET forming small nests and follicles (H&E stain); tumor with faint insulin positivity in the (B) cytoplasm of tumor cells. (C) NET with trabecular architecture (H&E stain); tumor with (D) strong glucagon positivity in tumor cells. (E) Islet cell hyperplasia with islets of varying size highlighted by chromogranin stain. (F) Ductal insular complexes (H&E stain). H&E, hematoxylin and eosin; NET, neuroendocrine tumor.\n\nAfter distal pancreatectomy, hypoglycemic episodes ceased and his gastrin and chromogranin A levels normalized. He is on cabergoline 0.25 mg biweekly for prolactinoma; hydrocortisone 20 mg in the morning and 10 mg in the evening, and fludrocortisone 0.05 mg daily for CAH; alendronate 70 mg weekly for osteoporosis; and cinacalcet 30 mg for primary hyperparathyroidism. He was prescribed testosterone gel 1.62%; however, the family decided not to start testosterone replacement. On follow-up, a 1.2-cm liver lesion was detected, for which he underwent partial hepatectomy. The tumor cells were positive for chromogranin, synaptophysin, and gastrin, with no reactivity for insulin, glucagon, and somatostatin. The patient will be monitored by repeat abdominal and pituitary imaging, tumor markers, and pituitary hormones for any evidence of recurrent or new neuroendocrine and pituitary tumors. There are no specific clinical guidelines for monitoring patients with classic-like EDS; therefore, we follow recommendations for classic EDS, which include annual echocardiogram in patients with abnormal findings on initial evaluation.\n\nDiscussion\nThe combination of the contiguous gene deletion syndrome CAH-X and MEN-1 has not been previously described in the literature. It illustrates the complex clinical scenario resulting from the coexistence of three multiorgan diseases as well as learning disability most likely resulting from consanguinity.\n\nHis MEN-1 manifestations include primary hyperparathyroidism, hyperprolactinemia, and multifocal neuroendocrine tumors. The hypoglycemia workup performed in the setting of MEN-1 and multiple pancreatic lesions made us suspicious for insulinoma, which was confirmed on pathology. Insulinomas are the second most common functioning pancreatic neuroendocrine tumor in the setting of MEN-1 after gastrinomas, occurring in about 18% of patients [6]. Diffuse endocrine hyperplasia, dysplasia, and microadenomas are also features of MEN-1 [7]. In addition, ductal/insular complexes with neuroendocrine cells arising from ducts and peliosis (i.e., cyst-like blood-filled cavities in islets) may rarely be encountered in patients with MEN-1 syndrome [7, 8], as seen in this case. This patient’s hypoglycemia was likely from insulinomas and islet cell abnormalities (hyperplasia, dysplasia, ductular-insular complexes), given the persistence of hypoglycemic episodes after resuming glucocorticoids while waiting for abdominal surgery.\n\nGastrinomas are seen in 20% to 70% of MEN-1 patients [6, 9]. Although gastrin stain was negative in the pancreatic and duodenal tumors, his liver metastases stained for gastrin. This may explain gastrointestinal lesions suggestive of Zollinger-Ellison syndrome, although his gastrin level was only moderately elevated while being on proton pump inhibitors. Similar to this case, neuroendocrine tumors metastases may produce hormones other than those found in the primary site [10].\n\nGlucagonomas are seen in 1% to 6% of patients with MEN-1 [6, 11]. Despite positive glucagon immunostaining in 1 of the tumors, this patient did not present any of the clinical findings associated with glucagonomas such as necrolytic migratory erythema or diabetes. In addition, his glucagon level was within the reference range, suggesting a nonfunctioning pancreatic neuroendocrine tumor that stained positive for glucagon, which can occur in about 24% to 52% of the surgical specimens of MEN-1 patients [11-13].\n\nMEN-1 syndrome most often is due to heterozygous loss-of-function mutations in the MEN1 tumor suppressor gene (OMIM 613733), located in chromosome 11q13, and encoding a protein called Menin [14, 15]. His MEN1 mutation, c.784-9G > A, affects intron 4 and has been described in 1.9% of 1133 reported MEN1-independent kindreds [16]. Pardi et al found 12 of 54 probands (22%) with this specific mutation [15]. Phenotypically, all of them developed primary hyperparathyroidism, 3 had pituitary tumors, and 10 had gastro-entero-pancreatic tumors, consistent with this patient presentation.\n\nSalt-wasting CAH is an autosomal recessive disease caused by mutations in CYP21A2 in about 95% of the cases [17]. This patient’s short stature seems secondary to excessive androgen exposure early in life because of noncompliance with glucocorticoids resulting in early epiphyseal fusion. His hormonal workup is consistent with hypergonadotropic hypogonadism. His gonadotropins were elevated despite hyperprolactinemia and persisted after prolactin was normalized, being consistent with a primary testicular dysfunction. Testicular ultrasound data are not available, but adrenal rest tumors can be present even in small testicles [18]. Therefore, the patient developed hypogonadism for 2 reasons: (1) hyperprolactinemia and (2) damaged testis from adrenal rest tumors. The past hyperandrogenism resulted in short stature, although other causes related to high level of homozygosity cannot be excluded.\n\nIn the abdominal computed tomography scan, we found bilateral adrenal lipomatous changes suggestive of large myelolipomas. Adults with CAH not adequately managed may present with a spectrum of imaging findings that includes large myelolipomatous changes of their adrenal glands, similar to our patient. It has been suggested that chronic elevations in ACTH and excessive androgen may act as the stimulatory factor to trigger polyclonal hyperplasia and differentiation of adrenal tissue into adipose and hematopoietic tissue with similar characteristics of bone marrow [19-21].\n\nClassic EDS is an autosomal dominant disease caused by mutations in the COLA5A1 (OMIM 130000) or COL5A2 (OMIM 130010) genes, coding for type V collagen subunits, in about 90% of the patients. In classic-like EDS, the mutations, either heterozygous or homozygous, are in the TNXB gene, which encodes for TN-X. TN-X is an extracellular matrix protein highly expressed in connective tissues [3]. It is involved processes related to cell adhesion, migration, and stabilization of collagen fibers, including types I, III, V, VII, and IX [22]. Therefore, when this protein is deficient, it is not surprising the resemblance with classic EDS. Classic-like EDS was first reported in 1997 in a patient with CAH and heterozygous large deletion of CYP21A2 and part of TNXB [1]. In 2001, 5 additional cases were described, demonstrating a form of EDS with an autosomal recessive pattern of inheritance [23]. Our patient presented joint hypermobility, hyperextensible, and soft and velvety skin, all known features of classic-like EDS [2]. Interestingly, a bladder diverticulum was incidentally found; this has been observed in classic ED, but to our knowledge not previously reported in the classic-like form [24].\n\nClassic-like EDS can occur without the presence of CAH when the defect is restricted to the TNXB gene, although in the original description of this form of EDS, the relationship with CAH was recognized [1]. In those with CAH, the EDS phenotype tend to be more severe that those without [3, 25]. This may be related to the large deletion when classic-like EDS is associated with CAH (in contrast to a point mutation) or indicate an interaction between these diseases beyond the genetic mutations. Perhaps the hormonal abnormalities seen in CAH play a role in the clinical presentation.\n\nThe contiguous gene deletion syndrome CAH-X has a prevalence of 8.5% in patients with CAH resulting from 21-hydroxylase deficiency [26]. Recent studies have further determined that there are monoallelic and biallelic forms of CAH-X, with the biallelic form being the least common of them [3]. Of 29 patients with CAH-X, 5 had biallelic CAH-X, like our patient. In this group, 4 were male, all of them had generalized hypermobility, severe hyperextensible skin, and easy bruising, and 2 showed cardiac chamber enlargement [3], as observed in our patient. The distinction of the different underlying recombination or chimera is also relevant because it translates into different CAH-X phenotypes [25]. Because TNXB and CYP21A2 are located in an area of chromosome 6, where there is high recombination, in addition to the presence of pseudogenes (TNXA and CYP21A1P), it is not surprising that misalignment occurs during meiosis. When TNXA and TNXB undergo chimeric recombination, CYP21A2 can be deleted, resulting in CAH-X. To date, 3 chimeric genes have been described. In the first one, called CAH-X CH-1, CYP21A2 is deleted, and TNXB exons 35 through 44 are replaced with TNXA producing a non-sense 120-bp deletion (c.11435_11524 + 30del) that leads to a nonfunctional gene causing reduced expression of TN-X, supporting a haploinsufficient behavior [3]. In CAH-X CH-2, CYP21A2 is deleted, and TNXB exons 40 through 44 are replaced by TNXA, which features 2 contiguous mutations of c.12150C > G (synonymous) and c.12174 C > G (p.C4058W) that has a more severe EDS phenotype [3, 25]. In CAH-X CH-3, CYP21A2 is deleted, and TNXB exons 41 through 44 are replaced by TNXA. Thus far, this chimera has been reported in 1 patient and has unclear significance [25]. As opposed to CAH-X CH1, in CH2 and CH3, TN-X is produced but with an abnormal structure, ultimately impairing its function [3].\n\nInterestingly, the TGF-β is dysregulated in both CAH-X and MEN 1, but in different ways. TN-X has an important role in promoting epithelial-mesenchymal transitions mediated by the TGF-β pathway [22]. In skin fibroblasts obtained from CAH-X patients, TGF-β2, TGF-β3, and SMAD 1, 5, and 8 were found elevated compared with CAH controls [4]. These 2 cytokines (TGF-β2 and TGF-β3) and their downstream proteins, SMADs, are important regulators of cardiac development, which could explain the cardiac abnormalities observed in these patients, including this case. SMADs 2, 3, and 4 are important tumor suppressors [5]. Menin acts as a scaffold protein in the nucleus to regulate the transcription of multiple genes, including SMAD3, a key protein in the TGF-β signaling pathway. In MEN-1, TGF-β signaling is disrupted because SMAD3 is not able to inhibit cell division, predisposing to proliferation, and tumorigenesis [5]. It seems that alterations in both CAH-X and MEN-1, via altering distinct proteins, lead to modifications in TGF-β signaling pathways. Because TGF-β has been associated with collagen synthesis, this might explain the forehead wrinkles observed in the patient.\n\nThe patient presented here has additional clinical features that are not part of CAH-X or MEN1, such as prognathism and prominent supraorbital ridges (had normal IGF-1 level), learning disability, deep-set eyes, mild hypertelorism, convex nasal ridge, broad distal phalanx, drumstick fingers, and possibly mild webbing between the index and middle finger. Differential diagnoses were considered including pachydermoperiostosis (because of the forehand wrinkles at a young age), arthrochalasia EDS, as well as other genetic mutation screening, including SYNGAP1 and CUL7; however, none was positive.\n\nIn conclusion, here we report a rare case with an unusual combination of diseases. The complex genetic situation with a large deletion causing continuous gene deletion syndrome (CAH-X), 12% homozygosity because of consanguinity, and an additional heterozygote disease results in a complex clinical picture, where attributing each of the phenotypic abnormality to 1 of the 3 genetic problems (CAH-X, MEN-1, high level of homozygosity) creates significant challenges. We draw the attention of endocrinologists to evaluate for signs of EDS in patients with CAH resulting from 21-hydroxylase deficiency.\n\n\nAcknowledgment: We are grateful for the help in the diagnostic workup and interpretation of the genetic results to Dr. Anju Sahdev, Barts Health NHS Trust, London, UK and Dr. Márton Doleschall, Semmelweis Medical School, Budapest, Hungary. Written consent was obtained from the patients to include their photographs. Additionally, all potential identifiers on the figures have been removed. For additional information on the genetic studies and pathology report, please email the corresponding author. \n\nAcknowledgments\n\nFinancial Support: This work was not supported by any grants.\n\nAbbreviations\nCAHcongenital adrenal hyperplasia\n\nEDSEhlers-Danlos syndrome\n\nMEN-1multiple endocrine neoplasia type 1\n\nTN-XTenascin-X\n\nAdditional Information\n\nDisclosure Summary: None of the authors have conflicts of interest to disclose.\n\n\nData Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences and Notes\n1. \nBurch GH , Gong Y , Liu W , et al. \nEhlers-Danlos syndrome\n. Nat Genet. 1997 ;17 :2 -6\n.\n2. \nBrady AF , Demirdas S , Fournel-Gigleux S , et al. \nThe Ehlers-Danlos syndromes, rare types\n. Am J Med Genet C Semin Med Genet. 2017 ;175 (1 ):70 -115\n.28306225 \n3. \nMiller WL , Merke DP \nTenascin-X, congenital adrenal hyperplasia, and the CAH-X syndrome\n. Horm Res Paediatr. 2018 ;89 (5 ):352 -361\n.29734195 \n4. \nMorissette R , Merke DP , McDonnell NB \nTransforming growth factor-β (TGF-β) pathway abnormalities in tenascin-X deficiency associated with CAH-X syndrome\n. Eur J Med Genet. 2014 ;57 (2-3 ):95 -102\n.24380766 \n5. \nCanaff L , Vanbellinghen JF , Kaji H , Goltzman D , Hendy GN \nImpaired transforming growth factor-β (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1)\n. J Biol Chem. 2012 ;287 (11 ):8584 -8597\n.22275377 \n6. \nYates CJ , Newey PJ , Thakker RV \nChallenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1\n. Lancet Diabetes Endocrinol. 2015 ;3 (11 ):895 -905\n.26165399 \n7. \nKlöppel G , Willemer S , Stamm B , Häcki WH , Heitz PU \nPancreatic lesions and hormonal profile of pancreatic tumors in multiple endocrine neoplasia type I. An immunocytochemical study of nine patients\n. Cancer. 1986 ;57 (9 ):1824 -1832\n.2420439 \n8. \nJabri AL , Bayard C \nNesidioblastosis associated with hyperinsulinemic hypoglycemia in adults: review of the literature\n. Eur J Intern Med. 2004 ;15 (7 ):407 -410\n.15581742 \n9. \nGibril F , Schumann M , Pace A , Jensen RT \nMultiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature\n. Medicine (Baltimore). 2004 ;83 (1 ):43 -83\n.14747767 \n10. \nKimura H , Ohtsuka T , Fujimoto T , et al. \nDifferent hormonal expression patterns between primary pancreatic neuroendocrine tumors and metastatic sites\n. Pancreas. 2016 ;45 (7 ):947 -952\n.26684862 \n11. \nJensen RT , Berna MJ , Bingham DB , Norton JA \nInherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies\n. Cancer. 2008 ;113 (7 Suppl ):1807 -1843\n.18798544 \n12. \nNewey PJ , Jeyabalan J , Walls GV , et al. \nAsymptomatic children with multiple endocrine neoplasia type 1 mutations may harbor nonfunctioning pancreatic neuroendocrine tumors\n. J Clin Endocrinol Metab. 2009 ;94 (10 ):3640 -3646\n.19622622 \n13. \nThakker RV , Newey PJ , Walls GV , et al. ; Endocrine Society \nClinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)\n. J Clin Endocrinol Metab. 2012 ;97 (9 ):2990 -3011\n.22723327 \n14. \nKamilaris CDC , Stratakis CA \nMultiple endocrine neoplasia type 1 (MEN1): an update and the significance of early genetic and clinical diagnosis\n. Front Endocrinol (Lausanne). 2019 ;10 :339 .31263451 \n15. \nPardi E , Borsari S , Saponaro F , et al. \nMutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features\n. PLoS One. 2017 ;12 (10 ):e0186485 .29036195 \n16. \nLemos MC , Thakker RV \nMultiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene\n. Hum Mutat. 2008 ;29 (1 ):22 -32\n.17879353 \n17. \nEl-Maouche D , Arlt W , Merke DP \nCongenital adrenal hyperplasia\n. Lancet. 2017 ;390 (10108 ):2194 -2210\n.28576284 \n18. \nCabrera MS , Vogiatzi MG , New MI \nLong term outcome in adult males with classic congenital adrenal hyperplasia\n. J Clin Endocrinol Metab. 2001 ;86 (7 ):3070 -3078\n.11443169 \n19. \nKok HK , Sherlock M , Healy NA , Doody O , Govender P , Torreggiani WC \nImaging features of poorly controlled congenital adrenal hyperplasia in adults\n. Br J Radiol. 2015 ;88 (1053 ):20150352 .26133223 \n20. \nGerman-Mena E , Zibari GB , Levine SN \nAdrenal myelolipomas in patients with congenital adrenal hyperplasia: review of the literature and a case report\n. Endocr Pract. 2011 ;17 (3 ):441 -447\n.21324823 \n21. \nNermoen I , Rørvik J , Holmedal SH , et al. \nHigh frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency\n. Clin Endocrinol (Oxf). 2011 ;75 (6 ):753 -759\n.21689130 \n22. \nAlcaraz LB , Exposito JY , Chuvin N , et al. \nTenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β\n. J Cell Biol. 2014 ;205 (3 ):409 -428\n.24821840 \n23. \nSchalkwijk J , Zweers MC , Steijlen PM , et al. \nA recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency\n. N Engl J Med. 2001 ;345 (16 ):1167 -1175\n.11642233 \n24. \nBurrows NP , Monk BE , Harrison JB , Pope FM \nGiant bladder diverticulum in Ehlers-Danlos syndrome type I causing outflow obstruction\n. Clin Exp Dermatol. 1998 ;23 (3 ):109 -112\n.9861737 \n25. \nLao Q , Brookner B , Merke DP \nHigh-throughput screening for CYP21A1P-TNXA/TNXB chimeric genes responsible for Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia\n. J Mol Diagn. 2019 ;21 (5 ):924 -931\n.31229653 \n26. \nMorissette R , Chen W , Perritt AF , et al. \nBroadening the spectrum of Ehlers Danlos syndrome in patients with congenital adrenal hyperplasia\n. J Clin Endocrinol Metab. 2015 ;100 (8 ):E1143 -E1152\n.26075496\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2472-1972",
"issue": "4(8)",
"journal": "Journal of the Endocrine Society",
"keywords": "Ehlers-Danlos syndrome; adrenal myelolipoma; congenital adrenal hyperplasia; contiguous gene deletion syndrome; multiple endocrine neoplasia type 1; neuroendocrine tumor",
"medline_ta": "J Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "101697997",
"other_id": null,
"pages": "bvaa077",
"pmc": null,
"pmid": "32715272",
"pubdate": "2020-08-01",
"publication_types": "D002363:Case Reports",
"references": "22275377;28306225;22723327;24821840;28576284;31229653;18798544;14747767;19622622;21324823;9861737;29734195;26075496;26684862;2420439;29036195;21689130;26133223;17879353;24380766;9288108;26165399;31263451;11443169;15581742;11642233",
"title": "Unusual Combination of MEN-1 and the Contiguous Gene Deletion Syndrome of CAH and Ehlers-Danlos Syndrome (CAH-X).",
"title_normalized": "unusual combination of men 1 and the contiguous gene deletion syndrome of cah and ehlers danlos syndrome cah x"
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"companynumb": "US-AMGEN-USASP2020186707",
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"activesubstancename": "ALENDRONATE SODIUM"
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"abstract": "Allopurinol hypersensitivity syndrome (AHS) is a severe drug reaction. It is characterized by rash, fever, and internal organ involvement. It may present in different clinical forms. We present a case of acute generalized exanthematous pustulosis occurring as a manifestation of AHS.",
"affiliations": "Department of Pharmacology, Faculty of Medicine of Sousse, Tunisia.;Department of Dermatology, Farhat Hached University Hospital, Tunisia.;Department of Pharmacology, Faculty of Medicine of Sousse, Tunisia.;Department of Pharmacology, Faculty of Medicine of Sousse, Tunisia.;Department of Pharmacology, Faculty of Medicine of Sousse, Tunisia.;Department of Pharmacology, Faculty of Medicine of Sousse, Tunisia.",
"authors": "Ben Salem|Chaker|C|;Saidi|Wafa|W|;Larif|Sofiene|S|;Fathallah|Neila|N|;Slim|Raoudha|R|;Hmouda|Houssem|H|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D006074:Gout Suppressants; D000493:Allopurinol",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.150378",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-47-12310.4103/0253-7613.150378Drug WatchPustular drug hypersensitivity syndrome due to allopurinol Salem Chaker Ben Saidi Wafa 1Larif Sofiene Fathallah Neila Slim Raoudha Hmouda Houssem Department of Pharmacology, Faculty of Medicine of Sousse, Tunisia1 Department of Dermatology, Farhat Hached University Hospital, TunisiaCorrespondence to: Dr. Chaker Ben Salem, E-mail: bensalem.c@gmail.comJan-Feb 2015 47 1 123 124 31 10 2014 21 11 2014 22 12 2014 Copyright: © Indian Journal of Pharmacology2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Allopurinol hypersensitivity syndrome (AHS) is a severe drug reaction. It is characterized by rash, fever, and internal organ involvement. It may present in different clinical forms. We present a case of acute generalized exanthematous pustulosis occurring as a manifestation of AHS.\n\nKEY WORDS\nAllopurinolhypersensitivity syndromepustulosis\n==== Body\nIntroduction\nDrug hypersensitivity syndrome (DHS), also known as drug rash with eosinophilia and systemic symptoms (DRESS), is a severe drug reaction. It was first associated with the aromatic antiepileptic drugs. The syndrome can also be caused by other drugs, such as allopurinol, sulfonamides, beta-lactam antimicrobials, antidepressants, and nonsteroidal anti-inflammatory drugs. Allopurinol hypersensitivity syndrome (AHS) is characterized by rash, fever, and internal organ involvement. Acute generalized exanthematous pustulosis (AGEP) is a very rare manifestation of AHS.[12] We report a case of an exceptional presentation of AGEP as a manifestation of AHS.\n\nCase Report\nA 67-year-old male was admitted to the Dermatology Department with history of widespread skin eruption since 10 days. He was started on allopurinol (200 mg/day) for hyperuricemia 8 weeks earlier. He was pyrexial above 38.5° for a few days. He was on candesartan and aspirin since many years.\n\nClinical examination showed maculopapular eruptions involving trunk, arms and legs, as well as pinhead-sized follicular and nonfollicular pustules on patient's face and trunk. Laboratory investigations revealed a white blood cell count of 13.2 × 109/L with atypical lymphocytes and hypereosinophilia (eosinophil count 1.9 × 109/L). Liver enzymes were increased: Aspartate aminotransferase 76 IU/L (reference range 3–40) and alanine aminotransferase 409 IU/L (3–45). Serum uric acid and renal function tests were normal. Viral serology showed previous infection for cytomegalovirus, but was negative for Epstein–Barr virus, hepatitis B, C, HIV, parvovirus B19 and human herpesvirus 6. Skin biopsy showed subcorneal spongiform pustules and some single scattered necrolytic keratinocyte [Figure 1]. The superficial dermis was edematous, with mixed inflammatory infiltration, including numerous neutrophils and rare eosinophils consistent with the diagnosis of AGEP. AHS was highly suspected, and allopurinol was withdrawn.\n\nFigure 1 Subcorneal spongiform pustules and some single scattered necrolytic keratinocytes\n\nThe patient improved markedly within 72 h on prednisone 30 mg daily (dose of 0.5 mg/kg body weight). He became afebrile, and skin eruption disappeared within a few days. After initiation of steroid therapy, exfoliation was observed in the involved skin areas. Full dose corticosteroid therapy was continued for two weeks, and tapered by 2.5 mg every 5–7 days, with a total duration of 3 months. Liver enzymes were within normal range in 3 weeks.\n\nCausality assessment by the Naranjo probability scale showed that AHS had probable causal association with the adverse effect.[3] The patient was firmly instructed to avoid allopurinol in the future.\n\nDiscussion\nAllopurinol hypersensitivity syndrome is a rare adverse reaction characterized by a spectrum of cutaneous reactions and systemic manifestations. AHS is more frequently associated with chronic renal insufficiency and concurrent use of thiazide diuretics. Symptoms generally begin 2–6 weeks after the initiation of therapy. Severe forms of AHS have been associated with high mortality.\n\nThe exact pathogenesis of this syndrome is yet unclear, but different hypothesis are proposed.[4] It seems to be related to the accumulation of allopurinol or oxipurinol a (major metabolite of allopurinol) in patients with renal insufficiency. Immunological factors, genetic factors, and human herpes virus-type 6 are also implicated.\n\nCutaneous manifestations of hypersensitivity syndrome are heterogeneous, ranging from mild morbilliform exanthema to severe toxic epidermal necrolysis and Stevens–Johnson syndrome. Pustular-type DHS is rare. Patients with DHS develop AGEP-like pustules particularly in the early phase. Pustules in DHS differ from the typical pattern of AGEP, in which pustules are more numerous and predominant in main body folds. Antiepileptics are the most frequently reported drugs causing pustular-type DHS.[56]\n\nWe scored both the European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria for DRESS and EuroSCAR AGEP score. The score was 7 for DRESS indicating a definite case and 5 for AGEP indicating a probable case. The clinical features which most differentiated DRESS from AGEP in our patient were the delayed onset (8 weeks), protracted course and multi-organ involvement.\n\nAn extensive literature search showed only two similar reports. The first case of AHS with generalized nonfollicular pustulosis was described in a 47-year-old man.[1] The second is a 65-year-old man who developed AHS manifested as generalized follicular pustulosis mimicking AGEP.[2] Our patient developed both follicular and nonfollicular pustules.\n\nThe exact mechanism of pustule formation in DHS has not been elucidated. Allopurinol directly inhibits the lymphocytes enzyme purine nucleoside phosphorylase and may affect certain components of the immune system with an alteration of CD4/CD8 rate. The concomitant release of several mediators from eosinophils and/or activation of neutrophils might be important for the clinical evolution of lesions, with appearance of pustules, or aggravation of skin detachment, as well as internal organ involvement in DRESS. A drug reaction leading to folliculitis and then pustule formation has also been proposed.\n\nAllopurinol hypersensitivity syndrome may present with different clinical forms. Clinicians should be observant of cutaneous manifestations of hypersensitivity syndrome that may be a nonfollicular and/or follicular pustular eruption as well as the more commonly associated maculopapular rash or erythroderma.\n\nSource of Support: Nil.\n\nConflict of Interest: No.\n==== Refs\n1 Teo WL Pang SM Koh HY Allopurinol hypersensitivity syndrome with acute generalized exanthematous pustulosis manifestations Cutan Ocul Toxicol 2011 30 243 4 21345152 \n2 Huang YC Shih PY Chin SY Chiang YY Allopurinol-induced drug rash with eosinophilia and systemic symptoms mimicking acute generalized exanthematous pustulosis J Dermatol 2012 39 1077 8 22901319 \n3 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n4 Camous X Calbo S Picard D Musette P Drug reaction with eosinophilia and systemic symptoms: An update on pathogenesis Curr Opin Immunol 2012 24 730 5 23062470 \n5 Matsuda H Saito K Takayanagi Y Okazaki T Kashima K Ishikawa K Pustular-type drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to carbamazepine with systemic muscle involvement J Dermatol 2013 40 118 22 23216243 \n6 Ben Salem C Fathallah N Saidi W Jeddi C Ghariani N Hmouda H Acute generalized exanthematous pustulosis as a manifestation of anticonvulsant hypersensitivity syndrome Ann Pharmacother 2010 44 1681 2 20841519\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "47(1)",
"journal": "Indian journal of pharmacology",
"keywords": "Allopurinol; hypersensitivity syndrome; pustulosis",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000305:Adrenal Cortex Hormones; D000368:Aged; D000493:Allopurinol; D001706:Biopsy; D006074:Gout Suppressants; D006801:Humans; D033461:Hyperuricemia; D008297:Male; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "123-4",
"pmc": null,
"pmid": "25821326",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22901319;23216243;7249508;20841519;21345152;23062470",
"title": "Pustular drug hypersensitivity syndrome due to allopurinol.",
"title_normalized": "pustular drug hypersensitivity syndrome due to allopurinol"
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"companynumb": "TN-ACCORD-030128",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
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"activesubstancename": "ALLOPURINOL"
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"abstract": "Recently, implantable cardioverter-defibrillators (ICD) have become capable of monitoring intrathoracic impedance to detect an increased fluid volume and heart failure. Pregnancy is a well-known cause of an increased body fluid volume; however, it is not clear whether the measurement of intrathoracic impedance by ICD is clinically useful for precisely detecting heart failure in pregnant women. We herein report the case of a 39-year-old woman with an ICD that had been implanted after an event of ventricular fibrillation due to severe aortic regurgitation with a bicuspid aortic valve. Elevated right ventricular pressure and brain natriuretic peptide levels were detected at 37 weeks of gestation and postpartum. At the same time, the ICD's stored fluid index gradually increased and exceeded the threshold on the 10th day after delivery. She was treated with diuretics and recovered from postpartum heart failure. The physiological volume changed in the perinatal period, but we were still able to detect heart failure by ICD. Intrathoracic impedance monitoring is effective in the perinatal field.",
"affiliations": "Department of Obstetrics and Gynecology, Osaka Medical College.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.;Cardiovascular Department, National Cerebral and Cardiovascular Center.;Cardiovascular Department, National Cerebral and Cardiovascular Center.;Department of Perinatology and Gynecology, National Cerebral and Cardiovascular Center.",
"authors": "Daimon|Atsushi|A|;Kamiya|Chizuko A|CA|;Sawada|Masami|M|;Ueda|Yusuke|Y|;Horiuchi|Chinami|C|;Miyoshi|Takekazu|T|;Tsuritani|Mitsuhiro|M|;Iwanaga|Naoko|N|;Neki|Reiko|R|;Okamura|Hideo|H|;Kusano|Shingo|S|;Yoshimatsu|Jun|J|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.17-096",
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"issn_linking": "1349-2365",
"issue": "59(2)",
"journal": "International heart journal",
"keywords": "Congenital heart diseases; Implantable cardioverter-defibrillators; Pregnancy",
"medline_ta": "Int Heart J",
"mesh_terms": "D000328:Adult; D017147:Defibrillators, Implantable; D017097:Electric Impedance; D005260:Female; D006333:Heart Failure; D006801:Humans; D058725:Peripartum Period; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D014693:Ventricular Fibrillation; D014882:Water-Electrolyte Balance",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Utility of Fluid Assessment Based on the Intrathoracic Impedance Monitoring in a Peripartum Woman with Heart Disease.",
"title_normalized": "utility of fluid assessment based on the intrathoracic impedance monitoring in a peripartum woman with heart disease"
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"abstract": "Celery root belongs to a group of plants classified as the umbelliferous family, which contains phytoestrogens. Phytoestrogens are structurally similar to estrogen as they share a pair of hydroxyl groups and phenolic ring, which enables them to bind to estrogen receptors directly, making them a herbal remedy for low estrogen states such as menopause. We present a case of a female patient with depression who was stabilized on venlafaxine and St John's Wort, and who developed a manic episode due to elevated serum venlafaxine levels after she started taking celery extracts for menopausal related issues. We proffer a hypothesis for this unusual occurrence.",
"affiliations": "a Department of Psychiatry , Central Michigan University College of Medicine , Saginaw , MI , USA.;a Department of Psychiatry , Central Michigan University College of Medicine , Saginaw , MI , USA.;b Department of Family medicine , Central Michigan University College of Medicine , Saginaw , MI , USA.;a Department of Psychiatry , Central Michigan University College of Medicine , Saginaw , MI , USA.;a Department of Psychiatry , Central Michigan University College of Medicine , Saginaw , MI , USA.;a Department of Psychiatry , Central Michigan University College of Medicine , Saginaw , MI , USA.",
"authors": "Khalid|Zaira|Z|;Osuagwu|Ferdnand C|FC|;Shah|Bilal|B|;Roy|Nikita|N|;Dillon|James E|JE|;Bradley|Ronald|R|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D028321:Plant Preparations; D000069470:Venlafaxine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1080/00325481.2016.1218263",
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"issn_linking": "0032-5481",
"issue": "128(7)",
"journal": "Postgraduate medicine",
"keywords": "Celery root; St John’s worth; bipolar disorder; mania; venlafaxine",
"medline_ta": "Postgrad Med",
"mesh_terms": "D018687:Antidepressive Agents, Second-Generation; D000077102:Apium; D001714:Bipolar Disorder; D003865:Depressive Disorder, Major; D005260:Female; D041743:Herb-Drug Interactions; D006801:Humans; D020902:Hypericum; D008593:Menopause; D008875:Middle Aged; D008517:Phytotherapy; D028321:Plant Preparations; D018517:Plant Roots; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride; D028761:Withholding Treatment",
"nlm_unique_id": "0401147",
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"pages": "682-3",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Celery root extract as an inducer of mania induction in a patient on venlafaxine and St John's Wort.",
"title_normalized": "celery root extract as an inducer of mania induction in a patient on venlafaxine and st john s wort"
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"abstract": "Extranodal NK/T-cell lymphoma (ENKTL), nasal type, is a rare type of non-Hodgkin lymphoma that is commonly seen in East Asian countries and is associated with Epstein-Barr virus infection. This is a retrospective study where we describe nine cases of ENKTL; nasal type diagnosed and treated at our center over a period of 2 years. These cases were analyzed retrospectively for clinical presentation (age, sex, site of involvement), immunophenotype, treatment, response and toxicity profile. Sino-nasal symptoms (blocked nose, headache, epistaxis, regurgitation) were the most common presenting complaints (n = 8). Almost 67 % (n = 6/9) of the cases were referred from Bhutan. Necrosis and angiocentricity were the commonest histological features. Depending on the stage of the disease patient were initially treated with chemotherapy (SMILE/CHOP) and Radiotherapy (IFRT). We describe our experience of management of ENKTL, where we observe that Bhutan could be endemic region for this rare tumour.",
"affiliations": "Department of Laboratory Haematology & Molecular Genetics, Tata Medical Center, Kolkata, India.;Department of Laboratory Haematology & Molecular Genetics, Tata Medical Center, Kolkata, India.;Department of Clinical Haematology, Tata Medical Center, Kolkata, India.;Department of Pathology, Tata Medical Center, Kolkata, India.;Department of Radiation Oncology, Tata Medical Center, Kolkata, India.;Department of Clinical Haematology, Tata Medical Center, Kolkata, India.;Department of Clinical Haematology, Tata Medical Center, Kolkata, India.;Department of Clinical Haematology, Tata Medical Center, Kolkata, India.;Department of Clinical Haematology, Tata Medical Center, Kolkata, India.",
"authors": "Arora|Neeraj|N|;Mehta|Arpan|A|;Ravichandran|Sriram|S|;Arun|Indu|I|;Achari|Rimpa Basu|RB|;Chakrapani|Anupam|A|;Bhave|Saurabh Jayant|SJ|;Chandy|Mammen|M|;Nair|Reena|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-016-0675-x",
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"issn_linking": "0971-4502",
"issue": "33(1)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "NK/T cell lymphoma; SMILE in NK/T cell lymphoma; SMILE therapy; T-cell lymphomas in India",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "69-73",
"pmc": null,
"pmid": "28194059",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "12933580;22919026;11332147;18509641;16382127;21990393;8388175;12182990;15668271;11012982;23098105;19812381;15234048;24597982",
"title": "NK/T Cell Lymphoma: A Tertiary Centre Experience.",
"title_normalized": "nk t cell lymphoma a tertiary centre experience"
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"abstract": "Corticosteroids have been widely used for the treatment of various inflammatory diseases because they provide an acute response of immunosuppression. Numerous side effects of corticosteroids have also been known, with varying degrees of severity. Osteonecrosis of the femoral head (ONFH) is a rare and serious complication that directly inhibits walking because of femoral head collapse. However, sometimes, clinicians who consider that corticosteroids are required for primary disease do not recognize steroid-induced ONFH. The final stage of ONFH is severe osteoarthritis, requiring total hip arthroplasty. We describe a 23-year-old woman with bilateral ONFH after corticosteroid treatment for alopecia areata (AA). She was administered several intralesional corticosteroid injections to the scalp and repeated systemic corticosteroid therapy for extensive AA. While undergoing therapy, she lost her balance and complained of right groin pain when standing. The patient was subsequently diagnosed with bilateral ONFH. She recovered from AA, but she complained of persistent right hip pain, which subsequently required total hip arthroplasty. We would like to emphasize that patients on corticosteroid therapy for any common disease should be considered as having a potential risk for ONFH. An early stage detection of ONFH is crucial for its treatment. MRI evaluation warrants a higher level of accuracy in early diagnosis of ONFH for the opportunity to undergo joint-preservation surgery in patients with ONFH.",
"affiliations": "Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan, ykuromd@kuhp.kyoto-u.ac.jp.;Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan, ykuromd@kuhp.kyoto-u.ac.jp.;Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan, ykuromd@kuhp.kyoto-u.ac.jp.;Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan, ykuromd@kuhp.kyoto-u.ac.jp.",
"authors": "Kuroda|Yutaka|Y|;Kawai|Toshiyuki|T|;Goto|Koji|K|;Matsuda|Shuichi|S|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/TCRM.S164999",
"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.S164999tcrm-14-1399Case ReportBilateral osteonecrosis of the femoral head associated with corticosteroid therapy for alopecia areata: a case report and review of the literature Kuroda Yutaka Kawai Toshiyuki Goto Koji Matsuda Shuichi Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan, ykuromd@kuhp.kyoto-u.ac.jpCorrespondence: Yutaka Kuroda, Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Kawaharacho 54, Sakyo-ku, Kyoto 606-8507, Japan, Tel +81 75 751 3366, Fax +81 75 751 8409, Email ykuromd@kuhp.kyoto-u.ac.jp2018 14 8 2018 14 1399 1405 © 2018 Kuroda et al. This work is published and licensed by Dove Medical Press Limited2018The 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.Corticosteroids have been widely used for the treatment of various inflammatory diseases because they provide an acute response of immunosuppression. Numerous side effects of corticosteroids have also been known, with varying degrees of severity. Osteonecrosis of the femoral head (ONFH) is a rare and serious complication that directly inhibits walking because of femoral head collapse. However, sometimes, clinicians who consider that corticosteroids are required for primary disease do not recognize steroid-induced ONFH. The final stage of ONFH is severe osteoarthritis, requiring total hip arthroplasty. We describe a 23-year-old woman with bilateral ONFH after corticosteroid treatment for alopecia areata (AA). She was administered several intralesional corticosteroid injections to the scalp and repeated systemic corticosteroid therapy for extensive AA. While undergoing therapy, she lost her balance and complained of right groin pain when standing. The patient was subsequently diagnosed with bilateral ONFH. She recovered from AA, but she complained of persistent right hip pain, which subsequently required total hip arthroplasty. We would like to emphasize that patients on corticosteroid therapy for any common disease should be considered as having a potential risk for ONFH. An early stage detection of ONFH is crucial for its treatment. MRI evaluation warrants a higher level of accuracy in early diagnosis of ONFH for the opportunity to undergo joint-preservation surgery in patients with ONFH.\n\nKeywords\nosteonecrosisfemoral headalopecia areataavascular necrosissteroidcase report\n==== Body\nIntroduction\nCorticosteroids are synthesized from cholesterol and produced in the adrenal cortex. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiologic processes. Cortisol or hydrocortisone is the most important human glucocorticoid, which is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Glucocorticoids affect carbohydrate, fat, and protein metabolism, and have antiinflammatory effects by blocking the inflammatory mediators, immunosuppressive effects by suppressing delayed hypersensitivity reaction directly on T-lymphocytes, and antiproliferative effects by inhibition of DNA synthesis and cell turnover.1 Therefore, various synthetic corticosteroids have been developed and widely used in a variety of clinical conditions, ranging from life-threatening diseases, such as lymphoma, to common inflammatory status, such as skin diseases. Various severe conditions are treated with systemic corticosteroids, such as crisis of autoimmune diseases, severe exacerbation of COPD, lymphoma, leukemia, Crohn disease, organ transplantation for preventing acute transplant rejection, and sepsis. However, corticosteroids not only have therapeutic effects, but also side effects, some of which may be severe. Typical undesired effects present as drug-induced Cushing syndrome, ulcer formation, muscle weakness, hyperglycemia, adrenal insufficiency, cataracts, teratogenic effect, depression, and inhibition of wound healing by the immunosuppressive effects.1,2 In regard to the musculoskeletal field, steroid-induced osteoporosis is well known as a major side effect after corticosteroid therapy. In addition to osteoporosis, osteonecrosis of the femoral head (ONFH) is considered one of the most serious corticosteroid-associated diseases in terms of daily activity, and not related to life prognosis. Steroid-induced ONFH, in contrast to steroid-induced osteoporosis, occurs in a younger and more active age group. However, physicians who considered corticosteroid therapy sometimes do not recognize ONFH as an adverse event.3–5 ONFH is characterized by severe pain and walking disability following femoral head collapse.5–7 Although the pathogenesis of ONFH remains unexplained, corticosteroid use was the most common causative factor identified, as well as alcohol intake. The most important clinical factor affecting ONFH is femoral head collapse, which is a sign of the final stage of ONFH that comprises destructive osteoarthritis of the hip joint. The definitive major treatment is total hip arthroplasty (THA), regardless of age and sex. Even if ONFH is identified during daily medical examination, 80% of untreated patients experience femoral head collapse and have to undergo THA.6 Based on the high collapse rate of ONFH,8 a recent strategy for ONFH treatment has shifted the approach to early diagnosis and early intervention to prevent femoral head collapse. The focus of research is shifting to joint-preserving surgery.6,9–11 MRI can be useful for early diagnosis, but the symptoms corresponding to the initial stages are usually absent or present as slight pain that intensifies after the femoral head collapses.6,10 Here, we describe the rare case of a 23-year-old woman with bilateral ONFH after corticosteroid treatment for alopecia areata (AA), which was diagnosed after right femoral head collapse, and forced to undergo THA.\n\nCase report\nA 23-year-old woman was diagnosed with AA by the end of 2010. In recent years, she has not had any immune system-related serious illnesses and conditions, such as asthma, allergies, and atopic dermatitis. Because of her condition, she experienced psychological changes in the workplace. She was initially treated with mometasone furoate, a topical corticosteroid, and oral cepharanthine to enhance blood flow. Despite compliance to treatment, AA progressed to diffuse AA. Initially, she was treated with intralesional triamcinolone acetonide (40 mg) five times per week between January and February 2011; triamcinolone acetonide has a potency that is five times that of methylprednisolone. However, her symptoms persisted.\n\nShe was referred to the dermatology department of our university hospital in June 2012. The result of the pull test at the margin of the alopecic lesions was positive. As further treatment to resolve alopecia, narrowband ultraviolet B phototherapy and squaric acid dibutylester (SADBE) as a local autoimmune treatment were administered as an outpatient for four courses between June 2011 and March 2013. Her response was erratic. Therefore, systemic corticosteroid pulse therapy was administered (Figure 1). The first course of 1,500 mg corticosteroid therapy in the hospital was administered in May 2013. The first course comprised 500 mg methylprednisolone administered intravenously for 3 days. However, the clinical recurrence of extensive AA, nearly alopecia universalis (Figure 2A and B), was observed 3 months after the first course. She was administered repeated corticosteroid pulse therapy until the end of 2013. A second course of 1,500 mg corticosteroid therapy was administered for 3 days, but her symptoms did not improve. After the third course of the same corticosteroid pulse therapy, extensive alopecia finally improved to small diffuse alopecia. In March 2014, SADBE treatment was started again as an outpatient. By September 2015, SADBE treatment was replaced by administration of 25 mg/day prednisolone, which was gradually tapered down to 5 mg/day. Her alopecia was resolved through the multidisciplinary approach to the treatment of AA.\n\nIn February 2016, she complained of right groin pain immediately after sustaining injury in the right leg after almost falling off her bicycle. She was referred to our department for orthopedic evaluation 1 month after the incident. Steroid-induced ONFH was suspected because of prior repeated systemic corticosteroid pulse therapy. Physical examination and MRI scan of the bilateral hip joints showed abnormal signs. The range of motion of the right hip joint was restricted in the direction of flexion, abduction, and internal rotation. Pain in the right groin increased when standing or climbing up the stairs. The T1-weighted MRI of the hip showed the characteristic band pattern on the right and a large diffused low signal area in the left femoral head. Based on these findings, she was diagnosed with stage three postcollapse ONFH on the right and stage one precollapse ONFH on the left (Figure 3). Thereafter, she complained of continuous and severe right hip joint pain. THA was scheduled and performed for the right ONFH in March 2017. For the left ONFH, she wanted a joint-preserving surgery, wherein core decompression and autologous bone graft were performed (Figure 4). One year postoperatively, three clinical scores in her hip improved (University of California, Los Angeles [UCLA] activity score, 4; Oxford hip score, 19 points; and Harris hip score [HHS], right: 90.0 points, left: 85.5 points) compared with those preoperatively (UCLA activity score, 2; Oxford hip score, 41 points; HHS, right: 36.0 points, left: 46.0 points). The postoperative course went well, and the patient became ambulatory with a single cane and was discharged after rehabilitation therapy. At the Department of Dermatology, 5 mg/day corticosteroid was administered as maintenance dose for AA. The patient was carefully followed up as an outpatient if the symptoms on the left side worsened.\n\nEthics approval and informed consent\nWritten informed consent for the publication of case details, including consent for publication of the patient’s images, was obtained from the patient. This study was approved by the Kyoto University institutional review board.\n\nDiscussion\nHistorically, systemic corticosteroid therapy has been widely used for various inflammatory diseases that are life-threatening because of its immediate action against severe inflammatory status.1,2 For immunologists and orthopedic surgeons, ONFH has been well recognized as an adverse event of systemic corticosteroid therapy because corticosteroid-associated ONFH affects young adults in their 20s and 30s, especially in young patients with collagen disease, such as systemic lupus erythematosus.6,7 ONFH is considered to be caused by the critical loss of the vascular supply to the femoral head, and several causative factors may influence its development. The etiology of ONFH is considered to be multifactorial and associated in certain risk factors (Table 1).5–10 In corticosteroid-associated ONFH, hypercoagulability of vascular vessels is thought to diminish perfusion.5\n\nFew studies on corticosteroid-associated ONFH following primary disease in the field of dermatology were reported.5 AA is a common disease of unknown etiology, which has a large impact on the appearance and mental status of afflicted people.12 Many treatment methods have been applied, but none have been effective to date.12,13 Over the decades, corticosteroids have shown some therapeutic results and are currently the most widely used because of their effect on the inflammatory process occurring in AA.12–14 Many other treatment modalities, such as dinitrochlorobenzene, cyclosporine, sulfasalazine, minoxidil, tacrolimus, and SADBE, target associated autoimmune diseases.12–15 Therefore, AA has been recently considered a systemic autoimmune disease.14,16 For each treatment modality, a balance between adverse effects and cosmetically acceptable improvement must be considered. In this case, the patient had no history of autoimmune or allergic diseases. The mechanism of AA was not identified, but this might be due to environmental factors, such as emotional stress. However, emotional stress as a contributing factor to reduced hair proliferation is controversial. Some studies have suggested that psychological factors inhibited hair growth.17 In our case, despite the initial combination of therapies, a single localized patch progressed to extensive and recurrent AA. The dermatologists and patient gradually became worried because of the possibility of permanent alopecia totalis. Therefore, administration of repeated corticosteroid pulse therapy was easy to understand in such a situation.\n\nAmong the corticosteroid-associated diseases, ONFH is the most serious adverse event that leads to irreversible, destructive, femoral head collapse, which requires THA even in young patients.6,10 Reduction or avoidance of this adverse effect of steroid compounds has not been established. Therefore, ONFH cannot be avoided to some extent despite the predicted number of patients with ONFH being relatively small. The onset of steroid-induced ONFH was reported to range from several weeks to several months.18 In the present case, the patient received two different high-dose corticosteroid therapies at different times because of refractory and recurrent AA. The initial therapy was five intralesional injections of a corticosteroid that had a potency equivalent to 1,000 mg methylprednisolone. Two years later, a second corticosteroid therapy was administered as three courses of systemic pulse steroid therapy, each with a potency equivalent to 1,500 mg methylprednisolone. The last three courses of corticosteroid pulse therapy led to improvement from an extensively large area of alopecia to a small, diffuse area. Dosages considered to be associated with ONFH are >20 mg of prednisone (or equivalent) per day20 or >2 g within a 2- to 3-month period.5,19 Powell et al reported that even a cumulative dose as low as 1,000 mg of prednisone administered within a short period will increase risk.21 Luggen et al reported that better response was achieved with high-dose intravenous methylprednisolone (500 mg given on three consecutive days); 147 of 218 patients (67%) treated for multifocal AA had more than 50% hair regrowth.22 Few studies regarding topical corticosteroid-induced ONFH following the long-term use of corticosteroids in psoriasis have been reported.23,24 In the present case, topical, systemic (intravenous), and oral corticosteroid therapies were administered. We could not verify when ONFH had occurred. In any case, we suspected that ONFH may have been clinically asymptomatic for a long time and only started to manifest with symptoms when the affectation became bilateral. Right groin pain has been recognized as a symptom of femoral head collapse in patients with ONFH. Correlating with the case, femoral head collapse may have been triggered when she lost her footing to prevent her bicycle from being turned over. In routine clinical practice, some ONFH cases, particularly idiopathic or alcohol abuse-associated type, are diagnosed after the femoral head collapses.\n\nSeveral reports have indicated that patients with disorders requiring corticosteroid therapy have a potential risk of developing ONFH.6,10 Peretz et al reported that patients with rare diseases, including uveitis, Behcet disease, Crohn disease, Cushing syndrome, sarcoidosis, spondyloarthropathy, osteoporosis, and cataracts, required corticosteroids or immunosuppressive drugs and were at risk of developing side effects.3 They concluded that corticosteroid-associated ONFH was a rare but serious complication. Smith et al reported that one of six patients with uveitis with ONFH had Vogt–Koyanagi–Harada (VKH) syndrome, corresponding to a small prevalence of 0.25%.4 We previously reported a rare case of ONFH associated with groin pain during intravenous corticosteroid pulse therapy for VKH syndrome. Patients with ONFH following VKH syndrome could be diagnosed early and successfully treated by joint-preserving regenerative therapy.25\n\nTo the best of our knowledge, this was the first case of a patient with ONFH due to corticosteroid use for AA. Although the prevalence of such cases has not been reported and is uncertain, the increase of the prevalence of these cases is possible in the future because of the wide use of corticosteroids for dermatologic diseases. The patient was dissatisfied because she developed bilateral ONFH after extensive AA treatment. Therefore, she wants other patients to know that such complications can occur in the course of common disease such as AA treatment. The onset of corticosteroid-associated ONFH is difficult to predict, even in patients with potential risk. A high collapse rate of 80% was reported for untreated patients who experience femoral head collapse.8 Early diagnosis of ONFH evaluated by MRI and early treatment are important in preventing femoral head collapse. MRI is considered the most accurate test and is both highly sensitive and highly specific for early ONFH without symptoms.5–7,10,25\n\nConsidering the susceptible age of patients with ONFH and the high collapse rate, recent therapy for ONFH has shifted the concept to early diagnosis and aggressive intervention.10 The focus of research for the early stage of ONFH is shifting to various joint-preserving therapies, such as bisphosphonate use, cell therapy, artificial bone, and growth factors.6,9–11,19 In recent years, bisphosphonates and parathyroid hormone are also being used to prevent end-stage ONFH.10 Patients with end-stage ONFH usually require THA, which involves risk of infection, dislocation, limitation of sports activities, and repeated revisions throughout a patient’s life. In this patient, autologous bone graft was performed successfully, and the hip joint of left ONFH was preserved. In any case, early diagnosis of ONFH is crucial to prevent femoral head collapse by joint-preserving therapies. We would like to emphasize that ONFH may be a burden to a patient’s life more than the primary disease, such AA, which required corticosteroid pulse therapy. To diagnose ONFH at an early stage, a higher level of suspicion and MRI evaluations may be warranted in patients on systemic corticosteroid use.\n\nConclusion\nWe experienced a rare case of bilateral ONFH associated with corticosteroid therapy for AA. Identification of corticosteroid-associated ONFH is difficult, even in patients with potential risk. Therefore, patients on corticosteroid therapy should be carefully monitored for the potential risk of ONFH, which can start any time. Early diagnosis of ONFH by MRI and early treatment are crucial in preventing femoral head collapse.\n\nAcknowledgments\nThe authors thank Akiko Kuroda, Kyoto University Hospital, who provided and cared for the study patient and served as a clinical research coordinator.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Clinical course of a 23-year-old woman with refractory alopecia areata.\n\nNote: Because of refractory alopecia areata, the patient was administered five courses of intralesional corticosteroid therapy and three courses of systemic corticosteroid pulse therapy.\n\nAbbreviations: NB UVB, narrowband ultraviolet B; ONFH, osteonecrosis of the femoral head; SADBE, squaric acid dibutylester; THA, total hip arthroplasty.\n\nFigure 2 Therapeutic effect of a 23-year-old woman with refractory alopecia areata.\n\nNotes: Localized patch progressed to extensive alopecia areata despite the first systemic corticosteroid pulse therapy. Therapeutic effect after the topical, systemic, and oral corticosteroid therapy is shown. (A) Hair loss and alopecic eyebrow. (B) Extensive loss of hair on the crown of the head.\n\nFigure 3 Radiographic images of the hips on high-dose corticosteroid therapy for refractory alopecia areata.\n\nNotes: After the onset of right groin pain, (A) coronal view T1-weighted MRI shows characteristic low-signal band patterns (yellow arrows) on the bilateral femoral heads, which are suggestive of avascular necrosis. One year after diagnosis of bilateral osteonecrosis in the hip, (B) anterior–posterior radiograph shows massive broken and flattened (yellow arrows) subchondral bone of the right femoral head and progressive femoral head collapse. In the left femoral head, band-like sclerotic change (arrow heads) is observed.\n\nFigure 4 Anterior–posterior radiograph of bilateral hips demonstrating cementless right total hip arthroplasty and left joint preservation following the surgery of core decompression and autologous bone graft.\n\nTable 1 Classification of risk factors for developing osteonecrosis of the femoral head\n\nTraumatic factors\t\n Femoral neck fracture, femoral head fracture, dislocation of the hip joint\t\nAtraumatic factors\t\n Glucocorticoid use\t\n Excessive alcohol intake\t\n Coagulopathy (antiphospholipid syndrome, hyperlipidemia, systemic lupus erythematosus)\t\n Others (Caisson disease, sickle cell disease, Gaucher disease, smoking, radiation)\n==== Refs\nReferences\n1 Liu D Ahmet A Ward L A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy Allergy Asthma Clin Immunol 2013 9 1 30 23947590 \n2 Buchman AL Side effects of corticosteroid therapy J Clin Gastroenterol 2001 33 4 289 294 11588541 \n3 Peretz A Guillaume MP Casper-Velu L Uveitis management: a multidisciplinary approach to assess systemic involvement and side effects of treatments Acta Clin Belg 2002 57 3 142 147 12212355 \n4 Smith WM Larson TA Meleth AD Krishnadev N Nussenblatt RB Sen HN Corticosteroid-associated osteonecrosis: a rare, but serious, complication in uveitis Ocul Immunol Inflamm 2013 21 2 102 107 23252656 \n5 Nowak DA Yeung J Steroid-induced osteonecrosis in dermatology: a review J Cutan Med Surg 2015 19 4 358 360 25825195 \n6 Moya-Angeler J Gianakos AL Villa JC Ni A Lane JM Current concepts on osteonecrosis of the femoral head World J Orthop 2015 6 8 590 601 26396935 \n7 Mont MA Cherian JJ Sierra RJ Jones LC Lieberman JR Nontraumatic osteonecrosis of the femoral head: where do we stand today? a ten-year update J Bone Joint Surg Am 2015 97 19 1604 1627 26446969 \n8 Min BW Song KS Cho CH Lee SM Lee KJ Untreated asymptomatic hips in patients with osteonecrosis of the femoral head Clin Orthop Relat Res 2008 466 5 1087 1092 18327630 \n9 Marker DR Seyler TM Mcgrath MS Delanois RE Ulrich SD Mont MA Treatment of early stage osteonecrosis of the femoral head J Bone Joint Surg Am 2008 90 Suppl 4 175 187 18984729 \n10 Kuroda Y Matsuda S Akiyama H Joint-preserving regenerative therapy for patients with early-stage osteonecrosis of the femoral head Inflamm Regen 2016 36 1 4 29259677 \n11 Kuroda Y Asada R So K A pilot study of regenerative therapy using controlled release of recombinant human fibroblast growth factor for patients with pre-collapse osteonecrosis of the femoral head Int Orthop 2016 40 8 1747 1754 26715504 \n12 Gilhar A Etzioni A Paus R Areata A Alopecia areata N Engl J Med 2012 366 16 1515 1525 22512484 \n13 Harries MJ Sun J Paus R King LE Management of alopecia areata Br Med J 2010 341 c3671 20656774 \n14 Garg S Messenger AG Alopecia areata: evidence-based treatments Semin Cutan Med Surg 2009 28 1 15 18 19341938 \n15 Delamere FM Sladden MM Dobbins HM Interventions for alopecia areata Cochrane Database Syst Rev 2008 16 2 CD004413 \n16 Mcelwee KJ Freyschmidt-Paul P Hoffmann R Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(−) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model J Invest Dermatol 2005 124 5 947 957 15854035 \n17 Picardi A Pasquini P Cattaruzza MS Psychosomatic factors in first-onset alopecia areata Psychosomatics 2003 44 5 374 381 12954911 \n18 Kubo T Yamazoe S Sugano N Initial MRI findings of non-traumatic osteonecrosis of the femoral head in renal allograft recipients Magn Reson Imaging 1997 15 9 1017 1023 9364947 \n19 Mont MA Jones LC Hungerford DS Nontraumatic osteonecrosis of the femoral head: ten years later J Bone Joint Surg Am 2006 88 5 1117 1132 16651589 \n20 Aaron RK Voisinet A Racine J Ali Y Feller ER Corticosteroid-associated avascular necrosis: dose relationships and early diagnosis Ann N Y Acad Sci 2011 1240 38 46 22172038 \n21 Powell C Chang C Naguwa SM Cheema G Gershwin ME Steroid induced osteonecrosis: an analysis of steroid dosing risk Autoimmun Rev 2010 9 11 721 743 20621176 \n22 Luggen P Hunziker T High-dose intravenous corticosteroid pulse therapy in alopecia areata: own experience compared with the literature J Dtsch Dermatol Ges 2008 6 5 375 378 18205838 \n23 Reichert-Pénétrat S Tréchot P Barbaud A Gillet P Schmutz JL Bilateral femoral avascular necrosis in a man with psoriasis: responsibility of topical corticosteroids and role of cyclosporine Dermatology 2001 203 4 356 357 11752834 \n24 Kane D Barnes L Fitzgerald O Topical corticosteroid treatment: systemic side-effects Br J Dermatol 2003 149 2 417 12932255 \n25 Kuroda Y So K Goto K Matsuda S Extremely early stage osteonecrosis of the femoral head in a patient with hip pain secondary systemic steroid pulse therapy for Vogt-Koyanagi-Harada syndrome: a case report Int J Surg Case Rep 2016 25 97 101 27343734\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6336",
"issue": "14()",
"journal": "Therapeutics and clinical risk management",
"keywords": "alopecia areata; avascular necrosis; case report; femoral head; osteonecrosis; steroid",
"medline_ta": "Ther Clin Risk Manag",
"mesh_terms": null,
"nlm_unique_id": "101253281",
"other_id": null,
"pages": "1399-1405",
"pmc": null,
"pmid": "30147323",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "16651589;12932255;12954911;11588541;20621176;18205838;29259677;20656774;26396935;23252656;9364947;26446969;26715504;23947590;25825195;22512484;19341938;22172038;15854035;18425901;11752834;18327630;18984729;12212355;27343734",
"title": "Bilateral osteonecrosis of the femoral head associated with corticosteroid therapy for alopecia areata: a case report and review of the literature.",
"title_normalized": "bilateral osteonecrosis of the femoral head associated with corticosteroid therapy for alopecia areata a case report and review of the literature"
} | [
{
"companynumb": "PHHY2019JP004717",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Freezing of gait (FOG) and postural instability are challenging motor symptoms that present a serious therapeutic dilemma in Parkinson's disease. Appropriate distinction between FOG subtypes may be difficult during routine clinical visits, as shown in the case we present. The patient was examined in three different states in relation to levodopa (L-DOPA) and apomorphine subcutaneous (sc) tests with video documentation: (1) 'overnight-off', after 12 hours without medication; (2)'on', 60 min after intake of regular levodopa dose (200 mg) and 20 min after 2 mg of apomorphine sc; and (3) 'supra-on', after 350 mg of L-DOPA and 3 mg of apomorphine sc. The patient clearly showed a dose-dependent paradoxical response to L-DOPA treatment with the emergence of severe FOG and postural instability. The tendency to develop these axial symptoms was less pronounced with apomorphine at doses that achieved similar improvements of other Parkinsonian features.",
"affiliations": "Division of Movement Disorders, Department of Neurology, Coimbra Hospital and University Centre, Coimbra, Portugal.;Department of Neurology, Coimbra Hospital and University Centre, Coimbra, Portugal.;Division of Movement Disorders, Department of Neurology, Coimbra Hospital and University Centre, Coimbra, Portugal.",
"authors": "Moreira|Fradique|F|http://orcid.org/0000-0002-5881-4950;Rebelo Gomes|Inês|I|;Januário|Cristina|C|",
"chemical_list": "D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D010069:Oxadiazoles; D007980:Levodopa; C549349:opicapone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229224",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(7)",
"journal": "BMJ case reports",
"keywords": "drugs: CNS (not Psychiatric); neurology; parkinson’s disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D004305:Dose-Response Relationship, Drug; D020233:Gait Disorders, Neurologic; D006801:Humans; D007980:Levodopa; D008297:Male; D010069:Oxadiazoles; D010300:Parkinson Disease; D004856:Postural Balance; D012678:Sensation Disorders",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31337633",
"pubdate": "2019-07-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "26762797;26018594;26018593;30363872;20880751;24396010;22262741;24132839;30055903",
"title": "Freezing of gait and postural instability: the unpredictable response to levodopa in Parkinson's disease.",
"title_normalized": "freezing of gait and postural instability the unpredictable response to levodopa in parkinson s disease"
} | [
{
"companynumb": "PT-MYLANLABS-2020M1001330",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
},
"drugadditional": "1"... |
{
"abstract": "OBJECTIVE\nIron deficiency is associated with impaired dopaminergic signaling and externalizing behavior. The authors examine, whether iron stores in toddlerhood influence later response to psychostimulants.\n\n\nMETHODS\nYouth participating in a study monitoring the long-term safety of risperidone were included in this analysis if they had received psychostimulant monotherapy for at least 3 weeks and had a complete blood count obtained before psychostimulant treatment. Sensitivity to psychostimulants was defined based on the weight-adjusted dose during the 1st year of treatment. Regression analysis examined whether the hematological tests based on the characteristics of red blood cells were associated with sensitivity to psychostimulants.\n\n\nRESULTS\nA total of 29 participants (93% men; 76% Whites), primarily with ADHD (93%), comprised the current sample. The hematological tests were obtained, on average, 3 years before the initiation of psychostimulants monotherapy that occurred at 5.8 years of age and continued for a median of 0.85 years, at an average daily dose of 0.98 mg/kg (SD = 0.38) in methylphenidate equivalent. Compared with those who were poorly sensitive to psychostimulants, after adjusting for age, mean corpuscular volume was significantly higher in the highly and moderately psychostimulants sensitive groups.\n\n\nCONCLUSIONS\nIf replicated, these findings suggest that more attention should be paid to optimizing body iron in early childhood.",
"affiliations": "University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.",
"authors": "Turner|Catharyn A|CA|;Xie|Diqiong|D|;Zimmerman|Bridget M|BM|;Calarge|Chadi A|CA|",
"chemical_list": "D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1177/1087054710385067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-0547",
"issue": "16(4)",
"journal": "Journal of attention disorders",
"keywords": null,
"medline_ta": "J Atten Disord",
"mesh_terms": "D018798:Anemia, Iron-Deficiency; D014150:Antipsychotic Agents; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008774:Methylphenidate; D018967:Risperidone; D016896:Treatment Outcome",
"nlm_unique_id": "9615686",
"other_id": null,
"pages": "295-303",
"pmc": null,
"pmid": "20978274",
"pubdate": "2012-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15583094;11509198;18279203;11053528;17581453;17073984;19205783;11389261;21186968;10742372;16832322;20331935;18054688;16966351;8094018;17158406;17101454;15909765;10638065;17667480;10501650;16504789;19364288;9405575;15732057;11160596;16713640;7524105",
"title": "Iron status in toddlerhood predicts sensitivity to psychostimulants in children.",
"title_normalized": "iron status in toddlerhood predicts sensitivity to psychostimulants in children"
} | [
{
"companynumb": "US-JNJFOC-20121017169",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Background: Androgenetic alopecia (AGA) is a common form of hair loss in Asian men. Although AGA is often regarded as a relatively minor dermatological condition, hair loss can impact self-image and is a main cause for anxiety and depression in some men. We have treated patients with AGA for seven years. Objective: The goal of this study was to evaluate the effectiveness of our combination therapy in Asian men with AGA. Participants: Between the years 2011 and 2017, 18,918 male patients were treated in our center. Our combination therapy consists of oral finasteride once daily, oral and topical minoxidil twice daily, and an injectable treatment of lidocaine and an AGA treatment solution comprising minoxidil, arginine, aspartic acid, caffeine, copper tripeptide, lysine, niacin, panthenol, propanediol, propylen glycol, retinyl palmitate, pyridoxine, sodium hyaluronate, and ubiquinone once monthly for more than six months. Measurements: Digital photographs were taken pre- and post-treatment, and patient assessments were recorded after six and 12 months post-treatment. Results: Significant improvement was observed in all patients in the digital photographs. Ninety-six and 80 percent of the patients reported satisfaction with the results of the treatment after six and 12 months post-treatment. Minor complications were observed in 802 (4.2%) patients, characterized by slight pain and bleeding due to injection, swelling, dizziness, itching, and erythema of the scalp. Slight pain was reported in 651 patients (3.4%), and slight bleeding was reported in 56 patients (0.3%). Sexual dysfunctions were uncommon. These minor complications resolved spontaneously. No treatment-related adverse events were observed. Conclusion: A combination of these therapeutic options offers safe and highly efficacious treatment for AGA with minimal complications.",
"affiliations": "Dr. Tanaka is with Clinica Tanaka Plastic, Reconstructive Surgery and Anti-aging Center in Matsumoto, Nagano, Japan, and the AGA Skin Clinic in Tokyo, Japan.;Dr. Tanaka is with Clinica Tanaka Plastic, Reconstructive Surgery and Anti-aging Center in Matsumoto, Nagano, Japan, and the AGA Skin Clinic in Tokyo, Japan.;Dr. Tanaka is with Clinica Tanaka Plastic, Reconstructive Surgery and Anti-aging Center in Matsumoto, Nagano, Japan, and the AGA Skin Clinic in Tokyo, Japan.;Dr. Tanaka is with Clinica Tanaka Plastic, Reconstructive Surgery and Anti-aging Center in Matsumoto, Nagano, Japan, and the AGA Skin Clinic in Tokyo, Japan.;Dr. Tanaka is with Clinica Tanaka Plastic, Reconstructive Surgery and Anti-aging Center in Matsumoto, Nagano, Japan, and the AGA Skin Clinic in Tokyo, Japan.",
"authors": "Tanaka|Yohei|Y|;Aso|Toru|T|;Ono|Jumpei|J|;Hosoi|Ryu|R|;Kaneko|Takuto|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-2789",
"issue": "11(7)",
"journal": "The Journal of clinical and aesthetic dermatology",
"keywords": "Androgenetic alopecia (AGA); Combination therapy; Finasteride; Hair loss; Minoxidil",
"medline_ta": "J Clin Aesthet Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101518173",
"other_id": null,
"pages": "32-35",
"pmc": null,
"pmid": "30057663",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": "22879715;26380504;26339482;6239893;12227482;9580790;11069460;3549806;11763381;9492438;9777765;14674898;24184140;11359394;28761311;23364150;24959691;14819896;10534633;20927235;25268732;20105167;79579;2180995;23717009;10494708;3214816;8326149;3301926;3549802",
"title": "Androgenetic Alopecia Treatment in Asian Men.",
"title_normalized": "androgenetic alopecia treatment in asian men"
} | [
{
"companynumb": "JP-DENTSPLY-2018SCDP000377",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Immune checkpoint inhibitors have ushered in a new era in cancer management. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor. This inhibits suppression of the T-cell activity, which can in turn cause increased killing of cancer cells. This alteration in the activity of the T cells can cause them to lose their ability to identify host cells and leads to immune-related adverse effects (irAE). Nivolumab-induced hepatotoxicity is rare and accounts for 3-6% of all irAE. We present a case of nivolumab-induced hepatitis. A woman who was treated for recurrent renal cell carcinoma presented with hepatitis. Workup for other causes was negative and the hepatitis was attributed to the administration of nivolumab. She was started on oral steroids followed which she initially improved. However, she later presented with massive upper gastrointestinal bleeding secondary to gastroduodenal ulcers and subsequently developed acute tubular necrosis and passed from the complications. Immune checkpoint inhibitors have proven to be a promising approach in the management of a wide array of neoplasms by immunomodulation. As these agents are becoming standard of therapy in the management of cancers, a heightened vigilance in the diagnosis of irAE is warranted. With heightened vigilance, early recognition can lead to decreased mortality and morbidity.",
"affiliations": "UConn Health, Farmington, CT, USA.;UConn Health, Farmington, CT, USA.;Christian Medical College, Ludhiana, India.;Saint Francis Hospital and Medical Center, Hartford, CT, USA.",
"authors": "Mathew Thomas|Vinay|V|https://orcid.org/0000-0001-9916-730X;Bindal|Poorva|P|https://orcid.org/0000-0003-3459-0099;Ann Alexander|Swetha|S|;McDonald|Kymberly|K|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219837342",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(2)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Hyperbilirubinemia; immunotherapy; liver injury; nivolumab",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D002292:Carcinoma, Renal Cell; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006505:Hepatitis; D006801:Humans; D007167:Immunotherapy; D007680:Kidney Neoplasms; D009364:Neoplasm Recurrence, Local; D000077594:Nivolumab",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "459-461",
"pmc": null,
"pmid": "30909794",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nivolumab-induced hepatitis: A rare side effect of an immune check point inhibitor.",
"title_normalized": "nivolumab induced hepatitis a rare side effect of an immune check point inhibitor"
} | [
{
"companynumb": "NVSC2020US069448",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Clindamycin is widely used in the prophylaxis and treatment of infections due to its broad spectrum of antimicrobial activity. Hypersensitivity to clindamycin seems to be not very common (less than 1% of drug-allergic reactions) and it mostly appears as delayed T-cell mediated. For the diagnosis, skin testing is considered to be highly sensitive and rather safe, but cutaneous and systemic reactions have been described. Provocation test is considered the gold standard. However, it includes the possibility of severe reactions. We reported two cases of delayed allergic reaction to clindamycin, confirmed with a positive lymphocyte transformation test, showing this in vitro test like a promising diagnostic method because of its usefulness and safety.",
"affiliations": "Department of Allergy, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain.;Department of Immunology, Hospital La Paz, Madrid, Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain.;Department of Allergy, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain.",
"authors": "Vílchez-Sánchez|F|F|;Domínguez-Ortega|J|J|;González Muñoz|M|M|;Loli-Ausejo|D|D|;Heredia-Revuelto|R|R|;Fiandor Román|A|A|;Quirce|S|S|",
"chemical_list": "D000485:Allergens; D002981:Clindamycin",
"country": "Italy",
"delete": false,
"doi": "10.23822/EurAnnACI.1764-1489.117",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1764-1489",
"issue": "52(2)",
"journal": "European annals of allergy and clinical immunology",
"keywords": "allergy; clindamycin; delayed reaction; diagnosis; lymphocyte transformation test",
"medline_ta": "Eur Ann Allergy Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000485:Allergens; D002471:Cell Transformation, Neoplastic; D002981:Clindamycin; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D007118:Immunoassay; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D012867:Skin; D012882:Skin Tests; D013601:T-Lymphocytes",
"nlm_unique_id": "101466614",
"other_id": null,
"pages": "91-93",
"pmc": null,
"pmid": "31668055",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two case reports of delayed-allergic reactions to clindamycin confirmed with a positive lymphocyte transformation test.",
"title_normalized": "two case reports of delayed allergic reactions to clindamycin confirmed with a positive lymphocyte transformation test"
} | [
{
"companynumb": "ES-PFIZER INC-2019519834",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Recurrence of anginal symptoms following coronary artery bypass surgery is usually secondary to graft closure or progression of native vessel disease. The present case demonstrates severe exercise-induced saphenous vein graft (SVG) spasm associated with transmural ischemia refractory to maximal vasodilator therapy. Symptoms resolved and exercise electrocardiography normalized following stenting of SVG regions demonstrating spasm. © 2017 Wiley Periodicals, Inc.",
"affiliations": "Baptist Health Lexington, Lexington, Kentucky.;The Christ Hospital Heart and Vascular Center, The Lindner Research Center, Cincinnati, Ohio.;Baptist Health Lexington, Lexington, Kentucky.",
"authors": "Boliek|William G|WG|;Kereiakes|Dean J|DJ|http://orcid.org/0000-0003-1086-127X;Chugh|Atul|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/ccd.27026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-1946",
"issue": "90(6)",
"journal": "Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions",
"keywords": "balloon angioplasty; coronary bypass grafts; saphenous vein graft interventions",
"medline_ta": "Catheter Cardiovasc Interv",
"mesh_terms": "D000368:Aged; D019917:Blood Vessel Prosthesis Implantation; D006328:Cardiac Catheterization; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease; D054855:Drug-Eluting Stents; D004562:Electrocardiography; D000068338:Everolimus; D015444:Exercise; D005080:Exercise Test; D006083:Graft Occlusion, Vascular; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D011183:Postoperative Complications; D012086:Reoperation; D012501:Saphenous Vein; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "100884139",
"other_id": null,
"pages": "937-944",
"pmc": null,
"pmid": "28303667",
"pubdate": "2017-11-15",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Exercise-induced saphenous vein graft spasm prevented by stenting.",
"title_normalized": "exercise induced saphenous vein graft spasm prevented by stenting"
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"companynumb": "US-TEVA-2017-US-835253",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"abstract": "BACKGROUND\nSeveral paediatric malignancies, including anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumour (IMT), neuroblastoma, and rhabdomyosarcoma, harbour activation of anaplastic lymphoma kinase (ALK) through different mechanisms. Here, we report the safety, pharmacokinetics, and efficacy of ceritinib in paediatric patients with ALK-positive malignancies.\n\n\nMETHODS\nThis multicentre, open-label, phase 1 trial was done at 23 academic hospitals in ten countries. Children (aged ≥12 months to <18 years) diagnosed with locally advanced or metastatic ALK-positive malignancies that had progressed despite standard therapy, or for which no effective standard therapy were available, were eligible. ALK-positive malignancies were defined as those with ALK rearrangement, amplification, point mutation, or in the case of rhabdomyosarcoma, expression in the absence of any genetic alteration. Eligible patients had evaluable or measurable disease as defined by either Response Evaluation Criteria in Solid Tumours, version 1.1 for patients with non-haematological malignancies, International Neuroblastoma Response Criteria scan for patients with neuroblastoma, or International Working Group criteria for patients with lymphoma. Other eligibility criteria were Karnofsky performance status score of at least 60% for patients older than 12 years or Lansky score of at least 50% for patients aged 12 years or younger. This study included a dose-escalation part, followed by a dose-expansion part, in which all patients received treatment at the recommended dose for expansion (RDE) established in the dose-escalation part. Both parts of the study were done in fasted and fed states. In the dose-escalation part, patients were treated with once-daily ceritinib orally, with dose adjusted for body-surface area, rounded to the nearest multiple of the 50 mg dose strength. The starting dose in the fasted state was 300 mg/m2 daily and for the fed state was 320 mg/m2 daily. The primary objective of this study was to establish the maximum tolerated dose (ie, RDE) of ceritinib in the fasted and fed states. The RDE was established on the basis of the incidence of dose-limiting toxicities in patients who completed a minimum of 21 days of treatment with safety assessments and at least 75% drug exposure, or who discontinued treatment earlier because of dose-limiting toxicity. Overall response rate (defined as the proportion of patients with a best overall response of complete response or partial response) was a secondary endpoint. Activity and safety analyses were done in all patients who received at least one dose of ceritinib. This trial is registered with ClinicalTrials.gov (NCT01742286) and is completed.\n\n\nRESULTS\nBetween Aug 28, 2013, and Oct 17, 2017, 83 children with ALK-positive malignancies were enrolled to the dose-escalation (n=40) and dose-expansion (n=43) groups. The RDE of ceritinib was established as 510 mg/m2 (fasted) and 500 mg/m2 (fed). 55 patients (30 with neuroblastoma, ten with IMT, eight with ALCL, and seven with other tumour types) were treated with ceritinib at the RDE (13 patients at 510 mg/m2 fasted and 42 patients at 500 mg/m2 fed). The median follow-up was 33·3 months (IQR 24·8-39·3) for patients with neuroblastoma, 33·2 months (27·9-35·9) for those with IMT, 34·0 months (21·9-46·4) for those with ALCL, and 27·5 months (22·4-36·9) for patients with other tumour types. An overall response was recorded in six (20%; 95% CI 8-39) of 30 patients with neuroblastoma, seven (70%; 33-93) of ten patients with IMT, six (75%; 35-97) of eight patients with ALCL, and one (14%; <1-58) of seven patients with other tumours. The safety profile of ceritinib was consistent with that observed in adult patients. All patients had at least one adverse event. Grade 3 or 4 adverse events occurred in 67 (81%) of 83 patients and were mostly increases in aminotransferases (alanine aminotransferase increase in 38 [46%] patients and aspartate aminotransferase increase in 27 [33%] patients). At least one serious adverse event was reported in 40 (48%) of 83 patients and 31 (37%) of 83 patients had at least one grade 3 or 4 serious adverse event. 14 (17%) deaths occurred during the study, of which 12 were on-treatment deaths and two were after 30 days of the last dose. Of the 12 on-treatment deaths, ten were due to disease progression (neuroblastoma), one due to sepsis, and one due to intractable hypotension.\n\n\nCONCLUSIONS\nCeritinib 500 mg/m2 once daily with food is the recommended dose for paediatric patients with ALK-positive malignancies. Ceritinib showed promising preliminary antitumour activity in patients with ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsed or refractory neuroblastoma, with a manageable safety profile. Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for paediatric patients with malignancies with genetic ALK alterations.\n\n\nBACKGROUND\nNovartis Pharmaceutical Corporation.",
"affiliations": "Experimental Paediatric Oncology, University Children's Hospital of Cologne, and Centre for Molecular Medicine, Medical Faculty, University of Cologne, Cologne, Germany.;Paediatric Oncology Department, Hospital Infantil Universitario Nino Jesus, Madrid, Spain; Division of Paediatric Haematology and Oncology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.;Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.;Paediatric and Adolescent Oncology Drug Development, Royal Marsden NHS Foundation Trust & The Institute of Cancer Research, London, UK.;Department of Paediatric Oncology, Erasmus MC-Sophia Children's Hospital, and Princess Máxima Centre, Utrecht, Netherlands.;Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.;Paediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Division of Paediatric Haematology and Oncology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.;Paediatric Haemato-Oncology, University Children's Hospital III Essen, Essen, Germany.;Global Development Operations-Trial Management/Oncology, Novartis Pharma, Basel, Switzerland.;Novartis Pharmaceuticals, East Hanover, NJ, USA.;Novartis Pharmaceuticals, East Hanover, NJ, USA.;Clinical Development and Analytics, Oncology Global Development, Novartis Pharma, Basel, Switzerland.;Department of Paediatric and Adolescent Oncology, Gustave Roussy Cancer Centre, Université Paris-Saclay, INSERM U1015, Villejuif, France.;Department of Paediatrics, Division of Oncology and Haematology, Charité-Universitätmedizin Berlin, Berlin, Germany; The German Cancer Consortium, partner site Berlin, Berlin, Germany; German Cancer Research Center, Heidelberg, Germany. Electronic address: johannes.schulte@charite.de.",
"authors": "Fischer|Matthias|M|;Moreno|Lucas|L|;Ziegler|David S|DS|;Marshall|Lynley V|LV|;Zwaan|C Michel|CM|;Irwin|Meredith S|MS|;Casanova|Michela|M|;Sabado|Constantino|C|;Wulff|Beate|B|;Stegert|Mario|M|;Wang|Luojun|L|;Hurtado|Felipe K|FK|;Branle|Fabrice|F|;Geoerger|Birgit|B|;Schulte|Johannes H|JH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(21)00536-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "22(12)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": null,
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1764-1776",
"pmc": null,
"pmid": "34780709",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study.",
"title_normalized": "ceritinib in paediatric patients with anaplastic lymphoma kinase positive malignancies an open label multicentre phase 1 dose escalation and dose expansion study"
} | [
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"companynumb": "DE-002147023-PHHO2015DE013727",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nKEYNOTE-063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second-line therapy in Asian patients with advanced programmed death ligand 1 (PD-L1)-positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer.\n\n\nMETHODS\nThis randomized, open-label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m2 of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression-free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety.\n\n\nRESULTS\nBetween February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE-061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4-10 months) with pembrolizumab versus 8 months (95% CI, 5-11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63-1.54). Median PFS was 2 months (95% CI, 1-3 months) with pembrolizumab versus 4 months (95% CI, 3-6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04-2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any-grade treatment-related adverse events occurred in 28 pembrolizumab-treated patients (60%) and 42 paclitaxel-treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively.\n\n\nCONCLUSIONS\nDefinitive conclusions about the efficacy of second-line pembrolizumab in Asian patients with advanced PD-L1-positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE-061 trial.",
"affiliations": "Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.;Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.;Hospital of Anhui Medical University, Hefei, China.;Harbin Medical University Cancer Hospital, Harbin, China.;Clinical Oncology Unit, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia.;St. Vincent's Hospital, The Catholic University of Korea, Gyeonggi-Do, South Korea.;National Cancer Center, Goyang-si, South Korea.;Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.;The People's Liberation Army General Hospital, Beijing, China.;CHA Bundang Medical Center, Seongnam, South Korea.;China Medical University Hospital and China Medical University, Taichung, Taiwan.;Xiangya Hospital, Central South University, Changsha, China.;Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.;Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Hospital of Anhui Medical University, Hefei, China.;MSD China, Shanghai, China.;MSD China, Beijing, China.;Merck & Co., Inc., Kenilworth, New Jersey.;People's Liberation Army Cancer Centre of Nanjing Bayi Hospital, Nanjing, China.",
"authors": "Chung|Hyun Cheol|HC|https://orcid.org/0000-0002-0920-9471;Kang|Yoon-Koo|YK|;Chen|Zhendong|Z|;Bai|Yuxian|Y|;Wan Ishak|Wan Zamaniah|WZ|;Shim|Byoung Yong|BY|;Park|Young Lee|YL|;Koo|Dong-Hoe|DH|;Lu|Jianwei|J|;Xu|Jianming|J|;Chon|Hong Jae|HJ|;Bai|Li-Yuan|LY|;Zeng|Shan|S|;Yuan|Ying|Y|;Chen|Yen-Yang|YY|;Gu|Kangsheng|K|;Zhong|Wen Yan|WY|;Kuang|Shu|S|;Shih|Chie-Schin|CS|;Qin|Shu-Kui|SK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.34019",
"fulltext": "\n==== Front\nCancer\nCancer\n10.1002/(ISSN)1097-0142\nCNCR\nCancer\n0008-543X\n1097-0142\nJohn Wiley and Sons Inc. Hoboken\n\n34878659\n10.1002/cncr.34019\nCNCR34019\nOriginal Article\nOriginal Articles\nDiscipline\nClinical Trials\nPembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE‐063): A randomized, open‐label, phase 3 trial in Asian patients\nPembrolizumab for Gastric/GEJ Cancer in Asia\nChung et al\nChung Hyun Cheol MD, PhD https://orcid.org/0000-0002-0920-9471\n1 unchung8@yuhs.ac\n\nKang Yoon‐Koo MD, PhD 2\nChen Zhendong MD 3\nBai Yuxian MD 4\nWan Ishak Wan Zamaniah MD 5\nShim Byoung Yong MD 6\nPark Young Lee MD 7\nKoo Dong‐Hoe MD, PhD 8\nLu Jianwei MD 9\nXu Jianming MD 10\nChon Hong Jae MD 11\nBai Li‐Yuan MD 12\nZeng Shan MD 13\nYuan Ying MD 14\nChen Yen‐Yang MD 15\nGu Kangsheng MD 3\nZhong Wen Yan PhD 16\nKuang Shu MD 17\nShih Chie‐Schin MD 18\nQin Shu‐Kui MD, PhD 19\n1 Yonsei Cancer Center Yonsei University College of Medicine Seoul South Korea\n2 Asan Medical Center University of Ulsan College of Medicine Seoul South Korea\n3 Hospital of Anhui Medical University Hefei China\n4 Harbin Medical University Cancer Hospital Harbin China\n5 Clinical Oncology Unit, Faculty of Medicine University Malaya Kuala Lumpur Malaysia\n6 St. Vincent's Hospital The Catholic University of Korea Gyeonggi‐Do South Korea\n7 National Cancer Center Goyang‐si South Korea\n8 Kangbuk Samsung Hospital Sungkyunkwan University School of Medicine Seoul South Korea\n9 Jiangsu Cancer Hospital Jiangsu Institute of Cancer Research The Affiliated Cancer Hospital of Nanjing Medical University Nanjing China\n10 The People's Liberation Army General Hospital Beijing China\n11 CHA Bundang Medical Center Seongnam South Korea\n12 China Medical University Hospital and China Medical University Taichung Taiwan\n13 Xiangya Hospital Central South University Changsha China\n14 Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang China\n15 Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung Taiwan\n16 MSD China Shanghai China\n17 MSD China Beijing China\n18 Merck & Co., Inc. Kenilworth New Jersey\n19 People's Liberation Army Cancer Centre of Nanjing Bayi Hospital Nanjing China\n* Corresponding Author: Hyun Cheol Chung, MD, PhD, Yonsei Cancer Center, Yonsei University College of Medicine, 50‐1 Yonsei‐RO, Seoul, 3722 South Korea (unchung8@yuhs.ac).\n\n08 12 2021\n01 3 2022\n128 5 10.1002/cncr.v128.5 9951003\n23 8 2021\n12 5 2021\n24 8 2021\n© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nBackground\n\nKEYNOTE‐063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second‐line therapy in Asian patients with advanced programmed death ligand 1 (PD‐L1)–positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer.\n\nMethods\n\nThis randomized, open‐label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m2 of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression‐free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety.\n\nResults\n\nBetween February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE‐061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4‐10 months) with pembrolizumab versus 8 months (95% CI, 5‐11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63‐1.54). Median PFS was 2 months (95% CI, 1‐3 months) with pembrolizumab versus 4 months (95% CI, 3‐6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04‐2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any‐grade treatment‐related adverse events occurred in 28 pembrolizumab‐treated patients (60%) and 42 paclitaxel‐treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively.\n\nConclusions\n\nDefinitive conclusions about the efficacy of second‐line pembrolizumab in Asian patients with advanced PD‐L1–positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE‐061 trial.\n\nIn this small sample of Asian patients with advanced PD‐L1–positive (combined positive score [CPS] ≥1) gastric/gastroesophageal junction (GEJ) cancer enrolled in the randomized, open‐label, phase 3 KEYNOTE‐063 study, definitive conclusions on clinical outcomes are limited; however, second‐line pembrolizumab monotherapy seems to be well tolerated in this patient population. These findings are consistent with those of the larger global KEYNOTE‐061 study in patients with CPS ≥1 gastric/GEJ cancer.\n\nAsia\nchemotherapy\ngastric cancer\ngastroesophageal junction cancer\npembrolizumab\nprogrammed death 1\nMerck Sharp and Dohme Corp 10.13039/100009947 Merck & Co., Inc. 10.13039/100009947 source-schema-version-number2.0\ncover-dateMarch 1, 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:20.07.2022\nWe thank the patients and their families and caregivers as well as all primary investigators and site personnel for participating in the study.\n\nMedical writing and/or editorial assistance was provided by Kathleen Richards, PhD, and Holly C. Cappelli, PhD, CMPP, of ApotheCom (Yardley, Pennsylvania). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey.\n\nThis trial is registered at ClinicalTrials.gov (NCT03019588).\n==== Body\npmcIntroduction\n\nGastric cancer, including gastroesophageal junction (GEJ) cancer, is the fifth most commonly diagnosed cancer worldwide, accounting for >1 million new cases and ~800,000 deaths in 2018. 1 However, incidence and mortality vary geographically. Compared with other regions of the world, Eastern Asia has the highest incidence of gastric cancer. 1 , 2 Specifically, the age‐standardized incidence rate of gastric cancer per 100,000 people in East Asia is 32.1 for men and 13.2 for women, nearly twice the rate observed in the second highest region, East Europe (17.1 and 7.5, respectively). 1 South Korea has the highest incidence of gastric cancer in East Asia, with age‐standardized incidence rates of 57.8 and 23.5 in men and women, respectively, followed by Mongolia (47.2 and 21.7), Japan (40.7 and 16.0), and China (29.5 and 12.3). 2 The higher incidence of gastric cancer in East Asia may be attributable to the increased Helicobacter pylori infection rate, interleukin (IL) gene polymorphisms (IL‐17 and IL‐10), and diets rich in salt and pickled foods. 2\n\nStandard first‐line treatment recommendations for unresectable locally advanced recurrent or metastatic gastric cancer include fluoropyrimidine plus a platinum agent (recommended by the Chinese Society of Clinical Oncology, 3 the National Comprehensive Cancer Network, 4 and the Korean Gastric Cancer Association 5 ) and S‐1 (tegafur, 5‐chloro‐2,4‐dihydroxypyridine, and potassium oxonate) or capecitabine in combination with cisplatin, as indicated by the Japanese Gastric Cancer Association. 6 Recently reported data in the first‐line setting have demonstrated the efficacy and safety of the anti–programmed death 1 (PD‐1) monoclonal antibody nivolumab in combination with chemotherapy versus chemotherapy alone. Data from the global CheckMate‐649 study reported superior overall survival (OS) and progression‐free survival (PFS) in patients with advanced gastric cancer/GEJ cancer/esophageal adenocarcinoma with manageable safety; 7 a survival advantage with nivolumab plus chemotherapy versus chemotherapy alone was observed in 606 patients with a programmed death ligand 1 (PD‐L1) combined positive score (CPS) ≥5 (median OS, 14.4 vs 11.1 months; hazard ratio [HR], 0.70) but not in 955 patients with CPS <5 (median OS, 12.4 vs 12.3 months; HR, 0.94). Data from the Asian ATTRACTION‐4 study showed improvement with nivolumab plus chemotherapy versus chemotherapy in PFS (median, 10.5 vs 8.3 months; HR, 0.68; [98.5% CI, 0.51‐0.90]) and objective response rate (ORR) (57.5% vs 47.8%), but not in OS (median, 17.5 vs 17.2 months; HR, 0.90; 95% CI, 0.75‐1.08), in patients with human epidermal growth factor receptor 2 (HER2)–negative advanced or recurrent gastric/GEJ cancer. 8 Although second‐ and third‐line chemotherapies are commonly administered to patients with advanced or metastatic gastric cancer in Asia (up to 85% and 69% of patients, respectively), 9 , 10 , 11 , 12 , 13 treatment options are limited, and patients are encouraged to participate in clinical studies. 3 , 4\n\nVariations in geographic location have also been observed in survival rates of patients with advanced gastric cancer. OS is typically longer among Asian than non‐Asian patients. 9 , 14 , 15 , 16 For example, the 5‐year OS rate was 41% among Asian patients compared with 30% among Caucasian patients. 15 Differences in tumor burden and location and use of postprogression chemotherapy have been suggested as underpinning ethnic differences in survival rates, 9 , 16 although data are conflicting. 15\n\nPembrolizumab, another anti–PD‐1 monoclonal antibody, has demonstrated antitumor activity with a manageable safety profile in patients with gastric/GEJ cancer. 17 Based on the results of the phase 2 KEYNOTE‐059 study, pembrolizumab was approved in the United States for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD‐L1 (CPS ≥1) who experience disease progression on or after ≥2 previous lines of therapy, including fluoropyrimidine‐ and platinum‐containing chemotherapy and, if appropriate, HER2/neu‐targeted therapy. 18 However, in July 2021, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, voluntarily withdrew pembrolizumab in this treatment setting with a 6‐month delay, consistent with the recommendation from the Food and Drug Administration Oncologic Drugs Advisory Committee to ensure access to pembrolizumab for current patients who may not have received immunotherapy in earlier lines. 19 Pembrolizumab is also approved in the United States for patients with unresectable or metastatic microsatellite instability–high or mismatch repair–deficient solid tumors or tumor mutational burden‐high (≥10 mut/Mb) solid tumors who experience disease progression after previous treatment and who have no satisfactory alternative treatment options. 18\n\nThe efficacy of pembrolizumab versus paclitaxel in advanced PD‐L1–positive gastric/GEJ cancer that progressed after first‐line treatment was further investigated in the KEYNOTE‐061 and KEYNOTE‐063 phase 3 studies. 20 In KEYNOTE‐061, in which 26% of enrolled patients were Asian (from Hong Kong, Israel, Japan, Malaysia, Russia, Singapore, South Korea, Taiwan, and Turkey), pembrolizumab did not significantly improve OS compared with paclitaxel. 20 After 2 years of follow‐up, median OS was longer with pembrolizumab monotherapy (9.1 months) than with paclitaxel monotherapy (8.3 months) in patients with CPS ≥1 tumors (HR, 0.82; 95% CI, 0.66‐1.03; 1‐sided P = 0.0421). 20 In a long‐term follow‐up analysis after 4 years of follow‐up, the OS benefit achieved with pembrolizumab was greater with increasing tumor PD‐L1 expression (HR, 0.81 [CPS ≥1]; 0.72, [CPS ≥5]; 0.69 [CPS ≥10]); similar trends were observed for ORR and duration of response (DOR). 21 The safety profile of pembrolizumab continued to be favorable, with fewer treatment‐related adverse (AEs) reported in patients receiving pembrolizumab (53%) than paclitaxel (84%). 21 An exploratory analysis from this study also demonstrated a strong association between tissue tumor mutational burden and clinical efficacy with second‐line pembrolizumab using whole exome sequencing or the FoundationOne®CDx (Foundation Medicine). 22 , 23 One potential limitation of KEYNOTE‐061 was that the comparison arm received paclitaxel alone when paclitaxel plus ramucirumab had shown superior OS compared with paclitaxel, although these data were not available at the initiation of the study; paclitaxel plus ramucirumab is now one of many standard‐of‐care second‐line therapies available for Asian patients with advanced gastric cancer whose disease has progressed on first‐line chemotherapy. 13\n\nHere, we present results of the phase 3 KEYNOTE‐063 study of pembrolizumab versus paclitaxel as second‐line therapy in Asian patients with advanced PD‐L1–positive (CPS ≥1) gastric/GEJ cancer.\n\nMaterials and Methods\n\nStudy Design and Patients\n\nKEYNOTE‐063 was a randomized, open‐label, phase 3 study conducted at 36 medical centers across 4 countries in Asia (China, Malaysia, South Korea, and Taiwan). Eligible patients were men and women aged ≥18 years with histologically or cytologically confirmed diagnoses of locally advanced unresectable or metastatic PD‐L1–positive (CPS ≥1) gastric or GEJ adenocarcinoma. Patients must also have had Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)–measurable disease, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, documented disease progression during or after first‐line therapy containing any platinum/fluoropyrimidine doublet chemotherapy, and a tumor sample for PD‐L1 assessment. Patients with HER2‐negative tumors were eligible; those with HER2‐positive tumors had to have documentation of disease progression on treatment containing trastuzumab, and those with unknown tumor status had to have their HER2 status determined locally.\n\nThe study protocol and all amendments were approved by the institutional review board or ethics committee at each institution. The study was conducted in accordance with the protocol and its amendments, the Declaration of Helsinki, the International Conference on Harmonisation Guidelines for Good Clinical Practice, and local and national regulations. All patients provided written informed consent.\n\nRandomization\n\nPatients were randomly assigned 1:1 to receive 200 mg of pembrolizumab intravenously every 3 weeks or 80 mg/m2 of paclitaxel intravenously on days 1, 8, and 15 of each 4‐week cycle. Patients were stratified by time to progression on first‐line therapy (<6 vs ≥6 months) and ECOG PS (0 vs 1). Treatment continued for 35 cycles (~2 years; pembrolizumab only) or until disease progression, intolerable toxicity, investigator decision, or patient withdrawal of consent.\n\nProcedures\n\nTumor response was assessed every 6 weeks according to RECIST v1.1 by blinded central radiology review. AEs were evaluated throughout treatment and for 30 days after treatment discontinuation (90 days for serious AEs) and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. PD‐L1 expression was centrally assessed during screening using PD‐L1 IHC 22C3 pharmDx (Agilent). PD‐L1 expression was reported as CPS, defined as the number of PD‐L1–staining cells (tumor cells, macrophages, and lymphocytes) divided by the total number of viable tumor cells, multiplied by 100. PD‐L1–positive tumors were defined as CPS ≥1.\n\nOutcomes\n\nDual primary end points were OS, defined as time from randomization to death from any cause, and PFS per RECIST v1.1, defined as time from randomization to the first documented disease progression or death from any cause, whichever occurred first. Secondary end points were ORR per RECIST v1.1, defined as the proportion of patients who experienced complete or partial response, and safety and tolerability. DOR per RECIST v1.1, defined as the time from first documented complete or partial response to disease progression or death from any cause, was investigated as an exploratory end point.\n\nStatistical Analysis\n\nEfficacy was assessed in the intention‐to‐treat (ITT) population, which comprised all patients who were randomly assigned to treatment. OS, PFS, and DOR were analyzed using Kaplan‐Meier estimates; a stratified Cox proportional hazards model with the Efron method for handling ties was used to estimate HRs and associated 95% CIs. ORR was analyzed using the stratified Miettinen and Nurminen method to detect between‐group differences. Safety was assessed in the as‐treated population, which comprised all patients who received ≥1 dose of study treatment.\n\nThis study planned to enroll 360 patients; the timing of the final analysis was event driven. After 290 OS events had been observed, the study was expected to have ~91% power to demonstrate the superiority of pembrolizumab compared with paclitaxel in this setting at a 1‐sided α of 0.0215 if the underlying HR for OS was 0.67. However, because of early termination of the study, statistical power is lacking for the current analysis, which used a database cutoff date of October 8, 2019. This trial is registered with ClinicalTrials.gov (NCT03019588).\n\nResults\n\nAfter the KEYNOTE‐063 study began, results of the global KEYNOTE‐061 study (NCT02370498) showed that pembrolizumab did not significantly prolong OS compared with paclitaxel in patients previously treated for advanced gastric cancer. 20 As a result, screening and enrollment was terminated for the KEYNOTE‐063 study on March 12, 2018. The study ended on June 21, 2021, after the last patient's last visit.\n\nBetween February 6, 2017, and March 12, 2018, 94 patients had been randomly assigned to pembrolizumab (n = 47) or paclitaxel (n = 47) (Fig. 1). As of October 8, 2019, the median time from randomization to data cutoff was 24 months (range, 19‐31). One of 47 patients (2%) in the pembrolizumab group completed all 35 cycles of treatment. No patients remained on paclitaxel, whereas 2 patients (4%) in the pembrolizumab group remained on pembrolizumab. Most patients discontinued treatment because of progressive disease (n = 64; 70%) (Fig. 1). Overall, 50 patients (53%) went on to receive third‐line therapy.\n\nFigure 1 Patient disposition.\n\naIntended enrollment for KEYNOTE‐063 was 360 but was halted at 94 because pembrolizumab did not significantly prolong overall survival over paclitaxel in the KEYNOTE‐061 study (NCT02370498). 18\n\nbThere was no maximum number of doses of paclitaxel. ITT indicates intention‐to‐treat.\n\nBaseline demographics and disease characteristics were generally well balanced between treatment groups (Table 1). Median age was 61 years in both treatment groups, and most patients were men (73%) and had ECOG PS 1 (72%). Most patients were enrolled at centers in China (n = 44; 47%) and South Korea (n = 38; 40%). Overall, 60 patients (64%) experienced disease progression within 6 months of treatment with first‐line therapy.\n\nTABLE 1 Baseline Characteristics\n\nCharacteristic, No. (%)\tPembrolizumab (n = 47)\tPaclitaxel (n = 47)\t\nAge, median (range), y\t61 (32‐75)\t61 (37‐91)\t\nMale\t32 (68)\t37 (79)\t\nECOG PS\t\t\t\n0\t14 (30)\t12 (26)\t\n1\t33 (70)\t35 (74)\t\nCountry\t\t\t\nChina\t23 (49)\t21 (45)\t\nMalaysia\t2 (4)\t2 (4)\t\nSouth Korea\t20 (43)\t18 (38)\t\nTaiwan\t2 (4)\t6 (13)\t\nTTP on first‐line therapy\t\t\t\n≥6 months\t17 (36)\t17 (36)\t\n<6 months\t30 (64)\t30 (64)\t\nPrimary location at diagnosis\t\t\t\nGEJ\t6 (13)\t3 (6)\t\nStomach\t41 (87)\t44 (94)\t\nMetastatic disease\t47 (100)\t46 (98)\t\nNumber of metastatic sites\t\t\t\n0‐2 sites\t23 (49)\t23 (49)\t\n≥3 sites\t24 (51)\t24 (51)\t\nPrevious surgery for gastric cancer\t24 (51)\t22 (47)\t\nGastric ulceration\t\t\t\nYes\t8 (17)\t11 (23)\t\nNo\t26 (55)\t18 (38)\t\nUnknown\t13 (28)\t18 (38)\t\nHistology\t\t\t\nAdenocarcinoma\t46 (98)\t46 (98)\t\nMucinous carcinoma\t1 (2)\t1 (2)\t\nAbbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; GEJ, gastroesophageal junction; TTP, time to progression.\n\nJohn Wiley & Sons, Ltd\n\nTwenty‐four of 47 patients (51%) in the pembrolizumab group and 26 of 47 patients (55%) in the paclitaxel group received subsequent therapy; 2 of 47 patients (4%) and 7 of 47 patients (15%), respectively, received subsequent immunotherapy.\n\nAt the time of data cutoff, 83 patients had died (41 of 47 patients [87%] in the pembrolizumab group and 42 of 47 patients [89%] in the paclitaxel group). Median OS was 8 months (95% CI, 4‐10) in the pembrolizumab group and 8 months (95% CI, 5‐11) in the paclitaxel group (HR, 0.99; 95% CI, 0.63‐1.54) (Fig. 2). Eighty‐eight patients experienced disease progression or died (45 of 47 patients [96%] in the pembrolizumab group and 43 of 47 patients [92%] in the paclitaxel group). Median PFS was 2 months (95% CI, 1‐3) in the pembrolizumab group and 4 months (95% CI, 3‐6) in the paclitaxel group (HR, 1.62; 95% CI, 1.04‐2.52) (Fig. 3).\n\nFigure 2 Kaplan‐Meier estimates of overall survival.\n\nFigure 3 Kaplan‐Meier estimates of progression‐free survival.\n\nConfirmed responses were observed in 6 of 47 patients in the pembrolizumab group (ORR, 13%) and 9 of 47 patients in the paclitaxel group (ORR, 19%); complete response was observed in 2 of 47 patients (4%) in the pembrolizumab group and 3 of 47 patients (6%) in the paclitaxel group (Table 2). Median DOR was 8 months (range, 3‐20+) in the pembrolizumab group and 12 months (range, 2‐17+) in the paclitaxel group (Fig. 4; Table 2). Notably, 4 patients in each treatment group had responses lasting ≥6 months. Response duration with paclitaxel by patient, including country of enrollment, is shown in Supporting Table 1.\n\nTABLE 2 Summary of BICR‐Confirmed Responses\n\nResponse, No. (%)\tPembrolizumab (n = 47)\tPaclitaxel (n = 47)\t\nObjective response\t6 (13)\t9 (19)\t\nComplete response\t2 (4)\t3 (6)\t\nPartial response\t4 (9)\t6 (13)\t\nStable disease a\t10 (21)\t15 (32)\t\nDisease control rate b\t16 (34)\t24 (51)\t\nProgressive disease\t25 (53)\t12 (26)\t\nNot available c\t6 (13)\t11 (23)\t\nTime to response, median (range), mo\t3 (1‐3)\t1 (1‐4)\t\nDuration of response, median (range), mo d\t8 (3‐20+)\t12 (2‐17+)\t\nAbbreviation: BICR, blinded independent central review.\n\na Included patients with stable disease and patients with noncomplete response/nonprogressive disease.\n\nb Disease control rate defined as proportion of patients with complete response, partial response, or stable disease.\n\nc Patients with no postbaseline assessment available for response evaluation or patients who were not evaluable.\n\nd “+” indicates there was no progressive disease at the time of last disease assessment.\n\nJohn Wiley & Sons, Ltd\n\nFigure 4 Kaplan‐Meier estimates of duration of response.\n\nAEs attributed by the investigator to study treatment (treatment‐related AEs) occurred in 28 of 47 pembrolizumab‐treated patients (60%) and 42 of 44 paclitaxel‐treated patients (96%) (Table 3). Grades 3 to 5 treatment‐related AEs occurred in 5 of 47 pembrolizumab‐treated patients (11%) and 28 of 44 paclitaxel‐treated patients (64%). The most common any‐grade treatment‐related AEs (incidence >10%) were fatigue (13%) and hypothyroidism (11%) in the pembrolizumab group and alopecia (48%), decreased neutrophil count (39%), decreased white blood cell count (30%), decreased appetite (25%), anemia (18%), asthenia (14%), neutropenia (14%), fatigue (11%), nausea (11%), increased aspartate aminotransferase (11%), and peripheral neuropathy (11%) in the paclitaxel group (Table 3). Treatment‐related AEs led to discontinuation in 1 of 47 pembrolizumab‐treated patients (2%) (pneumonitis) and 6 of 44 paclitaxel‐treated patients (14%) (2 cases each of herpes zoster and pneumonia, 1 case each of asthenia and peripheral sensory neuropathy). No pembrolizumab‐treated patients (0%) but 2 of 44 paclitaxel‐treated patients (5%) had a treatment‐related AE (treatment‐related pneumonia in each) that resulted in death.\n\nTABLE 3 Adverse Event Summary\n\nAE, No. (%)\tPembrolizumab (n = 47)\tPaclitaxel (n = 44)\t\nAny\t46 (98)\t43 (98)\t\nTreatment‐related AE\t28 (60)\t42 (96)\t\nGrades 3‐5\t5 (11)\t28 (64)\t\nLed to discontinuation\t1 (2)\t6 (14)\t\nLed to death a\t0\t2 (5)\t\nTreatment‐related AEs occurring in ≥10% of patients in either group\t\t\t\nFatigue\t6 (13)\t5 (11)\t\nHypothyroidism\t5 (11)\t0\t\nNausea\t2 (4)\t5 (11)\t\nAlopecia\t1 (2)\t21 (48)\t\nAnemia\t1 (2)\t8 (18)\t\nDecreased appetite\t1 (2)\t11 (25)\t\nNeutrophil count decreased\t1 (2)\t17 (39)\t\nWhite blood cell count decreased\t1 (2)\t13 (30)\t\nAspartate aminotransferase increased\t0\t5 (11)\t\nAsthenia\t0\t6 (14)\t\nPeripheral neuropathy\t0\t5 (11)\t\nNeutropenia\t0\t6 (14)\t\nAbbreviation: AE, adverse event.\n\na Two paclitaxel‐treated patients died of treatment‐related pneumonia.\n\nJohn Wiley & Sons, Ltd\n\nImmune‐mediated AEs and infusion reactions occurred in 9 of 47 pembrolizumab‐treated patients (19%) and 5 of 44 paclitaxel‐treated patients (11%). Among pembrolizumab‐treated patients, the observed immune‐mediated AEs were hypothyroidism (n = 5; 11%), hyperthyroidism (n = 3; 6%), and adrenal insufficiency, drug hypersensitivity, pneumonitis, and thyroiditis (n = 1 each; 2%).\n\nDiscussion\n\nThere is an unmet need for second‐line treatment options in Asian patients with advanced or metastatic PD‐L1–positive gastric/GEJ cancer. Second‐line immunotherapy studies in Asian patients with gastric/GEJ cancer are limited, but recent data suggest immunotherapy may provide survival benefits for patients with advanced or metastatic gastric cancer compared with best supportive care. 12 Given that pembrolizumab did not significantly prolong OS compared with paclitaxel in patients participating in the global phase 3 KEYNOTE‐061 study; 20 however, KEYNOTE‐063 enrollment was discontinued after 94 patients. Consequently, the current analysis from KEYNOTE‐063 was underpowered for the planned comparison between treatment groups, limiting interpretation of the outcomes, but it can provide important insights into this patient population.\n\nIn general, baseline characteristics were consistent between Asian patients with PD‐L1 CPS ≥1 in the current study and in the global population of KEYNOTE‐061 with PD‐L1 CPS ≥1 (Supporting Table 2). However, Asian patients in the current study had marginally worse functional status than the global KEYNOTE‐061 population (72% vs 54%, respectively, had ECOG PS 1) and higher rates of stomach as the primary location at diagnosis (90% vs 66%), adenocarcinoma histology (98% vs 80%), and previous surgery for gastric cancer (49% vs 35%), which might have influenced treatment outcomes (Supporting Table 2). 19\n\nIn the limited KEYNOTE‐063 patient population, pembrolizumab did not numerically improve clinical outcomes compared with paclitaxel in Asian patients with advanced PD‐L1–positive gastric cancer. Although cross‐study comparisons should be interpreted with caution, efficacy and safety findings were consistent with the larger global KEYNOTE‐061 study in patients with PD‐L1 CPS ≥1 (Supporting Table 3). 20 Interestingly, DOR in pembrolizumab‐treated patients was relatively shorter in KEYNOTE‐063 than in KEYNOTE‐061 (median, 8 vs 18 months) but increased in paclitaxel‐treated patients (median, 12 vs 5 months, respectively). 20\n\nIn the phase 3 RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric/GEJ adenocarcinoma, the median OS with paclitaxel in patients enrolled in Japan, South Korea, Hong Kong, Singapore, and Taiwan was better than in other regions (11 vs 6 months). 13 Similarly, the Asian subgroup analysis for OS from KEYNOTE‐061 demonstrated an HR for death of 0.90 (95% CI, 0.59‐1.38) compared with other regions (HR, 0.81; 95% CI, 0.61‐1.06), indicating better performance with paclitaxel in Asian patients. 20 Taken together, when planning a treatment strategy for Asian patients with advanced gastric cancer, continuum of care should be taken into account, with appropriate timing of immunotherapy and safe and effective use of cytotoxic chemotherapy.\n\nIn KEYNOTE‐063, pembrolizumab was well tolerated and led to comparatively fewer treatment‐related AEs than paclitaxel. The safety profiles of both treatment groups were consistent with what has been reported in the literature, and no new safety concerns were observed.\n\nThis study is limited by its early termination, which resulted in a smaller than planned sample size of Asian patients with advanced PD‐L1–positive gastric/GEJ cancer; hence, definitive conclusions cannot be drawn. Additionally, microsatellite instability status was not tested. Further studies are needed to establish which patients are most likely to benefit from pembrolizumab immunotherapy. Another limitation is that the comparison arm received paclitaxel alone when paclitaxel plus ramucirumab is currently one of the standard‐of‐care therapies available for patients with advanced gastric cancer whose disease progressed on chemotherapy; this therapy option was not available at the initiation of KEYNOTE‐063.\n\nIn Asian patients with advanced PD‐L1–positive gastric/GEJ cancer, efficacy data should be viewed with caution and definitive conclusions are limited; however, second‐line pembrolizumab monotherapy was well tolerated in this patient population. As immune checkpoint inhibitors are increasingly becoming part of the first‐line treatment in combination with chemotherapy in advanced gastric/GEJ cancer, further evaluation of their role in second‐line treatment is needed.\n\nFunding Support\n\nFunding for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey.\n\nConflict of Interest Disclosures\n\nHyun Cheol Chung reports grants (for research to institution) from Amgen, Bristol‐Myers Squibb/Ono, Eli Lilly, GSK, Incyte, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, Merck‐Serono, Taiho, and Zymework; honoraria from Eli Lilly and Merck‐Serono; and consultancy fees from Amgen, BeiGene, Bristol‐Myers Squibb, Celltrion, Eli Lilly, Gloria, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, Merck‐Serono, Quintiles, Taiho, and Zymeworks. Yoon‐Koo Kang reports advisory fees from ALX Oncology, Amgen, Bristol‐Myers Squibb, Daehwa, Macrogenics, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, Novartis, Surface Oncology, and Zymeworks. Wan Zamaniah Wan Ishak reports honoraria for lectures from Amgen Malaysia, DKSH Malaysia, Eisai Malaysia, Eli Lilly Malaysia, Ipsen Malaysia, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, Merck Serono Malaysia, Pfizer Malaysia, and Roche Malaysia; travel grants from Amgen Malaysia, Celgene Malaysia, Eisai Malaysia, Eli Lilly Malaysia, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, and Roche Malaysia; and is an advisory board member for Celgene Malaysia, Eli Lilly Malaysia, Eisai Malaysia, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey. Wen Yan Zhong is an employee of MSD China, Beijing, China. Shu Kuang is an employee of MSD China, Beijing, China. Chie‐Schin Shih is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey and a stockholder of Merck & Co., Inc., Kenilworth, New Jersey.\n\nAuthor Contributions\n\nHyun Cheol Chung: Data acquisition, data analysis, interpretation of the results, drafting of the manuscript, and critically reviewing or revising the manuscript for important intellectual content. Yoon‐Koo Kang: Data acquisition, interpretation of the results, and critically reviewing or revising the manuscript for important intellectual content. Zhendong Chen: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Yuxian Bai: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Wan Zamaniah Wan Ishak: Data acquisition, drafting of the manuscript, and critically reviewing or revising the manuscript for important intellectual content. Byoung Yong Shim: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Young Lee Park: Data acquisition, interpretation of the results, and critically reviewing or revising the manuscript for important intellectual content. Dong‐Hoe Koo: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Jianwei Lu: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Jianming Xu: Data acquisition, data analysis, interpretation of the results, and critically reviewing or revising the manuscript for important intellectual content. Li‐Yuan Bai: Data acquisition, interpretation of the results, and critically reviewing or revising the manuscript for important intellectual content. Shan Zeng: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Ying Yuan: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Yen‐Yang Chen: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Kangsheng Gu: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Chie‐Schin Shih: Data acquisition, data analysis, interpretation of the results, drafting of the manuscript, and critically reviewing or revising the manuscript for important intellectual content. Shu‐Kui Qin: Data acquisition and critically reviewing or revising the manuscript for important intellectual content. Wen Yan Zhong: Analysis of the data and critically reviewing or revising the manuscript for important intellectual content. Hong Jae Chon: Interpretation of the results and critically reviewing or revising the manuscript for important intellectual content. Shu Kuang: Interpretation of the results and critically reviewing or revising the manuscript for important intellectual content. All coauthors have given final approval to the manuscript.\n\nSupporting information\n\nTable S1‐S3\n\nClick here for additional data file.\n\nData Availability\n\nMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey (MSD), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data‐sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the United States and Europe or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region‐specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis‐driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data‐sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.\n==== Refs\nReferences\n\n1 Bray F , Ferlay J , Soerjomataram I , et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68 :394‐424.30207593\n2 Rawla P , Barsouk A . Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol. 2019;14 :26‐38.30944675\n3 Wang FH , Shen L , Li J , et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer. Cancer Commun. 2019;39 :10.\n4 National Comprehensive Cancer Network . NCCN clinical practice guidelines in oncology (NCCN guidelines): Gastric cancer (version 4.2020). Published December 23, 2020. Accessed April 23, 2021. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf\n5 Guideline Committee of the Korean Gastric Cancer Association (KGCA), Development Working Group & Review Panel . Korean Practice Guideline for Gastric Cancer 2018: an evidence‐based, multi‐disciplinary approach. J Gastric Cancer. 2019;19 :1‐48.30944757\n6 Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer. 2021;24 :1‐21.32060757\n7 Janjigian YY , Shitara K , Moehler M , et al. First‐line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro‐esophageal junction, and esophageal adenocarcinoma (CheckMate 649): a randomized, open‐label, phase 3 trial. Lancet. 2021;398 :27‐40.34102137\n8 Boku N , Ryu MH , Oh DY , et al. Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION‐4 (ONO‐4538‐37) study [abstract]. Ann Oncol. 2020;31 :S1192.\n9 Takashima A , Iizumi S , Boku N . Survival after failure of first‐line chemotherapy in advanced gastric cancer patients: differences between Japan and the rest of the world. Jpn J Clin Oncol. 2017;47 :583‐589.28398526\n10 Carter GC , Kaltenboeck A , Ivanova J , et al. Real‐world treatment patterns among patients with advanced gastric cancer in South Korea. Cancer Res Treat. 2017;49 :578‐587.27618820\n11 Choi IS , Choi M , Lee JH , et al. Treatment patterns and outcomes in patients with metastatic gastric cancer receiving third‐line chemotherapy: a population‐based outcomes study. PLoS One. 2018;13 :e0198544.29879177\n12 Smyth EC , Moehler M . Late‐line treatment in metastatic gastric cancer: today and tomorrow. Ther Adv Med Oncol. 2019;11 :1758835919867522.31489035\n13 Wilke H , Muro K , Van Cutsem E , et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro‐esophageal junction adenocarcinoma (RAINBOW): a double‐blind, randomized phase 3 trial. Lancet Oncol. 2014;15 :1224‐1235.25240821\n14 Gill S , Shah A , Le N , et al. Asian ethnicity‐related differences in gastric cancer presentation and outcome among patients treated at a Canadian cancer center. J Clin Oncol. 2003;21 :2070‐2076.12775731\n15 Jin H , Pinheiro PS , Callahan KE , et al. Examining the gastric cancer survival gap between Asians and Whites in the United States. Gastric Cancer. 2017;20 :573‐582.27866287\n16 Sawaki A , Yamada Y , Yamaguchi K , et al. Regional differences in advanced gastric cancer: exploratory analyses of the AVAGAST placebo arm. Gastric Cancer. 2018;21 :429‐438.29058097\n17 Fuchs CS , Doi T , Jang RW , et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE‐059 trial. JAMA Oncol. 2018;4 :e180013.29543932\n18 KEYTRUDA® (pembrolizumab) injection, for intravenous use. 10/2021. Merck Sharp & Dohme Corp.: Whitehouse Station, NJ; 2021.\n19 Merck & Co., Inc. Merck provides update on KEYTRUDA® (pembrolizumab) indication in third‐line gastric cancer in the US. Kenilworth, NJ: Merck and Co., Inc.; 2021.\n20 Shitara K , Ozguroglu M , Bang YJ , et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro‐esophageal junction cancer (KEYNOTE‐061): a randomized, open‐label, controlled, phase 3 trial. Lancet. 2018;392 :123‐133.29880231\n21 Fuchs CS , Özgüroğlu M , Bang YJ , et al. Pembrolizumab versus paclitaxel for previously treated patients with PD‐L1–positive advanced gastric or gastroesophageal junction cancer (GC): update from the phase III KEYNOTE‐061 trial [abstract]. J Clin Oncol. 2020;38 :4503.\n22 Fuchs CS , Özgüroğlu M , Bang YJ , et al. The association of molecular biomarkers with efficacy of pembrolizumab versus paclitaxel in patients with gastric cancer (GC) from KEYNOTE‐061 [abstract]. J Clin Oncol. 2020;38 :4512.\n23 Shitara K , Özgüroğlu M , Bang YJ , et al. The association of tissue tumor mutational burden (tTMB) using the Foundation Medicine genomic platform with efficacy of pembrolizumab versus paclitaxel in patients (pts) with gastric cancer (GC) from KEYNOTE‐061 [abstract]. J Clin Oncol. 2020;38 :4537.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0008-543X",
"issue": null,
"journal": "Cancer",
"keywords": "Asia; chemotherapy; gastric cancer; gastroesophageal junction cancer; pembrolizumab; programmed death 1",
"medline_ta": "Cancer",
"mesh_terms": null,
"nlm_unique_id": "0374236",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34878659",
"pubdate": "2021-12-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients.",
"title_normalized": "pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer keynote 063 a randomized open label phase 3 trial in asian patients"
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"abstract": "Although poorly understood, interstitial lung disease has been reported as a possible complication of tumor necrosis factor alpha inhibitors. We report a case of interstitial lung disease in a 64-year-old man with psoriasis 3 weeks after the initiation of infliximab treatment. The patient had received two fortnightly infusions of infliximab following a short course of methotrexate. Thoracic computed tomography showed bilateral ground glass and interstitial infiltrates, while the results of microbiology and immunologic workup were negative. Likewise, bronchoalveolar lavage detected neither typical nor atypical pathogens. Infliximab-induced interstitial lung injury was suspected and corticosteroid therapy was administered which resulted in rapid clinical and radiological improvement. This is one of the few reported cases of interstitial lung disease due to infliximab in the psoriasis population. The patient had no pre-existing lung pathology, while his previous exposure to methotrexate was minimal and was not temporally associated with the induction of interstitial lung disease.",
"affiliations": "Pulmonary Department, Evangelismos General Hospital of Athens, Ypsilanti 45-47, 10676 Athens, Greece. Electronic address: sotikaka@yahoo.com.",
"authors": "Kakavas|Sotiris|S|;Balis|Evangelos|E|;Lazarou|Vasiliki|V|;Kouvela|Marousa|M|;Tatsis|Georgios|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D003879:Dermatologic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "United States",
"delete": false,
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"issn_linking": "0147-9563",
"issue": "42(6)",
"journal": "Heart & lung : the journal of critical care",
"keywords": "Drug-induced interstitial pneumonia; Infliximab; Interstitial lung disease; Psoriasis; Tumor necrosis factor inhibitor",
"medline_ta": "Heart Lung",
"mesh_terms": "D000911:Antibodies, Monoclonal; D018893:Bronchoalveolar Lavage; D003879:Dermatologic Agents; D006801:Humans; D000069285:Infliximab; D008168:Lung; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012131:Respiratory Insufficiency; D014057:Tomography, X-Ray Computed; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0330057",
"other_id": null,
"pages": "480-2",
"pmc": null,
"pmid": "23969008",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Respiratory failure due to infliximab induced interstitial lung disease.",
"title_normalized": "respiratory failure due to infliximab induced interstitial lung disease"
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"companynumb": "PHHY2013GR133355",
"fulfillexpeditecriteria": "1",
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{
"abstract": "Hemocoagulase has been successfully used for the management of bleeding in patients undergoing surgery. Local spray of hemocoagulase during endoscopic therapy may be effective for the management of gastrointestinal bleeding. In China, intravenous infusion of hemocoagulase is given by some physicians for the treatment of gastrointestinal bleeding. However, the potential adverse events secondary to hemocoagulase, such as hypofibrinogenemia, are poorly recognized. In this paper, we reported an elderly patient with type II respiratory failure in whom hemocoagulase might induce hypofibrinogenemia and further worsen gastrointestinal bleeding. We highlighted that fibrinogen levels should be cautiously monitored in patients receiving hemocoagulase.",
"affiliations": "Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Hematology, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Transfusion, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Institute of Hematology, Catholic University, Rome, Italy.;Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Respiratory Medicine, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Pharmacology, General Hospital of Shenyang Military Area, Shenyang 110840, China.;Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China.",
"authors": "Qi|Xingshun|X|;Wang|Jigang|J|;Yu|Xiaonan|X|;De Stefano|Valerio|V|;Li|Hongyu|H|;Wu|Chunyan|C|;Zeng|Qingwei|Q|;Zhang|Yongguo|Y|;Ren|Linan|L|;Lin|Hao|H|;Deng|Jiao|J|;Guo|Xiaozhong|X|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/tgh.2017.08.08",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2415-1289",
"issue": "2()",
"journal": "Translational gastroenterology and hepatology",
"keywords": "Hemocoagulase; endoscopy; fibrinogen; gastrointestinal bleeding; transfusion",
"medline_ta": "Transl Gastroenterol Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101683450",
"other_id": null,
"pages": "71",
"pmc": null,
"pmid": "29034344",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "24987614;15280019;8556923;15095007;20367987;27433096;23922080;28483015;9360849;16908038;21490373;27769944;25340841;28678111;28325889;22310222;18718083;14577148;23746903;27197462;24602733;26658430;7627034;28238301;25720848;21471571;26417980",
"title": "Hemocoagulase might not control but worsen gastrointestinal bleeding in an elderly patient with type II respiratory failure.",
"title_normalized": "hemocoagulase might not control but worsen gastrointestinal bleeding in an elderly patient with type ii respiratory failure"
} | [
{
"companynumb": "CN-BAYER-2017-198977",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BATROXOBIN"
},
"drugadditional": null,
... |
{
"abstract": "We analyzed 50 patients who achieved at least a very good partial response in the RV-MM-EMN-441 study. Patients received consolidation with autologous stem-cell transplantation (ASCT) or cyclophosphamide-lenalidomide-dexamethasone (CRD), followed by Lenalidomide-based maintenance. We assessed minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. By MFC analysis, 19/50 patients achieved complete response (CR) after consolidation, and 7 additional patients during maintenance. A molecular marker was identified in 25/50 patients, 4/25 achieved molecular-CR after consolidation, and 3 additional patients during maintenance. A lower MRD value by MFC was found in ASCT patients compared with CRD patients (p=0.0134). Tumor burden reduction was different in patients with high-risk vs standard-risk cytogenetics (3.4 vs 5.2, ln-MFC; 3 vs 6 ln-PCR, respectively) and in patients who relapsed vs those who did not (4 vs 5, ln-MFC; 4.4 vs 7.8 ln-PCR). MRD progression anticipated clinical relapse by a median of 9 months while biochemical relapse by a median of 4 months. MRD allows the identification of a low-risk group, independently of response, and a better characterization of the activity of treatments.",
"affiliations": "Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Division of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy.;Division of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy.;Division of Nuclear Medicine, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Azienda Ospedaliera-Universitaria di Udine, DISM Università di Udine, Udine, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.;Ematologia e Centro TMO, Ospedale Centrale Bolzano, Bozen, Italy.;AO S.Maria di Terni, SC Oncoematologia, Terni, Italy.;UOC Ematologia S.Eugenio ASL RM2 Roma, Rome, Italy.;Divisione di Ematologia, Azienda Policlinico-OVE, Università di Catania, Catania, Italy.;Department of Haematology, Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.;Scientific Direction, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.;Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.",
"authors": "Oliva|Stefania|S|;Gambella|Manuela|M|;Gilestro|Milena|M|;Muccio|Vittorio Emanuele|VE|;Gay|Francesca|F|;Drandi|Daniela|D|;Ferrero|Simone|S|;Passera|Roberto|R|;Pautasso|Chiara|C|;Bernardini|Annalisa|A|;Genuardi|Mariella|M|;Patriarca|Francesca|F|;Saraci|Elona|E|;Petrucci|Maria Teresa|MT|;Pescosta|Norbert|N|;Liberati|Anna Marina|AM|;Caravita|Tommaso|T|;Conticello|Concetta|C|;Rocci|Alberto|A|;Musto|Pellegrino|P|;Boccadoro|Mario|M|;Palumbo|Antonio|A|;Omedè|Paola|P|",
"chemical_list": "D014408:Biomarkers, Tumor; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.12641",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 277791051264110.18632/oncotarget.12641Research PaperMinimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis Oliva Stefania 1*Gambella Manuela 1*Gilestro Milena 1Muccio Vittorio Emanuele 1Gay Francesca 1Drandi Daniela 2Ferrero Simone 2Passera Roberto 3Pautasso Chiara 1Bernardini Annalisa 1Genuardi Mariella 1Patriarca Francesca 4Saraci Elona 1Petrucci Maria Teresa 5Pescosta Norbert 6Liberati Anna Marina 7Caravita Tommaso 8Conticello Concetta 9Rocci Alberto 10Musto Pellegrino 11Boccadoro Mario 1Palumbo Antonio 1Omedè Paola 11 Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospeadliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy2 Division of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy3 Division of Nuclear Medicine, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy4 Azienda Ospedaliera-Universitaria di Udine, DISM Università di Udine, Udine, Italy5 Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy6 Ematologia e Centro TMO, Ospedale Centrale Bolzano, Bozen, Italy7 AO S.Maria di Terni, SC Oncoematologia, Terni, Italy8 UOC Ematologia S.Eugenio ASL RM2 Roma, Rome, Italy9 Divisione di Ematologia, Azienda Policlinico-OVE, Università di Catania, Catania, Italy10 Department of Haematology, Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK11 Scientific Direction, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), ItalyCorrespondence to: Paola Omedè, paolaomede@yahoo.com* Both authors share first authorship of the manuscript\n\n24 1 2017 13 10 2016 8 4 5924 5935 11 6 2016 21 9 2016 Copyright: © 2017 Oliva et al.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.We analyzed 50 patients who achieved at least a very good partial response in the RV-MM-EMN-441 study. Patients received consolidation with autologous stem-cell transplantation (ASCT) or cyclophosphamide-lenalidomide-dexamethasone (CRD), followed by Lenalidomide-based maintenance. We assessed minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. By MFC analysis, 19/50 patients achieved complete response (CR) after consolidation, and 7 additional patients during maintenance. A molecular marker was identified in 25/50 patients, 4/25 achieved molecular-CR after consolidation, and 3 additional patients during maintenance. A lower MRD value by MFC was found in ASCT patients compared with CRD patients (p=0.0134). Tumor burden reduction was different in patients with high-risk vs standard-risk cytogenetics (3.4 vs 5.2, ln-MFC; 3 vs 6 ln-PCR, respectively) and in patients who relapsed vs those who did not (4 vs 5, ln-MFC; 4.4 vs 7.8 ln-PCR). MRD progression anticipated clinical relapse by a median of 9 months while biochemical relapse by a median of 4 months. MRD allows the identification of a low-risk group, independently of response, and a better characterization of the activity of treatments.\n\nmyelomaMRDASO-RQ-PCRnovel agentsflow cytometry\n==== Body\nINTRODUCTION\nMultiple Myeloma (MM) is an incurable hematological disease. Nevertheless, the availability of novel agents, incorporated into pre-transplant and post-transplant consolidation and/or maintenance strategies, strongly improved outcome and response rates [1, 2]. Several studies have demonstrated a direct correlation between depth of response to front-line therapy and prolonged survival [3–6].\n\nMoreover, newer outcome measures and the definition of specific subcategories of complete response (CR) with different degrees of stringency allow a more precise definition of response, a better comparison of efficacy between treatments, and a more accurate detection and monitoring of relapse. In this regard, the International Myeloma Working Group (IMWG) introduced stringent CR (sCR) criteria by adding the normalization of serum free-light chain and the absence of clonal plasma cells to the classical definition of CR [7]. Minimal residual disease (MRD) assessment by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) on bone marrow (BM) is a sensitive strategy to accurately measure response [8–13] and has been recently included in the IMWG criteria (immunophenotypic and molecular CR, respectively) [14]. The achievement of MRD negativity is highly predictive of outcome in MM both in transplant-eligible and -ineligible patients [14].\n\nThe aim of this study is to evaluate the role of MRD monitoring by MFC and ASO-RQ-PCR and its impact on outcome of MM patients receiving novel agents with or without autologous stem cell transplantation (ASCT), and to evaluate the role of MRD during maintenance therapy.\n\nRESULTS\nPatients characteristics and response evaluation\nThe MRD sub-study started after approximately 2 years from the start of the clinical study, therefore only 54 out of 134 patients enrolled in the main study who achieved at least a very good partial response (VGPR) after consolidation were included [15]. Baseline clinical characteristics of patients in the sub-study were comparable to those with at least a VGPR in the main study (data not shown). Four patients were excluded because they had polyclonal immunophenotype. After consolidation, 34 patients (68%) achieved a VGPR (16 received Cyclophosphamide-Lenalidomide-Dexamethasone [CRD] vs 18 ASCT); 16 (32%) a CR (9 received CRD vs 7 ASCT) (Appendix Figure 1). Median age was 57 years (IQR 54 to 61 years); 8 patients (16%) had International Staging System (ISS) stage III and 11 (22%) had high-risk cytogenetic profile [at least one chromosomal abnormalities among deletion 17p, t (4;14) and t (14;16)] (Table 1). Twenty-five patients out of 50 (50%) received ASCT and 25 (50%) received CRD consolidation. All 50 patients started maintenance: 27 (54%) with Lenalidomide and Prednisone, 23 (46%) with Lenalidomide alone.\n\nFigure 1 Observed marginal means of ln-MFC values according to consolidation regimen\nTable 1 Demographic and baseline characteristics of the MRD sub-study group\n\tMRD sub-study (n=50)\t\nAge (years)\t\t\nMedian\t57\t\nIQR\t54-61\t\nGender N (%)\t\t\nMale\t23 (46%)\t\nISS Stage N (%)\t\t\nI\t27 (54%)\t\nII\t15 (30%)\t\nIII\t8 (16%)\t\nCreatinine (mg/dL)\t\t\nMedian\t0,9\t\nIQR\t0.73-1.10\t\nMissing data N (%)\t2 (4%)\t\nLDH (U/L)\t\t\nMedian\t321\t\nIQR\t237-386\t\nMissing data N (%)\t12 (24%)\t\nHemoglobin (g/L)\t\t\nMedian\t11,8\t\nIQR\t10.60-12.43\t\nMissing data N (%)\t1 (2%)\t\nCytogenetic features N (%)\t\t\nDeletion 17p\t3 (6%)\t\nTranslocation (4;14)\t5 (10%)\t\nTranslocation (14;16)\t4 (8%)\t\nHigh-risk\t11 (22%)\t\nMissing data\t8 (16%)\t\nRandom\t\t\nCRD\t25 (50%)\t\nMel200\t25 (50%)\t\nIQR: Interquartile range, ISS: International Staging System, LDH: lactate dehydrogenase, CRD: Cyclophosphamide, Lenalidomide, Dexamethasone, Mel200: Melphalan 200 mg/m2\n\nAt data cut-off, the median duration of maintenance was 27.2 months (IQR 16-34), 5 patients discontinued maintenance due to adverse events, including 1 with a second cancer.\n\nAfter a median follow-up of 57 months from enrollment, 27 (54%) progressions and 9 (18%) deaths were recorded, with a 5-year progression-free survival (PFS) of 45% and a 5-year overall survival (OS) of 80%.\n\nMRD assessment by MFC\nIn the MFC analysis, 50 patients have been evaluated: 19 patients (38%) achieved MRD-negativity after consolidation, including 12 patients in the ASCT group and 7 in the CRD group (63% vs 37%, respectively). Patients receiving ASCT showed a lower value of residual cells (median 0.002%, range 0 – 1%) compared with patients receiving CRD (median 0.2%, range 0 – 2.9%, p=0.0134) and this was confirmed using the time series plots of the log- transformed repeated measures (5.1 vs 3.9 ln-MFC tumor burden reduction, respectively): a deeper MRD shrinkage (approximately 2 log units) was detected at consolidation in the ASCT group vs the CRD group. Subsequently, MRD values remained stable in both subgroups (Figure 1). After consolidation, 5-year PFS was 72% for MRD negative vs 30% for MRD positive patients (p=0.005) (Figure 2A). Importantly, patients who experienced clinical relapse showed different tumor burden kinetics after consolidation (4 ln-MFC tumour burden decrease) when compared with patients who did not relapse (5 ln-MFC tumour burden decrease): specifically, approximately 1.5 log units of higher tumor shrinkage were observed in patients with favorable outcome (Figure 3A); a progressive MRD increase in the following MRD time points was seen in patients who relapsed in contrast to a substantially stable disease in patients who did not relapse. In addition, unfavorable tumor kinetics was observed in patients with high-risk cytogenetic (3.4 ln-MFC reduction) vs standard-risk (5.2 ln-MFC reduction) (Appendix Figure 2A). In the PFS analysis, we observed a significant difference in patients with high-risk cytogenetics and MRD negativity after consolidation compared with patients with standard-risk cytogenetics and MRD negativity: median PFS was 24,1 months vs not reached (p=0.03), respectively.\n\nFigure 2 Progression-free survival analysis by MFC after consolidation A. and 1 year of maintenance B\nFigure 3 Observed marginal means of ln-MFC A. and ln-PCR B. values according to relapse or no relapse\nTables report the analyzed cases at each time-point for each group (relapse and no relapse)\n\nDuring maintenance 7 additional patients (14%) achieved MRD negativity: 2 in the Lenalidomide-Prednisone group and 5 in the Lenalidomide alone group. In particular, 4 upgraded their MRD response after 3 months of starting maintenance, 2 after 6 months and 1 after 24 months. Of these, 5 received ASCT consolidation. Overall among the 26 patients who were MRD negative, 8 (31%) relapsed; whereas among the 24 patients who did not obtain MRD negativity, 19 (79%) relapsed. In all patients who achieved MRD negativity, the median PFS was not reached vs 35 months in those who did not achieve MRD negativity (p=0.0004).\n\nTwenty-three out of 27 relapsing patients were accurately monitored for MRD, while 4 patients could not be evaluated due to the lack of samples. In 22/23 patients, MFC progression anticipated clinical relapse by a median of 9 months (IQR 4-17 months), while in one patient clinical extramedullary progression anticipated MFC and biochemical progression. On the other hand, in 10/23 patients, biochemical relapse or relapse from CR anticipated clinical relapse by a median of 4 months (IQR: 2-10) (Figure 4)\n\nFigure 4 Evaluation of immunophenotypic, molecular and biochemical relapse and correlation with clinical relapse\nPost cons: after consolidation, post 3M: after 3 months of maintenance, post 6M: after 6 months of maintenance, post 12M: after 12 months of maintenance, post 18M: after 18 months of maintenance, post 24M: after 24 months of maintenance, post 30M: after 30 months of maintenance, post 36 M: after 36 months of maintenance, post 42 M: after 42 months of maintenance; VGPR: very good partial response, CR: complete response, R: clinical relapse, ER: extramedullary relapse, NA: not available, IF: immunophenotypic; PTS: patients.\n\n.\n\nPFS analysis was performed at different time-points during maintenance and the 5-year PFS was 94% for MRD negative vs 33% for MRD positive patients at 12 months of maintenance (p<0.001) (Figure 2B).\n\nMRD assessment by ASO-RQ-PCR\nA specific IgH molecular marker was identified in 25 patients (50%) and they were monitored for MRD: 14 (28%) had a BM infiltration rate at diagnosis lower than 5% and 11 out of 50 (22%) did not obtain a successful sequencing, due to the elevated somatic hypermutation (SHM) rate of the immunoglobulin gene loci.\n\nASO-RQ-PCR results showed that overall 7 patients out of 25 achieved a molecular CR: 4 (16%) after consolidation, 3 (12%) during Lenalidomide maintenance. Among the 7 patients who achieved molecular CR, 2 (28%) progressed after a median of 34.4 months (1 patient became MRD positive and relapsed and 1 patient had a clinical extra-medullary progression). Among the 18 patients who did not achieve a molecular CR, 15 (83%) progressed after a median of 35.8 months (p=0.02). In 16 out of 17 patients who experienced disease progression, molecular-progression anticipated clinical relapse by a median of 10 months (IQR 5-19) confirming MFC results.\n\nSimilarly to the MFC analysis, different tumor burden kinetics were observed among patients who relapsed vs patients who did not (4.4 vs 7.8 ln-PCR reduction, respectively) (Figure 3B), high-risk cytogenetic vs standard-risk groups (3 vs 6 ln-PCR reduction, respectively) (Appendix Figure 2B) with approximately 3 log units of higher tumor shrinkage for patients with favorable outcome. Due to the limited patient series evaluable by ASO-RQ-PCR, no PFS analysis could be performed.\n\nDISCUSSION\nIn this prospective analysis, we monitored MRD using both MFC and ASO-RQ-PCR methods in 50 newly diagnosed MM patients who achieved at least a VGPR after ASCT or CRD consolidation, followed by Lenalidomide maintenance. Although in this sub-study the VGPR rate was equal in the CRD and ASCT arms, we found a deeper MRD shrinkage with ASCT vs CRD consolidation, confirming the clinical advantage of ASCT [15]. Moreover, the prognostic role of MRD was confirmed, with a 5-year PFS after consolidation of 72% vs 30% for MRD-negative and MRD-positive patients, respectively (P=0.005). These results suggest that in CR/VGPR patients a deeper characterization of response is needed in order to detect residual tumor cells and possibly to apply an MRD-driven approach. Importantly, BM evaluation, both by MFC and ASO-RQ-PCR, allowed anticipating clinical relapse by a median of 9-10 months (thus confirming our previous reports) [16] and biochemical relapse by electrophoretic evaluation by a median of 4 months. Therefore, MRD analysis could help to promptly identify relapsing patients with unsustained responses. Moreover, Lenalidomide maintenance was able to maintain MRD shrinkage and, in some patients, increased depth of response, from MRD positive to MRD negative status. This may be due to a delayed effect of transplant, considering that 3 patients became MRD negative after 3 months and 2 after 6 months. Nevertheless, the median time to MRD negativity from transplant was 8 months, supporting the idea that also an effect of lenalidomide could influence tumor burden in this population. We could not evaluate the possible difference between Lenalidomide-Prednisone and Lenalidomide alone arms due to the limited number of cases.\n\nThe detection and prognostic role of MRD in myeloma patients showed to be of great interest in the past ten years. Several techniques and new methodologies are emerging to define response to therapy more rigorously, making the scenario very confusing [17]. Serological biomarkers, such as immunofixation or immunoglobulin free-light chains, are widely available today, and have the advantage of being non-invasive procedures [18]. Of note, they allow the diagnosis and monitoring of MM, and they improve risk stratification [19–21]. However, results from available studies are contradictory and the incorporation of serum free-light chains in the measurement of MRD is still controversial [22–25]. MFC and ASO-RQ-PCR are sensitive approaches to detect MRD in the BM of MM patients receiving novel agents and/or ASCT [26]. To the best of our knowledge, this is the first MRD study comparing transplant vs no transplant MRD negativity by MFC and ASO-RQ-PCR.\n\nIn two PETHEMA/GEM trials (GEM2000 and GEM2005<65y), risk assessment by FISH and MRD monitoring by flow cytometry had an independent prognostic value in transplant-eligible patients [8]. Conversely, Rawstron et al. confirmed that the presence of MRD was a strong predictor of outcome in patients with both favorable and adverse cytogenetic profile [27].\n\nIn our study, high-risk cytogenetic profile by FISH was associated with lower reduction of tumor burden and higher rates of MRD reappearance when compared with standard-risk cytogenetic profile. Consistently with results reported by the Spanish group [28], these data suggest that combining cytogenetics and MRD data could be a valid option to identify a subset of CR/VGPR patients with a worse outcome and who should be candidates for novel treatment strategies.\n\nThe present MRD sub-study was started 2 years after the beginning of the clinical trial, thus a low number of patients was included (50 for MFC and 25 for ASO-RQ-PCR). This could be a limitation to the sub-study, which has also hampered an extensive comparison between the two methods.\n\nSome technical issues regarding both MRD methods also need to be considered. ASO-RQ-PCR in MM is a complex and time-consuming technique. Moreover, despite the high sensitivity (up to 10-5) of this method, currently 40-50% of patients lack a molecular marker due to the elevated SHM rate of the immunoglobulin gene loci, thus negatively affecting sequencing. Several studies employed a mono-targeted strategy (IGH); the complexity in detecting and sequencing Ig target in low infiltrated baseline samples (<5% of plasma cells) is largely known and the low quality of samples, deriving from multicenter trials, might hamper the applicability of this technique. MFC seems to be more easily applicable and does not require patient-specific diagnostic phenotypic profiles. The need for high quality BM sampling, the lack of standardization of different protocols, and the variability of technique sensitivity and data interpretation among different laboratories are some of the major drawbacks of MFC [17, 26]. In light of these considerations, our study showed the higher feasibility of MFC compared with ASO-RQ-PCR due to the low marker detection rate and the complex profile of the molecular technique.\n\nIn order to overcome these limitations, newer strategies have been tested such as Next Generation Sequencing (NGS) by using the LymphoSIGHT platform, which allows the amplification and sequencing of all rearranged immunoglobulin gene segments present in myeloma clone, reaching a sensitivity of 10-6 or better [29–31]. In a Spanish trial, MRD negative status was associated with significantly longer time to progression (median 80 vs 31 months, P<0.001) and OS (median not reached vs 81 months, P=0.02) [30].\n\nUnlike other hematological disorders, BM infiltration pattern is not uniform in MM and hemodiluited BM aspirates may lead to false-negative results. MM presents high frequency of extramedullary relapses and sensitive imaging techniques have become relevant in assessing low levels of disease outside BM [32–35]. In our study, one patient with BM negative MRD experienced extramedullary relapse, confirming the importance of imaging techniques in patients with MRD negativity. A recent Italian retrospective analysis also confirmed the prognostic role of PET/CT when performed at baseline in combination with ISS stage. Furthermore, PET/CT showed to be a valuable technique to improve the definition of CR after treatment and to detect otherwise unidentifiable progression in the follow-up phase of the disease [36].\n\nIn conclusion, this sub-study showed that persistence of MRD is an adverse prognostic factor, even among CR or VGPR patients. In addition, MRD monitoring during and after treatment should be considered at least in the context of clinical trials as a more sensitive approach compared with routine evaluation, in order to explore MRD-guided therapeutic decisions. Indeed, MRD may become a valuable tool for clinicians to understand which patients may benefit from continuous treatment and which ones may be considered for an alternative strategy. Moreover, future analyses on larger cohorts are needed to overcome the current limitations associated with repeated bone marrow assessments. New MRD strategies using peripheral blood may be a valid alternative [37, 38], and new, more sensitive techniques such as NGS may play a crucial role.\n\nMETHODS\nThe RV-MM-EMN-441 trial was a multicenter, randomized phase III trial (ClinicalTrials.gov identifier: NCT01091831) [15]. The main study was approved by the institutional review boards of each participating center, and was conducted according to the Declaration of Helsinki. All patients provided written informed consent.\n\nPatients and study design\nResults from the main study have been recently reported [15], and the study protocol is summarized in Figure 5. Briefly, all patients received four cycles of Lenalidomide+low-dose Dexamethasone (RD) as induction, followed by mobilization of BM stem cells using Cyclophosphamide and Granulocyte-Colony Stimulating Factor (G-CSF), and stem cell collection. Subsequently patients received either consolidation with six cycles of CRD or high-dose Melphalan and ASCT. After the consolidation phase, patients were further randomized to maintenance with either Lenalidomide or Lenalidomide-Prednisone until relapse or intolerance. Response to treatment was assessed according to the IMWG criteria [14]. Patients who achieved at least a VGPR after consolidation were eligible for the present MRD sub-study. Biochemical relapse was defined as an increase of 25% from lowest response value in any of the following: serum M-component (absolute increase ≥0.5 g/100 ml) and/or urine M-component (absolute increase ≥200 mg per 24 hours); relapse from CR was defined as the reappearance of serum or urine M-protein by immunofixation or electrophoresis.\n\nFigure 5 Study design and MRD time-points\nRD: Lenalidomide-Dexamethasone, CTX: Cyclophosphamide, PBSC: peripheral blood stem cell, CRD: Cyclophosphamide-Lenalidomide-Dexamethasone, MEL200: Melphalan 200 mg/m2, R: Lenalidomide, MRD: minimal residual disease.\n\nMRD analysis was performed on BM aspirates collected at different time-points: after consolidation, after 3 and 6 courses of maintenance, and then every 6 months until clinical relapse.\n\nMRD assessment by multiparameter flow cytometry\nMFC analysis was performed in a centralized laboratory (Laboratory of Cytofluorimetry-University of Turin, Italy). Plasma cells phenotypic aberrations were identified at diagnosis and were used as patient-specific profile in the follow-up analyses. BM cells for MRD detection by MFC were lysed following the EuroFlow recommendations [39].\n\nThe following monoclonal antibodies (MoAbs) combinations were employed:\n\n1) CD138FITC/CD56PE/CD20PerCp/CD117APC/CD45APC-H7/CD38PE-Cy7\n\n2) cyKappaFITC/cyLambdaPE/CD19PerCp/CD56APC/CD45APC-H7/CD38PE-Cy7.\n\nFrom the first combination, we obtained plasma cells quantification; from the second combination, we evaluated plasma cells immunophenotype and clonality. Acquisition and analyses were performed using FACSCanto II (BD Biosciences, San Josè, CA) and DiVa software: a minimum of 1-2 × 106 of events for each sample were acquired.\n\nMFC analysis had a sensitivity of 10−4 cells. MFC-CR was defined as <0.01% monoclonal plasma cells in the BM sample confirmed on two consecutive BM assessments. MFC relapse was defined by confirmed 25% increase of malignant plasma cells in two subsequent samples.\n\nMRD assessment by allelic-specific oligonucleotide real-time quantitative polymerase chain reaction\nGenomic DNA from total white blood cells of BM samples was isolated using DNAzol reagent (Life Technologies-Invitrogen, Carlsbad, CA, USA), following the manufacturer's instructions. Patient-specific IgH rearrangements were amplified and directly sequenced from genomic DNA at diagnosis [40]. Sequences were analyzed by IMGT/V-QUEST tool [41, 42], and patient-specific ASO-primers and consensus probes were designed as previously described [40]. IgH-based MRD detection by ASO-RQ-PCR was performed using an AbiPrism7900HT (Life Technologies-Applied Biosystems, Carlsbad, CA, USA) [17]. MRD analysis was interpreted following the Euro-MRD guidelines [43].\n\nMoreover, molecular-CR was defined as two consecutive negative MRD results by ASO-RQ-PCR with minimal sensitivity of 10−5. Molecular progression was defined as the reappearance of positivity or a confirmed 25% increase of ASO-RQ-PCR values in two repeated follow-up samples.\n\nStatistical methods\nThe primary endpoint was to investigate MRD response rates by using MFC and ASO-RQ-PCR methods, at different time-points. Secondary endpoints were the duration of MRD response and progression-free survival (PFS) stratified on MRD response. PFS was defined as the time from start of treatment to documented progression or death from myeloma; patients still alive were censored at last contact date. PFS was analyzed by the Kaplan-Meier method, comparing the two groups by the log-rank test and calculating 95% confidence intervals for the following covariates: gender (female vs. male), age at diagnosis (56+ yrs vs. ≤55 yrs), International Staging System (ISS) stage, cytogenetics (high-risk vs. standard-risk FISH).\n\nThe main patient characteristics were tested by the Fisher's exact test for categorical variables and by the Mann-Whitney test for continuous ones. Since the natural logarithms ln-MFC and ln-PCR were not normally distributed by time-points, it was impossible to test them by the mixed linear model for repeated measures. Therefore, we compared the observed marginal means of ln-MFC and ln-PCR for each time-point, by the Friedman test (non-parametric analysis of variance for repeated measures), undertaking a post-hoc analysis by the Wilcoxon signed-rank test (non-parametric t-test for repeated measures) and adjusting the p-values by Bonferroni correction as already published [11]. All reported p-values were obtained by the two-sided exact method, at the conventional 5% significance level. Data were analyzed as of December 2015 by IBM SPSS 21.0.\n\nSUPPLEMENTARY MATERIALS FIGURES\n This study was supported by a research grant from the Multiple Myeloma Research Foundation (MMRF). The source study was sponsored by Fondazione Neoplasie Sangue Onlus and supported by Celgene. The sponsor had no role in the writing of the manuscript. The authors thank the patients who participated in the study, the nurses Mario Goria and Sonia Grandi, the data managers Antonella Fiorillo and Angela Jang, the editorial assistant Giorgio Schirripa, and Dr Marco Ladetto for scientific support.\n\nCONFLICTS OF INTEREST\n\nSO has received honoraria from Takeda and Celgene; FG has received honoraria from Celgene and Takeda, served on the advisory committee for Janssen, Mundipharma, Takeda; FP has received honoraria from MSD, Janssen, Celgene, and served on the advisory board for Mundipharma, Bristol, Janssen, MSD; SF has received honoraria from Mundipharma, Celgene, Janssen and Pfizer; MTP has received honoraria from Celgene, Janssen-Cilag, BMS, Amgen, Takeda, Mundipharma, Sanofi; TC has received honoraria from Celgene, Janssen, Amgen, BMS and consultancy fees from Takeda; AR has received honoraria from Celgene; PM has received honoraria from Celgene, Janssen, Novartis, Sanofi, BMS, Takeda, Amgen; MB has received consultancy fees from Janssen, Sanofi, Onyx, Amgen, Celgene; AP has received consultancy fees, honoraria and research funding from Celgene.\n==== Refs\nREFERENCES\n1 Palumbo A Anderson K Multiple Myeloma N Engl J Med 2011 364 1046 1060 21410373 \n2 Palumbo A Cavallo F Gay F Di Raimondo F Ben Yehuda D Petrucci MT Pezzatti S Caravita T Cerrato C Ribakovsky E Genuardi M Cafro A Marcatti M Autologous transplantation and maintenance therapy in multiple myeloma N Engl J Med 2014 371 895 905 25184862 \n3 Lahuerta JJ Mateos MV Martínez-López J Rosiñol L Sureda A de la Rubia J García-Laraña J Martínez-Martínez R Hernández-García MT Carrera D Besalduch J de Arriba F Ribera JM Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival J Clin Oncol 2008 26 5775 5782 19001321 \n4 Gay F Larocca A Wijermans P Cavallo F Rossi D Schaafsma R Genuardi M Romano A Liberati AM Siniscalchi A Petrucci MT Nozzoli C Patriarca F Complete response correlates with long-term progression-free survival and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients Blood 2011 117 3025 3031 21228328 \n5 Martinez-Lopez J Blade J Mateos MV Grande C Alegre A García-Laraña J Sureda A de la Rubia J Conde E Martinez R de Arriba F Viguria MC Besalduch J Grupo Espanol de MM: Programa Para el Estudio de la Terapè Utica en Hemopatia maligna. Long term prognostic significance of response in multiple myeloma after transplantation Blood 2011 118 529 534 21482708 \n6 Kapoor P Kumar SK Dispenzieri A Lacy MQ Buadi F Dingli D Russell SJ Hayman SR Witzig TE Lust JA Leung N Lin Y Zeldenrust SR Importance of achieving stringent complete response after autologous stem-cell transplantation in mutiple myeloma J Clin Oncol 2013 31 4529 4535 24248686 \n7 Durie BGM Harousseau JL Miguel JS Bladé J Barlogie B Anderson K Gertz M Dimopoulos M Westin J Sonneveld P Ludwig H Gahrton G Beksac M International uniform response criteria for multiple myeloma Leukemia 2006 20 1467 1473 16855634 \n8 Paiva B Vidriales MB Cerveró J Mateo G Pérez JJ Montalbán MA Sureda A Montejano L Gutiérrez NC García de Coca A de Las Heras N Mateos MV López-Berges MC Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation Blood 2008 112 4017 4023 18669875 \n9 Paiva B Martinez-Lopez J Vidriales MB Mateos MV Montalban MA Fernandez-Redondo E Alonso L Oriol A Teruel AI de Paz R Laraña JG Bengoechea E Martin A Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma J Clin Oncol 2011 29 1627 1633 21402611 \n10 Rawstron AC Gregory WM de Tute RM Davies FE Bell SE Drayson MT Cook G Jackson GH Morgan GJ Child JA Owen RG Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction Blood 2015 125 1932 1935 25645353 \n11 Ladetto M Pagliano G Ferrero S Cavallo F Drandi D Santo L Crippa C De Rosa L Pregno P Grasso M Liberati AM Caravita T Pisani F Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma J Clin Oncol 2010 28 2077 2084 20308672 \n12 Sarasquete ME García-Sanz R González D Martínez J Mateo G Martínez P Ribera JM Hernández JM Lahuerta JJ Orfão A González M San Miguel JF Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry Haematologica 2005 90 1365 1372 16219573 \n13 Puig N Sarasquete ME Balanzategui A Martínez J Paiva B García H Fumero S Jiménez C Alcoceba M Chillón MC Sebastián E Marín L Montalbán MA Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry Leukemia 2014 28 391 397 23860448 \n14 Rajkumar SV Harousseau JL Durie B Anderson KC Dimopoulos M Kyle R Blade J Richardson P Orlowski R Siegel D Jagannath S Facon T Avet-Loiseau H International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1 Blood 2011 117 4691 5 21292775 \n15 Gay F Oliva S Petrucci MT Conticello C Catalano L Corradini P Siniscalchi A Magarotto V Pour L Carella A Malfitano A Petrò D Evangelista A Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial Lancet Oncol 2015 16 1617 1629 26596670 \n16 Ferrero S Ladetto M Drandi D Cavallo F Genuardi E Urbano M Caltagirone S Grasso M Rossini F Guglielmelli T Cangialosi C Liberati AM Callea V Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics’ impact on survival Leukemia 2015 29 689 95 25027515 \n17 Fulciniti M Munshi NC Martinez-Lopez J Deep Response in Multiple Myeloma: A Critical Review Biomed Res Int 2015 2015 832049 10.1155/2015/832049 Epub 2015 Dec 10. Review 26783530 \n18 Singhal S Vickrey E Krishnamurthy J Singh V Allen S Mehta J The relationship between the serum free light chain assay and serum immunofixation electrophoresis, and the definition of concordant and discordant free light chain ratios Blood 2009 114 38 39 19411633 \n19 Kyrtsonis MC Vassilakopoulos TP Kafasi N Sachanas S Tzenou T Papadogiannis A Galanis Z Kalpadakis C Dimou M Kyriakou E Angelopoulou MK Dimopoulou MN Siakantaris MP Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma Br J Haematol 2007 137 240 243 17408464 \n20 van Rhee F Bolejack V Hollmig K Pineda-Roman M Anaissie E Epstein J Shaughnessy JD Jr Zangari M Tricot G Mohiuddin A Alsayed Y Woods G Crowley J High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis Blood 2007 110 827 32 17416735 \n21 Dispenzieri A Kyle R Merlini G Miguel JS Ludwig H Hajek R Palumbo A Jagannath S Blade J Lonial S Dimopoulos M Comenzo R Einsele H International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders Leukemia 2009 23 215 24 19020545 \n22 Mead GP Drayson MT Sensitivity of serum free light chain measurement of residual disease in multiple myeloma patients Blood 2009 114 1717 19696211 \n23 Giarin MM Giaccone L Sorasio R Sfiligoi C Amoroso B Cavallo F Cipriani A Palumbo A Boccadoro M Serum free light chain ratio, total kappa/lambda ratio, and immunofixation results are not prognostic factors after stem cell transplantation for newly diagnosed multiple myeloma Clin Chem 2009 55 1510 6 19520760 \n24 Kapoor P Kumar SK Dispenzieri A Kumar SK Dispenzieri A Lacy MQ Buadi F Dingli D Russell SJ Hayman SR Witzig TE Lust JA Leung N Lin Y Zeldenrust SR Importance of achieving stringent complete response after autologous stem-cell transplantation in multiple myeloma J Clin Oncol 2013 31 4529 4535 24248686 \n25 Martínez-López J Paiva B López-Anglada L Mateos MV Cedena T Vidríales MB Sáez-Gómez MA Contreras T Oriol A Rapado I Teruel AI Cordón L Blanchard MJ Critical analysis of the stringent complete response in multiple myeloma: contribution of sFLC and bone marrow clonality Blood 2015 126 858 862 26089396 \n26 Paiva B van Dongen JJ Orfao A New criteria for response assessment: role of minimal residual disease in multiple myeloma Blood 2015 125 3059 3068 25838346 \n27 Rawstron AC Child JA de Tute RM Davies FE Gregory WM Bell SE Szubert AJ Navarro-Coy N Drayson MT Feyler S Ross FM Cook G Jackson GH Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study J Clin Oncol 2013 31 2540 2547 23733781 \n28 Paiva B Gutiérrez NC Rosiñol L Gutiérrez NC Rosiñol L Vídriales MB MÁ Montalbán Martínez-López J Mateos MV Cibeira MT Cordón L Oriol A Terol MJ Echeveste MA de Paz R High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma Blood 2012 119 687 91 22128143 \n29 Faham M Zheng J Moorhead M Carlton VE Stow P Coustan-Smith E Pui CH Campana D Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia Blood 2012 120 5173 5180 23074282 \n30 Martinez-Lopez J Lahuerta JJ Pepin F Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma Blood 2014 123 3073 9 24646471 \n31 Ladetto M Brüggemann M Monitillo L Ferrero S Pepin F Drandi D Barbero D Palumbo A Passera R Boccadoro M Ritgen M Gökbuget N Zheng J Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders Leukemia 2014 28 1299 1307 24342950 \n32 Hillengass J Ayyaz S Kilk K Weber MA Hielscher T Shah R Hose D Delorme S Goldschmidt H Neben K Changes in magnetic resonance imaging before and after autologous stem cell transplantation correlate with response and survival in multiple myeloma Haematologica 2012 97 1757 1760 22689673 \n33 Bartel TB Haessler J Brown TL Shaughnessy JD Jr van Rhee F Anaissie E Alpe T Angtuaco E Walker R Epstein J Crowley J Barlogie B F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma Blood 2009 114 2068 2076 19443657 \n34 Zamagni E Cavo M The role of imaging techniques in the management of multiple myeloma Br J Haematol 2012 159 499 513 22881361 \n35 Bladé J Fernández de Larrea C Rosiñol L Cibeira MT Jiménez R Powles R Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach J Clin Oncol 2011 29 3805 3812 21900099 \n36 Zamagni E Nanni C Mancuso K Tacchetti P Pezzi A Pantani L Zannetti B Rambaldi I Brioli A Rocchi S Terragna C Martello M Marzocchi G PET/CT Improves the Definition of Complete Response and Allows to Detect Otherwise Unidentifiable Skeletal Progression in Multiple Myeloma Clin Cancer Res 2015 21 4384 4390 26078390 \n37 Korthals M Sehnke N Kronenwett R Schroeder T Strapatsas T Kobbe G Haas R Fenk R Molecular monitoring of minimal residual disease in the peripheral blood of patients with multiple myeloma Biol Blood Marrow Transplant 2013 19 1109 1115 23644045 \n38 Kubiczkova-Besse L Drandi D Sedlarikova L Oliva S Gambella M Omedè P Adam Z Pour L Sevcikova S Boccadoro M Palumbo A Hajek R Cell-Free DNA for Minimal Residual Disease Monitoring in Multiple Myeloma Patients [abstract] Blood 2014 3423 \n39 Rawstron AC Orfao A Beksac M Bezdickova L Brooimans RA Bumbea H Dalva K Fuhler G Gratama J Hose D Kovarova L Lioznov M Mateo G Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders Haematologica 2008 93 431 438 18268286 \n40 Ladetto M Donovan JW Harig S Trojan A Poor C Schlossnan R Anderson KC Gribben JG Real-Time polymerase chain reaction of immunoglobulin rearrangements for quantitative evaluation of minimal residual disease in multiple myeloma Biol Blood Marrow Transplant 2000 6 241 253 10871149 \n41 Giudicelli V Lefranc MP IMGT/junctionanalysis: IMGT standardized analysis of the V-J and V-D-J junctions of the rearranged immunoglobulins (IG) and T cell receptors (TR) Cold Spring Harb Protoc 2011 2011 716 725 21632777 \n42 Brochet X Lefranc MP Giudicelli V IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis Nucleic Acids Res 2008 36 W503 508 18503082 \n43 van der Velden VH Cazzaniga G Schrauder A Hancock J Bader P Panzer-Grumayer ER Flohr T Sutton R Cave H Madsen HO Cayuela JM Trka J Eckert C Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data Leukemia 2007 21 604 611 17287850\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(4)",
"journal": "Oncotarget",
"keywords": "ASO-RQ-PCR; MRD; flow cytometry; myeloma; novel agents",
"medline_ta": "Oncotarget",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D060830:Consolidation Chemotherapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D018365:Neoplasm, Residual; D011446:Prospective Studies; D013792:Thalidomide; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "5924-5935",
"pmc": null,
"pmid": "27779105",
"pubdate": "2017-01-24",
"publication_types": "D016428:Journal Article",
"references": "20308672;24342950;19443657;10871149;21410373;21482708;19020545;17408464;19411633;26783530;22689673;21292775;21402611;22881361;19001321;26078390;23644045;18503082;25645353;17287850;23074282;22128143;21632777;19696211;17416735;26089396;23733781;25184862;24248686;24646471;16219573;25838346;16855634;23860448;18669875;18268286;25027515;26596670;19520760;21900099;21228328",
"title": "Minimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis.",
"title_normalized": "minimal residual disease after transplantation or lenalidomide based consolidation in myeloma patients a prospective analysis"
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"abstract": "Although the use of opioids is increasing in South Korea, there have been no studies on the serious complications caused by the opioids. The aim of this study was to investigate the rare but serious complications through medicolegal analysis.\nFrom January 1994 to December 2019, we retrospectively reviewed the closed cases of lawsuits involving the complications of opioids using the database of judgments of the Supreme Court of Korea. General characteristics, opioid-induced complications, and judicial characteristics were analyzed.\nOf the 46 cases, 31 cases of complications were finally included in the analysis. There were 28 (90.3%) cases of opioid administration for acute pain and 3 (9.7%) cases for chronic pain. The most commonly prescribed opioid was pethidine (n = 13, 41.9%), and the most common complication was respiratory depression (n = 17, 54.8%). All except two cases were associated with permanent injuries, including 18 (58%) deaths. Twelve (38.7%) cases were ruled in favor of the plaintiff in the claims for damages, with a median payment of United States dollar (USD) 126,346 (IQR: USD 77,275-379,219). Of these cases, the most frequently admitted complaint by the court was the neglect of observation (n = 10, 32.3%), followed by the inappropriate drug choice (n = 4, 12.9%). Eleven (36.7%) cases were plaintiffs' claims for violating explanation obligations, of which 2 (6.7%) were recognized in the court.\nOur results suggest that physicians must be aware of the serious complications related to opioids and health policies to prevent such complications and malpractice should be adopted.",
"affiliations": "Department of Anesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea.;Department of Medical Law and Ethics, Graduate School, Yonsei University, Seoul, Republic of Korea.;Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea.;Division of Medical Law and Bioethics, Department of Medical Humanities and Social Sciences, Yonsei University College of Medicine, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea.",
"authors": "Kim|Jeongsoo|J|;Shin|SuHwan|S|0000-0002-2812-1985;Jeong|YoungHyun|Y|;Kim|So Yoon|SY|;Lee|Ho-Jin|HJ|0000-0002-7134-5044",
"chemical_list": null,
"country": "New Zealand",
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"doi": "10.2147/JPR.S256759",
"fulltext": "\n==== Front\nJ Pain Res\nJ Pain Res\nJPR\njpainres\nJournal of Pain Research\n1178-7090 Dove \n\n256759\n10.2147/JPR.S256759\nOriginal Research\nMedicolegal Consideration to Prevent Medical Malpractice Regarding Opioid Administration: An Analysis of Judicial Opinion in South Korea\nKim et alKim et alKim Jeongsoo 1 http://orcid.org/0000-0002-2812-1985Shin SuHwan 23 Jeong YoungHyun 4 Kim So Yoon 56 http://orcid.org/0000-0002-7134-5044Lee Ho-Jin 47 1 Department of Anesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea\n2 Department of Medical Law and Ethics, Graduate School, Yonsei University, Seoul, Republic of Korea\n3 Blue Urology Clinic, Seoul, Republic of Korea\n4 Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea\n5 Division of Medical Law and Bioethics, Department of Medical Humanities and Social Sciences, Yonsei University College of Medicine, Seoul, Korea\n6 Asian Institute for Bioethics and Health Law, Yonsei University, Seoul, Korea\n7 Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea\nCorrespondence: Ho-Jin Lee Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaTel +82-2-2072-0039Fax +82-2-747-8363 Email zenerdiode03@gmail.com\n25 6 2020 \n2020 \n13 1525 1532\n03 4 2020 03 6 2020 © 2020 Kim et al.2020Kim 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).Purpose\nAlthough the use of opioids is increasing in South Korea, there have been no studies on the serious complications caused by the opioids. The aim of this study was to investigate the rare but serious complications through medicolegal analysis.\n\nMaterials and Methods\nFrom January 1994 to December 2019, we retrospectively reviewed the closed cases of lawsuits involving the complications of opioids using the database of judgments of the Supreme Court of Korea. General characteristics, opioid-induced complications, and judicial characteristics were analyzed.\n\nResults\nOf the 46 cases, 31 cases of complications were finally included in the analysis. There were 28 (90.3%) cases of opioid administration for acute pain and 3 (9.7%) cases for chronic pain. The most commonly prescribed opioid was pethidine (n = 13, 41.9%), and the most common complication was respiratory depression (n = 17, 54.8%). All except two cases were associated with permanent injuries, including 18 (58%) deaths. Twelve (38.7%) cases were ruled in favor of the plaintiff in the claims for damages, with a median payment of United States dollar (USD) 126,346 (IQR: USD 77,275–379,219). Of these cases, the most frequently admitted complaint by the court was the neglect of observation (n = 10, 32.3%), followed by the inappropriate drug choice (n = 4, 12.9%). Eleven (36.7%) cases were plaintiffs’ claims for violating explanation obligations, of which 2 (6.7%) were recognized in the court.\n\nConclusion\nOur results suggest that physicians must be aware of the serious complications related to opioids and health policies to prevent such complications and malpractice should be adopted.\n\nKeywords\nacute painadverse drug eventscomplicationslegislation and jurisprudencemedical liabilityopioids\n==== Body\nIntroduction\nOpioid analgesics have played a pivotal role in the management of acute pain and chronic cancer pain since the 1990s.1,2 More recently, it has also played an important role in the management of chronic non-cancer pain.3,4 Opioids have strong analgesic potency without a ceiling effect unlike other analgesics, and it can be administered through various routes such as transdermal, submucosal, intranasal, oral, neuraxial, or intravenous routes.4 As a result, opioids are now being widely used for pain management, and their use has increased dramatically in South Korea.5 According to the Adequacy of Consumption Measure (ACM) of opioids in 2010, opioid usage in South Korea has grown exponentially, with a 77-fold increase in ACM ratio between 2006 and 2010.6 In addition, a recent study conducted in South Korea also showed a dramatic increase in opioid use.7 Understandably, with the increase in opioid use, there is growing concern about the side effects of opioids in South Korea.8,9\n\nOpioids can cause serious side effects despite its many advantages, so physicians need to be careful when prescribing them.10 Opioid usage can cause a wide range of side effects, from mild symptoms such as nausea and vomiting to fatal complications such as respiratory depression in the acute period of administration.11 Long-term use of opioids can result in addiction and abuse, with its prevalence reported to be 26% in the United States.12 In addition, chronic opioid use has recently been reported to be associated with long-term mortality.7 As opioid prescription increases rapidly, the serious complications caused by opioids are expected to increase as well.\n\nHowever, to our knowledge, there have been no previous studies evaluating serious complications as a result of opioid administration in South Korea. Therefore, in this study, we attempted to investigate the very rare but serious complications associated with opioid administration through the analysis of medical malpractice lawsuits.13 Through this study, we hope to increase awareness regarding catastrophic complications of opioids and to prevent medical malpractice associated with opioid administration.\n\nMaterials and Methods\nWe analyzed adjudicated lawsuits that are publicly accessible in the database of the Supreme Court of Korea’s judgments. This database contains both civil and criminal proceedings sentenced from the levels of the district court to the Supreme Court. The details of each case were provided to the researcher without identifiable personal information. All medical malpractice litigations that were sentenced from January 1, 1994 to December 31, 2019 were queried using the search terms “opioid” and “narcotic analgesics”. We included the cases in which the malpractice associated with opioid administration was contained in the plaintiff’s claims. We excluded cases unrelated to opioid administration based on the pain physician’s judgment (J Kim and H-J Lee). This study was approved by the institutional review board (IRB) of Seoul National University Hospital (IRB no. 2003–048-1106).\n\nEach lawsuit text contained a detailed description of the case, the malpractice claims of the plaintiff, and the court decisions regarding medical malpractice. Two board-certified pain physicians (J Kim and H-J Lee) reviewed the judgment texts and collected the following information: year of the event, age, sex, underlying medical diseases, causes of opioid administration, parameters related to opioid administration (type, route, number of doses), and the types and severity of the complications.\n\nThe severity of complications was evaluated using the 10-point National Association of Insurance Commissioners (NAIC) scale where 0 is “no obvious injury” and 9 is “death” (0: No obvious injury; 1: Emotional only; 2: Temporary insignificant; 3: Temporary minor; 4: Temporary major; 5: Permanent minor; 6: Permanent significant; 7: Permanent major; 8: Permanent grave; 9: Death).14\n\nData regarding the detailed claims of plaintiffs, the opinion of the court, and the final financial compensation awarded were also collected. The plaintiffs’ allegations that were related to opioid administration were classified into the following two categories; violation of the duty of care and violation of the duty of explanation. Each case was also investigated to determine if it was accepted by the court. After the first review, the violation of duty of care that was identified in our data was further classified into the following three categories; “Neglect of observation”, “Inappropriate drug choice”, and “Overdose”. “Neglect of observation” was defined as inappropriate monitoring after opioid administration. “Inappropriate drug choice” was defined as when the administration of opioids was not appropriate considering the patient’s condition. “Overdose” was defined as the inappropriate dosage of opioids that resulted in the occurrence of complications. The classification and judgment of medical malpractice was conducted independently by two pain physicians (J Kim and H-J Lee). In the case of a conflict between the authors, a review by an author of medical law and ethics (SH Shin) was conducted.\n\nDescriptive statistics were conducted using the MedCalc Statistical Software version 18.6 (MedCalc Software bvba, Ostend, Belgium). Categorical data are described as percentages, and continuous data are described as medians (interquartile range [IQR]).\n\nResults\nThere was a total of 46 cases (from 69 judicial precedents) during the study period. Of these cases, 15 cases were excluded and a total of 31 cases were included in the final analysis (Figure 1). Detailed information of our cases is provided in supplementary Table 1. The clinical characteristics of the patients are presented in Table 1. There were 28 (90.3%) cases of opioid administration for acute pain and 3 (9.7%) cases for chronic pain. The most common cause of opioid administration was acute abdominal pain (n = 9, 29%), followed by acute postoperative pain (n=8, 25.8%). There were two fetuses (case no. 5, 23) and one 6-month old infant (case no. 21) among those who were adversely affected by opioid use. In the case of the fetuses, the opioid was administered to the pregnant woman for labor pain relief.Table 1 General Characteristics of the Cases\n\nCharacteristics\tTotal (n = 31)\t\nYear of judgment\t\t\n <2010\t11 (35.5)\t\n ≥2010\t20 (64.5)\t\nSex\t\t\n M/F\t9 (29)/13 (41.9)\t\n Not described\t9 (29)\t\nAge at the time of the procedure (years)\t\t\n <40\t8a (25.8)\t\n 40–59\t6 (19.4)\t\n ≥60\t5 (16.1)\t\n Not described\t12 (38.7)\t\nCause of opioid administration\t\t\n Acute pain\t28 (90.3)\t\n Abdominal pain\t9 (29)\t\n Postoperative pain\t8 (25.8)\t\n Diagnostic test\t3 (9.7)\t\n Headache\t2 (6.4)\t\n Traumatic pain\t3 (9.7)\t\n Labor pain\t2 (6.5)\t\n Septic arthritis\t1 (3.2)\t\n Chronic painb\t3 (9.7)\t\n History of opioid use before event\t10 (32.2)\t\nUnderlying diseases\t\t\n Liver diseases\t5 (16.1)\t\n Kidney diseases\t3 (9.6)\t\n Cerebrovascular diseases\t2 (6.4)\t\n Not described\t5 (16.1)\t\nNotes: Values are presented as median (interquartile range) or number (%). aThis included two fetuses and one 6-month-old infant. bThis included low back (n = 2) and calf pain (n = 1).\n\n\nFigure 1 Flowchart of the study.\n\n\n\nTable 2 shows the detailed information of opioid administration and opioid-induced complications. The most commonly used opioid was pethidine (n = 13, 41.9%). The most common complication following opioid administration was respiratory depression (n = 17, 54.8%). All except two were associated with permanent injuries, with a total of 18 deaths.Table 2 Detailed Information of Opioid Administration and Opioid-Induced Complications\n\nCharacteristics\tTotal (n = 31)\t\nOpioids type\t\t\n Pethidine\t13 (41.9)\t\n Fentanyl/Morphine\t3 (9.7)/2 (6.5)\t\n Pentazocine/Morphine/Sufentanil/Nalbuphine\t1 (3.2)/1 (3.2)/1 (3.2)/1 (3.2)\t\n Combineda\t9 (29)\t\nConcomitant use of non-opioid sedative medications\t4 (12.9)\t\nNumber of opioid administration\t\t\n Single dose\t14 (45.1)\t\n 2 times\t4 (12.9)\t\n ≥3 times\t7 (22.5)\t\n Continuous infusionb\t6 (19.3)\t\nAdverse event or outcome contended by plaintiffs of the total cases/Cases recognized by the court as opioid-related malpracticec\t\t\n Respiratory depression\t17 (54.8)/8c (25.8)\t\n Delayed diagnosis\t2 (6.5)/2 (6.5)\t\n Decreased consciousness\t3 (9.6)/0\t\n Opioids use disorder\t3 (9.6)/1 (3.2)\t\n Fetal hypoxia\t2 (6.5)/1 (3.2)\t\n Anaphylactic shock\t1 (3.2)/1 (3.2)\t\n Hypotension\t1 (3.2)/0\t\n Gastrointestinal dysfunction\t1 (3.2)/0\t\n Cardiac arrest\t1 (3.2)/0\t\nOnset of symptoms\t\t\n In medical institution\t28 (90.3)\t\n After discharge\t3 (9.6)\t\nSeverity of complications\t\t\n High (NAIC score 6–9)\t29d (93.5)\t\n Medium (NAIC score 3–5)\t2 (6.5)\t\n Low (NAIC score 0–2)\t0 (0)\t\nNotes: Values are presented as median (interquartile range) or number (%). aThis included one case with tramadol and transdermal fentanyl patch, one case with pethidine, tramadol, transdermal fentanyl patch, and patient-controlled analgesia using fentanyl, one case with pethidine, oxycontin, tramadol, and patient-controlled analgesia (unknown opioid), one case with pentazocine, pethidine, morphine and one case with tramadol, pethidine. bThis included patient-controlled analgesia (2 cases), transdermal fentanyl patch (2 cases), remifentanil infusion via infusion pump (1case) and sufentanil infusion via infusion pump (1 case). cThis included one criminal proceeding. dThis included a total of eighteen deaths.\n\nAbbreviation: NAIC, National Association of Insurance Commissioners.\n\n\n\n\nJudgment statuses are shown in Table 3. One case was a criminal proceeding while the others were all civil proceedings. In the criminal proceeding, the defendant was sentenced to 10 months in a suspended sentence for the negligence of observation after opioid administration (case no. 31). This criminal proceeding did not overlap with the civil proceedings. Of the 30 civil proceedings, 15 were dismissed by the court. Three of the remaining cases were not dismissed, but the malpractice associated with opioids claimed by the plaintiff was not recognized. The remaining 12 claims (38.7%) associated with malpractice of opioid administration resulted in payments to the plaintiffs, with a median payment of United States Dollar (USD) 126,346 (IQR: USD 77,275–379,219). Violation of the duty of care related to opioid prescription was claimed by plaintiffs in 30 cases. Of these cases, 12 (38.7%) were ruled as violation of the duty of care related to opioid prescription by the court. This violation of duty that was ruled physician malpractice included neglect of observation after opioid administration (n = 10), inappropriate drug choice (n = 4), and overdose (n = 3). Violation of the physician’s duty of informed consent was claimed by plaintiffs in 11 (36.7%) cases. Of these cases, 2 (6.7%) were ruled as medical malpractice by the court. Of the cases in which the court recognized opioid-related medical malpractices, there were four deaths, three cases of vegetative states, and three cases of quadriplegia.Table 3 Judicial Characteristics from 31 Cases Related to Opioid Administration\n\nCharacteristics\tn = 31\t\nCriminal proceeding\t1 (3.2)\t\n Neglect of observation\t1 (3.2)\t\nCivil proceeding\t30 (96.8)\t\n Dismissal of opioid-related malpractice\t18 (58.1)\t\n Violation of the duty of care related to opioid prescription\t\t\n Claims of plaintiffs\t30 (96.8)\t\n Recognition of the court\t12 (38.7)\t\n Neglect of observation\t10 (32.3)\t\n Inappropriate drug choice\t4 (12.9)\t\n Overdose\t3 (9.7)\t\nViolation of the duty of explanation related to opioid prescription\t\t\n Claims of plaintiffs\t11 (36.7)\t\n Recognition of the court\t2 (6.7)\t\nAmount for damage – median USDa\t\t\n Claims of plaintiffsb\t169,053 (98,418–627,662)\t\n Recognition of the courtc\t126,346 (77,275–379,219)\t\nNotes: Values are presented as median (interquartile range) or number (%). aThe exchange rate was converted to 1 United States Dollar =1165 Korean Won considering the mean exchange rate for 2019. bThe amount was not described in one opioid case. cThis included only events that opioid-related malpractice had not been dismissed.\n\n\n\n\nDiscussion\nThis study analyzed 31 medical malpractice lawsuits related to the complications of opioid administration in the Korean court system. Our major findings were that in the majority of cases, opioids were administered for acute pain, not chronic pain. The most common opioid encountered in this study was pethidine and the most common type of complication was respiratory depression. Neglect of observation after opioid administration was the most commonly ruled physician malpractice. Except for two, all cases were associated with permanent injuries.\n\nPrevious medicolegal studies on the complications of opioid administration have been reported. According to the analysis of the closed claims database of the American Society of Anesthesiologists (ASA) from 2005 to 2008, 48 claims were related to opioid prescriptions, which accounted for 94% of medication management claims (n = 51) in chronic pain management.15 In that study, the most common outcome was death (n = 29, 57%), followed by addiction (n = 12, 24%). In another analysis of 35 malpractice lawsuits involving opioid-related overdose in patients with chronic pain in the United States, there were a total of 20 deaths and the most commonly implicated opioid was methadone (n = 10, 50%).16 Unlike the above two studies, we did not limit the study population to chronic pain patients, and consequently, the results of our study were different from them. Until the 2000s, the use of opioids for treatment, especially in chronic non-cancer pain, was limited in South Korea.17 However, the use of opioids in patients with chronic non-cancer pain has increased recently in Korea5,7 and the guidelines for their use in these patients were recently published.4 Therefore, in our study, most cases were associated with acute pain rather than chronic pain. In addition, few cases were associated with addiction and the most commonly used opioid in our study was pethidine, and it was mainly used for the treatment of acute pain.\n\nAlthough we searched for cases from 1994, there were only two cases in the 1990s and two-thirds of the cases occurred post 2010. Since we included only the closed cases, some lawsuits from recent years may not be included in our study. Therefore, there may be more cases in reality than those reported here since 2010. An analysis of the trends in pain medicine claims of the ASA closed claims database reported that only 2% of pain medicine claims in the 1980s were related to medication mismanagement; however, this has increased significantly since 2000 by 17%.18 The authors described that this finding was associated with the national trends of opioid prescriptions. As described in the introduction, opioid use in Korea has also increased steadily, and the problems related to opioid overuse are expected to increase gradually in the future. Therefore, it is meaningful to investigate the serious complications of opioid administration in Korea and to raise its awareness among pain physicians who commonly prescribe them.\n\nIn our study, respiratory depression was the most common complication after opioid administration. Opioids have a direct inhibitory effect on neurons expressing μ - opioid peptide receptors at the respiratory centers in the brainstem. Opioid-induced respiratory depression (OIRD) leads to decreased oxygen supply to the brain, resulting in hypoxic brain injury. An analysis of ASA closed claim database from 1990 to 2009 found that of the 357 claims associated with postoperative pain management, 92 claims were associated with OIRD, of which 77% resulted in severe brain damage or death.19 In this study, respiratory depression was the most common complication, with very poor outcomes.\n\nTo prevent catastrophic outcomes after opioid administration, physicians need to be mindful of the possible complications of opioids. In our study, negligence of observation after opioid administration was the most common opioid-related malpractice recognized by the court. In addition, despite most of these complications occurring in inpatients, there was only one instance of administration of naloxone, the only antidote for OIRD. Based on these findings, we cautiously claim that there may be a lack of vigilance and a proper monitoring system of OIRD in Korea. According to the American society for pain management nursing (ASPMN) guidelines on monitoring for opioid-induced sedation and respiratory depression, serial sedation and respiratory assessments are recommended during opioid therapy.20 The assessment of sedation is very important in patients receiving opioid administration because sedation precedes OIRD. It is also important to assess the patients’ respiratory rate periodically, because a decreased respiratory rate is a premonitory sign of OIRD. If a patient is at risk for OIRD, it is recommended that continuous pulse oximetry and capnography monitoring be performed.21 A recent multicenter study reported that the implementation of ASPMN guidelines related to OIRD had a positive effect on the management of OIRD.22\n\nIt is recommended that in the outpatient setting, opioid administration should be started with the minimum dose and gradually increased as necessary.4 In one of the cases not dismissed by the court, a transdermal fentanyl patch was prescribed to an opioid-naive patient with an initial dose of 50 mcg in an outpatient setting (case no. 18). Although the analgesic effect may be insufficient in the early stage, this should be explained to the patient and the opioid titration performed over a safe period of time. Since OIRD is not an unavoidable complication like anaphylaxis, rather a preventable one, medical staff should be watchful for this complication and a system to aid its early detection and prevention must be in place.\n\nIn addition to practices to prevent OIRD, the following precautions are necessary while administering opioids. Firstly, the patient’s complete medical history which includes pre-existing diseases should be obtained before opioid administration. In one case in our study, pethidine use in a patient with increased intracranial pressure from intracranial bleeding was recognized as a malpractice (case no. 16). Pethidine, which was most commonly implicated in this study, requires caution in its use because it has many contraindications such as bronchial asthma, heart failure, convulsive disorders, and increased intracranial pressure, different from other opioids.23 Pethidine is not recommended in both acute and chronic pain because it has a wider side-effect profile than other opioids but no specific advantage.24 In one case related to anaphylaxis, it was recognized as a malpractice to re-administer pentazocine to a patient who had previously experienced a hypersensitivity reaction to it (case no. 1). In patients with a history of hypersensitivity to a specific drug, additional exposure to that may result in anaphylaxis.25 Therefore, history taking of drug hypersensitivity is very important. In addition, patients with liver or kidney disease can overdose inadvertently if their doses are not adjusted for impaired renal or hepatic drug clearance, with side effects occurring at doses considered safe for the general population.26 Secondly, opioid administration can cause the physician to miss important diagnostic clues. In two cases of the study, the delayed diagnoses (postoperative compartment syndrome and small bowel perforation) due to opioid administration were recognized as the malpractice by the court (case no. 10, 13). In the past, the use of opioids had been discouraged in emergencies such as acute abdominal pain due to the concerns about masking important diagnostic clues. However, it has been reported that opioid analgesia is safe and does not delay diagnosis in emergencies.27 Nevertheless, accurate diagnosis should be given significance over analgesic administration during emergencies and physicians should not neglect the diagnosis of pain-causing diseases while providing adequate analgesia. Lastly, opioid abuse should be considered especially when opioids are prescribed for long-term use.4,28 There is only one such case in our study (case no. 3), and to date, Korea has seemed relatively safe from this problem.9 However, the opioid use in chronic non-cancer pain patients has recently increased in South Korea7 and the recent legalization of medical marijuana in South Korea could provoke the problem related to opioid abuse.29 A recently reported single-center study in South Korea reported that one-fourth of the study participants showed opioid use disorders.30 In the future, this problem is expected to increase in South Korea as seen in the Western countries. Therefore, Korean physician will have to pay attention to this problem.\n\nThe results of our study should be interpreted cautiously for several reasons. Firstly, our study could not represent the comprehensive features of opioid-related complications. Due to the highly contentious nature of our data, the complications in our study skewed toward rare and serious complications. Further, cases that ended in agreement or arbitration have not been included here. In a previous study of medical disputes regarding pain management in Korea using insurance database, there were no cases related to opioids.31 Another recent study using the Korea Medical Dispute Medication and Arbitration Agency (KMDMAA) data from 2012 to 2016 reported that a total of four cases were associated with medical complications or drug side effects.32 According to the additional data that we directly obtained through the KMDMAA, there were a total of six cases associated with opioids from 2012 to 2018. However, we excluded this data from the analysis because of the unavailability of detailed clinical information to determine the causality between opioid use and outcomes. In addition, in Korea, the act of medical malpractice damage’s relief and medication for medical dispute resolution has been enacted since 2012.33 Considering the previous legal environment, many medical malpractices before 2012 might not lead to litigation. Secondly, the clinical features described in judicial sentences had limitations, especially in cases that were dismissed. Lastly, although medical appraisers’ opinions play an important role in judges’ malpractice decisions, a judge’s subjectivity may also affect the decision. Despite these limitations, this study provides useful information on rare adverse events that would be difficult to study prospectively without an expensive and time-consuming large multicenter design. Awareness of these rare, but critical, adverse events may help pain physicians to recognize these complications earlier, and prompt them to take remedial action before it is too late.\n\nConclusion\nIn conclusion, healthcare professionals should be acquainted with the risk of serious adverse events surrounding the prescription of opioids. In addition, national health policies to prevent such fatal complications are necessary to ensure patient safety and to mitigate medical liability.\n\nAcknowledgments\nWe would like to thank Editage for English language editing.\n\nDisclosure\nThe authors declare no conflicts of interest in this work.\n==== Refs\nReferences\n1. Austrup \nML , Korean \nG . Analgesic agents for the postoperative period: opioids\n. Surg Clin North Am . 1999 ;79 (2 ):253 –273\n. doi:10.1016/S0039-6109(05)70382-0 10352654 \n2. Moon \nDE . Treatment of cancer pain\n. Korean J Pain . 2002 ;15 (1 ):1 –12\n.\n3. Park \nHJ , Moon \nDE . 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"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7090",
"issue": "13()",
"journal": "Journal of pain research",
"keywords": "acute pain; adverse drug events; complications; legislation and jurisprudence; medical liability; opioids",
"medline_ta": "J Pain Res",
"mesh_terms": null,
"nlm_unique_id": "101540514",
"other_id": null,
"pages": "1525-1532",
"pmc": null,
"pmid": "32612380",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "31169740;20234314;31558315;21668758;22786463;18443635;23342201;26495080;26378399;10352654;31091504;11798222;28119768;21249672;31425231;20556211;32114483;29064874;10393001;31569915;21893302;7471736;25536092;20712819;31094877;21668754;23870413",
"title": "Medicolegal Consideration to Prevent Medical Malpractice Regarding Opioid Administration: An Analysis of Judicial Opinion in South Korea.",
"title_normalized": "medicolegal consideration to prevent medical malpractice regarding opioid administration an analysis of judicial opinion in south korea"
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"abstract": "We report 3unusual cases of cancer of unknown primary(CUP)with a long-term survival after chemotherapy. A 56-yearold man was diagnosed as having CUP with invasion of an enlarged carcinoma 20 cm in size to the pancreas and peritoneal dissemination. He received chemotherapy with paclitaxel, carboplatin, and gemcitabine. After the chemotherapy, CT scan and PET-CT revealed no evidence of disease, so tumor resection was performed. The subsequent pathological findings revealed no cancer and a complete pathological response. The patient is currently alive 4 years after the first surgery, without evidence of recurrence and adjuvant chemotherapy. A 60-year-old man was diagnosed as having CUP with an undifferentiated carcinoma and lymph node metastasis. He received chemotherapy with paclitaxel, carboplatin, and gemcitabine. However, unanticipated adverse events(finger ulcer)occurred. Thus, the chemotherapy was changed to paclitaxel, carboplatin, and etoposide. The patient is currently alive 4.2 years after the first chemotherapy, without evidence of recurrence. A 59-year-old man was diagnosed as having CUP with neuroendocrine carcinoma(NEC)and lymph node metastasis. He received chemotherapy with irinotecan and cisplatin. The lymph node metastases disappeared, but bone metastasis was found. The chemotherapy was changed to paclitaxel, carboplatin, and etoposide. The patient is currently alive 3.5 years after the first chemotherapy, without evidence of recurrence. We report 3rare cases of high-grade malignant CUP with complete pathological response, partial response, stable disease, and long-term survival after chemotherapy.",
"affiliations": "Dept. of Surgery, Japan Community Healthcare Organization Nihonmatsu Hospital.",
"authors": "Gonda|Kenji|K|;Shibata|Masahiko|M|;Yasuda|Masami|M|;Tachiya|Yosuke|Y|;Hatakeyama|Yuichi|Y|;Kono|Koji|K|;Rokkaku|Yuichi|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009382:Neoplasms, Unknown Primary; D049268:Positron-Emission Tomography; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "950-952",
"pmc": null,
"pmid": "29066706",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three Cases of High-Grade Malignant Cancer of Unknown Primary with a Long-Term Survival.",
"title_normalized": "three cases of high grade malignant cancer of unknown primary with a long term survival"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-169324",
"fulfillexpeditecriteria": "1",
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"abstract": "Islet cell transplantation is a promising functional cure for type 1 diabetes; however, maintaining long-term islet graft function and insulin independence is difficult to achieve. In this short report we present a patient with situs inversus, who at the time of islet transplantation had a 26-year history of type 1 diabetes, complicated by hypoglycemic unawareness and severe hypoglycemic events. After a single allogeneic islet transplant of a low islet mass, and despite developing de novo anti-insulin and anti-GAD65 autoantibodies, the patient has remarkably maintained insulin independence with tight glycemic control and normal metabolic profiles for 10 years, after receiving prolonged non-T-cell depleting immunosuppression.",
"affiliations": "a Division of Transplant, Department of Surgery , University of Illinois at Chicago, Chicago , Illinois.;a Division of Transplant, Department of Surgery , University of Illinois at Chicago, Chicago , Illinois.;a Division of Transplant, Department of Surgery , University of Illinois at Chicago, Chicago , Illinois.;a Division of Transplant, Department of Surgery , University of Illinois at Chicago, Chicago , Illinois.;a Division of Transplant, Department of Surgery , University of Illinois at Chicago, Chicago , Illinois.;a Division of Transplant, Department of Surgery , University of Illinois at Chicago, Chicago , Illinois.;a Division of Transplant, Department of Surgery , University of Illinois at Chicago, Chicago , Illinois.",
"authors": "Williams|Jack|J|;Jacus|Nicholas|N|;Kavalackal|Kevin|K|;Danielson|Kirstie K|KK|;Monson|Rebecca S|RS|;Wang|Yong|Y|;Oberholzer|Jose|J|",
"chemical_list": "D001786:Blood Glucose; D007328:Insulin",
"country": "United States",
"delete": false,
"doi": "10.1080/19382014.2018.1451281",
"fulltext": "\n==== Front\nIsletsIsletsKISLkisl20Islets1938-20141938-2022Taylor & Francis 30024826145128110.1080/19382014.2018.1451281Short ReportOver ten-year insulin independence following single allogeneic islet transplant without T-cell depleting antibody induction J. WILLIAMS ET AL.IsletsWilliams Jack a*Jacus Nicholas a*Kavalackal Kevin aDanielson Kirstie K. abMonson Rebecca S. aWang Yong aOberholzer Jose aa Division of Transplant, Department of Surgery, University of Illinois at Chicago, Chicago, Illinoisb Division of Epidemiology & Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IllinoisCONTACT José Oberholzer jober@uic.eduDivision of Transplant, Department of Surgery, University of Illinois at Chicago, 840 S. Wood Street, Rm 428, Chicago, IL 60612* Equal contribution.\n\n2018 19 7 2018 19 7 2018 10 4 168 174 1 9 2017 28 2 2018 7 3 2018 © 2018 The Authors.2018The AuthorsThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.ABSTRACT\nIslet cell transplantation is a promising functional cure for type 1 diabetes; however, maintaining long-term islet graft function and insulin independence is difficult to achieve. In this short report we present a patient with situs inversus, who at the time of islet transplantation had a 26-year history of type 1 diabetes, complicated by hypoglycemic unawareness and severe hypoglycemic events. After a single allogeneic islet transplant of a low islet mass, and despite developing de novo anti-insulin and anti-GAD65 autoantibodies, the patient has remarkably maintained insulin independence with tight glycemic control and normal metabolic profiles for 10 years, after receiving prolonged non-T-cell depleting immunosuppression.\n\nKEYWORDS\nautoimmunityimmunosuppressioninsulin independenceislet transplantationT-cell depletionNational Institute of Diabetes and Digestive and Kidney Diseases10.13039/100000062R25DK105924This work was supported by the Chicago Diabetes Project; and the National Institute of Diabetes and Digestive and Kidney Diseases under Grant R25DK105924.\n==== Body\nIntroduction\nIn 2000, Shapiro et al. reported improvement in the efficacy of islet transplantation as a functional cure for type 1 diabetes (T1D) using the Edmonton Protocol, which involved standardizing islet cell isolation procedures, the number (dose) of transplanted islets, and the use of steroid-free immunosuppression.1 However, only 1 of the 36 recipients from the International Trial of the Edmonton Protocol remained insulin independent after three years.2 With continuing progress in both islet isolation and clinical management after transplant, the rate of insulin independence following islet transplantation has steadily improved. For patients transplanted between 2007 and 2010, 44% were insulin independent at three years.3 More recently, our research group demonstrated that 60% of patients remained insulin independent at five years, without the use of T-cell depleting antibody induction immunosuppression.4 Despite these improvements, in a substantial number of cases, islet cell transplantation is still followed by a gradual decrease in the production of insulin and partial (to complete) graft loss.5 Long-term maintenance of islet graft function will be central to islet transplantation becoming a viable treatment option for T1D patients.\n\nPatient and methods\nA 35-year-old, Non-Hispanic white female with situs inversus and a 26-year history of T1D complicated by hypoglycemia unawareness and resultant severe hypoglycemic events received an islet transplant at the University of Illinois at Chicago (UIC) Hospital (consent obtained under Institutional Research Board approval 2004-0532). In the months prior to transplant, she was experiencing approximately four episodes per week of blood glucose <3.1 mmol/L, the majority of times without symptoms, and within the nine months prior to her transplant she had a severe hypoglycemic event that required EMS intervention, therefore meeting inclusion criteria for the UIC clinical trial (NCT00679041). The patient's HbA1c at the time of transplant was 50 mmol/mol (6.7%) and she was requiring 0.5–0.7 units of insulin per kilogram weight per day (U/kg/day) via subcutaneous pump. The patient's other medical history included: a right partial thyroidectomy for follicular adenoma sixteen years prior to transplant; a left vitrectomy eight years before transplant; and subsequent surgical treatment for both glaucoma and a cataract in the same eye three years prior to transplant. Additionally, four years before transplant, the patient had an episode of idiopathic pancreatitis. The patient was CMV and EBV positive prior to transplant.\n\nRegarding the islet isolation, the pancreas donor was a 60-year-old woman, weighing 98 kg (BMI of 34.9), who died of a stroke after approximately a four-day hospital stay. The donor was CMV and EBV positive. The pancreatic cold ischemia time was six hours, two minutes. The islet isolation was performed at UIC's islet isolation facility, using Liberase (lot# 93456920, Roche, Basel, CH) according to the UIC isolation protocol,6 and yielded a total of 387,092 islet equivalents (IEq), with a viability of 90%, and a glucose stimulation insulin secretion (GSIS) index of 3.5. At transplant, the patient weighed 58.6 kg and thus received an islet dose of 6,606 IEq/kg; the total transplanted tissue volume was 5.5 mL. Because of her situs inversus, an ultrasound vein mapping was performed pre-transplant to visualize the hepatic vasculature. There were minor vascular access difficulties noted, attributed to the unique anatomy of her situs inversus, but only one venous puncture was performed.\n\nThe post-transplant hospital course was notable for minor pulmonary sub-segmental atelectasis, as well as the development of a relatively large hepatic hematoma (9 × 12 cm). The patient remained hospitalized for eight days following transplant for monitoring of the hepatic hematoma, as well as management of both pain and significant nausea and vomiting. The patient completed the standard seven day course of prophylactic enoxaparin sodium (Lovenox, Sanofi, Paris, FR) following transplant, with no increase in the hematoma size. Approximately two months after transplant, the patient fell, striking her abdomen. As her hemoglobin after the fall was 64 g/L (down from 81 g/L the week before), the patient was hospitalized to rule out a new traumatic intra-hepatic bleed (a slight increase to 13 × 11 cm was seen), and for transfusion of three units of blood. The hematoma gradually resolved over the next 11 months, decreasing to a final size of 3.7 × 3 cm.\n\nResults\nAfter receiving the islet cell transplant, the patient had no further episodes of severe hypoglycemia, and the episodes of asymptomatic hypoglycemia (not meeting criteria for severe) tapered to almost none. The patient developed several additional medical conditions over the years as well. One year following transplant, due to concerning abnormalities seen on ultrasound, the patient had a completion right thyroidectomy. Pathologic examination found papillary carcinoma, as well as a follicular adenoma. Four years following transplant, the patient had a cholecystectomy due to chronic cholecystitis. Throughout follow-up, the patient has not developed any opportunistic infections.\n\nThe patient's induction immunosuppression regimen included etanercept (50 mg pre-transplant and 25 mg on days 3, 7, and 10 post-transplant; Enbrel, Amgen, Thousand Oaks, CA) and daclizumab (150 mg IV every 4 weeks; Zenapax, Roche, Basel, CH). The patient's maintenance immunosuppression included tacrolimus (Prograf, Astellas, Tokyo, JP) with targeted trough levels of 3–6 ng/mL throughout the study, and sirolimus (Rapamune, Pfizer, New York, NY) with targeted trough levels of 10–15 ng/mL for the first three months post-transplant, then 7–10 ng/mL thereafter. Two years following transplant, the patient had an anaphylactoid reaction to daclizumab, which was then immediately discontinued. Due to persistent oral ulcers, sirolimus was also switched to mycophenolate mofetil 1000 mg twice daily (CellCept, Genentech, South San Francisco, CA), then switched to mycophenolic acid (Myfortic, Novartis, Basel, CH) at 720 mg twice daily five years post-transplant. The patient is currently on a regimen of tacrolimus and mycophenolic acid at 1 mg twice daily and 720 mg twice daily, respectively.\n\nThe patient had 0% panel reactive antibodies (PRA), and was negative for anti-GAD65, anti-ICA, and anti-IA2 antibodies prior to transplant. Since transplant, the patient has not developed any PRA (remains at 0%). However at year two, anti-insulin antibodies developed at >50 IU/mL, which have remained at ∼40 IU/mL since. At year three post-transplant, anti-GAD antibodies increased to ∼24 IU/mL through year six, and then decreased (Figure 1; arrows represent change in immunosuppression noted above). Anti-ICA and anti-IA2 antibodies remained negative throughout follow-up.\nFigure 1. Anti-GAD65 autoantibody levels over 10 year follow-up.\n\n\n\n\nIn the first days following transplant, the patient required 8 units per day (U/d) of insulin glargine (Lantus, Sanofi, Paris, FR). Ten days after transplant, the dose was reduced to 4 U/d. Approximately two months after transplant, the patient became insulin independent. As part of the UIC protocol, the patient was on exenatide (Byetta, AstraZeneca, London, UK) from 5–10 µg twice a day intermittently until ten weeks following the transplant, when it was discontinued due to severe intolerance with intractable nausea and vomiting. The patient was started on sitagliptin (Januvia, Merck, Kenilworth, NJ) 100 mg daily two years following transplant to help improve glycemic control, and during years 2–3 post-transplant the patient intermittently required low dose (∼4 U/month) insulin aspart (Novolog, Novo Nordisk, Bagsværd, DK) for occasional high fasting glucose readings, but since that time she has again been insulin independent. The 10-year glycemic and HbA1c profiles (Figure 2) show that the patient maintained normal fasting blood glucose levels at ∼5.5 mmol/L and HbA1c levels between 40 and 51 mmol/mol (5.8% – 6.8%).\nFigure 2. HbA1c and fasting blood glucose levels over 10 year follow-up.\n\n\n\n\nTo monitor graft function, metabolic tests were performed periodically over the 10 years including: the oral glucose tolerance test, the intravenous glucose tolerance test, the mixed meal test, and the glucagon stimulation test. As shown in Figure 3, the transplanted islet graft consistently produced detectable fasting C-peptide levels which then appropriately increased in response to glucose/glucagon stimulation during metabolic testing over the 10 years following transplant. Figure 4 depicts the insulin and glucose responses from the individual metabolic tests conducted at 10-years of insulin independence, with appropriate responses to glucose/glucagon stimulation in all cases (see Figure 3 for corresponding C-peptide levels at 10-years). Figures 3 & 4 graphically illustrate the ongoing islet graft function.\nFigure 3. C-Peptide levels obtained during metabolic testing over 10-year follow up. (A): Oral Glucose Tolerance Test. (B): Intravenous Glucose Tolerance Test. (C): Mixed Meal Test. (D): Glucagon Stimulation Test.\n\n\nFigure 4. Insulin and glucose levels from metabolic testing at 10 years (see Figure 2 for corresponding C-peptide levels). (A): Oral Glucose Tolerance Test. (B): Intravenous Glucose Tolerance Test. (C): Mixed Meal Test. (D): Glucagon Stimulation Test.\n\n\n\n\nDespite the long-term use of immunosuppression, which can potentially have nephrotoxic effects, the patient's creatinine post-transplantation remained stable and normal (Figure 5A). In addition, the patient's overall cardiovascular risk profile improved over time as indicated by regression of carotid intima-media thickness (CIMT), specifically the common carotid artery (Figure 5B).\nFigure 5. Renal function and carotid intima-media thickness over 10 year follow-up. (A): Serum creatinine level. (B): Carotid intima-media thickness of the common and internal carotid arteries.\n\n\n\n\nDiscussion\nThis short report describes a patient achieving more than ten years of insulin independence following a single low mass islet cell transplant. A recent study reported a median duration of insulin independence after a single islet transplant (mean 7459 IEq/kg) of 11.3 months.7 It is notable that the current patient received an approximately similar islet mass of only 6,606 IEq/kg and has remained insulin independent for over 10 years. It is currently thought that 9,000-10,000 IEq/kg (over multiple transplants) is required to attain insulin independence.8 After transplant, the patient has consistently displayed substantial improvement in glycemic control, insulin independence, and islet graft function as indicated by metabolic testing. While the patient's HbA1c was relatively low prior to transplant, the Diabetes Control and Complications Trial has clearly established the benefits of lowering HbA1c as close to normal as possible, with a reduction in both incidence and progression of long-term complications.9\n\nSuccess of islet transplantation is based on both donor and recipient factors. In this case the donor was a female, with highly potent islets as evident by a GSIS value >3, both factors that have been previously associated with enhanced islet transplant success.3,10 In contrast, the donor's older age potentially resulted in a lower quantity of islets isolated, resulting in 6,606 IEq/kg for the recipient, which is less than the currently recommended infusion amount. In addition, pancreata from donors where the cause of death is non-traumatic (as in this case) yield a lower beta-cell mass for the recipient than donors where the cause of death is trauma.11 Furthermore, certain recipient factors are integral to long-term graft success. For example, this patient only required 0.6 U/kg/day insulin on average prior to transplant indicating the patient was insulin sensitive. Moreover, the patient had a favorable immune profile for islet transplant. She had ∼0% panel reactive antibodies, as well as being negative for anti-GAD65, anti-ICA, and anti-IA2 prior to transplant.\n\nIn general, transplant patients receive intense induction immunosuppression immediately post-transplant, followed by a less intense maintenance regimen.12 This patient was maintained on IL-2 receptor blockade (daclizumab) for two years to reduce the risk of rejection while maintaining relatively low target trough levels of tacrolimus. Interestingly, after cessation of daclizumab, the patient presented with de novo anti-insulin (year two) and anti-GAD65 autoantibodies (year three, Figure 1) and worsening glycemic control (Figure 2). A prior study has shown that the development of new autoantibodies after transplant is associated with significantly lower graft survival.13 Due to this development of T1D autoimmunity, target tacrolimus trough levels were increased from 3–6 ng/mL to 5–7 ng/mL. Subsequently, glycemic control improved, despite persistently elevated autoantibodies. The remarkable duration of graft function with the prolonged use of daclizumab is unique,14 when several prior studies have found T-cell depleting immunosuppression to be associated with more durable graft function.15 The patient also received etanercept as part of the immunosuppression regimen, which has been shown to be associated with higher rates of insulin independence,15 and exenatide, which is unique to the UIC Protocol,4 both of which may have played a role in the patient's excellent graft function.\n\nThis case highlights the challenges in the field of islet cell transplantation: inter-individual variability in outcomes and limited predictors of success.3 Some patients achieve long-term insulin independence with an unexceptional islet preparation, while other patients never achieve euglycemia despite multiple islet cell transplants. Because of this patient's frequent clinical visits following transplant, she received highly personalized care, which likely contributed to her prolonged insulin independence. Additionally, characteristics of the islets (e.g., potency) and recipient (e.g., low insulin requirement pre-transplant, zero PRA) were present that have been associated with better long term graft function. The use of etanercept, and possibly exenatide, and prolonged, non-T-cell depleting immunosuppression may also have played a role in the patient's long-term graft function. Conversely, long-term function has occurred despite a low transplanted islet mass, a post-infusion liver hematoma, the lack of T-cell depleting antibody induction, and the development of de novo anti-insulin and anti-GAD65 autoantibodies after islet transplant. The patient has continued to maintain remarkable insulin independence and glycemic control more than 10 years after a single islet cell infusion, however no definitive conclusions can be made from this case with regards to donor, recipient or transplant characteristics predictive of transplant success.\n\nDisclosure of potential conflicts of interest\nNo potential conflicts of interest were disclosed.\n\nAcknowledgments\nThe authors thank the UIC Islet Isolation team for the isolation of islet cells for transplantation, and Joan Martellotto, RN, PhD and Leelamma George, RN, MSN, of UIC for their collaboration in the care of the patients.\n==== Refs\nReferences\n1. Shapiro AM , Lakey JR , Ryan EA , Korbutt GS , Toth E , Warnock GL , Kneteman NM , Rajotte RV \nIslet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen . N Engl J Med. \n2000 ;343 (4 ):230 –8 . doi:10.1056/NEJM200007273430401 . PMID:1091100410911004 \n2. Shapiro AM , Ricordi C , Hering BJ , Auchincloss H , Lindblad R , Robertson RP , Secchi A , Brendel MD , Berney T , Brennan DC , et al. \nInternational trial of the Edmonton protocol for islet transplantation . N Engl J Med. \n2006 ;355 (13 ):1318 –30 . doi:10.1056/NEJMoa061267 . PMID:1700594917005949 \n3. Barton FB , Rickels MR , Alejandro R , Hering BJ , Wease S , Naziruddin B , Oberholzer J , Odorico JS , Garfinkel MR , Levy M , et al. \nImprovement in outcomes of clinical islet transplantation: 1999–2010 . Diabetes Care. \n2012 ;35 (7 ):1436 –45 . doi:10.2337/dc12-0063 . PMID:2272358222723582 \n4. Qi M , Kinzer K , Danielson KK , Martellotto J , Barbaro B , Wang Y , Bui JT , Gaba RC , Knuttinen G , Garcia-Roca R , et al. \nFive-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience . Acta Diabetol. \n2014 :51 (5 ):833 –43 . doi:10.1007/s00592-014-0627-6 . PMID:2503431125034311 \n5. Wisel SA , Braun HJ , Stock PG \nCurrent outcomes in islet versus solid organ pancreas transplant for beta-cell replacement in type 1 diabetes . Curr Opin Organ Transplant. \n2016 ;21 (4 ):399 –404 . doi:10.1097/MOT.0000000000000332 . PMID:2725857827258578 \n6. Gangemi A , Salehi P , Hatipoglu B , Martellotto J , Barbaro B , Kuechle JB , Qi M , Wang Y , Pallan P , Owens C , et al. \nIslet transplantation for brittle type 1 diabetes: the UIC protocol . Am J Transplant. \n2008 ;8 (6 ):1250 –61 . doi:10.1111/j.1600-6143.2008.02234.x . PMID:1844492018444920 \n7. Al-Adra DP , Gill RS , Imes S , O'Gorman D , Kin T , Axford SJ , Xinzhe S , Senior PA , Shapiro AM \nSingle-donor islet transplantation and long-term insulin independence in select patients with type 1 diabetes mellitus . Transplantation. \n2014 ;98 (9 ):1007 –12 . doi:10.1097/TP.0000000000000217 . PMID:2491103724911037 \n8. Ahearn AJ , Parekh JR , Posselt AM \nIslet transplantation for Type 1 diabetes: where are we now? \nExpert Rev Clin Immunol. \n2015 ;11 (1 ):59 –68 . doi:10.1586/1744666X.2015.978291 . PMID:2545481625454816 \n9. The Diabetes Control and Complications Trial Research Group \nThe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus . N Engl J Med. \n1993 ;329 (14 ):977 –86 . doi:10.1056/NEJM199309303291401 . PMID:83669228366922 \n10. Marchese E , Rodeghier C , Monson RS , McCracken B , Shi T , Schrock W , Martellotto J , Oberholzer J , Danielson KK \nEnumerating beta-cells in whole human islets: sex differences and associations with clinical outcomes after islet transplantation . Diabetes Care. \n2015 ;38 :e176 –177 . doi:10.2337/dc15-0723 . PMID:2638438826384388 \n11. Balamurugan AN , Naziruddin B , Lockridge A , Tiwari M , Loganathan G , Takita M , Matsumoto S , Papas K , Trieger M , Rainis H , et al. \nIslet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR) 1999–2010 . Am J Transplant. \n2014 ;14 (11 ):2595 –606 . doi:10.1111/ajt.12872 . PMID:2527815925278159 \n12. Kirk AD \nInduction immunosuppression . Transplantation. \n2006 ;82 (5 ):593 –602 . doi:10.1097/01.tp.0000234905.56926.7f . PMID:1696928016969280 \n13. Piemonti L , Everly MJ , Maffi P , Scavini M , Poli F , Nano R , Cardillo M , Melzi R , Mercalli A , Sordi V , et al. \nAlloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes . Diabetes. \n2013 ;62 (5 ):1656 –64 . doi:10.2337/db12-1258 . PMID:2327490223274902 \n14. Gabardi S , Martin ST , Roberts KL , Grafals M \nInduction immunosuppressive therapies in renal transplantation . Am J Health Syst Pharm. \n2011 ;68 (3 ):211 –8 . doi:10.2146/ajhp090636 . PMID:2125802621258026 \n15. Bellin MD , Barton FB , Heitman A , Harmon JV , Kandaswamy R , Balamurugan AN , Sutherland DE , Alejandro R , Hering BJ \nPotent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes . Am J Transplant. \n2012 ;12 (6 ):1576 –83 . doi:10.1111/j.1600-6143.2011.03977.x . PMID:2249460922494609\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1938-2014",
"issue": "10(4)",
"journal": "Islets",
"keywords": "T-cell depletion; autoimmunity; immunosuppression; insulin independence; islet transplantation",
"medline_ta": "Islets",
"mesh_terms": "D000328:Adult; D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D005260:Female; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007328:Insulin; D016381:Islets of Langerhans Transplantation; D008991:Monitoring, Physiologic; D010346:Patient Care Management; D016896:Treatment Outcome",
"nlm_unique_id": "101495366",
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"pages": "168-174",
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"pmid": "30024826",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "8366922;18444920;25454816;23274902;25278159;22494609;25034311;24911037;17005949;22723582;21258026;27258578;16969280;10911004;26384388",
"title": "Over ten-year insulin independence following single allogeneic islet transplant without T-cell depleting antibody induction.",
"title_normalized": "over ten year insulin independence following single allogeneic islet transplant without t cell depleting antibody induction"
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"abstract": "A 23-year-old male presented with a three-week-history of crampy abdominal pain and melaena. Colonoscopy revealed a friable mass filling the entire lumen of the cecum; histologically, it was classified as perivascular epithelioid cell tumor (PEComa). An magnetic resonance imaging scan showed, in addition to the primary tumor, two large mesenteric lymph node metastases and four metastatic lesions in the liver. The patient underwent right hemicolectomy and left hemihepatectomy combined with wedge resections of metastases in the right lobe of the liver, the resection status was R0. Subsequently, the patient was treated with sirolimus. After 4 mo of adjuvant mammalian target of rapamycin inhibition he developed two new liver metastases and a local pelvic recurrence. The visible tumor formations were again excised surgically, this time the resection status was R2 with regard to the pelvic recurrence. The patient was treated with 12 cycles of doxorubicin and ifosfamide under which the disease was stable for 9 mo. The clinical course was then determined by rapid tumor growth in the pelvic cavity. Second line chemotherapy with gemcitabine and docetaxel was ineffective, and the patient died 23 mo after the onset of disease. This case report adds evidence that, in malignant PEComa, the mainstay of treatment is curative surgery. If not achievable, the effects of adjuvant or palliative chemotherapy are unpredictable.",
"affiliations": "Wolfgang Scheppach, Nikolaus Reissmann, Department of Medicine, Juliusspital Wuerzburg, D-97070 Wuerzburg, Germany. gastroenterologie@juliusspital.de",
"authors": "Scheppach|Wolfgang|W|;Reissmann|Nikolaus|N|;Sprinz|Thomas|T|;Schippers|Ekkehard|E|;Schoettker|Bjoern|B|;Mueller|Justus G|JG|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D007069:Ifosfamide; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v19.i10.1657",
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"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "19(10)",
"journal": "World journal of gastroenterology",
"keywords": "Chemotherapy; Colon; Doxorubicin; Ifosfamide; Liver metastases; Mammalian target of rapamycin inhibitor; Perivascular epithelioid cell tumor; Sirolimus",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D017024:Chemotherapy, Adjuvant; D003082:Colectomy; D003110:Colonic Neoplasms; D003113:Colonoscopy; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm; D017809:Fatal Outcome; D006498:Hepatectomy; D006801:Humans; D007069:Ifosfamide; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D010386:Pelvic Neoplasms; D054973:Perivascular Epithelioid Cell Neoplasms; D011237:Predictive Value of Tests; D012086:Reoperation; D020123:Sirolimus; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "1657-60",
"pmc": null,
"pmid": "23539498",
"pubdate": "2013-03-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20048174;16359539;20567010;19237273;22619565;19092636;21218021;17455882;16327428;19124450",
"title": "PEComa of the colon resistant to sirolimus but responsive to doxorubicin/ifosfamide.",
"title_normalized": "pecoma of the colon resistant to sirolimus but responsive to doxorubicin ifosfamide"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-335107",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "Mycophenolate mofetil (MMF) with prednisolone has been associated with high remission rates when used as induction treatment for lupus nephritis. This prospective, multicentre, cohort study investigates the efficacy and safety of this regimen over 24 weeks in 213 Chinese patients with active lupus nephritis (Classes III, IV, V or combination). Baseline activity index (AI) was 6.91+/-3.33 and chronicity index (CI) was 1.9+/-1.2. The remission rate was 82.6% at 24 weeks (complete remission, 34.3%; partial remission, 48.4%). There were significant (P<0.01) improvements in kidney function shown by reductions in proteinuria, serum albumin, serum creatinine and creatinine clearance, as well as in systemic lupus erythematosus disease activity index (SLEDAI) scores. Independent risk factors influencing remission were pathological classification (including Class V and III or Class V and IV nephritis) and elevated serum creatinine at baseline (OR 2.967, 95% CI: 1.479-6.332, P=0.001 and OR 1.007, 95% CI: 1.002-1.011, P=0.001, respectively). Patients with concomitant membranous features on biopsy had a lower remission rate than those with Class III and IV nephritis (66.7% vs 87.3%, P=0.002). Renal biopsy was repeated in 25 patients following treatment. There was a transition to less severe pathological morphologies in majority of subjects. Infections were monitored throughout treatment: eight patients (3.8%) experienced bacterial infections, whereas herpes zoster occurred in seven patients. Nine patients (4.2%) suffered from gastrointestinal upset, which resolved without discontinuation of MMF. One patient became leucopenic, whereas another died from active disease unrelated to kidney symptoms. MMF combined with prednisolone is an effective and well-tolerated induction treatment for patients with active lupus nephritis and for controlling SLE systemic activity.",
"affiliations": "The Nephrology Division, Huashan Hospital, Fudan University, Shanghai, China. lufuming@medmail.com.cn",
"authors": "F|Lu|L|;Y|Tu|T|;X|Peng|P|;L|Wang|W|;H|Wang|W|;Z|Sun|S|;H|Zheng|Z|;Z|Hu|H|;|||",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1177/0961203308089428",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "17(7)",
"journal": "Lupus",
"keywords": null,
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000893:Anti-Inflammatory Agents; D001706:Biopsy; D002681:China; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D008297:Male; D009173:Mycophenolic Acid; D011239:Prednisolone; D011446:Prospective Studies; D012074:Remission Induction; D012189:Retrospective Studies",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "622-9",
"pmc": null,
"pmid": "18625634",
"pubdate": "2008-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A prospective multicentre study of mycophenolate mofetil combined with prednisolone as induction therapy in 213 patients with active lupus nephritis.",
"title_normalized": "a prospective multicentre study of mycophenolate mofetil combined with prednisolone as induction therapy in 213 patients with active lupus nephritis"
} | [
{
"companynumb": "NVSC2020CN062965",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Background Transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) frequently causes feeding artery stenosis or occlusion that may interfere with repeated treatment. Purpose To investigate the incidence and predictors of hepatic arterial damage (HAD) after drug-eluting bead-TACE (DEB-TACE) in comparison with conventional TACE (Conv-TACE). Material and Methods We retrospectively analyzed 54 patients who underwent DEB-TACE for HCC as an initial treatment with follow-up angiography and 54 patients who underwent Conv-TACE using doxorubicin-lipiodol mixture and gelfoam particles for comparison. HAD was evaluated after a single session of TACE and graded as follows: grade I, no significant wall irregularity; grade II, overt stenosis; grade III, occlusion. Results The incidence of HAD was significantly higher in the DEB-TACE group than the Conv-TACE group when analyzed per branch (odds ratio [OR], 6.36; P < 0.001) and per patient (OR, 3.15; P = 0.005). For each HAD grade, the mean doxorubicin dose was greater in the DEB-TACE group than in the Conv-TACE group ( P < 0.001, P = 0.053, and P = 0.01 for grades I, II, and III, respectively). In multivariate analysis, risk factors of HAD included mean doxorubicin dose and selective embolization in the Conv-TACE group ( P = 0.03 and P < 0.001, respectively) and mean doxorubicin dose in the DEB-TACE group ( P = 0.004). Conclusion The incidence and grade of HAD were higher after DEB-TACE compared to Conv-TACE with doxorubicin dose as a possible risk factor. HAD was independent of overall survival in both groups.",
"affiliations": "1 Department of Radiology, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Republic of Korea.;1 Department of Radiology, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Republic of Korea.;1 Department of Radiology, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Republic of Korea.;1 Department of Radiology, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Republic of Korea.;1 Department of Radiology, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Republic of Korea.;1 Department of Radiology, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Republic of Korea.;2 Department of Internal Medicine, Institute of Gastroenterology, Yonsei University, College of Medicine, Seoul, Korea.;2 Department of Internal Medicine, Institute of Gastroenterology, Yonsei University, College of Medicine, Seoul, Korea.;1 Department of Radiology, Research Institute of Radiological Science, Yonsei University, College of Medicine, Seoul, Republic of Korea.",
"authors": "Lee|Seungsoo|S|;Kim|Kyoung Min|KM|;Lee|Shin Jae|SJ|;Lee|Kwang-Hun|KH|;Lee|Do Yun|DY|;Kim|Man Deuk|MD|;Kim|Do Young|DY|;Kim|Seung Up|SU|;Won|Jong Yun|JY|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004998:Ethiodized Oil; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1177/0284185116648501",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0284-1851",
"issue": "58(2)",
"journal": "Acta radiologica (Stockholm, Sweden : 1987)",
"keywords": "Drug-eluting bead; doxorubicin; hepatic arterial damage; transarterial chemoembolization",
"medline_ta": "Acta Radiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000792:Angiography; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D004317:Doxorubicin; D004998:Ethiodized Oil; D005260:Female; D006499:Hepatic Artery; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8706123",
"other_id": null,
"pages": "131-139",
"pmc": null,
"pmid": "27217418",
"pubdate": "2017-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Hepatic arterial damage after transarterial chemoembolization for the treatment of hepatocellular carcinoma: comparison of drug-eluting bead and conventional chemoembolization in a retrospective controlled study.",
"title_normalized": "hepatic arterial damage after transarterial chemoembolization for the treatment of hepatocellular carcinoma comparison of drug eluting bead and conventional chemoembolization in a retrospective controlled study"
} | [
{
"companynumb": "KR-JNJFOC-20170215739",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "As a result of improved diagnostic and reparative techniques, congenital heart diseases are becoming a significant problem for women of childbearing age. Nowadays, more pregnant women in the West are being diagnosed with an acquired heart disease because of the tendency to delay childbearing and increasing age-related risk of developing complications of hypertension, diabetes, obesity and other diseases. According to the Lithuanian Health Information Centre, the incidence of cardiovascular diseases in pregnancy is decreasing in Lithuania, from 1.4% in 2014 to 1% in 2016 (1). Heart diseases can aggravate maternal adaptive capabilities and complications that pose a threat to mother and foetus can occur. Management of such conditions presents a serious therapeutic challenge to multidisciplinary team. The aim of this article is to discuss the course of pregnancy and peculiarities of maternal and foetal care in a woman with hemodynamically significant heart disease.\nWe present a clinical case of a 30-year-old nuliparous woman who was diagnosed with mitral valve disease with critical stenosis, grade II/III mitral valve insufficiency, moderate-severe pulmonary hypertension, heart failure stage C, and NYHA functional class II.\nPregnancy in conjunction with heart disease is a complicated condition that requires multidisciplinary prenatal care (consisting of an obstetrician gynaecologist, cardiologist, anaesthesiologist). Low molecular weight heparins should be the first choice medication for antithrombotic prophylaxis. Since pregnancy can aggravate a heart disease, preconception counselling and evaluation of the heart function are recommended.",
"affiliations": "Faculty of Medicine, ilnius University Vilnius, Lithuania.;Faculty of Medicine, ilnius University Vilnius, Lithuania.;Centre of Obstetrics and Gynaecology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.;Faculty of Medicine, ilnius University Vilnius, Lithuania.;Faculty of Medicine, ilnius University Vilnius, Lithuania.;Faculty of Medicine, ilnius University Vilnius, Lithuania.",
"authors": "Bužinskienė|Diana|D|;Domža|Gintautas|G|;Dulko|Justyna|J|;Olšauskaitė|Miglė|M|;Drąsutienė|Gražina|G|;Liekienė|Daina|D|",
"chemical_list": null,
"country": "Lithuania",
"delete": false,
"doi": "10.6001/actamedica.v25i3.3861",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1392-0138",
"issue": "25(3)",
"journal": "Acta medica Lituanica",
"keywords": "heart disease; heart failure; mitral valve insufficiency; pregnancy; valvular heart disease",
"medline_ta": "Acta Med Litu",
"mesh_terms": null,
"nlm_unique_id": "9442465",
"other_id": null,
"pages": "140-150",
"pmc": null,
"pmid": "30842703",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "10709851;1157366;12685620;12840093;17210844;17643825;18848134;20083915;20922410;21091604;21962953;22658765;23395071;23726261;26140720;26651557;471869;6356942;984086",
"title": "Valvular heart disease during pregnancy: a clinical case and a literature review.",
"title_normalized": "valvular heart disease during pregnancy a clinical case and a literature review"
} | [
{
"companynumb": "PHHY2019LT024029",
"fulfillexpeditecriteria": "1",
"occurcountry": "LT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nThe objective of the study was to determine the longer-term efficacy and safety of initiating treatment for urgency-predominant urinary incontinence (UUI) in women diagnosed using a simple questionnaire rather than an extensive evaluation.\n\n\nMETHODS\nWomen completing a 12 week randomized controlled trial of fesoterodine therapy for UUI diagnosed by questionnaire were invited to participate in a 9 month, open-label continuation study. UUI and voiding episodes were collected using voiding diaries. Participant satisfaction was measured by questionnaire. Safety was assessed by the measurement of postvoid residual volume and adverse event monitoring; if necessary, women underwent a specialist evaluation. The longitudinal changes in UUI and voiding episodes were evaluated using linear mixed models adjusting for baseline.\n\n\nRESULTS\nOf the 567 women completing the randomized trial, 498 (87.8%) took at least 1 dose of medication during this open-label study. Compared with the baseline visit in the randomized trial, fesoterodine was associated with a reduction in total incontinence episodes per day and urgency incontinence episodes per day at the end of the open-label study (adjusted mean [SE], 4.6 [0.12] to 1.2 [0.13] and 3.9 [0.11] to 0.9 [0.11], respectively, P < .0001 for both). Most women were satisfied with treatment (89%, 92%, and 93% at 3, 6, and 9 months, respectively). Twenty-six women experienced 28 serious adverse events, 1 of which was considered possibly treatment related. Twenty-two women had a specialist evaluation: 5 women's incontinence was misclassified by the 3 Incontinence Questions; none experienced harm because of misclassification.\n\n\nCONCLUSIONS\nUsing a simple validated questionnaire to diagnose and initiate treatment for UUI in community-dwelling women is safe and effective, allowing timely treatment by primary care practitioners.",
"affiliations": "Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. hessr@upmc.edu",
"authors": "Hess|Rachel|R|;Huang|Alison J|AJ|;Richter|Holly E|HE|;Ghetti|Chiara C|CC|;Sung|Vivian W|VW|;Barrett-Connor|Elizabeth|E|;Gregory|W Thomas|WT|;Pinkerton|JoAnn V|JV|;Bradley|Catherine S|CS|;Kraus|Stephen R|SR|;Rogers|Rebecca G|RG|;Subak|Leslee L|LL|;Johnson|Karen C|KC|;Arya|Lily A|LA|;Schembri|Michael|M|;Brown|Jeanette S|JS|",
"chemical_list": "D001559:Benzhydryl Compounds; D018727:Muscarinic Antagonists; C526675:fesoterodine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "209(3)",
"journal": "American journal of obstetrics and gynecology",
"keywords": "primary care; treatment; urgency urinary incontinence",
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001559:Benzhydryl Compounds; D005260:Female; D006801:Humans; D008875:Middle Aged; D018727:Muscarinic Antagonists; D017060:Patient Satisfaction; D011795:Surveys and Questionnaires; D014549:Urinary Incontinence",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "244.e1-9",
"pmc": null,
"pmid": "23659987",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "12074774;11979208;15747340;11982676;15716204;16460875;12670569;22542122;16582131;17670805;8857788;16702587;11374317;10332441;12517660;15572498;17565727;10894308;12549638;15705086;11145628;10902644",
"title": "Long-term efficacy and safety of questionnaire-based initiation of urgency urinary incontinence treatment.",
"title_normalized": "long term efficacy and safety of questionnaire based initiation of urgency urinary incontinence treatment"
} | [
{
"companynumb": "US-PFIZER INC-2010084826",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to determine whether osteonecrosis of the jaw (ONJ) developed more rapidly in patients who switched from bisphosphonates (BP) treatment to denosumab than in patients who received only denosumab.\n\n\nMETHODS\nThis was a retrospective cohort study conducted at a tertiary referral center. Thirty-one patients with ONJ met the inclusion criteria.\n\n\nRESULTS\nTwenty-two patients who had been on BP were switched to denosumab (BP + D), whereas 9 patients received only denosumab. Both groups were similar for the known ONJ risk factors, that is, age, diabetes mellitus, and smoking. The number and cumulative doses of denosumab before the onset of ONJ symptoms were significantly lower among the BP + D group compared with the denosumab-only group (P = .025 and .018, respectively). In the BP + D group, ONJ symptoms developed in 9 patients (41%) following the administration of ≤3 denosumab doses compared with ONJ developing in only 1 patient (11%) who was naïve to BP. ONJ developed spontaneously without any known triggering event in 72.7% of patients in the BP + D group and in 77.8% of patients in the denosumab-only group.\n\n\nCONCLUSIONS\nDenosumab-induced ONJ might develop rapidly in patients previously treated with BP. ONJ developed spontaneously in most patients treated with denosumab. In light of our sample being small, there is need for further investigation on our conclusions.",
"affiliations": "Oral Medicine Unit, Sheba Medical Center, Tel-Hashomer, Israel; Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: Noam.yarom@sheba.health.gov.il.;Department of Oral and Maxillofacial Surgery, Sheba Medical Center, Tel-Hashomer, Israel.;Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Department of Oral and Maxillofacial Surgery, Sheba Medical Center, Tel-Hashomer, Israel.;Department of Otolaryngology - Head and Neck Surgery and Maxillofacial Surgery, Tel Aviv Sourasky Medical Center, affiliated to Tel-Aviv University, Tel-Aviv, Israel.;Department of Oral and Maxillofacial Surgery, Sheba Medical Center, Tel-Hashomer, Israel.",
"authors": "Yarom|Noam|N|;Lazarovici|Towy Sorel|TS|;Whitefield|Sara|S|;Weissman|Tal|T|;Wasserzug|Oshri|O|;Yahalom|Ran|R|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.oooo.2017.09.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "125(1)",
"journal": "Oral surgery, oral medicine, oral pathology and oral radiology",
"keywords": null,
"medline_ta": "Oral Surg Oral Med Oral Pathol Oral Radiol",
"mesh_terms": "D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "101576782",
"other_id": null,
"pages": "27-30",
"pmc": null,
"pmid": "29102242",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rapid onset of osteonecrosis of the jaw in patients switching from bisphosphonates to denosumab.",
"title_normalized": "rapid onset of osteonecrosis of the jaw in patients switching from bisphosphonates to denosumab"
} | [
{
"companynumb": "IL-AMGEN-ISRSP2017191378",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Idiopathic pulmonary arterial hypertension is associated with high morbidity and mortality. In recent years, the use of targeted therapies has led to an improvement in prognosis. Prostacyclin analogues treprostinil and epoprostenol require continuous subcutaneous or intravenous infusion and are generally administered in a stepwise approach. However, there are no clear recommendations for transition in high-risk patients requiring high doses of prostacyclin analogues.\nIn this report, we describe the case of a 20-year-old woman under combined treatment with sildenafil, macitentan, and treprostinil who required transition from subcutaneous treprostinil therapy to intravenous epoprostenol due to erratic drug absorption and functional class progression. The transition was performed over 48 h in a stepwise approach reducing treprostinil dose 4 ng/kg/min every 3 h while increasing epoprostenol infusion 2 ng/kg/min until achieving a maintenance dose of 32 ng/kg/min. There were no side effects requiring changes in the infusion rate.\nPatients with advanced pulmonary arterial hypertension may necessitate switching from subcutaneous treprostinil to epoprostenol. Although many protocols have been used to date, there are no guidelines to direct this process safely. This 48-h scheme based on the pharmacokinetic properties of each drug was successful and well-tolerated.",
"affiliations": "Cardiology Division, Department of Medicine, Hospital General de Agudos \"Dr Cosme Argerich\", Pi y Margall 750 C1155 AHD, Buenos Aires, Argentina.;Cardiology Division, Department of Medicine, Hospital General de Agudos \"Dr Cosme Argerich\", Pi y Margall 750 C1155 AHD, Buenos Aires, Argentina.;Chief of Cardiology Division, Department of Medicine, Hospital General de Agudos \"Dr Cosme Argerich\", Pi y Margall 750 C1155 AHD, Buenos Aires, Argentina.;Department of Medicine, Hospital General de Agudos \"Dr Cosme Argerich\", Pi y Margall 750 C1155 AHD, Buenos Aires, Argentina.",
"authors": "Mori|Ana Laura|AL|https://orcid.org/0000-0002-2851-6610;Rodríguez|Andrea|A|https://orcid.org/0000-0002-7098-5007;Gagliardi|Juan Alberto|JA|;Stewart Harris|Alejandro|A|https://orcid.org/0000-0001-9925-1018",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytaa578",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytaa578\nytaa578\nCase Report\nAcademicSubjects/MED00200\nCase report: Stepwise transition from subcutaneous treprostinil to epoprostenol in high-risk pulmonary arterial hypertension\nhttps://orcid.org/0000-0002-2851-6610\nMori Ana Laura 1\nhttps://orcid.org/0000-0002-7098-5007\nRodríguez Andrea 1\nGagliardi Juan Alberto 2\nhttps://orcid.org/0000-0001-9925-1018\nStewart Harris Alejandro 3\n1 Cardiology Division, Department of Medicine, Hospital General de Agudos “Dr Cosme Argerich”, Pi y Margall 750 C1155 AHD, Buenos Aires, Argentina\n2 Chief of Cardiology Division, Department of Medicine, Hospital General de Agudos “Dr Cosme Argerich”, Pi y Margall 750 C1155 AHD, Buenos Aires, Argentina\n3 Department of Medicine, Hospital General de Agudos “Dr Cosme Argerich”, Pi y Margall 750 C1155 AHD, Buenos Aires, Argentina\nTamura Yuichi Handling Editor\nGiannakoulas George Editor\nSantoro Ciro Editor\nAmin Reshma Editor\nThomson Ross Editor\nCorresponding author. Tel: +54 11 65932802, Email: analauramori@gmail.com\n10 2021\n22 10 2021\n22 10 2021\n5 10 ytaa57813 3 2020\n07 5 2020\n23 12 2020\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nIdiopathic pulmonary arterial hypertension is associated with high morbidity and mortality. In recent years, the use of targeted therapies has led to an improvement in prognosis. Prostacyclin analogues treprostinil and epoprostenol require continuous subcutaneous or intravenous infusion and are generally administered in a stepwise approach. However, there are no clear recommendations for transition in high-risk patients requiring high doses of prostacyclin analogues.\n\nCase summary\n\nIn this report, we describe the case of a 20-year-old woman under combined treatment with sildenafil, macitentan, and treprostinil who required transition from subcutaneous treprostinil therapy to intravenous epoprostenol due to erratic drug absorption and functional class progression. The transition was performed over 48 h in a stepwise approach reducing treprostinil dose 4 ng/kg/min every 3 h while increasing epoprostenol infusion 2 ng/kg/min until achieving a maintenance dose of 32 ng/kg/min. There were no side effects requiring changes in the infusion rate.\n\nDiscussion\n\nPatients with advanced pulmonary arterial hypertension may necessitate switching from subcutaneous treprostinil to epoprostenol. Although many protocols have been used to date, there are no guidelines to direct this process safely. This 48-h scheme based on the pharmacokinetic properties of each drug was successful and well-tolerated.\n\nCase report\nIdiopathic pulmonary hypertension\nProstacyclin analogues\nTreprostinil\nEpoprostenol\n==== Body\npmcFor the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast\n\nLearning points\n\nTreprostinil and epoprostenol are prostacyclin analogues that need to be administrated by continuous infusion and cannot be discontinued abruptly due to the potential for rebound pulmonary hypertension.\n\nCurrently, there are no established protocols to guide switching from one drug to another.\n\nThis case describes a 48-h protocol that resulted in a safe and well-tolerated transition from one prostacyclin analogue to another in a high-risk patient.\n\nIntroduction\n\nPulmonary arterial hypertension (PAH) is a relatively rare disease with an incidence of five to ten cases per million adults per year.1 It is characterized by precapillary involvement leading to an increase in pulmonary vascular resistance. The consensus resulting from the 2018 6th World Symposium on Pulmonary Hypertension redefined it as a medium pulmonary arterial pressure greater than 20 mmHg and a pulmonary vascular resistance greater or equal to 3 WU.2 Conditions classified within this group share haemodynamic characteristics and treatment strategies. Nevertheless, the prognosis and clinical presentation may be widely variable. Idiopathic pulmonary arterial hypertension (IPAH) represents the most frequent type of sporadic PAH and has no identifiable risk factors.\n\nIn Argentina, data from the RECOPILAR registry show a prevalence of 67% for this subgroup.3 The prognosis of IPAH, particularly in patients with WHO functional Class III/IV, has improved in recent years due to specific therapy.4\n\nThe goals of treatment are to reduce symptoms, improve functional capacity, and slow down the progression of the disease by avoiding remodelling and subsequent failure of the right ventricle. It includes general support measures and specific drugs to target the major pathophysiological pathways: calcium channel blockers, phosphodiesterase-5 inhibitors, endothelin antagonists, and prostacyclin analogues (prostanoids). Combination treatment is widely extended, mainly in the advanced forms of the disease (WHO functional Class III and IV).\n\nEpoprostenol and treprostinil are synthetic prostacyclin analogues that stimulate the IP receptor—a Gs protein‐coupled receptor—leading to vasodilation, inhibition of platelet aggregation, and anti‐proliferative and anti‐inflammatory effects.5\n\nThese drugs are titrated up to a maximum according to tolerability. Continuous intravenous epoprostenol therapy has demonstrated an impact on survival; however, there are no established protocols for transitioning from subcutaneous (SC) treprostinil to intravenous (IV) epoprostenol.\n\nTimeline\n\nTime\tIntervention\t\nDay 1\tAdmission to the Cardiac Intensive Care Unit; placement of a Hickman® line\t\nDay 2\tStart of drug transition\t\nDay 3\tEnd of drug transition\t\nDay 4\tTransfer to cardiology ward\t\nDay 5\tNon-pruritic macular rash\t\nDay 6\tSkin rash spontaneous disappearance\t\nDay 7\tHospital discharge.\t\nDay 14\tFollow-up visit: Persistence in functional Class III/IV; right-sided heart failure. Reference for pre-transplant assessment.\t\nDay 47 post-discharge\tOrthotopic double lung transplantation\t\nDay 77\tDischarge\t\n\nCase presentation\n\nWe present a 20-year-old woman (body weight, 55 kg; height, 1.60 m) with a history of IPAH diagnosed at the age of 16 after developing episodes of syncope. She initiated combination therapy with sildenafil and bosentan, which was switched to macitentan due to hepatotoxicity. Along the clinical course of the disease, the treatment was escalated to subcutaneous treprostinil due to a suboptimal response to dual therapy. Chronic adjuvant therapy included spironolactone and anticoagulation with acenocoumarol.\n\nHigh-risk categorization was based on clinical variables (WHO functional class 3/4); biochemical markers [Pro-B-type natriuretic peptide (BNP): 3000 ng/mL, age-related reference value <450 pg/mL]; echocardiographic parameters (right atrium area: 43.2 cm2, right atrial volume: 113 mL/m2, and a moderate pericardial effusion measuring 15 mm); and pulmonary catheterization (right atrial pressure: 17 mmHg). As a result, switching to intravenous infusion of epoprostenol was decided in accordance with local6 and European guidelines.7\n\nThe patient was admitted to the cardiac intensive care unit for placement of a tunnelled central line (Hickman®) and epoprostenol dose titration.\n\nVital signs recording on admission showed sinus tachycardia at 110 b.p.m., blood pressure 102/70 mmHg, and 97% SpO2 on room air. Cardiovascular physical examination revealed a loud and fixed S2 splitting, palpable parasternal lift at second left intercostal space with dullness on percussion, and mild peripheral oedema.\n\nFor target dose calculation, we used an approximate equivalent dose ratio of treprostinil to epoprostenol of 2:1 based on the equimolar potency of epoprostenol and the experience of other longer protocols in which the final dose reached this proportion.8 Thus, the target dose of epoprostenol was estimated at 32 ng/kg/min.\n\nDrug titration began after central line placement. The infusion rate of each drug was based on its half-life and adjusted every 180 min. Treprostinil dosage decreased 4 ng/kg/min every 3 h while epoprostenol increased 2 ng/kg/min. Epoprostenol was titrated up under close monitoring of respiratory rate, heart rate, blood pressure, and blood oxygen saturation. Dosage was reduced to the previous titration step if side effects developed. The transition from SC treprostinil to IV epoprostenol lasted 48 h. There were no adverse events. Pro-BNP level at the end of titration was 2928 pg/mL.\n\nThe patient was transferred from the cardiac intensive care unit to the cardiology ward 4 days after titration. On the fifth day, she developed a non-pruritic macular rash of the limbs that faded spontaneously within hours without any dosage change and was discharged from hospital 2 days later. There were no significant changes in cardiac ultrasound parameters during hospital stay.\n\nDespite the well-tolerated infusion of epoprostenol, absence of serious adverse events, and short length of stay, persistence in WHO functional class 3/4 and signs of right-sided heart failure on a 7-day follow-up appointment prompted referral to pre-transplant assessment. At this stage, a new echocardiogram showed a pulmonary artery systolic pressure (PASP) of 95 mmHg, impaired right ventricular systolic function, and persistent moderate pericardial effusion.\n\nOrthotopic double lung transplantation was performed 47 days after discharge, with marked echocardiographic improvement 1 month later (PASP = 31, preserved right ventricular function, and absence of pericardial effusion).\n\nExamination of the explanted lungs revealed medial wall thickening and muscularization, obliteration of small arteries, intimal fibrosis, and plexiform lesions consistent with IPAH.\n\nDiscussion\n\nEpoprostenol is the only drug with demonstrated impact on the survival of patients with PAH. This evidence comes from a randomized study conducted in patients with functional class III/IV, which showed a statistically significant improvement in survival at three months compared with conventional therapy.9\n\nIn comparison to other prostanoids, epoprostenol also showed better results in the 6-min walk test, functional class improvement, and lower all-cause mortality in a meta-analysis of 14 randomized clinical trials.10\n\nTherefore, the change in the strategy for treating this patient seems to be appropriate. However, the pharmacokinetic properties of both drugs may explain why epoprostenol is not the first option when starting a patient on prostanoids therapy.\n\nAs epoprostenol has a short half-life of approximately 2–6 min, it is only indicated for continuous infusion by intravenous route. Therefore, it requires the placement of a central venous catheter with strict hygiene precautions for manipulation and the correct use and control of an infusion pump. Moreover, abrupt interruption of the infusion can induce rebound pulmonary vasoconstriction that may result in haemodynamic instability and death.\n\nOn the other hand, treprostinil is a prostacyclin analogue developed after epoprostenol that can be administered by SC infusion due to its longer half-life (3–4 h). Currently, there are also implantable subcutaneous systems that reduce the daily burden of external pump handling. For this reason, treprostinil results are superior to epoprostenol in terms of patients’ satisfaction and quality of life.10,11 These characteristics explain why treprostinil is prioritized despite the lack of evidence in terms of improved survival or long-term outcomes.\n\nIn the present case, treprostinil therapy was ineffective at the maximum tolerated dose, either due to progression of disease or pain and reactions at multiple infusion sites over several months, which are common side effects of the drug.12 Thus, the clinical status of the patient made the transition necessary.\n\nTo our knowledge, there are no practical guidelines in literature for the transition between these prostacyclin analogues or 48-h high dose titration.\n\nIn a systematic review carried out in 2017,13 the authors reported on three studies involving a total of 18 patients in which transition from SC or IV treprostinil to epoprostenol had a success rate of 67%.\n\nReisbig et al.14 presented a stepwise transition protocol limited by signs of under-dosage or excessive pharmacological effects. The dosage of treprostinil was reduced to 5 ng/kg/min, while epoprostenol was increased every 4 h in a variable range depending on the occurrence of side effects. The total transition time was 62 h.\n\nAlkukhun et al.15 reported four cases of transition from SC treprostinil to epoprostenol with different protocols. The maximum incremental dose of epoprostenol was 2 ng/kg/min. None of the patients exceeded a final epoprostenol dose of 20 ng/kg/min or a basal treprostinil dose of 30 ng/kg/min. These figures differ from those used in the present case.\n\nLastly, a recent publication16 suggested a transition scheme that could result in less titration time but with different adjustment intervals for each drug.\n\nConclusion\n\nThis 48-h protocol resulted in safe and well-tolerated transition from one prostacyclin analogue to another in a high-risk patient. Moreover, switching to epoprostenol enabled a more realistic assessment of the disease and timely referral to lung transplantation.\n\nLead author biography\n\nGraduated from the University of Buenos Aires in 2015. Nowadays finishing my Cardiology residency at Hospital General de Agudos “ Dr. Cosme Argerich” Buenos Aires, Argentina.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSupplementary Material\n\nytaa578_Supplementary_Data Click here for additional data file.\n\nAcknowledgements\n\nTo Dr Patricia Arce for her assistance and dedication, to Dr Jorge Szarfer for his support and to Dr Dora Haag for the patient’s referral.\n\nSlide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n==== Refs\nReferences\n\n1 Badesch DB , RaskobGE, ElliottCG, KrichmanAM, FarberHW, FrostAE et al Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010;137 :376–387.19837821\n2 Simonneau G , MontaniD, CelermajerDS, DentonCP, GatzoulisMA, KrowkaM et al Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53 :1801913.30545968\n3 Echazarreta D , PernaE, CoronelM, DiezM, LescanoA, AtamañukN et al I Registro Colaborativo de Hipertensión Pulmonar en Argentina (RECOPILAR). Rev Fed Arg Cardiol 2014;43 :146–149.\n4 Farber HW , MillerDP, PomsAD, BadeschDB, Le-RouzicEM, RomeroAJ et al Five-year outcomes of patients enrolled in the REVEAL registry. Chest 2015;148 :1043–1054.26066077\n5 Oudiz RJ , FarberHW. Dosing considerations in the use of intravenous prostanoids in pulmonary arterial hypertension: an experience-based review. Am Heart J 2009;157 :625–635.19332188\n6 Sociedad Argentina de Cardiología. Guías argentinas de consenso en diagnóstico y tratamiento de la hipertensión pulmonar. Rev Argent de Cardiol 2017;85 (suplemento 3 ).\n7 Galiè N , HumbertM, VachieryJ-L, GibbsS, LangI, TorbickiA et al 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Heart J 2016;37 :67–119.26320113\n8 Gomberg-Maitland M , TapsonVF, BenzaRL, McLaughlinVV, KrichmanA, WidlitzAC et al Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med 2005;172 :1586–1589.16151039\n9 Barst RJ , RubinLJ, LongWA, McGoonMD, RichS, BadeschDB et al A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334 :296–301.8532025\n10 Zhang H , LiX, HuangJ, LiH, SuZ, WangJ. Comparative efficacy and safety of prostacyclin analogs for pulmonary arterial hypertension: a network meta-analysis. Medicine (Baltimore) 2016;95 :e2575.26825901\n11 Minai OA , ParambilJ, DweikRA, DavilaGH, PetersonL, RollinsKD et al Impact of switching from epoprostenol to IV treprostinil on treatment satisfaction and quality of life in patients with pulmonary hypertension. Respir Med 2013;107 :458–465.23266038\n12 Sadushi-Koliçi R , Skoro-SajerN, ZimmerD, BondermanD, SchemperM, KlepetkoW et al Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension. J Heart Lung Transpl 2012;31 :735–743.\n13 Sofer A , RyanMJ, TedfordRJ, WirthJA, FaresWH. A systematic review of transition studies of pulmonary arterial hypertension specific medications. Pulm Circ 2017;7 :326–338.28597769\n14 Reisbig KA , CoffmanPA, FloreaniAA, BultsmaCJ, OlsenKM. Staggered transition to epoprostenol from treprostinil in pulmonary arterial hypertension. Ann Pharmacother 2005;39 :739–743.15755791\n15 Alkukhun L , BairND, DweikRA, TonelliAR. Subcutaneous to intravenous prostacyclin analog transition in pulmonary hypertension. J Cardiovasc Pharmacol 2014;63 :4–8.24084219\n16 Mouratoglou SA , PatsialaA, FeloukidisC, KarvounisH, GiannakoulasG. Transition protocol from subcutaneous treprostinil to intravenous epoprostenol in deteriorating patients with pulmonary arterial hypertension. Int J Cardiol 2020;306 :187–189.32115272\n\n",
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"journal": "European heart journal. Case reports",
"keywords": "Case report; Epoprostenol; Idiopathic pulmonary hypertension; Prostacyclin analogues; Treprostinil",
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"title": "Case report: Stepwise transition from subcutaneous treprostinil to epoprostenol in high-risk pulmonary arterial hypertension.",
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"abstract": "A sarcomatoid variant of urothelial carcinoma in the female urethral diverticulum has not been reported previously. A 66-year-old woman suffering from dysuria presented with a huge urethral mass invading the urinary bladder and vagina. Histopathological examination of the resected specimen revealed predominantly undifferentiated pleomorphic sarcoma with sclerosis. Only a small portion of conventional urothelial carcinoma was identified around the urethral diverticulum, which contained glandular epithelium and villous adenoma. The patient showed rapid systemic recurrence and resistance to immune checkpoint inhibitor therapy despite high expression of programmed cell death ligand-1. We report the first case of urethral diverticular carcinoma with sarcomatoid features.",
"affiliations": "Department of Pathology, Ewha Womans University Seoul Hospital, Seoul, Korea.",
"authors": "Park|Heae Surng|HS|",
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"doi": "10.4132/jptm.2021.04.23",
"fulltext": "\n==== Front\nJ Pathol Transl Med\nJ Pathol Transl Med\nJPTM\nJournal of Pathology and Translational Medicine\n2383-7837\n2383-7845\nThe Korean Society of Pathologists and the Korean Society for Cytopathology\n\n34058799\n10.4132/jptm.2021.04.23\njptm-2021-04-23\nCase Study\nSarcomatoid urothelial carcinoma arising in the female urethral diverticulum\nhttp://orcid.org/0000-0003-1849-5120\nPark Heae Surng\nDepartment of Pathology, Ewha Womans University Seoul Hospital, Seoul, Korea\nCorresponding Author: Heae Surng Park, MD, PhD, Department of Pathology, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, 260 Gonghang-daero, Gangseo-gu, Seoul 07804, Korea Tel: +82-2-6986-5253, Fax: +82-2-6986-3423, E-mail: turtle98p@naver.com\n7 2021\n1 6 2021\n55 4 298302\n9 3 2021\n16 4 2021\n23 4 2021\n© 2021 The Korean Society of Pathologists/The Korean Society for Cytopathology\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nA sarcomatoid variant of urothelial carcinoma in the female urethral diverticulum has not been reported previously. A 66-year-old woman suffering from dysuria presented with a huge urethral mass invading the urinary bladder and vagina. Histopathological examination of the resected specimen revealed predominantly undifferentiated pleomorphic sarcoma with sclerosis. Only a small portion of conventional urothelial carcinoma was identified around the urethral diverticulum, which contained glandular epithelium and villous adenoma. The patient showed rapid systemic recurrence and resistance to immune checkpoint inhibitor therapy despite high expression of programmed cell death ligand-1. We report the first case of urethral diverticular carcinoma with sarcomatoid features.\n\nSarcomatoid carcinoma\nUrothelial carcinoma\nUrethral diverticulum\n==== Body\nUrethral diverticular carcinoma (UDC) is extremely rare; the most common histological subtype is adenocarcinoma [1,2]. Sarcomatoid urothelial carcinoma (UC) is also unusual. Due to the scarcity of UDC and sarcomatoid UC, related studies have been limited to small series and single case reports. Herein, we report the first case of sarcomatoid UC of the female urethral diverticulum and her treatment response to immune checkpoint inhibitor therapy.\n\nCASE REPORT\n\nA 66-year-old woman with dysuria was referred to the urology department after visiting the emergency room and undergoing several urinary catheterization procedures. She was hospitalized for a cerebral infarction 7 months prior and had a history of cholecystectomy owing to acute cholecystitis 6 months before. A urethral diverticulum was identified through abdominopelvic computed tomography (CT) performed during admission for cholecystectomy (Fig. 1A), although no urological evaluation was conducted at that time. On presentation, abdominopelvic CT revealed a large mass involving the urethra, posterior wall of the urinary bladder, and vagina with enlarged lymph nodes at both femoral, both inguinal, and both internal and external iliac areas (Fig. 1B). Ultrasound-guided transvaginal core needle biopsy of the urethral mass was performed, and histopathological examination revealed unspecified spindle cell sarcoma with stromal sclerosis. The patient underwent anterior pelvic exenteration with pelvic lymph node dissection.\n\nThe surgical specimen showed a 10-cm-sized, hard white mass in the urethra that had invaded the uterine cervix, anterior wall of the vagina, posterior wall of the urinary bladder, and perivesical fat (Fig. 2A). The cut surface of the mass showed central necrosis with cystic space formation. Histopathologically, the tumor was predominantly composed of pleomorphic spindle cells with moderate to severe nuclear atypia, brisk mitosis, and necrosis (Fig. 2B). The tumor nuclei were oval shaped and had vesicular chromatin and prominent nucleoli. The tumor occasionally produced abundant collagen, but neither specific mesenchymal differentiation nor a heterologous component was observed. Intratumoral lymphoplasmacytic infiltration was noted. The cystic space was focally lined by urothelial or glandular epithelium (Fig. 2C) and associated villous adenoma (Fig. 2D). The lining epithelium and premalignant lesion were juxtaposed with tumor tissue, suggesting tumor formation in the urethral diverticulum. A minimal conventional urothelial carcinoma component was present (less than 1%) near the diverticulum, and areas of epithelial-to-mesenchymal transition were noted (Fig. 2E). Although lymphovascular invasion was present, nodal metastasis was not identified among the 30 pelvic lymph nodes. Immunohistochemical staining for cytokeratin (CK) 7 highlighted the glandular epithelium and invasive carcinoma component (Fig. 3A). The invasive carcinoma component was positive for high molecular weight CK, p63, and GATA3, indicating a urothelial nature. Urothelial carcinoma in situ was not identified. Spindle cell component was negative for panCK, CK7, GATA3, p63, smooth muscle actin, myoglobin, anaplastic lymphoma kinase (clone, 5A4), S-100, and human melanoma black-45 immunostaining, but positive for vimentin. Programmed death ligand-1 (PD-L1) SP142 (Ventana Medical Systems, Tucson, AZ, USA) immunohistochemistry showed diffuse positivity (90%) in tumor-infiltrating immune cells (IC) of the sarcoma component, while no positive ICs were identified in the urothelial carcinoma component (Fig 3B). PD-L1 immunostaining was performed using three different tissue sections and the results were similar. The final pathological diagnosis was sarcomatoid UC arising from the urethral diverticulum (pT4N0).\n\nDuring follow-up, multiple newly developed lung nodules were detected on chest CT 49 days postoperative. The patient underwent one cycle of palliative chemotherapy (adriamycin and cisplatin), but showed intolerance to the chemotherapeutic agent, and the disease progressed. She next underwent four cycles of atezolizumab and radiation therapy, but the disease continued to progress. She then received gemcitabine plus cisplatin, and the tumor showed a partial response, but tumor progresssion occurred after 4 months of treatment. The patient next received weekly paclitaxel for 2 months and exhibited stable disease. Recently, she stopped chemotherapy temporarily and is alive 24 months postoperative.\n\nDISCUSSION\n\nPrimary female urethral carcinomas are rare, and the most common histological subtype is urothelial carcinoma (45%), followed by adenocarcinoma (29%), squamous cell carcinoma (19%), and undifferentiated carcinoma (6%), according to a national urethral cancer survey conducted in the Netherlands [3]. UDC is very unusual, accounting for only 5% of all female urethral carcinomas [1,2]. More than 120 cases of UDC have been reported, and adenocarcinoma is the most common pathology (75%), while urothelial carcinoma (15%) and squamous cell carcinoma (10%) are less frequent [1,2].\n\nUDC is hypothesized to arise from a periurethral gland or metaplastic epithelium with chronic irritation, and Gartner or mesonephric duct remnants [2]. UDC might contain premalignant lesions such as villous adenoma, intestinal metaplasia, or highgrade dysplasia [4]. The present case is suggestive of tumor origination from metaplastic change because of its relation to the glandular epithelium as well as villous adenoma.\n\nThe sarcomatoid variant of urothelial carcinoma is rare, but has been reported in the urinary bladder [5], bladder diverticulum [6], ureter [7], renal pelvis [8], and urethra [9]. As far as we know, this is the first case report of sarcomatoid UC arising from a urethral diverticulum. One meta-analysis showed that sarcomatoid urothelial carcinoma of the bladder tended to present as more advanced disease than conventional urothelial carcinoma, which might lead to worse survival outcomes [5]. Sarcomatoid urothelial carcinoma is defined as a biphasic tumor composed of both malignant epithelial and mesenchymal elements, and the latter element is morphologically indistinguishable from sarcoma [10,11]. For most cases, the carcinomatous component is urothelial, but variable degrees of squamous cell carcinoma, adenocarcinoma, and small cell carcinoma components can be present [10,11]. The sarcomatous component is reported to constitute 20% to 100% of the tumor volume [12] and usually presents as undifferentiated high-grade sarcoma [11]. A heterologous component can be seen, most commonly osteosarcoma, followed by chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, and angiosarcoma [10,11]. In tumors in the urinary system and those exclusively consisting of malignant spindle cells, the first differential diagnostic consideration should be sarcomatoid UC, since it can show a wide range of morphologies, and primary sarcoma of the urinary tract is rare. In such cases, extensive gross examination and immunohistochemistry must be performed to confirm the existence of a carcinoma component. In this case, transvaginal needle biopsy showed only high-grade sarcoma, suggesting primary urethral sarcoma. However, a very small urothelial carcinoma component was identified in the surgically resected specimen after extensive tissue examination.\n\nRecently, immune checkpoint inhibitor therapy has demonstrated anti-tumor effects in advanced urothelial carcinoma. Atezolizumab is a Food and Drug Administration (FDA)-approved anti–programmed death-1/PD-L1 agent used for the treatment of advanced bladder cancer. PD-L1 SP142 immunohistochemistry was approved by the FDA as a companion diagnostic test in urothelial carcinoma patients based on the results of a phase 2 clinical trial, IMvigor210 [13]. However, a phase 3 randomized controlled trial, IMvigor211 [14], revealed higher PD-L1 SP142 expression (≥ 5% positivity in ICs) to be associated with response to both atezolizumab and chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Li et al. [15] evaluated PD-L1 SP142 expression in bladder UC and showed that the sarcomatoid variant was significantly associated with higher PD-L1 expression. In our case, the UDC showed high PD-L1 SP142 expression (IC 90%), but the tumor progressed despite atezolizumab administration. The PD-L1–negative urothelial carcinoma component could be the driver of progression in this patient, although the progressed lesion was not confirmed histologically. We report a very unusual case of sarcomatoid UC in the female urethral diverticulum, which showed aggressive behavior and resistance to atezolizumab therapy despite high PD-L1 expression. Consideration of a broad range of histologic features is needed to diagnose sarcomatoid UC of the urinary system.\n\nFig. 1. Enhanced abdominopelvic computed tomography. (A) Axial image taken 7 months prior to presentation showed a urethral diverticulum (asterisk) at the level of the symphysis pubis. (B) Preoperative image revealed a large urethral mass (UB, urinary bladder; arrow, urinary catheter within the urethra).\n\nFig. 2. Histopathological findings. (A) Gross examination revealed a 10-cm-sized, hard white urethral mass invading the uterus, vagina, urinary bladder, and perivesical fat. The cut surface showed necrosis and cystic space (arrowheads). (B) Microscopically, the majority of the tumor was composed of pleomorphic spindle cells with occasional collagen deposition. Intratumoral lymphoplasmacytic infiltration was noted. (C, D) The cystic space was lined focally by glandular epithelium (C) and associated villous adenoma (D). (E) A conventional urothelial carcinoma component was minimally present, and areas of epithelial-to-mesenchymal transition were noted.\n\nFig. 3. Results of immunohistochemical staining. (A) Immunostaining for cytokeratin 7 highlighted the glandular epithelium (left side) and urothelial carcinoma component, whereas there was no staining of the sarcoma component. (B) Programmed death ligand-1 SP142 (Ventana Medical Systems, Tucson, AZ, USA) immunostaining showed diffuse positivity (90%) in tumor-infiltrating immune cells (ICs) of the sarcoma component, while ICs of the carcinoma component were negative.\n\nEthics Statement\n\nThis study was approved by the Institutional Review Board (IRB) of Ewha Womans University Seoul Hospital (IRB No. 2021-02-23) and the need for informed consent was waived.\n\nAvailability of Data and Material\n\nAll data generated or analyzed during the study are included in this published article.\n\nCode Availability\n\nNot applicable.\n\nConflicts of Interest\n\nThe author declare that they has no potential conflicts of interest.\n\nFunding Statement\n\nNo funding to declare.\n==== Refs\nReferences\n\n1 Ahmed K Dasgupta R Vats A Urethral diverticular carcinoma: an overview of current trends in diagnosis and management Int Urol Nephrol 2010 42 331 41 19649767\n2 O’Connor E Iatropoulou D Hashimoto S Takahashi S Ho DH Greenwell T Urethral diverticulum carcinoma in females: a case series and review of the English and Japanese literature Transl Androl Urol 2018 7 703 29 30211061\n3 Derksen JW Visser O de la Riviere GB Meuleman EJ Heldeweg EA Lagerveld BW Primary urethral carcinoma in females: an epidemiologic study on demographical factors, histological types, tumour stage and survival World J Urol 2013 31 147 53 22614443\n4 Rajan N Tucci P Mallouh C Choudhury M Carcinoma in female urethral diverticulum: case reports and review of management J Urol 1993 150 1911 4 8230535\n5 Gu L Ai Q Cheng Q Sarcomatoid variant urothelial carcinoma of the bladder: a systematic review and meta-analysis of the clinicopathological features and survival outcomes Cancer Cell Int 2020 20 550 33292281\n6 Lembo F Subba E Lagana AS Vitale SG Valenti G Magno C Intradiverticular sarcomatoid carcinoma of the bladder: an overview starting from a peculiar case Urol J 2016 13 2800 2 27576890\n7 Wang Y Liu H Wang P Primary sarcomatoid urothelial carcinoma of the ureter: a case report and review of the literature World J Surg Oncol 2018 16 77 29653574\n8 Rashid S Akhtar M Sarcomatoid variant of urothelial carcinoma of the renal pelvis with inferior vena cava tumour thrombus: a case report and literature review Case Rep Pathol 2018 2018 1837510 29581908\n9 D’Arrigo L Costa A Fraggetta F Pennisi M Pepe P Aragona F Carcinosarcoma of the female urethra Urol Int 2016 96 370 2 24481023\n10 Moch H Humphrey PA Ulbright TM Reuter VE WHO classification of tumours of the urinary system and male genital organs 4th ed Lyon International Agency for Research on Cancer 2016 92\n11 Bostwick DG Cheng L Urologic surgical pathology 3rd ed Philadelphia Saunders-Elsevier 2014 298 9\n12 Sanfrancesco J McKenney JK Leivo MZ Gupta S Elson P Hansel DE Sarcomatoid urothelial carcinoma of the bladder: analysis of 28 cases with emphasis on clinicopathologic features and markers of epithelial-to-mesenchymal transition Arch Pathol Lab Med 2016 140 543 51 27031776\n13 Balar AV Galsky MD Rosenberg JE Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial Lancet 2017 389 67 76 27939400\n14 Powles T Duran I van der Heijden MS Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, openlabel, phase 3 randomised controlled trial Lancet 2018 391 748 57 29268948\n15 Li H Zhang Q Shuman L Evaluation of PD-L1 and other immune markers in bladder urothelial carcinoma stratified by histologic variants and molecular subtypes Sci Rep 2020 10 1439 31996725\n\n",
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"issue": "55(4)",
"journal": "Journal of pathology and translational medicine",
"keywords": "Sarcomatoid carcinoma; Urethral diverticulum; Urothelial carcinoma",
"medline_ta": "J Pathol Transl Med",
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"pages": "298-302",
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"pubdate": "2021-07",
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"references": "27031776;19649767;29653574;30211061;29581908;24481023;33292281;31996725;27576890;27939400;22614443;8230535;29268948",
"title": "Sarcomatoid urothelial carcinoma arising in the female urethral diverticulum.",
"title_normalized": "sarcomatoid urothelial carcinoma arising in the female urethral diverticulum"
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"abstract": "Inflammatory bowel disease (IBD) is a chronic condition of the bowel that can be further categorized into ulcerative colitis and Crohn's disease. Rarely, this condition can be associated with pericarditis, which can be an extraintestinal manifestation of the disease or drug-induced. This review aims to determine the pathogenesis and management of pericarditis in IBD. In this review, the goal is to elucidate the pathogenesis of pericarditis in IBD and determine if pericarditis is an extraintestinal manifestation of IBD or a complication of current drug therapy used to manage IBD. Additionally, this review intends to explain the first-line management of pericarditis in IBD and explore the role of biologicals in attenuating pericarditis. An electronic search was conducted to identify relevant reports of pericarditis in IBD, and a quality assessment was conducted to identify high-quality articles according to the inclusion criteria. Full-text articles from inception to November 2020 were included, while non-English articles, gray literature, and animal studies were excluded. The majority of studies suggest that pericarditis arises as a complication of drug therapy by 5-aminosalicylic acid derivatives such as sulfasalazine, mesalamine, and balsalazide, and it occurs due to IgE-mediated allergic reactions, direct cardiac toxicity, cell-mediated hypersensitivity reactions, and humoral antibody response to therapy. Drug cessation or the initiation of a corticosteroid regimen seems to be the most effective means of managing pericarditis in IBD due to drug therapy or an extraintestinal manifestation.",
"affiliations": "Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.;Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.;Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.;Behavioral Neurosciences and Psychology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.;Plastic and Reconstructive Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.;Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.;Emergency Department, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.;Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.",
"authors": "Patel|Ravi S|RS|;Rohit Reddy|Sai|S|;Llukmani|Adiona|A|;Hashim|Ayat|A|;Haddad|Dana R|DR|;Patel|Dutt S|DS|;Ahmad|Farrukh|F|;Gordon|Domonick K|DK|",
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"doi": "10.7759/cureus.14010",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14010\nCardiology\nInternal Medicine\nGastroenterology\nCardiovascular Manifestations in Inflammatory Bowel Disease: A Systematic Review of the Pathogenesis and Management of Pericarditis\nMuacevic Alexander\nAdler John R\nPatel Ravi S 1\nRohit Reddy Sai 1\nLlukmani Adiona 1\nHashim Ayat 2\nHaddad Dana R 3\nPatel Dutt S 1\nAhmad Farrukh 4\nGordon Domonick K 1\n1 Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA\n2 Behavioral Neurosciences and Psychology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA\n3 Plastic and Reconstructive Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA\n4 Emergency Department, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA\nRavi S. Patel docrsp23@gmail.com\n20 3 2021\n3 2021\n13 3 e1401026 1 2021\n20 3 2021\nCopyright © 2021, Patel et al.\n2021\nPatel et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/50960-cardiovascular-manifestations-in-inflammatory-bowel-disease-a-systematic-review-of-the-pathogenesis-and-management-of-pericarditis\nInflammatory bowel disease (IBD) is a chronic condition of the bowel that can be further categorized into ulcerative colitis and Crohn’s disease. Rarely, this condition can be associated with pericarditis, which can be an extraintestinal manifestation of the disease or drug-induced. This review aims to determine the pathogenesis and management of pericarditis in IBD. In this review, the goal is to elucidate the pathogenesis of pericarditis in IBD and determine if pericarditis is an extraintestinal manifestation of IBD or a complication of current drug therapy used to manage IBD. Additionally, this review intends to explain the first-line management of pericarditis in IBD and explore the role of biologicals in attenuating pericarditis. An electronic search was conducted to identify relevant reports of pericarditis in IBD, and a quality assessment was conducted to identify high-quality articles according to the inclusion criteria. Full-text articles from inception to November 2020 were included, while non-English articles, gray literature, and animal studies were excluded. The majority of studies suggest that pericarditis arises as a complication of drug therapy by 5-aminosalicylic acid derivatives such as sulfasalazine, mesalamine, and balsalazide, and it occurs due to IgE-mediated allergic reactions, direct cardiac toxicity, cell-mediated hypersensitivity reactions, and humoral antibody response to therapy. Drug cessation or the initiation of a corticosteroid regimen seems to be the most effective means of managing pericarditis in IBD due to drug therapy or an extraintestinal manifestation.\n\ninflammatory bowel disease\npericarditis\nextraintestinal manifestations\ncrohn’s disease\nulcerative colitis\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction and background\n\nOver 1.5 million Americans currently live with inflammatory bowel disease (IBD) [1]. IBD is a chronic gastrointestinal tract condition that includes either ulcerative colitis or Crohn’s disease. Ulcerative colitis involves mucosal inflammation that primarily involves the colon, while Crohn’s disease involves transmural inflammation that can manifest as skip lesions throughout the gastrointestinal tract [2]. IBD has equal gender predominance that usually affects young adults less than 30 years old or adults over 50 years of age [3]. Besides gastrointestinal involvement, IBD is associated with various extraintestinal manifestations that commonly involve the musculoskeletal, dermatologic, hepatic, pancreatic, biliary, ocular, renal, and pulmonary systems [4]. Although rare, extraintestinal manifestations involving the heart have been reported, including pericarditis, myocarditis, arrhythmia, and heart failure [5]. Pericarditis is the most common of cardiovascular manifestations, comprising 70% of all cardiovascular complications [5,6].\n\nCurrently, the pathogenesis of pericarditis in IBD is unclear. Some authors are unaware of the mechanism by which pericarditis arises, while others speculate or briefly outline the pathogenesis. These include immune-mediated pericarditis, drug-induced hypersensitivity reactions, and cardiotoxicity due to drug treatment [7-10]. Additionally, various treatment modalities are available for the management of extraintestinal pericarditis. However, a consensus on managing this condition has not been met, and various patient outcomes have been reported. 5-Aminosalicylic acid (5-ASA) derivatives, corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs) are among the various options that physicians have been prescribing currently [6-9]. As of now, there are various theories of how pericarditis arises in IBD. By understanding the pathogenesis in which pericarditis arises, we can better understand the mechanism of extraintestinal cardiac conditions and prevent them in the management of future patients. If a standard drug regimen is established to treat pericarditis in IBD, unnecessary drug complications and delay in effective treatment can be avoided, and outcomes in future patients can be improved.\n\nIn this systematic review, the goal is to elucidate the pathogenesis of pericarditis in IBD and determine if pericarditis is an extraintestinal manifestation of IBD or a complication of current drug therapy used to manage IBD. Additionally, this review intends to explain the first-line management of pericarditis in IBD and explore the role of biologicals in attenuating pericarditis.\n\nReview\n\nMethods\n\nThe following systematic review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search strategy included an electronic search through the PubMed database by two different authors. Keywords used were “Pericarditis and Inflammatory Bowel Disease,” “Pericarditis and Ulcerative Colitis,” and “Pericarditis and Crohn’s Disease.” Additionally, the following MeSH terms were used: (“Pericarditis”[Mesh]) AND “Inflammatory Bowel Diseases”[Mesh], (“Pericarditis”[Mesh]) AND “Colitis, Ulcerative”[Mesh], (“Pericarditis”[Mesh]) AND “Crohn Disease”[Mesh]. For each keyword or MeSH term, the number of hits on PubMed were noted. Each article was screened based on a title review initially by both authors. All articles included based on title review were further evaluated and either included or excluded for relevancy based on an abstract review. Following the abstract review, a complete article review was done to exclude any other irrelevant articles. Any duplicate articles that coincided with multiple key terms or MeSH terms were also excluded. Any disagreement was resolved with discussion.\n\nMultiple quality assessment tools were utilized to assess the selected articles. The Joanna Briggs Institute checklist was used for case report critical appraisal, while the Scale for the Quality Assessment of Narrative Review Articles checklist was used to assess narrative review articles and letters to the editor. Additionally, the Newcastle-Ottawa Scale was used to assess the quality of cross-sectional studies. For all the scales, a cut-off value of greater than or equal to seven was assigned to designate the articles included in this study.\n\nThe eligibility criteria were defined following the Patient, Intervention, Comparison, Outcome approach. The inclusion criteria include all study types and designs from inception to the present day that are related to the topic of pericarditis in IBD. All population groups were included in this study. Only full-text articles were used, and any gray literature was excluded. Non-English articles and animal studies were also excluded from this study. Table 1 and Table 2 show the keywords and MeSH terms used, respectively.\n\nTable 1 Regular keywords used in the data search and the number of results.\n\nRegular keywords\tDatabase used\tNumber of papers\t\nPericarditis and inflammatory bowel disease\tPubMed\t90\t\nPericarditis and ulcerative colitis\tPubMed\t60\t\nPericarditis and Crohn's disease\tPubMed\t35\t\n\nTable 2 MeSH keywords used in the data search and the number of results.\n\nMeSH keywords\tDatabase used\tNumber of papers\t\n(“Pericarditis”[Mesh]) AND “Inflammatory Bowel Diseases”[Mesh]\tPubMed\t69\t\n(“Pericarditis”[Mesh]) AND “Colitis, Ulcerative”[Mesh]\tPubMed\t43\t\n(“Pericarditis”[Mesh]) AND “Crohn Disease”[Mesh]\tPubMed\t25\t\n\nResults\n\nSearch Results\n\nInitial screening of the electronic database PubMed yielded 322 records. Of these, 226 were duplicates. Of the 96 records that were relevant, 31 were excluded based on the relevancy of title and abstract review. A total of 65 records underwent full title review, of which 15 were excluded due to irrelevancy. The remaining 50 articles underwent quality assessment, of which 11 articles were excluded as the score was less than seven. According to the inclusion criteria, 39 total articles were analyzed in this qualitative study.\n\nStudy Characteristics\n\nThis analysis included 36 patients, of whom 12 were female and 24 were male. The patients’ age ranged from nine to 76 years, with an average age of 30.8 years. Of the patients with IBD, 11 had Crohn’s disease and 25 had ulcerative colitis. Geographically, 19 studies were from the United States, 12 studies were from Europe, three studies were from Canada, three studies were from Japan, one study was from Israel, and one study was from Turkey.\n\nStudy Quality\n\nOf the 50 articles that underwent quality assessment, 39 were considered high quality with a score of greater than or equal to seven. A total of 11 articles were excluded due to a score of less than seven. Of the 39 included studies, 22 had a quality assessment score of 8/8, and 17 studies had a score of 7/8.\n\nActual Results\n\nA total of 16 studies offered information related to the pathogenesis of pericarditis arising in IBD. The majority of studies suggest that pericarditis arises from IBD complications due to drug therapy by 5-ASA derivatives such as sulfasalazine, mesalamine, and balsalazide. Additionally, drug-induced pericarditis in patients with IBD has been reported with infliximab and azathioprine therapy. Proposed mechanisms include IgE-mediated allergic reactions by 5-ASA drugs, direct cardiac toxicity induced by medical treatment, cell-mediated hypersensitivity reactions due to therapy, and humoral antibody response to therapy. Additionally, drug-induced lupus reactions and serum sickness-like reactions have been suggested. A total of 38 studies provided information related to the management of pericarditis in IBD patients. Nine cases of pericarditis resolved with drug cessation alone, and nine cases required drug cessation along with corticosteroid treatment. Eight cases only required steroid therapy to resolve the condition. Five cases required drug cessation and NSAID use, while two cases resolved solely with colectomy. Three patients developed a pericardial tamponade that resolved upon pericardiocentesis. In two cases, mesalamine drug treatment was stopped and replaced with either azathioprine or infliximab to resolve the patient’s pericarditis. Figure 1 illustrates the process of identifying relevant studies.\n\nFigure 1 PRISMA flow diagram showing the data selection process.\n\nPRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses\n\nDiscussion\n\nPathogenesis\n\nInterpretation: In most studies included in this review, pericarditis occurred after drug therapy was initiated to treat either Crohn’s disease or ulcerative colitis. Out of the 36 patients included in this study, only four presented with pericarditis that was not induced by drug therapy [11-14]. Although a rare complication, this suggests that pericarditis arises more often as an adverse drug reaction rather than as an extraintestinal manifestation of the disease course itself. Of the drug-induced cases, 5-ASA derivatives such as sulfasalazine, mesalamine, and balsalazide were responsible for pericarditis in most patients.\n\nAnalysis: Pericarditis arising due to 5-ASA derivatives have various pathological mechanisms. Mitchell et al. and Bernardo et al. suggest that an IgE-mediated hypersensitivity reaction may be responsible [15,16]. Direct cardiotoxicity has also been proposed where 5-ASA derivatives directly damage myocytes, exposing antigens and releasing inflammatory mediators, with the latter eliciting an immune response [17]. Cell-mediated hypersensitivity and humoral antibody responses to 5-ASA derivatives have also been suggested. The humoral antibody theory, where antibodies are generated against pericardial antigens due to 5-ASA drug exposure, is considered to be one of the most plausible explanations. Owing to sulfasalazine or mesalamine intake, antibodies are generated against pericardial antigens leading to inflammation [16-21]. Patients taking sulfasalazine who develop pericarditis are thought to have developed a lupus-like reaction [22-24]. This is supported by lab results seen in patients with sulfasalazine-induced pericarditis. Patients present with positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), fevers, arthralgia, and arthritis months to years after starting treatment, which suggest lupus-like reaction. Mesalamine is thought to induce a type IV drug-induced hypersensitivity reaction, which is supported by ANA +/-, ESR raised +/-, lymphocyte stimulation test +, with a resolution of pericarditis on drug cessation and initiation of a steroid regimen [23,25]. When pericarditis arises solely as an extraintestinal manifestation of IBD, lab reports usually show ANA - and ESR raised -. However, most cases in this study had ANA +, elevated ESR, and drug history of a 5-ASA derivative, which suggests that pericarditis is more likely to arise due to drug therapy rather than disease progression in IBD. In our study of 18 cases, drug cessation with or without initiating a steroid regimen was effective at resolving the patients’ condition.\n\nAdditionally, Ishikawa et al. and Coman et al. have presented cases where pericarditis arose after 5-ASA therapy, resolved upon drug cessation, and reoccurred on reinitiation of the causative drug [25,26]. Patients on 5-ASA therapy for the treatment of pericarditis usually develop symptoms within two weeks of treatment initiation, which resolves upon drug cessation and initiation of a steroid regimen [23]. This further suggests that drug therapy is more likely to lead to pericarditis versus an extraintestinal manifestation of IBD. In two cases, infliximab was suspected of causing pericarditis in IBD patients. Two different mechanisms have been proposed. Burke et al. suggests that infliximab can cause a drug-induced SLE reaction leading to various inflammatory manifestations such as pericarditis [27]. On the other hand, Devasahayam et al. suggests that infliximab therapy has a pro-inflammatory effect on the pericardium leading to a serum sickness-like reaction. This is supported by the fact that patients may develop fever, rash, myalgia, and polyarthralgia one to two weeks after initiating therapy [28]. One patient also developed pericarditis while on azathioprine therapy. Adverse reactions due to azathioprine have been known to be caused by a hypersensitivity reaction [29]. This patient developed pericarditis within one to two weeks after azathioprine was initiated, and his condition resolved once the drug was stopped. Azathioprine-induced hypersensitivity is more likely to be responsible for the development of pericarditis versus an extraintestinal manifestation because rechallenge causes symptoms to develop more rapidly than the initial one to two weeks of using the drug [29]. However, one case pointed more towards an extraintestinal manifestation of pericarditis. Perrot explains that when sulfasalazine was given to a patient, pericarditis developed two weeks later. After drug cessation, pericarditis resolved. To maintain remission, sulfasalazine was given once more, but pericarditis did not recur. Although uncertain, pericarditis may not have recurred as it may have arisen as an extraintestinal manifestation or possibly due to a lowered sulfasalazine dose to maintain remission [30]. Table 3 lists the intervention given during each study and the pathogenesis of pericarditis in IBD.\n\nTable 3 Detailing the results and pathogenesis of pericarditis in IBD.\n\nIBD, inflammatory bowel disease; 5-ASA, 5-aminosalicylic acid; UC, ulcerative colitis; NSAIDs, non-steroidal anti inflammatory drugs; EIM, extraintestinal manifestations; WBCs, white blood cells\n\nAuthor\tYear of publication\tType of study\tResult (intervention given)\tConclusion\t\nBunu et al. [17]\t2019\tClinical review\tNo specific intervention mentioned\tPericarditis can be caused by immune-mediated myocarditis in IBD as a result of exposure to autoantigens or cardiotoxicity as an adverse effect of the treatment with 5-ASA and its derivatives\t\nMitchell et al. [15]\t2018\tClinical review\tNo specific intervention mentioned\tAminosalicylate therapy leads to IgE-mediated allergic reactions, direct cardiac toxicity, cell-mediated hypersensitivity, or a humoral antibody response against 5-ASA derivatives\t\nDipasquale et al. [31]\t2017\tCase report\tInfliximab was given to treat IBD.Pericarditis occurred and was managed with steroids\tInfliximab-induced pericarditis can occur through the following mechanisms: direct cardiac toxicity, IgE-mediated allergic reaction, humoral antibody response, cell-mediated hypersensitivity, or serum sickness-like reaction, and drug-induced lupus\t\nBernardo et al. [16]\t2016\tCase report\tMesalamine therapy stopped after pericarditis occurred. Steroids and azathioprine therapy started to resolve pericarditis\tPericarditis arises due to: IgE-mediated allergic reaction, direct cardiac toxicity, cell-mediated hypersensitivity, or a humoral antibody response\t\nComan et al. [25]\t2014\tClinical review\tBalsalazide given with mesalamine which lead to pericarditis. Cessation of both drugs rapidly resolved the condition\tBalsalazide causes a drug-induced hypersensitivity reaction\t\nNair et al. [21]\t2014\tCase report\tMesalamine therapy lead to pericarditis and resolved on drug cessation\tMesalamine leads to a humoral-mediated hypersensitivity reaction where antibodies are generated against cardiac antigens\t\nSonu et al. [19]\t2013\tCase report\tPatient on mesalamine and sulfasalazine therapy developed pericarditis Both drugs were stopped, and pericarditis resolved. On initiation of another 5-ASA derivative, balsalazide, pericarditis recurred and was more severe. Balsalazide cessation resolved pericarditis\tA patient who develops pericarditis on 5-ASA derivatives may have a more severe reaction on replacement with another derivative. Immediate cessation of 5-ASA derivatives in both instances of myopericarditis suggests that there is a drug-induced hypersensitivity reaction\t\nBurke et al. [27]\t2007\tLetter to the editor\tInfliximab caused lupus-like symptoms, including pericarditis. Drug cessation resolved pericarditis\tInfliximab can cause a drug-induced SLE reaction leading to various inflammatory manifestations such as pericarditis\t\nDevasahayam et al. [28]\t2007\tLetter to the editor\tInfliximab therapy lead to pericarditis. Infliximab discontinued, and NSAIDS given to resolve the condition\tInfliximab may have pro-inflammatory activity in certain tissues, including the pericardium leading to a serum sickness-like reaction\t\nOxentenko et al. [20]\t2002\tCase report\tMesalamine given initially leading to pericarditis. Steroids were given to resolve pericarditis\tMesalamine can lead to pericarditis due to a direct cardiotoxic effect, cell-mediated hypersensitivity reaction, IgE-mediated allergic reaction, or a humoral antibody response. Most patients with mesalamine-induced pericarditis have presented within two weeks of initiating the drug\t\nMahajan et al. [22]\t2001\tCase report\tMesalamine treatment was initiated and then stopped after pericarditis occurred. Methylprednisolone was then given, which resolved pericarditis\tMesalamine may lead to a hypersensitivity reaction. Sulfasalazine can cause a lupus-like reaction\t\nVayre et al. [24]\t1998\tLetter to the editor\tPatient admitted with pericarditis and IBD. Mesalamine cessation resolved pericarditis\tSulfasalazine leads to a lupus-like reaction causing pericarditis\t\nGranot et al. [32]\t1988\tClinical review\tAspirin was given to resolve pericarditis\t5-ASA may inhibit prostaglandin function and metabolism and may also disrupt polymorphonuclear WBCs\t\n\nManagement\n\nInterpretation: Most patients responded well to drug cessation with or without initiation of corticosteroid treatment. Additionally, a handful of patients responded well to steroids alone. This accounted for 26 of the 36 patients, suggesting the efficacy of drug cessation and corticosteroid therapy as the first-line management of pericarditis in IBD. NSAID therapy, colectomy, pericardiocentesis, and initiation of alternative therapies to 5-ASA derivatives (e.g., azathioprine, infliximab) comprised the management of the remaining 10 patients, suggesting a less preferred or alternative management if drug cessation and corticosteroids are ineffective.\n\nAnalysis: As pericarditis is likely to occur due to a drug-induced hypersensitivity reaction, many pericarditis cases are resolved simply by drug cessation. Obtaining a thorough patient history and a past and present drug history is crucial to identify the etiology of the patient’s condition, which may be managed by changing the drug therapy. Most patients are advised to discontinue aminosalicylate therapy and are given a steroid regimen, which allows the condition to resolve within two weeks [15]. Several studies suggest that solely giving high-dose corticosteroids is adequate to resolve pericarditis [12,14,20,33-37]. However, Dias et al. suggests that the efficacy of corticosteroids is uncertain because the time of resolution of pericarditis with steroids is similar to the time of resolution by simply stopping drug therapy [38]. Sposato further supports this idea as corticosteroids alone were not sufficient to resolve their patient’s pericarditis. It was only until mesalazine therapy was withdrawn that their patient began to recover [39]. This suggests that when managing a patient with pericarditis in IBD, known causative drugs should be immediately stopped, and a corticosteroid regimen can be then considered. However, if pericarditis arises as an extraintestinal manifestation unrelated to drug therapy, corticosteroids are effective and preferred to manage the condition [40]. While tapering doses of steroids, it is essential to monitor for recurring pericarditis; if pericarditis recurs, the dose of steroids given should be increased [11]. Furthermore, it is essential to rule out any infectious etiology or contraindications to immunosuppressive therapy before initiating steroids. NSAIDs such as aspirin or indomethacin are other alternative treatments for managing pericarditis in IBD [17,18,32,40,41]. The treatment of IBD-induced pericarditis is steroids in 80% of the cases. The remainder of cases can be managed with aspirin or indomethacin, in which pericarditis responds well. Aspirin and indomethacin can be preferred before giving steroids as long as IBD is dormant. Although effective at managing pericarditis, both aspirin and indomethacin can exacerbate a patient’s IBD. In active bowel disease, selective COX-2 inhibitors such as celecoxib can be given [17,20]. Colchicine is another alternative drug that can be given, although active bowel disease should not be present as it may lead to exacerbation of diarrhea [17]. In two cases, azathioprine and infliximab were given to replace mesalamine therapy. Although pericarditis did not recur, these drugs are not recommended as they are responsible for leading to pericarditis in several other cases [31,33]. In three cases, a colectomy was done. However, steroids were also initiated in two of the three cases; hence, the efficacy of colectomy alone is difficult to ascertain [42-44]. As a complication of pericarditis, pericardial effusion and pericardial tamponade may arise. Drainage by pericardiocentesis is effective at resolving the effusion. Alternatively, pericardiectomy can be done if pericarditis complications arise [11,12,41,44].\n\nIt is difficult to distinguish that a patient who has developed pericarditis is due to an extraintestinal manifestation of IBD disease progression or an adverse effect of drug therapy. Thorough patient history and careful monitoring of the patient’s condition upon drug removal and initiation are needed to manage the patient better. There is also uncertainty about the use of infliximab and azathioprine therapy in managing pericarditis with IBD. Although some cases were resolved with such therapy, others were incited by the same. The risk factors leading to pericarditis in IBD are unclear. Understanding the risk factors and etiology can help in the prevention and immediate management of pericarditis in IBD. Table 4 shows the intervention given for each study and the management of pericarditis in IBD.\n\nTable 4 Detailing the intervention and management of pericarditis in IBD.\n\nIBD, inflammatory bowel disease; 5-ASA, 5-aminosalicylic acid; UC, ulcerative colitis; NSAIDs, non-steroidal anti-inflammatory drugs; EIM, extraintestinal manifestations\n\nAuthor\tYear of publication\tType of study\tResult (intervention given)\tConclusion\t\nBunu et al. [17]\t2019\tClinical review\tNo specific intervention was given\tNSAIDs can be given to treat pericarditis. Selective COX-2 inhibitors are preferred to avoid gastrointestinal toxicity. Colchicine is an option for therapy but causes diarrhea. Immunosuppressives (corticosteroids, azathioprine, cyclosporine) is another option, but you must rule out an infectious etiology first\t\nMitchell et al. [15]\t2018\tClinical review\tNo specific intervention was given\tThe majority of patients should discontinue aminosalicylates and give steroids, which leads to resolution within two weeks. Aspirin or colchicine must be used with caution because it has gastrointestinal side effects. Infliximab and azathioprine may induce pericarditis when treating IBD. Pericarditis can arise as an extraintestinal manifestation outside of drug induction\t\nDias et al. [38]\t2018\tCase report\tUC treated with mesalazine and pericarditis developed later and resolved after drug cessation. Pericarditis recurred once mesalazine therapy continued\t5-ASA drug cessation is adequate to treat pericarditis with IBD. Efficacy of corticosteroids is uncertain because the time of resolution of pericarditis with steroids is similar to just stopping drug therapy\t\nBernardo et al. [16]\t2016\tCase report\tMesalamine therapy stopped after pericarditis arose. Steroids and azathioprine therapy resolved pericarditis\tClinical manifestations occur 2-4 weeks of mesalamine treatment. Stopping mesalamine resolves pericarditis within 7-14 days. Reintroducing mesalamine leads to recurrent pericarditis. Changing the route of administration (oral to enema) for mesalamine may lead to pericarditis\t\nKiyomatsu et al. [45]\t2015\tCase report\tMesalamine induced pericarditis occurred and resolved on drug cessation. Infliximab therapy was used to replace mesalamine\tDrug cessation of mesalamine is adequate to resolve pericarditis in IBD. Pericarditis can arise as an EIM or due to drug therapy for IBD\t\nNair et al. [21]\t2014\tCase report\tMesalamine initiated, and pericarditis developed. It resolved on drug cessation\tTreatment includes drug cessation, supportive care, and monitoring of the patient. It is important to take a proper patient history, including past and present drug therapy, and carry out lab tests to differentiate EIM or drug-induced pericarditis\t\nSonu et al. [19]\t2013\tCase report\tA patient on mesalamine and sulfasalazine developed pericarditis. When both drugs stopped, pericarditis resolved. On initiation of another 5-ASA derivative, balsalazide, pericarditis recurred and was more severe. Balsalazide cessation resolved the pericarditis\tA patient who developed pericarditis on 5-ASA derivatives may have a more severe reaction if therapy is replaced with an alternative derivative. Immediate cessation of 5-ASA derivatives in both instances of myopericarditis suggests that there is a drug-induced hypersensitivity reaction\t\nAbu-Hijleh et al. [33]\t2010\tCase report\tMesalamine and azathioprine were given to the patient and pericardial effusion developed. The patient was given prednisolone and effusion resolved. On tapering the steroid dose, pericarditis recurred\tSteroids are effective at treating IBD with pericarditis and pericardial effusion\t\nSposato et al. [39]\t2010\tCase report\tMesalazine was given, stopped, and corticosteroids were added to resolve pericarditis\tCorticosteroids are not enough to resolve pericarditis. Mesalazine treatment must also be stopped due to direct drug toxicity as evidence shows mesalazine and steroids together still did not resolve pericarditis. Cessation of mesalazine alone can be effective\t\nCappell et al. [11]\t2008\tCase report\tMesalamine treatment stopped eight years before pericarditis occurred, and lab studies suggest pericarditis arose as an EIM. Indomethacin initially given for pericarditis, but UC recurred. Steroids were given to resolve both IBD and pericarditis\tPrednisolone should be preferred over NSAIDS as it can treat both IBD and pericarditis, while NSAIDS only treat the latter and exacerbate the former. While tapering doses of steroids, always check for recurring pericarditis; if present, increase dose of steroid. Pericardiectomy can be done to resolve life-threatening cardiac tamponade\t\nPerrot et al. [30]\t2007\tCase report\tSulfasalazine given, and pericarditis occurred. Drug therapy was stopped, and pericarditis resolved. On reinitiation of therapy, pericarditis did not recur\tIBD causes pericarditis if bowel disease is active, and pericarditis is not solely drug-induced\t\nJackson et al. [40]\t2005\tLetter to the editor\tCorticosteroids were given to resolve pericarditis\tIn non-medication-induced pericarditis, corticosteroids are effective at resolving the condition. NSAIDs are also useful but should be avoided in active bowel disease as they can worsen the condition\t\nHyttinnen et al. [13]\t2003\tCase report\tImmunosuppressive therapy given on the first three episodes of IBD. No mesalamine was given until the fifth episode occurred. Pericarditis developed in the first three episodes without mesalamine\tPericarditis can arise as an EIM not related to 5-ASA derivatives\t\nOxentenko et al. [20]\t2002\tCase report\tMesalamine was given to treat IBD and pericarditis occurred. Mesalamine was discontinued, and steroids resolved pericarditis\tTreatment of IBD-induced pericarditis is steroids in 80% of cases. Remainder of cases can be managed with aspirin or indomethacin. Pericarditis responds well to aspirin and indomethacin and can be preferred before giving steroids as long as IBD is dormant\t\nDubowitz et al. [43]\t2001\tCase report\tNo 5-ASA given (patient was intolerant). Prednisolone and subtotal colectomy was done. Pericarditis then manifested with effusion later and pericardiocentesis was done to resolve the condition with the continuation of steroids (steroids alone were not sufficient)\tPericarditis can arise as an extraintestinal manifestation not related to drug use. In the case of pericardial effusion, pericardiocentesis is needed\t\nOrii et al. [37]\t2001\tCase report\tThe patient was given salazosulfapyridine and pericarditis occurred. Pericarditis resolved with steroids\tCorticosteroids helped resolve pericarditis\t\nMolnar et al. [36]\t1999\tCase report\tSulfasalazine given to treat IBD, then discontinued. Methylprednisolone given to manage IBD and pericarditis\tPericarditis resolved with corticosteroids\t\nGujral et al. [18]\t1996\tCase report\tMesalamine therapy caused pericarditis. Mesalamine then discontinued. Aspirin given, which resolved pericarditis\tDrug cessation and NSAIDS can be given to manage pericarditis in IBD\t\nSarrouj et al. [35]\t1994\tCase report\tIndomethacin therapy given initially without resolution of pericarditis. IV methylprednisolone was given and aspirin then initiated later, which led to resolution.\tCorticosteroids are effective in treating pericarditis\t\nGranot et al. [32]\t1988\tClinical review\t5-Aminosalicylates led to pericarditis. Aspirin given in tapering doses to resolve condition\tAspirin may help resolve pericarditis, but most cases respond to corticosteroids\t\nFarley et al. [41]\t1986\tCase report\tSulfasalazine was continuously given throughout the management of the patient. Steroids were then given, which resolved the pericarditis. A rapid drop in tapered steroid doses caused pericarditis to recur\tSteroids are effective at treating pericarditis. NSAIDs can be used as an alternative treatment. Pericardiecetomy can be done to resolve cardiac tamponade. Gradual tapering of steroid therapy is needed. Recurrence can be treated by introducing or increasing the dose of steroids or alternatively using NSAIDs\t\nManomohan et al. [34]\t1984\tCase report\tIV steroids and parenteral nutrition was given to manage IBD and pericarditis\tHigh-dose corticosteroids are adequate enough for treating pericarditis\t\nLevin et al. [42]\t1979\tCase report\tColectomy resolved both IBD and pericarditis. Prednisolone was given after\tColectomy can be curative for both diseases\t\nRheingold [44]\t1975\tLetter to the editor\tColectomy was done to treat IBD and pericarditis arose after colectomy. It was treated with pericardial drainage and no steroids given\tCardiac tamponade can frequently arise following pericarditis. Usually, pericarditis resolves after colectomy. Effusion can be effectively treated with drainage\t\nBreitenstein et al. [12]\t1974\tLetter to the editor\tPericarditis arose as an EIM. Steroid treatment resolved the pericarditis. Pericardiocentesis was done to resolve the pericardial tamponade\tSteroids are effective at treating IBD with pericarditis. Cardiac tamponade can be managed with pericardiocentesis\t\n\nLimitations\n\nThis study’s limitations include the limited availability of clinical reviews, systematic reviews, cohort, and case-control studies. Although some clinical reviews and systematic reviews were included, most studies were case reports and letters to the editor. Additionally, non-English papers were excluded, and animal studies were not used in this review. The studies used in this review included all available studies from the inception to the present rather than only recent studies. Full-text articles, if not available, were also not included in this study. The studies that were excluded or not available could have provided relevant information about the pathogenesis or management of pericarditis in IBD and improved the overall results.\n\nConclusions\n\nCardiovascular manifestations of IBD, particularly pericarditis, is an uncommon occurrence in which the pathogenesis and management have previously not been explored in detail. Pericarditis in IBD can arise due to drug therapy or, less commonly, as an extraintestinal manifestation. 5-ASA derivatives are primarily responsible for inducing pericarditis through IgE-mediated hypersensitivity reactions, direct cardiotoxicity, cell-mediated hypersensitivity, and humoral antibody reactions. Infliximab and azathioprine are less common causes of pericarditis and are most likely caused by a lupus-like reaction and drug-induced hypersensitivity, respectively, making them less suitable options when trying to replace 5-ASA drug therapy. Most patients respond well to drug cessation and corticosteroid therapy. Aspirin, indomethacin, and colchicine can be used as an alternative therapy as long as bowel disease is not active, and drainage may be required in the case of effusion or cardiac tamponade. Additional studies should be conducted to identify how to differentiate drug-induced pericarditis from extraintestinal manifestations of IBD. Additionally, the risk factors associated with developing pericarditis in an IBD patient should be studied to help prevent and manage this condition.\n\nThe authors have declared that no competing interests exist.\n==== Refs\nReferences\n\n1 ACG clinical guideline: preventive care in inflammatory bowel disease Am J Gastroenterol Farraye FA Melmed GY Lichtenstein GR Kane SV 241 258 112 2017 28071656\n2 Pleuropericarditis in a patient with inflammatory bowel disease: a case presentation and review of the literature Lung Abu-Hijleh M Evans S Aswad B 505 510 188 2010 20827555\n3 Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD) Gut Shivananda S Lennard-Jones J Logan R Fear N Price A Carpenter L van Blankenstein M 690 697 39 1996 9014768\n4 Extraintestinal manifestations of inflammatory bowel disease Gastroenterol Hepatol (N Y) Levine JS Burakoff R 235 241 7 2011 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127025/ 21857821\n5 Heart under attack: cardiac manifestations of inflammatory bowel disease Inflamm Bowel Dis Mitchell NE Harrison N Junga Z Singla M 2322 2326 24 2018 29788235\n6 The heart in inflammatory bowel disease Ann Gastroenterol Katsanos KH Tsianos EV 124 133 15 2002 http://www.annalsgastro.gr/index.php/annalsgastro/article/view/129\n7 Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases Eur Heart J Caforio AL Pankuweit S Arbustini E 2636 2648 34 2013 23824828\n8 Mesalazine induced myopericarditis in a patient with ulcerative colitis Echo Res Pract Asadi J Bhandari SS Ahmed N 1 5 5 2017 29258998\n9 Update on myocarditis and inflammatory cardiomyopathy: reemergence of endomyocardial biopsy Rev Esp Cardiol (Engl Ed) Dominguez F Kühl U Pieske B Garcia-Pavia P Tschöpe C 178 187 69 2016 26795929\n10 Cardiac autoimmunity: myocarditis Adv Exp Med Biol Bracamonte-Baran W Čiháková D 187 221 1003 2017 28667560\n11 Chronic pericarditis and pericardial tamponade associated with ulcerative colitis Dig Dis Sci Cappell MS Turkieh A 149 154 53 2008 17574528\n12 Letter: chronic inflammatory bowel disease: acute pericarditis and pericardial tamponade Ann Intern Med Breitenstein RA Salel AF Watson DW 406 81 1974\n13 Recurrent myopericarditis in association with Crohn's disease J Intern Med Hyttinen L Kaipiainen-Seppänen O Halinen M 386 388 253 2003 12603508\n14 Myopericarditis complicating ulcerative colitis Br Heart J Mowat NA Bennett PN Finlayson JK Brunt PW Lancaster WM 724 727 36 1974 4414769\n15 Heart under attack: cardiac manifestations of inflammatory bowel disease Inflamm Bowel Dis Mitchell NE Harrison N Junga Z Singla M 2322 2326 24 2018 29788235\n16 Mesalamine-induced myopericarditis - a case report Rev Esp Enferm Dig Bernardo S Fernandes SR Araújo-Correia L 753 756 108 2016 26876057\n17 Cardiovascular manifestations of inflammatory bowel disease: pathogenesis, diagnosis, and preventive strategies Gastroenterol Res Pract Bunu DM Timofte CE Ciocoiu M Floria M Tarniceriu CC Barboi OB Tanase DM 3012509 2019 2019 30733802\n18 Pleuropericarditis related to the use of mesalamine Dig Dis Sci Gujral N Friedenberg F Friedenberg J Gabriel G Kotler M Levine G 624 626 41 1996 8617147\n19 5-ASA induced recurrent myopericarditis and cardiac tamponade in a patient with ulcerative colitis Dig Dis Sci Sonu I Wong R Rothenberg ME 2148 2150 58 2013 23361575\n20 Constrictive pericarditis in chronic ulcerative colitis J Clin Gastroenterol Oxentenko AS Loftus EV Oh JK Danielson GK Mangan TF 247 251 34 2002 11873106\n21 Mesalamine-induced myopericarditis in a paediatric patient with Crohn's disease Cardiol Young Nair AG Cross RR 783 786 25 2015 24915235\n22 Atlantoaxial subluxation and pericarditis in a child with Crohn's disease Am J Gastroenterol Mahajan L Klein A Wyllie R Kay M Applegate K Sabella C Kuivila T 3190 3191 96 2001 11721771\n23 Recurrent pericarditis due to mesalamine hypersensitivity: a pediatric case report and review of the literature J Pediatr Gastroenterol Nutr Sentongo TA Piccoli DA 344 347 27 1998 9740210\n24 Pericarditis associated with longstanding mesalazine administration in a patient Int J Cardiol Vayre F Vayre-Oundjian L Monsuez JJ 243 245 68 1999 10189017\n25 Febrile pleuropericarditis, a potentially life-threatening adverse event of Balsalazide--case report and literature review of the side effects of 5-aminosalicylates Expert Rev Clin Immunol Coman RM Glover SC Gjymishka A 667 675 10 2014 24689504\n26 Acute pericarditis associated with 5-aminosalicylic acid (5-ASA) treatment for severe active ulcerative colitis Intern Med Ishikawa N Imamura T Nakajima K 901 904 40 2001 11579953\n27 Pericarditis as a complication of infliximab therapy in Crohn's disease Inflamm Bowel Dis Burke JP Kelleher B Ramadan S Quinlan M Sugrue D O'Donovan MA 428 429 14 2008 17924565\n28 A rare case of pericarditis, complication of infliximab treatment for Crohn's disease J Crohns Colitis Devasahayam J Pillai U Lacasse A 730 731 6 2012 22465046\n29 Azathioprine-induced pericarditis in a patient with ulcerative colitis Can J Gastroenterol Simpson CD 217 219 11 1997 9167028\n30 Sulfasalazine-induced pericarditis in a patient with ulcerative colitis without recurrence when switching to mesalazine Int J Colorectal Dis Perrot S Aslangul E Szwebel T Gadhoum H Romnicianu S Le Jeunne C 1119 1121 22 2007 17440739\n31 Pericarditis during infliximab therapy in paediatric ulcerative colitis J Clin Pharm Ther Dipasquale V Gramaglia SMC Catena MA Romano C 107 109 43 2018 28646522\n32 Carditis complicating inflammatory bowel disease in children. Case report and review of the literature Eur J Pediatr Granot E Rottem M Rein AJ 203 205 148 1988 3215196\n33 Pleuropericarditis in a patient with inflammatory bowel disease: a case presentation and review of the literature Lung Abu-Hijleh M Evans S Aswad B 505 510 188 2010 20827555\n34 Crohn's disease and pericarditis Postgrad Med J Manomohan V Subbuswamy SG Willoughby CP 682 684 60 1984 6494090\n35 Pericarditis as the initial manifestation of inflammatory bowel disease Chest Sarrouj BJ Zampino DJ Cilursu AM 1911 1912 106 1994 7988229\n36 Pericarditis associated with inflammatory bowel disease: case report Am J Gastroenterol Molnár T Hôgye M Nagy F Lonovics J 1099 1100 94 1999 10201492\n37 Pleuropericarditis and disseminated intravascular coagulation in ulcerative colitis J Clin Gastroenterol Orii S Chiba T Nakadate I 251 254 32 2001 11246357\n38 Recurrent mesalazine-induced myopericarditis in a patient with ulcerative colitis BMJ Case Rep Dias T Santos A Santos RM Carvalho A 228037 12 2019\n39 Mesalazine-induced multi-organ hypersensitivity Clin Drug Investig Sposato B Allegri MP Riccardi MP 413 417 30 2010\n40 Pericarditis as the presenting sign of Crohn's disease Inflamm Bowel Dis Jackson JF Sitaraman SV 81 82 11 2005 15674122\n41 Pericarditis and ulcerative colitis J Clin Gastroenterol Farley JD Thomson AB Dasgupta MK 567 568 8 1986 3782756\n42 Pericarditis in association with ulcerative colitis West J Med Levin EN Hirschfeld DS Hersch RA 369 370 130 1979 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1238637/ 442630\n43 Cardiomyopathy and pericardial tamponade in ulcerative colitis Eur J Gastroenterol Hepatol Dubowitz M Gorard DA 1255 1258 13 2001 11711786\n44 Letter: inflammatory bowel disease and pericarditis Ann Intern Med Rheingold OJ 592 82 1975\n45 Mesalazine-induced pleuropericarditis in a patient with Crohn's disease Intern Med Kiyomatsu H Kawai K Tanaka T 1605 1608 54 2015 26134190\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(3)",
"journal": "Cureus",
"keywords": "crohn’s disease; extraintestinal manifestations; inflammatory bowel disease; pericarditis; ulcerative colitis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e14010",
"pmc": null,
"pmid": "33884251",
"pubdate": "2021-03-20",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "17440739;7988229;26795929;28071656;4852723;28646522;30709886;9014768;6494090;26876057;10189017;1119781;23824828;9740210;8617147;4414769;23361575;11246357;11579953;442630;3782756;3215196;11711786;17924565;29138234;28667560;9167028;20441247;24915235;11721771;26134190;24689504;10201492;15674122;11873106;20827555;29788235;12603508;22465046;30733802;17574528;21857821",
"title": "Cardiovascular Manifestations in Inflammatory Bowel Disease: A Systematic Review of the Pathogenesis and Management of Pericarditis.",
"title_normalized": "cardiovascular manifestations in inflammatory bowel disease a systematic review of the pathogenesis and management of pericarditis"
} | [
{
"companynumb": "US-ALLERGAN-1663725US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": null,
... |
{
"abstract": " When a patient with major depressive disorder experiences inadequate response to an antidepressant, clinicians should employ measurement-based care strategies to improve outcomes. Evidence suggests that adjunctive therapies, such as the FDA-approved atypical antipsychotics, are efficacious when the initial treatment is well tolerated but not improving symptoms. Clinicians should consult guidelines, peer-reviewed journals, CME programs, and other sources to stay up-to-date with current and emerging treatments in this area. They should also be familiar with the available options for psychotherapy, neurostimulation, supplements, and exercise for patients who prefer alternative therapies. .",
"affiliations": null,
"authors": "Papakostas|George I|GI|;Jackson|W Clay|WC|;Rafeyan|Roueen|R|;Trivedi|Madhukar H|MH|",
"chemical_list": "D000928:Antidepressive Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "81(3)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000928:Antidepressive Agents; D003865:Depressive Disorder, Major; D006801:Humans; D017211:Treatment Failure",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32412698",
"pubdate": "2020-05-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Overcoming Challenges to Treat Inadequate Response in Major Depressive Disorder.",
"title_normalized": "overcoming challenges to treat inadequate response in major depressive disorder"
} | [
{
"companynumb": "US-OTSUKA-2021_015203",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nIvabradine is a unique medication that reduces the intrinsic heart rate by specifically blocking the inward funny current that controls the pacemaker activity of the sinus node. We conducted a retrospective cohort study to assess the efficacy of ivabradine in children suffering from postural orthostatic tachycardia syndrome.\n\n\nMETHODS\nA chart review was conducted of patients less than 18 years of age who were diagnosed with postural orthostatic tachycardia syndrome who had received ivabradine as treatment from January 2015 to February 2019 at our institution. Twenty-seven patients (25 females, 92.5%) were identified for the study. The outcomes which were assessed included a change in the severity and frequency of symptoms, heart rate, and blood pressure before and after starting ivabradine.\n\n\nRESULTS\nThere was an improvement in the symptoms of 18 (67%) out of 27 patients. The most notable symptom affected was syncope/presyncope with a reduction in 90%, followed by lightheadedness (85%) and fatigue (81%). The vital signs of the patients showed an overall significant lowering of the heart rate during sitting (89.7 ± 17.9 versus 73.2 ± 12.1; p-value <0.05) and standing (100.5 ± 18.1 versus 80.9 ± 10.1; p-value <0.05) without a significant change in the blood pressure. Two patients had visual disturbances (luminous phenomena). Severe bradycardia and excessive flushing were seen in two patients, respectively. Another one patient reported joint pain and fatigue.\n\n\nCONCLUSIONS\nThis study indicates that 67% of children treated with ivabradine report an improvement in symptoms.",
"affiliations": "Department of Cardiovascular Disease, University of Toledo, Toledo, OH, USA.;Department of Internal Medicine, University of Toledo, Toledo, OH, USA.;Department of Cardiovascular Disease, University of Toledo, Toledo, OH, USA.;Department of Cardiovascular Disease, University of Toledo, Toledo, OH, USA.;Department of Cardiovascular Disease, University of Toledo, Toledo, OH, USA.",
"authors": "Towheed|Arooge|A|https://orcid.org/0000-0002-6266-1133;Nesheiwat|Zeid|Z|;Mangi|Muhammad A|MA|;Karabin|Beverly|B|;Grubb|Blair P|BP|",
"chemical_list": "D000077550:Ivabradine",
"country": "England",
"delete": false,
"doi": "10.1017/S1047951120001341",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "30(7)",
"journal": "Cardiology in the young",
"keywords": "Orthostatic intolerance; children; medications",
"medline_ta": "Cardiol Young",
"mesh_terms": "D002648:Child; D005260:Female; D006339:Heart Rate; D006801:Humans; D000077550:Ivabradine; D054972:Postural Orthostatic Tachycardia Syndrome; D012189:Retrospective Studies; D012849:Sinoatrial Node",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "975-979",
"pmc": null,
"pmid": "32498748",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ivabradine in children with postural orthostatic tachycardia syndrome: a retrospective study.",
"title_normalized": "ivabradine in children with postural orthostatic tachycardia syndrome a retrospective study"
} | [
{
"companynumb": "US-AMGEN-USASP2020095086",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IVABRADINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report post hoc results on how adjustments to baseline antiseizure medications (ASMs) in a subset of study sites (10 US sites) from a long-term, open-label phase 3 study of adjunctive cenobamate affected tolerability, efficacy, and retention.\n\n\nMETHODS\nPatients with uncontrolled focal seizures taking stable doses of one to three ASMs were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50 mg/day biweekly increments were allowed during maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until last visit, at data cut-off, on or after September 1, 2019.\n\n\nRESULTS\nA total of 240 patients meeting eligibility criteria were assessed (median [max] exposure 30.2 [43.0] months), with 177 patients continuing cenobamate at data cut-off. Most common baseline concomitant ASMs were lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam. For most baseline concomitant ASMs, ~70% of patients taking that ASM were continuing cenobamate at data cut-off. Patients continuing cenobamate had greater mean ASM dose reductions and percent dose changes from baseline vs those who discontinued. Of patients continuing cenobamate, 24.6% discontinued one or more concomitant ASMs completely. Dose decreases for all concomitant ASMs generally occurred during titration or early maintenance phases and were mostly due to central nervous system (CNS)-related adverse events such as somnolence, dizziness, unsteady gait, and fatigue. Responder rates from ≥50% through 100% for patients continuing cenobamate were generally similar regardless of concomitant ASMs (of those most commonly taken), with ~81% being ≥50% responders and ~12% achieving 100% seizure reduction in the maintenance phase, which lasted up to 40.2 (median = 29.5) months.\n\n\nCONCLUSIONS\nConcomitant ASM dose reductions were associated with more patients remaining on cenobamate. This is likely due to efficacy and improved tolerability, with overall reduced concomitant drug burden in patients with uncontrolled seizures despite taking one to three baseline concomitant ASMs.",
"affiliations": "Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, Missouri, USA.;Vanderbilt University Medical Center, Nashville, Tennessee, USA.;Austin Epilepsy Care Center, Austin, Texas, USA.;Neuro-Pain Medical Center, Fresno, California, USA.;Arkansas Epilepsy Program, Little Rock, Arkansas, USA.;Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;University of Washington School of Medicine, Seattle, Washington, USA.;Mid-Atlantic Epilepsy and Sleep Center, Bethesda, Maryland, USA.;Consultants in Epilepsy & Neurology, PLLC, Boise, Idaho, USA.",
"authors": "Rosenfeld|William E|WE|https://orcid.org/0000-0002-9504-3980;Abou-Khalil|Bassel|B|;Aboumatar|Sami|S|;Bhatia|Perminder|P|;Biton|Victor|V|;Krauss|Gregory L|GL|https://orcid.org/0000-0002-0338-6039;Sperling|Michael R|MR|https://orcid.org/0000-0003-0708-6006;Vossler|David G|DG|https://orcid.org/0000-0003-4823-0537;Klein|Pavel|P|https://orcid.org/0000-0001-7244-3722;Wechsler|Robert|R|https://orcid.org/0000-0002-3146-986X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/epi.17092",
"fulltext": "\n==== Front\nEpilepsia\nEpilepsia\n10.1111/(ISSN)1528-1167\nEPI\nEpilepsia\n0013-9580\n1528-1167\nJohn Wiley and Sons Inc. Hoboken\n\n34633074\n10.1111/epi.17092\nEPI17092\nFull‐length Original Research\nFull‐length Original Research\nPost hoc analysis of a phase 3, multicenter, open‐label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications\nROSENFELD et al.\nRosenfeld William E. https://orcid.org/0000-0002-9504-3980\n1 werosenfeldmd@gmail.com\n\nAbou‐Khalil Bassel 2\nAboumatar Sami 3\nBhatia Perminder 4\nBiton Victor 5\nKrauss Gregory L. https://orcid.org/0000-0002-0338-6039\n6\nSperling Michael R. https://orcid.org/0000-0003-0708-6006\n7\nVossler David G. https://orcid.org/0000-0003-4823-0537\n8\nKlein Pavel https://orcid.org/0000-0001-7244-3722\n9\nWechsler Robert https://orcid.org/0000-0002-3146-986X\n10 11\n1 Comprehensive Epilepsy Care Center for Children and Adults St. Louis Missouri USA\n2 Vanderbilt University Medical Center Nashville Tennessee USA\n3 Austin Epilepsy Care Center Austin Texas USA\n4 Neuro‐Pain Medical Center Fresno California USA\n5 Arkansas Epilepsy Program Little Rock Arkansas USA\n6 Johns Hopkins University School of Medicine Baltimore Maryland USA\n7 Thomas Jefferson University Philadelphia Pennsylvania USA\n8 University of Washington School of Medicine Seattle Washington USA\n9 Mid‐Atlantic Epilepsy and Sleep Center Bethesda Maryland USA\n10 Consultants in Epilepsy & Neurology PLLC Boise Idaho USA\n11 Idaho Comprehensive Epilepsy Center Boise Idaho USA\n* Correspondence\nWilliam E. Rosenfeld, Comprehensive Epilepsy Care Center for Children and Adults, 11134 Conway Road, St. Louis, MO 63131, USA.\nEmail: werosenfeldmd@gmail.com\n\n11 10 2021\n12 2021\n62 12 10.1111/epi.v62.12 30163028\n23 9 2021\n28 7 2021\n23 9 2021\n© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nObjective\n\nTo report post hoc results on how adjustments to baseline antiseizure medications (ASMs) in a subset of study sites (10 US sites) from a long‐term, open‐label phase 3 study of adjunctive cenobamate affected tolerability, efficacy, and retention.\n\nMethods\n\nPatients with uncontrolled focal seizures taking stable doses of one to three ASMs were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2‐week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50 mg/day biweekly increments were allowed during maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until last visit, at data cut‐off, on or after September 1, 2019.\n\nResults\n\nA total of 240 patients meeting eligibility criteria were assessed (median [max] exposure 30.2 [43.0] months), with 177 patients continuing cenobamate at data cut‐off. Most common baseline concomitant ASMs were lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam. For most baseline concomitant ASMs, ~70% of patients taking that ASM were continuing cenobamate at data cut‐off. Patients continuing cenobamate had greater mean ASM dose reductions and percent dose changes from baseline vs those who discontinued. Of patients continuing cenobamate, 24.6% discontinued one or more concomitant ASMs completely. Dose decreases for all concomitant ASMs generally occurred during titration or early maintenance phases and were mostly due to central nervous system (CNS)–related adverse events such as somnolence, dizziness, unsteady gait, and fatigue. Responder rates from ≥50% through 100% for patients continuing cenobamate were generally similar regardless of concomitant ASMs (of those most commonly taken), with ~81% being ≥50% responders and ~12% achieving 100% seizure reduction in the maintenance phase, which lasted up to 40.2 (median = 29.5) months.\n\nSignificance\n\nConcomitant ASM dose reductions were associated with more patients remaining on cenobamate. This is likely due to efficacy and improved tolerability, with overall reduced concomitant drug burden in patients with uncontrolled seizures despite taking one to three baseline concomitant ASMs.\n\nantiepileptics\nantiseizure medications\ncenobamate\nconcomitant medications\nfocal epilepsy\nSK Life Science, Inc. source-schema-version-number2.0\ncover-dateDecember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:18.07.2022\nRosenfeld WE , Abou‐Khalil B , Aboumatar S , Bhatia P , Biton V , Krauss GL , et al. Post hoc analysis of a phase 3, multicenter, open‐label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications. Epilepsia. 2021;62 :3016–3028. 10.1111/epi.17092 34633074\n==== Body\npmc Key Points\n\nPatients who continued cenobamate tended to have greater reductions in concomitant antiseizure medication (ASM) doses than patients who discontinued cenobamate.\n\nConcomitant phenytoin, phenobarbital, clobazam, valproate, and lacosamide were decreased earliest in the clinical study.\n\nCenobamate's efficacy was demonstrated by many patients remaining seizure‐free for long periods and high retention rates even after reducing or completely discontinuing one or more of their concomitant ASMs.\n\nAs experience was accumulated and physicians learned about the potential interactions during this study, concomitant ASM doses were reduced for many patients very early on in cenobamate titration.\n\n1 INTRODUCTION\n\nThe ultimate goal of epilepsy treatment is to achieve seizure freedom (100% seizure reduction) with minimal adverse events (AEs). For drug‐refractory patients, polytherapy has become widespread, even though the probability of additional efficacy diminishes with each successive antiseizure medication (ASM) regimen tried. 1 , 2 Moreover, evidence indicates that reducing treatment with one or more ASMs can occur in drug‐resistant patients who are receiving polytherapy, with no increases in seizure frequency. 3 Despite this, many patients continue to experience uncontrolled seizures and increased side effects due to polypharmacy that provides little additional therapeutic value.\n\nTaking multiple concomitant ASMs can cause drug interactions that may lead to changes in efficacy and safety, including increases in AEs. 4 , 5 Adjustments in dosing and/or medications in patients taking multiple drugs can help optimize efficacy while minimizing side effects. However, with numerous possible drug combinations and the individualized nature of epilepsy treatment, physicians may find themselves in a continual cycle of transitional polytherapy with refractory patients.\n\nFor new medications, it is difficult to assess dose adjustments and achieve optimized efficacy and safety in the customary double‐blind, fixed‐dose, adjunctive therapy clinical trials. 6 , 7 This can confound determination of the true efficacy and tolerability of an adjunctive ASM, given the variable effects of concomitant medications and treatment combinations. Medication management during transitional therapy with new drugs thus requires close monitoring of a patient's AEs and efficacy along with an understanding of possible drug interactions and their effects on plasma concentrations of multiple ASMs.\n\nFlexible‐dose open‐label studies allow for medication adjustments, including dose adjustments of concomitant ASMs. Data from these studies provide insights into the efficacy and tolerability of a newly introduced ASM, given that they measure all reasons for discontinuation, including lack of efficacy and AEs. 7 Moreover, retention data from these open‐label studies can serve as a surrogate for efficacy and provide information about which AEs patients are able to tolerate vs those they cannot.\n\nCenobamate (XCOPRI) is an ASM that is approved by the US Food and Drug Administration (FDA) for the treatment of adults with focal (partial‐onset) seizures. 8 Although cenobamate's mechanism of action is not fully understood, it has been shown to preferentially inhibit the persistent sodium current and to be a positive allosteric modulator of the γ‐aminobutyric acid A (GABAA) ion channel, through a non‐benzodiazepine GABAA receptor site. 8 , 9 , 10 This dual mechanism of action suggests that cenobamate may have the potential to both prevent seizure initiation and limit seizure spread. 11 , 12 , 13 , 14 , 15 , 16 , 17\n\nTwo phase 2, placebo‐controlled, randomized, double‐blind clinical studies (NCT01397968 [C013; Chung et al. 2020 18 ] and NCT01866111 [C017; Krauss et al. 2020 19 ]), in adults with uncontrolled focal epilepsy who had previously failed multiple ASMs, demonstrated substantial reductions in seizure frequency and high responder rates, including seizure freedom, with adjunctive cenobamate at 200 mg/day (C013) and 100, 200, and 400 mg/day (C017). 18 , 19 Cenobamate was generally safe and well tolerated across studies, and the most common AEs were central nervous system (CNS) related. The two adequate and well‐controlled studies (C013 and C017) along with a large (N = 1340) long‐term, open‐label, phase 3 study that focused on safety (NCT02535091 [C021; Sperling et al. 2020 20 ]) supported the FDA approval of the efficacy and safety of cenobamate.\n\nThe C021 study differed from the randomized placebo‐controlled trials in that dose adjustments to concomitant ASMs were allowed and a titration scheme was used that started with a low dose of cenobamate (12.5 mg/day), and the dose was increased slowly (titrated up every other week). 20 Although seizure outcomes were not assessed in the C021 study, given the utility of data on long‐term efficacy, a protocol amendment allowed post hoc collection of seizure data. The current post hoc analysis examined how dose adjustments to baseline concomitant ASMs from 10 US study sites of the C021 study affected tolerability, efficacy, and retention.\n\n2 METHODS\n\n2.1 Study design and patients\n\n2.1.1 Full C021 study\n\nDetailed study design and patient eligibility for the C021 study have been published previously. 20 Briefly, C021 was a multicenter, open‐label safety study in adults with uncontrolled focal seizures despite taking stable doses of one to three ASMs. Focal epilepsy was defined by International League Against Epilepsy (ILAE) seizure classification criteria. 20 , 21 , 22\n\nA screening period of up to 21 days was followed by an open‐label treatment period consisting of a 12‐week titration phase, followed by an open‐label maintenance phase. Patients initiated cenobamate treatment at 12.5 mg/day for 2 weeks, followed by 25 mg/day for 2 weeks and 50 mg/day for 2 weeks; doses were then increased by 50 mg/day biweekly to a target dose of 200 mg/day (Figure S1). 20 Further increases up to 400 mg/day using biweekly increments of 50 mg/day were allowed during the maintenance phase. Reductions below 200 mg were allowed by investigators’ judgment, with a minimum allowed dose of 50 mg/day. Cenobamate monotherapy was not allowed. Patient visits occurred biweekly for 16 weeks and then every 1 to 3 months.\n\n2.1.2 Post hoc analysis\n\nData for this post hoc analysis were collected from US sites in which ≥11 patients had started treatment with cenobamate. Eligible patients were required to have experienced one or more focal aware motor (FAM), focal impaired awareness (FIA), or focal to bilateral tonic‐clonic (FBTC) seizure per 13 weeks prior to screening visit; to have seizure data of FAM, FIA, or FBTC seizures while on treatment; and to have consistent documentation of raw seizure data. In addition, patients were required to have high‐quality seizure data for ≥85% of the total length of the study.\n\nConcomitant ASMs (except phenobarbital and phenytoin) could be removed, added, or adjusted throughout the trial, and cenobamate doses could be adjusted during the titration phase, as clinically needed. For patients taking concomitant phenobarbital and phenytoin, no other concomitant ASMs could be lowered and no adjustments to the cenobamate titration schedule could be made during the titration phase. Phenobarbital and phenytoin dose adjustments were permitted and anticipated to be necessary, with dose reductions of up to ~50% of the original dose for phenytoin. 8 Once the maintenance phase was reached, adjustments to any concomitant ASM doses were allowed in patients taking concomitant phenobarbital or phenytoin.\n\nNumbers of baseline concomitant ASMs, dose adjustments to concomitant ASMs, cenobamate dose at initiation of concomitant ASM dose reduction, and efficacy (using responder rates) by concomitant ASMs were compared among the following four patient outcome groups: all analysis patients (n = 240; “all patients”), all analysis patients in the maintenance phase (n = 214; “maintenance population”), patients continuing cenobamate at data cut‐off (ie, still taking cenobamate, n = 177), and patients who discontinued cenobamate (n = 63).\n\nDuration of 100% seizure reduction was assessed moving backward from the last clinic visit (ie, interval includes last clinic visit). Patients with any missing seizure frequency data could not be counted as having 100% seizure reduction. For ≥50%, ≥75%, and ≥90% responder rates, the seizure frequency was analyzed as observed with imputation for missing seizure data during the assessed interval. Baseline demographics, exposure, reasons for discontinuation, rates of retention, treatment‐emergent adverse events (TEAEs), and efficacy by responder rates were summarized using descriptive statistics.\n\nThe C021 study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines. 20 , 23 An independent ethics committee or institutional review board reviewed and approved the study protocol, amendments, and post hoc analysis at each site in agreement with local requirements. Written informed consent was obtained from each patient prior to study participation.\n\n3 RESULTS\n\n3.1 Baseline demographics, exposure, and baseline ASMs\n\nAmong the 1340 patients within the larger C021 study, 12 US study sites (n = 299) were eligible for inclusion in the post hoc study. Two sites were unable to participate, resulting in 10 sites that were included in the post hoc analysis, with a total of 255 patients. Of these patients, 15 did not meet the post hoc inclusion criteria, leaving 240 patients who could be evaluated. The first of these patients was enrolled on July 20, 2016, and the last patient was enrolled on January 19, 2018.\n\nPatients included in the current post hoc analysis had a mean age of 41.8 years, with a somewhat higher percentage of male patients (Table S1). The median duration of cenobamate exposure was 30.2 months (range: 0.10–43.0 months) including the titration phase, and 29.5 months (range: 0.80–40.2) for the maintenance phase alone. Of the analysis population (all patients, n = 240), 177 (73.8%) were still taking cenobamate (patients continuing cenobamate) at the data cut‐off visit on or after September 1, 2019 (median duration of exposure 32.9 months [range: 22.1–43.0 months]). Mean baseline seizure frequency/28 days was 18.1 (median 2.8) for all patients, 88% of whom (211/240) were taking two or three other ASMs prior to receiving the first cenobamate dose (Table S1). Demographic and disease characteristics of the 240 patients were generally similar to the remaining patient population from the primary study, except that there was a greater preponderance of concomitant lacosamide, clobazam, and zonisamide.\n\n3.2 Patients continuing cenobamate vs patients who discontinued cenobamate, by concomitant ASM\n\nBaseline concomitant ASMs, number of patients who continued or discontinued cenobamate by concomitant ASM, mean doses, dose reductions, and percentage dose change for each ASM are shown in Table 1. Greater percentages of patients remained on cenobamate than discontinued cenobamate for all concomitant ASMs taken at baseline, except for patients on phenobarbital (n = 7) and rufinamide (n = 2). For most baseline concomitant ASMs, ~70% of patients continued cenobamate treatment. In addition, the ASM dose reductions were greater in patients continuing cenobamate compared with those who discontinued cenobamate. The most common concomitant ASMs taken at baseline were lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam (Table 1). For these ASMs, mean dose reductions and percentage change in dose from baseline to last dose were greater in patients continuing cenobamate vs those who discontinued (Figure 1A–E). The greater study retention (for the five most common baseline ASMs, retention range: 71.9% to 78.9% for those continuing cenobamate; 21.1% to 28.1% for those who discontinued cenobamate) observed among patients with larger concomitant ASM dose reductions (for the five most common baseline ASMs, % dose change range: −65.8% to −23.4% for those continuing cenobamate; −7.8% to −25.0% for those who discontinued cenobamate) suggests that cenobamate efficacy was not impaired by decreasing the dose of concomitant ASMs, and that cenobamate tolerability may have improved with greater concomitant ASM dose reductions.\n\nTABLE 1 Patients taking concomitant ASMs at baseline, patients continuing cenobamate at data cut‐off, or patients who discontinued cenobamate, and mean dose adjustments by ASM at time of post hoc analysis\n\nConcomitant ASM\tTaking at baseline, n (%) a\tPatients continuing cenobamate, n (%) b\tPatients who discontinued cenobamate, n (%) b\tMean dose at baseline in patients continuing cenobamate, mg\tMean last dose in patients continuing cenobamate, mg\tMean dose adjustment in patients continuing cenobamate, change in mg (% dose change)\tMean dose adjustment in patients who discontinued cenobamate, change in mg (% dose change)\t\nLacosamide\t98 (40.8)\t77 (78.6)\t21 (21.4)\t513.3\t336.7\t−176.6 (−34.9)\t−98.8 (−18.6)\t\nLevetiracetam\t89 (37.1)\t64 (71.9)\t25 (28.1)\t2746.1\t1898.4\t−847.7 (−30.9)\t−350.0 (−11.5)\t\nLamotrigine\t66 (27.5)\t48 (72.7)\t18 (27.3)\t487.0\t377.6\t−109.4 (−23.4)\t−101.4 (−21.6)\t\nZonisamide\t39 (16.3)\t30 (76.9)\t9 (23.1)\t473.3\t333.3\t−140.0 (−32.6)\t−33.3 (−7.8)\t\nClobazam\t38 (15.8)\t30 (78.9)\t8 (21.1)\t38.0\t12.7\t−25.3 (−65.8)\t−11.2 (−25.0)\t\nCarbamazepine\t24 (10.0)\t16 (66.7)\t8 (33.3)\t906.3\t443.8\t−462.5 (−46.3)\t−287.5 (−29.8)\t\nTopiramate\t23 (9.6)\t15 (65.2)\t8 (34.8)\t336.7\t253.3\t−83.4 (−21.7)\t−193.8 (−35.3)\t\nValproate c\t21 (8.8)\t15 (71.4)\t6 (28.6)\t1400.0\t950.0\t−450.0 (−30.0)\t−125.0 (−16.7)\t\nOxcarbazepine\t20 (8.3)\t15 (75.0)\t5 (25.0)\t1870.0\t1330.0\t−540.0 (−34.6)\t−360.0 (−31.5)\t\nEslicarbazepine\t20 (8.3)\t13 (65.0)\t7 (35.0)\t1307.7\t600.0\t−707.7 (−50.6)\t0.0 (0.0)\t\nPerampanel\t19 (7.9)\t19 (100.0)\t0 (0.0)\t8.0\t3.4\t−4.6 (−62.3)\t0.0 (0.0)\t\nPhenytoin\t18 (7.5)\t12 (66.7)\t6 (33.3)\t390.8\t139.2\t−251.6 (−60.8)\t−238.3 (−50.6)\t\nBrivaracetam\t14 (5.8)\t11 (78.6)\t3 (21.4)\t195.5\t109.1\t−86.4 (−42.4)\t−12.5 (−8.3)\t\nPregabalin\t12 (5.0)\t11 (91.7)\t1 (8.3)\t472.7\t259.1\t−213.6 (−50.8)\t−300.0 (−100.0)\t\nClonazepam\t7 (2.9)\t5 (71.4)\t2 (28.6)\t0.8\t0.9\t+0.1 (20.0)\t0.0 (0.0)\t\nPhenobarbital\t7 (2.9)\t3 (42.9)\t4 (57.1)\t116.4\t75.6\t−40.8 (−40.0)\t−101.7 (−58.3)\t\nGabapentin\t4 (1.7)\t3 (75.0)\t1 (25.0)\t1566.7\t300.0\t−1266.7 (−75.0)\t0.0 (0.0)\t\nClorazepate\t4 (1.7)\t3 (75.0)\t1 (25.0)\t27.5\t18.8\t−8.7 (−31.9)\t−7.5 (−40.0)\t\nFelbamate\t3 (1.3)\t3 (100.0)\t0 (0.0)\t2733.3\t2200.0\t−533.3 (−33.3)\t0.0 (0.0)\t\nRufinamide\t2 (0.8)\t1 (50.0)\t1 (50.0)\t800.0\t0.0\t−800.0 (−100.0)\t0.0 (0.0)\t\nAbbreviation: ASMs, antiseizure medications.\n\na Most patients were taking >1 concomitant ASM. Percentages calculated from a total of 240 patients.\n\nb Percentages calculated from total number of patients taking the specific concomitant drug at baseline.\n\nc Includes valproic acid, sodium valproate, and divalproex sodium.\n\nJohn Wiley & Sons, Ltd\n\nFIGURE 1 Mean dose at baseline vs at last dose and percent dose adjustment from baseline to last dose in patients continuing cenobamate vs patients who discontinued cenobamate by concomitant (A) lacosamide, (B) levetiracetam, (C) lamotrigine, (D) clobazam, and (E) zonisamide\n\nAmong patients continuing cenobamate, 97/395 (24.6%; most were taking more than one concomitant ASM) completely discontinued one or more of their concomitant ASMs (Table 2). Lacosamide, levetiracetam, and perampanel were the ASMs discontinued in the greatest number of patients overall, with n = 18, n = 13, and n = 11 patients, respectively, discontinuing these concomitant ASMs completely.\n\nTABLE 2 Patients continuing cenobamate at data cut‐off who discontinued their baseline concomitant ASMs\n\nConcomitant ASM a , n/N (%)\tPatients continuing cenobamate (n = 177)\t\nLacosamide\t18/77 (23.4)\t\nLevetiracetam\t13/64 (20.3)\t\nPerampanel\t11/19 (57.9)\t\nClobazam\t8/30 (26.7)\t\nLamotrigine\t7/48 (14.6)\t\nZonisamide\t6/30 (20.0)\t\nCarbamazepine\t5/16 (31.3)\t\nPregabalin\t5/11 (45.5)\t\nValproate b\t4/15 (26.7)\t\nOxcarbazepine\t4/15 (26.7)\t\nPhenytoin\t4/12 (33.3)\t\nBrivaracetam\t4/11 (36.4)\t\nEslicarbazepine\t3/13 (23.1)\t\nGabapentin\t2/3 (66.7)\t\nFelbamate\t1/3 (33.3)\t\nPhenobarbital\t1/3 (33.3)\t\nTopiramate\t1/15 (7.0)\t\nClonazepam\t0/5 (0.0)\t\nClorazepate\t0/3 (0.0)\t\nAbbreviation: ASM, antiseizure medication.\n\na Most patients were taking >1 concomitant ASM.\n\nb Includes valproic acid, sodium valproate, and divalproex sodium.\n\nJohn Wiley & Sons, Ltd\n\n3.3 Timing and reason for dose adjustments to concomitant ASMs\n\nDoses of concomitant phenytoin, phenobarbital, clobazam, valproate, and lacosamide were reduced earliest for all patients (Figure 2). Concomitant ASM doses were generally reduced during titration or early maintenance phases of the study. The study visits at which these concomitant ASMs were reduced and the mean cenobamate dose at the time of the dose reduction were generally similar for all patients and those continuing cenobamate (data not shown).\n\nFIGURE 2 Mean cenobamate dose at initiation of concomitant ASM dose reduction by study visit (all patients, n = 240). aVPA includes valproic acid, sodium valproate, and divalproex sodium. ASM, antiseizure medication; BVR, brivaracetam; CBZ, carbamazepine; CLB, clobazam; CZP, clorazepate; ESL, eslicarbazepine; FBM, felbamate; GBP, gabapentin; LCM, lacosamide; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PGB, pregabalin; PHB, phenobarbital; PHT, phenytoin; PRL, perampanel; TPM, topiramate; VPA, valproate; ZNS, zonisamide\n\nDoses of concomitant ASMs were most often lowered due to TEAEs. CNS‐related TEAEs such as somnolence, dizziness, and ataxia, as well as fatigue, were cited most often as the reasons for dose decreases in patients continuing cenobamate (Table 3). Other than TEAEs, reasons for dose decreases cited by investigators included reduction of polypharmacy, patient doing well, patient request, consolidation of treatment, and decreased seizure frequency. The TEAEs observed overall, those reported as leading to dose reductions of concomitant ASMs, and the safety profile seen for all patients were generally consistent with those that are known to occur with cenobamate and with the concomitant ASMs taken at baseline (Table 3 and Table S2). The most commonly reported TEAEs in ≥10% of patients were fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%).\n\nTABLE 3 Adverse events leading to first dose reduction of concomitant ASMs for which ≥11 patients experienced AEs leading to dose reductions of that drug (all patients)\n\nConcomitant ASM\t\t\nAdverse event\tn/total (%) a\t\nLacosamide, n = 56\t\nAtaxia\t15/56 (26.8)\t\nDizziness\t12/56 (21.4)\t\nSomnolence\t12/56 (21.4)\t\nPhysician/patient choice (decreased medication load)\t12/56 (21.4)\t\nFatigue\t8/56 (14.3)\t\nLamotrigine, n = 39\t\nAtaxia\t9/39 (23.1)\t\nFatigue\t9/39 (23.1)\t\nDizziness\t7/39 (17.9)\t\nSomnolence\t7/39 (17.9)\t\nLevetiracetam, n = 38\t\nSomnolence\t10/38 (26.3)\t\nPhysician/patient choice (decreased medication load)\t7/38 (18.4)\t\nNo decreased reason reported\t6/38 (15.8)\t\nCognitive dysfunction\t4/38 (10.5)\t\nClobazam, n = 28\t\nSomnolence\t14/28 (50.0)\t\nFatigue\t5/28 (17.9)\t\nAtaxia\t5/28 (17.9)\t\nDysarthria\t4/28 (14.3)\t\nZonisamide, n = 18\t\nFatigue\t7/18 (38.9)\t\nNo decreased reason reported\t3/18 (16.7)\t\nSomnolence\t2/18 (11.1)\t\nPhysician/patient choice (decreased medication load)\t2/18 (11.1)\t\nCarbamazepine, n = 16\t\nDizziness\t4/16 (25.0)\t\nPhysician/patient choice (decreased medication load)\t4/16 (25.0)\t\nSomnolence\t3/16 (18.8)\t\nPhenytoin, n = 16\t\nSomnolence\t5/16 (31.3)\t\nElevated phenytoin levels\t4/16 (25.0)\t\nDizziness\t3/16 (18.8)\t\nAtaxia\t3/16 (18.8)\t\nFatigue\t3/16 (18.8)\t\nPhysician/patient choice (decreased medication load)\t2/16 (12.5)\t\nPerampanel, n = 15\t\nPhysician/patient choice (decreased medication load)\t5/15 (33.3)\t\nSomnolence\t3/15 (20.0)\t\nDizziness\t2/15 (13.3)\t\nAtaxia\t2/15 (13.3)\t\nFatigue\t2/15 (13.3)\t\nDysarthria\t2/15 (13.3)\t\nNo decreased reason reported\t2/15 (13.3)\t\nOxcarbazepine, n = 13\t\nDizziness\t8/13 (61.5)\t\nAtaxia\t2/13 (15.4)\t\nDiplopia\t2/13 (15.4)\t\nSomnolence\t2/13 (15.4)\t\nPhysician/patient choice (decreased medication load)\t2/13 (15.4)\t\nTopiramate, n = 12\t\nPhysician/patient choice (decreased medication load)\t4/12 (33.3)\t\nDifficulty finding words\t2/12 (16.7)\t\nCognitive dysfunction\t2/12 (16.7)\t\nFatigue\t2/12 (16.7)\t\nEslicarbazepine, n = 11\t\nDizziness\t3/11 (27.3)\t\nAtaxia\t2/11 (18.2)\t\nFatigue\t2/11 (18.2)\t\nAbbreviations: AEs, adverse events; ASM, antiseizure medication.\n\na AEs occurring in ≥10% of patients.\n\nJohn Wiley & Sons, Ltd\n\nOther ASMs such as carbamazepine, oxcarbazepine, eslicarbazepine, and lamotrigine, which enhance rapid inactivation of sodium channels, usually did not require dose reductions until the cenobamate maintenance phase (range of mean visit number at first dose reduction: 9.5–11.0). Given that cenobamate induces the cytochrome P450 (CYP)3A4 enzyme, 8 which metabolizes these drugs, plasma levels of these ASMs would likely be decreased, resulting in possible reduced TEAEs. Despite these reductions, mean percentage dose changes from study start to endpoint for these sodium channel drugs ranged from −23.4% (lamotrigine) to −50.6% (eslicarbazepine) in patients who received dose reductions (Table 1), and efficacy was generally maintained (data not shown).\n\n3.4 Efficacy\n\nNo particular concomitant ASMs were associated with patients achieving seizure freedom when treated with adjunctive cenobamate. Among patients who were seizure‐free for ≥3, ≥6, or ≥12 months (data not shown), the proportion of patients taking any particular concomitant ASM was similar to that of the baseline population (Table 1). The similarity in these percentages suggests that these numbers reflect the proportion of patients on that particular concomitant ASM, and that the observed seizure reduction was due to treatment with cenobamate rather than an effect of the specific baseline ASM taken. Moreover, these seizure‐freedom rates were observed even as doses of concomitant ASMs were being decreased in patients continuing cenobamate, regardless of the specific ASM, further suggesting that cenobamate was effective in reducing seizures.\n\nResponder rates from ≥50% through 100% for patients continuing cenobamate were generally similar regardless of whether patients were taking concomitant lacosamide, levetiracetam, lamotrigine, clobazam, or zonisamide (Figure 3A,B), except that fewer patients on concomitant lamotrigine reached 100% seizure reduction. Percentages of responders by concomitant ASM in the maintenance population (n = 214; median [max] 29.5 [40.2] months) ranged from ~75% of patients for ≥50% response to ~13% for 100% response. For patients continuing cenobamate at data cut‐off by concomitant ASM, ~81% were ≥50% responders and ~12% achieved 100% reduction in seizures for the entire maintenance phase, the duration of which was much longer than what is typically reported in open‐label long‐term extension studies that provide 100% seizure reduction rates.\n\nFIGURE 3 (A) Responder rates during the entire maintenance phase by concomitant ASM among all patients in the maintenance phase (maintenance population, n = 214), and (B) patients continuing cenobamate at data cut‐off (n = 177). Note: The median treatment duration for all patients in the maintenance phase was 29.5 months. The median treatment duration for patients continuing cenobamate at data cut‐off was 30.2 months. ASM, antiseizure medication\n\nTemporary increases in seizures occurred at an individual visit in up to ~12% of patients; however, retention rates overall were high and 33.9% of patients continuing cenobamate at data cut‐off were seizure‐free for a mean 23.5 months at last visit (range: 11.6–40.1 months), indicating that efficacy was very good overall.\n\n4 DISCUSSION\n\nThe flexible‐dose design of the C021 trial allowed investigators to make changes to concomitant ASMs early, while up‐titrating adjunctive cenobamate, which is more reflective of actual clinical practice. These data may be useful in informing physicians on the appropriate adjustment of concomitant ASMs while adding cenobamate in practice. As physicians in this trial became more experienced and learned about possible interactions and how to minimize them, concomitant ASM doses were reduced earlier in cenobamate titration. Thus for general neurologic practice, ASM dose reductions may occur sooner than seen here, depending on the early efficacy and tolerability observed while titrating patients onto cenobamate.\n\nDoses of phenytoin, phenobarbital, clobazam, valproate, and lacosamide were decreased earliest in the current study (see Figure 2), while patients were still in the titration phase of cenobamate (as low as 12.5–50 mg/day cenobamate). In contrast, dosages of carbamazepine, oxcarbazepine, and eslicarbazepine were decreased later, during the maintenance phase (mean cenobamate dose range: 188.6–197.5 mg/day). These differences in timing of dose reductions across varying concomitant ASMs may be attributed to pharmacokinetic interactions that could cause changes in drug exposures and alterations in tolerability. Doses of concomitant ASMs were reduced most often due to TEAEs. Both the TEAEs leading to dose reductions and the overall safety profile seen throughout were consistent with those known to occur with these medications, and no new safety issues were observed. Some concomitant ASM doses were reduced for reasons other than AEs; for example, the concomitant ASMs reduced latest in the maintenance phase (levetiracetam and brivaracetam) may have been adjusted by investigators to reduce the overall drug load rather than because of specific issues with tolerability.\n\nThe specific adjustments made to concomitant ASMs throughout this study provide information on practical dosing changes that can improve tolerability and reduce drug‐drug interactions (DDIs) in patients receiving adjunctive cenobamate. As indicated, these data suggest that some concomitant ASMs may be lowered relatively early in cenobamate titration, with most dose adjustments recommended to mitigate pharmacokinetic interactions. For example, phenobarbital and phenytoin are both metabolized, in part, by the CYP2C19 isoenzyme. Cenobamate inhibits CYP2C19 and data have shown that plasma exposures of phenobarbital and phenytoin increase by a mean 37% and 84%, respectively, following multiple doses of adjunctive cenobamate. 8 , 24 Elevation of phenytoin levels may lead to increased risk of dizziness/ataxia, thus physicians should be aware that dose alterations may be necessary if these symptoms occur, or proactive reduction of phenytoin dose may be required. In this study, investigators reduced phenytoin doses in patients continuing cenobamate by a mean 60.8%, starting at a mean (min) cenobamate dose of 142.0 (0.0) mg/day (mean visit 7). Similarly, investigators reduced phenobarbital doses by a mean 40.0% starting early in titration (mean visit 6.5) at a mean (min) cenobamate dose of 131.3 (12.5) mg/day. Patients and caregivers should be aware that early reduction of phenobarbital doses may be required if drowsiness/somnolence occurs, or doses may be proactively decreased.\n\nThe active metabolite of clobazam, N‐desmethylclobazam, is also mainly metabolized by the CYP2C19 enzyme. Data on interactions between cannabidiol (another CYP2C19 inhibitor) and clobazam suggest that during coadministration of a CYP2C19 inhibitor, such as cenobamate, 8 , 24 N‐desmethylclobazam levels may increase by between 2 and 6 times, which can result in increased TEAEs. 25 Patients and caregivers should be aware that adjunctive cenobamate with clobazam may lead to increased somnolence. In the current analysis, for those continuing cenobamate, investigators started reducing doses of clobazam at a mean (min) cenobamate dose of 135.0 (0.0) mg/day, with most patients (~65%) receiving dose reductions at 50–150 mg/day cenobamate (data not shown). Due to the rate of somnolence (50.0%) leading to the first dose reduction of concomitant clobazam, as well as probable elevations in plasma N‐desmethylclobazam when coadministered with cenobamate, early reduction of clobazam is recommended when initiating cenobamate, which should often be proactively reduced.\n\nInvestigators made the above dose alterations based on probable pharmacokinetic interactions leading to alterations in blood levels. However, pharmacodynamic interactions may also arise and could require dose adjustments. For example, dizziness and somnolence were reported in some patients receiving lacosamide and cenobamate. At lower doses of cenobamate, there are no apparent pharmacokinetic interactions between these drugs; however, at 400 mg/day cenobamate, there can be up to 50% inhibition of CYP2C19 and possible small elevations of total lacosamide levels. This suggests that these side effects could be due to a pharmacodynamic interaction at lower cenobamate dosages and a possible minimal pharmacokinetic CYP2C19 interaction at 400 mg/day.\n\nBoth cenobamate and lacosamide exert their therapeutic effects through sodium channels but with different mechanisms of action. 10 Clinically, patients on higher doses of lacosamide, particularly at >500 mg/day range, will be more likely to require lacosamide dose decreases when adding cenobamate. In this analysis of patients continuing cenobamate who had their lacosamide dose reduced, ~70% of those taking >500 mg/day lacosamide at baseline had their dose reduced (mean lacosamide reduction: 229.3 mg/day), whereas ~40% of those receiving <500 mg/day lacosamide at baseline had their dose reduced (mean lacosamide reduction: 98.4 mg/day; data not shown).\n\nOther blocking ASMs that alter sodium channel conductance, including carbamazepine, oxcarbazepine, eslicarbazepine, and lamotrigine, usually did not require dose reductions until the cenobamate maintenance phase. Because these ASMs are largely metabolized by CYP3A4, and cenobamate enhances this effect, blood levels for these concomitant drugs may be decreased. 8 These decreases may lead to a reduction in TEAEs that would allow cenobamate to be successfully up‐titrated. Once in the maintenance phase, some further reductions of these sodium channel drugs may be necessary.\n\nFor patients continuing cenobamate, valproate was lowered in the late titration phase (mean visit: 8.0) at a mean (minimum) dose of 167.9 (0.0) mg/day cenobamate, but no major pharmacokinetic interactions were noted. Drugs such as levetiracetam have few or no known interactions with cenobamate and lowering levetiracetam usually did not occur until the maintenance phase (mean visit: 11.5) at a mean (minimum) cenobamate dose of 217.0 (12.5) mg/day (see Figure 2).\n\nThe current post hoc analysis indicates that patients who remained on cenobamate had greater dose reductions of concomitant ASMs than patients who discontinued, suggesting that reducing the doses of these drugs may lead to greater retention over a long maintenance phase. This retention benefit could have been due to improved tolerability as a result of the reduced overall drug burden.\n\nBecause retention can serve as both a surrogate for efficacy and an indication of tolerability, the current analysis offers key insights into the clinical use of various concomitant ASMs with adjunctive cenobamate. The high retention rate observed here, even after reducing doses of or completely discontinuing concomitant ASMs, supports the efficacy of cenobamate. The high percentages of responders observed in patients continuing cenobamate, regardless of their concomitant ASM, further suggest that cenobamate treatment was effective in reducing seizures in these patients whose seizures were previously uncontrolled despite treatment with up to three other ASMs. Moreover, these responses were sustained over a lengthy maintenance phase. In most studies, the maintenance phase represents a 6‐ or 12‐week portion of the double‐blind studies; in open‐label studies, intervals of 3 months, 6 months, or a year are typically described for 100% reduction in seizures, or are not described at all. However, in this open‐label study, the maintenance phase represents the entire length of the study except the 12‐week titration phase (ie, up to 40.2 months of data), and sustained seizure reductions over this extensive period were still observed.\n\nThe current findings must be interpreted in context with the limitations of both the post hoc analyses and the larger C021 study. Because this was a retrospective analysis of a population from a subset of clinical sites, selection bias may exist, although the present cohort resembled the broader C021 sample. In addition, the C021 study was open label and was not originally designed to assess effects of changes to concomitant ASMs; therefore it was analyzed post hoc. As previously indicated, the open‐label study design allowed clinicians to make changes to cenobamate doses and concomitant ASMs, which may better reflect actual clinical practice.\n\nBecause patients with refractory epilepsy often experience tolerability issues due to polypharmacy, reducing concomitant medications during the addition of new therapy is frequently necessary. Many patients with uncontrolled epilepsy have excessive drug load, most commonly through use of combination therapy, which can result in significant TEAEs, DDIs, and reduced quality of life. 26 , 27 , 28 The ultimate goal of treatment is to reach 100% seizure reduction with the fewest possible TEAEs. When initiating treatment, slowly reducing the concomitant ASM dose in patients who experience TEAEs while adding another drug may aid in reducing drug burden while allowing for optimal efficacy. 26 Proper treatment with a combination of many ASMs requires transitional polytherapy during titration of a new drug, with a goal of monotherapy or reduced ASM polytherapy. 29 Titration allows for dose adjustment and a more personalized treatment regimen because some patients may experience efficacy at lower than recommended target doses. This strategy also provides greater opportunities to evaluate patients who may be able to transition to monotherapy. The information presented here offers physicians a data‐driven clinical approach to adjusting concomitant ASMs while up‐titrating adjunctive cenobamate in patients with uncontrolled focal seizures.\n\n5 CONCLUSIONS\n\nIn the current study of adjunctive cenobamate, reducing doses of concomitant medications likely led to greater patient retention due to the combination of appropriate levels of efficacy and reduced concomitant drug burden in a population who were largely taking two to three concomitant ASMs at baseline. This post hoc analysis of a subset of the C021 study provides some direction to physicians on adjusting concomitant ASMs when adding on cenobamate treatment. As investigators gained experience and learned about potential interactions, concomitant ASM doses were reduced for many patients very early in cenobamate titration. Doses of concomitant phenytoin, phenobarbital, clobazam, valproate, and lacosamide, in particular, may be gradually reduced early on when adding cenobamate treatment to avoid possible tolerability issues. The number of patients who remained seizure‐free for prolonged periods and the high retention rates, even after reducing or discontinuing concomitant ASMs, suggest that cenobamate was efficacious. Post hoc efficacy analyses from the C021 safety study are also presented in a companion paper (Sperling et al. 2021), 30 and together, these analyses allow for a broader view of the effects of cenobamate on seizure reduction over the long term.\n\nCONFLICTS OF INTEREST\n\nWER: Consultant/advisor: SK Life Science, Inc.; Speaker: Eisai, Greenwich Biosciences (GW Pharmaceuticals), SK Life Science, Inc., Sunovion, and UCB Pharma; and Research support: Greenwich Biosciences, Marinus, Medtronic, Neurelis, Ovid, SK Life Science, Inc., Takeda, UCB Pharma, and Upsher‐Smith.\n\nBAK: Research support: Cerevel, Otsuka, SK Life Science, Inc., UCB Pharma, and Xenon.\n\nSA: Consultant/advisor: Eisai, SK Life Science, Inc.; and Speaker: Eisai, Sunovion.\n\nPB: Research support: SK Life Science, Inc.\n\nVB: Research support: SK Life Science, Inc.\n\nGLK: Consultant/advisor: Adamas, Eisai, Otsuka, and Shire; and Research support: Biogen, SK Life Science, Inc., UCB Pharma, and Upsher‐Smith.\n\nMRS: Consultant/advisor: Medtronic and Neurelis; Speaker: Eisai, International Medical Press, Medscape, NeurologyLive, Projects in Knowledge, and UCB Pharma; Research support: Cavion, Cerevel, Eisai, Engage, Medtronic, Neurelis, SK Life Science, Inc., Takeda, UCB Pharma, and Xenon; and Royalty: Oxford University Press.\n\nDGV: Consultant/advisor: Otsuka and SK Life Science, Inc.; Speaker: Greenwich Biosciences, Neurelis, SK Life Science, Inc., and UCB Pharma; and Research support: Biogen, Eisai, SK Life Science, Inc., UCB Pharma, and Xenon.\n\nPK: Consultant/advisor: Abbott, Aquestive, Arvelle, Eisai, Engage, Neurelis, SK Life Science, Inc., and UCB Pharma; Speaker: Aquestive, Eisai, Neurelis, Sunovion, and UCB Pharma; Research support: Eisai and Lundbeck; Member, Medical Advisory Board for Alliance‐Stratus and Scientific Advisory Board for OB Pharma; and CEO, PrevEp, LLC.\n\nRW: Consultant/advisor: Brain Sentinel, Eisai, Engage, Greenwich Biosciences, Lundbeck, SK Life Science, Inc., Sunovion, and UCB Pharma; Speaker: Aquestive, Eisai, Greenwich Biosciences, LivaNova, Sunovion, and UCB Pharma; and Research support: Aquestive, Biogen, Eisai, Engage, Greenwich Biosciences, Lundbeck, Pfizer, SK Life Science, Inc., Sunovion, UCB Pharma, Xenon, and Zogenix.\n\nETHICAL PUBLICATION STATEMENT\n\nThe authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\n\nDATA SHARING\n\nThe data for the analyses described in this manuscript are available by request from the corresponding author or SK Life Science, Inc., the company sponsoring the clinical development of cenobamate for the treatment of focal epilepsy.\n\nPREVIOUS PRESENTATION\n\nRosenfeld WE, et al. Dose adjustments to concomitant antiseizure medications: post‐hoc analysis of a phase 3, open‐label study of cenobamate for treatment of uncontrolled focal seizures. Presented at the American Epilepsy Society Virtual Annual Meeting, December 4–8, 2020, poster 336, and encored at the American Academy of Neurology Virtual Annual Meeting 2021.\n\nSupporting information\n\nFigure S1\n\nTable S1‐S2\n\nClick here for additional data file.\n\nACKNOWLEDGEMENTS\n\nThis study was funded by SK Life Science, Inc. Medical writing and editorial assistance were provided by Debika Chatterjea, PhD, and Don Fallon, ELS, of MedVal Scientific Information Services, LLC (Princeton, NJ, USA), and were funded by SK Life Science, Inc. This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company‐Sponsored Medical Research: GPP3.”\n==== Refs\nREFERENCES\n\n1 Brodie MJ , Sills GJ . Combining antiepileptic drugs–rational polytherapy? Seizure. 2011;20 (5 ):369–75.21306922\n2 Chen Z , Brodie MJ , Liew D , Kwan P . Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30‐year longitudinal cohort study. JAMA Neurol. 2018;75 (3 ):279–86.29279892\n3 Dash D , Aggarwal V , Joshi R , Padma MV , Tripathi M . Effect of reduction of antiepileptic drugs in patients with drug‐refractory epilepsy. Seizure. 2015;27 :25–9.25891923\n4 Patsalos PN , Perucca E . Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol. 2003;2 (8 ):473–81.12878435\n5 Perucca E . Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol. 2006;61 (3 ):246–55.16487217\n6 Perucca E . From clinical trials of antiepileptic drugs to treatment. Epilepsia Open. 2018;3 (s2 ):220–30.30564781\n7 Chung S , Wang N , Hank N . 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Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51 (4 ):676–85.20196795\n22 International League Against Epilepsy . Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1981;22 (4 ):489–501.6790275\n23 International Council for Harmonisation . Integrated Addendum to ICH E6(R1): Guideline For Good Clinical Practice E6(R2). https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. (2016). Accessed 25 Feb, 2020.\n24 Greene S , Kwak C , Kamin M , Vernillet L . The effect of cenobamate on the single dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects [poster]. Presented at American Society for Clinical Pharmacology & Therapeutics Annual Meeting, March 13‐16, 2019, Washington, DC.\n25 Geffrey AL , Pollack SF , Bruno PL , Thiele EA . Drug‐drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56 (8 ):1246–51.26114620\n26 Schmidt D . Strategies to prevent overtreatment with antiepileptic drugs in patients with epilepsy. Epilepsy Res. 2002;52 (1 ):61–9.12445961\n27 Perucca E . Overtreatment in epilepsy: adverse consequences and mechanisms. Epilepsy Res. 2002;52 (1 ):25–33.12445957\n28 St Louis EK . Minimizing the adverse effects of epilepsy therapies: principles and practice. In: St. Louis EK , Ficker DM , O'Brien TJ, editors. Epilepsy and the interictal state: co‐morbidities and quality of life. Chichester, UK: John Wiley & Sons, Ltd.; 2015. p. 120–6.\n29 St Louis EK . Truly \"rational\" polytherapy: maximizing efficacy and minimizing drug interactions, drug load, and adverse effects. Curr Neuropharmacol. 2009;7 (2 ):96–105.19949567\n30 Sperling MR , Abou‐Khalil B , Aboumatar S , Bhatia P , Biton V , Klein P , et al. Efficacy of cenobamate for uncontrolled focal seizures: post‐hoc analysis of a phase 3, multicenter, open‐label study. Epilepsia. 2021 (in press); 10.1111/epi.17091\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "62(12)",
"journal": "Epilepsia",
"keywords": "antiepileptics; antiseizure medications; cenobamate; concomitant medications; focal epilepsy",
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"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
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"title": "Post hoc analysis of a phase 3, multicenter, open-label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications.",
"title_normalized": "post hoc analysis of a phase 3 multicenter open label study of cenobamate for treatment of uncontrolled focal seizures effects of dose adjustments of concomitant antiseizure medications"
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"abstract": "BACKGROUND\nWe evaluated the efficacy and feasibility of docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CRT) for locally advanced head and neck squamous cell carcinoma (HNSCC) with a high risk of distant metastases compared with CRT alone.\n\n\nMETHODS\nWe retrospectively analyzed 29 HNSCC patients with clinical nodal stage N2c, N3, or N2b disease and supraclavicular lymph node metastases receiving CRT alone (CRT group; n = 16) or TPF induction chemotherapy followed by CRT (TPF group; n = 13) between April 2008 and May 2012.\n\n\nRESULTS\nThe median follow-up periods were 14.5 (range 5.0-65.0) and 25.0 (range 14.0-32.0) months for CRT and TPF groups, respectively. A greater proportion of patient characteristics in the CRT group had advanced T and N stages. The overall response rate to induction TPF was 50.0%; grade 3-4 toxicities included neutropenia, febrile neutropenia, anorexia, and hyponatremia. Complete response rates after CRT completion were 55.5% in the TPF and 42.9% in the CRT group; median overall survival was not reached in the TPF group and was 14.0 months in the CRT group (p = 0.037). Multivariate analysis revealed that induction TPF and T stage were independent prognostic factors [hazard ratio (HR) = 0.196; 95% confidence interval (CI) 0.043-0.898; p = 0.036, HR = 9.966; 95% CI 2.270-43.75; p = 0.002, respectively).\n\n\nCONCLUSIONS\nTPF followed by CRT is tolerated and may be an option for the treatment of locally advanced stage N2c, N3, or N2b HNSCC.",
"affiliations": "Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi Sunto-gun, Shizuoka, 411-8777, Japan.",
"authors": "Izawa|Naoki|N|;Onozawa|Yusuke|Y|;Hikosaka|Tomomi|T|;Hamauchi|Satoshi|S|;Tsushima|Takahiro|T|;Todaka|Akiko|A|;Machida|Nozomu|N|;Haraguchi|Yutaka|Y|;Ogawa|Hirofumi|H|;Nishimura|Tetsuo|T|;Nakagawa|Masahiro|M|;Fuke|Tomohito|T|;Iida|Yoshiyuki|Y|;Kamijo|Tomoyuki|T|;Onitsuka|Tetsuro|T|;Boku|Narikazu|N|;Yasui|Hirofumi|H|;Yokota|Tomoya|T|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-014-0749-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "20(3)",
"journal": "International journal of clinical oncology",
"keywords": null,
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D000077143:Docetaxel; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D060828:Induction Chemotherapy; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "455-62",
"pmc": null,
"pmid": "25248339",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23414589;8417385;11002323;17960012;17960013;10718426;14645636;23991649;24256848;14657228;16847186;12506176;15277256;8656441;10768432;14501507;21296855;19446902;1739921",
"title": "Efficacy and feasibility of docetaxel, cisplatin, and 5-fluorouracil induction chemotherapy for locally advanced head and neck squamous cell carcinoma classified as clinical nodal stage N2c, N3, or N2b with supraclavicular lymph node metastases.",
"title_normalized": "efficacy and feasibility of docetaxel cisplatin and 5 fluorouracil induction chemotherapy for locally advanced head and neck squamous cell carcinoma classified as clinical nodal stage n2c n3 or n2b with supraclavicular lymph node metastases"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2016INT000007",
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Eight cases of resistant recurrent depression were treated with a combination of nortriptyline and a new serotonin reuptake inhibitor, with or without concurrent lithium therapy. Significant improvement was seen in all patients where other drug regimes and ECT had been ineffective. No adverse reactions occurred in any of our patients, seven of whom were elderly. The combination treatment was more effective than individual therapies alone.",
"affiliations": "Maudsley Hospital, Denmark Hill, London.",
"authors": "Seth|R|R|;Jennings|A L|AL|;Bindman|J|J|;Phillips|J|J|;Bergmann|K|K|",
"chemical_list": "D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine; D015057:1-Naphthylamine; D008094:Lithium; D009661:Nortriptyline; D020280:Sertraline",
"country": "England",
"delete": false,
"doi": "10.1192/bjp.161.4.562",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1250",
"issue": "161()",
"journal": "The British journal of psychiatry : the journal of mental science",
"keywords": null,
"medline_ta": "Br J Psychiatry",
"mesh_terms": "D015057:1-Naphthylamine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003866:Depressive Disorder; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine; D006801:Humans; D008094:Lithium; D008297:Male; D008875:Middle Aged; D009661:Nortriptyline; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D012008:Recurrence; D012189:Retrospective Studies; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"nlm_unique_id": "0342367",
"other_id": null,
"pages": "562-5",
"pmc": null,
"pmid": "1327396",
"pubdate": "1992-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combination treatment with noradrenalin and serotonin reuptake inhibitors in resistant depression.",
"title_normalized": "combination treatment with noradrenalin and serotonin reuptake inhibitors in resistant depression"
} | [
{
"companynumb": "GB-MYLANLABS-2020M1088003",
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"occurcountry": "GB",
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"activesubstancename": "FLUPENTIXOL"
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{
"abstract": "To report a case of possible post-lensectomy vancomycin-induced retinal hemorrhages in a 9-month-old infant to raise awareness of this rare postoperative complication in the pediatric age group.\nA retinal vascular occlusion-like findings were noted bilaterally after sequential uneventful parsplicata lensectomy in a 9-month-old infant during the very early postoperative follow-up (1-2 days). The case was recorded with no remarkable intraoperative events and received intraoperative vancomycin 20μg/ml in irrigating solution (a routine endophthalmitis prophylactic protocol).\nVancomycin-associated hemorrhagic occlusive retinal vasculitis (HORV) is a rare reported postoperative complication of intraocular prophylactic vancomycin injection. Although all documented cases were reported in elderly patients aged 50 years and above, all presented with almost common findings of occlusive retinal vasculitis. To the best of author's knowledge, this is the first reported case of presumed HORV in pediatric age group. The author finds this of utmost importance to demonstrate the case to expand awareness of this possible complication in the pediatric age group as well.",
"affiliations": "Professor of Ophthalmology, Faculty of Medicine, Cairo University, Egypt.",
"authors": "El Gendy|Heba A|HA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100880",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30195-X\n10.1016/j.ajoc.2020.100880\n100880\nCase Report\nVancomycin-associated retinal hemorrhages in pediatric age group: A case report.\nEl Gendy Heba A. hebagendy2000@gmail.com Professor of Ophthalmology, Faculty of Medicine, Cairo University, Egypt\n21 8 2020 \n12 2020 \n21 8 2020 \n20 10088011 10 2019 27 3 2020 16 8 2020 © 2020 The Author2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report a case of possible post-lensectomy vancomycin-induced retinal hemorrhages in a 9-month-old infant to raise awareness of this rare postoperative complication in the pediatric age group.\n\nObservation\nA retinal vascular occlusion-like findings were noted bilaterally after sequential uneventful parsplicata lensectomy in a 9-month-old infant during the very early postoperative follow-up (1–2 days). The case was recorded with no remarkable intraoperative events and received intraoperative vancomycin 20μg/ml in irrigating solution (a routine endophthalmitis prophylactic protocol).\n\nConclusions and Importance\nVancomycin-associated hemorrhagic occlusive retinal vasculitis (HORV) is a rare reported postoperative complication of intraocular prophylactic vancomycin injection. Although all documented cases were reported in elderly patients aged 50 years and above, all presented with almost common findings of occlusive retinal vasculitis. To the best of author's knowledge, this is the first reported case of presumed HORV in pediatric age group. The author finds this of utmost importance to demonstrate the case to expand awareness of this possible complication in the pediatric age group as well.\n\nKeywords\nHemorrhagic occlusive retinal vasculitisVancomycin retinal vasculitisPediatric retinal hemorrhagesPediatric retinal vasculitis\n==== Body\n1 Introduction\nThe term hemorrhagic occlusive retinal vasculitis (HORV) was first reported in literature in 2014 as case presentation of two cases following uneventful cataract extraction, which has been postulated as an immune repose to intracameral vancomycin injected by the end of surgery, with four additional cases reported in 2015.1,2\n\nFor reported cases, a picture of ischemic vasculitis with retinal hemorrhages and mild anterior segment reaction was common along with a marked drop of visual potential.2\n\nIn response to these reports, the HORV task force was formed and a report including 36 eyes with HORV has been published for the clinical characteristics, possible pathogenesis, and management of the disease. All eyes shared common clinical features of unremarkable undilated examination on the first postoperative day, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, predilection for venules and peripheral involvement, and a common documentation ofintraocular prophylactic vancomycin administrationduring uneventful surgical procedures.3\n\nIn this case report, the author presents a case that manifested as a picture of retinal vein-like occlusion retinopathy following sequential bilateral parsplicata lensectomies with intraocular vancomycin administration on irrigating intraocular solution.\n\n1.1 Case report\nA mother presented her 9-month-old male infant with an accidental discovery of a white pupil in his left eye. A thorough ophthalmological examination revealed a case of bilateral lamellar cataract more dense in the left eye, fundus details could not be elicited by indirect ophthalmoscopy; therefore, a bilateral B-scan ultrasonography was done and revealed no ultrasonographic abnormalities regarding the axial lengths, retina, and optic nerve. The infant was orthophoric, fixing and following light with no nystagmus. Routine preoperative laboratory investigations in the form of complete blood count (CBC) with differential count and blood coagulation profile were within normal values. Toxoplasma, rubella, cytomegalovirus, and herpes simplex (TORCH) screen to rule out intrauterine infection was within the normal range. Full family, and perinatal history taking revealed irrelevant data with a negative consanguinity.\n\nBased on the preoperative ophthalmological examination and adjuvant investigations, the infant was diagnosed as a case of bilateral lamellar cataract in an otherwise normal healthy infant and was scheduled for bilateral sequential lensectomies and anterior vitrectomy with the left eye being clinically denser than the right eye.\n\nA 20-gauge parsplicata lensectomy and anterior vitrectomy was done by an expert pediatric cataract surgeon with unremarkable intraoperative course.\n\nOn routine fundus examination at the first postoperative day, vein occlusion-like retinopathy with mildly dilated retinal veins was noted in the fundus. Retinal hemorrhages involving both posterior pole and peripheral retina were also elicited in all retinal quadrants, with few hemorrhages showing a white-centered appearance (Fig. 1) in an otherwise quiet anterior segment.Fig. 1 Fundus phtoto Left eye captured by Retcam 1st post-operative day.\n\nFig. 1\n\nSince preoperative fundus examination was not feasible because of the bilateral dense cataract, the possibility of a systemic disease-related bilateral retinopathy was postulated as a possible cause of these retinal findings, and a complete workup to exclude possible blood dyscrasias and associated systemic conditions was performed postoperatively. CBC with differential count, TORCH screen, and blood coagulation profiles were repeated and compared to preoperative reports. Further laboratory workup to exclude hemoglobinopathies and abdominal ultrasound to exclude hepatosplenomegaly or abdominal masses revealed no relevant explanation.\n\nSince it was not common in the pediatric age group before and its clinical presentation was not as classical as the described HORV clinical picture, the possibility of vancomycin-induced retinal hemorrhages was not considered as a priority at that time.\n\nThe patient was scheduled for another eye surgery one week later, with the same surgeon, and the fundus was examined by the end of the procedure with unremarkable findings.\n\nOne day later, the eye was quiet with no anterior segment reaction. Surprisingly, fundus examination showed a picture similar to that elicited in the first eye with more evident venous dilatation, more retinal hemorrhages, and mild vitreous hemorrhage in a previously noted normal fundus a day before the surgical procedure.\n\nAs systemic causes were excluded before, the possibility of vancomycin-induced retinal vasculitis was postulated based on the clinical findings and the course of clinical presentation, as well as the fact that vancomycin was used on the irrigation solutions for both eyes and the patient received bilateral posterior subtenon injection of 1ml betamethasone and systemic oral dexamethasone two daily doses of 0.6 mg/kg/dose for 10 days as recommended by a specialized pediatrician.\n\nUnfortunately, fluorescein angiography could not be done, as the author failed to obtain guardian's consent to inject the dye for the test.\n\nThe patient was scheduled for regular follow-up visits on a weekly basis with a noted gradual improvement of his retinal condition (Fig. 2, Fig. 3, Fig. 4), improvement of vascular dilatation, a decrease of retinal hemorrhages, and disappearance of retinal edema as well as improved vitreous hemorrhage in the right eye over a period of 11 weeks.Fig. 2 Left eye 4 weeks post-operative showing white-center retinal hemorrhages (Black arrows), improvement of retinal hemorrhages and no venous dilatation.\n\nFig. 2Fig. 3 Left eye 6 weeks post-operative.\n\nFig. 3Fig. 4 Fundus photo Right eye 6 weeks post-operative showing inferior paravascular retinal hemorrhages and areas of vitreous hemorrhages.\n\nFig. 4\n\nThe patient was monitored for the rise of intraocular pressure (IOP) and showed normal measurements and normal ocular alignment with acceptable visual potential all through his follow-up visits.\n\n2 Discussion\nThe ophthalmology practice showed a great drift toward the use of prophylactic antibiotics during intraocular surgeries to decrease the risk of postoperative endophthalmitis during the last decade.4,5 Being a wide-spectrum antibiotic against most gram positive species with a potential safe effect on the retina and different ocular structures, the use of intraocular vancomycin has been preferred by many ophthalmologists.3,6\n\nHORV—a term describing a group of clinical characteristics of postoperative occlusive vasculitis—was recently introduced in literature with the use of intraocular vancomycin claimed as a possible association.3\n\nVancomycin-associated HORV has been described in elderly patients following cataract surgery with intraocular use of vancomycin being common among all described cases.1, 2, 3\n\nIn the present case, the author encountered a vascular occlusion-like fundus findings in an otherwise normal healthy infant on the first day post uneventful lensectomy procedure with a mirror image like more aggressive findings occurring in the fellow eye after sequential surgery one week apart.\n\nDetection of these vascular changes in a considerably quiet anterior segment during a routine dilated postoperative fundus examination, the involvement of both eyes with a noticeably more aggressive presentation in the second one, common use of intraoperative vancomycin in irrigating solution, and the profound response to posterior subtenon and systemic corticosteroids favor the postulation of vancomycin-associated retinal vasculitis, although the author failed to obtain the guardian's consent to perform fluorescein angiography to confirm evident retinal vasculitis.\n\nNonetheless, the difference in the age group between the previously recorded cases and the present case may explain the few dissimilarities regarding fundus presentation and the course progression3: in previously reported cases the retina commonly showed sectoral involvement with high prevalence of retinal neovascularization and possible neovascular glaucoma with devastating visual disabilities.\n\nAlthough fundus examination showed an extensive presentation of retinal hemorrhages involving all retinal quadrants, regular periodic clinical follow-ups revealed no retinal neovascularizations and no rise of IOP with the infant, showing a favorable bilateral steady fixation with no clinical evidence of either strabismus or nystagmus.\n\nIn this case report, the author could not surely ignore the possibility of vancomycin-induced retinal toxicity, although it is being considered as a safe antibiotic to the retina in different reports; however, the use of the standard prescribed adult dose of 20 μg/ml on irrigating solution still may be questionable in the pediatric age group.7\n\nTo author's knowledge, this is the first report of possible vancomycin-associated retinal vasculitis in the pediatric age group, which may help raise awareness toward the possibility of encountering this rare complication among the pediatric age group as well.\n\nA routine dilated postoperative fundus examination is highly recommended in all cases and should not be applied only for eventful cases or cases with postoperative reaction given that most of the cases can be easily missed unless a dilated fundus examination is conducted.\n\nSurgeons must reconsider the weight of benefits concerning the intraocular prophylactic antibiotics versus the potential risks of postoperative endophthalmitis as well as other postulated complications such as HORV in cases treated with intraocular vancomycin. Moreover, the dose of intraocular prophylactic vancomycin may be reevaluated in the pediatric age group cases considering the possibility of the dose-related reaction of vancomycin-induced retinal vasculitis.\n\nPatient consent\nWritten informed consent for the surgical intervention and post operative treatment was received from the patient's guardian. Consent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nFunding\nThe author declare no funding was received for this work.\n\nIntellectual property\nThe author confirms that I have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing I confirms that I have followed the regulations of my institution concerning intellectual property.\n\nResearch ethics\nThe author further confirms that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.\n\nWritten informed consent for the surgical intervention and post operative treat was recieved from the patient's guardian. Consent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nAuthorship\nThe International Committee of Medical Journal Editors (ICMJE) recommends that authorship be based on the following four criteria:\n\n1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND\n\n2. Drafting the work or revising it critically for important intellectual content; AND\n\n3. Final approval of the version to be published; AND\n\n4. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\n\n\nAll those designated as authors should meet all four criteria for authorship, and all who meet the four criteria should be identified as authors. For more information on authorship, please see http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html#two.\n\nAll listed authors meet the ICMJE criteria. \nWe attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.\n\nDeclartion of competing interest\nThe author wishes to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.\n==== Refs\nReferences\n1 Nicholson L.B. Kim B.T. Jardon J. Severe bilateral ischemic retinal vasculitis following cataract surgery Ophthalmic Surg Lasers Imaging Retina 45 4 2014 338 342 25127533 \n2 Witkin A.J. Shah A.R. Engstrom R.E. Postoperative hemorrhagic occlusive retinal vasculitis: expanding the clinical spectrum and possible association with vancomycin Ophthalmol 122 7 2015 1438 1451 \n3 Witkin Andre J. Chang David F. Jumper J Michael Vancomycin-associated hemorrhagic occlusive retinal vasculitis clinical characteristics of 36 eyes Ophthalmology 124 2017 583 595 28110950 \n4 Chang D.F. Braga-Mele R. Henderson B.A. Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2014 ASCRS member survey J Cataract Refract Surg 41 6 2015 1300 1305 26189384 \n5 Behndig A. Cochener B. Guell J.L. Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns in 9 European countries J Cataract Refract Surg 39 9 2013 1421 1431 23988244 \n6 Braga-Mele R. Chang D.F. Henderson B.A. Intracameral antibiotics: safety, efficacy, and preparation J Cataract Refract Surg 40 12 2014 2134 2142 25465691 \n7 Borhani H. Peyman G.A. Wafapoor H. Use of vancomycin in vitrectomy infusion solution and evaluation of retinal toxicity Int Ophthalmol 17 1993 85 10.1007/BF00942780 8407120\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "20()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Hemorrhagic occlusive retinal vasculitis; Pediatric retinal hemorrhages; Pediatric retinal vasculitis; Vancomycin retinal vasculitis",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "100880",
"pmc": null,
"pmid": "32913922",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "25886796;25127533;25465691;8407120;23988244;26189384;28110950",
"title": "Vancomycin-associated retinal hemorrhages in pediatric age group: A case report.",
"title_normalized": "vancomycin associated retinal hemorrhages in pediatric age group a case report"
} | [
{
"companynumb": "EG-AZURITY PHARMACEUTICALS, INC.-2020AZY00066",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nCisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy improves survival in muscle-invasive urothelial bladder cancer (MIBC). The use of NAC before chemoradiation (CRT) has been limited, as these patients are often elderly, frail, and ineligible for cisplatin. However, the role of NAC in fit, cisplatin-eligible patients who opt for bladder preservation warrants further evaluation.\n\n\nMETHODS\nPatients with MIBC treated with NAC followed by CRT at the Princess Margaret and Durham Regional cancer centers from 2008 to 2017 were retrospectively reviewed. Gemcitabine-cisplatin NAC was given for 2 to 4 cycles, followed by reassessment for CRT. External-beam radiotherapy (60-66 Gy) over 6 weeks was given with concurrent weekly cisplatin at 40 mg/m2. Kaplan-Meier method was used for survival analyses.\n\n\nRESULTS\nWe identified 57 consecutive patients. Median age was 72 (range 45-87), and all had an Eastern Cooperative Oncology Group performance status of 0 (60%) or 1 (40%). Stage II disease (65%), stage III disease (25%), and regional nodal metastases (11%) were included. Most completed planned NAC (95%). All patients completed external-beam radiotherapy, and 84% completed at least 60% of the planned concurrent weekly cisplatin doses. Median (range) follow-up was 19.3 (4.8-96.1) months. Median overall survival (OS) was not reached. Two-year OS and disease-specific survival rates were 74% (95% confidence interval, 57.7-84.9) and 88% (95% confidence interval, 78.5-98.1), respectively. Two-year bladder-intact disease-free survival was 64%. Salvage cystectomy was performed in 14%. Distant relapse occurred in 11%, and 9% died of metastatic disease. OS was associated with baseline hydronephrosis and with bladder-intact disease-free survival with residual disease on cystoscopy.\n\n\nCONCLUSIONS\nNAC followed by CRT can result in encouraging outcomes and tolerability in cisplatin-eligible patients.",
"affiliations": "Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Canada.;Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada.;Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Canada.;Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Canada.;Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada.;Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada.;Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Canada.;Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Department of Medical Oncology, R. S. McLaughlin Durham Regional Cancer Centre, Lakeridge Health, Oshawa, Canada.;Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. Electronic address: Srikala.sridhar@uhn.ca.",
"authors": "Jiang|Di Maria|DM|;Jiang|Haiyan|H|;Chung|Peter W M|PWM|;Zlotta|Alexandre R|AR|;Fleshner|Neil Eric|NE|;Bristow|Robert G|RG|;Berlin|Alejandro|A|;Kulkarni|Girish S|GS|;Alimohamed|Nimira S|NS|;Lo|Gregory|G|;Sridhar|Srikala S|SS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clgc.2018.09.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "17(1)",
"journal": "Clinical genitourinary cancer",
"keywords": "Bladder preservation; Combined-modality therapy; Gemcitabine–cisplatin; Trimodal therapy; Urothelial carcinoma",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D002295:Carcinoma, Transitional Cell; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D015653:Cystectomy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D019042:Muscle Neoplasms; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D059351:Organ Sparing Treatments; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "38-45",
"pmc": null,
"pmid": "30686350",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neoadjuvant Chemotherapy Before Bladder-Sparing Chemoradiotherapy in Patients With Nonmetastatic Muscle-Invasive Bladder Cancer.",
"title_normalized": "neoadjuvant chemotherapy before bladder sparing chemoradiotherapy in patients with nonmetastatic muscle invasive bladder cancer"
} | [
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"companynumb": "CA-HQ SPECIALTY-CA-2019INT000058",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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... |
{
"abstract": "There are various mechanisms underlying the resistance of EGFR-mutant lung adenocarcinoma to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We herein report a case of pulmonary adenocarcinoma with EGFR mutation (exon 19 deletion and T790M) that acquired resistance to osimertinib treatment because of transformation into small-cell lung carcinoma (SCLC). A 67-year-old ex-smoking woman was diagnosed with left upper lobe adenocarcinoma of clinical stage IIIA (cT2bN2M0). She was treated with chemoradiotherapy (cisplatin and vinorelbine plus radiation), gefitinib, cisplatin, and pemetrexed followed by pemetrexed maintenance therapy and erlotinib. Since a sample extracted from the metastatic lung tumor taken obtained via a transbronchial lung biopsy was found to be positive for the T790M mutation at the time of disease progression during erlotinib treatment, she received osimertinib treatment for 15 months until progressive disease. She developed resistance to osimertinib due to the histologic transformation to SCLC. Although the standard chemotherapy of carboplatin and etoposide for SCLC was administered, she died due to metastatic liver failure.",
"affiliations": "Division of Respirology, NTT Medical Center Tokyo, Tokyo, Japan.;Department of Diagnostic Pathology, NTT Medical Center Tokyo, Tokyo, Japan.;Department of Diagnostic Pathology, NTT Medical Center Tokyo, Tokyo, Japan.;Division of Respirology, NTT Medical Center Tokyo, Tokyo, Japan.",
"authors": "Taniguchi|Yuri|Y|;Horiuchi|Hajime|H|;Morikawa|Teppei|T|;Usui|Kazuhiro|K|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1159/000489603",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000489603cro-0011-0323Case ReportSmall-Cell Carcinoma Transformation of Pulmonary Adenocarcinoma after Osimertinib Treatment: A Case Report Taniguchi Yuri a*Horiuchi Hajime bMorikawa Teppei bUsui Kazuhiro aaDivision of Respirology, NTT Medical Center Tokyo, Tokyo, JapanbDepartment of Diagnostic Pathology, NTT Medical Center Tokyo, Tokyo, Japan*Yuri Taniguchi, Division of Respirology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda Shinagawa, Tokyo 141-0022 (Japan), E-Mail yuri.taniguchi.ew@east.ntt.co.jpMay-Aug 2018 29 5 2018 29 5 2018 11 2 323 329 24 4 2018 24 4 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.There are various mechanisms underlying the resistance of EGFR-mutant lung adenocarcinoma to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We herein report a case of pulmonary adenocarcinoma with EGFR mutation (exon 19 deletion and T790M) that acquired resistance to osimertinib treatment because of transformation into small-cell lung carcinoma (SCLC). A 67-year-old ex-smoking woman was diagnosed with left upper lobe adenocarcinoma of clinical stage IIIA (cT2bN2M0). She was treated with chemoradiotherapy (cisplatin and vinorelbine plus radiation), gefitinib, cisplatin, and pemetrexed followed by pemetrexed maintenance therapy and erlotinib. Since a sample extracted from the metastatic lung tumor taken obtained via a transbronchial lung biopsy was found to be positive for the T790M mutation at the time of disease progression during erlotinib treatment, she received osimertinib treatment for 15 months until progressive disease. She developed resistance to osimertinib due to the histologic transformation to SCLC. Although the standard chemotherapy of carboplatin and etoposide for SCLC was administered, she died due to metastatic liver failure.\n\nKeywords\nOsimertinibT790MAcquired resistanceSmall-cell carcinoma transformationNon-small-cell carcinomaEpidermal growth factor receptor\n==== Body\nIntroduction\nOsimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that shows great effectiveness against pulmonary adenocarcinoma with an EGFR T790M mutation, which induces acquired resistance to first- and second-generation EGFR-TKIs. Since about 50% of acquired resistance cases have the T790M mutation, examining the EGFR T790M status when the disease progresses during first- or second-generation EGFR-TKI treatment is essential for delivering osimertinib adequately.\n\nHowever, re-examination of the EGFR status when patients acquire resistance to osimertinib treatment is controversial, as no EGFR-TKIs have yet been developed to overcome resistance to osimertinib induced by an EGFR mutation and/or other resistance mechanisms. Small-cell lung carcinoma (SCLC) transformation from adenocarcinoma during osimertinib treatment is rare but has been reported in cases of acquired resistance to first- and second-generation EGFR-TKIs. When SCLC transformation is confirmed in patients with acquired resistance to osimertinib treatment, we treat these patients with cytotoxic chemotherapy for SCLC. If the clinical features of the SCLC transformation cases after osimertinib treatment were examined, we might be able to decide on the indication and timing of a re-biopsy when the disease progresses during osimertinib treatment.\n\nWe herein report a patient with pulmonary adenocarcinoma who acquired resistance to a first-generation EGFR-TKI with a T790M mutation and then acquired resistance to osimertinib by transforming to SCLC without a T790M mutation.\n\nCase Presentation\nA 67-year-old woman visited our hospital due to a chest X-ray abnormality found on a routine screening. Chest computed tomography showed a mass in the left upper lobe that was later diagnosed as pulmonary adenocarcinoma harboring a deletion within exon 19 of the EGFR gene. According to positron emission tomography computed tomography and head magnetic resonance imaging results, her lung cancer was diagnosed as cT2bN2M0 stage IIIA. She received chemoradiotherapy, which consisted of three courses of cisplatin and vinorelbine, 32 Gy/16 fractions radiation and 42 Gy of proton beam therapy on the tumor.\n\nEighteen months later, the mediastinal lymph nodes on the right side were swollen, and progressive disease was confirmed. She received gefitinib for 19 months until progressive disease and then cisplatin and pemetrexed followed by pemetrexed monotherapy for 4 months and erlotinib for 9 months. At the time of progressive disease during erlotinib treatment, transbronchial lung biopsy of a pulmonary metastatic nodule (Fig. 1a) was performed to examine the status of the EGFR mutation. The DNA extracted from the tissue taken by the transbronchial lung biopsy showed the presence of EGFR T790M.\n\nThe patient received osimertinib, and her cancer was well controlled for 13 months (Fig. 1b); however, a hematoma was noted on the right temporal part (Fig. 1d). A craniotomy procedure to verify the subdural hematoma showed that the hematoma was in fact a tumor. The tumor was partly resected and sent for pathologic examination. While she received additional radiotherapy (39 Gy/13 fractions) in the right temporal bone, the tissue was finally diagnosed as small-cell carcinoma (Fig. 2) morphologically showing poorly differentiated cells with a high nuclear-to-cytoplasmic ratio and stained with neuroendocrine markers (synaptophysin and NCAM). An EGFR mutation analysis showed that the exon 19 deletion was persistent in the small-cell carcinoma, but the T790M mutation had been lost, and C797S was not detected. Although we treated her with chemotherapy (carboplatin and etoposide), her liver function rapidly deteriorated due to the progression of her liver metastasis. She passed away 4 days after the initiation of therapy.\n\nDiscussion\nResistance to osimertinib is induced by tertiary EGFR mutations, such as C797S, pL7981, pL692V, and pL692V, and the T790M reduction or disappearance along with EGFR amplification and phenotype alterations, such as a histologic transformation to neuroendocrine morphology [1, 2]. Although histologic transformation to SCLC is observed in 3–14% of patients with EGFR-mutant non-SCLC as the acquired resistance to first- or second-generation EGFR-TKIs [1, 3], the transformation to SCLC after third-generation EGFR-TKI (osimertinib) treatment is rare, with only 7 cases reported to our knowledge [1, 4, 5]. Since all of the cases maintained the original EGFR mutations, it is unclear whether adenocarcinoma evolved into SCLC metachronously or developed from a common precursor.\n\nThe response rate to standard chemotherapy for usual SCLC is 70–90% in limited disease and 60–70% in extended disease. The overall survival is reported to be 14–20 months for limited disease and 9–11 months for extended disease [6]. SCLC transformation from adenocarcinoma after TKI therapy has a relatively poor prognosis, with an overall survival of 7.1 months. However, the response rate of combination therapy with platinum and etoposide can be as high as 83% [6]. As a result, a re-biopsy should be performed if the patient is young, a nonsmoker, or has an EGFR mutation or mixed histology, and NSE/proGRP and CEA should also be monitored accordingly so that the appropriate treatment can be administered.\n\nIn our case, proGRP was routinely monitored throughout the treatment course (Fig. 3). Since the proGRP levels remained the same and the CEA levels were elevated at the time of progression, except for the terminal phase, we were unable to predict the SCLC transformation in this case. Although inactivation of Rb1 and p53 is reported to be a predictor for transformation into SCLC [7], we did not examine the status of these genes in this case. As patients with transformation into SCLC tend to show a poor prognosis, a re-biopsy to confirm the SCLC transformation should be considered promptly when encountering unexpected rapid disease progression during EGFR-TKI treatment.\n\nConclusion\nThis was a case of resistance to a third-generation EGFR-TKI due to SCLC transformation. A re-biopsy should be a priority when EGFR-mutant non-SCLC shows unexpected aggressive progression.\n\nStatement of Ethics\nThe authors declare that they have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have nothing to disclose.\n\nFig. 1. Chest computed tomography (a, b, c) and brain computed tomography (d) of our case. a T790M positivity at the diagnosis of EGFR mutation. b After 8 months of osimertinib treatment. c, d After 17 months of osimertinib treatment with disease progression.\n\nFig. 2. Small-cell lung carcinoma transformation of adenocarcinoma after osimertinib treatment. a Histology of the primary tumor at diagnosis. b–d Histology of the cranium and surrounding soft tissue, stained with hematoxylin and eosin (b), TTF-1 (c), and synaptophysin (d).\n\nFig. 3. The clinical course and EGFR mutation status of our case. Numbers show the timing of the EGFR mutation analysis. CRT, chemoradiation; CDDP+PEM, cisplatin + pemetrexed.\n==== Refs\nReferences\n1 Kim TM Song A Kim DW Kim S Ahn YO Keam B Mechanisms of acquired resistance to AZD9291 a mutation-selective, irreversible EGFR inhibitor J Thorac Oncol 2015 12 10 (12) 1736 44 26473643 \n2 Minari R Bordi P Tiseo M Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer review on emerged mechanisms of resistance Transl Lung Cancer Res 2016 12 5 (6) 695 708 28149764 \n3 Lu H Chen B Qin J Xie F Han N Huang Z Transformation to small-cell lung cancer following treatment with icotinib in a patient with lung adenocarcinoma Oncol Lett 2018 4 15 (4) 5799 802 29552210 \n4 Ham JS Kim S Kim HK Byeon S Sun JM Lee SH Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment J Thorac Oncol 2016 1 11 (1) e1 4 26762749 \n5 Minari R Bordi P Del Re M Facchinetti F Mazzoni F Barbieri F Primary resistance to osimertinib due to SCLC transformation issue of T790M determination on liquid re-biopsy Lung Cancer 2018 1 115 21 7 29290257 \n6 Jiang SY Zhao J Wang MZ Huo Z Zhang J Zhong W Small-cell lung cancer transformation in patients with pulmonary adenocarcinoma A case report and review of literature Medicine (Baltimore) 2016 2 95 (6) e2752 26871823 \n7 Lee JK Lee J Kim S Kim S Youk J Park S Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas J Clin Oncol 2017 9 35 (26) 3065 74 28498782\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(2)",
"journal": "Case reports in oncology",
"keywords": "Acquired resistance; Epidermal growth factor receptor; Non-small-cell carcinoma; Osimertinib; Small-cell carcinoma transformation; T790M",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "323-329",
"pmc": null,
"pmid": "29928211",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "26871823;28149764;29290257;26762749;28498782;29552210;26473643",
"title": "Small-Cell Carcinoma Transformation of Pulmonary Adenocarcinoma after Osimertinib Treatment: A Case Report.",
"title_normalized": "small cell carcinoma transformation of pulmonary adenocarcinoma after osimertinib treatment a case report"
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"abstract": "Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses.\n\n\n\nPOETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.\n\n\n\nBetween Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1-74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75-1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9-92·0) for patients in the POAI group and 90·4% (88·7-91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low-low) was 4·3% (95% CI 2·9-6·3), 8·4% (6·8-10·5) with high Ki67B and low Ki672W (high-low) and 21·5% (17·1-27·0) with high Ki67B and Ki672W (high-high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2-31·3), 7·7% (3·4-17·5) in the high-low group, and 15·7% (10·1-24·4) in the high-high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported.\n\n\n\nPOAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies.\n\n\n\nCancer Research UK.",
"affiliations": "The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK. Electronic address: poetic-icrctsu@icr.ac.uk.;University of Nottingham, Nottingham, UK; University Hospitals of Derby and Burton, Derby, UK.;The Institute of Cancer Research, London, UK.;Independent Cancer Patients Voice, London, UK.;Poole Hospital NHS Foundation Trust, Poole, UK.;Liverpool University Hospitals Foundation Trust, Liverpool, UK.;Bexley Cancer Centre, Leeds, UK.;University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK.;Queen Elizabeth University Hospital Glasgow, Govan, UK.;University Hospitals of Derby and Burton, Derby, UK.;Royal Bournemouth and Christchurch NHS Foundation Trust, Bournemouth, UK.;University of Birmingham and Royal Wolverhampton NHS Trust, Wolverhampton, UK.;The Institute of Cancer Research, London, UK.;The Institute of Cancer Research, London, UK.;The Institute of Cancer Research, London, UK.;The Royal Marsden NHS Foundation Trust, London, UK.;The Royal Marsden NHS Foundation Trust, London, UK.;The Institute of Cancer Research, London, UK.;The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.",
"authors": "Smith|Ian|I|;Robertson|John|J|;Kilburn|Lucy|L|;Wilcox|Maggie|M|;Evans|Abigail|A|;Holcombe|Chris|C|;Horgan|Kieran|K|;Kirwan|Cliona|C|;Mallon|Elizabeth|E|;Sibbering|Mark|M|;Skene|Anthony|A|;Vidya|Raghavan|R|;Cheang|Maggie|M|;Banerji|Jane|J|;Morden|James|J|;Sidhu|Kally|K|;Dodson|Andrew|A|;Bliss|Judith M|JM|;Dowsett|Mitch|M|",
"chemical_list": "D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D019394:Ki-67 Antigen; C000628856:MKI67 protein, human; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2",
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"doi": "10.1016/S1470-2045(20)30458-7",
"fulltext": "\n==== Front\nLancet Oncol\nLancet Oncol\nThe Lancet. Oncology\n1470-2045 1474-5488 Lancet Pub. Group \n\nS1470-2045(20)30458-7\n10.1016/S1470-2045(20)30458-7\nArticles\nLong-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial\nSmith Ian ProfMDpoetic-icrctsu@icr.ac.ukab** Robertson John ProfMDcj* Kilburn Lucy MScb Wilcox Maggie d Evans Abigail FRCSe Holcombe Chris ProfMDf Horgan Kieran ProfFRCSg Kirwan Cliona ProfPhDh Mallon Elizabeth MBChBi Sibbering Mark FRCSj Skene Anthony FRCSk Vidya Raghavan FRCSl Cheang Maggie PhDb Banerji Jane BScb Morden James MScb† Sidhu Kally BSca Dodson Andrew MPhila Bliss Judith M ProfMScb‡ Dowsett Mitch ProfPhDab‡ a The Royal Marsden NHS Foundation Trust, London, UK\nb The Institute of Cancer Research, London, UK\nc University of Nottingham, Nottingham, UK\nd Independent Cancer Patients Voice, London, UK\ne Poole Hospital NHS Foundation Trust, Poole, UK\nf Liverpool University Hospitals Foundation Trust, Liverpool, UK\ng Bexley Cancer Centre, Leeds, UK\nh University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK\ni Queen Elizabeth University Hospital Glasgow, Govan, UK\nj University Hospitals of Derby and Burton, Derby, UK\nk Royal Bournemouth and Christchurch NHS Foundation Trust, Bournemouth, UK\nl University of Birmingham and Royal Wolverhampton NHS Trust, Wolverhampton, UK\n* Correspondence to: Prof Ian Smith, c/o The Institute of Cancer Research, Clinical Trials and Statistics Unit, London SM2 5NG, UK poetic-icrctsu@icr.ac.uk* Joint first authors\n\n† Mr Morden died in September, 2017\n\n‡ Joint last authors\n\n\n1 11 2020 \n11 2020 \n21 11 1443 1454\n© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Summary\nBackground\nPreoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses.\n\nMethods\nPOETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0–1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.\n\nFindings\nBetween Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1–74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75–1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9–92·0) for patients in the POAI group and 90·4% (88·7–91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported.\n\nInterpretation\nPOAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical–pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies.\n\nFunding\nCancer Research UK.\n==== Body\nResearch in context\nEvidence before this study\n\nLongstanding experimental evidence from 1989 led to the hypothesis that short duration, presurgical endocrine therapy for early oestrogen receptor-positive breast cancer might improve clinical outcome. We carried out a PubMed search for relevant clinical studies published from Jan 1, 1989 until Dec 31, 2019 using the terms “neoadjuvant endocrine”, “breast cancer”, “clinical trial”, and “presurgical and endocrine therapy”. No reasonably sized randomised trial addressed this issue by the time POETIC commenced recruitment in 2008. Subsequently, a randomised clinical trial reported that depot progesterone for 5–14 days before surgery improved outcome in node-positive early breast cancer. Before the initiation of POETIC, two small clinical neoadjuvant trials, IMPACT and Z1031, reported that tumour Ki67 2–4 weeks after starting preoperative endocrine treatment predicted outcome better than baseline Ki67. POETIC was designed to establish whether the gain in prognostic accuracy merited routine application of presurgical endocrine therapy for this purpose. An additional PubMed search was done with “Ki67” added to the above search terms. One small study of low dose tamoxifen was identified, but this did not substantially add to the earlier evidence. Another modestly sized trial used to triage patients with 2–4 week Ki67>10% to chemotherapy and reporting the long-term outcome for those less than 10%, has led to a larger ongoing trial. One other large ongoing trial applies 10% as a cutoff at 2 weeks of tamoxifen or an aromatase inhibitor for directing patients to different adjuvant therapy. The concept of complete cell cycle arrest has been developed as an additional possible cutoff for on-treatment Ki67.\n\nAdded value of this study\n\nResults from POETIC suggest that 2 weeks' preoperative endocrine therapy makes no perceptible improvement in long-term outcome, but was nevertheless a safe treatment practice. The trial confirmed the low risk of recurrence for those with a low baseline Ki67. In patients with a high baseline Ki67 value (>10%) a biopsy 2 weeks after starting preoperative endocrine therapy provides additional clinical utility by predicting long-term outcomes. The trial documents the relationship of 2-week Ki67 with risk of recurrence for estimating whether the prognosis of individual patients is sufficiently good on endocrine therapy alone or whether additional treatment such as chemotherapy or new targeted therapies should be considered.\n\nImplications of all the available evidence\n\nThe data show no reason for short-term presurgical treatment to be applied for its direct therapeutic potential, but support prescribing an aromatase inhibitor for the short-term period before breast cancer surgery in oestrogen receptor-positive tumours with a high proliferation rate to derive information on early endocrine responsiveness that can be used to predict a patient's 5-year prognosis on standard adjuvant therapy. The clinical manoeuvres to incorporate this in the patient pathway with reliable quality assured Ki67 are straightforward and the measurement of Ki67 is inexpensive, potentially making this an attractive approach to estimating the prognosis of patients with early breast cancer.\n\n\n\nIntroduction\nThe POETIC (Peri-Operative Endocrine Therapy—Individualising Care) trial was designed to address two important hypotheses in the treatment of post-menopausal women with oestrogen receptor-positive early breast cancer.\n\nThe first was that short duration presurgical endocrine therapy might improve clinical outcome. This hypothesis was plausible because 2 weeks' preoperative endocrine therapy had been shown to markedly reduce proliferation in human breast cancer as measured by Ki67.1, 2 Longstanding experimental evidence had shown that the stimulatory effect of surgery on the growth of metastases in mice could be inhibited by perioperative endocrine therapy.3, 4 Any improvement in long-term outcome following short exposure to preoperative or perioperative endocrine therapy would be achieved with no additional toxicity or resource implications and be of considerable clinical importance.\n\nThe second hypothesis concerned identifying which patients with hormone receptor-positive early breast cancer have a sufficiently good prognosis such that standard of care medical treatment, often comprising adjuvant endocrine therapy alone, was sufficient and which group should be considered for additional therapies. Traditional approaches to this problem had used standard prognostic parameters including size, grade, nodal involvement, and age, often integrated into a prognostic tool (eg, Nottingham Prognostic Index,5 Adjuvant Online,6 NHS PREDICT7), but these merely provided the predicted probability of benefit for a patient population with given tumour and demo-graphic characteristics. More recently, genomic platforms have been developed aimed at providing more accurate prognostic and predictive information for the individual patient.8, 9 However, these genomic tests are expensive, by no means universally available, and differ among themselves in terms of the information they provide.10\n\nA simple test which predicts outcome after short duration preoperative endocrine therapy could therefore be helpful in accurately selecting appropriate treatment in the individual patient, if it incorporated an in-vivo response to aromatase inhibitor. A small neoadjuvant trial (IMPACT) had already suggested this might be feasible: results showed that tumour Ki67 after 2 weeks (Ki672w) of endocrine treatment predicted outcome better than at baseline (Ki67B), remaining significant in multivariable analysis, whereas Ki67B did not.11, 12 Similar results have subsequently been reported from another small trial comparing letrozole with tamoxifen13 and from a further trial comparing anastrozole, letrozole, and exemestane with one another.14 POETIC, with a much larger patient population, aimed to build on these findings to provide the definitive clinical evidence to inform future practice.\n\nMethods\nStudy design and participants\nThis open-label, multicentre, parallel group, randomised, phase 3 trial recruited participants from 130 UK hospitals (appendix p 25–27). Eligible patients were postmenopausal women (aged at least 50 years with amenorrhoea for more than 12 months, bilateral oophorectomy or hysterectomy, or had been on hormone replacement therapy within the previous 12 months, and with follicle-stimulating hormone concentrations in the postmenopausal range if aged less than 55 years) with oestrogen receptor-positive or progesterone receptor- positive (Allred ≥3, H-score ≥2, or ≥1% of positive cells, assessed in local pathology laboratories), HER2-positive or HER2-negative (assessed locally), operable primary breast cancer and no evidence of metastatic spread investigated according to local guidelines. If palpable, a tumour of any size was sufficient, otherwise requiring an ultrasound size of at least 1·5 cm. Women required WHO performance status 0–1 and an indication for standard adjuvant endocrine therapy. Required staging investigations were according to local practice with no additional trial specific investigations. Exclusion criteria were typical for this patient population. Previous endocrine therapy or chemotherapy was not allowed, nor was concurrent use of hormone replacement therapy or any other oestrogen-containing medication (within 4 weeks of randomisation). No previous use of oestrogen implants at any time, current, continuous, long-term systemic steroid usage, or treatment with an unlicensed or investigational drug within 4 weeks of randomisation was allowed. Patients with invasive malignancy diagnosed within the previous 5 years or any severe co-incident medical disease were ineligible (appendix p 1).\n\nPatients provided written informed consent before enrolment. POETIC was sponsored by the Institute of Cancer Research (ICR) and Royal Marsden NHS Foundation Trust and approved by the London–South East Research Ethics Committee (reference 08/H1102/37) and managed and analysed by the ICR Clinical Trials and Statistics Unit (ICR-CTSU; appendix p 1 for study oversight details). The protocol is in the appendix.\n\nRandomisation and masking\nParticipants were randomly allocated (2:1) to perioperative aromatase inhibitor (POAI) treatment or no perioperative treatment (control) by computer-generated permuted block method (variable block size six or nine) derived centrally by ICR-CTSU using its dedicated randomisation system, stratified by hospital. To randomly assign a patient, staff at the recruiting site telephoned ICR-CTSU and thus had no knowledge of future treatment assignment. The allocation ratio weighted trial information to study of biological perioperative drug effects, in particular to assess how these effects relate to long-term outcome. No placebo was used; clinicians and patients were not masked to treatment allocation, but central laboratory staff were masked.\n\nProcedures\nPOAI was a non-steroidal aromatase inhibitor in standard dosage (oral anastrozole 1 mg per day or oral letrozole 2·5 mg per day); choice of agent was declared by each participating hospital at trial outset. Before randomisation, all patients had excisional surgery prebooked for around 2 weeks (minimum 10 days) later to ensure timing of surgery was not biased by treatment allocation. POAI was to commence immediately after randomisation allowing duration of treatment before surgery to be as close as possible to 14 days. If surgery was delayed, the pretreatment duration was extended. Treatment continued without interruption until 14 days after surgery.\n\nAll non-trial adjuvant therapy, laboratory investigations, and disease staging were established on clinical grounds according to standard of care local practice (appendix p 1). All patients had pretreatment mammography and breast ultrasound according to local diagnostic practice. In December, 2010, the independent data monitoring committee expressed caution relating to the potential influence of POAI therapy on tumour grade measured at surgery. In February, 2011, a letter to investigators, followed by an approved protocol amendment, recommended that local multidisciplinary teams gave due consideration to other factors, including pretreatment grade on diagnostic core where available, when considering use of adjuvant chemotherapy.\n\nFollow-up data were submitted annually to ICR-CTSU; disease-related events, second cancers and deaths were reported on occurrence. There was no specific safety endpoint. Adverse event data were restricted to three menopausal symptoms (hot flushes, sweating, and musculoskeletal pain) at baseline, surgery, and at follow-up 2 weeks postsurgery (assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 3) as the safety profiles of the aromatase inhibitors used were well established. Serious adverse events were reported or recorded (as per protocol). Participants were able to withdraw from the trial at any time for any reason.\n\nFormalin-fixed paraffin-embedded tissue samples were required before randomisation (baseline) and at surgery. Baseline samples could be a core-cut diagnostic biopsy, a subsequent research core-cut biopsy, or sections from the diagnostic sample. At surgery, samples could be either core biopsies or sections cut from the routine excision.\n\nTissue samples were processed, stored, and analysed for Ki67 staining centrally in the Ralph Lauren Centre for Breast Cancer Research at the Royal Marsden NHS Foundation Trust. Ki67 was analysed immunohistochemically in a core biopsy taken at baseline (Ki67B), and in either a core biopsy or the excision biopsy taken at surgery (Ki672W), and was estimated as the percentage of cancer cells staining positive. We used MIB1 as the primary antibody to Ki67 and detection was done with the REAL EnVision system, both from DAKO (Glostrup, Denmark until 2016; now Agilent Technologies, Didcot, UK). Scoring was according to methodology including between-batch quality control procedures as described by the International Ki67 in Breast Cancer Working Group Party.15 Analysis of 2-week samples from the control group was restricted to a randomly selected subset since minimal change from baseline was expected.16\n\nOutcomes\nThe primary endpoint was time to recurrence (time from randomisation to local, regional, or distant tumour recurrence or death from breast cancer without previous notification of relapse) with second primary cancers and intercurrent deaths censored. Secondary clinical endpoints included relapse-free survival (as per time to recurrence but also including deaths from any cause as events), time to local recurrence (time from randomisation to first confirmed local recurrence, censoring at previous distant recurrence, second primary cancer, or death), time to distant recurrence (time from randomisation to first confirmed distant recurrence or breast cancer death without previous relapse, censoring at second primary cancer or intercurrent death) and overall survival (time from randomisation to death from any cause). Breast cancer-free survival duplicated the definition of time to recurrence, and was listed in the protocol in error.\n\nKi67 was evaluated as a biomarker in relation to its effect on predicting disease outcomes (one of the trial's two key objectives) and as the molecular secondary endpoint to assess proliferation rate at baseline (Ki67B) and at surgery (Ki672w), thus assessing the impact of POAI. The additional molecular secondary endpoint of gene expression profile at core biopsy and at surgical excision is not reported here as data analysis is ongoing.\n\nStatistical analysis\nThe sample size assumed the proportion of patients with recurrence by 5 years would be low (approximately 10%) given known recurrence rates for similar populations.17, 18 With 4350 patients it would be possible to detect a 3% improvement in time to recurrence at 5 years (10% to 7% recurrences) with 91% power (two-sided α of 5%). The sample size was increased originally from 4000 to 4350 patients to allow for underestimation of the relapse rate potentially owing to patients dying from other causes before breast cancer relapse. This change was endorsed by the trial steering committee and independent data monitoring committee and managed via a protocol amendment approved on Dec 31, 2012.\n\nAnalyses relating to clinical endpoints were done according to modified intention-to-treat—removing patients who subsequently withdrew consent for use of data. For analyses that assessed the predictive value of Ki67B and Ki672W, the population was defined as all randomly assigned patients who had paired Ki67 values available. Patients who did not have primary breast surgery as planned were censored at the date of that decision.\n\nBaseline demographic details, tumour characteristics, adjuvant treatment, and Ki67 data are presented with descriptive statistics. Protocol compliance between treatment groups (time from randomisation to surgery and number of inpatient days for surgery) was compared using Wilcoxon rank-sum tests; differences in tumour grade at surgery were assessed using a χ2 test for trend in prespecified analyses. Worst grade of adverse events and serious adverse reactions to POAI were summarised descriptively. Ki67B and Ki672W were reported by HER2 status. Analysis of percentage change between Ki67B and Ki672W used Wilcoxon sign rank tests within treatment groups and Wilcoxon rank-sum test between treatment groups. In a post-hoc exploratory analysis, following initial planned analyses on the trial data, a multivariable logistic regression model was created, using a forward stepwise approach, to determine factors affecting chemotherapy use.\n\nFor survival-related endpoints, Kaplan-Meier curves were plotted and treatment groups compared with the log-rank test. Hazard ratios (HRs) and 95% CIs were calculated within Cox proportional hazards regression models, with HRs of less than one taken to favour POAI. The proportional hazards assumption was assessed using Schoenfeld residuals and was found to hold. Comparisons between treatment groups were made with and without adjustment for progesterone receptor status (positive, negative, unknown), HER2 status (positive, negative, unknown), presurgical tumour grade (G1, G2, and G3), pathological tumour size (continuous), presurgical histological type (ductal, lobular, special type), nodal status (N0, N1–3, and N4+), age at randomisation (continuous) and vascular invasion (yes, no). Subgroup analyses were done for baseline clinical characteristics and presented using a forest plot.\n\nAssociations between Ki67B and Ki672W and time to recurrence were done separately in the POAI and control groups with the principal focus being to study the on-treatment effect of POAI. A post-hoc analysis of all patients combined for Ki67B was included for completeness. Assessment of Ki67 in the control group was considered of low additional value because patients were not exposed to perioperative treatment and because of the lack of association between POAI and time to recurrence. Survival analysis included adjustment for clinical factors as mentioned previously, except for HER2 status which was a stratifying factor. HER2-positive tumours have a different pattern of recurrence and were typically additionally treated with specific HER2-targeted therapy. To explore associations between Ki67 and disease outcome in the POAI group, Ki67 scores were dichotomised and patients divided into four groups as follows: low–low (Ki67B and Ki672W <10%); high–low (Ki67B ≥10%, Ki672W <10%); high–high (Ki67B and Ki672W ≥10%); and low–high (Ki67B <10%, Ki672W ≥10%). Few POAI patients were classified into the low–high group. These are reported for completeness but not further analysed as their apparent response is probably due to measurement variability around the dichotomisation cut-point. Post-hoc subgroup analyses explored associations between Ki67 and disease outcome by chemotherapy use and age with a view to avoid confounding of interpretation. In addition to the predefined 10% Ki67 dichotomisation, chosen to ensure consistency with other neoadjuvant trials,12, 14 other cut-points were explored using Harrell's C coefficient19 including that for complete cell cycle arrest (CCCA; Ki67 ≤2·7%20).\n\nPrevious analyses21 of change in Ki67 in 679 control group patients with paired samples available indicated that in patients with a core-cut surgery sample the median proportional reduction was −4·1% (IQR −27·8 to 34·8), whereas in those with a resection sample at surgery, the median proportional reduction in Ki67 between baseline and surgery was −17·7% (IQR −44·2 to 12·7) in contrast with an earlier small pilot study.16 From these findings, it was assumed that, for a given surgical sample, change in Ki67 score would be proportionally approximately 15% less if the sample was core-cut rather than resection (eg, 10% reduction with resection sample translated to 8·5% for core-cut). To account for this difference, Ki67 data and the analyses linking Ki67 and time to recurrence were done with Ki672W corrected according to surgical sample type. Ki672W scores from resection samples were increased proportionally by 15%. This correction factor was derived (and used) in control participants and similarly applied to participants in the POAI group. The correction was also made for patients for whom surgical sample type was unknown. For cases where Ki672W was 0%, no adjustment was made.\n\nThis manuscript describes the primary endpoint analysis, time to recurrence after a 5-year median follow-up for both hypotheses; first by randomised POAI allocation and second exploring the ability of Ki67 to predict disease outcome. No formal interim analyses were planned or done before the primary analysis. For this purpose, a database snapshot was taken on Aug 8, 2017 for data presented at the San Antonio Breast Cancer Conference 2017 and updated with a second database snapshot taken on Feb 6, 2018. All analyses were done by means of Stata (version 13.1). A p value of less than 0·05 was deemed to be significant.\n\nThis study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543.\n\nRole of the funding source\nThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit for publication.\n\nResults\nBetween Oct 13, 2008, and April 16, 2014, 4486 patients were entered from 130 UK centres. Six patients subsequently withdrew consent for data to be used and therefore 4480 patients (2976 POAI, 1504 control) were included in the modified intention-to-treat analysis (figure 1).Figure 1 Trial profile\n\n\n\nMedian age at randomisation was 67·1 years (IQR 61·5–74·8), 2536 (57%) of 4480 patients had a tumour size up to 2 cm, and all but eight (<1%) patients were confirmed locally to have hormone receptor-positive tumours (table 1). 23 (1%) of 4480 patients did not have surgery as planned (16 patients in the POAI group and seven in the control group; figure 1). Adherence to trial treatment and timelines are shown in the appendix (p 14). 177 (6%) of 2976 patients did not have the protocol defined duration of POAI (preoperatively <10 days or >21 days, postoperatively <10 days). The most common reasons were 63 (2%) had their surgery changed, 35 (1%) had less owing to adverse events (16 were in the presurgical period), and 30 (1%) had less owing to patient choice or omission. Surgical details and postsurgery tumour characteristics were well balanced between groups with the exception of pathological tumour grade, which was higher in the control group (p<0·0001; table 1). Adjuvant radiotherapy and anti-HER2 therapy were given after surgery with similar frequency for the two groups and in line with UK standard of care. Adjuvant chemotherapy was given to 770 (26%) of 2957 patients in the POAI group and 460 (31%) of 1493 patients in the control group (appendix p 15) with multivariable analyses attributing this to differences observed in postsurgical grade (appendix p 16). Following surgery, most (POAI 2507 [86%] of 2960 patients; control 1186 [81%] of 1497 patients) women were prescribed aromatase inhibitor monotherapy (appendix p 17).Table 1 Baseline characteristics\n\n\t\t\tDemographics at randomisation and tumour characteristics from the diagnostic core\tSurgery details and tumour characteristics from surgery\t\n\t\t\tPerioperative aromatase inhibitor group (n=2976)\tControl group (n=1504)\tPerioperative aromatase inhibitor group (n=2960)\tControl group (n=1497)\t\nAge group at randomisation, years\t\n\t<50\t9 (<1%)\t3 (<1%)\t..\t..\t\n\t50–59\t579 (19%)\t291 (19%)\t..\t..\t\n\t60–69\t1245 (42%)\t609 (40%)\t..\t..\t\n\t70–79\t808 (27%)\t429 (29%)\t..\t..\t\n\t≥80\t335 (11%)\t172 (11%)\t..\t..\t\nAge, years\t67·1 (61·5–74·9)\t67·3 (61·5–74·8)\t..\t..\t\nPlanned aromatase inhibitor\t\n\tAnastrozole\t954 (32%)\t483 (32%)\t..\t..\t\n\tLetrozole\t2022 (68%)\t1021 (68%)\t..\t..\t\nHormone receptor status\t\n\tPositive\t2971 (100%)\t1501 (100%)\t..\t..\t\n\tNegative\t4 (<1%)\t1 (<1%)\t..\t..\t\n\tMissing\t1 (<1%)\t2 (<1%)\t..\t..\t\nHER2 status\t\n\tPositive\t..\t..\t317 (11%)\t152 (10%)\t\n\tNegative\t..\t..\t2606 (88%)\t1316 (88%)\t\n\tUnknown or missing\t..\t..\t37 (1%)\t29 (2%)\t\n\tHormone receptor and HER2 status*\t\n\tHormone receptor-positive\t\n\t\tHER2 positive\t..·\t..\t317 (11%)\t152 (10%)\t\n\t\tHER2 negative\t..\t..\t2606 (88%)\t1316 (88%)\t\n\t\tHER2 unknown\t..\t..\t37 (1%)\t29 (2%)\t\n\tHormone receptor-negative\t\n\t\tHER2 negative\t..\t..\t4 (<1%)\t1 (<1%)\t\nHistological type\t\n\tDuctal†\t2404 (81%)\t1198 (80%)\t2364 (80%)\t1199 (80%)\t\n\tLobular\t428 (14%)\t224 (15%)\t454 (15%)\t236 (16%)\t\n\tSpecial type‡§\t105 (4%)\t58 (4%)\t124 (4%)\t50 (3%)\t\n\tDuctal carcinoma in situ or lobular carcinoma in situ¶\t0\t0\t3 (<1%)\t2 (<1%)\t\n\tNot breast cancer‖\t0\t0\t1 (<1%)\t0\t\n\tNot known\t39 (1%)\t24 (2%)\t14 (<1%)\t10 (1%)\t\nTumour grade\t\n\tG1\t417 (14%)\t234 (16%)\t465 (16%)\t184 (12%)\t\n\tG2\t1757 (59%)\t843 (56%)\t1968 (66%)\t838 (56%)\t\n\tG3\t521 (18%)\t279 (19%)\t502 (17%)\t463 (31%)\t\n\tGX\t0\t1 (<1%)\t..\t..\t\n\tNot known**\t278 (9%)\t145 (10%)\t17 (1%)\t6 (<1%)\t\n\tMissing\t3 (<1%)\t2 (<1%)\t8 (<1%)\t6 (<1%)\t\nTumour size, cm††\t\n\t≤2\t1666 (56%)\t870 (60%)\t1372 (46%)\t671 (45%)\t\n\t>2–5\t1238 (42%)\t599 (40%)\t1448 (49%)\t745 (50%)\t\n\t>5\t54 (2%)\t28 (2%)\t129 (4%)\t74 (5%)\t\n\tMissing\t18 (1%)\t7 (<1%)\t11 (<1%)\t7 (<1%)\t\nDefinitive breast surgery\t\n\tMastectomy\t..\t..\t1051 (36%)\t503 (34%)\t\n\tConservative surgery\t..\t..\t1902 (64%)\t992 (66%)\t\n\tMissing\t..\t..\t7 (<1%)\t2 (<1%)\t\nDefinitive axillary surgery\t\n\tYes\t..\t..\t2911 (98%)\t1470 (98%)\t\n\tClearance\t..\t..\t916 (31%)\t468 (31%)\t\n\tSampling\t..\t..\t287 (10%)\t150 (10%)\t\n\tSentinal lymph node biopsy\t..\t..\t1708 (58%)\t852 (57%)\t\n\tNo\t..\t..\t42 (1%)\t25 (2%)\t\n\tMissing\t..\t..\t7 (<1%)\t2 (<1%)\t\nNodal status\t\n\tN0\t..\t..\t1815 (61%)\t892 (60%)\t\n\tN1–3\t..\t..\t801 (27%)\t434 (29%)\t\n\tN4+\t..\t..\t334 (11%)\t165 (11%)\t\n\tMissing\t..\t..\t10 (<1%)\t6 (<1%)\t\nVascular invasion\t\n\tYes\t..\t..\t813 (27%)\t445 (30%)\t\n\tNo\t..\t..\t1990 (67%)\t981 (66%)\t\n\tNot reported\t..\t..\t143 (5%)\t63 (4%)\t\n\tMissing\t..\t..\t14 (<1%)\t8 (1%)\t\nMulti-focal disease\t\n\tYes\t..\t..\t381 (13%)\t223 (15%)\t\n\tNo\t..\t..\t2563 (87%)\t1266 (85%)\t\n\tMissing\t..\t..\t16 (1%)\t8 (1%)\t\nData are n (%) and median (IQR). Surgery details exclude patients for whom surgery was permanently cancelled.\n\n* One patient (perioperative aromatase inhibitor) with hormone receptor status unknown was HER2 negative; the remaining two patients (control) with hormone receptor status unknown also had HER2 status unknown.\n\n† Ductal includes patients with mixed ductal and lobular tumours.\n\n‡ Special types on the diagnostic core include mucinous, papillary, tubular, metaplastic carcinoma, microcapillary, anaplastic with basaloid nuclear pattern.\n\n§ Special types from surgery specimen include mucinous, papillary, tubular, endocrine cell carcinoma, pure special type, metaplastic carcinoma clear cell, and basaloid, tubular, and cribiform carcinoma.\n\n¶ Presurgical histological types for these patients were coded as ductal carcinoma.\n\n‖ Prehistological type was not known (this patient is recorded as ineligible).\n\n** Some UK hospitals do not routinely report grade on the diagnostic core.\n\n†† Presurgery this measurement is either by ultrasound or clinical examination. Patients are eligible if they have either a palpable tumour (clinical examination) of any size or a tumour with an ultrasound size of ≥1·5 cm. 618 patients had tumour size <1·5 cm, of which 607 had a tumour confirmed as palpable.\n\n\n\nWith 62·9 months' median follow-up (IQR 58·1–74·1), 434 (10%) of 4480 women had a breast cancer recurrence (POAI 280 [9%] of 2976 patients, control 154 [10%] of 1504 patients; table 2) with no significant difference observed between the treatment groups (HR 0·92, 95% CI 0·75–1·12; p=0·40, adjusted HR 0·96, 0·77–1·19; p=0·70; figure 2A) with the proportion free from breast cancer recurrence at 5 years of 91·0% (89·9–92·0) in the POAI group and 90·4% (88·7–91·9) in the control group. Subgroup analyses according to clinical characteristics, including nodal status, were consistent with the overall effect (appendix p 2). Likewise, no significant differences between treatment groups were observed for relapse-free survival, time to local recurrence, and time to distant recurrence (table 3). Second breast cancer primaries developed in 26 (<1%) of 2976 women in the POAI group compared with 24 (2%) of 1504 in the control group. 561 patients had died (POAI 365 [12%] of 2976; control 196 [13%] of 1504). Almost half of deaths were attributable to a non-breast cancer cause; none were treatment related (table 2). There was no difference in overall survival between treatment groups. 5-year overall survival was 88·9% (95% CI 87·7–90·1) in the POAI group versus 88·9% (87·2–90·5) in the control group (unadjusted HR 0·94, 95% CI 0·79–1·12; p=0·50, adjusted HR 0·91, 0·75–1·10; p=0·33; figure 2B).Table 2 Disease-related first events and deaths\n\n\tPerioperative aromatase inhibitor group (n=2976)\tControl group (n=1504)\t\nAny disease-related first event\t\nYes\t541 (18%)\t309 (21%)\t\nNo\t2435 (82%)\t1195 (80%)\t\nEvent contributing to primary endpoint (time to recurrence)\t\nTotal\t280 (9%)\t154 (10%)\t\nLocal recurrence (isolated)\t25 (1%)\t13 (1%)\t\nDistant recurrence*\t236 (8%)\t131 (9%)\t\nBreast cancer death†\t19 (1%)\t10 (1%)\t\nOther event\t\nTotal\t261 (9%)\t155 (10%)\t\nBreast second primary cancer\t26 (1%)\t24 (2%)\t\nNon-breast second primary cancer\t136 (5%)\t80 (5%)\t\nIntercurrent death\t99 (3%)\t51 (3%)\t\nDeaths\t\nTotal\t365 (12%)\t196 (13%)\t\nBreast cancer\t201 (7%)\t110 (7%)\t\nOther (intercurrent deaths)\t164 (6%)\t86 (6%)\t\nCardiovascular\t41 (1%)\t25 (2%)\t\nOther cancer\t59 (2%)\t35 (2%)\t\nRespiratory\t37 (1%)\t15 (1%)\t\nSepsis\t14 (<1%)\t5 (<1%)\t\nOther‡\t13 (<1%)\t6 (<1%)\t\nData are n (%). If more than one first event was reported on the same date, it was included in the row here according to the following order of priority: distant recurrence, local recurrence, breast second primary cancer, non-breast second primary cancer, and intercurrent death.\n\n* Distant recurrence row included patients for whom distant recurrence is reported within 6 weeks of local recurrence.\n\n† Included 25 patients (18 perioperative aromatase inhibitor, seven in the control group) with unknown cause of death and no previous event; one patient had a second primary cancer before unknown cause of death and was not included here.\n\n‡ Other causes in the perioperative aromatase inhibitor group (n=13) were accident (n=2), acute kidney injury, Alzheimer's disease, ascending aortic aneurysm, haematemesis secondary to gastric ulcer, hepatic cirrhosis, multiorgan failure, myelofibrosis, old age with vascular deterioration and chronic kidney disease, portal hypertension, a fall, ascites, evidence of cirrhosis, postoperative complications relating to pituitary tumour operation, and renal failure; other causes in the control group (n=6) were complications post laparotomy, dementia, diabetes, meningioma, subdural haematoma, and suicide.\n\nFigure 2 Kaplan-Meier survival curve by randomised treatment group for time to recurrence (A) and overall survival (B)\n\nIn part A test for proportionality, p=0·58. In part B test for proportionality, p=0·82.\n\nTable 3 Summary of disease-related endpoints\n\n\tNumber of events\tUnadjusted hazard ratio\tAdjusted hazard ratio\t5-year survival estimate\t\n\tPerioperative aromatase inhibitor group\tControl group\t\t\tPerioperative aromatase inhibitor group\tControl group\t\nRelapse-free survival\t385 (13%)\t207 (14%)\t0·94 (0·79–1·11); 0·47\t0·95 (0·79–1·14); 0·59\t87·9% (86·6–89·1)\t87·6% (85·7–89·2)\t\nTime to local recurrence\t41 (1%)\t24 (2%)\t0·86 (0·52–1·43); 0·57\t0·92 (0·54–1·56); 0·75\t98·6% (98·1–99·0)\t98·5% (97·6–99·0)\t\nTime to distant recurrence\t262 (9%)\t147 (10%)\t0·90 (0·73–1·10); 0·30\t0·94 (0·75–1·18); 0·59\t91·7% (90·5–92·6)\t90·9% (89·2–92·3)\t\nData are n (%), hazard ratio (95% CI); p value, and % (95% CI). Models adjusted for progesterone receptor status (positive, negative, unknown), HER2 status (positive, negative, unknown), presurgical tumour grade (G1, G2, and G3), pathological tumour size (continuous), presurgical histological type (ductal, lobular, special type), nodal status (N0, N1–3, and N4+), age at randomisation (continuous), and vascular invasion (yes, no). Test for proportionality for relapse-free survival, p=0·69; for time to local recurrence, p=0·97, and for time to distant recurrence, p=0·52.\n\n\n\nSelected menopausal symptoms were assessed in 4201 (94%) of 4480 women, with higher symptom rates observed for POAI (appendix p 18). The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). 11 patients each reported a single serious adverse reaction (appendix p 19); all in the POAI group. The most common were pulmonary embolism (n=3) and musculoskeletal pain (n=3).\n\n3913 (87%) of 4480 participants had Ki67B data available. 2528 (85%) of 2976 patients in the POAI group and 678 (45%) of 1504 in the control group had paired Ki67B and Ki672W data available (figure 1). In 2316 (72%) of 3206 participants with paired Ki67 data, the surgical sample was a resection (1834 [73%] of 2528 patients in the POAI group; 474 [70%] of 678 patients in the control group) or the surgical sample type was unknown (six in the POAI group and two in the control group) and the Ki672W scores for these resections and unknown surgical sample types were corrected as described. 688 (27%) of 2528 POAI and 202 (30%) of 678 control patients' surgical sample type was core-cut biopsy.\n\nThe median Ki67B score in the 3913 of 4480 patients with a sample available was 15·2% (IQR 8·6–26·0; POAI 15·3% [8·5–26·4]; control: 14·9% [8·6–25·1]). Ki67B values were different between HER2-negative and HER2-positive tumours (median 14·3% [IQR 8·2–24·6] in HER2-negative tumours, median 26·6% [17·0–37·4] in HER2-positive tumours; p<0·0001). After 2 weeks of POAI, Ki67 was significantly suppressed compared with little change in the control group. Ki672W was markedly lower in the HER2-negative tumours compared with HER2-positive tumours (appendix p 3). In the control group, given the little overall change, Ki672W was again lower in the HER2-negative tumours than in HER2-positive tumours (appendix p 3).\n\nIn patients with HER2-negative tumours in the POAI group (2235 of 2528 patients), 209 (9%) time to recurrence events were reported. For the time to recurrence endpoint, women with Ki67B less than 10% (732 [33%] of 2235 patients) had a better prognosis than those with a Ki67B of at least 10% (1503 [67%] of 2235 patients; appendix p 20). Women whose Ki672W remained high (high–high group) were significantly more likely to have a recurrence than those whose Ki672W had dropped below 10% (high–low group; unadjusted HR 2·59, 95% CI 1·93–3·47; p<0·0001, adjusted HR 2·10, 1·48–2·98; p<0·0001; figure 3A). Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high-low group, and 15·7% (10·1–24·4) in the high–high group. Adding a high versus low classification at 2 weeks segregated groups in relation to their baseline Ki67 (appendix p 21).Figure 3 Kaplan-Meier survival curve for time to recurrence by Ki67B and Ki672W for patients with hormone receptor-positive and HER2-negative breast cancer (A) and hormone receptor-positive, HER2-positive breast cancer (B) in the perioperative aromatase inhibitor group\n\nLow–low=Ki67B and Ki672W <10%. High–low=Ki67B ≥10% and Ki672W <10%. High–high=Ki67B and Ki672W ≥10%. B=baseline. 2w=2weeks. 28 patients with hormone receptor-positive breast cancer and HER2-negative breast cancer and four patients with hormone receptor-positive and HER2-positive breast cancer in the low-high group were omitted from the figure.\n\n\n\nThe HER2-negative POAI-treated subpopulation post-hoc exploratory analyses relating to the combined effects of age and chemotherapy use suggested that in patients with Ki67B of at least 10%, who did not receive adjuvant chemotherapy, the residual Ki672W (high or low) conferred a differential effect on prognosis as assessed by time to recurrence for both those aged less than 70 years and aged at least 70 years (appendix pp 4–9). Numbers were too small to fully define effects for the corresponding group (ie, Ki67B ≥10%) who did receive chemotherapy.\n\nIn patients with HER2-negative breast cancer in the control group, 56 time to recurrence events were reported in the 597 of 678 patients for whom Ki672W was available. There was no difference in time to recurrence between the high–high and high–low groups (appendix pp 10, 22).\n\nA post-hoc sensitivity analysis in the HER2-negative subgroup combining the baseline data for POAI and control gave a 5-year recurrence risk of 4·7% (95% CI 3·5–6·3) for low Ki67B and 11·5% (95% CI 10·1–13·1) for high Ki67B (appendix p 24).\n\nPrespecified exploratory analysis in the HER2-negative subgroup suggested an optimal cut-point around 15–20% for Ki67B and around 6–8% for Ki672W and that using the CCCA threshold for Ki672W had prognostic discrimination (appendix pp 11–13).\n\nIn patients with hormone receptor-positive, HER2-positive breast cancer in the POAI group (273 [10%] of 2528 patients), 33 time to recurrence events were reported. 143 women in the Ki67 high–high group had a recurrence compared with 94 in the high–low group, although the difference was not significant (unadjusted HR 2·08, 95% CI 0·88–4·90; p=0·093, adjusted HR 1·83, 0·71–4·73; p=0·21; figure 3B). Similar to the HER2-negative group, absolute risk of recurrence at 1, 3, and 5 years was higher in the high-high group than in the high–low group (appendix p 23). 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. In the 70 women with HER2-positive breast cancer in the control group, nine time to recurrence events were reported.\n\nDiscussion\nPOETIC is, to our knowledge, the largest trial of its kind to assess the potential of POAI therapy in patients with postmenopausal, hormone receptor-positive early breast cancer and it did not show any significant long-term improvement in disease outcomes with this approach. This was despite preclinical experimental evidence in a mouse model suggesting the contrary.3, 4 A smaller phase 3 clinical trial, which reported after POETIC was initiated, randomly assigned operable breast cancer patients (n=976, 50% hormone receptor-positive, 45% hormone receptor-negative, and 5% hormone receptor unknown) to surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5–14 days before surgery; no significant benefit was observed in the overall population (HR 0·87, 95% CI 0·68–1·09; p=0·23), but the results suggested a hypothesis-generating potential disease-free survival improvement in node-positive subgroups (HR 0·72, 0·54–0·97; p=0·02).22 In contrast, consistent with the overall finding, POETIC showed no suggestion of long-term outcome improvement with POAI overall or in the node-positive subgroup.\n\nIn POETIC, the frequency of chemotherapy was slightly lower in patients in the POAI group than in those in the control group. Multivariable regression supported the suggestion that this was probably because of multidisciplinary teams being influenced by pathological tumour grade, which was on average lower in the patients in the POAI group. This absolute difference was small however (5%), and since the overall event rate was less than 20% would have had an imperceptible effect on outcome comparisons.\n\nOn a pragmatic note, it is common practice to start some patients on preoperative endocrine therapy if there has to be a significant delay in surgery for any reason. Despite not showing any statistical evidence of clinical benefit, our results provide reassurance that there is no detriment to this practice.\n\nThe second aim of this trial was to explore whether the measurement of tumour Ki67 2 weeks after starting treatment could predict disease outcome better than baseline Ki67 alone, thus providing the basis of a simple and inexpensive test to personalise adjuvant treatment in patients with hormone receptor-positive, HER2-negative breast cancer. Previously, IMPACT had shown that 2-week on-treatment Ki67 predicted outcome better than baseline and, unlike baseline, was significant in multivariable analysis.12 POETIC has provided evidence for the clinical validity of on-treatment aromatase inhibitor Ki672W in addition to Ki67B to predict those with high residual risk of recurrence in spite of standard-of-care therapy. At the initiation of POETIC, we believed that the evidence was insufficient to withhold or direct therapy on the basis of the Ki672W. Our results provide an early indication of endocrine sensitivity or resistance including for the large number of patients who are not routinely considered for adjuvant chemotherapy.\n\nSeparate clearly defined adjuvant treatment pathways for HER2-positive and HER2-negative breast cancers now exist and we therefore analysed these groups separately when considering prognostic risk. The HER2-positive subgroup was small with relatively few events. Focus for exploratory analysis was therefore on the HER2-negative subgroup, which comprised approximately 90% of the POETIC population.\n\nPreviously, it had been shown that patients with a low Ki67B have a better prognosis than those with a high Ki67B value.23 POETIC confirmed this in a larger prospective population, dichotomising Ki67B at 10% with 5-year recurrence risk in HER2-negative patients in the POAI group of 4·4% for low Ki67B and 11·8% for high Ki67B. To our knowledge, this is the first large published dataset that makes use of the Ki67 scoring methodology recommended by the International Ki67 in Breast Cancer Working Group; the strong association of Ki67 at baseline with prognosis served as a clinical validation of that methodology.15 Patients whose Ki67B was low did well on standard of care, with approximately 85% of those receiving endocrine therapy alone. It could be the case that if the patient's clinical pathological features led to chemotherapy being given, this approach might have contributed to the good outcomes. But irrespective of adjuvant treatment, it is reasonable to conclude that Ki672w did not add significant prognostic or predictive information in this subgroup.\n\nIn contrast, for patients whose tumours had a high baseline Ki67 in the POAI group, 73% had a low Ki672w 2 weeks after starting treatment; those patients had a better prognosis at 5 years than those who continued to have a high Ki672W (8·4% vs 21·5% 5-year recurrence risk). To what extent could this observation be applied to clinical practice?\n\nThe answer to this question is influenced by the limitations of this trial. The first concerns the optimal cutoff for Ki67, and we have shown that dichotomising for cutoffs other than 10% merit further exploration. The second limitation concerns interpreting the data in relation to age and chemotherapy usage. Older age has already been shown to be an independent prognostic factor in breast cancer24 and POETIC patients aged at least 70 years had poorer outcomes than those aged below 70 years. Since a substantial minority (26%) of POAI patients had adjuvant chemotherapy, this could be a potential confounding factor in the interpretation of Ki672W in relation to prognosis and prediction of the value of endocrine therapy alone. To address this, we repeated our analyses in patients according to their receipt of adjuvant chemotherapy. This confirmed a persisting worse outcome for tumours high–high after 2 weeks of an aromatase inhibitor compared with high–low in the 74% of patients not receiving chemotherapy. In the corresponding groups who received chemotherapy, numbers were insufficient to determine a prognostic Ki67 effect or to define a plausible beneficial chemotherapy effect.\n\nIn the two-thirds of patients below the age of 70 years not receiving chemotherapy, the overall outcome in terms of recurrence risk was better, probably reflecting the choice of omitting chemotherapy for better prognosis patients. But the key point was that in this population of patients non-confounded by chemotherapy, 21% with high Ki67B remained high at surgery (high–high) and those had 11·2% 5-year recurrence risk (arguably meriting chemotherapy in addition), compared with the low–low groups in which recurrence by 5 years was only 1·6% and the high–low group in which recurrence by 5 years was only 2·9% (indicating that additional chemotherapy would be of no clinically relevant benefit). This exploratory outcome must be interpreted with caution but further supports the prognostic value of measuring Ki67 at 2 weeks.\n\nSimilar findings were observed for patients aged at least 70 years. Only 59 of those patients received chemotherapy, too few to provide statistical confidence in the relationship between Ki67 and outcome. In those aged at least 70 years who did not receive chemotherapy, there was again a large difference in outcome between the high–low and high–high groups (5-year recurrence risk 12·3% vs 34·5%), again supporting the discriminatory power of measuring Ki67 at 2 weeks, even though the absolute risks were greater.\n\nThe prespecified Ki672w 10% cut-point was chosen for consistency with ongoing clinical trials (ALTERNATE [NCT01953588]; ADAPT [NCT01779206]). The relationship of Ki672w with recurrence risk is continuous and as illustrated by our analysis by means of CCCA, other cut-points might be selected if appropriate for a specific use (eg, assessing the value of well-tolerated additional treatment).\n\nIn conclusion, in POETIC, giving perioperative endocrine therapy with an aromatase inhibitor had no significant effect on long-term outcome. The trial also showed that using Ki67B and aromatase inhibitor on-treatment Ki672w could help guide adjuvant treatment decisions. First, we believe that we have identified a subgroup with a low baseline Ki67 who have a sufficiently good prognosis that the majority will do well on standard endocrine therapy alone (except perhaps for a minority as dictated by other clinical–pathological factors) and who do not require a repeat 2-week biopsy. Second, giving POAI to the subgroup with high baseline Ki67 can differentiate two groups of patients according to their 2-week Ki67 value: those who convert to a low Ki67 might not need anything beyond adjuvant endocrine therapy (taking consideration of other clinical-pathological factors), whereas those with a high Ki67 that has remained high, should be considered for further adjuvant treatments and trials. There are, of course, now several commercially available genomic platforms developed to provide the same kind of prognostic and predictive information for the individual patient.8, 9 But these tests are expensive, they often involve central testing of tissue, which has to be sent long distances with inevitable time delay, and results can differ between the platforms. Ki67 as used in POETIC potentially offers an inexpensive, easy and quick alternative in situations in which genomic testing is not readily available.\n\nData sharing\nDe-identified data will be made available to other researchers on request, subject to approval of a formal data access request in accordance with the ICR-CTSU data and sample access policy. Trial documentation including the protocol are available on request by contacting poetic-icrctsu@icr.ac.uk. The ICR-CTSU supports the wider dissemination of information from the research it does, and increased cooperation between investigators. Trial data is collected, managed, stored, shared, and archived according to ICR-CTSU Standard Operating Procedures in order to ensure the enduring quality, integrity, and utility of the data. Formal requests for data sharing are considered in line with the Institute of Cancer Research Clinical Trials and Statistics Unit (ICR-CTSU) procedures with due regard given to funder and sponsor guidelines. Requests are via a standard proforma describing the nature of the proposed research and extent of data requirements. Data recipients are required to enter a formal data sharing agreement which describes the conditions for release and requirements for data transfer, storage, archiving, publication and intellectual property. Requests are reviewed by the Trial Management Group (TMG) in terms of scientific merit and ethical considerations including patient consent. Data sharing is allowed if proposed projects have a sound scientific or patient benefit rationale as agreed by the TMG and approved by the Trial Steering Committee as required. Restrictions relating to patient confidentiality and consent will be limited by aggregating and anonymising identifiable patient data. Additionally all indirect identifiers that might lead to deductive disclosures will be removed in line with Cancer Research UK Data Sharing Guidelines. Additional documents might be shared if approved by the TMG and Trial Steering Committee (eg, statistical analysis plan and informed consent form).\n\nSupplementary Material\nSupplementary appendix\n \n\nAcknowledgments\nPOETIC is co-sponsored by The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. We are grateful for the support from the National Institute for Health Research (NIHR) Clinical Research Network and for the study grant from Cancer Research UK (CRUK/07/015 grant reference A8671). ICR-CTSU also receives programme grant funding from Cancer Research UK, grant number C1491–A15955. The POETIC trial represents independent research supported by the National Institute for Health Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. We thank all the patients and their families who participated in this study, all staff involved at the 132 participating hospitals, the staff involved in the trial at ICR-CTSU, Ralph Lauren Centre for Breast Cancer Research at the Royal Marsden NHS Foundation Trust, and the Centre for Molecular Pathology at the Institute of Cancer Research. Finally, we thank the past and present colleagues on the POETIC Trial Management Group, and the POETIC Independent Data Monitoring Committee and Trial Steering Committee.\n\nContributors\nIS was chief investigator. IS and JR assisted with trial design, protocol development, participant recruitment, data collection, data interpretation, and writing and were Trial Management Group members. LK assisted with statistical analysis, data interpretation, and writing and was a Trial Management Group member. MW was a patient advocate and a Trial Management Group member. AE, CH, KH, MS, AS, and RV assisted with participant recruitment and data collection and were Trial Management Group members. CK and EM assisted with data collection, data analysis, and data interpretation, and were Trial Management Group members. MC assisted with data analysis and data interpretation, and was a Trial Management Group member. JB assisted with trial management, data collection, and data management, and was a Trial Management Group member. JM assisted with trial design, protocol development, statistical analysis, and data interpretation, and was a Trial Management Group member. KS assisted with data collection. AD assisted with data analysis and data interpretation. JMB assisted with trial design, protocol development, statistical analysis, data interpretation, and writing and was a Trial Management Group member. MD assisted with trial design, protocol development, data analysis, data interpretation, and writing, and was a Trial Management Group member. All authors reviewed the manuscript before submission.\n\nDeclaration of interests\nMD reports grants from Cancer Research UK, during the conduct of the study; and personal fees from Radius, Roche, Myriad, Orion, G1 Therapeutics, Nanostring, AbbVie, H3 Biomedicine, Lilly, and the ICR Rewards for Inventors Scheme, outside the submitted work. JMB reports grants from Cancer Research UK, during the conduct of the study; grants from Medivation; grants and non-financial support from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, and Roche, outside the submitted work. LK reports grants from Cancer Research UK, during the conduct of the study. All other authors declare no competing interests.\n==== Refs\nReferences\n1 Dowsett M Smith IE Ebbs SR Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival Clin Cancer Res 11 2005 951s 958s 15701892 \n2 Ellis MJ Coop A Singh B Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status Cancer Res 63 2003 6523 6531 14559846 \n3 Fisher B Gunduz N Coyle J Rudock C Saffer E Presence of a growth-stimulating factor in serum following primary tumor removal in mice Cancer Res 49 1989 1996 2001 2702641 \n4 Fisher B Saffer E Rudock C Coyle J Gunduz N Effect of local or systemic treatment prior to primary tumor removal on the production and response to a serum growth-stimulating factor in mice Cancer Res 49 1989 2002 2004 2522814 \n5 Haybittle JL Blamey RW Elston CW A prognostic index in primary breast cancer Br J Cancer 45 1982 361 366 7073932 \n6 Ravdin PM Siminoff LA Davis GJ Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer J Clin Oncol 19 2001 980 991 11181660 \n7 Candido Dos Reis FJ Wishart GC Dicks EM An updated PREDICT breast cancer prognostication and treatment benefit prediction model with independent validation Breast Cancer Res 19 2017 58 28532503 \n8 van de Vijver MJ He YD van't Veer LJ A gene-expression signature as a predictor of survival in breast cancer N Engl J Med 347 2002 1999 2009 12490681 \n9 Paik S Shak S Tang G A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer N Engl J Med 351 2004 2817 2826 15591335 \n10 Sestak I Buus R Cuzick J Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial JAMA Oncol 4 2018 545 553 29450494 \n11 Dowsett M Smith IE Ebbs SR Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer Clin Cancer Res 12 2006 1024s 1030s 16467120 \n12 Dowsett M Smith IE Ebbs SR Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer J Natl Cancer Inst 99 2007 167 170 17228000 \n13 Ellis MJ Tao Y Luo J Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics J Natl Cancer Inst 100 2008 1380 1388 18812550 \n14 Ellis MJ Suman VJ Hoog J Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype-ACOSOG Z1031 J Clin Oncol 29 2011 2342 2349 21555689 \n15 Leung SCY Nielsen TO Zabaglo L Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration NPJ Breast Cancer 2 2016 16014 \n16 Pinhel IF Macneill FA Hills MJ Extreme loss of immunoreactive p-Akt and p-Erk1/2 during routine fixation of primary breast cancer Breast Cancer Res 12 2010 R76 20920193 \n17 Baum M Budzar AU Cuzick J Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial Lancet 359 2002 2131 2139 12090977 \n18 Thürlimann B Keshaviah A Coates AS A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer N Engl J Med 353 2005 2747 2757 16382061 \n19 Harrell FE Jr Lee KL Califf RM Pryor DB Rosati RA Regression modelling strategies for improved prognostic prediction Stat Med 3 1984 143 152 6463451 \n20 Ma CX Gao F Luo J NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer Clin Cancer Res 23 2017 4055 4065 28270497 \n21 Bliss J Morden J Evans A Clinico-pathological relationships with Ki67 in POETIC (CRUK/07/015)—critical lessons for assessing Ki67 for prognosis and as a pharmacodynamic marker Cancer Res 77 suppl 2017 P2-05-1-P2—1 (abstr). \n22 Badwe R Hawaldar R Parmar V Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial J Clin Oncol 29 2011 2845 2851 21670457 \n23 Urruticoechea A Smith IE Dowsett M Proliferation marker Ki-67 in early breast cancer J Clin Oncol 23 2005 7212 7220 16192605 \n24 Høst H Lund E Age as a prognostic factor in breast cancer Cancer 57 1986 2217 2221 3697919\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1470-2045",
"issue": "21(11)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000368:Aged; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent; D017698:Postmenopause; D011379:Prognosis; D018719:Receptor, ErbB-2",
"nlm_unique_id": "100957246",
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"pages": "1443-1454",
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"pmid": "33152284",
"pubdate": "2020-11",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "15591335;18812550;12090977;17228000;21670457;2522814;20920193;28532503;16382061;6463451;14559846;3697919;2702641;28721378;29450494;21555689;16467120;7073932;16192605;11181660;28270497;12490681;15701892",
"title": "Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial.",
"title_normalized": "long term outcome and prognostic value of ki67 after perioperative endocrine therapy in postmenopausal women with hormone sensitive early breast cancer poetic an open label multicentre parallel group randomised phase 3 trial"
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"abstract": "CONCLUSIONS\nColonoscopy is a useful tool in modern medicine and is increasingly employed for both diagnostic and treatment reasons. However, its effectiveness is highly reliant on the quality of bowel cleansing. Among different bowel-cleansing agents available, PEG (polyethylene glycol) is considered to be the safest cleansing agent, especially in relation to fluid and electrolyte problems. We present here a case of severe symptomatic hyponatremia that developed after the use of PEG for an elective colonoscopy. This case highlights that despite the use of PEG-based preparations, life-threatening fluid and electrolyte disturbances can still occur in patients with risk factors, such as old age, use of thiazide diuretics and SSRIs, chronic kidney disease, heart failure and a history of electrolyte problems. These patients should be closely monitored when undertaking bowel cleansing and should receive prompt care in the event of complications, to avoid permanent neurological sequelae and death. Rapid correction of sodium levels in patients requiring treatment of hyponatremia should be avoided to prevent complications such as osmotic demyelination syndrome.\nPEG is considered to be the safest bowel-cleansing agents among different options available, but it can still cause significant side effects in susceptible individuals.Those at risk of developing adverse events include elderly individuals, patients with chronic kidney disease, heart failure or previous history of electrolyte problems and those taking thiazide diuretics and SSRIs.All such patients should be closely monitored i.e. have their metabolic profile checked prior to the commencement of bowel cleansing and a low threshold should be kept for the initiation of investigations and treatment in case of development of symptoms.Medications with a potential of causing fluid and electrolytes such as thiazide diuretics and SSRIs should be withheld while patient is undertaking bowel preparation.Hyponatremia in a hospitalized patient can be multifactorial, and the treatment principles are based on duration of onset, presence of symptoms and patients volume status.Overzealous correction of sodium levels during treatment of hyponatremia can result in serious complications such as osmotic demyelination syndrome.",
"affiliations": "Epworth HealthCare, Melbourne, Victoria, Australia.;Epworth HealthCare, Melbourne, Victoria, Australia.",
"authors": "Samad|Navira|N|;Fraser|Ian|I|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1530/EDM-16-0119",
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-16-0119EDM160119Unusual Effects of Medical TreatmentSevere symptomatic hyponatremia associated with the use of polyethylene glycol-based bowel preparation N Samad and I FraserHyponatremia and bowel preparationSamad Navira Fraser Ian Epworth HealthCare, Melbourne, Victoria, AustraliaCorrespondence should be addressed to N Samad; Email: navira7@hotmail.com23 2 2017 2017 2017 16-011912 12 2016 19 1 2017 © 2017 The authors2017The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nColonoscopy is a useful tool in modern medicine and is increasingly employed for both diagnostic and treatment reasons. However, its effectiveness is highly reliant on the quality of bowel cleansing. Among different bowel-cleansing agents available, PEG (polyethylene glycol) is considered to be the safest cleansing agent, especially in relation to fluid and electrolyte problems. We present here a case of severe symptomatic hyponatremia that developed after the use of PEG for an elective colonoscopy. This case highlights that despite the use of PEG-based preparations, life-threatening fluid and electrolyte disturbances can still occur in patients with risk factors, such as old age, use of thiazide diuretics and SSRIs, chronic kidney disease, heart failure and a history of electrolyte problems. These patients should be closely monitored when undertaking bowel cleansing and should receive prompt care in the event of complications, to avoid permanent neurological sequelae and death. Rapid correction of sodium levels in patients requiring treatment of hyponatremia should be avoided to prevent complications such as osmotic demyelination syndrome.\n\nLearning points:\nPEG is considered to be the safest bowel-cleansing agents among different options available, but it can still cause significant side effects in susceptible individuals.\n\nThose at risk of developing adverse events include elderly individuals, patients with chronic kidney disease, heart failure or previous history of electrolyte problems and those taking thiazide diuretics and SSRIs.\n\nAll such patients should be closely monitored i.e. have their metabolic profile checked prior to the commencement of bowel cleansing and a low threshold should be kept for the initiation of investigations and treatment in case of development of symptoms.\n\nMedications with a potential of causing fluid and electrolytes such as thiazide diuretics and SSRIs should be withheld while patient is undertaking bowel preparation.\n\nHyponatremia in a hospitalized patient can be multifactorial, and the treatment principles are based on duration of onset, presence of symptoms and patients volume status.\n\nOverzealous correction of sodium levels during treatment of hyponatremia can result in serious complications such as osmotic demyelination syndrome.\n==== Body\nBackground\nPopulation-based screening for bowel cancer is performed using the fecal occult blood test (FOBT). Colonoscopy is the recommended follow-up test for those with positive findings on FOBT screening and as a primary tool for cancer surveillance in people with an increased risk of bowel cancer, such as those with a first-degree relative who was diagnosed with bowel cancer under the age of 55 years (1) (see reference for Cancer Council). Moreover, endoscopic surveillance for colorectal cancers has been shown to significantly reduce mortality (see reference – Cancer Council Australia). An excellent bowel preparation is critical for a colonoscopy (2) because it permits the visualization of the entire colonic mucosa and increases the safety of therapeutic maneuvers (3). Two main types of bowel preparations are available including hyperosmotic and iso-osmotic preparations, combined with stimulant laxatives to maximize the bowel-cleansing effect (3).\n\nHyperosmotic formulations include sodium phosphate, sodium sulfate, sodium pico sulfate and magnesium citrate. However, these are usually avoided because of concerns over their safety and their potential to cause fluid and electrolyte problems and renal impairment. PEG-based preparations are iso-osmotic and have a better safety profile, as they are minimally absorbed in the gastrointestinal tract (4). Although they are the preferred agents of choice worldwide, there have been documented case reports of adverse events including seizures, renal impairment, upper gastrointestinal bleeding, cardiac events and death (5, 6). Here, we report a case of a 68-year-old female presenting with generalized tonic–clonic seizures and hyponatremia after administration of a PEG-based preparation for bowel cleansing as per the recommended protocol.\n\nCase presentation\nA 68-year-old lady was admitted to ICU for the management of seizures due to hyponatremia. She had a medical history of breast cancer with a recurrence in 2011 requiring partial right-sided mastectomy, adjuvant radiotherapy and hormone therapy. She also had a history of right-sided nephrectomy, esophageal dysmotility, hypertension, tonsillectomy and a previous episode of colonic bleeding. Her regular medications included irbesartan, hydrochlorothiazide, tamoxifen, rabeprazole, atorvastatin, vitamin D and ezetimibe.\n\nShe had been feeling unwell and nauseous after a couple of hours of commencing bowel cleansing. She took two doses of Pico Prep and one dose of colonlytely (PEG) according to the instructions. She later developed profuse vomiting and had to cancel the colonoscopy due to ongoing nausea, vomiting and malaise. Her symptoms continued for two days during which she had minimal oral intake. She subsequently developed a generalized tonic–clonic seizure culminating in her presentation to the emergency department. Before commencing bowel cleansing, she had been perfectly well and took her prescription medications as usual.\n\nOn arrival, her vital signs were stable with a blood pressure of 150/70 mmHg, pulse rate of 84 beats per min and oxygen saturation of 98% on room air. On physical examination, she appeared confused but had no focal neurological deficits. She had normal skin turgor and moist mucous membranes, with a normal cardio-respiratory and abdominal examination.\n\nInvestigation\nInitial investigations showed severe hyponatremia with a serum Na+ of 106 mmol/L (135–145), mild hypokalemia with K+ of 3.1 mmol/L (3.5–5.5) and a reduced serum osmolality of 224 mosmol/kg (280–300). The urine osmolality was 525 mosmol/kg (50–1200) and the urine Na+ was 74 mmol/L (40–300). She had normal kidney function, and no evidence of thyroid or adrenal insufficiency. Imaging revealed a normal chest X-ray and CT brain.\n\nTreatment\nShe was admitted to intensive care unit for management of severe symptomatic hyponatremia. She was initially treated with 3% normal saline, and the infusion rates were adjusted according to the 2 hourly electrolyte checks with target sodium increments of 1–2 mmol/L/h. The sodium levels increased to 112 mmol/L after 6 h; hence, the hypertonic saline infusion was ceased and she was placed on fluid restriction. Subsequently, the sodium levels gradually increased to 118 mmol/L and 125 mmol/L after 36 and 48 h respectively. Her mental status improved during this time, and she did not have any further seizures. The sodium levels normalized after 5 days and remained stable until discharge. Her antihypertensive medications were ceased during the admission.\n\nOutcome and follow-up\nShe made a full recovery without any permanent neurological damage.\n\nOne-month follow-up showed normal serum sodium levels; however, her blood pressure was elevated, therefore, irbesartan was recommenced.\n\nDiscussion\nHyponatremia is one of the most common electrolyte disorders encountered in clinical practice with a reported incidence of 15–30% (7). Clinical manifestations directly attributable to hyponatremia depend on its duration and severity. They are primarily neurologic and reflect the changes in cerebral hydration in response to changing serum sodium concentration. Symptoms can range from subtle confusion, gait disturbances and attention deficit in chronic cases to seizures coma and obtundation in the acute hyponatremia. It is often multifactorial, and multiple aetiologies can be found in an individual patient, which can sometimes present a diagnostic and management dilemma to the clinicians.\n\nThe general approach for treating patients with hyponatremia depends on the duration and severity of hyponatremia and the presence of symptoms. Patient receiving intravenous fluids for severe hyponatremia should be closely monitored to avoid overzealous correction of sodium, as this can lead to ‘osmotic demyelination syndrome’. It is generally agreed that the correction of sodium should not exceed 1–2 mmol/h and 8 mmol/day on any given day of treatment. The target should not be to normalize serum sodium but to raise it to safe levels (>120 mmol/L) after which conservative measures such as fluid restriction can be deployed (7). Patients with chronic hyponatremia are at even higher risk of osmotic demyelination due to brain adaptation, which can even develop with water restriction alone; hence, sodium correction in these patients should be very slow and gradual.\n\nHyponatremia in our patient was most likely the result of large volume loss and diuretic use combined with physiological non-osmotic ADH response, in an older patient. The sodium increments throughout her treatment remained within the recommended range i.e. 6–8 mmol/L/day, and she did not suffer from any complications of osmotic demyelination.\n\nADH secretion is regulated primarily by changes in osmolarity and tonicity. Other non-osmotic signals such as stress, pain, hypoglycemia, nausea and manipulation of abdominal contents also stimulate ADH secretion (8).\n\nADH release helps reabsorption of water by acting through v2 receptors on the basolateral membrane of distal convoluted tubules and collecting ducts. Binding of ADH to these receptors stimulates the recruitment of selective water channels (aquaporins), which allow reabsorption of renal tubular water and concentration of urine (8).\n\nIn our patient, ADH release was stimulated by two mechanisms, including acute loss of fluid leading to hypovolemia and hyperosmolarity and secondly by ongoing vomiting and nausea.\n\nShe was also taking thiazide diuretics, which further compounded the problem. Thiazides block reabsorption of sodium from the distal tubules and enhance water retention by both ADH-dependent and ADH-independent mechanisms (9). The combination of increased sodium and potassium excretion (due to the diuretic) and enhanced water reabsorption can result in the excretion of urine with a sodium plus potassium concentration higher than that of the plasma. Loss of this fluid can directly promote the development of hyponatremia independent of the degree of water intake (9).\n\nAnother differential diagnosis, in this case, was SIADH, which occurs if ADH secretion is not suppressed when plasma sodium concentration falls below the osmotic threshold for ADH release (8). SIADH can be secondary to a variety of problems, including malignancies, drugs, CNS disturbances, pulmonary disease, and sometimes, it may be multifactorial (8). Bartter and Schwartz criteria for diagnosis of SIADH include a decreased plasma osmolality of less than 275 mosmol/kg, inappropriately concentrated urine (>100 mosmol/kg), a euvolemic state, elevated urine Na (>20 mEq/L), the absence of diuretic use and thyroid or adrenal insufficiency (10). Because of her history of cancers, we ordered an imaging of chest, abdomen and pelvis to look for a paraneoplastic source of ectopic ADH that may have resulted in SIADH. However, we could not find any evidence. Although the urine sodium concentration in this case was above 30 mmol/L, diagnosis of SIADH was excluded due to the use of diuretics.\n\nThere have been previous case reports of hyponatremia, associated with PEG intake, which have resulted in serious adverse events requiring hospitalization (Table 1). Most of the patients were over 60 years of age, and only two were in their 50s. There was a female preponderance; 7 patients were female and only one patient was male. The majority of patients had known risk factors for hyponatremia; one patient (#7) had chronic kidney disease with defective free water clearance. Three patients (#1, #2 and #8) were taking thiazides, which would have impaired water excretion. One patient (#6) was taking SSRIs and had inadequate thyroxine replacement. Patients #4, #5 and #9 did not have prior risk factors, and the most likely mechanism of hyponatremia in these patients was significant volume loss and physiological non-osmolar antidiuretic hormone stimulation. Hyponatremia patient #3 was attributed to newly developed SIADH, resulting from PEG use. All patients had complete recovery except for 1 patient who had dialysis-dependent CKD and died as a result of cardiac arrest (5, 11, 12).\nTable 1 Summary of clinical findings in patients with polyethylene (PEG)-related hyponatremia.\n\n\tReference\t\n\t(11)\t(12)\t(5)\t(5)\t(5)\t(5)\t(5)\t(5)\t(5)\t\nAge in years\t53\t79\t69\t70\t65\t73\t51\t62\t59\t\nGender\tF\tF\tF\tF\tF\tF\tM\tF\tF\t\nPast\tAsthma\tNA\tDiabetes\tHypertension\tBreast cancer\tHypothyroidism\tDiabetes\tDyslipidemia\tHysterectomy\t\n History\tHypertension\t\tDyslipidemia\tICA stenosis\tRI therapy\tDepression\tESRD\tHypertension\tOophorectomy\t\n\tOsteoporosis\t\t\tOsteoporosis\tThyroidectomy\t\t\t\t\t\n\tPsoriatic\t\t\t\t\t\t\t\t\t\n\tArthritis\t\t\t\t\t\t\t\t\t\nMedications\tAtenolol\tThiazides\tAorvastatin\tAmlodipine\tLevothyroxine\tCitalopram\tAmlodipne\tThiazides\tAspirin\t\n\tChlorothalidone\t\tGlimeperide\tCloidogrel\t\tLevothyroxine\tAtenolol\t\tEstradiol\t\n\tDenosumab\t\tMetformin\tIbandronic acid\t\t\tCalcium acetate\t\t\t\n\tIrbesartan\t\tSitagliptin\t\t\t\tFrusemide\t\t\t\n\tKCL\t\t\t\t\t\tOmeprazole\t\t\t\nBowel preparation\tNA\t10 mg bisacodyl and PEG mixed with 120 c.c. gatorade\t4 L PEG\t4 L PEG+ 3 L clear water\t4 L PEG\t255 g PEG and 64 ounces gatorade\tNA\t4 L PEG\t3 L PEG and 4 L weak tea\t\nClinical presentation\tFatigue\tConfusion\tHeadache\tSeizure\tSeizure\tSeizure\tCardiac arrest\tSeizure\tConfusion\t\n\tNausea\tMuscle twitching\tNausea\t\t\t\tIdioventricular rhythm\t\t\t\n\tSeizures\tNausea\tSeizures\t\t\t\tVomiting\t\t\t\n\tVertigo\tVomiting\tWeakness\t\t\t\t\t\t\t\n\tVomiting\tDiarrhoea\t\t\t\t\t\t\t\t\nBlood pressure (mm/Hg)\t150/86\tNA\t143/74\t190/100\t156/85\tNormal\t167/78\t130/90\t110/70\t\nPulse (/min)\t79\tNA\t76\t84\t86\tNA\t103\t90\t60\t\nSodium (mmo/L)\t\t\t\t\t\t\t\t\t\t\nBase line\tNA\tNA\t113\t140\t144\tNA\t138\t138\tNA\t\nOn admission\t115\t118\tNA\t110\t127\t117\t122\t116\t120\t\nOn discharge\tNA\t133\t135\t138\t141\t130\tNA\t131\t138\t\nPotassium (mmol/L)\t2.5\tNA\t3.4\t3.4\t4.3\t3.3\t5.1\t3.9\t4.6\t\nChloride (mmol)\tNA\tNA\t72\t72\t104\t79\t94\t79\t\t\nBicarbonate (mmol/L)\tNA\tNA\t17.3\t17.3\t20\t21\t20\t26\t17.2\t\nUrea (mg/dL)\tNA\tNA\t11.8\t11.8\t14.6\t6\t24.3\t2.5\tNA\t\nCreatinine (mg/dL)\tNA\tNA\t0.67\t0.67\t0.71\t0.6\t7.7\tNA\tNA\t\nGlucose (mg/dL)\tNA\tNA\t148\t148\t235\tNA\t95.5\tNA\t93\t\nCTB/MRIB\tCerebral edema\tNormal\tSmall vessel disease and tiny restriction focus in temporal lobe\tNormal\tNormal\tNA\tNA\tCerebral edema\tNormal\t\nOutcome\tComplete recovery\tComplete recovery\tComplete recovery\tComplete recovery\tComplete recovery\tComplete recovery\tDeath\tComplete recovery\tComplete recovery\t\nF: Female, M: Male, NA: Not available, ICA: Internal Carotid Artery, ESRD: End-stage renal disease, RI: Radioactive Iodine, KCL: Potassium chloride, PEG: Polyethylene Glycol.\n\n\n\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nA written informed consent has been obtained from the patient for publication of the submitted article.\n\nAuthor contribution statement\nNavira Samad (70%): Literature review and drafting of the paper; read and approved the final version of the paper to be published. Ian Fraser (30%): Critical review and editing of the manuscript for intellectual content; read and approved the final version of the paper to be published.\n==== Refs\nReferences\n1 Cancer Council Australia Colonoscopy Surveillance Working Party \n2011 \nClinical Practice Guidelines for Surveillance Colonoscopy – in adenoma follow-up; following curative resection of colorectal cancer; and for cancer surveillance in inflammatory bowel disease. Sydney: Cancer Council Australia; (cited 2016 Oct) . (Available from: https://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/exbib8_colonoscopy_guideline_120314.pdf)\n2 Rex DK Petrini JL Baron TH Chak A Cohen J Deal SE Hoffman B Jacobson BC Mergener K Petersen BT \n2015 \nQuality indicators for colonoscopy . Gastrointestinal Endoscopy \n81 \n31 –53 . (10.1016/j.gie.2014.07.058 )25480100 \n3 Zauber AG Winawer SJ O’Brien MJ Lansdorp-Vogelaar I van Ballegooijen M Hankey BF Shi W Bond JH Schapiro M Panish JF \n2012 \nColonoscopic polypectomy and long-term prevention of colorectal-cancer deaths . New England Journal of Medicine \n366 \n687 –696 . (10.1056/NEJMoa1100370 )22356322 \n4 Moon W \n2013 \nOptimal and safe bowel preparation for colonoscopy . Clinical Endoscopy \n46 \n219 –223 . (10.5946/ce.2013.46.3.219 )23767029 \n5 Ko SH Lim CH Kim JY Kang SH Baeg MK Oh HJ \n2014 \nCase of inappropriate ADH syndrome: hyponatremia due to polyethylene glycol bowel preparation . World Journal of Gastroenterology \n20 \n12350 –12354 . (10.3748/wjg.v20.i34.12350 )25232272 \n6 Hasan AG Brown WR \n2011 \nColonic cleansing for colonoscopy: a risk to be taken seriously . Gastrointestinal Endoscopy \n73 \n616 –618 . (10.1016/j.gie.2010.11.050 )21353860 \n7 Biswas M Davies JS \n2007 \nHyponatraemia in clinical practice . Postgraduate Medical Journal \n83 \n373 –378 . (10.1136/pgmj.2006.056515 )17551067 \n8 Hannon MJ Thompson CJ \n2016 \nEndocrinology: Adult and Pediatric; Cellular Action of Vasopressin , 7th ed., Vol. 1 N.P.: Saunders .\n9 Cesar KR Magaldi AJ \n1999 \nThiazide induces water absorption in the inner medullary collecting duct of normal and Brattleboro rats . American Journal of Physiology \n277 \nF756 –F760 .10564239 \n10 Bartter FC Schwartz WB \n1967 \nThe syndrome of inappropriate secretion of antidiuretic hormone . American Journal of Medicine \n42 \n790 –806 . (10.1016/0002-9343(67)90096-4 )5337379 \n11 Brousseau SB \n2015 \nSeizure associated with hyponatremia possibly related to the use of polyethylene glycol and electrolytes preparation . Journal of Clinical Toxicology \n229 .\n12 Pazderka P Hollensteiner C \n2015 \nSevere Hyponatremic Encephalopathy Following Bowel Prep for Colonoscopy . Emergency Physicians.\n\n",
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"pubdate": "2017",
"publication_types": "D016428:Journal Article",
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"title": "Severe symptomatic hyponatremia associated with the use of polyethylene glycol-based bowel preparation.",
"title_normalized": "severe symptomatic hyponatremia associated with the use of polyethylene glycol based bowel preparation"
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"abstract": "Ongoing development of new drugs, as well as novel indications in the treatment of autoimmune diseases leads to the increasing use of immunomodulatory and immunosuppressive drugs. Immunomodulatory agent-related lymphoproliferative disorders are a known and potentially life threatening complication of chronic administration of these drugs, but are less well characterized compared with post-transplant lymphoproliferative disorders. The heterogeneous drug targets, various underlying disease indications, different drug combinations used and relatively low incidence render data collection and interpretation difficult. In this retrospective paper, we describe the clinicopathological characteristics of a larger single-center series of 72 immunomodulatory agent-related lymphoproliferative disorder cases. We divided the cases according to the therapy, administered in the year preceding diagnosis of a lymphoproliferative disorder, in an immunosuppressive drug, an immunomodulatory drug and a combination of immunosuppressive and immunomodulatory drugs group. We observed differences in \"time to lymphoproliferative disorder development\" with a shorter time for all the immunomodulatory drug-related cases combined (immunomodulatory and immunomodulatory + immunosuppressive = immunomodulatory-all) vs immunosuppressive-only (p = 0.0031). The proportion of malignant cases in patients receiving immunomodulatory therapy was, however, also significantly lower when compared with the immunosuppressive treated cases (43 vs 88%; p = 0.0184). The immunomodulatory/suppressive agent-related lymphoproliferative disorders were less often associated with the Epstein-Barr virus (EBV) (31 vs 66%; p = 1.829e-05) and the lymphoproliferative disorders incidence in the first year after immunomodulatory/immunosuppressive therapy initiation was lower (18 vs 41%; p = 0.04151)-compared with a published series of 140 post-transplant lymphoproliferative disorder cases from the same center. However, a similar histopathological spectrum from nondestructive, to polymorphic and monomorphic lesions as in post-transplant lymphoproliferative disorders is observed. With increasing use of immunosuppressive and especially immunomodulatory therapy, a higher incidence of immunomodulatory/suppressive agent-related lymphoproliferative disorders is to be expected. Life-long awareness for development of immunomodulatory/suppressive agent-related lymphoproliferative disorders with clinical follow-up and timely biopsies of suspicious lesions is required since these lymphoproliferative disorders arise both early after therapy initiation and many years later. Histopathological confirmation and correct classification is necessary to guide therapy and EBV ISH should be a part of routine pathological diagnostics.",
"affiliations": "Department of Imaging and Pathology, Translational Cell and Tissue Research Lab, KU Leuven, Leuven, Belgium.;Department of Radiation Oncology, UZ Leuven, University Hospitals, Leuven, Belgium.;Department of Imaging and Pathology, Translational Cell and Tissue Research Lab, KU Leuven, Leuven, Belgium.;Department of Imaging and Pathology, Translational Cell and Tissue Research Lab, KU Leuven, Leuven, Belgium.;Department of Hematology, UZ Leuven, University Hospitals, Leuven, Belgium.;Department of Hematology, UZ Leuven, University Hospitals, Leuven, Belgium.;Department of Nuclear Medicine, UZ Leuven, University Hospitals, Leuven, Belgium.;Department of Imaging and Pathology, Translational Cell and Tissue Research Lab, KU Leuven, Leuven, Belgium.;Department of Hematology, UZ Leuven, University Hospitals, Leuven, Belgium.;Department of Imaging and Pathology, Translational Cell and Tissue Research Lab, KU Leuven, Leuven, Belgium. thomas.tousseyn@uzleuven.be.",
"authors": "Marcelis|Lukas|L|;Berghen|Charlien|C|;De Zutter|Alexandra|A|;Biesemans|Pauline|P|;Vandenberghe|Peter|P|;Verhoef|Gregor|G|;Gheysens|Olivier|O|;Sagaert|Xavier|X|;Dierickx|Daan|D|;Tousseyn|Thomas|T|",
"chemical_list": "D007166:Immunosuppressive Agents",
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"doi": "10.1038/s41379-018-0054-2",
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"issue": "31(9)",
"journal": "Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc",
"keywords": null,
"medline_ta": "Mod Pathol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D055815:Young Adult",
"nlm_unique_id": "8806605",
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"pages": "1457-1469",
"pmc": null,
"pmid": "29765143",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Other immunomodulatory agent-related lymphoproliferative diseases: a single-center series of 72 biopsy-confirmed cases.",
"title_normalized": "other immunomodulatory agent related lymphoproliferative diseases a single center series of 72 biopsy confirmed cases"
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"companynumb": "BE-ROCHE-2208432",
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"abstract": "Background: Hypothyroidism can lead to bradycardia, reduced cardiac output, cardiac enlargement, and abnormal electrocardiogram. However, hemodynamic instability and malignant arrhythmias due to hypothyroidism is rarely reported in children. Patient Findings: We report the case of a child with third-degree atrioventricular block, cardiogenic shock, and Adams Stokes Syndrome, who was initially misdiagnosed with fulminant myocarditis and was later found to have hypothyroidism during treatment. Summary: The child's condition did not improve after the administration of gamma globulin, methylprednisolone, and isoproterenol. Even after the placement of temporary pacemakers, the therapeutic effect was still not ideal. Upon reviewing the medical history, the child's condition improved rapidly after levothyroxine supplementation. Conclusions: Hypothyroidism is a common disease, but secondary severe cardiovascular lesions are particularly rare in children. Therefore, the delay in diagnosis can lead to serious cardiovascular manifestations. When pediatric patients develop severe AVB and bradycardia, hypothyroidism should be considered as a possible cause.",
"affiliations": "Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China.",
"authors": "Zhang|Nanjun|N|;Shao|Shuran|S|;Yan|Yu|Y|;Hua|Yimin|Y|;Zhou|Kaiyu|K|;Wang|Chuan|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fcvm.2021.698089",
"fulltext": "\n==== Front\nFront Cardiovasc Med\nFront Cardiovasc Med\nFront. Cardiovasc. Med.\nFrontiers in Cardiovascular Medicine\n2297-055X\nFrontiers Media S.A.\n\n10.3389/fcvm.2021.698089\nCardiovascular Medicine\nCase Report\nCase Report: Hypothyroidism Misdiagnosed as Fulminant Myocarditis in a Child\nZhang Nanjun 12†\n\nShao Shuran 12†\nYan Yu 12\nHua Yimin 1345\nZhou Kaiyu 1345*\n\nWang Chuan 1345*\n\n1Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China\n2West China Medical School of Sichuan University, Chengdu, China\n3The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China\n4Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China\n5Key Laboratory of Development and Diseases of Women and Children of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China\nEdited by: Juan Pablo Kaski, University College London, United Kingdom\n\nReviewed by: Silvia Passantino, Meyer Children's Hospital, Italy; Giulia Tuo, Giannina Gaslini Institute (IRCCS), Italy\n\n*Correspondence: Kaiyu Zhou kaiyuzhou313@163.com\nChuan Wang 805101396@qq.com\nThis article was submitted to Pediatric Cardiology, a section of the journal Frontiers in Cardiovascular Medicine\n\n†These authors have contributed equally to this work\n\n11 6 2021\n2021\n8 69808921 4 2021\n12 5 2021\nCopyright © 2021 Zhang, Shao, Yan, Hua, Zhou and Wang.\n2021\nZhang, Shao, Yan, Hua, Zhou and Wang\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.\nBackground: Hypothyroidism can lead to bradycardia, reduced cardiac output, cardiac enlargement, and abnormal electrocardiogram. However, hemodynamic instability and malignant arrhythmias due to hypothyroidism is rarely reported in children.\n\nPatient Findings: We report the case of a child with third-degree atrioventricular block, cardiogenic shock, and Adams Stokes Syndrome, who was initially misdiagnosed with fulminant myocarditis and was later found to have hypothyroidism during treatment.\n\nSummary: The child's condition did not improve after the administration of gamma globulin, methylprednisolone, and isoproterenol. Even after the placement of temporary pacemakers, the therapeutic effect was still not ideal. Upon reviewing the medical history, the child's condition improved rapidly after levothyroxine supplementation.\n\nConclusions: Hypothyroidism is a common disease, but secondary severe cardiovascular lesions are particularly rare in children. Therefore, the delay in diagnosis can lead to serious cardiovascular manifestations. When pediatric patients develop severe AVB and bradycardia, hypothyroidism should be considered as a possible cause.\n\nchildren\nhypothyroidism\natrioventricular block\nfulminant myocarditis\ncardiogenic shock\n==== Body\nBackground\n\nThyroid hormone (TH) is the basic hormone that maintains the functional activity of the body, regulates metabolism and growth in many ways, and affects the function of almost all organs and systems to varying degrees. In cardiovascular terms, hypothyroidism often leads to bradycardia; in severe cases, it could lead to dull heart sound, decreased cardiac output, cardiac enlargement, and abnormal electrocardiogram (ECG). In recent years, some authors have reported cases of advanced atrioventricular block (AVB) caused by hypothyroidism in adults, which improved after the administration of TH (1–5). However, hemodynamic instability and malignant arrhythmias caused by hypothyroidism, which develop into cardiogenic shock and Adams Stokes Syndrome, are rarely reported in children.\n\nFulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation, often leading to death from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure (6). The diagnosis of FM always needs to exclude other diseases such as congenital coronary artery anomalies, cardiomyopathy, rheumatic heart disease, and congenital AVB, since they may share manifestations. However, congenital hypothyroidism is often overlooked as a differential diagnosis for FM in the clinic; the presence of third-degree AVB, cardiogenic shock, and Adams Stokes Syndrome have rarely been observed in patients with congenital hypothyroidism.\n\nWe report for the first time in the Chinese population a child with third-degree AVB, cardiogenic shock, and Adams Stokes Syndrome, who was initially misdiagnosed with FM and was later found to have hypothyroidism during treatment. This case report will improve the understanding of the serious cardiovascular complications caused by hypothyroidism. In addition, we suggest that hypothyroidism should be considered as a differential diagnosis of FM.\n\nMain Text\n\nCase Report\n\nA 6-year-old boy was urgently admitted to local hospital for frequent convulsions with loss of consciousness, and he had no symptoms prior to the onset (fever, shortness of breath, cough, headache, etc.). The initial ECG showed a third-degree AVB. Transthoracic echocardiography showed an enlarged left ventricle, mild mitral, tricuspid regurgitation, and normal left ventricular systolic function with an ejection fraction (EF) of 58% and a fractional shortening (FS) of 33%. He was primarily diagnosed with FM and was treated promptly with intravenous methylprednisolone (10 mg/Kg per day) and isoproterenol (0.05 ug/Kg/min). Unfortunately, the patient developed persistent abdominal pain, accompanied by vomiting during treatment, followed by sudden respiratory and cardiac arrest. After successful cardiopulmonary resuscitation, the child's heart rate fluctuated between 40 and 60 beats/min, and he was immediately transferred to our hospital.\n\nThe patient was conscious upon arrival to the emergency department in our hospital. Physical examination showed a heart rate of 47 beats/min, respiratory of 23 beats/min, blood pressure of 82/37 mmHg, and temperature of 36.5°C, SpO2 of 95%. His face was pale, a dull heart sound and third-degree systolic bruits in the fourth intercostal space could be heard, and abdomen was distent. The ECG showed a third-degree AVB with a minimum heart rate of 75 beats/min (on isoproterenol therapy) (Figures 1A,B). Echocardiography excluded other abnormalities (such as coronary artery disease, congenital heart disease, and cardiomyopathy) showing normal size of ventricle and atrium, normal left ventricular systolic function with an ejection fraction (EF) of 57% and a fractional shortening (FS) of 30%. A chest radiograph showed mild pulmonary edema, enlarged heart shadow, heart-to-chest ratio of 0.57, and intestinal dilatation with gas accumulation (Figures 1C,D). Laboratory findings showed myocardial injury with elevated N-terminal brain natiruretic peptide (NT-BNP) of 13,100 pg/mL (normal range 0–100 pg/mL) and cardiac troponin I (cTnI) of 0.748 μg/L (normal range 0–0.034 μg/L). Fasting blood glucose (22.30 mmol/L, normal range 4.1–5.9 mmol/L) increased significantly. Kidney and liver enzymes also slightly increased (AST 83 U/L, ALT 60 U/L and creatinine 61 μmol/L, normal range, respectively, were 17–59 U/L,21–72 U/L,17.3–54.6 umol/L). The arterial blood gas, Complete blood count, erythrocyte sedimentation rate, rheumatism screening, and autoantibody are normal. Based on our experience, we initially considered that these conditions were chiefly caused by FM. The patient was rapidly treated with intravenous methylprednisolone (20 mg/kg per day), immunoglobulin (500 mg/kg per day), and isoproterenol (0.2 ug/kg/min). Unfortunately, bradycardia persisted after 2 days of treatment. Finally, a temporary pacemaker was inserted with a ventricular rate of 80 beats/min.\n\nFigure 1 The ECG and chest radiograph of the patient before thyroxine supplementation (A–D). Follow-up with cardiologist and endocrinologist for repeat ECG in 4 weeks (E,F).\n\nAfter the operation, we reviewed the past medical history of the patient and found that he was diagnosed with hypothyroidism at the age of 3 years. He was treated with levothyroxine (50 ug/d) but he had not been regularly followed up by an endocrinologist and he had withdrawn hormone supplementation before hospital admission. His mental development, motor development, and language development lagged significantly behind those of children of his age. His thyroid stimulating hormone (TSH) level increased (>150 mIU/L), and free thyroxine (FT4) levels decreased (1.50 pmol/L) significantly. Therefore, we wondered whether hypothyroidism could lead to a third-degree AVB and cardiogenic shock. We reviewed the relevant literature and found similar reports in adults (1–5). However, there was no such case reported in children. After careful consideration, on the second day, we administered a supplement of oral levothyroxine (50 μgd−1) for observation, and stopped using methylprednisolone, immunoglobulin, and isoproterenol. Surprisingly, the patient recovered well-beyond expectations. His ECG on the Holter monitor showed a sinus rhythm of 81 beats/min and the AVB disappeared on the third day from disease onset, and echocardiography revealed normal and elevated EF (66%) and FS (35%), left ventricular end diastolic diameter of 34 mm. Laboratory findings showed reduced myocardial injury markers with NT-BNP (5,870 pg/mL) and cTnI (0.135 μg/L). Clinical findings were significantly improving. As a result, we reconsidered possible causes for these conditions in the patient. Eventually, we concluded that hypothyroidism, but not FM, was the real cause of the AVB and cardiogenic shock. On the eighth day of admission, the patient was discharged on levothyroxine 50 μg daily and was advised to follow-up with cardiologist and endocrinologist for repeat thyroid function testing and ECG in 4 weeks (Figures 1E,F). During follow-up, the child's cardiac function and thyroid function returned to normal.\n\nDiscussion\n\nIn this case report, we comprehensively discuss regarding a child with severe hypothyroidism who was misdiagnosed as having FM and whose sinus rhythm was successfully recovered after temporary pacemaker implantation and oral levothyroxine hormone supplementation. Based on our experience, we considered that the reasons for the misdiagnosis of FM were as follows: (1) The onset of the disease was sudden and the disease progressed rapidly; (2) the patient had frequent convulsions as the first symptom, followed by respiratory and cardiac arrest at another hospital; and (3) the patient developed hemodynamic instability, dull heart sounds, and bradycardia. The ECG showed a third-degree AVB, and abnormalities of other cardiac diseases were excluded by echocardiography (such as coronary artery disease, congenital heart disease, cardiomyopathy, and connective tissue diseases). However, given the ineffectiveness of intravenous methylprednisolone and immunoglobulin treatment for FM, rapid relief of the symptoms after thyroxine supplementation, slightly elevated cTnI and normal left ventricular systolic function at admission, we considered that hypothyroidism, but not FM, was the underlying cause of the AVB and cardiogenic shock. To our knowledge, this is the first case report in China of a child with a third-degree AVB and cardiogenic shock caused by hypothyroidism. This case report will improve clinician's understanding of the serious cardiovascular complications caused by hypothyroidism. In addition, we suggest that hypothyroidism should be considered as a differential diagnosis of FM.\n\nThe effects of hypothyroidism on the cardiovascular system mainly include decreased cardiac output, decreased myocardial contractility, decreased heart rate, and increased peripheral resistance (7). TH can directly promote the release of Ca2+ from the sarcoplasmic reticulum and activate proteins related to myocardial contraction and enhance the activity of myosin heavy chain adenosine triphosphate enzyme, thus enhancing myocardial contractility. However, TH can also increase the number and affinity of β-adrenergic receptors on the information cell membrane and improve the sensitivity of the myocardium to catecholamines. If TH synthesis is insufficient, it will lead to abnormal cardiac systolic function and cardiac electrical activity. Therefore, hypothyroidism could lead to bradycardia, dull heart sounds, reduced cardiac output, cardiac enlargement, and abnormal ECG. Although hypothyroidism could affect the cardiovascular system of patients, the symptoms and signs of cardiovascular dysfunction are not common or prominent. As a result, we did not initially consider hypothyroidism as a causative agent.\n\nWe conducted a literature review and found that there are few reported cases of cardiogenic shock and malignant arrhythmia caused by hypothyroidism, resulting in difficulties in the early identification and diagnosis. Previous reports of AVB caused by hypothyroidism have mainly been reported in adults (1–5), but rarely in children (8). Zaki (9) et al. reported a case of refractory cardiogenic shock in an infant with congenital hypothyroidism. The reasons for the rarity in children may be as follows: (1) congenital hypothyroidism can lead to developmental delay and growth disorder in children, which enables many children to receive intervention and treatment at an early stage before cardiac manifestations occur and (2) although short-term or long-term hypothyroidism does affect cardiac function, which results in cardiac dysfunction, it is not commonly seen in clinical practice and has not attracted enough attention.\n\nAlthough there were few cases of cardiogenic shock and malignant arrhythmias caused by hypothyroidism seen in our literature review, we found that timely thyroxine supplementation in the early stage of the disease can significantly improve the prognosis of adults in the short term. In view of our experience and this information, we reported this case in order to raise the awareness of our colleagues regarding this rare phenomenon. When we diagnose FM in children, in addition to excluding other diseases, we should rule out metabolic causes such as hypothyroidism, thereby avoiding delays in the diagnosis and leading to prompt treatment.\n\nConclusions\n\nHypothyroidism is a common disease in clinical practice, but secondary cardiovascular lesions are rare. The delay in diagnosis is quite serious because of the low awareness and recognition of the situation. This will continue to be challenging in the future, especially in developing countries. Based on comprehensive history collection, when patients develop severe AVB and bradycardia, we need to consider hypothyroidism as a possible causative factor. To our knowledge, our case is the first report in the Chinese population of hypothyroidism in a child misdiagnosed with FM. We hope that our findings benefit other pediatricians when managing patients with cardiogenic shock and AVB.\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 authors.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s), and 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\nNZ and SS drafted the manuscript, contributed to the case collection, provided Figures 1A–D, and approved the final manuscript as submitted. YY contributed to the study design and approved the final manuscript as submitted. YH provided Figures 1E,F, funding support, and approved the final manuscript as submitted. KZ and CW provided major treatment on the patient while admitted, provided financial support, and approved the final manuscript as submitted. All authors contributed to the article and approved the submitted version.\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\nAbbreviations\n\nAVB atrioventricular block\n\ncTnI cardiac troponin I\n\nECG electrocardiogram\n\nEF, ejection fraction;FM fulminant myocarditis\n\nFS fractional shortening\n\nFT4 free thyroxine\n\nMb myohemoglobin\n\nNT-BNP N-terminal brain natiruretic peptide\n\nTSH thyroid stimulating hormone.\n\nFunding. This work was supported by the National Key R&D Program of China (No. 2018YFC1002301), National Natural Science Foundation of China (Nos. 81800288 and 81971457), and Science-technology Support Plan Projects in Sichuan province (Nos. 2017SZ0117 and 2020YFS0101).\n==== Refs\nReferences\n\n1. Waseem H Hashmi AT Anser M Wali N Rodriguez D Greenberg Y . A pacemaker that was avoided. Cureus. (2018) 10 :e2555. 10.7759/cureus.2555 29974011\n2. Seol SH Kim DI Park BM Kim DK Song PS Kim KH . Complete atrioventricular block presenting with syncope caused by severe hypothyroidism. Cardiol Res. (2012) 3 :239–41. 10.4021/cr221w 28348695\n3. Schoenmakers N de Graaff WE Peters RH . Hypothyroidism as the cause of atrioventricular block in an elderly patient. Neth Heart J. (2008) 16 :57–9. 10.1007/BF03086119 18335023\n4. Nakayama Y Ohno M Yonemura S Uozumi H Kobayakawa N Fukushima K . A case of transient 2:1 atrioventricular block, resolved by thyroxine supplementation for subclinical hypothyroidism. Pacing Clin Electrophysiol. (2006) 29 :106–8. 10.1111/j.1540-8159.2006.00284.x 16441726\n5. Singh JB Starobin OE Guerrant RL Manders EK . Reversible atrioventricular block in myxedema. Chest. (1973) 63 :582–5. 10.1378/chest.63.4.582 4695358\n6. Kociol RD Cooper LT Fang JC Moslehi JJ Pang PS Sabe MA . Recognition and initial management of fulminant myocarditis: a scientific statement from the American heart association. Circulation. (2020) 141 :e69–92. 10.1161/CIR.0000000000000745 31902242\n7. Klein I Ojamaa K . Thyroid hormone and the cardiovascular system. N Engl J Med. (2001) 344 :501–9. 10.1056/NEJM200102153440707 11172193\n8. Olguntürk R Tunaoglu FS Oguz D Cinaz P Bideci A . Complete atrioventricular heart block in congenital hypothyroidism. Turk J Pediatr. (1998) 40 :431–5.9763909\n9. Zaki SA Dolas A . Refractory cardiogenic shock in an infant with congenital hypothyroidism. Indian J Crit Care Med. (2012) 16 :151–3. 10.4103/0972-5229.102086 23188956\n\n",
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"journal": "Frontiers in cardiovascular medicine",
"keywords": "atrioventricular block; cardiogenic shock; children; fulminant myocarditis; hypothyroidism",
"medline_ta": "Front Cardiovasc Med",
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"pages": "698089",
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"references": "4695358;29974011;16441726;31902242;11172193;28348695;18335023;9763909;23188956",
"title": "Case Report: Hypothyroidism Misdiagnosed as Fulminant Myocarditis in a Child.",
"title_normalized": "case report hypothyroidism misdiagnosed as fulminant myocarditis in a child"
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"abstract": "A 55-year-old patient with mant e cels underwent a cytotoxic chemotherapy (D.H.A.P. + Rituximab). During the medullar aplasia related to the third cycle, diarrhoea due to Clostridium difficile arised and relapsed 15 days later despite normal blood counts. This colitis was very severe with pluribacterial peritonitis, but resolved with intensive medical treatment. The incidence, the patient's risk factors, the iatrogenic and nosocomial characters of cl. difficile colitis are discussed.",
"affiliations": "CHRH Huy, Belgique.",
"authors": "Laret|V|V|;Sion|C|C|;Bataille|C|C|;Hustinx|R|R|;Reginster|M|M|",
"chemical_list": "D000900:Anti-Bacterial Agents",
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"issue": "61(11)",
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"medline_ta": "Rev Med Liege",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016360:Clostridioides difficile; D004761:Enterocolitis, Pseudomembranous; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D010538:Peritonitis",
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"title": "Clinical case of the month: clostridium difficile colitis.",
"title_normalized": "clinical case of the month clostridium difficile colitis"
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"abstract": "Methods that enable monitoring of therapeutic efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy will be clinically useful. The aim of this study is to demonstrate the feasibility of blood-derived cell-free DNA (cfDNA) to predict CAR T-cell therapy response in patients with refractory B-cell lymphomas. Whole blood was collected before and throughout CAR T-cell therapy until day 154. Low-coverage (∼0.4×), genome-wide cfDNA sequencing, similar to that established for noninvasive prenatal testing, was performed. The genomic instability number (GIN) was used to quantify plasma copy number alteration level. Twelve patients were enrolled. Seven (58%) patients achieved a complete response (CR); 2 (25%), a partial response. Median progression-free survival was 99 days; median overall survival was not reached (median follow-up, 247 days). Altogether, 127 blood samples were analyzed (median, 10 samples/patient [range 8-13]). All 5 patients who remained in CR at the time of last measurement had GIN <170 (threshold). Two patients who attained CR, but later relapsed, and all but one patient who had best response other than CR had last GIN measurement of >170. In 5 of 6 patients with relapsed or progressive disease, increasing GIN was observed before the diagnosis by imaging. The abundance of CAR T-cell construct (absolute number of construct copies relative to the number of human genome equivalents) also showed a trend to correlate with outcome (day 10, P = .052). These data describe a proof-of-concept for the use of multiple liquid biopsy technologies to monitor therapeutic response in B-cell lymphoma patients receiving CAR T-cell therapy.",
"affiliations": "Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego, La Jolla, California. Electronic address: a1goodman@health.ucsd.edu.;Laboratory Corporation of America, San Diego, California.;Department of Medicine, Division of Hematology/Oncology, University of California San Diego, La Jolla, California.;Laboratory Corporation of America, San Diego, California.;Laboratory Corporation of America, San Diego, California.;Laboratory Corporation of America, San Diego, California.;Laboratory Corporation of America, San Diego, California.;Laboratory Corporation of America, Burlington, North Carolina.;Department of Radiology, University of California San Diego, La Jolla, California.;Department of Radiology, University of California San Diego, La Jolla, California.;Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego, La Jolla, California.;Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego, La Jolla, California.;Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego, La Jolla, California.;Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego, La Jolla, California.;Laboratory Corporation of America, San Diego, California; Laboratory Corporation of America, Durham, North Carolina.;WIN Consortium for Precision Medicine, Villejuif, France.",
"authors": "Goodman|Aaron M|AM|;Holden|Kimberly A|KA|;Jeong|Ah-Reum|AR|;Kim|Lisa|L|;Fitzgerald|Kerry D|KD|;Almasri|Eyad|E|;McLennan|Graham|G|;Eisenberg|Marcia|M|;Jahromi|Amin H|AH|;Hoh|Carl|C|;Hurley|Michael|M|;Mulroney|Carolyn|C|;Tzachanis|Dimitrios|D|;Ball|Edward D|ED|;Jensen|Taylor J|TJ|;Kurzrock|Razelle|R|",
"chemical_list": null,
"country": "United States",
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"keywords": "CAR T-cell therapy; Cell-free DNA; Cellular therapy; Tumor marker",
"medline_ta": "Transplant Cell Ther",
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"pmid": "34655803",
"pubdate": "2021-10-13",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Assessing CAR T-Cell Therapy Response Using Genome-Wide Sequencing of Cell-Free DNA in Patients With B-Cell Lymphomas.",
"title_normalized": "assessing car t cell therapy response using genome wide sequencing of cell free dna in patients with b cell lymphomas"
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"abstract": "In the past 6 years, 11 children on valproic acid have developed pancreatitis in our children's hospital. Valproic acid has been used as one of the primary anticonvulsants for generalized seizures in children for the past 25 years. A literature review reveals mostly singular reports of pancreatitis over the past decade. The charts of the 11 patients with valproic acid-induced pancreatitis were reviewed. Dosage, valproic acid serum levels, duration of therapy, and concomitant medications were examined. Families were contacted by telephone to determine the formulation (brand name vs generic) of valproic acid at the time of diagnosis. Six girls and five boys were studied. The ages ranged from 4 to 16 years. Eight of 11 children presented with an acute abdomen. Unexpectedly, three children presented with a flulike illness. Serum lipase values ranged from 341 to 5576 U/L (normal range < 190 U/L). The dose of valproic acid ranged from 20 to 50 mg/kg. Serum levels ranged from 334 to 884 micromol/L (therapeutic range 350-800 micromol/L). Six of the patients were on monotherapy. Seven children were on brand-name drugs. Four of the children had an abnormal neurologic syndromic diagnosis (West syndrome, Rett syndrome, Lowe syndrome, and Angelman's syndrome). Six of the children had a history of drug allergies with a skin rash. Valproic acid was reintroduced in one child and resulted in a second episode of pancreatitis. Resolution of symptoms usually took several weeks following discontinuation of the drug. No association was found with valproic acid dosage, type of preparation, serum levels, duration of therapy, or presence of concomitant medications. Pancreatitis is a severe adverse effect of valproic acid use in children. Dose, duration of treatment, serum valproic acid levels, generic preparation, and the presence of concomitant antiepileptic drugs do not appear to be risk factors. Children with known drug sensitivity might be at risk. Lipase levels at the time of an acute abdomen or a flulike illness in epileptic children taking valproic acid can reveal early stages of pancreatitis and are recommended.",
"affiliations": "Division of Pediatric Neurology, 2C3 Walter MacKenzie Health Sciences Centre, University of Alberta, Edmonton, AB T6G 2R7, Canada. bsinclai@cha.ab.ca",
"authors": "Sinclair|D Barry|DB|;Berg|Marjorie|M|;Breault|Rene|R|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid; D008049:Lipase",
"country": "United States",
"delete": false,
"doi": "10.1177/08830738040190070401",
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"issn_linking": "0883-0738",
"issue": "19(7)",
"journal": "Journal of child neurology",
"keywords": null,
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004827:Epilepsy; D005260:Female; D006801:Humans; D007251:Influenza, Human; D008049:Lipase; D008297:Male; D010195:Pancreatitis; D012189:Retrospective Studies; D013577:Syndrome; D014635:Valproic Acid",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "498-502",
"pmc": null,
"pmid": "15526953",
"pubdate": "2004-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Valproic acid-induced pancreatitis in childhood epilepsy: case series and review.",
"title_normalized": "valproic acid induced pancreatitis in childhood epilepsy case series and review"
} | [
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"companynumb": "CA-VISTAPHARM, INC.-VER201802-000432",
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"activesubstance": {
"activesubstancename": "VALPROIC ACID"
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"abstract": "BACKGROUND\nImmune thrombocytopenia (ITP) is a benign hematological disorder characterized by low platelet counts in peripheral blood and spectrum of various bleeding manifestations. Azathioprine is one of the effective, readily available, and affordable immunosupressants available for ITP management in developing countries. We aimed to study the efficacy and long-term safety profile of our patients with ITP who were treated with azathioprine.\n\n\nMETHODS\nThis was a retrospective, single-center study conducted at a tertiary care hospital in Northern India. The patients who had received at least one line of therapy before receiving azathioprine were included in this study. All patients received oral azathioprine at a dose of 1 mg/kg/day (50 mg or 100 mg tablet formulations were used), which was increased up to 2 mg/kg/day depending upon the response and adverse effects.\n\n\nRESULTS\nSixty-three patients were analyzed. Their median age was 28 years (range 15-68); 29/63 patients (46.03%) were females. The median duration from diagnosis to azathioprine initiation was 539 days (323 days-980.5 days). The patients included in the study had received a median of 3 (range 1-6) prior lines of therapies; 38/63 patients (60.32%) had received ≥3 prior therapies. Six patients (9.5%) had relapsed after splenectomy, and 16 patients (25.4%) had relapsed after receiving rituximab. The mean baseline platelet count was 10000/μL. The median time to response was 95 days (90 days-not reached) and the cumulative overall response rate (complete and partial response) at day 90 was 38.1%. Only one patient achieved complete response with azathioprine in our study. The cumulative rate of relapse at five years was 21.2%. Twenty-six patients stopped azathioprine after achieving some response (CR/PR) with Azathioprine for a median duration of 1067.5 days (range: 236 days-2465 days). They were followed up for a median of 870 days (range: 392 days-1928 days), and twelve of them relapsed. Twenty-six patients (26/63, 41.27%) reported one or more adverse events while on azathioprine. Leucopenia was the most frequent adverse event, followed by anemia and hepatobiliary laboratory abnormalities. Serious adverse events (grade ≥3 CTCAEv4) were noted in three patients (4.7%). One patient succumbed to severe sepsis multiorgan dysfunction while being on treatment.\n\n\nCONCLUSIONS\nWe conclude that azathioprine has a good response rate in chronic ITP patients. It is well-tolerated with minimal and manageable side effects.",
"affiliations": "Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Radiotherapy and Oncology, IGMC Shimla Himachal Pradesh, India.;Department of Internal Medicine, PGIMER Chandigarh, India.;Division of Hematology and Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah Salt Lake City, Zip 84112, Utah, US.;Department of Lab Sciences and Molecular Medicine, Army Hospital (Research & Referral) Delhi, India.;Department of Pediatrics, Army Hospital (Research & Referral) Delhi, India.;Department of Internal Medicine, INHS Asvini Mumbai, India.;Department of Internal Medicine, Command Hospital (Southern Command) Pune, India.;Department of Lab Sciences and Molecular Medicine, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Lab Sciences and Molecular Medicine, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.;Department of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi, India.",
"authors": "Mishra|Kundan|K|;Pramanik|Suman|S|;Sandal|Rajeev|R|;Jandial|Aditya|A|;Sahu|Kamal Kant|KK|;Singh|Kanwaljeet|K|;Khera|Sanjeev|S|;Meshram|Ashok|A|;Khurana|Harshit|H|;Somasundaram|Venkatesan|V|;Kumar|Rajiv|R|;Kapoor|Rajan|R|;Verma|Tarun|T|;Sharma|Sanjeevan|S|;Singh|Jasjit|J|;Das|Satyaranjan|S|;Chaterjee|Tathagat|T|;Sharma|Ajay|A|;Nair|Velu|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-1992",
"issue": "11(3)",
"journal": "American journal of blood research",
"keywords": "Azathioprine; ITP; chronic ITP; immunosuppresents; resource constraint settings; thrombocytopenia",
"medline_ta": "Am J Blood Res",
"mesh_terms": null,
"nlm_unique_id": "101569577",
"other_id": null,
"pages": "217-226",
"pmc": null,
"pmid": "34322284",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "30007087;27260018;31794604;28864561;33224568;28295192;27935917;24621284;33100711;33651192;2317458;23094824;34267459;19005182;29856800;27053529;33724124;6459531;6388663;12648082",
"title": "Safety and efficacy of azathioprine in immune thrombocytopenia.",
"title_normalized": "safety and efficacy of azathioprine in immune thrombocytopenia"
} | [
{
"companynumb": "IN-CADILA HEALTHCARE LIMITED-IN-ZYDUS-072230",
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"occurcountry": "IN",
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"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
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"abstract": "Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors. SIGNIFICANCE: IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by \"isoform switching\" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.This article is highlighted in the In This Issue feature, p. 1494.",
"affiliations": "Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.;Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.;Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.;Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.;Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.;Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.;Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.;Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.;Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.;Celgene Corporation, Summit, New Jersey.;Celgene Corporation, Summit, New Jersey.;Celgene Corporation, Summit, New Jersey.;Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.;Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.;Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.;Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.;Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. intlekoa@mskcc.org steine@mskcc.org.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. intlekoa@mskcc.org steine@mskcc.org.",
"authors": "Harding|James J|JJ|;Lowery|Maeve A|MA|;Shih|Alan H|AH|;Schvartzman|Juan M|JM|0000-0002-8036-1361;Hou|Shengqi|S|;Famulare|Christopher|C|;Patel|Minal|M|;Roshal|Mikhail|M|;Do|Richard K|RK|0000-0002-6554-0310;Zehir|Ahmet|A|0000-0001-5406-4104;You|Daoqi|D|;Selcuklu|S Duygu|SD|;Viale|Agnes|A|;Tallman|Martin S|MS|;Hyman|David M|DM|;Reznik|Ed|E|0000-0002-6511-5947;Finley|Lydia W S|LWS|0000-0003-4023-7574;Papaemmanuil|Elli|E|;Tosolini|Alessandra|A|;Frattini|Mark G|MG|;MacBeth|Kyle J|KJ|;Liu|Guowen|G|;Fan|Bin|B|;Choe|Sung|S|;Wu|Bin|B|;Janjigian|Yelena Y|YY|;Mellinghoff|Ingo K|IK|;Diaz|Luis A|LA|;Levine|Ross L|RL|;Abou-Alfa|Ghassan K|GK|0000-0002-1522-8054;Stein|Eytan M|EM|;Intlekofer|Andrew M|AM|",
"chemical_list": "D004791:Enzyme Inhibitors; D007527:Isoenzymes; C538784:IDH2, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1158/2159-8290.CD-18-0877",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2159-8274",
"issue": "8(12)",
"journal": "Cancer discovery",
"keywords": null,
"medline_ta": "Cancer Discov",
"mesh_terms": "D000208:Acute Disease; D000230:Adenocarcinoma; D000368:Aged; D004351:Drug Resistance; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase; D007527:Isoenzymes; D007951:Leukemia, Myeloid; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes",
"nlm_unique_id": "101561693",
"other_id": null,
"pages": "1540-1547",
"pmc": null,
"pmid": "30355724",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "29056515;25599133;23630074;25017477;29346478;20171147;28481359;19935646;28588020;29670690;29860938;23264629;22343901;21598255;18772396;23393090;21130701;29805076;25043045;19657110;28297679;30013198;28588019;19228619;29950729",
"title": "Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition.",
"title_normalized": "isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition"
} | [
{
"companynumb": "US-CELGENEUS-USA-20181208943",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENASIDENIB"
},
"drugadditional": null,
... |
{
"abstract": "A 61-year-old man, without noteworthy medical history, presented with complaints of progressive fatigue and flushes. Diagnostic imaging revealed a large tumour in the stomach with liver metastases, and histopathological examination showed a well-differentiated gastric neuroendocrine tumour (NET). After chemotherapy, everolimus was administered, and upon progression, PD-1 inhibitor PDR001 was started. Two weeks after the first gift, he was admitted with loss of consciousness and a blood glucose level of 1.6 mmol/L. Plasma insulin was below 0.5 mU/L, C-peptide level was 250 pmol/L, insulin-like growth factor (IGF)-II was 804 ng/mL, and pro-IGF-IIE level was 80 µg/L. Based on the clinical findings, the patient was diagnosed with non-islet cell tumour hypoglycaemia (NICTH) with an overproduction of pro-IGF-IIE and eventually IGF-II due to progressive metastatic well-differentiated gastric NET. NICTH is a very rare condition. It has been reported in several tumour types but has never been described as a consequence of NET.",
"affiliations": "Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Clinical Chemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.",
"authors": "Versluis|Judith|J|;Valk|Gerlof|G|;van Rossum|Huub|H|;Tesselaar|Margot|M|",
"chemical_list": "D000970:Antineoplastic Agents; D001786:Blood Glucose",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231069",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(9)",
"journal": "BMJ case reports",
"keywords": "Endocrine Cancer; Metabolic Disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000970:Antineoplastic Agents; D001786:Blood Glucose; D004359:Drug Therapy, Combination; D004750:Enteral Nutrition; D017809:Fatal Outcome; D006801:Humans; D007003:Hypoglycemia; D007414:Intestinal Neoplasms; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D010190:Pancreatic Neoplasms; D013274:Stomach Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31527214",
"pubdate": "2019-09-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14710353;15936977;23545670;18045950;9628278;9032050;8960839;632300;26482044;658418;1379260;12447687;1665409;17624760;9722981;9660813;15229476;17346183;24459236;1281841;10207053;25312765;3185662;2558477",
"title": "Non-islet cell tumour hypoglycaemia in a patient with a well-differentiated gastric neuroendocrine tumour.",
"title_normalized": "non islet cell tumour hypoglycaemia in a patient with a well differentiated gastric neuroendocrine tumour"
} | [
{
"companynumb": "PHHY2019NL226113",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND Invasive mucinous adenocarcinoma (IMA) is a rare variant of adenocarcinoma of the lung. It frequently shows KRAS mutations, while ALK rearrangement is exceedingly rare. We present a case of ALK-rearranged IMA of the lung presenting with an unusual pattern of brain metastases, radiologically mimicking a cavernous angioma. CASE REPORT A 44-year-old non-smoker female was first diagnosed with lung right lower lobe IMA with ALK rearrangement. Five years after surgery followed by chemotherapy, she developed a sudden onset headache. Brain imaging revealed a hemorrhagic left frontal mass, suspicious for a cavernous angioma. However, the pathology of the resected lesion showed an ALK-rearranged brain metastasis from the IMA of the lung. Interestingly, the metastases showed perivascular tumor infiltrates, accompanied by focal mural invasion, vascular disruption, and hemorrhage. CONCLUSIONS To our knowledge, this is the first reported case of brain metastasis from an ALK-rearranged IMA of the lung. Further investigation of the clinical and pathological characteristics of the ALK-rearranged IMA, including awareness of the possibility for development of brain metastases with tumor-associated vasculopathy and hemorrhage, is warranted.",
"affiliations": "Department of Pathology and Translational Pathobiology, Louisiana State University Health Science Center, Shreveport, LA, USA.;Department of Pathology and Translational Pathobiology, Louisiana State University Health Science Center, Shreveport, LA, USA.;Division of Anatomic Pathology, Children's National Medical Center, Washington, DC, USA.;Department of Radiology, Louisiana State University Health Science Center, Shreveport, LA, USA.;Department of Pathology and Translational Pathobiology, Louisiana State University Health Science Center, Shreveport, LA, USA.",
"authors": "Shi|Mingxia|M|;Xu|Hongzhi|H|;DiPoto Brahmbhatt|Angela|A|;Gonzalez-Toledo|Eduardo|E|;Georgescu|Maria-Magdalena|MM|",
"chemical_list": "C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.906803",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2937158410.12659/AJCR.906803906803ArticlesHemorrhagic Brain Metastases in a Patient with Anaplastic Lymphoma Kinase (ALK)-Rearranged Invasive Mucinous Adenocarcinoma of the Lung Shi Mingxia ABCDEF1Xu Hongzhi B1Brahmbhatt Angela DiPoto BD2Gonzalez-Toledo Eduardo D3Georgescu Maria-Magdalena BCDEF1\n1 Department of Pathology and Translational Pathobiology, Louisiana State University Health Science Center, Shreveport, LA, U.S.A.\n2 Division of Anatomic Pathology, Children’s National Medical Center, Washington, DC, U.S.A.\n3 Department of Radiology, Louisiana State University Health Science Center, Shreveport, LA, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Mingxia Shi, e-mail: mshi@lsuhsc.edu2018 26 1 2018 19 99 104 24 8 2017 19 10 2017 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 44\n\nFinal Diagnosis: Brain metastases from invasive mucinous adenocarcinoma of the lung\n\nSymptoms: Coughing\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Pulmonology\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nInvasive mucinous adenocarcinoma (IMA) is a rare variant of adenocarcinoma of the lung. It frequently shows KRAS mutations, while ALK rearrangement is exceedingly rare. We present a case of ALK-rearranged IMA of the lung presenting with an unusual pattern of brain metastases, radiologically mimicking a cavernous angioma.\n\nCase Report:\nA 44-year-old non-smoker female was first diagnosed with lung right lower lobe IMA with ALK rearrangement. Five years after surgery followed by chemotherapy, she developed a sudden onset headache. Brain imaging revealed a hemorrhagic left frontal mass, suspicious for a cavernous angioma. However, the pathology of the resected lesion showed an ALK-rearranged brain metastasis from the IMA of the lung. Interestingly, the metastases showed perivascular tumor infiltrates, accompanied by focal mural invasion, vascular disruption, and hemorrhage.\n\nConclusions:\nTo our knowledge, this is the first reported case of brain metastasis from an ALK-rearranged IMA of the lung. Further investigation of the clinical and pathological characteristics of the ALK-rearranged IMA, including awareness of the possibility for development of brain metastases with tumor-associated vasculopathy and hemorrhage, is warranted.\n\nMeSH Keywords:\nAdenocarcinoma, MucinousGene RearrangementLung NeoplasmsNeoplasm Metastasis\n==== Body\nBackground\nInvasive mucinous adenocarcinoma (IMA), formerly known as mucinous bronchioloalveolar carcinoma, has been introduced as a new category in the most recent International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATC/ERS) multidisciplinary classification system [1]. This variant of adenocarcinoma of the lung, accounting for approximately 5% of lung adenocarcinomas [2], has distinct clinical, radiological, pathological, and genetic characteristics. IMAs frequently show KRAS mutation (in up to 90% of cases) [1,3], whereas nonmucinous adenocarcinomas are more likely to show epidermal growth factor receptor (EGFR) mutation. Recently, CD74-NRG1 fusions have been discovered in invasive mucinous adenocarcinoma, providing further evidence of a distinctive subtype [4].\n\nIn non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) is rearranged to create the EML4-ALK oncogene that causes the increased growth of cancer cells. EML4-ALK fusion gene is a potent oncogenic driver, reported in about 3% to 7% of all NSCLC patients [5]. Other fusion partners for ALK have also been discovered in NSCLC. ALK rearrangements are mutually exclusive with EGFR or KRAS mutations [6]. Most ALK-rearranged NSCLC are adenocarcinomas, which have a younger age of onset, high-stage disease, and most patients are never smokers or have a limited smoking history [7]. Crizotinib is the ALK tyrosine kinase inhibitor that has shown marked and durable efficacy for the treatment of patients with NSCLC positive for ALK rearrangement. Despite their initial response, however, such patients treated with crizotinib eventually develop progressive disease, with the brain being the most common site for the occurrence of new lesions [8].\n\nIMA of the lung harboring ALK rearrangement is exceedingly rare. There is no previous report of brain metastases from such patients. We present here a case of brain metastasis from ALK-rearranged IMA of the lung that also showed an unusual pattern of brain invasion radiologically mimicking a cavernous angioma.\n\nCase Report\nA 44-year-old non-smoker female was found to have an infiltrate in right lung lower lobe by chest imaging, and was diagnosed with IMA by lung biopsy. One year later, the patient underwent right thoracotomy and lobectomy (Figure 1). Histopathological examination of the resected specimen revealed neoplastic cells with a goblet and columnar cell morphology with abundant intracytoplasmic mucin and small basally located nuclei (Figure 2A). Abundant singly dispersed and clusters of signet ring cells were also present. Tumor cells showed a predominant lepidic growth with mixture of acinar and solid growth patterns. Spatial proximity between the bronchus and the tumor with frequent tumor cell infiltration of the adjacent bronchial epithelium was observed. Occasionally, the tumor cells showed a continuation with the non-neoplastic bronchiolar epithelium (Figure 2A, right image). By immunohistochemistry (IHC), the tumor was positive for CK7, TTF1, napsin A, p63 and was negative for p40 (Figure 2B) and CK20. A diagnosis of pulmonary IMA with hilar lymph node metastases (stage IIA) was rendered. Molecular studies of the tumor revealed the presence of an ALK rearrangement by fluorescence in situ hybridization (FISH) (Figure 2C) and the absence of EGFR and KRAS mutations by sequencing. Expression of epithelial to mesenchymal transition (EMT)-related markers such as E-cadherin and vimentin were also evaluated. Focal absence of E-cadherin expression and gain of vimentin expression in tumor cells (Figure 2D) were observed, suggesting EMT phenotype.\n\nThe patient subsequently underwent paclitaxel and carboplatin chemotherapy for four cycles. Five years later, surveillance imaging detected 18F-fluorodeoxyglucose (FDG)-avid mediastinal lymphadenopathy. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) of station 7 lymph nodes was performed, and a cytological diagnosis of metastatic mucinous adenocarcinoma of the lung with signet ring features (Figure 3) was rendered. The tumor cells were positive for CK7 and napsin A, focally positive for TTF1 and negative for CK20. ALK rearrangement and EGFR mutation were not detected.\n\nTwo months later, the patient presented to the emergency department with a sudden onset headache. A brain magnetic resonance imaging (MRI) revealed a hemorrhagic left frontal mass with cortical and subcortical deposits of hemosiderin (Figure 4A), suspicious for a cavernous malformation (cavernous angioma). The patient underwent left frontal craniotomy for the resection of the mass. Histopathological examination of the resected brain lesion revealed growth of mucinous tumor cells in the subarachnoid space around the small and large leptomeningeal vessels and diffuse invasion of the brain along the Virchow-Robin perivascular spaces (Figure 4B, left panel). Focal mural invasion, vascular disruption, and hemorrhage (Figure 4B, right and bottom panels) were present inside and outside the brain parenchyma. The tumor cells were positive for TTF1 and napsin A, and showed presence of ALK gene rearrangement by FISH. The pathological findings confirmed brain metastases from the ALK-rearranged IMA of the lung.\n\nDiscussion\nIMA of the lung is typified by columnar and/or goblet cell morphology with abundant intracytoplasmic mucin and small basally located nuclei. Nuclear atypia is usually inconspicuous or absent. Alveolar spaces often contain mucin. Patients with IMA frequently present with a pneumonia-like pattern and multifocal and multilobar lesions [9]. The tumor may show the same heterogeneous mixture of lepidic, acinar, papillary, and micro-papillary growth as non-mucinous tumors, but the lepidic pattern is most common, and solid growth is rare. Identical morphology may be seen in metastatic mucinous adenocarcinomas from sites such as the colon, pancreas and ovary, and therefore clinical and radiologic correlation should be made to exclude primary tumors in these locations. The immunoprofile of invasive mucinous adenocarcinoma of the lung may be different from that of other adenocarcinoma subtypes. The tumor is typically positive for CK7 (90%) and CK20 (50%), and less frequently express TTF1 (15%) and napsin A (11%) [10–12]. MUC 2-5-6 positivity is often seen due to its origin of bronchiolar mucinous goblet cells [1]. In the present case of ALK-positive IMA of the lung, the tumor cells demonstrated similar immunoprofile to nonmucinous adenocarcinoma, showing positivity for CK7, TTF1, napsin A, and negative for CK20.\n\nALK rearrangement is shown to be associated with a solid predominant growth pattern and signet ring cell features [7,13]. It has been reported that approximately 70% of pulmonary adenocarcinoma demonstrate ALK gene rearrangement when signet ring cells comprised >10% of the tumor cells [14]. Proper recognition of this feature may be important in determining whether further molecular testing is advisable. In the present case, the ALK-rearranged IMA showed largely lepidic pattern with foci of acinar and solid growth, and abundant signet ring cells. The EMT phenotype seen in this case, as well as in other cases with ALK rearrangement [13], could potentially contribute to tumor progression, metastasis, and drug resistance in ALK-rearranged tumors. Some studies reported that ALK-rearranged tumors have significantly higher p63 immunoreactivity compared to tumors that are negative for ALK rearrangement [5,13,15]. In contrast, positivity of p40 was rarely observed in ALK-rearranged tumors. Similar to these reports, our case of ALK-rearranged lung adenocarcinoma showed TTF1 and p63 co-expression and no reactivity to p40. It is known that EGFR-mutated tumors are originated from terminal respiratory units (TRU), which is positive for TTF1 but typically negative for p63. A close relationship to the adjacent bronchial epithelium was reported as a unique feature of ALK-rearranged tumors. In our case, we also observed spatial proximity between bronchus and the tumor with frequent tumor cell infiltration of the adjacent bronchial epithelium. Occasionally, the tumor cells showed a continuation with the non-neoplastic bronchiolar epithelium. These findings suggest that ALK-rearranged tumors might originate from different cell type, and may represent non-TRU-type adenocarcinoma. It was proposed that a cell type dually expressing TTF1and p63 may be the cell origin of ALK-rearranged tumors [5,13]. However, a specific cell type of ALK-rearranged tumors and the significance of p63 expression remain to be clarified. With regards to diagnosis, the frequent presence of the solid grow pattern with positive p63 immunoreactivity in ALK-rearranged tumors may make it difficult to differentiate from squamous cell carcinoma in a limited specimen. Being aware of these features may prove helpful for accurate diagnosis.\n\nStudies showed a high concordant rate of ALK rearrangement between primary tumors and their corresponding metastases [7,17]. However, discordance has also been reported, indicating intratumor heterogeneity of ALK rearrangement. Hou et al. identified two patients with discrepancy of ALK rearrangement showing an ALK fusion positive in primary tumor while not in paired metastatic lymph nodes [7]. Two patients were reported showing ALK rearrangement negative on primary lung tumor while harboring ALK fusion in metastatic peritoneal and soft tissue lesion, respectively [16,17], indicating that ALK alteration and ALK expression can be acquired during metastatic progression in NSCLC. A recent study reported that ALK rearrangement detected by IHC and RT-PCR was discordant among spatially separated tumor areas in the same primary tumor of ALK-positive patient. In the present case, the patient with ALK-rearranged primary lung tumor showed ALK rearrangement in the brain metastases, and no ALK rearrangement in the tumor metastatic to the mediastinal lymph node. It seems reasonable to infer that metastatic tumor cells in the lymph node may come from a clone of ALK-negative tumor cells within the primary lesion. Therefore, genetic intratumoral heterogeneity with different tumor clones may account for this discrepancy.\n\nBrain metastasis usually occurs at the gray and white matter junction or in the vascular border zone regions. This supports the notion that metastatic emboli tend to lodge in areas of reduced blood flow, such as those with sudden reduction of vascular caliber (gray/white matter junction) or areas of the most distal vascular field (border zone) [18]. In our case, the brain metastases from an ALK-rearranged IMA of the lung demonstrated an unusual pattern of brain metastases, with tumor cells seeding in the subarachnoid space, growing around the leptomeningeal vessels, and diffusely invading the brain along the Virchow-Robin perivascular spaces. This is a pattern of solid tumor metastases that is sometimes seen in melanoma or in breast metastatic to the brain, and rarely in lung cancers [19]. However, in our IMA case, the perivascular tumor infiltrates were accompanied by focal mural invasion, vascular disruption, and hemorrhage. This tumor-associated vasculopathy might be responsible for the radiological mimicry of cavernous angioma.\n\nConclusions\nTo our knowledge, the present case is the first reported instance of hemorrhagic brain metastasis in patients with lung IMA positive for ALK rearrangement. Further investigation of the clinical and pathological characteristics of the ALK rearrangement positive IMA and awareness of the possibility for the development of brain metastases with tumor-associated vasculopathy and hemorrhage in such patients are warranted.\n\nFigure 1. Time course of clinical progression of the IMA.\n\nFigure 2. IMA of the lung. (A) Shows neoplastic cells with a goblet and columnar cell morphology with abundant intracytoplasmic mucin and small basally located nuclei. The mucinous tumor cells continued with the non-neoplastic bronchiolar epithelium (black arrow in right image). (B) The neoplastic cells are positive by IHC for CK7, TTF1, napsin A, p63, and negative for p40. (C) Positive ALK FISH break-apart test is shown with split red and green signals, signifying the presence of an ALK rearrangement. (D) The neoplastic cells are positive for vimentin and negative for E-cadherin by IHC. Images in (A), (B), and (D) were acquired at 20× magnification except for center image in panel A and CK7 in panel B that was acquired at 40× magnification with an Olympus BX43 microscope.\n\nFigure 3. Aspirates of the metastatic IMA in mediastinal lymph node consist of abundant signet ring cells (magnification 20×).\n\nFigure 4. (A) Brain MRI shows hyperintense deposits of hemosiderin (arrow) on T1 images without contrast in a superficial intraaxial and extraaxial lesion located in the left frontal lobe. T2 FLAIR (fluid attenuated inversion recovery) images show the hyperintense superficial lesion. (B) Brain metastases show growth of mucinous tumor cells around the subarachnoid leptomeningeal vessels (blue arrow in left panel, 10×) and diffuse invasion of the brain along the Virchow-Robin perivascular spaces (black arrow in left panel). Mural invasion (black arrow in bottom panel, 40×), vascular disruption and hemorrhage (right panel, 20×) are present.\n==== Refs\nReferences:\n1. Tang ER Schreiner AM Pua BB Advances in lung adenocarcinoma classification: A summary of the new international multidisciplinary classification system (IASLC/ATS/ERS) J Thorac Dis 2014 6 S489 501 25349701 \n2. Siegel R Ma J Zou Z Jemal A Cancer statistics, 2014 Cancer J Clin 2014 64 9 29 \n3. Kadota K Yeh YC D’Angelo SP Associations between mutations and histologic patterns of mucin in lung adenocarcinoma: Invasive mucinous pattern and extracellular mucin are associated with KRAS mutation Am J Surg Pathol 2014 38 1118 27 25029118 \n4. Fernandez-Cuesta L Plenker D Osada H CD74-NRG1 fusions in lung adenocarcinoma Cancer Discov 2014 4 415 22 24469108 \n5. Kim H Chung JH Overview of clinicopathologic features of ALK-rearranged lung adenocarcinoma and current diagnostic testing for ALK rearrangement Transl Lung Cancer Res 2015 4 2 149 55 25870797 \n6. Zhang X Zhang S Yang X Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression Mol Cancer 2010 9 188 20624322 \n7. Hou L Ren S Su B High concordance of ALK rearrangement between primary tumor and paired metastatic lymph node in patients with lung adenocarcinoma J Thorac Dis 2016 8 6 1103 11 27293826 \n8. Otterson GA Riely GJ Shaw AT Clinical characteristics of ALK+ NSCLC patients (pts) treated with crizotinib beyond disease progression (PD): Potential implications for management. J Clin Oncol 2012 30 Suppl. abstr 7600 \n9. Casali C Rossi G Marchioni A A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: Clinicopathologic analysis, molecular features, and possible pitfalls in routine practice J Thorac Oncol 2010 5 830 36 20521350 \n10. Lau SK Desrochers MJ Luthringer DJ Expression of thyroid transcription factor-1, cytokeratin 7, and cytokeratin 20 in bronchioloalveolar carcinomas: An immunohistochemical evaluation of 67 cases Mod Pathol 2002 15 5 538 42 12011259 \n11. Tsuta K Ishii G Nitadori J Comparison of the immunophenotypes of signet-ring cell carcinoma, solid adenocarcinoma with mucin production, and mucinous bronchioloalveolar carcinoma of the lung characterized by the presence of cytoplasmic mucin J Pathol 2006 209 1 78 87 16463270 \n12. Wu J Chu PG Jiang Z Napsin A expression in primary mucin-producing adenocarcinomas of the lung: An immunohistochemical study Am J Clin Pathol 2013 139 2 160 66 23355200 \n13. Kim H Jang SJ Chung DH A comprehensive comparative analysis of the histomorphological features of ALK-rearranged lung adenocarcinoma based on driver oncogene mutations: Frequent expression of epithelialmesenchymal transition markers than other genotype PLoS One 2013 8 e76999 24194854 \n14. Choi E Lewis AL Takei H Ro JY Leptomeningeal carcinomatosis as initial presentation in adenocarcinoma of lung with signet ring cell features: An autopsy case report Int J Clin Exp Pathol 2012 5 9 972 76 23119115 \n15. Sakai Y Nakai T Ohbayashi C Immunohistochemical profiling of ALK fusion gene-positive adenocarcinomas of the lung Int J Surg Pathol 2013 21 5 476 82 23794492 \n16. Rossi A Galetta D Bottiglieri L Evaluation of ALK gene status in primary lung adenocarcinoma and matched metastases J Thorac Oncol 2011 6 1146 21623283 \n17. Kim H Xu X Yoo S-B Discordance between anaplastic lymphoma kinase status in primary non-small-cell lung cancers and their corresponding metastases Histopathology 2013 62 2 305 14 23020707 \n18. Hwang TL Close TP Grego JM Predilection of brain metastasis in gray and white matter junction and vascular border zones Cancer 1996 77 8 1551 55 8608542 \n19. Taillibert S Laigle-Donadey F Chodkiewicz C Leptomeningeal metastases from solid malignancy: A review J Neurooncol 2005 75 1 85 99 16215819\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D001932:Brain Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D015321:Gene Rearrangement; D020786:Hemangioma, Cavernous, Central Nervous System; D006801:Humans; D008175:Lung Neoplasms; D020794:Receptor Protein-Tyrosine Kinases",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "99-104",
"pmc": null,
"pmid": "29371584",
"pubdate": "2018-01-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25029118;23020707;8608542;23355200;16215819;16463270;25349701;23119115;12011259;21623283;25870797;27293826;20521350;20624322;24399786;23794492;24469108;24194854",
"title": "Hemorrhagic Brain Metastases in a Patient with Anaplastic Lymphoma Kinase (ALK)-Rearranged Invasive Mucinous Adenocarcinoma of the Lung.",
"title_normalized": "hemorrhagic brain metastases in a patient with anaplastic lymphoma kinase alk rearranged invasive mucinous adenocarcinoma of the lung"
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"abstract": "We present the case of a 26-year-old woman living at a high altitude diagnosed initially with nonfamilial and nonsecretory localized carotid body tumor managed with surgery, which developed into a recurrent metastatic tumor treated with cyclophosphamide, vincristine, and dacarbazine. The patient continued to progress and developed a left carotid artery thrombosis and worsening of her systemic symptoms. The patient was re-evaluated, and she decided on no further surgery or systemic therapy. DOTATATE positron emission tomography/computed tomography showed widespread somatostatin-avid disease involving the left carotid bulb mass, bilateral lung nodules, and liver metastases, with the largest in the right hepatic lobe measuring 8 × 7 cm. There were peripancreatic lymph nodes and scattered skeletal metastases. The patient sought a second opinion, on the basis of which she was prescribed pazopanib, to which she showed a dramatic clinical response after 1 month, followed by a durable response for 1 year. Tyrosine kinase inhibitors such as pazopanib are potentially useful in paraganglioma, with further studies needed to understand the role of vascular endothelial growth factor receptor-directed kinase inhibitors in this setting.",
"affiliations": "Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.",
"authors": "Alshamsan|Bader|B|;Atallah|Jean Paul|JP|",
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"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000510003\ncro-0013-1227\nCase Report\nDurable Response to Pazopanib in Recurrent Metastatic Carotid Body Paraganglioma\nAlshamsan Bader ab* Atallah Jean Paul a aMedical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia\nbDepartment of Medicine, Qassim Medical College, Qassim University, Qassim, Saudi Arabia\n*Bader Alshamsan, Department of Medicine, Qassim Medical College, Qassim University, PO Box 6655 Airport mail, Buraidah 51432 (Saudi Arabia), bshmsan@qu.edu.sa\nSep-Dec 2020 \n30 9 2020 \n30 9 2020 \n13 3 1227 1231\n5 7 2020 5 7 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We present the case of a 26-year-old woman living at a high altitude diagnosed initially with nonfamilial and nonsecretory localized carotid body tumor managed with surgery, which developed into a recurrent metastatic tumor treated with cyclophosphamide, vincristine, and dacarbazine. The patient continued to progress and developed a left carotid artery thrombosis and worsening of her systemic symptoms. The patient was re-evaluated, and she decided on no further surgery or systemic therapy. DOTATATE positron emission tomography/computed tomography showed widespread somatostatin-avid disease involving the left carotid bulb mass, bilateral lung nodules, and liver metastases, with the largest in the right hepatic lobe measuring 8 × 7 cm. There were peripancreatic lymph nodes and scattered skeletal metastases. The patient sought a second opinion, on the basis of which she was prescribed pazopanib, to which she showed a dramatic clinical response after 1 month, followed by a durable response for 1 year. Tyrosine kinase inhibitors such as pazopanib are potentially useful in paraganglioma, with further studies needed to understand the role of vascular endothelial growth factor receptor-directed kinase inhibitors in this setting.\n\nKeywords\nCarotid body paragangliomaPazopanibKinase inhibitor\n==== Body\nIntroduction\nCarotid body tumors (CBTs) are highly vascular rare neuroendocrine neoplasms [1]. The typical management of CBTs is by surgical resection. However, if a large lesion is fixed or unresectable because of size, radiation therapy is the preferred initial approach. There are no systemic therapies currently approved for patients with malignant paragangliomas [2]. Treatment options are limited, such as combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine with or without doxorubicin (CVD or CyVADIC regimen), iodine-131 meta-iodobenzylguanidine, 177 lutetium peptide (177 Lu-DOTATATE), and vascular endothelial growth factor (VEGF)-directed tyrosine kinase inhibitors (TKIs) such as sunitinib [3, 4]. Other TKIs, such as lenvatinib, cabozantinib, and axitinib, are also undergoing clinical trials [5]. To date, no clinical trials of TKIs have been completed. A phase II study of pazopanib monotherapy in metastatic paraganglioma has been halted due to slow recruitment [6].\n\nWe present the first case report of metastatic CBTs demonstrating a durable response to pazopanib and the second case showing a meaningful effect of pazopanib on metastatic paraganglioma [7].\n\nCase Description\nA 26-year-old woman living at a high altitude (2,500–2,750 m above sea level) was diagnosed with a CBT after a workup for recurrent syncopal episodes. She underwent excision of a left CBT and carotid artery repair in April 2015. Pathology revealed a 5-cm CBT/paraganglioma with immunohistochemistry positive for synaptophysin and chromogranin with Ki-67 >10%. The CBT had invaded the carotids and nerves, with lymphovascular invasion and positive resection margin. Seven lymph nodes were negative. The patient did not undergo re-resection or adjuvant radiation therapy. Metanephrines and chromogranin A were reported at normal levels. She remained asymptomatic, with no evidence of recurrence until March 2018, when she presented with a nonpainful lump in her left neck, 6 kg weight loss, and a nonproductive cough. Computed tomography (CT) of the head, neck, chest, abdomen, and pelvis revealed a recurrent left carotid mass along with a new bilateral pulmonary nodule, liver, and peripancreatic lymph node involvement. A liver biopsy was performed, which confirmed metastatic paraganglioma.\n\nThe patient was started on chemotherapy and completed 2 cycles of CVD in April 2018 before she presented to the emergency department with right-sided weakness. CT head and angiogram of the neck revealed ischemic stroke with left carotid artery thrombosis and recurrence of the tumor. She underwent re-resection with subsequent grafting and was started on anticoagulation with enoxaparin.\n\nThe patient was re-evaluated in June 2018 and chose no further therapy, given her systemic symptoms, back pain, and cough had worsened, with DOTATATE positron emission tomography/CT, which revealed widespread somatostatin-avid disease involving the left carotid bulb mass, with bilateral lung nodules, the largest measuring 1.3 cm. The liver metastases were also avid, with the largest in the right hepatic lobe measuring 8 × 7 cm. There were also peripancreatic lymph nodes and scattered skeletal metastases.\n\nThe patient sought a second opinion that recommended pazopanib, which was started at the end of June 2018 at an initial dose of 800 mg. She was administered bisphosphonates for her bone metastases. Clinical follow-up at one month revealed a dramatic clinical response with resolution of all her symptoms. She did not tolerate the full dose because of increased liver enzymes and anorexia, so she was kept on 400 mg daily. Regular follow-ups every 2–3 months for almost 1 year revealed excellent clinical response along with imaging showing stable disease by response evaluation criteria in solid tumors (RESIST) (shown in Fig. 1). She started to relapse clinically and biochemically in November 2019 and eventually developed a clear progression of the disease by December 2019.\n\nDiscussion\nCBTs, also known as paragangliomas, are highly vascular rare neuroendocrine neoplasms that arise near the carotid bifurcation within glomus cells, embryologically derived from neural crest cells of the autonomic nervous system [8]. Paragangliomas of the head and neck are frequently found in patients aged between 50 and 70 years, but they can occur at any age predominantly in females [9]; its incidence might increase in direct relation to altitude [10]. Most head and neck paragangliomas are benign and not catecholamine secretory. Familial cases are more likely to be secretory and can be bilateral. The criterion of malignancy is made based on the development of metastases rather than histological appearance [11].\n\nParagangliomas express multiple angiogenic growth factors, including VEGF, that contribute to angiogenesis and carcinogenesis [12]. The signal pathways underlying pathogenesis of these tumors and behind the treatment with TKI are the hypoxia-associated signal pathway regulated by hypoxia-inducible factor and kinase signal pathways [13, 14]. We will review the role of TKIs in this rare malignancy.\n\nSunitinib is a potent inhibitor of multiple tyrosine kinase receptors, including VEGFR-1 and VEGFR-2, platelet-derived growth factor receptor (PDGFR) beta, KIT, and FMS-like tyrosine kinase 3, and rearranged during transfection. Among 25 patients in an open-label phase II trial of sunitinib in patients with progressive pheochromocytoma and paraganglioma (SNIPP) [4], a disease control rate of 83% was reported (70% with stable disease and 13% with a partial response), with median progression-free survival (PFS) of 13 months. Grade 3 toxicities included fatigue and thrombocytopenia. Three patients discontinued therapy due to hypertension or cardiac events. In another retrospective study, 17 patients with progressive metastatic pheochromocytoma/sympathetic paraganglioma were treated with sunitinib, of whom 14 were evaluable; 3 (21%) demonstrated a partial response and 5 (36%) showed stable disease. Median PFS was 4.1 months. The median overall survival (OS) of the entire group was 27 months [3].\n\nPazopanib is another kinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, as well as fibroblast growth factors, KIT, and PDGFR, approved for the treatment of patients with advanced renal cell cancer and advanced soft tissue sarcoma after failure of prior chemotherapy. Pazopanib has been tested in a phase II clinical trial for malignant progressive pheochromocytoma and paraganglioma [6]. The primary endpoint was the best objective response rate. The intervention was pazopanib 400 mg daily for 2 weeks, then 800 mg daily. This study has been halted for poor accrual; 7 patients were recruited. One patient only exhibited a partial response that lasted for approximately 2.4 years. Another patient demonstrated an unconfirmed partial response. The median PFS and OS were 6.5 and 14.8 months, respectively. Several patients had severe adverse effects: 17% had grade 3–4 diarrhea, hematuria, headaches, and fatigue; 50% had severe hypertension, with the toxicity more evident after doubling the dose. Two patients with secretory tumors developed a hypertensive crisis and Takotsubo cardiomyopathy.\n\nCabozantinib is also active in paragangliomas. Of 14 patients reported by Jimenez [5], 93% had achieved clinical benefit. Hypertension was reported in 40% of the patients, mainly grade 1. The main grade 3 adverse effects were elevated pancreatic enzymes reported in 1 patient, and rectal fistula corrected with surgery reported in another [5].\n\nAxitinib at a starting dose of 5 mg twice daily was evaluated in a phase II clinical trial that enrolled 9 patients. Three achieved partial response, and 5 patients had tumor shrinkage but it was insufficient to meet the RESIST criteria for partial response. Only 1 patient tolerated titration to 7 mg, and 8 patients required a dose reduction [15].\n\nConclusion\nPazopanib demonstrated clinically meaningful activity in this refractory nonfamilial, nonsecretory, malignant CBT, with a durable response. TKIs are potentially useful, with further studies needed to investigate the efficacy of VEGFR-directed kinase inhibitors in paraganglioma.\n\nStatement of Ethics\nInformed consent was obtained from the patient to include treatment history and images in this case report.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNone.\n\nAuthor Contributions\nBader Alshamsan did the literature review, wrote, and edited the manuscript. He was also involved in patient management. Jean Paul Atallah master supervised the patient management, performed the literature review, and reviewed the manuscript.\n\nFig. 1 Computed tomography imaging of the chest at baseline (A) in April 2018, after 6 months (B), and at 14 months after starting therapy (C).\n==== Refs\nReferences\n1 Liu Q Djuricin G Staren ED Gattuso P Gould VE Shen J Tumor angiogenesis in pheochromocytomas and paragangliomas Surgery 1996 12 120 (6) 938 43 8957477 \n2 Lenders JW Duh QY Eisenhofer G Gimenez-Roqueplo AP Grebe SK Murad MH Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline J Clin Endocrinol Metab 2014 99 (6) 1915 42 24893135 \n3 Ayala-Ramirez M Chougnet CN Habra MA Palmer JL Leboulleux S Cabanillas ME Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas J Clin Endocrinol Metab 2012 11 97 (11) 4040 50 22965939 \n4 O'Kane GM Ezzat S Joshua AM Bourdeau I Leibowitz-Amit R Olney HJ A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial Br J Cancer 2019 6 120 (12) 1113 9 31105270 \n5 Jimenez C Treatment for patients with malignant pheochromocytomas and paragangliomas: a perspective from the hallmarks of cancer Front Endocrinol (Lausanne) 2018 5 9 277 29892268 \n6 Jasim S Suman VJ Jimenez C Harris P Sideras K Burton JK Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma Endocrine 2017 8 57 (2) 220 5 28685225 \n7 Patel S Owen D Schmidt CR Kirschner LS Phay J Shirley L Favorable and durable response to pazopanib in metastatic refractory paraganglioma J Oncol Pract 2017 12 13 (12) JOP2017024984 2 \n8 Jackson CG Neurotologic skull base surgery for glomus tumors. Diagnosis for treatment planning and treatment options Laryngoscope 1993 11 103 (11 Pt 2 Suppl 60) 17 22 \n9 Pellitteri PK Rinaldo A Myssiorek D Gary Jackson C Bradley PJ Devaney KO Paragangliomas of the head and neck Oral Oncol 2004 7 40 (6) 563 75 15063383 \n10 Rodríguez-Cuevas S López-Garza J Labastida-Almendaro S Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level Head Neck 1998 8 20 (5) 374 8 9663663 \n11 Lam AKY Update on adrenal tumours in 2017 World Health Organization (WHO) of endocrine tumours Endocr Pathol 2017 9 28(3) 213 27 28477311 \n12 Jyung RW LeClair EE Bernat RA Kang TS Ung F McKenna MJ Expression of angiogenic growth factors in paragangliomas Laryngoscope 2000 1 110 (1) 161 7 10646734 \n13 Liu Y Liu L Zhu F Therapies targeting the signal pathways of pheochromocytoma and paraganglioma Onco Targets Ther 2019 9 12 7227 41 31564906 \n14 Fishbein L Leshchiner I Walter V Danilova L Robertson AG Johnson AR Comprehensive molecular characterization of pheochromocytoma and paraganglioma Cancer Cell 2017 2 31 (2) 181 93 28162975 \n15 Burotto Pichun ME Edgerly M Velarde M Bates SE Daerr R Adams K Phase II clinical trial of axitinib in metastatic pheochromocytomas and paraganlgiomas (P/PG): preliminary results J Clin Oncol 2015 3 33 (7_Suppl) 457\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(3)",
"journal": "Case reports in oncology",
"keywords": "Carotid body paraganglioma; Kinase inhibitor; Pazopanib",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1227-1231",
"pmc": null,
"pmid": "33173489",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "8231589;28685225;31564906;9663663;31105270;28162975;24893135;28850312;29892268;8957477;15063383;10646734;28477311;22965939",
"title": "Durable Response to Pazopanib in Recurrent Metastatic Carotid Body Paraganglioma.",
"title_normalized": "durable response to pazopanib in recurrent metastatic carotid body paraganglioma"
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"companynumb": "NVSC2020SA285562",
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"abstract": "BACKGROUND\nAttention-deficit hyperactivity disorder is suggested to be closely related to epilepsy. A recent large-scale study revealed that ADHD in children is often accompanied by epilepsy. In Japan, methylphenidate (MPH) as a sustained-action tablet and atomoxetine (ATX) became commercially available as medications for children recently. Since then, the number of prescriptions of both medicines has increased rapidly. Methylphenidate, as a psychostimulant, has been a source of concern because of the perceived lowered threshold for convulsions in children. Based on this background, reappraisal of EEG findings in children with ADHD is important in order to detect indications of potential comorbid epilepsy and to investigate the developmental mechanisms of the neurophysiological manifestations in patients with ADHD.\n\n\nMETHODS\nEEG findings in children newly diagnosed with ADHD and their relationship with clinical findings were investigated. The author evaluated 208 patients with ADHD newly diagnosed between 2008 and 2013. Of these, there were 145 patients for whom EEG findings were obtained along with a clinical follow-up for at least three months. Patients with IQ<70 were excluded in order to obtain a homogenous group of patients with ADHD. The male-to-female ratio was 130:15, and the age range was between 5 years, 9 months and 19 years, 9 months, with mean age of 11 years, 4 months.\n\n\nRESULTS\nThe results revealed that about half (48.3%) of the children with ADHD had abnormal EEG findings and that 22.1% of them had epileptiform discharges. Patients without comorbidity of autism spectrum disorder (ore homogenous group with ADHD) were especially likely to show abnormal EEG findings (51.0%) including epileptiform discharges (24.5%). Afebrile seizures, that is, epileptic seizures, occurred in a boy three days after commencement of administration with MPH as a sustained-action tablet. In four patients with a past history of epilepsy, neither relapse of EEG abnormality nor epileptic seizures were observed during the follow-up period.\n\n\nCONCLUSIONS\nThere was to be a significantly close relationship between ADHD and epileptiform discharges. Therefore, in patients with ADHD, it is important to obtain more precise information about seizures and presence of epilepsy from the personal and family histories, as well as to undertake a thorough EEG examination.",
"affiliations": "Department of Neuropsychiatry and Psychosomatic Internal Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama Prefecture 350-0495, Japan. Electronic address: kanaosa@saitama-med.ac.jp.",
"authors": "Kanazawa|Osamu|O|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1525-5050",
"issue": "41()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Attention-deficit hyperactivity disorder (ADHD); Autism spectrum disorder (ASD); Electroencephalography (EEG); Epilepsy; Epileptiform discharge",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity; D002648:Child; D002675:Child, Preschool; D015897:Comorbidity; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "251-6",
"pmc": null,
"pmid": "25461225",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reappraisal of abnormal EEG findings in children with ADHD: on the relationship between ADHD and epileptiform discharges.",
"title_normalized": "reappraisal of abnormal eeg findings in children with adhd on the relationship between adhd and epileptiform discharges"
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"companynumb": "PHHY2014JP146012",
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"abstract": "BACKGROUND\nTaxane-based chemotherapy is one of the most commonly used agents in patients with advanced urothelial carcinoma who developed disease progression after gemcitabine and cisplatin combination chemotherapy. The response rates, however, are dismal reported around 10-20%. Recently, promising efficacy results of paclitaxel when combined with oral cyclophosphamide as metronomic therapy have been reported.\n\n\nMETHODS\nPatients received paclitaxel 175 mg/m(2) intravenously over 3 h on day 1 and cyclophosphamide 50 mg/day orally on days 1-7 every 3 weeks. For patients with ECOG, performance status was two or previous radiotherapy on 25% or more of their bone marrow, paclitaxel was given at a dose of 135 mg/m(2) for the first cycle, followed by intra-patient dose escalation to 175 mg/m(2) if clinically significant toxicities were not observed during the first cycle. Oral cyclophosphamide was administered for extended 3 weeks after the safety of 1-week metronomic therapy was confirmed. The primary end points were response rate (RECIST v.1.1) and progression-free survival.\n\n\nRESULTS\nFrom March 2012 to March 2014, 46 patients with bladder or upper urinary tract cancer were treated with this regimen in our institution after failure to gemcitabine and cisplatin combination chemotherapy. After excluding four patients with pathologies other than urothelial carcinoma (one collecting duct carcinoma, two small cell carcinoma, and one squamous cell carcinoma), a total of 42 patients were included in this study. The platinum-free interval was <6 months in 33 (78.6%) patients, and 39 (92.8%) were categorized into the intermediate or poor prognosis group according to Bajorin's risk model. The objective response rate was 33.3% (n = 14) with a median response duration of 4.3 months. The median time to progression was 3.0 months (95% CI 1.7-4.3 months), and the median OS was 6.3 months (95% CI 4.6-8.0 months). The most frequent and clinically significant non-hematologic toxicities were peripheral sensory neuropathy (56%), fatigue (35%), and myalgia (28%) in order, but none of them showed severity of grade 3 or more. Grade ≥ 3 neutropenia occurred only in two patients (6%), and one of them developed febrile neutropenia. The duration of metronomic cyclophosphamide did not significantly affect the toxicity profile, and it could be safely administered for whole cycles.\n\n\nCONCLUSIONS\nMetronomic oral cyclophosphamide combined with paclitaxel appears to be both efficacious and safe as a salvage chemotherapy, particularly in heavily pretreated patients with advanced urothelial carcinoma after gemcitabine-cisplatin failure.",
"affiliations": "Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 138-736, Korea.",
"authors": "Park|Ji Hyun|JH|;Lee|Jae-Lyun|JL|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D003520:Cyclophosphamide; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Germany",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D003841:Deoxycytidine; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D017239:Paclitaxel; D011379:Prognosis; D016879:Salvage Therapy; D016019:Survival Analysis; D017211:Treatment Failure; D016896:Treatment Outcome; D014571:Urologic Neoplasms",
"nlm_unique_id": "7806519",
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"pages": "247-54",
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"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intravenous 3-weekly paclitaxel and metronomic oral cyclophosphamide in patients with advanced urothelial cancer previously treated with gemcitabine and platinum.",
"title_normalized": "intravenous 3 weekly paclitaxel and metronomic oral cyclophosphamide in patients with advanced urothelial cancer previously treated with gemcitabine and platinum"
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"abstract": "The aim of this paper is to describe the possibility of using Electrical Impedance Tomography (EIT) as a treatment monitoring tool in the ICU. It was based on case report and literature review. A 19-year-old female was admitted to ICU due to severe acute respiratory distress syndrome. Despite aggressive treatment there was no improvement. We decided to use EIT in the monitoring of treatment because of difficulties in transporting the patient to the radiology department in order to perform a control CT scan. After identifying the causing factor (Pneumocyctis jiroveci), EIT monitoring was maintained to assess the effectiveness of targeted microbial treatment. In the following days, we observed an improvement of regional ventilation of the upper and middle segments of the left lung that corresponded well with laboratory test results, especially arterial blood gas analysis. The use of Electrical Impedance Tomography enables non-invasive, bedside, continuous assessment of regional lung ventilation. It is possible to use it in both mechanically ventilated and spontaneously breathing patients. It allows efficient and dynamic monitoring of the course of the therapeutic process. Interpretation of the results is relatively easy to learn and does not require specialist knowledge. Moreover, it is possible to use EIT in those cases where other methods are of high risk or contraindicated.",
"affiliations": "Department of Anaesthesiology and Intensive Care, Faculty of Medicine with Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, Poland. szymon.bialka@gmail.com.",
"authors": "Białka|Szymon|S|;Copik|Maja|M|;Rybczyk|Katarzyna|K|;Misiołek|Hanna|H|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5603/AIT.2017.0040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1642-5758",
"issue": "49(3)",
"journal": "Anaesthesiology intensive therapy",
"keywords": "electrical impedance tomography; intensive care; monitoring",
"medline_ta": "Anaesthesiol Intensive Ther",
"mesh_terms": "D001784:Blood Gas Analysis; D017097:Electric Impedance; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D016720:Pneumocystis Infections; D045363:Pneumocystis carinii; D012123:Pulmonary Ventilation; D012128:Respiratory Distress Syndrome; D014054:Tomography; D055815:Young Adult",
"nlm_unique_id": "101472620",
"other_id": null,
"pages": "222-226",
"pmc": null,
"pmid": "28803440",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Electrical impedance tomography for diagnosis and monitoring of pulmonary function disorders in the intensive care unit - case report and review of literature.",
"title_normalized": "electrical impedance tomography for diagnosis and monitoring of pulmonary function disorders in the intensive care unit case report and review of literature"
} | [
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"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-149204",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
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"actiondrug": "5",
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"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
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"abstract": "Transfusion-dependent β-thalassemia (TDT) is associated with several complications necessitating a multidisciplinary approach for diagnosis, treatment and follow-up. Hypogonadism in female TDT patients is one of the most common endocrine complications, requiring hormone replacement therapy (HRT) throughout reproductive life. Little is known about the balance of benefits versus risks of treatment with sex steroids.\n\n\n\nThe aim of this manuscript is to review the action and the associated adverse effects of HRT in hypogonadal TDT females.\n\n\n\nRetrospective medical database records from a single centre, over a period of 38 years (January 1980 to June 2018), were reviewed.\n\n\n\nForty-two cases of hypogonadism in TDT females followed in a pediatric and adolescent outpatient clinics, were in included in the study.\n\n\n\nAuxological, clinical, laboratory, hormonal and imaging investigations were reviewed, as well as all adverse events registered during HRT.\n\n\n\nIn general, HRT was safe for most patients. There were few minor side effects and a couple of rare but serious adverse events.\n\n\n\nThe study provides a representative clinical profile of long-term effects of HRT in hypogonadal adolescents and young adult TDT women. Our results highlight also the need for further research in other areas for which HRT may have a role. We hope this will contribute to a wider understanding, and potential improvement, of patient safety and quality of life.",
"affiliations": "Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy. vdesanctis@libero.it.",
"authors": "De Sanctis|Vincenzo|V|;Soliman|Ashraf T|AT|;Daar|Shahina|S|;Di Maio|Salvatore|S|;Yassin|Mohamed A|MA|;Canatan|Duran|D|;Vives Corrons|Joan-Lluis|JL|;Elsedfy|Heba|H|;Kattamis|Antonios|A|;Kattamis|Christos|C|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.23750/abm.v90i1.8143",
"fulltext": "\n==== Front\nActa BiomedActa BiomedActa Bio Medica : Atenei Parmensis0392-42032531-6745Mattioli 1885 Italy 30889170ACTA-90-15810.23750/abm.v90i1.8143Up to Date in Adolescentology - Original ArticleThe experience of a tertiary unit on the clinical phenotype and management of hypogonadism in female adolescents and young adults with transfusion dependent thalassemia Vincenzo De Sanctis 1Ashraf T. Soliman 2Shahina Daar 3Salvatore Di Maio 4Mohamed A Yassin 5Duran Canatan 6Joan-Lluis Vives Corrons 7Heba Elsedfy 8Antonios Kattamis 9Christos Kattamis 91 Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy2 Department of Pediatrics, Division of Endocrinology, Hamad General Hospital Doha, Qatar and Department of Pediatrics, Division of Endocrinology, Alexandria University Children’s Hospital, Alexandria, Egypt3 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Sultanate of Oman4 Emeritus Director in Pediatrics, Children’s Hospital “Santobono-Pausilipon”, Naples, Italy5 Hematology Section, National Center for Cancer Care and Research, Hamad Medical Corporation, (HMC), Doha, Qatar6 Director of Thalassemia Diagnosis Center of Mediterranean Blood Diseases Foundation Antalya, Turkey7 Red Blood Cell and Haematopoietic Disorders Unit. Institute for Leukaemia Research Josep Carreras (IJC) and University of Barcelona, Catalonia, Spain8 Department of Pediatrics, Ain Shams University, Cairo, Egypt9 First Department of Paediatrics, “Agia Sophia Children’s Hospital” National Kapodistrian University of Athens, Athens, GreeceCorrespondence: Vincenzo De Sanctis MD, Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital 44100 Ferrara, Italy Tel. +39 0532 770243 E-mail: vdesanctis@libero.it2019 90 1 158 167 23 1 2019 20 2 2019 Copyright: © 2019 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA2019This work is licensed under a Creative Commons Attribution 4.0 International LicenseBackground: Transfusion-dependent β-thalassemia (TDT) is associated with several complications necessitating a multidisciplinary approach for diagnosis, treatment and follow-up. Hypogonadism in female TDT patients is one of the most common endocrine complications, requiring hormone replacement therapy (HRT) throughout reproductive life. Little is known about the balance of benefits versus risks of treatment with sex steroids. Aim: The aim of this manuscript is to review the action and the associated adverse effects of HRT in hypogonadal TDT females. Design: Retrospective medical database records from a single centre, over a period of 38 years (January 1980 to June 2018), were reviewed. Study population: Forty-two cases of hypogonadism in TDT females followed in a pediatric and adolescent outpatient clinics, were in included in the study. Methods: Auxological, clinical, laboratory, hormonal and imaging investigations were reviewed, as well as all adverse events registered during HRT. Main results: In general, HRT was safe for most patients. There were few minor side effects and a couple of rare but serious adverse events. Conclusions: The study provides a representative clinical profile of long-term effects of HRT in hypogonadal adolescents and young adult TDT women. Our results highlight also the need for further research in other areas for which HRT may have a role. We hope this will contribute to a wider understanding, and potential improvement, of patient safety and quality of life. (www.actabiomedica.it)\n\ntransfusion-dependent β-thalassemiahypogonadismprimary and secondary amenorrheahormone replacement therapystrokethin endometriumadverse eventsICET-A\n==== Body\nIntroduction\nHypogonadism is one of the most common endocrine complications in transfusion dependent β-thalassemia patients (TDT). It is mainly caused by iron overload of the pituitary gland; in females it is clinically characterized by the absence of pubertal development or by menstrual cycle disturbances. Careful history, physical examination and selected laboratory testing can often detect the site of the defect. Hypogonadotropic hypogonadism (HH) is biochemically characterized by low serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and of sex steroids (1, 2).\n\nHormone replacement therapy (HRT) in patients with hypogonadism aims to alleviate symptoms of estrogen deficiency and prevent long-term complications, such as osteoporosis. Hormones are also important in female sexual functioning; low serum estrogen causes vaginal atrophy and higher vaginal pH, which predispose to infections, incontinence, and sexual dysfunction (3). Multiple formulations of estrogens are available for treatment: oral, micronized, vaginal, transdermal patches, and gel. Progesterone therapy is needed to avoid an unopposed estrogen effect and maintain endometrial health (3).\n\nThe dosage and route of administration of HRT is extremely complex because of the prolonged period of treatment which can run for decades and the changes in physical and psychological status of the individual over this period. Furthermore, HRT treatment is extremely complex in TDT patients because of associated co-morbidities, such as iron overload, thrombophilic status, chronic liver disease, impaired glucose tolerance or diabetes, and cardiomyopathy (4).\n\nDespite the large numbers of TDT patients for whom HRT is prescribed, few data exist to aid clinicians in making decisions on optimal treatment regimes. Furthermore, no reliable experiences or clinical studies about the potential risk factors and side effects of continuous hormonal therapy in adolescents and young adult TDT women with hypogonadism have been reported in the literature. Therefore the co-ordinator (VDS) of the International network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a retrospective study on the effects of HRT in hypogonadal women with TDT.\n\nIn this report the findings of the study are presented and discussed. We hope that our findings will promote further understanding of hypogonadism and will facilitate the management of young female TDT patients with HH.\n\nPatients and Methods\nForthy-two TDT patients were selected for the study: 26/42 (61.9%) patients regularly followed in Ferrara and 16/42 (38.1%) patients referred to the tertiary Ferrara clinic for endocrine investigations or second opinion. All patients were following the national (www.site-italia.org) and international guidelines of Thalassemia International Federation (TIF) (5).\n\nIn TDT patients regularly followed in Ferrara, transfusional management was changed over time. Before 1972, blood transfusions were given when anemia was severe enough to cause symptoms. Thereafter, patients were regularly transfused every 2-3 weeks to maintain the mean hemoglobin (Hb) level around 9.5 g/dl. Treatment with intramuscular desferrioxamine mesylate (DFO) at a dose of 20 mg/kg body weight (BW) was available for most patients since 1969. Regular subcutaneous (SC) DFO infusion was started in 1978 in patients older than 2 years. Initially, the recommended DFO dose was 20 mg/kg body weight administered daily at night, by infusion pump over 10 hours. Based on transfusional iron input the dose increased to 40 mg/kg BW in 1982 and up to 60 mg/kg BW in 1984. Ascorbic acid was added orally at a dose of 2-5 mg/kg (maximum dose 200 mg) in a selected group of patients. Since 1995, the oral chelator deferiprone (DFP) has been available; it was given at a dose of 75 mg/kg BW to some patients over the age of 11 years, as monotherapy or combined with DFO. In 2007, the new oral chelating agent deferasirox (DFX) was introduced at a dose of 25-30 mg/kg BW for patients in whom treatment with DFO was contraindicated or inadequate.\n\nA basic examination and a re-examination at 3-6-12 month intervals were carried out. Patients’ information were abstracted from medical database records, including: country of origin, demographic, clinical and pubertal characteristics, chelation therapy, diagnosis and treatment of hypogonadism, associated endocrine complications, bone metabolism and mineral density (BMD), pelvic ultrasonography, and associated adverse events (AE) registered during HRT.\n\nInclusion study criteria were: 1) diagnosis of TDT, based on universally accepted hematological criteria and 2) duration of follow-up not less than 4 years. Exclusion criteria were: 1) TDT patients with delayed puberty; 2) non-transfusion-dependent thalassemia patients (NTDT); 3) eating disorders; 4) renal insufficiency; 5) bone marrow transplanted patients; 6) patients positive for HIV and 7) TDT patients with incomplete data.\n\nHeights were routinely measured on a wall mounted stadiometer. Short stature was defined as height below the third percentile using the Italian growth charts of Cacciari et al. (6). Height velocity was calculated as the difference in height, divided by the difference in age between consecutive annual study visits. Body mass index (BMI) was assessed using the formula: kg/height in m2 (7). A subject was considered overweight when the BMI was between 25 and 30 and obese above 30 (8).\n\nSexual maturation was determined by physical examination. Tanner stage 2 breast (B2) development was used to define pubertal onset. Delayed puberty (DP) was diagnosed clinically as the absence of the first signs of pubertal development beyond the normal range for the population. In Italy, this means the absence of breast development (B2) by age of 13 years. Pubertal arrest was defined as the lack of pubertal progression for >2 years after spontaneous breast bud onset. Primary amenorrhoea (PA) was defined as the absence of menarche at the age of 16 years, and secondary amenorrhea (SA) as the cessation of menses for at least 6 months in an already cycling woman. HH was diagnosed in the presence of low serum concentrations of gonadotropins, in the setting of normal serum prolactin and low concentrations of 17 β-estradiol (E2 <20 pg/ml), in combination with signs and symptoms of estrogen deficiency.\n\nThe presence of associated endocrine complications was defined according to the I-CET guidelines, published in 2013 (8).\n\nSerum FSH, LH, prolactin, 17 β-estradiol, FT4, TSH, insulin, cortisol and ferritin were measured by radioimmunoassay, immunoradiometric assay or chemiluminescent assay.\n\nTo evaluate liver function, serum concentrations of alanine aminotransferase (ALT), gamma glutamyl transferase (γ GT), total and direct bilirubin, total proteins, and albumin were measured at 1-3 months intervals. Urea, creatinine, electrolytes, lipids [cholesterol, HDL, low-density lipoprotein (LDL), triglycerides], and coagulation tests (platelets count, prothrombin activity, activated thromboplastin time, fibrinogen, antithrombin III, protein C and S) were also assessed at 3-6 month intervals using routine laboratory methods.\n\nUterine development was evaluated by transabdominal ultrasound (US); size (uterine length and uterine volume), shape (by calculation of the fundus-to-cervix ratio) and maximum endometrial thickness (the highest value of endometrial thickness in the plane through the central longitudinal axis of the uterine body) were recorded. To characterize uterine maturity the following parameters were used: mature uterus: a length of ≥6.5 cm; transitional uterus: length 5.0-6.4 cm, and immature uterus: length <5.0 cm (9). The ovarian volume was calculated using the approximate formula for an ellipsoid: length × breath × width × 0.523.\n\nBone mineral densitometry (BMD) was measured at lumbar spine, from L2 to L4, and at the femoral neck using a DXA-scan (dual energy x-ray absorptiometry) device (Hologic). The diagnosis of osteopenia/osteoporosis was based on the definitions of the National Bone Health Alliance Working Group (10).\n\nIron overload was classified at the time of first examination, as mild (serum ferritin <1,000 ng/ml), moderate (serum ferritin >1,000 ng/ml to <2,000 ng/ml) or severe (serum ferritin >2,000 ng/ml). In females the manufacturer’s normal reference serum ferritin range values was 15-150 μg/l (11).\n\nHRT adverse event was defined as an unfavourable medical event that in coincidence may present during treatment with a pharmaceutical product, which does not necessarily have a causal relationship with the product. Attribution was also made if a major side effect resulted in discontinuation of the drug, even without re-challenge.\n\nAll procedures were carried out with the adequate understanding and consent of parents or patients. As the survey was a retrospective collection of data, research ethics committee approval was not required.\n\nStatistical analysis was carried by Student’s “t test”; a p value less than 0.05 was considered as the limit of significance. Linear regression analysis was employed for evaluating correlations between parameters.\n\nResults\nForty-two cases of hypogonadism in TM females of Italian ethnic origin were registered over a period of 38 years (January 1980 to June 2018). Sixteen out of 42 patients (38%) were examined for absence or arrested puberty, and 26 out of 42 patients (61.9%) for secondary amenorrhea which started from 6 months to 17.5 years (mean: 6.2±5.2 years) after menarche. Three patients (7.1%) reported a single menstrual cycle followed by a prolonged period of amenorrhea (6-9 months). At the first evaluation their median age was 21 years (range: 15-32 years), and their mean serum ferritin level was 2,470 ng/ml (range: 760-6,260 ng/ml).\n\nAt the last observation 32 patients were on treatment with subcutaneous DFO (76.1%), 8 with DFP (19%), and 2 with DFX (4.7%).\n\nThe diagnosis of HH was made based on the available medical records (Basal E2: 11.6±4.1 pg/mL - controls: 31.6±4.1 pg/mL, range: 28.0–40.0 pg/mL, p<0.01; basal FSH: 3.3±0.5 IU/L - controls: 10.2±3.8 IU/L, range: 7.3-13.2 IU/L, p<0.001; and basal LH: 3.6±1.0 IU/L - controls: 6.2±1.4 IU/L; range: 5.3-9.5 IU/L, p<0.001). After an acute Gn-RH stimulation test, a poor or lack of gonadotropins response was observed in all patients followed in Ferrara. Twenty-two healthy young adult women served as controls.\n\nFour patients were on treatment with L-thyroxine, (3 for primary and 1 for central hypothyroidism), 4 had insulin dependent diabetes, 5 an impaired glucose tolerance, and 4 were on treatment with calcitriol for hypoparathyroidism. Hypocortisolism (basal cortisol: 3.5 μg/dl=98 nmol/L or less) was not reported in the records of patients. None of them was on treatment with recombinant growth hormone.\n\nAll TDT patients received 6 different HRT regimes (Table 1). The majority (29/42, 69.0%) were taking either oral conjugated estrogens (CE) or oral contraceptive pills (CO). Relatively few were using transdermal or vaginal ring (Table 1). The latter treatment was mainly recommended by gynecologists. The patients were followed, regularly or occasionally, by the same clinician for a period of 4-24 years (median: 15 years).\n\nTable 1. Adverse events (AE) registered during hormone replacement therapy (HRT) in hypogonadal female TDT patients\n\nHRT treatments\tNumber of patients treated-(percentage)\t\nCyclic oral conjugated estrogen (CE: 0.3-0.625 mg daily, administered cyclically - e.g. three weeks on and one week off) combined with medroxyprogesterone acetate (MPA 5 mg in the last 12 days of CE)\t8/42 (19%)\t\nEthinyl estradiol (30 μg ) + gestodene (0,075 mg) (EE+GSD)\t13/42 (30.9%)\t\nEthinyl estradiol (20 μg) + desogestrel (0,15 mg) (EE+DSG)\t8/42 (19%)\t\nTransdermal estrogen (TE) patch (25-50 μg, administered cyclically - e.g. three weeks on and one week off) combined with medroxyprogesterone acetate (5 mg in the last 12 days of TE)\t9/42 (21.4%)\t\nVaginal ring (ethinyl estradiol/ etonogestrel) AE and HRT\t4/42 (9.5%)\t\nSkin irritation at the application site or discomfort on patch removal (TE)\t4/9 (44.4%)\t\nPartial patch detachment under conditions of heat, humidity, and exercise or partial peeling of the patch corner (TE)\t3/9 (33.3%)\t\nMild breast tenderness (EE+GSD)\t4/42 (9.5%)\t\nShorter duration of bleeding in patients with secondary amenorrhea (CE+ MPA and EE+DSG)\t5/42 (11.9%)\t\nFailure of endometrium to respond to estrogen (see results)\t3/42 (7.1%)\t\nDeterioration of glucose tolerance from normal to impaired (3 patients) from impaired to diabetes (1 patient) (EE+DSG and EE+DSG)\t4/42 (9.5%)\t\nMelasma of face (EE+DSG and EE+DSG)\t3/42 (7.1%)\t\nAcne (EE+DSG and EE+DSG)\t3/42 (7.1%)\t\nFluid retention (EE+GSD)\t2/42 (4.6%)\t\nMild elevation of liver enzymes (EE+DSG and EE+DSG)\t3/42 (7.1%)\t\nMild elevation of total bilirubin (EE+DSG and EE+DSG)\t3/42 (7.1%)\t\nMild elevation of lipids (EE+DSG and EE+DSG)\t3/42 (7.1%)\t\nHeadache (EE+GSD)\t2/42 (4.6%)\t\nUnusual weight gain (>3 kg) (EE+GSD)\t1/42 (2.3%)\t\nStroke (HRT: see results)\t1/42 (2.3%)\t\nRetinal artery spasm (HRT: see results)\t1/42 (2.3%)\t\nIn patients with PA, estrogen replacement was initiated at a low dose (ethinyl estradiol, 5 μg/d) and gradually increased, every 4-6 months, to a maximum dose of 20-30 μg/d. Medroxyprogesterone acetate (MPA 5 mg/d) was added when breakthrough bleeding occurred or after 24-28 months, on days 12-21 of each month, to induce menstrual flow. At this stage, HRT with oral conjugated equine estrogen (0.625 mg/d) combined with MPA, CO, 17 β-estradiol or by transdermal patch combined with MPA or ethinyl estradiol/ norelgestromin transdermal patch were advised and discussed (pros and cons) with the patient. CO was the most accepted method (49.9%) of HRT by the patients.\n\nThe compliance to HRT treatment was, in general, fair. Ten out of 42 TDT patients (23.8%) stopped HRT, after 6 months to 2 years, because of experience of discomfort, appearance of adverse events, or financial constraints.\n\nImaging of the uterus by transabdominal high-resolution US documented that only 50% of TM patients with PA had a mature, heart-shaped uterine configuration and endometrial thickness after 2-3 years of treatment; 19/42 patients (45.2%) presented a smaller sized uterus (transitional) with normal endometrial thickness and 2/42 patients (4.7%) a transitional uterus associated with thin endometrial lining (2-3 mm) with failure of endometrium to respond to long-term treatment with cyclic transdermal estrogen (TE: 37.5 μg and 50 μg, respectively; three weeks on and one week off) and MPA (5 mg in the last 12 days of TE). The same US finding was found in a patient with SA with failure of endometrium to respond to oral HRT with ethinyl estradiol 30 μg + gestodene 0.075 mg. In two patients with PA and transitional uterus, associated with thin endometrial lining, the serum ferritin levels were 3,420 ng/ml and 2,210 ng/ml, respectively, and 910 ng/ml in the patients with SA and failure of endometrium to respond to oral HRT. In spite of intensive iron chelation therapy, amenorrhea persisted. In general, ovarian US showed ovaries with a reduced volume, containing few small follicles.\n\nA reduction of BMD (osteopenia: Z score ≥-1.0 to -2.5 and osteoporosis: Z score ≤-2.5) at spine and/or femoral neck sites occurred in 81% of patients with PA and SA. The degree of low BMD was less evident in patients with a greater BMI and with recent development of SA [r (s)=0.239; p< and 0.172, respectively; p<0.01]. The BMD values increased during the first 2-3 years of treatment by an average of 7.7% at lumbar spine and of 8.9% at left femoral neck. Two patients with SA, during the HRT, presented fractures of ribs, secondary to a mild trauma.\n\nTwo severe adverse events (AE) were observed during the long-term HRT treatment: a stroke with right hemiparesis in a 31-year-old splenectomized TDT patient who had been taking sequential ethinyl estradiol (20 μg/d) combined with MPA for the last 3 years, and an episode of transient monocular visual loss in a 29-year-old splenectomised patient treated for the last 4 years, with a CO (ethinyl estradiol: 30 μg/d combined with a third-generation progestin). In both patients a family history of thromboembolism was negative. An immediate discontinuation of HRT was recommended in both patients.\n\nIn the first patient with stroke a systematic clinical and laboratory evaluation revealed normal blood pressure and BMI, negative history of migraine, severe iron overload (serum ferritin 3,215 ng/ml), diabetic curve after oral glucose tolerance test, and a hypercoagulable state condition (deficit protein C and S, and platelets count of 570 × 109). In the second patient, the vascular accident was due to central retinal artery spasm. It was not associated with migraine, smoking, obesity, hypertension, abnormal lipids or impaired glucose metabolism. Her serum ferritin level was 1,755 g/ml. Thrombocytosis post-splenectomy (platelets count: 480 x109), and a reduction of plasminogen <60% were documented. Both patients were on treatment with low dosage of acetylsalicylic acid (ASA:100 mg/d), as a thromboprophylaxis, but the compliance to treatment was inconsistent.\n\nSeven out of 9 patients (77.7%) complained of skin irritation at the patch application site, or patch detachment under conditions of heat, humidity, and exercise.\n\nShort stature (<2 SD below the mean height for age and sex) was reported in 10/16 patients (62.5%) with PA and in 6/26 patients (23.6%) with SA. A BMI between 25 and 30 kg/m2 was reported in 3 patients (32.1, 25.7 and 27.4 kg/m2, respectively). Reduced pubertal height gain (peak height velocity 5.8±2.0 cm, and pubertal growth gain to final height 13.7±3.0 cm) was observed in TDT patients with PA, while in European and British female population the average peak height velocity is 8.0±1.4 cm (12) and the contribution of pubertal growth to final height is ~25 cm, accounting for 17% of the final height.\n\nA deterioration of glucose tolerance was observed in 4 patients (2 with moderate and 2 with severe iron overload); in 3 patients from normal tolerance to impaired glucose tolerance (IGT) and 1 (with HCV related liver disease) from IGT to diabetes. The impact of HRT on blood pressure was negligible. The other AE registered in the database are reported in table 1.\n\nDiscussion\nThalassemic disorders have a spectrum of severity with different clinical phenotypes, complications, and strategies for treatment. The grade of this severity depends on the β-globin gene mutation and coinheritance of other genetic determinants. The degree of transfusion dependence is one of the elements considered in a recent classification of thalassemic disorders into TDT and NTDT. In TDT patients, iron accumulation in organ tissues is highly evident and leads to organ toxicity and dysfunction (1, 2).\n\nPatients with TDT have a variety of medical needs throughout their lives. Absent pubertal development and secondary amenorrhea due to HH are the most common complications in TDT patients. For the management of these patients no evidence-based guidelines exist, and recommendations are based on the theoretical knowledge of physiology and endocrinology, and extrapolated from the evidences of HRT in patients with estrogen deficiency, such as premature ovarian insufficiency.\n\nThe goals of therapy for hypogonadal adolescents or young adult females are the induction and maintenance of normal puberty, induction of fertility when the patient desires, psychosocial support, annual screening to assess metabolic and endocrine functions, and routine preventive health care. Young women with HH are also at risk for bone loss and fractures.\n\nMultiple formulations of estrogen are available and include oral estradiol, oral conjugated estrogens, transdermal estrogen patches, and gel. Transdermal estradiol may provide a more physiological mechanism for estrogen replacement than oral administration because of delivering estrogen into the systemic circulation and avoiding exposure of the liver to supraphysiological estrogen concentrations (13, 14).\n\nAt present, patients who have not yet started pubertal development, induction of puberty is initiated and carried out in a manner that simulates the normal growth and development of secondary sex characteristics as closely as possible. The inability to make an accurate differential diagnosis between delayed puberty and HH at initial presentation presents difficulties in providing appropriate counselling for prognosis; this may generate anxiety among adolescents and families, and can affect treatment decisions. Our policy is to treat these patients with a short low dose course of estrogens (3-4 months after the age of 13-14 years), and to monitor the following at regular intervals (3-4 months): sexual maturation (by Tanner staging on physical examination), gonadotropins and sex hormone levels, and bone age. In patients presenting with lack of spontaneous pubertal progression, estrogen therapy is restarted at low dose increased gradually (at intervals of 3-6 months).\n\nTransdermal E2 application avoids liver exposure to increased estrogen concentrations and provides a more physiologic mechanism for hormone delivery. Doses are adjusted to the response (Tanner stage, bone age or uterine growth), with the aim of completing feminization gradually over a period of 2-3 years, after which time cyclic progesterone is added (or after the first menstrual bleed) to maximize breast development.\n\nIn post-menarcheal TDT women who ceased menstruating due to acquired HH secondary to iron overload, estradiol is given orally (at a dose of 1-2 mg) or transdermally (50 μg daily by patch) as a maintenance dose with a cyclic progestin regimen (5 mg of MPA for 12-14 days of the month) to avoid endometrial hyperplasia. Oral contraceptives provide a variety of estrogen and progesterone forms and dosing options. Although there is no clinical trial to support an optimal length of time, HRT should continue at least until the average age of natural menopause (5).\n\nIf a risk of unwanted pregnancy cannot be ruled out, there is a need to consider contraception. Although no case of pregnancy was reported in our retrospective study, two patients (not included in the present study) complained of “irregular menstrual bleeding” during HRT; in both patients pregnancy test was positive. The first TDT patient had a spontaneous abortion after 3 weeks. The second patient, with successful bone-marrow transplantation, had a normal pregnancy and delivered a healthy boy (De Sanctis V, personal observations).\n\nDue to the long-term of treatment and the many physical and psychological changes that occur during this period, the treatment options should be carefully discussed with patient, considering the pros and cons of therapy, the patients’ age, the duration of hypogonadism, the medical history, and personal preferences (5).\n\nCO, containing ethinyl estradiol, or transdermal HRT are usually recommended by doctors and preferred by the patients. We assessed the attitudes and practices of doctors taking care of 2,326 females and males with TDT. Twelve different formulations and three routes of administration for HRT were used. In 33.3% of cases CO pill: ethinyl estradiol 30 μg/drospirenone 3 mg as first-line treatment choice followed by ethinyl estradiol 20 μg/drospirenone 3 (25%). Ethinyl estradiol 35 μg/cyproterone acetate 2 mg and ethinyl estradiol 20 μg/drospirenone 3 mg were reported, as second-line treatment choice, in 41.6% and 29.1%, respectively. Transdermal estrogen patch, ethinyl estradiol/ norelgestromin transdermal patch, and etonogestrel/ethinyl estradiol vaginal ring were used and recommended by 16.6%, 4.1%, and 4.1%, respectively (15).\n\nSimilar results emerged from an international survey conducted online, in July 2016. Oral HRT with different progestin contents were the first treatment choice in 11 centers (68.7%) (5).\n\nOral HRT has an increased risk for venous thromboembolic events (pulmonary embolism or deep vein thrombosis), and arterial thrombotic events (acute myocardial infarction, ischemic stroke), cardio metabolic changes (increase in blood pressure, unfavourable lipid profiles), and adverse liver dysfunction (16-18). In our patients, two severe AE have been observed during long-term HRT.\n\nIn a retrospective multicentre study, Taher et al. (19) reported that thromboembolic events (TE) occurred in a clinically relevant proportion (1.65%) of 8,860 thalassemia patients (75.3% with TDT). A survey, done in 9 Italian thalassemia Centres, disclosed that 32 patients out of a total of 735 (683 with TDT and 52 with NTDT), had venous thromboembolic events (VTEs) corresponding to an incidence of 3.95% and 9.61%, respectively. Localization of TE varied; the main one (16/32) involved central nervous system (20).\n\nSeveral factors have been implicated in the pathogenesis of the hypercoagulable state in patients with thalassemia, such as the specific changes in the lipid membrane composition of the abnormal red blood cells with increased expression of negatively charged phosphatidylserine at the outer surface, post splenectomy thrombocytosis, cardiac dysfunction, and liver dysfunction leading to protein C and protein S reduction. Furthermore, it has been suggested that absence of the spleen in a variety of hemolytic diseases may contribute to an increased propensity to thromboembolic complications, related to extreme thrombocytosis (21).\n\nThis potential risk was confirmed by Haghpanah and Karimi (22), The authors conducted an electronic search on PUBMED (MEDLINE), SCOPUS, and Google Scholar databases up to January 2011. Out of 152 thalassemic patients with cerebral thromboembolic events; 48% were splenectomised, Nine TDT patients had diabetes and activated protein C resistance, decreased protein C or protein S or plasminogen level were detected in 8 patients. In brief, cerebral involvement was associated with age (older patients), inadequate transfusion, splenectomy, thrombocytosis, and decreased protein C level (22).\n\nBefore prescribing any kind of HRT, physicians should be aware of the potential associated side effects of therapy and how best way to address them. Attention should be made before administration of HRT in TDT patients with splenectomy, impaired glucose tolerance/diabetes, hypercoagulable state (5), migraine with aura (23), and family history of thrombophilic defect. In TDT patients with a known hypercoagulable state (such as deficiency of antithrombin, protein C or protein S), that has been identified through screening, the pros and cons of HRT treatment should be discussed with a specialist. Patients should be informed that there is an increase in the risk of blood clots with HRT use and that there are symptoms that would prompt immediate medical attention, such as warning signs of VTEs (leg swelling or pain), visual disturbances, sensory or motor impairment, chest pain, and new headache.\n\nIn such patients, the application of transdermal estrogen can be considered after careful individual evaluation (24). Splenectomised TDT patients with hypogonadism on HRT should receive anti-platelet therapy with aspirin. Young women should be counselled as to alcohol and tobacco avoidance, daily exercise for obesity prevention, and an appropriate diet to achieve optimal cardiovascular health (5).\n\nPatients with a personal history of deep vein thrombosis, or pulmonary embolism are assigned to risk category 4, according to the World Health Organization Medical Eligibility Criteria (WHO MEC), “a condition which represents an unacceptable health risk if the contraceptive method is used” (25).\n\nIf HRT is contraindicated or declined, weight-bearing exercises, increased calcium and vitamin D intake, and avoidance of tobacco and alcohol should be recommended. It must be emphasized that these latter strategies have been shown to be inadequate at maintaining bone density in the reproductive-aged population (26). Clinicians should maintain serum 25-hydroxy-vitamin D levels in the normal range (30-80 ng/mL). Women with HH should take 1,000 to 2,000 IU of vitamin D3 (cholecalciferol) daily, along with 1200 mg of elemental calcium, either through dietary sources or supplements to optimize bone health. Bone density should be monitored every 12-24 months and follow-up visits should be scheduled at 6-12-month intervals with periodic laboratory testing.\n\nFailure of the endometrium to respond to oral or transdermal HRT was reported in 3 patients. A thin endometrium is mostly defined as an endometrial thickness of <7 mm and can result from various factors. The most common are inflammatory (acute or chronic infection can lead to the destruction of the basal layer of the endometrium) and iatrogenic (surgical, due to repeated or vigorous curettage damaging the basal layer of endometrium or indiscriminate use of drugs such as clomiphene citrate) (27). Thin endometrium may not necessarily be secondary to a disease process, because it can result from individual uterine architecture (28), intrinsic properties of endometrium that affect its growth (29), and inadequate estrogen stimulation for endometrial proliferation (30). In the general population, numerous treatments have been tried to improve refractory endometrium, but success has been limited (27).\n\nAn additional factor could be the increased iron content (hemosiderosis) of endometrium as documented by Birkenfeld et al. in 3 patients with TDT (31). Iron deposition was mainly evident in the apical part of endometrial glandular epithelium cells above the nuclei, and should be taken into consideration as a contributing factor to the infertility in these patients by altering endometrial receptivity for implantation (26). Iron chelating treatment with desferrioxamine induced a fully or significant regression of the endometrial hemosiderin (31).\n\nA deterioration of glucose tolerance was observed in 4 patients, from normal tolerance to impaired in 3 and from impaired to diabetes in 1 (with chronic HCV liver disease). Available data in a healthy population do not support a significant influence of OC on glucose and insulin homeostasis (32). It is highly likely that the risk of diabetes development depends on individual patient characteristics, such as family history of diabetes, age, ethnicity, BMI, severity of iron overload and presence of a chronic liver disease. Therefore, in patients with TDT a cardio-metabolic risk assessment needs to be performed, including a 75-g standard 2-hour OGTT and lipid profile at baseline and during follow-up at regular intervals. An annual visit is required to control for further compliance, side effects, and evaluation of glucose tolerance and lipids. Future studies evaluating the long-term effects and safety of oral HRT in the treatment of TDT patients with hypogonadism are needed.\n\nDespite an adequate HRT and general measures including control of anemia, adequate chelation therapy, healthy nutrition and lifestyle, two insufficiency fractures of ribs were registered in our patients with SA. Therefore, since the origin of bone disease in TDT is multifactorial and some of the underlying pathogenic mechanisms are still unclear, further research in this field is needed, to design the optimal therapeutic measures (33).\n\nMelasma of face was reported in 3 patients. It is a common dermatosis that involves changes in normal skin pigmentation, resulting from the hyperactivity of epidermal melanocytes, predominantly affecting women of childbearing age. The pathogenesis is not yet fully understood, but there is relation with a genetic component, sun exposure, OC, HRT, cosmetics, photosensitising medication, pregnancy, and psychological stress (34, 35).\n\nIn summary, TDT is a chronic disease associated with a number of complications and conditions which need the attention of specialised multidisciplinary teams for diagnosis, treatment and follow-up. TDT patients with complications need optimum surveillance strategies. Despite the wide agreement that hormonal substitution remains the most effective option for treating the signs and symptoms of hypogonadism, a careful evaluation of the benefit-risk balance is essential prior to prescribing a HRT regimen. Our results highlight also the need for further research in other areas for which HRT may have a role. These areas include: growth, skeletal development and mineralization, glucose tolerance, safety, social interactions, and sexuality. Therefore, research consortia should be established to allow investigation of these important questions, and to allow clinicians to make judicious analysis for the best possible health care decisions.\n\nConflict of interest:\nNone to declare\n==== Refs\nReferences\n1 Vogiatzi MG Macklin EA Trachtenberg FL Fung EB Cheung AM Vichinsky E Olivieri N Kirby M Kwiatkowski JL Cunningham M Holm IA Fleisher M Grady RW Peterson CM Giardina PJ Thalassemia Clinical Research Network. Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America Br J Haematol 2009 146 546 556 19604241 \n2 De Sanctis V Elsedfy H Soliman AT Elhakim IZ Soliman NA Elalaily R Kattamis C Endocrine profile of β-thalassemia major patients followed from childhood to advanced adulthood in a tertiary care center Indian J Endocrinol Metab 2016 20 451 459 27366710 \n3 Davenport ML Moving toward an understanding of hormone replacement therapy in adolescent girls: Looking through the lens of Turner syndrome Ann N Y Acad Sci 2008 1135 126 137 18574218 \n4 De Sanctis V Soliman AT Elsedfy H Albu A Al Jaouni S Anastasi S Bisconte MG Canatan D Christou S Daar S Di Maio S El Kholy M Khater D Elshinawy M Kilinc Y Mattei R Mosli HH Quota A Roberti MG Sobti P Yaarubi SA Canpisi S Kattamis C Review and Recommendations on Management of Adult Female Thalassemia Patients with Hypogonadism based on Literature Review and Experience of ICET-A Network Specialists Mediterr J Hematol Infect Dis 2017 Jan 1 9 1 e2017001 doi: 10.4084/MJHID.2017.001 28101307 \n5 Thalassemia International Federation Guidelines to the Clinical Management of Thalassaemia First Edition 2000 and Second Edition 2007 \n6 Cacciari E Milani S Balsamo A Dammacco F De Luca F Chiarelli F Pasquino AM Tonini G Vanelli M Italian cross-sectional growth charts for height, weight and BMI (6-20 y) Eur J Clin Nutr 2002 56 171 180 11857051 \n7 Cacciari E Milani S Balsamo A Spada E Bona G Cavallo L Cerutti F Gargantini L Greggio N Tonini G Cicognani A Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr) J Endocrinol Invest 2006 29 581 593 16957405 \n8 De Sanctis V Soliman AT Elsedfy H Skordis N Kattamis C Angastiniotis M Karimi M Yassin MA El Awwa A Stoeva I Raiola G Galati MC Bedair EM Fiscina B El Kholy M Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines Indian J Endocrinol Metab 2013 17 8 18 23776848 \n9 Snajderova M Mardesic T Lebl J Gerzova H Teslik L Zapletalova J The uterine length in women with Turner syndrome reflects the postmenarcheal daily estrogen dose Horm Res 2003 60 198 204 14530609 \n10 Siris ES Adler R Bilezikian J Bolognese M Dawson-Hughes B Favus MJ Harris ST Jan de Beur SM Khosla S Lane NE Lindsay R Nana AD Orwoll ES Saag K Silverman S Watts NB The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group Osteoporos Int 2014 25 1439 1443 24577348 \n11 De Sanctis V Elsedfy H Soliman AT Elhakim IZ Kattamis C Soliman NA Elalaily R Clinical and Biochemical Data of Adult Thalassemia Major patients (TM) with Multiple Endocrine Complications (MEC) versus TM Patients with Normal Endocrine Functions: A long-term Retrospective Study (40 years) in a Tertiary Care Center in Italy Mediterr J Hematol Infect Dis 2016 Apr 12 8 1 e2016022 doi: 10.4084/MJHID.2016.022 27158435 \n12 Preece MA Baines MJ A new family of mathematical models describing the human growth curve Ann Hum Biol 1978 5 1 24 646321 \n13 Kenigsberg L Balachandar S Prasad K Shah B Exogenous pubertal induction by oral versus transdermal estrogen therapy J Pediatr Adolesc Gynecol 2013 26 71 79 22112543 \n14 Ankarberg-Lindgren C Elfving M Wikland KA Norjavaara E Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls J Clin Endocrinol Metab 2001 86 3039 3044 11443165 \n15 De Sanctis V Soliman AT Elsedfy H Di Maio S Current practice in treating adult female thalassemia major patients with hypogonadism: An International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine survey from Italy Indian J Endocrinol Metab 2016 20 880 881 27867897 \n16 Hannaford P Croft P Kay C Oral contraception and stroke Stroke 1994 25 935 942 8165687 \n17 Sidney S Cheetham TC Connell FA Ouellet-Hellstrom R Graham DJ Davis D Sorel M Quesenberry CP Jr Cooper WO Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users Contraception 2013 87 93 100 23083525 \n18 Adlercreutz H Tenhunen R Some aspects of the interaction between natural and synthetic female sex hormones and the liver Am J Med 1970 49 630 648 4924590 \n19 Taher A Isma’eel H Mehio G Bignamini D Kattamis A Rachmilewitz EA Cappellini MD Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran Thromb Haemost 2006 96 488 491 17003927 \n20 Borgna Pignatti C Carnelli V Caruso V Dore F De Mattia D Di Palma A Di Gregorio F Romeo MA Longhi R Mangiagli A Melevendi C Pizzarelli G Musumeci S Thromboembolic events in beta thalassemia major: an Italian multicenter study Acta Haematol 1998 99 76 79 9554453 \n21 Cappellini CD Grespi E Cassinerio E Bignamini D Fiorelli G Coagulation and splenectomy: an overview Ann N Y Acad Sci 2005 1054 317 324 16339680 \n22 Haghpanah S Karimi M Cerebral thrombosis in patients with β-thalassemia: a systematic review Blood Coagul Fibrinolysis 2012 23 212 217 22322139 \n23 Agostoni EC Longoni M Migraine and cerebrovascular disease: still a dangerous connection? Neurol Sci 2018 39 Suppl 1 33 37 29904830 \n24 Canonico M Oger E Plu-Bureau G Conard J Meyer G Lévesque H Trillot N Barrellier MT Wahl D Emmerich J Scarabin PY Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study Circulation 2007 115 840 845 17309934 \n25 National Center for Chronic Disease Prevention and Health Promotion Division of Reproductive Health Medical Eligibility Criteria for Contraceptive Use Fourth Edition Available from: http://www.cdc. gov/mmwr/preview/mmwrhtml/rr59e0528a1.htm \n26 Cox L Liu JH Primary ovarian insufficiency: an update Int J Womens Health 2014 6 235 243 24591848 \n27 Mahajan N Sharma S The endometrium in assisted reproductive technology: How thin is thin? J Hum Reprod Sci 2016 9 3 8 27110071 \n28 Dain L Bider D Levron J Zinchenko V Westler S Dirnfeld M Thin endometrium in donor oocyte recipients: Enigma or obstacle for implantation? Fertil Steril 2013 100 1289 1295 23954352 \n29 Strohmer H Obruca A Radner KM Feichtinger W Relationship of the individual uterine size and the endometrial thickness in stimulated cycles Fertil Steril 1994 61 972 975 8174740 \n30 Scioscia M Lamanna G Lorusso F Serrati G Selvaggi LE Depalo R Characterization of endometrial growth in proliferative and early luteal phase in IVF cycles Reprod Biomed Online 2009 18 73 78 19146772 \n31 Birkenfeld A Goldfarb AW Rachmilewitz EA Schenker JG Okon E Endometrial glandular haemosiderosis in homozygous beta-thalassaemia Eur J Obstet Gynecol Reprod Biol 1989 31 173 178 2759323 \n32 Troisi RJ Cowie CC Harris MI Oral contraceptive use and glucose metabolism in a national sample of womenin the United States Am J Obstet Gynecol 2000 183 389 395 10942475 \n33 De Sanctis V Soliman AT Elsefdy H Soliman N Bedair E Fiscina B Kattamis C Bone disease in β thalassemia patients: past, present and future perspectives Metabolism 2018 80 66 79 28987275 \n34 Chang MW Bolognia J Jorizzo JL Schaffer JV Chapter 67: Disorders of hyperpigmentation Dermatology 2012 3rd ed Philadelphia Elsevier Saunders 1052 1054 \n35 Miot LD Miot HA Silva MG Marques ME Physiopathology of melasma An Bras Dermatol 2009 84 623 635 20191174\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "90(1)",
"journal": "Acta bio-medica : Atenei Parmensis",
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"medline_ta": "Acta Biomed",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001803:Blood Transfusion; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D007006:Hypogonadism; D010641:Phenotype; D012189:Retrospective Studies; D055815:Young Adult; D017086:beta-Thalassemia",
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"pubdate": "2019-01-23",
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"title": "The experience of a tertiary unit on the clinical phenotype and management of hypogonadism in female adolescents and young adults with transfusion dependent thalassemia.",
"title_normalized": "the experience of a tertiary unit on the clinical phenotype and management of hypogonadism in female adolescents and young adults with transfusion dependent thalassemia"
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"abstract": "Haploidentical stem cell transplantation provides a plausible alternative for the patients when a fully matched donor is unavailable. Historically, the decision of considering haploidentical transplant has remained elusive; however, with the recent advances, the consideration of haploidentical grafts as a treatment option has become more apparent for both allografting for diseases and engraftment failure. We are reporting here an anecdotal case of a successful haploidentical engraftment in a patient with the prior graft failure of an HLA-matched related donor. Since the patient was severely alloimmunized, desensitization protocol was utilized before the haploidentical transplant, and the patient after 8 months of her second allogeneic transplantation is doing great with successful engraftment, no relapse, and no graft-versus-host disease (GVHD). Numerous reports pertinent to haploidentical graft have shown favorable outcomes in the graft placement, a decline in the rate of GVHD, and an improvement in the morbidity and mortality in affected individuals. Based on the current reports, haploidentical transplantation might be more feasible and has meaningful implications in the situations where matched donors are infrequent.",
"affiliations": "Department of Internal Medicine, Seton Hall University (St Francis) Program, Trenton, USA.;Department of Internal Medicine, University at Buffalo (Catholic Health System-Sisters of Charity) Program, Buffalo, USA.;Department of Internal Medicine, Allegheny Health Network, Pennsylvania, USA.;Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.;Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.;King Faisal University Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.",
"authors": "Aslam|Hafiz Muhammad|HM|0000-0001-5489-4730;Iqbal|Shumaila Muhammad|SM|0000-0002-9476-9560;Shaikh|Hira|H|;Faizee|Faizan A|FA|;Merchant|Ambreen A|AA|;Shaheen|Marwan|M|;Hashmi|Shahrukh K|SK|0000-0002-8914-7927",
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"doi": "10.1155/2018/2573657",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/2573657Case ReportHaploidentical Stem Cell Transplantation: A Gateway to Infrequent Availability of HLA-Matched Related Donors http://orcid.org/0000-0001-5489-4730Aslam Hafiz Muhammad muhammadaslamsaleem@hotmail.com\n1\nhttp://orcid.org/0000-0002-9476-9560Iqbal Shumaila Muhammad \n2\nShaikh Hira \n3\nFaizee Faizan A. \n4\nMerchant Ambreen A. \n4\nShaheen Marwan \n5\nhttp://orcid.org/0000-0002-8914-7927Hashmi Shahrukh K. \n6\n\n1Department of Internal Medicine, Seton Hall University (St Francis) Program, Trenton, USA\n2Department of Internal Medicine, University at Buffalo (Catholic Health System-Sisters of Charity) Program, Buffalo, USA\n3Department of Internal Medicine, Allegheny Health Network, Pennsylvania, USA\n4Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan\n5King Faisal University Hospital and Research Center, Riyadh, Saudi Arabia\n6Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN 55905, USAAcademic Editor: Simone Cesaro\n\n2018 10 9 2018 2018 257365718 5 2018 19 7 2018 12 8 2018 Copyright © 2018 Hafiz Muhammad Aslam et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Haploidentical stem cell transplantation provides a plausible alternative for the patients when a fully matched donor is unavailable. Historically, the decision of considering haploidentical transplant has remained elusive; however, with the recent advances, the consideration of haploidentical grafts as a treatment option has become more apparent for both allografting for diseases and engraftment failure. We are reporting here an anecdotal case of a successful haploidentical engraftment in a patient with the prior graft failure of an HLA-matched related donor. Since the patient was severely alloimmunized, desensitization protocol was utilized before the haploidentical transplant, and the patient after 8 months of her second allogeneic transplantation is doing great with successful engraftment, no relapse, and no graft-versus-host disease (GVHD). Numerous reports pertinent to haploidentical graft have shown favorable outcomes in the graft placement, a decline in the rate of GVHD, and an improvement in the morbidity and mortality in affected individuals. Based on the current reports, haploidentical transplantation might be more feasible and has meaningful implications in the situations where matched donors are infrequent.\n==== Body\n1. Introduction\nAllogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment modality for hematological and nonhematological malignancies, primary immunodeficiency syndromes, and bone marrow failure syndromes. The pluripotent stem cells are acquired from the bone marrow or peripheral blood of an HLA-matched or HLA-unmatched donor in the cases of allogeneic HCT. Historically, matched-related donors were considered as the first preference for transplantation; however, only 20–30% patients have siblings that are HLA-identical [1, 2]. Matched-unrelated donors have been used with increasing frequencies in scenarios where matched-related donors are unavailable. Excessive amount is consumed to coordinate with some registries internationally, though some registries have a quicker turn around. Nonetheless, the time required for a readily available family member is shorter than that required for finding an unrelated donor; therefore, the chances of finding an unmatched donor for cases in which immediate HCT is required is lost [3]. HLA haploidentical stem cell transplantation (haplo HCT) is another alternative treatment modality where only one HLA haplotype is matched with an individual. The use of haplo HCT in the prior decade was mainly obscured by the high rates of graft failure, graft-versus-host disease, and infectious complications [4, 5]. Another predicament prohibiting its widespread use was the limited availability of prospective comparative studies. Furthermore, the presence of donor-specific antibodies (DSA) in the recipient created a significant hindrance to successful transplantation. Further clinical studies are ought to be done to contemplate the significance of haplo HCT and its preference over match-related and unrelated donors [6].\n\n2. Case\nA 40-year-old female, a known case of hypothyroidism, was discovered to have incidental pancytopenia while she was being managed for vocal cord papilloma at a tertiary care center. Extensive invasive workup for pancytopenia could not be ensued because of patient refusal. Almost a year later, the patient at 30 weeks of gestation presented to the hospital with severe fatigue. Her laboratory results revealed pancytopenia (white blood cell (WBC) count) of 2.8 × 109/L, hemoglobin (Hb) of 9.5 g/dL, platelet (Plt) count of 150 × 109/L, serum folate of 26 nmol/L, and serum B12 of 160 pg/mL along with normal renal/liver function profile and normal viral hepatitis serology reports. Peripheral blood morphology was performed, showing severe neutropenia and toxic granulation. Bone marrow biopsy demonstrated reduced cellularity (10–15%), reduced erythropoiesis, granulopoiesis, and megakaryocytes. Fluorescence in situ hybridization and flow cytometry studies revealed no evidence of bone marrow infiltration or leukemia.\n\nTwo months after uncomplicated normal vaginal delivery, the patient presented to the hospital with aplastic anemia, evident by her complete blood count: WBC of 1 × 109/L, absolute neutrophil count (ANC) of 0.05, Hb of 7.8 g/dL, and Plt of 5 × 109, and the bone marrow biopsy revealed markedly reduced cellularity with many lymphoid aggregates and no clear dysplastic changes or evidence of malignancy. Molecular study (BCR-ABL by PCR), cytogenetic study (Karyotyping), and chromosome breakage study were performed. The molecular study and chromosome breakage study came negative, and there was no growth on the karyotyping by G-banding.\n\nThe patient was kept under observation in the hospital while tests were performed on her family to search for a HLA-matched donor. Her brother was subsequently found to be a full HLA-match. The preparative regimen for transplantation consisted of cyclophosphamide (total dose: 200 mg/kg) and along with antithymocyte globulin (ATG; thymoglobulin Genzyme©).\n\nThe patient developed a fever on the 10th day of transplantation with skin redness and swelling on the intravenous line sites. She was administered cefepime and vancomycin, which was later switched to meropenem (blood cultures revealed positive Pseudomonas aeruginosa colonies). Furthermore, ultrasonography was performed, showing edema with mildly increased vascularity in accordance with inflammation and no signs of abscess. Skin biopsy was done, indicating dermal edema and dermal RBC extravasation. She also developed cyclosporine-related hypertension which was managed by amlodipine administration. The patient was started on granulocyte colony stimulating factor (G-CSF) at 300 mcg daily.The patient's cell counts did not rise significantly (WBC of 0.18 × 109/L, Hb of 9.8 mg/dL, and Plt of 2 × 109/L) ten days after administration of G-CSF; therefore, the dosage of G-CSF was further increased to 5 mcg/kg/day. Chimerism studies at day +30 after transplantation indicated 25% donor lymphoid cell engraftment on peripheral blood, and bone marrow (BM) biopsy showed a cellularity of 5%. The patient was eventually declared as graft failure.\n\nThe patient's state of health was discussed in the BMT didactic conference; the team decided to consider the patient for salvage haploidentical HCT after conditioning. It is worthwhile in general to wait until day +60 for engraftment failure before taking a major step like a second allogeneic transplant; however, the patient's risk of infections was significantly high, and thus waiting for an extra month would have possibly led to fatal infections. Thus, workup for second allogeneic transplant started around 5 weeks from the first transplant. The conditioning regimen comprised of antithymocyte globulin (ATG), total body irradiation (TBI), and fludarabine. ATG brand THYMOGLOBULIN (Genzyme) at a dose of 9 mg was used in conditioning. Same brand was used for both transplants. DSAs before the second transplant to the selected donor were found in DRB1 and DQB1 as follows: anti-DRB1 mean fluorescence intensity (MFI) = 3154 and anti-DQB1 MFI = 2141.\n\nThe patient received haploidentical stem cells from her other sibling. She received CD34+ count of 11.12 × 106/kg after conditioning with the aforementioned conditioning regimen. Total time difference between the 2 transplants was 65 days (first allogeneic transplant: 20th December 2016; second allogeneic transplant: 23rd February 2017). After transplantation, the patient remained asymptomatic with no signs or symptoms suggestive of acute GVHD or infections in acute posttransplant phase. Her laboratory results demonstrated ANC > 0.5 and platelet >200 × 109/L at day +10 after transplantation. The patient was further managed with intensified immunosuppressive therapy, which includes tacrolimus and mycophenolate. The patient was discharged on pertinent medications and was advised to follow up with her primary care physician.\n\nFive months after transplantation, the patient presented to the hospital with fever and diarrhea for 3 days; it was initially managed with antibiotics. However, her condition deteriorated without significant improvement. On performing further investigations, she was found to have Clostridium difficile (C. diff) positive stool, asymptomatic urinary tract infection (UTI) evident by E. coli positivity in urine culture report, acute kidney injury (AKI) possibly due to dehydration, and elevated tacrolimus blood levels. The patient's condition gradually improved after administration on antibiotics (metronidazole and ciprofloxacin for C. diff and UTI, respectively) and was eventually discharged.\n\nIn order to rule out GVHD, colonoscopy was performed; it demonstrated moderate ulcerative colitis, which came out negative for mucosal architectural distortion and ulceration, microorganism viral cytopathic effect, granuloma, and adenomatous dysplastic change. Typical morphological features of acute or chronic GVHD were not evident on colonic biopsy; a microbiological correlation was suggested to rule out the possibility of infectious colitis. Her laboratory results revealed the following: white blood cell (WBC) of 5.9 × 109/L, hemoglobin (Hb) of 13.2 mg/dL, platelets (Plt) of 189 × 109/L, and absolute neutrophil count (ANC) was normal. Renal function displayed improvement showing a precipitous decline in blood creatinine levels from 300 µmol/L to 74 µmol/L, GFR turned out to be greater than 60 mL/min/1.73 m2, and potassium levels were 4.4 mm/L. Tacrolimus levels were found to be therapeutic (serum level: 10.9 ng/mL).\n\nHer dose of tacrolimus was reduced, keeping in consideration the blood levels of tacrolimus. The patient was subsequently discharged on pertinent medications and was instructed to follow up with her primary care physician.\n\n3. Discussion\nMatched-related and matched-unrelated donor sources have served as a gold standard for many years in the field of HCT. The outcome of HCT has been proven to be greatly affected by the HLA incompatibilities between the host and the donor; the problem is dealt by finding a donor that is HLA compatible with the recipient. Due to the limited availability of HLA-matched donor, and the time spent to find matched-unrelated donors, haploidentical donors have provided us with a reasonable alternative because almost everyone has at least one haploidentical relative. Haploidentical transplantation method is considered to be a relatively novel technique but it poses challenges due to the limited availability of the clinical data.\n\nSeveral studies using haploidentical grafts resulted in high rates of graft failure in the past, leading to a decline in the use of haploidentical grafts. With recent advances, several strategies are implicated like administration of posttransplant immunosuppressive agents, and reduced intensity conditioning regimens have yielded encouraging results in the survival of patient receiving haploidentical grafts [5, 7–9].\n\nBased on a study by Esteves et al., transplant-associated fatalities due to bacterial sepsis, pulmonary aspergillosis, viral infections, toxoplasmosis, and severe GVHD can negatively influence a patient's prognosis with haplo HCT. The risk of severe GVHD occurrence can be abrogated by posttransplant cyclophosphamide to quite an extent [10]. Studies on HCT in severe refractory aplastic anemia, when posttransplant cyclophosphamide was utilized, have revealed remarkably less morbidities like GVHD, which are generally sensitive to steroids [5]. Another study demonstrated that the patients with secondary graft failure, at the time of neutrophil engraftment, received salvage transplantation which caused complete donor chimerism. Overall, 15 patients underwent neutrophilic engraftment out of which two died and one of the patient started on ELTROMBOPAG, after which cell count starts to improve. Remaining 12 obtained the platelet engraftment. Amidst 12, two went for salvage haplo HCT from a different donor due to secondary failure. Only one patient experienced a grade 4 GVHD and demanded treatment for refractory GVHD. Each patient died of transplant related mortality with no relapse. Those with hematological malignancies have a higher incidence of relapse following haplo HCT [10]. Another study showed 30% of patients with hematological malignancies like leukemia and lymphoma exhibited grade 3–5 toxicities after haplo HCT. Median follow-up after transplant was 375 days, and relapse was the cause of death [11]. Most prevalent infection after the administration of pretransplant cyclosporine was the reactivation of CMV. Majority of the patients died due to transplant-related mortality such as GVHD, regimen-associated toxicity, primitive graft failure, and EBV, respectively [12]. At approximately a year of enduring myeloid engraftment, 89 patients of haploidentical donor revealed increase combined incidence of 2–4 aGVHD, 3–4 aGVHD, and chronic GVHD but similar rate of chronic extensive GVHD. Increased amount of transfusion and lower performance status before HCT unfavorably influenced the overall survival rate [12].\n\nBased on the evidence-based data, we initially grafted a matched-related specimen in our patient to ensure the least chances of graft rejection; nevertheless, the failure led us to haploidentical grafting, and it exhibited surprisingly affirmative result. Engraftment was stable without any clinical evidence of GVHD. Razari et al. reported successful haploidentical engraftment in approximately 94% of patients with hematological malignancies. For this series, they selected adult patients with nonmyeloablative transplant using 3/6 HLA-matched family donors [13]. The series demonstrated promising result in the survival of the patient in comparison with matched-related/unrelated donor. O'Donnell et al. conducted unrelated-haploidentical transplant with immunosuppression with cyclophosphamide which showed favorable results in promoting engraftment and preventing GVHD [14].\n\nHaplo HCT could be a good alternative in transplantation, as several case reviews have shown encouraging outcomes and improved survival rates amongst the patients. Further clinical studies are warranted to reach a more definite conclusion. Our case represents favorable results that haploidentical engraftment might have on patients' survival after engraftment failure from the first allograft. It is, however, too early to draw definite conclusions to consider this as a standard of care for engraftment failure. Further advances and more prospective clinical studies might turn out in the favor of haploidentical engraftment procedures. Additionally, many different desensitization strategies are being utilized by different institutions globally [15].\n\n4. Conclusion\nNumerous studies pertinent to haploidentical graft have shown favorable outcomes in the graft placement, a decline in the rate of GVHD, and an improvement in the morbidity and mortality in affected individuals. Based on the current reports, haploidentical HCT might be more feasible and has meaningful implications in the situations where matched donors are infrequent for engraftment failure.\n\nAcknowledgments\nThe authors specially acknowledge to all hematology department members of King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.\n\nConsent\nThe authors declare that they took informed consent from the patient.\n\nConflicts of Interest\nNone of the authors declare any relevant conflicts of interest.\n==== Refs\n1 Kernan N. A. Bartsch G. Ash R. C. Analysis of 462 transplantations from unrelated donors facilitated by the national marrow donor program New England Journal of Medicine 1993 328 9 593 602 10.1056/nejm199303043280901 2-s2.0-0027526116 8429851 \n2 Dominietto A. Raiola A. M. van Lint M. T. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose British Journal of Haematology 2001 112 1 219 227 10.1046/j.1365-2141.2001.02468.x 2-s2.0-0035130796 11167808 \n3 Weisdorf D. J. Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation Blood 2002 99 6 1971 1977 10.1182/blood.v99.6.1971 2-s2.0-0037085807 11877268 \n4 Mattsson J. Ringdén O. Storb R. Graft failure after allogeneic hematopoietic cell transplantation Blood and Marrow Transplantation 2008 14 1 165 170 10.1016/j.bbmt.2007.10.025 2-s2.0-37348999625 \n5 DeZern A. E. Zahurak M. Symons H. Cooke K. Jones R. J. Brodsky R. A. Alternative donor transplantation with high-dose post-transplantation cyclophosphamide for refractory severe aplastic anemia Biology of Blood and Marrow Transplantation 2017 23 3 498 504 10.1016/j.bbmt.2016.12.628 2-s2.0-85009755014 28013015 \n6 Han L. J. Wang Y. Fan Z.-P. Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard-risk acute lymphoblastic leukaemia in first complete remission British Journal of Haematology 2017 179 1 120 130 10.1111/bjh.14854 2-s2.0-85029780443 28737249 \n7 Bethge W. A. Haegele M. Faul C. Haploidentical allogeneic hematopoietic cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity Experimental Hematology 2006 34 12 1746 1752 10.1016/j.exphem.2006.08.009 2-s2.0-33751545241 17157172 \n8 Chiusolo P. Bug G. Olivieri A. A modified post-transplant cyclophosphamide regimen, for unmanipulated haploidentical marrow transplantation, in acute myeloid leukemia: a multicenter study Biology of Blood and Marrow Transplantation 2018 24 6 1243 1249 10.1016/j.bbmt.2018.01.031 2-s2.0-85042846121 29421292 \n9 McCurdy S. R. Kanakry C. G. Tsai H.-L. Grade II acute graft-versus-host disease and higher nucleated cell graft dose improve progression-free survival after HLA-haploidentical transplant with post-transplant cyclophosphamide Biology of Blood and Marrow Transplantation 2018 24 2 343 352 10.1016/j.bbmt.2017.10.023 2-s2.0-85037029493 29055682 \n10 Esteves I. Bonfim C. Pasquini R. Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study Bone Marrow Transplantation 2015 50 5 p. 685 10.1038/bmt.2015.20 2-s2.0-84928927765 \n11 Miao M. Zhang X. Xu T. Haploidentical hematopoietic stem cell transplantation for acquired severe aplastic anemia American Society of Hematology 2015 126 23 p. 3227 \n12 Xu L.-P. Jin S. Wang S.-Q. Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant Journal of Hematology and Oncology 2017 10 1 p. 25 10.1186/s13045-017-0398-y 2-s2.0-85009962381 28107815 \n13 Sierra J. Storer B. Hansen J. A. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience Bone Marrow Transplantation 2000 26 4 397 404 10.1038/sj.bmt.1702519 10982286 \n14 O’Donnell P. V. Luznik L. Jones R. J. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide Biology of Blood and Marrow Transplantation 2002 8 7 377 386 10.1053/bbmt.2002.v8.pm12171484 2-s2.0-0036045174 12171484 \n15 Gladstone D. E. Zachary A. A. Fuchs E. J. Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies Biology of Blood and Marrow Transplantation 2013 19 4 647 652 10.1016/j.bbmt.2013.01.016 2-s2.0-84875503612 23353119\n\n",
"fulltext_license": "CC BY",
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"title": "Haploidentical Stem Cell Transplantation: A Gateway to Infrequent Availability of HLA-Matched Related Donors.",
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"abstract": "BACKGROUND\nSodium-glucose co-transporter 2 (SGLT-2) inhibitors are relatively new antihyperglycemic agents that lower renal glucose reabsorption. They are used as adjunctive therapy to standard diabetes treatment.\n\n\nMETHODS\nWe present the case of a 62-year-old woman with a past medical history of type 2 diabetes mellitus and sudden-onset diabetic ketoacidosis (DKA). Use of canagliflozin, a SGLT-2 inhibitor, was determined to be the cause of the DKA. The patient ultimately recovered after 5 days in the intensive care unit. She was changed to long- and short-acting insulins and instructed to avoid canagliflozin.\n\n\nCONCLUSIONS\nAlthough SGLT-2 inhibitors are effective at lowering a patient's hemoglobin A1C, physicians must be aware of the rare but dangerous potential adverse effect of inducing DKA. This article reports an illustrative case and presents a review of the literature.",
"affiliations": "Texas Tech University Health Sciences Center, Amarillo, TX, USA.;Texas Tech University Health Sciences Center, Amarillo, TX, USA.;Texas Tech University Health Sciences Center, Amarillo, TX, USA.",
"authors": "Turner|Jessica|J|;Begum|Tahmina|T|;Smalligan|Roger D|RD|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961666323110.1177_2324709616663231Case ReportCanagliflozin-Induced Diabetic Ketoacidosis Case Report and Review of the LiteratureTurner Jessica MSIV1Begum Tahmina MD1Smalligan Roger D. MD, MPH11 Texas Tech University Health Sciences Center, Amarillo, TX, USAJessica Turner, MSIV, 1400 S. Coulter Street, Amarillo, TX 79106, USA. Email: jessica.turner@ttuhsc.edu29 8 2016 Jul-Sep 2016 4 3 23247096166632311 5 2016 28 6 2016 17 7 2016 © 2016 American Federation for Medical Research2016American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Introduction: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are relatively new antihyperglycemic agents that lower renal glucose reabsorption. They are used as adjunctive therapy to standard diabetes treatment. Case Report: We present the case of a 62-year-old woman with a past medical history of type 2 diabetes mellitus and sudden-onset diabetic ketoacidosis (DKA). Use of canagliflozin, a SGLT-2 inhibitor, was determined to be the cause of the DKA. The patient ultimately recovered after 5 days in the intensive care unit. She was changed to long- and short-acting insulins and instructed to avoid canagliflozin. Conclusion: Although SGLT-2 inhibitors are effective at lowering a patient’s hemoglobin A1C, physicians must be aware of the rare but dangerous potential adverse effect of inducing DKA. This article reports an illustrative case and presents a review of the literature.\n\ndiabetic ketoacidosiscanagliflozinSGLT-2 inhibitorscover-dateJuly-September 2016\n==== Body\nIntroduction\nAs of 2012, 29 million people in the United States suffered from diabetes mellitus.1 Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a new class of antihyperglycemic agents used as adjunctive therapy to standard treatment regimens. SGLT-2 inhibitors are sold as both single-ingredient products and also in combination with metformin and other diabetic medications. These drugs lower renal glucose reabsorption and increase urinary glucose excretion2 (Figure 1).\n\nFigure 1. Mechanism of action of canagliflozin on SGLT-2 in the renal proximal tubule.\n\nCommon side effects of SGLT-2 inhibitors include genital yeast infections, urinary tract infections, and hypotension. However, in May 2015, the Food and Drug Administration (FDA) issued a drug safety communication which reported that these medications may lead to diabetic ketoacidosis (DKA).3 We present the case of a previously stable patient with type 2 diabetes mellitus who was treated with canagliflozin and developed severe DKA.\n\nCase Report\nA 62-year-old woman with type 2 diabetes mellitus, hypertension, gastroesophageal reflux disease, and depression presented with 4 days of nausea, vomiting, and generalized weakness. Her symptoms became progressively worse such that by the day of admission she had decreased appetite, polydipsia, polyuria, and could not walk. The patient denied fever, chills, abdominal pain, diarrhea, or sick contacts. Home medications were atorvastatin, metformin, sucralfate, pioglitazone, canagliflozin, exenatide, omeprazole, fluoxetine, ranitidine, lisinopril, and alprazolam.\n\nOn physical examination, the patient’s vital signs included a temperature of 38.3°C, blood pressure 134/61, heart rate 107, respiratory rate 24, and oxygen saturation of 100% on 2 liters nasal cannula oxygen. The patient appeared ill and distressed. She had dry mucous membranes, clear lung sounds bilaterally, and her heart was regular without murmurs, gallops, or rubs. Her abdomen was soft and nontender with present bowel sounds. Extremities showed no edema, and she had no focal neurological findings. Laboratory revealed a metabolic acidosis with a pH of 7.08 and anion gap >17. Chemistry panel indicated sodium 134 mEq/L, potassium 5.2 mEq/L, chloride 112 mEq/L, CO2 <5 mEq/L, blood urea nitrogen 22 mg/dL, and creatinine 1.3 mg/dL. Blood glucose was 213 mg/dL, and urinalysis revealed glucose 2+ and ketones 3+. Serum ketones were present at 1:8 dilution, with a lactic acid of 0.8 mmol/L. The patient’s hemoglobin A1C (HbA1c) was 11.1.\n\nThe patient was admitted to the intensive care unit for severe metabolic acidosis secondary to DKA. Aggressive fluid resuscitation was undertaken and an insulin drip initiated. Within 6 hours, the anion gap metabolic acidosis improved. On further review of her medication history, it was discovered that canagliflozin had been started several months prior. Further study of that medication and its uncommon side effects led to the etiology of the DKA. The patient required 5 days of hospitalization for complete resolution of her symptoms. She was sent home with a regimen of long- and short-acting insulins, as well as instructions to avoid canagliflozin. Her endocrinologist was advised of this adverse reaction.\n\nDiscussion\nDKA is a rare but serious adverse event seen increasingly with canagliflozin and other SGLT-2 inhibitors.4-10 The FDA Adverse Event Reporting System (FAERS) database identified 73 cases of DKA from March 2013 through May 2015 for patients using this class of medications. Though 73 cases have been officially reported to the FAERS database, it is likely that there are additional cases of patients that required hospitalization for DKA. In fact, on notifying our patient’s endocrinology office, the nurse commented that they had seen 2 other similar cases recently from their office practice. At least 15 of the reported cases were type 1 diabetics, suggesting off-label use of canagliflozin. Canagliflozin is only FDA approved for type 2 diabetes treatment. A revised drug label reporting the risk of new DKA with the use of these medications has since been issued by the FDA.11 Patients should be advised to look closely for any signs of ketoacidosis including shortness of breath, nausea, vomiting, abdominal pain, altered mental status, and fatigue. If signs of DKA are present, patients should be advised to stop taking their SGLT-2 inhibitor and seek immediate medical attention. The median time of DKA onset was 43 days, though a range of 1 day to 1 year has been reported.11 All 73 reported cases of canagliflozin-induced DKA required hospitalization.\n\nIt is still unknown why there appears to be DKA development associated with canagliflozin use. Prior research has found that SGLT-2 inhibitors are associated with an increase in plasma glucagon levels.12 The mechanism behind this is unknown. Although somewhat complex, one hypothesis regarding the occurrence of DKA in this setting is that some patients may be misdiagnosed as type 2 diabetics when they actually have an antibody-mediated ketoacidosis prone type of diabetes giving them low beta cell reserves. This would lead to insufficient insulin levels when a patient is stressed by an acute illness. In the setting of SGLT-2-induced increased glucagon levels, this would permit ongoing hepatic ketogenesis and peripheral lipolysis, leading to the DKA.13\n\nTypically DKA is associated with hyperglycemia above 250 mg/dL; however, for many patients in the reported cases and in ours, the blood glucose levels were lower, with a mean of 211 mg/dL.11 This euglycemic DKA (euDKA) may be underrecognized and result in delayed treatment with the necessary aggressive intravenous hydration and insulin.13 It is always important to rule out other potential causes of DKA including major illness, dehydration, and inadequate insulin intake as was done in our case. The dosage of SGLT-2 inhibitors does not appear to correlate with development of new DKA.11\n\nSince the release of the FDA drug safety communication, the safety of canagliflozin and the risk of DKA development have been studied using large databases of patients treated. Erondu et al14 analyzed a database of 17,596 patients from 15 trials assessing the adverse effects of canagliflozin therapy. The incidence of DKA and related events (ketoacidosis, metabolic acidosis, and acidosis) was 0.07%, corresponding to 12 events out of the 17,596 patients. Of these 12 patients, 4 had received 100 mg canagliflozin, 6 had received 300 mg canagliflozin, and only 2 patients were in the comparator arm of the study. However, of the 10 patients taking canagliflozin who developed DKA or a related event, 6 patients were later discovered to have autoimmune diabetes such as latent autoimmune diabetes, type 1 diabetes, or a positive GAD65 antibody. The authors do acknowledge the possibility of underreporting of events and are fair to report that the study was funded by the manufacturer.\n\nTo date there is not an established phenotype to help clinicians accurately predict the risk of DKA events when using an SGLT-2 inhibitor.14 However, the risk of DKA is higher in the following groups: older white males and those with a lower body mass index, higher HbA1c level, lower glomerular filtration rate, and longer duration of diabetes. However, P values are not reported in the table listing these risk factors.14 Our patient was a 63-year-old female with a body mass index of 26.63, HbA1c 11.1%, estimated glomerular filtration rate 41.5 mL/min/1.73 m2, and an unknown duration of diabetes. Other than being female, all of the details mentioned for our patient fit the risks seen in other studies.\n\nThough our patient was febrile and had episodes of vomiting, these are common symptoms of DKA; and testing was negative for a source of infection or other medical problems that could have led to the event. Specifically, she did not report abdominal pain, icterus, diarrhea, or sick contacts. Her urine culture, blood cultures, chest X-ray, troponins, liver function tests, and lipase were all unremarkable. Though other studies have linked alcohol usage with development of DKA, our patient denied alcohol intake and had a negative blood alcohol level and urine toxicology screen.13\n\nConclusion\nAs canagliflozin is prescribed more and more by clinicians due to its proven ability to lower HbA1c levels, physicians must be aware of the potential, albeit uncommon, dangerous side effect of new DKA in a patient with type 2 diabetes, even months after initiating the drug. Further research and monitoring of adverse events is clearly needed to determine the frequency and severity of these reactions.15\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 \nCenters for Disease Control and Prevention . National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014 . Atlanta, GA : US Department of Health and Human Services ; 2014 .\n2 \nDevineni D Curtin CR Polidori D \nPharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus . J Clin Pharmacol . 2013 ;53 :601 -610 .23670707 \n3 \nFDA Safety Communication . FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood . http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed July 15, 2015 .\n4 \nGelaye A Haidar A Kassab C Kazmi S Sinha P \nSevere ketoacidosis associated with canagliflozin (Invokana): a safety concern . Case Rep Crit Care . 2016 ;2016 :1656182 .27088018 \n5 \nPeters AL Henry RR Thakkar P Tong C Alba M \nDiabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes . Diabetes Care . 2016 ;39 :532 -538 .26989182 \n6 \nSyed SH Gosavi S Shami W \nA review of sodium glucose co-transporter 2 inhibitors canagliflozin, dapagliflozin and empagliflozin . Cardiovasc Hematol Agents Med Chem . 2015 ;13 :105 -112 .26549321 \n7 \nHine J Paterson H Abrol E Russell-Jones D Herring R \nSGLT inhibition and euglycaemic diabetic ketoacidosis . Lancet Diabetes Endocrinol . 2015 ;3 :503 -504 .26025388 \n8 \nStorgaard H Bagger JI Knop FK Vilsbøll T Rungby J \nDiabetic ketoacidosis in a patient with type 2 diabetes after initiation of sodium-glucose cotransporter 2 inhibitor treatment . Basic Clin Pharmacol Toxicol . 2016 ;118 :168 -170 .26291182 \n9 \nOgawa W Sakaguchi K \nEuglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors . J Diabetes Investig . 2016 ;7 :135 -138 .\n10 \nHayami T Kato Y Kamiya H \nCase of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet . J Diabetes Investig . 2015 ;6 :587 -590 .\n11 \nFDA Drug Safety Communication . FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections . http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Accessed April 26, 2016 .\n12 \nFerrannini E Muscelli E Frascerra S \nMetabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients . J Clin Invest . 2014 ;124 :499 -508 .24463454 \n13 \nPeters A Buschur E Buse J Cohan P Diner J Hirsch I \nEuglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition . Diabetes Care . 2015 ;38 :1687 -1693 .26078479 \n14 \nErondu N Desai M Ways K Meininger G \nDiabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program . Diabetes Care . 2015 ;38 :1680 -1686 .26203064 \n15 \nHandelsman Y Henry RR Bloomgarden ZT \nAmerican Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis . Endocr Pract . 2016 ;22 :753 -762 .27082665\n\n",
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"title": "Canagliflozin-Induced Diabetic Ketoacidosis: Case Report and Review of the Literature.",
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{
"abstract": "Direct-acting antivirals (DAAs) have revolutionized treatment for patients with chronic hepatitis C virus (HCV) infection, leading to a high rates of sustained virologic response. This study assessed the real-world safety and effectiveness of DAA-based antiviral therapy for the treatment of cirrhotic patients with chronic HCV infection.\n\n\n\nThis international, multicenter cohort study included all consecutive patients with chronic HCV infection and cirrhosis who underwent antiviral therapy with second-generation DAAs. Data on all patients were analyzed to assess treatment response. Predictors of hepatic decompensation during antiviral therapy were assessed using Cox proportional hazards regression analyses.\n\n\n\nUntil June 2015, 433 cirrhotic patients with chronic HCV infection started DAA-based treatment. Their mean age was 57.8 (±8.7) years, 277 (64.0%) patients were male, and 114 (26.3%) had a Child-Pugh (CP) score of B/C cirrhosis. The sustained virologic response rate at 12 weeks was similar among patients with a CP score of A (261 of 304 [85.9%]) and a CP score of B/C (83 of 101 [82.2%]; P = .37). A baseline albumin level less than 35 g/L (hazard ratio [HR], 3.11; 95% confidence interval [CI], 1.23-7.84; P = .005), baseline MELD score of 14 or higher (HR, 1.63; 95% CI, 1.03-2.61; P = .037), and HCV genotype 3 (HR, 2.05; 95% CI, 1.09-3.88; P = .033) were associated independently with hepatic decompensation during antiviral treatment among patients with a CP score of B/C.\n\n\n\nThis large cohort study showed that therapy is safe and effective in patients with compensated (CP score of A) cirrhosis. For patients with decompensated (CP score of B/C) cirrhosis, albumin level less than 35 g/L, MELD score of 14 or greater, and HCV genotype 3 are important risk factors for hepatic decompensation during DAA-based treatment. Therefore, these patients require close monitoring during antiviral therapy or treatment should be deferred until after transplantation.",
"affiliations": "Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, University of Toronto, Toronto, Canada; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: r.maan@erasmusmc.nl.;Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Medicine, Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.;Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, University of Toronto, Toronto, Canada.;Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, University of Toronto, Toronto, Canada.;Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, University of Toronto, Toronto, Canada.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, University of Toronto, Toronto, Canada; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.;Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, University of Toronto, Toronto, Canada.",
"authors": "Maan|Raoel|R|;van Tilborg|Marjolein|M|;Deterding|Katja|K|;Ramji|Alnoor|A|;van der Meer|Adriaan J|AJ|;Wong|Florence|F|;Fung|Scott|S|;Sherman|Morris|M|;Manns|Michael P|MP|;Cornberg|Markus|M|;Hansen|Bettina E|BE|;Wedemeyer|Heiner|H|;Janssen|Harry L A|HL|;de Knegt|Robert J|RJ|;Feld|Jordan J|JJ|",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2016.07.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "14(12)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Chronic Hepatitis C; Decompensation; Direct-Acting Antivirals; Safety",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D048550:Hepatic Insufficiency; D019698:Hepatitis C, Chronic; D006801:Humans; D007391:International Cooperation; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D000072230:Sustained Virologic Response; D016896:Treatment Outcome",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1821-1830.e6",
"pmc": null,
"pmid": "27404965",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Safety and Effectiveness of Direct-Acting Antiviral Agents for Treatment of Patients With Chronic Hepatitis C Virus Infection and Cirrhosis.",
"title_normalized": "safety and effectiveness of direct acting antiviral agents for treatment of patients with chronic hepatitis c virus infection and cirrhosis"
} | [
{
"companynumb": "CA-JNJFOC-20161223154",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
},
"drugadditional": "3",
"... |
{
"abstract": "Lenalidomide, a thalidomide analogue, is an immunomodulatory drug currently used as a chemotherapeutic agent in treating certain hematologic malignancies, including multiple myeloma. The antineoplastic effect of lenalidomide may be due to its ability to modulate different components of the immune system as well as its antiangiogenic, antiproliferative, and direct cytotoxic activity. Given its immunomodulatory effects, lenalidomide may potentially elicit unintended immune activity against allografts in solid organ transplant recipients. Here, we present a case of a renal transplant recipient who developed multiple myeloma after transplantation and was treated with the use of lenalidomide, which precipitated severe acute T-cell-mediated rejection. Lenalidomide was thought to be causative, and after cessation of the drug her renal function stabilized.",
"affiliations": "Department of Pathology, University of California, San Francisco, California.;Division of Nephrology, University of California, San Francisco, California.;Department of Pathology, University of California, San Francisco, California.;Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, California. Electronic address: kyjen@ucdavis.edu.",
"authors": "Walavalkar|V|V|;Adey|D B|DB|;Laszik|Z G|ZG|;Jen|K-Y|KY|",
"chemical_list": "D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.01.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D006084:Graft Rejection; D006801:Humans; D016030:Kidney Transplantation; D000077269:Lenalidomide; D008875:Middle Aged; D009101:Multiple Myeloma; D013792:Thalidomide",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "873-876",
"pmc": null,
"pmid": "29661456",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Renal Allograft Rejection Resulting from Lenalidomide Therapy for Multiple Myeloma: Case Report.",
"title_normalized": "severe renal allograft rejection resulting from lenalidomide therapy for multiple myeloma case report"
} | [
{
"companynumb": "US-CELGENEUS-USA-20180606062",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": n... |
{
"abstract": "Immune tolerance seems to correlate with disease progression and T regulatory cells (Tregs) and myeloid-derived suppressor cells play a relevant role in immunosuppression. Cyclophosphamide (Cyt) and Fluorouracil (FU) seem to reduce these cell populations.\n\n\n\nEstablishing safety, feasibility, activity and impact on the immune system (neutrophil/lymphocyte [N/L], platelet/L [Plt/L], monocyte [M] and lymphocyte subpopulation (CD3, CD4, CD8, CD16, HLADR/CD3, Tregs, cells count), CD8/Treg and C-reactive protein (CRP).\n\n\n\n1) Cyt 300 mg/sqm ± FU 500 mg/sqm day (d) 1 and interleukin 2 (IL-2) 18 MUI/sqm intravenous (I.V.) d 4-6, 18-20 or 2) Cyt 300 mg/sqm + FU 500 mg/sqm day d 1, IL-2 4.5 MUI subcutaneous (S.C.) d 3-6, 17-20. The cycle was repeated every four weeks for 2 cycles. Stable or responding patients (pts) continued therapy for 3 cycles.\n\n\n\nFrom February 2014 to December 2016, 13/14 pre-treated pts (mean 3 lines) with solid tumors were enrolled. Male/Female: 1/1. The median age and Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 68 years and 1 respectively. Mean 2 cycles of therapy were administered. G3-4 toxicities presented as diarrhea and bleeding anemia in 2 pts and proteinuria and erhytroderma in 1pt, respectively. Regarding the hematological profile, a more reduction in Plt, less decrease of Plt/Ly, and less increase of Treg with I.V. than S.C. IL-2 administration was observed. However a transient decrease of Treg on day 7 of first cycle in the I.V. IL-2 was reported.\n\n\n\nPR 3 (23%), SD 3 (23%), PD 7 (54%). The response duration was 2+ and 3 months in 2 HCC and 18+ months in the pancreatic cancer (PC). Pathological CR was reported in one HCC treated with I.V. IL-2. The median progression-free-survival (PFS) and overall survival (OS) were 1 and 7 months.\n\n\n\nCyt-FU-IL-2 can be considered safe, feasible and moderately active in heavily pre-treated pts. Plt, Plt/Ly, CD8/Treg and a transient Tregs reduction were observed without significative difference on survival.",
"affiliations": "CRO Pordenone-S. Vito Oncology, Pordenone, Italy. Electronic address: giovanni.lore@cro.it.;Study University, Milan, Italy. Electronic address: francesco.lore@hotmail.com.;Clinical Patholgy, AAS5 Pordenonese, Pordenone, Italy. Electronic address: paolo.doretto@aas5.sanita.fvg.it.;CRO Pordenone-S. Vito Oncology, Pordenone, Italy. Electronic address: alessandro.delconte@cro.it.;Medical Direction, AAS5 Pordenonese, Pordenone, Italy. Electronic address: maria.amadio@aas5.sanita.fvg.it.;Pharmacy, AAS5 Pordenonese, Pordenone, Italy. Electronic address: cinzia.cozzi.farm@aas5.sanita.fvg.it.;Obstetrics and Gynecology Unit, AAS5 Pordenonese, Pordenone, Italy. Electronic address: maddalena.casarotto@aas5.sanita.fvg.it.;Urology Unit, AAS5 Pordenonese, Pordenone, Italy. Electronic address: daniele.maruzzi@aas5.sanita.fvg.it.;Pathology Unit, AAS5 Pordenonese, Pordenone, Italy. Electronic address: wally.marus@aas5.sanita.fvg.it.;Surgery Unit, AAS5 Pordenonese, Pordenone, Italy. Electronic address: paolo.ubiali@aas5.sanita.fvg.it.;CRO Pordenone-S. Vito Oncology, Pordenone, Italy. Electronic address: paolo.sandri@cro.it.",
"authors": "Lo Re|Giovanni|G|;Lo Re|Francesco|F|;Doretto|Paolo|P|;Del Conte|Alessandro|A|;Amadio|Maria|M|;Cozzi|Cinzia|C|;Casarotto|Maria Maddalena|MM|;Maruzzi|Daniele|D|;Marus|Wally|W|;Ubiali|Paolo|P|;Sandri|Paolo|P|",
"chemical_list": "D007376:Interleukin-2; D003520:Cyclophosphamide; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1016/j.cyto.2018.06.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-4666",
"issue": "113()",
"journal": "Cytokine",
"keywords": "Cancer; Cyclophosphamide; Fluorouracil; Interleukin-2",
"medline_ta": "Cytokine",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007376:Interleukin-2; D008297:Male; D009369:Neoplasms; D056687:Off-Label Use; D000077982:Progression-Free Survival",
"nlm_unique_id": "9005353",
"other_id": null,
"pages": "50-60",
"pmc": null,
"pmid": "29958796",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cyclophosphamide with or without fluorouracil followed by subcutaneous or intravenous interleukin-2 use in solid tumors: A feasibility off-label experience.",
"title_normalized": "cyclophosphamide with or without fluorouracil followed by subcutaneous or intravenous interleukin 2 use in solid tumors a feasibility off label experience"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1001593",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALDESLEUKIN"
},
"drugadditional": "3",
... |
{
"abstract": "Retinoblastoma usually recurs within the first few years after treatment completion. We report a rare case of very late relapse in a 6-month-old girl who was diagnosed with bilateral retinoblastoma. The patient achieved first remission after treatment with neoadjuvant chemotherapy, enucleation of the right eye, local laser therapy of the left eye, and adjuvant chemotherapy. Extraocular relapse with multiple metastases occurred 13 years and 8 months after treatment. The patient is currently in second complete remission after receiving high-dose chemotherapy and autologous stem cell transplantation. In conclusion, long-term follow-up is needed for early detection of recurrent retinoblastoma.",
"affiliations": "Departments of *Pediatrics §Ophthalmology ∥Pathology ¶Radiology, Seoul National University College of Medicine †Cancer Research Institute, Seoul National University ‡Department of Pediatrics, Seoul National University Boramae Medical Center, Seoul, Korea.",
"authors": "Choi|Jung Yoon|JY|;Kang|Hyoung Jin|HJ|;Lee|Ji Won|JW|;Ju|Hee Young|HY|;Hong|Che Ry|CR|;Kim|Hyery|H|;Yu|Young Suk|YS|;Park|Sung-Hye|SH|;Cheon|Jung-Eun|JE|;Park|Kyung Duk|KD|;Shin|Hee Young|HY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000310",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D005260:Female; D006801:Humans; D007223:Infant; D009364:Neoplasm Recurrence, Local; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D033581:Stem Cell Transplantation; D013997:Time Factors",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e264-7",
"pmc": null,
"pmid": "25757022",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Very late relapse of bilateral retinoblastoma.",
"title_normalized": "very late relapse of bilateral retinoblastoma"
} | [
{
"companynumb": "KR-FRESENIUS KABI-FK201602070",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Neurologic manifestations, such as myoclonus, asterixis, seizures and altered level of consciousness, may be induced in patients with impaired renal function receiving β-lactam antibiotics, which stem in part from drug accumulation because of altered pharmacokinetics. Because of its long half-life and easy penetration into the cerebrospinal fluid, the third generation cephalosporin, ceftriaxone (CTRX), is often chosen to treat patients with end-stage renal disease (ESRD). Here, the authors describe 4 patients with ESRD complicated with bacterial infection and choreoathetosis after the administration of CTRX. Choreoathetosis disappeared without leaving sequelae after CTRX therapy was withdrawn, although the severity and symptom duration varied. To our knowledge, there are few reports on choreoathetosis associated with β-lactam antibiotic administration in patients with kidney diseases. To prevent delayed diagnosis, one should bear in mind that choreoathetosis might occur in patients with ESRD treated with CTRX, when it is given in high or even regular doses.",
"affiliations": "Division of Nephrology, Showa University Fujigaoka Hospital, Yokohama, Japan.",
"authors": "Sato|Yoshinori|Y|;Morita|Hiroyuki|H|;Wakasugi|Harue|H|;Iijima|Shoji|S|;Kawashima|Eri|E|;Wakayama|Yoshihiro|Y|;Yoshimura|Ashio|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone",
"country": "United States",
"delete": false,
"doi": "10.1097/MAJ.0b013e3181ec063b",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "340(5)",
"journal": "The American journal of the medical sciences",
"keywords": null,
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001264:Athetosis; D002443:Ceftriaxone; D002819:Chorea; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "382-4",
"pmc": null,
"pmid": "20724905",
"pubdate": "2010-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible choreoathetosis after the administration of ceftriaxone sodium in patients with end-stage renal disease.",
"title_normalized": "reversible choreoathetosis after the administration of ceftriaxone sodium in patients with end stage renal disease"
} | [
{
"companynumb": "JP-PFIZER INC-2011154466",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Various paraneoplastic syndromes (PNS) are reported to be associated with breast cancer and can range from mild dermatological symptoms to severe neurological complications. Neurological and dermatological manifestations tend to be the more commonly seen paraneoplastic manifestations, albeit both are relatively rare. Diagnosis of the underlying malignancy is often delayed since the presence and severity of paraneoplastic manifestations are not dependent on the tumor size or stage. Herein, we describe a unique case of unilateral arm urticaria presenting as a paraneoplastic manifestation of metachronous bilateral breast cancer. Similar reports and other PNS associated with breast cancer are described. Recognition of PNS associated with underlying malignancies and age-appropriate screening can facilitate diagnosis of the underlying occult malignancy. Resection of the underlying malignancy can lead to resolution and/or improvement of the PNS for some patients.",
"affiliations": "Department of Oncology, Mayo Clinic, College of Medicine, Mayo Clinic, Rochester, Minn., USA.;Department of Surgery, College of Medicine, Mayo Clinic, Rochester, Minn., USA.;Department of Oncology, Mayo Clinic, College of Medicine, Mayo Clinic, Rochester, Minn., USA.",
"authors": "Kasi|Pashtoon Murtaza|PM|;Hieken|Tina J|TJ|;Haddad|Tufia C|TC|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000443661",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000443661cro-0009-0033Published online: January, 2016Unilateral Arm Urticaria Presenting as a Paraneoplastic Manifestation of Metachronous Bilateral Breast Cancer Kasi Pashtoon Murtaza a*Hieken Tina J. bHaddad Tufia C. aaDepartment of Oncology, Mayo Clinic, College of Medicine, Mayo Clinic, Rochester, Minn., USAbDepartment of Surgery, College of Medicine, Mayo Clinic, Rochester, Minn., USA*Pashtoon Murtaza Kasi, MD, Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 (USA), E-Mail kasi.pashtoon@mayo.eduJan-Apr 2016 14 1 2016 14 1 2016 9 1 33 38 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Various paraneoplastic syndromes (PNS) are reported to be associated with breast cancer and can range from mild dermatological symptoms to severe neurological complications. Neurological and dermatological manifestations tend to be the more commonly seen paraneoplastic manifestations, albeit both are relatively rare. Diagnosis of the underlying malignancy is often delayed since the presence and severity of paraneoplastic manifestations are not dependent on the tumor size or stage. Herein, we describe a unique case of unilateral arm urticaria presenting as a paraneoplastic manifestation of metachronous bilateral breast cancer. Similar reports and other PNS associated with breast cancer are described. Recognition of PNS associated with underlying malignancies and age-appropriate screening can facilitate diagnosis of the underlying occult malignancy. Resection of the underlying malignancy can lead to resolution and/or improvement of the PNS for some patients.\n\nKey Words\nParaneoplastic syndromesUrticariaDermatological symptomsNeurological complicationsBreast cancerOccult malignancyRashAdenocarcinoma\n==== Body\nIntroduction\nBreast cancer is one of the malignancies that can present with varied paraneoplastic manifestations. Herein, we describe a unique case of unilateral arm urticaria presenting as a paraneoplastic manifestation of metachronous bilateral breast cancer. Similar reports and other paraneoplastic syndromes (PNS) associated with breast cancer are described.\n\nCase Presentation\nA 49-year-old premenopausal woman in good health with no chronic disease initially established care at our clinic in February 2013 due to an abnormal mammogram. The screening mammogram revealed abnormal calcifications in the superior lateral and superior medial quadrants of the left breast. Review of systems was notable only for a #12-week history of unilateral left arm urticaria of indeterminate etiology. She had no prior history of urticaria or other dermatological conditions and she denied any new contact or exposures to the left arm. Her physical examination, including clinical breast exam, was normal. Only one of the two areas of calcifications, over a span of 4 mm at the 1:00 position, was reproducible on the diagnostic mammogram. Stereotactic-guided biopsy was consistent with atypical ductal hyperplasia with calcifications as well as atypical lobular hyperplasia. A subsequent excisional left breast biopsy by seed localization showed multifocal, grade 1 invasive lobular carcinoma with 3 foci of disease, the largest of which measured 1.2 cm. Postoperatively, breast MRI and second-look ultrasound suggested residual foci of disease. The patient therefore elected treatment with a left skin-sparing mastectomy with immediate breast reconstruction and left axillary sentinel lymph node biopsy followed by left axillary lymph node dissection after frozen section pathology demonstrated node-positive disease. Pathology demonstrated multifocal and multicentric invasive lobular carcinoma, grade II (out of III), in a total of four masses comprising a total area of 10 cm. All surgical margins were negative, with 2 (out of 28) lymph nodes sampled positive for metastatic carcinoma (final staging – T2 N1 M0, stage IIB; estrogen receptor and progesterone receptor positive, HER2 negative with a Ki-67 20%). Interestingly, the left-sided arm urticaria resolved after resection of the breast cancer without any specific intervention.\n\nShe received adjuvant dose-dense doxorubicin and cyclophosphamide for 4 cycles followed by 12 weekly doses of paclitaxel. This was followed by radiotherapy to the left reconstructed breast mound and the regional nodal areas. Given the hormone receptor-positive disease, she was started on endocrine therapy in the form of tamoxifen with a plan for a minimum 5 years of adjuvant therapy. She experienced amenorrhea as a result of chemotherapy.\n\nOne year after initiation of tamoxifen and 11 months after a normal screening right mammogram, the patient presented again with severe unilateral arm urticaria and associated excoriations, on the contralateral, right, side (fig. 1). This prompted reimaging in the form of a mammogram which showed a 5 × 3 mm group of heterogeneous calcification in the right breast at 12 o'clock anterior depth. In addition, there was a 1-mm cluster of calcifications adjacent to the index group. MRI of the breast, however, did not show any features suspicious for malignancy. The mammographic findings led to biopsy of the suspicious calcifications, and pathology showed atypical lobular hyperplasia involving 3 or more foci with columnar cell changes. Calcifications were also noted in benign ducts and in foci of atypical lobular hyperplasia. Given her prior history of urticaria representing a possible PNS, her prior node-positive breast cancer despite optimal screening, as well as the high-risk of future breast cancer based on a diagnosis of multifocal atypia, the consensus was to proceed with what was thought to be a risk-reducing nipple-sparing mastectomy and immediate reconstruction on the right side. Pathology showed multiple foci of atypical lobular hyperplasia and a single focus of grade I invasive tubular carcinoma, 0.3 cm in greatest dimension (final staging – pT1a NX M0, stage IA; estrogen receptor and progesterone receptor positive, HER2/Neu negative with a Ki-67 0.4%). There was no indication for adjuvant chemotherapy or postmastectomy radiation; she resumed tamoxifen for adjuvant therapy. The urticaria that was thought to be a paraneoplastic manifestation of the breast cancer again resolved completely and spontaneously after the tumor was resected.\n\nDiscussion\nThe estimated frequency of PNS in patients with cancer is about 8% [1]. There are, however, very few studies addressing the incidence of these various PNS in patients with breast cancer and other malignancies [2]. While uncommon, breast cancer can present with varied PNS (table 1). These PNS can range from mild dermatological symptoms to severe neurological complications and respiratory failure [3, 4, 5, 6, 7]. From review of the literature, neurological and dermatological manifestations tend to be the more commonly seen paraneoplastic manifestations, albeit both are relatively rare (table 1) [8]. The incidence of various paraneoplastic neurological disorders, for example, was estimated to be around 4% in all patients with breast cancer [9]. These estimates vary based on the criteria and definitions used to describe these disorders [2].\n\nOther malignancies more commonly associated with paraneoplastic manifestations include lymphoma, gynecologic (ovary) cancers, germ cell tumors, thymomas and lung cancer [10, 11, 12]. Observation of these PNS or manifestations without clear etiology should prompt diagnostics to evaluate for underlying cancers as the etiology. The selection of cancer screening procedures should be guided by patient age and risk factors, with emphasis on the more commonly associated malignancies [13].\n\nEarly diagnosis in some of these situations is vital to prevent ongoing harm and debility [14]. This, however, is often delayed since the severity of the PNS is not necessarily dependent on the size or stage of the tumor [8].\n\nTreatment and the overall prognosis are variable depending on the severity and presentation of the paraneoplastic manifestation [8, 15]. Focused efforts to support symptom management and rehabilitation are important considerations to improve quality of life of patients while concurrently diagnosing and treating the underlying malignancy [16]. Removal of the underlying malignancy has been reported to improve or resolve the underlying paraneoplastic process for some of the patients, as in our case [17, 18]. This, however, does not necessarily abrogate PNS symptoms in all cases.\n\nConclusions\nPNS, including dermatological manifestations, can present with a wide range of signs and symptoms of variable severity. Diagnosis of the underlying malignancy is often delayed and is not necessarily dependent on the size or stage of the tumor. Knowledge of likely associations with underlying malignancies and age- and risk factor-based appropriate screening in these situations may facilitate prompt diagnosis and treatment of the underlying occult malignancy.\n\nStatement of Ethics\nThis study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient. The authors are deeply indebted to the patient for allowing us to share her case as a case report.\n\nDisclosure Statement\nThe authors declare that there is no conflict of interest regarding the publication of this article.\n\nAcknowledgement\nThis work was supported by NIH Grant K12 CA90628 (T.C.H.).\n\nFig. 1 Severe urticaria leading to excoriations presenting as a paraneoplastic manifestation of breast cancer in a 49-year-old woman.\n\nTable 1 Commonly reported PNS seen in association with breast cancer\n\nPNS/manifestations\tRecent citations\t\n\t\nNeurologic: neuropathy, cerebellar ataxia/degeneration, motor neuron disease, limbic encephalitis, neuromyelitis optica, opsoclonus-myoclonus syndrome\t[5, 8, 10, 19, 20, 21, 22, 23, 24, 25]\t\n\t\nDermatologic: rash, erythroderma, dermatitis, dermatomyositis, Sweet syndrome, scleroderma, bullous pemphigoid, acanthosis\t[7, 17, 22, 26, 27, 28, 29]\t\nMuscular: myositis, myelopathy\t[5, 6, 22, 26]\t\nEndocrine: hypercalcemia, hypoglycemia\t[8, 30, 31]\t\nOcular: cancer-associated retinopathy\t[32, 33]\t\nOther: stiff-person syndrome, adult-onset Still disease, palmar fascitis and polyarthritis, autoimmune pancreatitis (IgG4 mediated)\t[3, 14, 15, 18, 34]\n==== Refs\nReferences\n1 Pelosof LC Gerber DE Paraneoplastic syndromes: an approach to diagnosis and treatment Mayo Clin Proc 2010 85 838 854 20810794 \n2 Rees JH Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage J Neurol Neurosurg Psychiatry 2004 75 suppl 2 ii43 ii50 15146039 \n3 Sun NZ Brezinski EA Berliner J Updates in adult-onset Still disease: atypical cutaneous manifestations and associations with delayed malignancy J Am Acad Dermatol 2015 73 294 303 26054431 \n4 Taib BG Kinshuck AJ Milburn-McNulty P Opsoclonus-myoclonus syndrome associated with a nasopharyngeal tumor in an adult: a case report J Med Case Rep 2015 9 128 26033370 \n5 Alsharabati M Oh SJ Paraneoplastic myeloneuropathy in a man with breast cancer Muscle Nerve 2015 52 685 686 25976734 \n6 Jaeger B de Visser M Aronica E van der Kooi AJ Respiratory failure as presenting symptom of necrotizing autoimmune myopathy with anti-melanoma differentiation-associated gene 5 antibodies Neuromuscul Disord 2015 25 457 460 25891278 \n7 Protopsaltis I Drossou A Katsantonis I Breast cancer presenting as paraneoplastic erythroderma: an extremely rare case Case Rep Med 2014 2014 351065 25295062 \n8 Rosenfeld MR Dalmau J Diagnosis and management of paraneoplastic neurologic disorders Curr Treat Options Oncol 2013 14 528 538 23900965 \n9 Croft PB Wilkinson M The incidence of carcinomatous neuromyopathy in patients with various types of carcinoma Brain 1965 88 427 434 5830593 \n10 Afzal S Recio M Shamim S Paraneoplastic cerebellar ataxia and the paraneoplastic syndromes Proc (Bayl Univ Med Cent) 2015 28 217 220 25829659 \n11 Kumar S Mahajan BB Kaur S Singh A Paraneoplastic dermatomyositis with carcinoma cervix: a rare clinical association Case Rep Dermatol Med 2014 2014 836246 25587465 \n12 Nomani AZ Wazir M Kashmir SB Qureshi MS Diffuse large B-cell lymphoma of stomach presenting with paraneoplastic cerebellar degeneration syndrome J Coll Physicians Surg Pak 2014 24 suppl 1 S11 S13 24717988 \n13 Horta ES Lennon VA Lachance DH Neural autoantibody clusters aid diagnosis of cancer Clin Cancer Res 2014 20 3862 3869 24833664 \n14 Manger B Schett G Palmar fasciitis and polyarthritis syndrome – systematic literature review of 100 cases Semin Arthritis Rheum 2014 44 105 111 24684975 \n15 Baizabal-Carvallo JF Jankovic J Stiff-person syndrome: insights into a complex autoimmune disorder J Neurol Neurosurg Psychiatry 2015 86 840 848 25511790 \n16 Fu JB Raj VS Asher A Inpatient rehabilitation performance of patients with paraneoplastic cerebellar degeneration Arch Phys Med Rehabil 2014 95 2496 2499 25051460 \n17 Primiano G Plantone D Sauchelli D Resolution of muscle inflammation after tumor removal in a woman with paraneoplastic dermatomyositis J Rheumatol 2012 39 2359 2360 23204312 \n18 Lekakis L Tryfonopoulos D Fakinos G A case of paraneoplastic autoimmune pancreatitis: mini-review of paraneoplastic syndromes in breast cancer Anticancer Res 2012 32 3311 3314 22843907 \n19 Spataro R La Bella V Paraneoplastic motor neuron disease associated with breast cancer Eur J Neurol 2014 21 e5 e6 25133280 \n20 Kattepur AK Patil D Shankarappa A Anti-NMDAR limbic encephalitis – a clinical curiosity World J Surg Oncol 2014 12 256 25106449 \n21 Al-Harbi T Al-Sarawi A Binfalah M Dermime S Paraneoplastic neuromyelitis optica spectrum disorder associated with stomach carcinoid tumor Hematol Oncol Stem Cell Ther 2014 7 116 119 24954081 \n22 Kannan MA Sundaram C Uppin M Incidence of malignancies in biopsy-proven inflammatory myopathy Neurol India 2013 61 152 155 23644314 \n23 Key RG Root JC Anti-Yo mediated paraneoplastic cerebellar degeneration in the context of breast cancer: a case report and literature review Psychooncology 2013 22 2152 2155 23585287 \n24 Barata PC Morgado J Sousa AP Breast cancer presents with a paraneoplastic neurologic syndrome Case Rep Oncol 2012 5 616 621 23275775 \n25 Klaas JP Ahlskog JE Pittock SJ Adult-onset opsoclonus-myoclonus syndrome Arch Neurol 2012 69 1598 1607 22986354 \n26 Dias LP Faria AL Scandiuzzi MM A rare case of severe myositis as paraneoplastic syndrome on breast cancer World J Surg Oncol 2015 13 134 25890160 \n27 Kaszewski S Czajkowski R Protas-Drozd F Sweet's syndrome with idiopathic thrombocythemia Postepy Dermatol Alergol 2014 31 47 52 24683399 \n28 Reynolds TD Knights SE Recurrent metastatic breast cancer presenting with paraneoplastic scleroderma. BMJ Case Rep 2014;2014 . pii: bcr2014203575.\n29 Ng SS Teo RY Seah PP A case of bullous pemphigoid in a patient with dual cancers, fortuitous or paraneoplastic? Ann Acad Med Singapore 2012 41 313 314 22892611 \n30 Trisal D Kumar N Sundriyal D Gadpayle AK Hypercalcaemia of malignancy: two primaries in the same patient. BMJ Case Rep 2014 ; 2014. pii: bcr2014204368.\n31 Richters L Ortmann M Faust M The oncological emergency case: paraneoplastic hypoglycemia in metastatic breast cancer – case report and brief review of the literature Breast Care 2013 8 368 370 24415991 \n32 Adamus G Latest updates on antiretinal autoantibodies associated with vision loss and breast cancer Investig Ophthalmol Vis Sci 2015 56 1680 1688 25754855 \n33 Eadie JA Ip MS Ver Hoeve JN Localized retinal manifestations of paraneoplastic autoimmune retinopathy Retin Cases Brief Rep 2014 8 318 321 25372537 \n34 Kelly PA Kuberski C Stiff person syndrome: a case report Clin J Oncol Nurs 2014 18 465 467 25095302\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "9(1)",
"journal": "Case reports in oncology",
"keywords": "Adenocarcinoma; Breast cancer; Dermatological symptoms; Neurological complications; Occult malignancy; Paraneoplastic syndromes; Rash; Urticaria",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "33-8",
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"pmid": "26933416",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "25890160;24954081;23204312;24684975;23644314;24962487;24833664;26054431;22843907;24415991;25133280;25295062;25891278;23585287;25754855;24717988;15146039;25976734;23900965;26033370;24618872;23275775;22986354;24683399;25829659;25587465;5830593;25095302;25372537;25051460;22892611;25106449;25511790;20810794",
"title": "Unilateral Arm Urticaria Presenting as a Paraneoplastic Manifestation of Metachronous Bilateral Breast Cancer.",
"title_normalized": "unilateral arm urticaria presenting as a paraneoplastic manifestation of metachronous bilateral breast cancer"
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"abstract": "Anti-epidermal growth factor receptor (EGFR) antibodies and anti-programmed cell death 1 protein (PD-1) antibodies have been used separately to treat metastatic cutaneous squamous cell carcinoma (cSCC). While two anti-EGFR antibodies have similar clinical activity, cetuximab is administered weekly, whereas panitumumab is administered every two weeks. This report details findings using panitumumab in combination with anti-PD-1 antibody in patients with relapsed refractory cSCC. Three consecutive patients with poor performance status and rapidly progressive recurrent cutaneous squamous cell carcinoma (cSCC) of the face or scalp signed informed consent to receive an anti-PD-1 antibody with the option to add panitumumab were there inadequate response. After 2, 5, and 7 cycles of anti-PD-1 antibody treatment, respectively, panitumumab was added and the combination was continued for 27, 7, and 5 cycles, respectively. Fatigue, rash, and hypomagnesemia were reported, consistent with expectations for either agent alone. All three patients achieved durable complete response. The favorable clinical outcomes support further evaluation of the combination of anti-PD1 and anti-EGFR antibodies to control refractory cSCC of the face or scalp. J Drugs Dermatol. 2021;20(8):901-904. doi:10.36849/JDD.6175.",
"affiliations": null,
"authors": "Hsu|Emily|E|;Eton|Omar|O|;Patel|Akshay V|AV|;Cartun|Richard|R|;Earle|Jonathan S|JS|;Mnayer|Laila O|LO|;Kotowitz|Jennifer|J|;Yu|Peter P|PP|",
"chemical_list": "D000077544:Panitumumab",
"country": "United States",
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"doi": "10.36849/JDD.6175",
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"issue": "20(8)",
"journal": "Journal of drugs in dermatology : JDD",
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"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D002294:Carcinoma, Squamous Cell; D006258:Head and Neck Neoplasms; D006801:Humans; D009364:Neoplasm Recurrence, Local; D000077544:Panitumumab; D012878:Skin Neoplasms; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "101160020",
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"pmid": "34397194",
"pubdate": "2021-08-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combining Panitumumab With Anti-PD-1 Antibody in Cutaneous Squamous Cell Carcinoma of the Head and Neck After Inadequate Response to Anti-PD-1 Antibody Alone.",
"title_normalized": "combining panitumumab with anti pd 1 antibody in cutaneous squamous cell carcinoma of the head and neck after inadequate response to anti pd 1 antibody alone"
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"abstract": "Immunomodulators remain fundamental for the medical treatment of Crohn's disease (CD). Methotrexate (MTX) is widely used as a second-line immunomodulator; however, there is a lack of recent data on MTX monotherapy among the Asian population with CD. Therefore, in this study, we aimed to investigate the tolerability and clinical outcomes of MTX in Korean patients with CD.\nA retrospective chart review was performed for CD patients treated with MTX monotherapy or in combination with 5-aminosalicylic acid (5-ASA), at the Asan Medical Center, Seoul, South Korea. The tolerability of MTX monotherapy within 6 months was assessed and the clinical effectiveness of MTX was evaluated based on the Crohn's disease activity index (CDAI).\nIn total, 85 patients were included, of which 29 (34.1%) discontinued MTX due to intolerability during the follow-up. Adverse events (AEs) were reported in 41 (48.2%) patients. The most common AE was gastrointestinal disorders (17/41) and only one patient experienced a serious AE, a systemic infection that required hospitalization. Among the 56 patients who tolerated MTX within 6 months, 44 (65.9%) showed a clinical response. Moreover, no factor was significantly associated with intolerability. The administration method was the only factor significantly associated with a response to MTX (p = 0.041). The adjusted odds ratio of parenteral injection compared to oral administration was 5.68 (95% confidence interval (CI), 1.07-30.08).\nIn this study, one-third of patients were intolerant to MTX; nonetheless, the response rate was as high as 65.9% among tolerant patients. In addition, no significant factors affected intolerability. In terms of the clinical response, parenteral injection could be better than oral administration.",
"affiliations": "Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.;Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.",
"authors": "Hong|Hee Seung|HS|https://orcid.org/0000-0002-3618-9760;Kim|Kyuwon|K|;Oh|Kyunghwan|K|;Lee|Jae Yong|JY|;Hong|Seung Wook|SW|;Park|Jin Hwa|JH|;Hwang|Sung Wook|SW|;Yang|Dong-Hoon|DH|;Ye|Byong Duk|BD|https://orcid.org/0000-0001-6647-6325;Byeon|Jeong-Sik|JS|;Myung|Seung-Jae|SJ|;Yang|Suk-Kyun|SK|https://orcid.org/0000-0003-2772-2575;Park|Sang Hyoung|SH|https://orcid.org/0000-0002-5366-5749",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/17562848211043017",
"fulltext": "\n==== Front\nTherap Adv Gastroenterol\nTherap Adv Gastroenterol\nTAG\nsptag\nTherapeutic Advances in Gastroenterology\n1756-283X\n1756-2848\nSAGE Publications Sage UK: London, England\n\n10.1177/17562848211043017\n10.1177_17562848211043017\nOriginal Article\nShort-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn’s disease: a retrospective study\nhttps://orcid.org/0000-0002-3618-9760\nHong Hee Seung Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nKim Kyuwon Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nOh Kyunghwan Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nLee Jae Yong Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nHong Seung Wook Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nPark Jin Hwa Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nHwang Sung Wook Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nYang Dong-Hoon Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nhttps://orcid.org/0000-0001-6647-6325\nYe Byong Duk Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nByeon Jeong-Sik Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nMyung Seung-Jae Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nhttps://orcid.org/0000-0003-2772-2575\nYang Suk-Kyun Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea\n\nhttps://orcid.org/0000-0002-5366-5749\nPark Sang Hyoung Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea\n\numdalpin@hanmail.net\n13 9 2021\n2021\n14 1756284821104301730 5 2021\n3 8 2021\n© The Author(s), 2021\n2021\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nIntroduction:\n\nImmunomodulators remain fundamental for the medical treatment of Crohn’s disease (CD). Methotrexate (MTX) is widely used as a second-line immunomodulator; however, there is a lack of recent data on MTX monotherapy among the Asian population with CD. Therefore, in this study, we aimed to investigate the tolerability and clinical outcomes of MTX in Korean patients with CD.\n\nMethods:\n\nA retrospective chart review was performed for CD patients treated with MTX monotherapy or in combination with 5-aminosalicylic acid (5-ASA), at the Asan Medical Center, Seoul, South Korea. The tolerability of MTX monotherapy within 6 months was assessed and the clinical effectiveness of MTX was evaluated based on the Crohn’s disease activity index (CDAI).\n\nResults:\n\nIn total, 85 patients were included, of which 29 (34.1%) discontinued MTX due to intolerability during the follow-up. Adverse events (AEs) were reported in 41 (48.2%) patients. The most common AE was gastrointestinal disorders (17/41) and only one patient experienced a serious AE, a systemic infection that required hospitalization. Among the 56 patients who tolerated MTX within 6 months, 44 (65.9%) showed a clinical response. Moreover, no factor was significantly associated with intolerability. The administration method was the only factor significantly associated with a response to MTX (p = 0.041). The adjusted odds ratio of parenteral injection compared to oral administration was 5.68 (95% confidence interval (CI), 1.07–30.08).\n\nConclusion:\n\nIn this study, one-third of patients were intolerant to MTX; nonetheless, the response rate was as high as 65.9% among tolerant patients. In addition, no significant factors affected intolerability. In terms of the clinical response, parenteral injection could be better than oral administration.\n\nCrohn’s disease\ninflammatory bowel disease\nmethotrexate\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\npmcIntroduction\n\nDespite the development of novel biologic agents, conventional immunomodulators such as thiopurines and methotrexate remain fundamental to the medical treatment of inflammatory bowel disease (IBD), including Crohn’s disease (CD).1,2 Immunomodulators are recommended for inducing remission in patients with moderate-to-severe CD and for maintaining a remission in patients with steroid-dependent CD.1–3 In addition, it is recommended that immunomodulators can be used in combination with anti-tumor necrosis factor (TNF) agents to reduce immunogenicity.2,4\n\nMethotrexate (MTX) is an economical and established drug that inhibits folic acid and purine synthesis.5 Initially, MTX was introduced as a cytotoxic agent; however, it was later found to have an anti-inflammatory effect at low doses. Thus, it was widely introduced for the treatment of various diseases such as rheumatoid arthritis (RA) and psoriasis.6,7 The role of MTX in the treatment of IBD was initially assessed in the 1990s. In 1995, Feagan and colleagues8 conducted a randomized controlled trial and reported that 25 mg/week of intramuscular MTX was effective in inducing remission in steroid-dependent CD. In 2000, the same research group reported that 15 mg/week of intramuscular MTX was also effective in maintaining CD remission.9 Oren and colleagues10 demonstrated that 12.5 mg/week of oral MTX was effective in active CD.\n\nAs MTX exhibits more adverse events (AEs) than thiopurines,11,12 MTX is usually considered a second-line immunomodulator for patients intolerant or unresponsive to thiopurines, despite having similar efficacy with remission rates of approximately 40%.11,13–15 Wahed and colleagues16 reported that MTX achieved a clinical response in 60% of CD patients who were unresponsive or intolerant to thiopurines at 6 months and 17.4% of patients experienced side effects of MTX. Recently, systematic reviews, meta-analyses, and retrospective studies have supported the clinical effectiveness of MTX in CD patients.17,18\n\nAs all of the aforementioned studies are from Western countries and most of them were published before 2010, recent data on the role of MTX in CD among Asian populations are lacking, except for small single-center data from China.19 The incidence and prevalence of IBD in Asian countries has increased recently,20–23 and thus the use of immunomodulators and biologics in Asia is increasing.24,25\n\nTherefore, in this study, we aimed to investigate the clinical role of MTX for treating Korean patients with CD.\n\nMethods\n\nPatients\n\nA retrospective chart review was performed for all 269 patients with CD treated with MTX at Asan Medical Center, Seoul, South Korea, from January 2008 to December 2020. Patients aged ⩾ 18 years, who received a diagnosis of CD, and were administered MTX therapy for the first time were included. We excluded patients who were administered MTX as a combination therapy with other IBD medications, such as corticosteroids, thiopurines, and biologics (except for 5-aminosalicylic acid (5-ASA)) and those who were prescribed MTX for reasons other than CD. We collected their demographic data, including sex, age at diagnosis, age at the start of MTX, disease duration from diagnosis to the start of MTX; baseline disease characteristics such as the location, upper gastrointestinal (GI) tract involvement, behavior, perianal modifier, prior bowel resection history, and prior medication history; and details of concomitant 5-ASA medication, laboratory data, MTX dose, and route of administration. We assessed the disease activity using Crohn’s disease activity index (CDAI) score. Each patient’s CDAI score was evaluated at every visit as a routine practice in our center. We collected the patient’s clinical data, including CDAI score, laboratory data, and all AEs observed during the 6 months after the start of MTX monotherapy. Moreover, we collected the maintenance duration of the MTX monotherapy of the study population through long-term follow-up until March 2021.\n\nOutcomes\n\nThe primary outcome was tolerability of MTX during the 6 months after the start of MTX monotherapy. Patients who stopped MTX due to AEs or poor compliance within 6 months were classified as the intolerant group. Data about AEs, such as GI disorder, hepatotoxicity, leukopenia, and general weakness, were collected during the 6 months after the start of MTX therapy. The secondary outcomes included the long-term durability of MTX monotherapy, the clinical response at 6 months of MTX therapy, the factors associated with intolerability and response, and the biochemical responses. The clinical response was defined as maintenance of a CDAI score < 150 among patients whose baseline CDAI score was < 150 and the achievement of a clinical remission (CDAI score < 150) or a reduction of the CDAI score ⩾ 100 from the baseline CDAI score among patients whose baseline CDAI score was > 150. Patients who had switched or escalated to biologics due to disease aggravation, but not because of AEs, were classified as the nonresponse group. Clinical factors such as demographic, drug-related, and disease-related factors were analyzed to verify if these were associated with intolerability and response. Biochemical responses were assessed based on the changes in blood markers, including erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), and serum albumin.\n\nStatistical analysis\n\nIn the descriptive analysis, categorical variables are expressed as a number with percentage. Continuous variables are expressed as median with interquartile range (IQR). To assess the factors associated with tolerability and response, we performed univariate and multivariate logistic regression analyses. The multivariate analyses included variables with p < 0.1 in univariate analysis and were performed using the backward elimination method. The results are presented as the odds ratios (ORs) with 95% confidence intervals (CIs). Linear mixed modeling was used to evaluate the significance of the changes over time in the laboratory values during 6 months of MTX monotherapy. Time was considered a continuous covariate to investigate the trends. Statistical analyses were performed using R statistical package version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria) and SPSS version 24.0 for Windows (IBM Corp., Armonk, NY, USA).\n\nEthical considerations\n\nOur study protocol was approved by the Institutional Review Board of Asan Medical Center (IRB No. 2020-1746).\n\nResults\n\nPatients’ characteristics\n\nIn total, 85 patients who received MTX monotherapy from 2008 to 2019 were included in this study (Figure 1). The demographic data and disease-related characteristics of the study population are summarized in Table 1. The median age at diagnosis and the start of MTX treatment were 23.0 (IQR: 18.0–30.0) and 31.0 (IQR: 24.0–38.0) years, respectively. The median disease duration was 66.0 (IQR: 24.0–114.0) months. Regarding the administration method, 48 (56.5%) patients received oral administration and 37 (43.5%) patients received parenteral injections, including intramuscular and subcutaneous injections. The median dose of MTX was 15.0 mg/week. Eighty-two (96.5%) patients had a history of prior thiopurine use, and 13 (15.3%) patients had a history of prior biologics use. Furthermore, 70 (82.4%) patients simultaneously received 5-ASA with MTX. The median baseline CDAI score among the total population was 90.7 (IQR: 41.4–159.3).\n\nFigure 1. Flow diagram of the study population.\n\nTable 1. Baseline characteristics of the study population.\n\n\tTotal patients (n = 85)\t\nMale, No (%)\t65 (76.5%)\t\nAge at diagnosis, years, median (IQR)\t23.0 (18.0–30.0)\t\nAge at start of MTX, years, median (IQR)\t31.0 (24.0–38.0)\t\nDisease duration, months, median (IQR)\t66.0 (24.0–114.0)\t\nAdministration method, No (%)\t\n Oral administration\t48 (56.5%)\t\n Parenteral injection\t37 (43.5%)\t\nMTX dose, mg/week, median (range)\t15.0 (10.0–25.0)\t\nPrior thiopurine use, No (%)\t82 (96.5%)\t\nPrior biologic use, No (%)\t13 (15.3%)\t\nPrior bowel resection history, No (%)\t43 (50.6%)\t\nConcomitant 5-ASA use, No (%)\t70 (82.4%)\t\nLocation, No (%)\t\n L1 ileal\t32 (37.6%)\t\n L2 colonic\t3 (3.5%)\t\n L3 ileocolonic\t50 (58.8%)\t\nUGI involvement, No (%)\t17 (20.0%)\t\nBehavior, No (%)\t\n B1 non-stricturing, non-penetrating\t42 (49.4%)\t\n B2 stricturing\t13 (15.3%)\t\n B3 penetrating\t30 (35.3%)\t\nPerianal manifestation, No (%)\t42 (49.4%)\t\nBaseline Laboratory data, median (IQR)\t\n White blood cell count, /µL\t6000 (4800–8100)\t\n Erythrocyte sedimentation rate, mm/hr\t21.0 (12.0–38.5)\t\n Serum C-reactive protein, mg/dL\t0.6 (0.2–1.3)\t\n Serum albumin, g/dL\t3.9 (3.6–4.1)\t\n Fecal calprotectin, µg/g\t486.0 (142.5–1044.0)\t\nBaseline CDAI score, median (IQR)\t90.7 (41.4–159.3)\t\n5-ASA, 5-aminosalicylic acid; CDAI, Crohn’s disease activity index; IQR, interquartile range; MTX, methotrexate; UGI, upper gastrointestinal.\n\nTolerability and AE profile during 6 months of MTX therapy\n\nAmong 85 patients, 29 (34.1%) discontinued MTX due to intolerability within 6 months. Out of 29 patients who were intolerant to MTX, 27 and 2 patients discontinued MTX because of AEs and poor compliance, respectively.\n\nIn terms of AE, 41/85 (48.2%) experienced AEs during 6 months of MTX therapy (Table 2). Among these patients, only one patient experienced a serious AE, disseminated pulmonary infection with a chemoport insertion site abscess caused by Mycobacterium abscessus that required hospitalization. Hepatotoxicity and general weakness were found in 9 (10.6%) patients, respectively. In addition, leukopenia occurred in 10 (11.8%) patients, and among these, 7 patients experienced grade 1 leukopenia (3000 < WBC ⩽ 4000) and 3 patients experienced grade 2 leukopenia (2000 < WBC ⩽ 3000). Moreover, 6 (7.1%) patients complained of headaches. Other AEs included upper respiratory tract infection, fever, arthralgia, alopecia, and drug eruption.\n\nTable 2. AEs during 6 months of MTX monotherapy.\n\n\tNo (%)\t\nAny adverse events\t41 (48.2%)\t\nAE-related discontinuation of MTX\t27 (31.8%)\t\nAE-related hospitalization\t1 (1.2%)\t\nPulmonary/extrapulmonary infection by M. abscessus\t\n GI disorder\t17 (20.0%)\t\n Hepatotoxicity\t9 (10.6%)\t\n General weakness\t9 (10.6%)\t\n Leukopenia\t10 (11.8%)\t\n Leukopenia grade 1 (3000 < WBC ⩽ 4000)\t7 (8.2%)\t\n Leukopenia grade 2 (2000 < WBC ⩽ 3000)\t3 (3.5%)\t\n Headache\t6 (7.1%)\t\n Fever\t2 (2.4%)\t\n Upper respiratory tract infection\t1 (1.2%)\t\n Arthralgia\t1 (1.2%)\t\n Alopecia\t1 (1.2%)\t\n Drug eruption\t1 (1.2%)\t\nAE, adverse event; GI, gastrointestinal; MTX, methotrexate; WBC, white blood cell.\n\nLong-term durability of MTX monotherapy\n\nWe collected the long-term maintenance duration data of MTX monotherapy until March 2021. The maintenance duration of all patients is illustrated in Figure 2. The longest follow-up duration of MTX monotherapy was 92 months, whereas the median duration was 11 months. Moreover, 50% and approximately 25% of the patients maintained MTX monotherapy at 11 and 30 months, respectively. During a follow-period of up to 92 months, 61/85 (71.8%) patients discontinued MTX monotherapy due to AEs (35/61, 57.4%), loss of response (21/61, 34.4%), poor compliance (3/61, 4.9%), and pregnancy planning (2/61, 3.3%).\n\nFigure 2. Kaplan-Meier curve of the long-term maintenance duration of MTX monotherapy.\n\nClinical response to MTX monotherapy\n\nAmong the total study population, 25 (29.4%) patients had active disease at baseline and 60 (70.6%) patients were in clinical remission at baseline (the baseline characteristics of the two groups classified according to the underlying disease activity are summarized in Supplementary Table 1). Excluding 29 intolerant patients, the response was assessed in the remaining 15 patients who had active disease and 41 patients who were in clinical remission. Among the 15 patients with initially active disease, 7/15 (46.7%) were responsive to MTX monotherapy after 6 months. Among the 41 patients who were in clinical remission at baseline, 37/41 (90.2%) were responsive to MTX monotherapy (Figure 3). Out of 56 patients in total, 44 (78.6%) were responsive to MTX monotherapy after 6 months. Among the total study population, 44/85 (51.8%) were responsive to MTX monotherapy and 12/85 (14.1%) were unresponsive to MTX monotherapy despite tolerating MTX.\n\nFigure 3. The proportion of patients according to intolerability and response after 6 months of MTX monotherapy.\n\nFactors associated with intolerability and response to MTX\n\nThe results of univariate analysis of clinical factors associated with intolerability to MTX within 6 months are summarized in Table 3. No factor in the univariate analysis exhibited a value of p < 0.1. No clinical characteristics including demographic, drug-related, and disease-related factors were significantly associated with intolerability to MTX (a comparison of baseline characteristics between the tolerable group and the intolerable group is presented in Supplementary Table 2).\n\nTable 3. Univariate analysis of factors associated with intolerability.\n\n\tOR (95% CI)\tp-value\t\nFemale gender\t1.84 (0.66–5.14)\t0.244\t\nAge at diagnosis (per year)\t1.00 (0.96–1.04)\t0.929\t\nAge at the start of MTX (per year)\t1.01 (0.97–1.05)\t0.531\t\nDisease duration (per month)\t1.00 (1.00–1.01)\t0.253\t\nAdministration method\t\t0.774\t\n Oral administration\tReference\t\t\n Parenteral injection\t0.88 (0.35–2.17)\t\t\nMTX dose (per mg/week)\t1.05 (0.90–1.24)\t0.531\t\nPrior thiopurine use\t0.00 (not estimated)\t0.990\t\nPrior biologic use\t0.30 (0.06–1.47)\t0.139\t\nPrior bowel resection history\t1.32 (0.54–3.25)\t0.543\t\nConcomitant 5-ASA use\t2.36 (0.61–9.16)\t0.213\t\nLocation\t\t0.249\t\n L1 ileal\tReference\t\t\n L2 colonic\t6.00 (0.48–75.34)\t\t\n L3 ileocolonic\t1.36 (0.83–2.22)\t\t\nUGI involvement\t1.07 (0.35–3.25)\t0.909\t\nBehavior\t\t0.437\t\n B1 non-stricturing, non-penetrating\tReference\t\t\n B2 stricturing\t0.99 (0.26–3.81)\t\t\n B3 penetrating\t1.22 (0.75–1.99)\t\t\nPerianal manifestation\t1.15 (0.47–2.82)\t\t\n5-ASA, 5-aminosalicylic acid; CI, confidence interval; MTX, methotrexate; OR, odds ratio; UGI, upper gastrointestinal.\n\nThe factors associated with a response to MTX monotherapy at 6 months are summarized in Table 4. In the univariate analysis, age at diagnosis and the administration method exhibited a value of p < 0.1. In the multivariate analysis, the adjusted OR of age at diagnosis per year was 0.94 (95% CI: 0.88–1.01; p = 0.087), and the adjusted OR of parenteral administration compared to oral administration was 5.68 (95% CI: 1.07–30.08; p = 0.041). The administration method was the only significant factor associated with a response in multivariate analysis (a comparison of the baseline characteristics between the response group and the nonresponse group is presented in Supplementary Table 3).\n\nTable 4. Univariate and multivariate analysis of factors associated with a response.\n\n\tUnivariate\tMultivariate\t\n\tOR (95% CI)\tp-value\tOR (95% CI)\tp-value\t\nFemale gender\t0.67 (0.15–3.03)\t0.600\t\t\t\nAge at diagnosis (per year)\t0.94 (0.89–1.01)\t0.074\t0.94 (0.88–1.01)\t0.087\t\nAge at the start of MTX (per year)\t0.96 (0.90–1.01)\t0.127\t\t\t\nDisease duration (per month)\t1.00 (0.99–1.01)\t0.758\t\t\t\nAdministration method\t\t0.041\t\t0.041\t\n Oral administration\tReference\t\tReference\t\t\n Parenteral injection\t5.48 (1.07–27.93)\t\t5.68 (1.07–30.08)\t\t\nMTX dose (per mg/week)\t0.93 (0.68–1.26)\t0.620\t\t\t\nPrior thiopurine use\t–\t–\t\t\t\nPrior biologic use\t0.38 (0.09–1.61)\t0.188\t\t\t\nPrior bowel resection history\t1.17 (0.34–4.03)\t0.808\t\t\t\nConcomitant 5-ASA use\t1.30 (0.29–5.80)\t0.734\t\t\t\nLocation\t\t0.411\t\t\t\n L1 ileal\tReference\t\t\t\t\n L2 colonic\tNot estimated\t\t\t\t\n L3 ileocolonic\t0.76 (0.39–1.48)\t\t\t\t\nUGI involvement\t1.29 (0.24–6.94)\t0.770\t\t\t\nBehavior\t\t0.622\t\t\t\n B1 non-stricturing, non-penetrating\tReference\t\t\t\t\n B2 stricturing\t2.09 (0.22–20.09)\t\t\t\t\n B3 penetrating\t0.82 (0.42–1.63)\t\t\t\t\nPerianal manifestation\t0.38 (0.10–1.45)\t0.157\t\t\t\n5-ASA, 5-aminosalicylic acid; CI, confidence interval; MTX, methotrexate; OR, odds ratio; UGI, upper gastrointestinal.\n\nBiochemical response during MTX monotherapy\n\nThe blood inflammatory markers, ESR and serum CRP, and serum albumin revealed significant changes during 6 months of MTX monotherapy (Figure 4). ESR and serum CRP were significantly decreased (for ESR, ptrend = 0.01; for serum CRP, ptrend = 0.03). The median level of ESR at baseline and week 24 was 21 mm/h (95% CI: 12.0–38.5) and 11 mm/h (95% CI, 3.75–23.75), respectively. Moreover, the median level of serum CRP at baseline and at week 24 was 0.6 mg/dL (95% CI: 0.2–1.3) and 0.29 mg/dL (95% CI: 0.13–0.69), respectively. Serum albumin revealed a significantly increasing trend over 6 months (ptrend = 0.028). Furthermore, the median level of serum albumin at baseline and week 24 was 3.9 g/dL (95% CI: 3.6–4.1) and 4.1 g/dL (95% CI: 3.8–4.3), respectively.\n\nFigure 4. The changes in biochemical markers during 6 months of MTX monotherapy. Erythrocyte sedimentation rate (ESR) (a), serum C-reactive protein (CRP) (b), and serum albumin (c).\n\nDiscussion\n\nRecently, novel drugs for CD treatment are gaining immense attention, particularly after the emergence of biologics; however, immunomodulators, which are old drugs compared to biologics, are still used in the medical treatment of CD as monotherapy or in combination therapy with biologics. Despite being economical and widely used, recent data on the real clinical role of MTX among CD patients are lacking. This study revealed that MTX is intolerable in about one-third of patients but can be clinically and biochemically effective in tolerant patients when used as a monotherapy.\n\nOne of the most important concerns regarding MTX is its tolerability. During 6 months of MTX therapy, 48.2% of patients experienced certain AEs, 31.8% of patients discontinued MTX due to AEs, but only one patient experienced serious AE in this study. In the randomized study by Feagan and colleagues,8 17% of patients discontinued MTX within 16 weeks due to AEs. The incidences of AEs ranged from 37% to 45%, but, serious AEs were rarely observed in previous retrospective studies.9,12,18 Discontinuation of MTX due to AEs within 6 months occurred in 7.4%, 11.4%, 12.2%, 16%, and 17% of patients in previous studies, respectively.8,12,18,19,26 In addition, discontinuation of MTX increased gradually over time, and 29.6%–32% of patients discontinued MTX within 24 months.12,19 The incidences of AEs from previous studies are consistent with our finding, but discontinuation of MTX was more frequent in our patients. As only one serious AE was reported, we presume that the patients in this study discontinued MTX due to minor AEs.\n\nAmong all AEs, the most common AE in previous studies was GI disorders, including nausea and vomiting, which occurred in 15.2%–22.2% patients, even up to 40%.9,12,18,19,27 Subsequently, general weakness and hepatotoxicity were reported in 8.2%–16% and 6.78%–10% patients, respectively.8,9,12,18,19,27,28 This AE profile is consistent with that of the present study, as general weakness and hepatoxicity occurred in 10.6% of patients, respectively. The incidence of leukopenia was higher in our study population. The previously reported incidence of leukopenia during MTX treatment ranged from 1% to 7%.12,18,27,29–31 Leukopenia occurred in 11.8% of our study population; of 10 patients with leukopenia, 7 (8.2%) had grade 1 leukopenia with little clinical significance; the other 3 (3.5%) patients who had grade 2 leukopenia can be considered clinically significant.\n\nThe serious AE requiring hospitalization that occurred in one patient was pulmonary and extrapulmonary infection caused by nontuberculous Mycobacteria (NTM). The patient developed a chemoport insertion site abscess and active disseminated pulmonary infection due to NTM after 12 weeks of MTX therapy. There are previous case reports of NTM infection in RA patients treated with low-dose MTX.32,33 Notably, MTX use was not significantly associated with NTM infection among RA patients,33,34 and CD itself and active disease status can cause immunologic disorders,35 so it is unclear whether MTX is directly associated with the development of NTM infections. Therefore, close monitoring of opportunistic infections among CD patients under immunomodulators is necessary.\n\nThere was no clinical factor associated with intolerability in this study. Vasudevan and colleagues12 explored the tolerability and discontinuation of immunomodulators among patients with IBD and found that no clinical factor, except smoking, was associated with the discontinuation of immunomodulators. Low dose and oral administration of MTX revealed lower rates of discontinuation, but both were statistically insignificant. Among patients with RA treated with low-dose MTX, the administration method was independent of AEs and tolerability.36,37 These are consistent with our study results. Oral administration may be preferred for fear of intolerability; however, in practice, oral administration is not beneficial.\n\nApart from the short-term tolerability of MTX, our results for the long-term maintenance duration of MTX monotherapy are disappointing. Nearly 50% of the patients discontinued MTX monotherapy at 11 months, and two-thirds discontinued at 30 months. In the retrospective cohort study by Vasudevan and colleagues,12 withdrawal from MTX increased over time from 16% at 6 months to 26% and 32% at 12 and 24 months, respectively, and the median time for discontinuation was 7.2 months. As their study included UC patients and allowed for combination therapy with biologics, this result may have to be interpreted differently from our study results.\n\nIn this study, MTX monotherapy was effective in 78.6% of tolerable patients and 51.8% of the whole study population. When classified according to the baseline disease activity, MTX was effective in 28.0% of the patients who had initially active disease and in 61.7% of the patients who were in clinical remission at baseline. In the randomized controlled study by Feagan and colleagues,8 39.4% of the patients achieved a clinical remission after 16 weeks of intramuscular MTX monotherapy. Wahed and colleagues16 revealed that a clinical response was achieved in approximately 60% of CD patients, who were unresponsive or intolerant to azathioprine/mercaptopurine, within 6 months of MTX therapy. In a retrospective study comparing MTX and thiopurine, the clinical remission rate at week 16 was 68.6% among patients treated with MTX.38 Furthermore, 62.9% and 48.1% of patients achieved a clinical response and clinical remission after 12 months of MTX monotherapy in a single-center experience in China.19 Among patients refractory to anti-TNF agents, the short-term clinical response and remission rates were 60% and 30.9%, respectively.18 The clinical response rate in the present study was similar to or slightly lower than that of previous studies. While previous studies included a subset of patients with CD, this study included a heterogeneous population of CD patients and revealed the short-term effectiveness of MTX therapy in this population, especially for the maintenance of clinical remission.\n\nAccording to our results, the administration method was the only significant factor associated with a response, and parenteral injection was more strongly associated with a response than oral administration. In randomized controlled studies that proved the effectiveness of MTX monotherapy compared to placebo, MTX was administered intramuscularly.8,9 In other randomized studies in which MTX was administered orally, MTX was not superior to placebo.10,39 Moreover, in retrospective studies revealing the effectiveness of MTX, most of the study population was administered MTX parenterally.28,38 Thus, the current guidelines recommend MTX monotherapy to be administered parenterally for maintaining remission in steroid-dependent CD patients.1,2 Oral administration of MTX is widely used in clinical practice because it is convenient. However, the rationale for the effectiveness of oral administration of MTX among CD patients is weak. To achieve a better response to MTX therapy, parenteral injection is preferable.\n\nThere are certain limitations to this study. First is the possibility of confounding factors and selection bias since this was a retrospective single-center study. Second, a majority of the study population was prescribed 5-ASA along with MTX, so the outcome of this study might not be considered to be the outcome of true “monotherapy”. However, current guidelines recommend against the use of 5-ASA for induction and maintenance of remission in patients with CD, because 5-ASA was not superior to placebo in previous studies.1,2 Thus, the role of 5-ASA is insignificant. Third, endoscopic and radiologic data were not available during the short-term follow-up for most patients. Hence, it was impossible to evaluate the effectiveness of MTX in mucosal healing. Fourth, analysis of the change in fecal calprotectin, which is one of the important parameters while evaluating responses in CD, could not be performed due to a lack of follow-up data. Despite the absence of such data, CDAI is a valuable and practical parameter widely used in the real medical field, so the results of this study using CDAI are worthwhile. Fifth, considering the biochemical response, not all patients underwent laboratory tests every 4 weeks; therefore, the number of patients evaluated each time was different. Finally, as patients who discontinued MTX monotherapy were excluded, the possibility of selection bias in evaluating the biochemical response cannot be ignored.\n\nDespite these limitations, this is the first study to evaluate the utility of MTX among adult CD patients using a meaningful number of samples in Asia. Our study confirmed that despite the intolerability in one-third of the patients, MTX can be considered a treatment option for Asian CD patients with little safety concern because serious AEs were extremely rare. A better response can be expected from parenteral injection than oral administration, as recommended by the current guidelines.\n\nSupplemental Material\n\nsj-docx-1-tag-10.1177_17562848211043017 – Supplemental material for Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn’s disease: a retrospective study\n\nClick here for additional data file.\n\nSupplemental material, sj-docx-1-tag-10.1177_17562848211043017 for Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn’s disease: a retrospective study by Hee Seung Hong, Kyuwon Kim, Kyunghwan Oh, Jae Yong Lee, Seung Wook Hong, Jin Hwa Park, Sung Wook Hwang, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang and Sang Hyoung Park in Therapeutic Advances in Gastroenterology\n\nsj-docx-2-tag-10.1177_17562848211043017 – Supplemental material for Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn’s disease: a retrospective study\n\nClick here for additional data file.\n\nSupplemental material, sj-docx-2-tag-10.1177_17562848211043017 for Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn’s disease: a retrospective study by Hee Seung Hong, Kyuwon Kim, Kyunghwan Oh, Jae Yong Lee, Seung Wook Hong, Jin Hwa Park, Sung Wook Hwang, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang and Sang Hyoung Park in Therapeutic Advances in Gastroenterology\n\nsj-docx-3-tag-10.1177_17562848211043017 – Supplemental material for Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn’s disease: a retrospective study\n\nClick here for additional data file.\n\nSupplemental material, sj-docx-3-tag-10.1177_17562848211043017 for Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn’s disease: a retrospective study by Hee Seung Hong, Kyuwon Kim, Kyunghwan Oh, Jae Yong Lee, Seung Wook Hong, Jin Hwa Park, Sung Wook Hwang, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang and Sang Hyoung Park in Therapeutic Advances in Gastroenterology\n\nConflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iDs: Hee Seung Hong https://orcid.org/0000-0002-3618-9760\n\nByong Duk Ye https://orcid.org/0000-0001-6647-6325\n\nSuk-Kyun Yang https://orcid.org/0000-0003-2772-2575\n\nSang Hyoung Park https://orcid.org/0000-0002-5366-5749\n\nSupplemental material: Supplemental material for this article is available online.\n==== Refs\nReferences\n\n1 Torres J Bonovas S Doherty G , et al . 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Efficacy and safety of methotrexate in the management of inflammatory bowel disease: a systematic review and meta-analysis of randomized, controlled trials. EClinicalMedicine 2020; 20 : 100271.32300735\n18 Mesonero F Castro-Poceiro J Benitez JM , et al . Effectiveness and safety of methotrexate monotherapy in patients with Crohn’s disease refractory to anti-TNF-alpha: results from the ENEIDA registry. Aliment Pharmacol Ther 2021; 53 : 1021–1029.33715177\n19 Wang TR Qiao YQ Zou DW , et al . A single-center experience with methotrexate in the treatment of Chinese Crohn’s disease patients. J Dig Dis 2018; 19 : 753–758.30516330\n20 Park SH Kim YJ Rhee KH , et al . A 30-year trend analysis in the epidemiology of inflammatory bowel disease in the Songpa-Kangdong District of Seoul, Korea in 1986-2015. J Crohns Colitis 2019; 13 : 1410–1417.30989166\n21 Yen HH Weng MT Tung CC , et al . 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Inflamm Bowel Dis 2014; 20 : 488–494.24412992\n26 Domenech E Manosa M Navarro M , et al . Long-term methotrexate for Crohn’s disease: safety and efficacy in clinical practice. J Clin Gastroenterol 2008; 42 : 395–399.18277899\n27 Chande N Abdelgadir I Gregor J. The safety and tolerability of methotrexate for treating patients with Crohn’s disease. J Clin Gastroenterol 2011; 45 : 599–601.21224737\n28 Kopylov U Katsanos KH van der Woude CJ , et al . European experience with methotrexate treatment in Crohn’s disease: a multicenter retrospective analysis. Eur J Gastroenterol Hepatol 2016; 28 : 802–806.26894634\n29 Lim AY Gaffney K Scott DG. Methotrexate-induced pancytopenia: serious and under-reported? Our experience of 25 cases in 5 years. Rheumatology 2005; 44 : 1051–1055.15901903\n30 Yan K Zhang Y Han L , et al . Safety and efficacy of methotrexate for Chinese adults with psoriasis with and without psoriatic arthritis. JAMA Dermatol 2019; 155 : 327–334.30698628\n31 Lalevee S Lebrun-Vignes B Simon C , et al . Cytopenia induced by low-dose methotrexate: an analysis of 433 cases from the French pharmacovigilance database. Eur J Intern Med 2019; 67 : 97–101.31350129\n32 Park JS Jung ES Choi W , et al . Mycobacterium intracellulare pulmonary disease with endobronchial caseation in a patient treated with methotrexate. Tuberc Respir Dis 2013; 75 : 28–31.\n33 Lim DH Kim YG Shim TS , et al . Nontuberculous mycobacterial infection in rheumatoid arthritis patients: a single-center experience in South Korea. Korean J Intern Med 2017; 32 : 1090–1097.28063416\n34 Liao TL Lin CF Chen YM , et al . Risk factors and outcomes of nontuberculous mycobacterial disease among rheumatoid arthritis patients: a case-control study in a TB endemic area. Sci Rep 2016; 6 : 29443.27404002\n35 Lee SH Kwon JE Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res 2018; 16 : 26–42.29422795\n36 Goodman SM Cronstein BN Bykerk VP. Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: a systematic literature review. Clin Exp Rheumatol 2015; 33 : 272–278.25536122\n37 Bujor AM Janjua S LaValley MP , et al . Comparison of oral versus parenteral methotrexate in the treatment of rheumatoid arthritis: a meta-analysis. PLoS ONE 2019; 14 : e0221823.\n38 Huang Z Chao K Li M , et al . Methotrexate for refractory Crohn’s disease compared with thiopurines: a retrospective non-head-to-head controlled study. Inflamm Bowel Dis 2017; 23 : 440–447.28129286\n39 Arora S Katkov W Cooley J , et al . Methotrexate in Crohn’s disease: results of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology 1999; 46 : 1724–1729.10430331\n\n",
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"issue": "14()",
"journal": "Therapeutic advances in gastroenterology",
"keywords": "Crohn’s disease; inflammatory bowel disease; methotrexate",
"medline_ta": "Therap Adv Gastroenterol",
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"title": "Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn's disease: a retrospective study.",
"title_normalized": "short term tolerability and effectiveness of methotrexate monotherapy in adult patients with crohn s disease a retrospective study"
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"abstract": "Malignant pleural mesothelioma (MPM) is a highly aggressive disease, with few, if any, curative interventions. While there is growing interest in using immunotherapy and immuno-gene therapy to treat MPM, very limited data currently exist for combining these modalities with radiotherapy. Preclinical data suggest that radiotherapy may be combined with immunotherapy to produce disease regression, with abscopal effects in mice with MPM. We report the first-ever case of abscopal effect in a patient with MPM, following radiotherapy and immuno-gene therapy. The patient was a 67-year-old male with prior asbestos exposure who presented with progressive dyspnea and thoracic pain. He underwent partial right pleurectomy, pleural biopsy, and talc pleurodesis, with pathology revealing epithelioid MPM. A subsequent chest computed tomography (CT) scan and fluoro-deoxyglucose positron-emission tomography (FDG-PET) CT scan showed extensive, right-sided, fluoro-deoxyglucose (FDG) avid mass-like pleural thickening encasing the right lung, with likely mediastinal extension, nodal metastases, and vascular compression. He enrolled in a clinical trial in which he received intrapleural interferon-alpha gene therapy but needed to discontinue therapy due to supraventricular tachycardia and superior vena cava syndrome induced from tumor burden. He was emergently treated with palliative radiotherapy to 30 Gy in 10 fractions. He was then started on pemetrexed and cisplatin chemotherapy. His subsequent chest CT scan two months after radiotherapy completion showed a dramatic treatment response within, as well as outside of, the irradiated field. After completion of radiotherapy, he did experience radiation esophagitis requiring nasogastric tube placement. Herein, we highlight the feasibility and efficacy of combining immuno-gene therapy with palliative radiotherapy to produce a substantial treatment response and an abscopal effect in a patient with unresectable MPM.",
"affiliations": "Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.;Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.;Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.;Internal Medicine, New York University School of Medicine, New York, USA.;Radiation Oncology, University of Maryland School of Medicine, Baltimore, USA.",
"authors": "Barsky|Andrew R|AR|;Cengel|Keith A|KA|;Katz|Sharyn I|SI|;Sterman|Daniel H|DH|;Simone|Charles B|CB|",
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"doi": "10.7759/cureus.4102",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 3105799610.7759/cureus.4102Radiation OncologyOncologyPulmonologyFirst-ever Abscopal Effect after Palliative Radiotherapy and Immuno-gene Therapy for Malignant Pleural Mesothelioma Muacevic Alexander Adler John R Barsky Andrew R 1Cengel Keith A 1Katz Sharyn I 2Sterman Daniel H 3Simone Charles B 2nd4\n1 \nRadiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA \n2 \nRadiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA \n3 \nInternal Medicine, New York University School of Medicine, New York, USA \n4 \nRadiation Oncology, University of Maryland School of Medicine, Baltimore, USA \nAndrew R. Barsky andrew.barsky@uphs.upenn.edu20 2 2019 2 2019 11 2 e41026 1 2019 19 2 2019 Copyright © 2019, Barsky et al.2019Barsky et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/17208-first-ever-abscopal-effect-after-palliative-radiotherapy-and-immuno-gene-therapy-for-malignant-pleural-mesotheliomaMalignant pleural mesothelioma (MPM) is a highly aggressive disease, with few, if any, curative interventions. While there is growing interest in using immunotherapy and immuno-gene therapy to treat MPM, very limited data currently exist for combining these modalities with radiotherapy. Preclinical data suggest that radiotherapy may be combined with immunotherapy to produce disease regression, with abscopal effects in mice with MPM. We report the first-ever case of abscopal effect in a patient with MPM, following radiotherapy and immuno-gene therapy. The patient was a 67-year-old male with prior asbestos exposure who presented with progressive dyspnea and thoracic pain. He underwent partial right pleurectomy, pleural biopsy, and talc pleurodesis, with pathology revealing epithelioid MPM. A subsequent chest computed tomography (CT) scan and fluoro-deoxyglucose positron-emission tomography (FDG-PET) CT scan showed extensive, right-sided, fluoro-deoxyglucose (FDG) avid mass-like pleural thickening encasing the right lung, with likely mediastinal extension, nodal metastases, and vascular compression. He enrolled in a clinical trial in which he received intrapleural interferon-alpha gene therapy but needed to discontinue therapy due to supraventricular tachycardia and superior vena cava syndrome induced from tumor burden. He was emergently treated with palliative radiotherapy to 30 Gy in 10 fractions. He was then started on pemetrexed and cisplatin chemotherapy. His subsequent chest CT scan two months after radiotherapy completion showed a dramatic treatment response within, as well as outside of, the irradiated field. After completion of radiotherapy, he did experience radiation esophagitis requiring nasogastric tube placement. Herein, we highlight the feasibility and efficacy of combining immuno-gene therapy with palliative radiotherapy to produce a substantial treatment response and an abscopal effect in a patient with unresectable MPM.\n\nmesotheliomaradiation therapyabscopal effectimmunotherapygene therapyThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nMalignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the mesothelial surface of the pleura, with an incidence of one case per 100,000 people per year in the United States [1]. MPM has a strong causal relationship with asbestos exposure, and to a lesser extent, prior in-field radiotherapy [2] and the germline breast cancer type 1 susceptibility protein-associated protein-1 mutation [3]. The majority of MPM cases are of the epitheliod histologic subtype, which portends a more favorable prognosis [4], with the remainder composed predominantly of sarcomatoid and biphasic subtypes [5].\n\nThe management of MPM depends largely upon the patient’s staging, tumor histology, co-morbidities, and performance status. The standard of care for patients with stage IV disease and for non-epithelioid histologies is chemotherapy alone or observation for progression. The standard of care for physically fit patients with stage I-III disease and epithelioid histology is surgical resection, with or without induction or adjuvant therapies [6]. In patients with unresectable disease, definitive chemotherapy is the standard of care, with pemetrexed and cisplatin or carboplatin, with or without bevacizumab every three weeks for up to six cycles [7]. Unfortunately, even with surgery, MPM remains largely an incurable malignancy. In the definitive chemotherapy setting, a recent phase III randomized trial comparing pemetrexed, cisplatin, and bevacizumab to pemetrexed and cisplatin alone, showed a median overall survival of 18.8 months and 16.1 months, respectively, demonstrating a need for further improvement in therapeutic options [8].\n\n As such, there has been an interest in immunotherapy and immuno-gene therapy to treat MPM. Studies have investigated the use of interleukin-2 [9], tremelimumab [10], pembrolizumab [11], nivolumab [12], and avelumab [13] in MPM. A study of immuno-gene therapy in MPM investigated the use of a modified adenoviral vector harboring the human interferon-alpha-2b gene (Ad.IFN) via intrapleural infusion, followed by systemic chemotherapy, with an impressive median overall survival of 21.5 months for MPM patients with epithelial histology in the second-line setting [14]. While there is evidence that radiotherapy may independently have an immunomodulatory effect [15], and that local radiotherapy has been observed in some cases to achieve an “abscopal” effect, or radiation-induced cell death within the irradiated field, with disease regression outside of the irradiated field, potentially due to systemic immune stimulation from local radiotherapy effects [16], there currently are very few published reports combining radiotherapy with immunotherapy in MPM. Furthermore, no abscopal response has been reported to date when combining radiotherapy with immunotherapy for MPM. Herein, we report the first case of an abscopal effect for a patient with MPM treated with Ad.IFN immuno-gene therapy followed by radiotherapy with an exaggerated local response as well as out-of-field regression.\n\nCase presentation\nHistory and physical\n\nA 67-year-old male former smoker with a history of prior occupational asbestos exposure and recurrent bronchitis presented with progressive dyspnea and thoracic pain to the point that he could not lie down in bed. A computed tomography (CT) scan of the chest was performed, which was interpreted as right-sided pneumonia with right parapneumonic effusion. He was sent to his local emergency department, where he was admitted for antibiotics and thoracentesis, the latter which demonstrated the presence of atypical mesothelial cells with inflammatory cells. He was readmitted two weeks later for progressive thoracic pain, was found to have a recurrent right-sided pleural effusion, and was managed with partial right pleurectomy with pleural biopsy, and talc pleurodesis. Right pleural pathology demonstrated atypical mesothelial proliferation at the pleural surface, without true invasion or definitive pathologic evidence of malignancy. Following surgery, he felt substantially better, such that he could sleep in the bed again, and he was able to return to his baseline activity levels. He underwent repeat chest CT five months later, which showed right pleural thickening and a small loculated pleural effusion, favored to represent a combination of calcification, pleurodesis, and atelectasis. He remained clinically well for another five months until he presented with cough and sinus congestion unrelieved by guaifenesin, dextromethorphan, and antibiotics. He underwent repeat chest CT that showed extensive mass-like pleural thickening completely encasing the right lung, with prominent involvement of the mediastinal pleura, and probable mediastinal extension into the right paratracheal and precarinal space, with pericardial effusion and probable pericardial metastases. There was no definite invasion into the right chest wall and no evidence of disease outside of the thorax.\n\nHe then established care at our institution’s mesothelioma and pleural disease multi-disciplinary program. Pathology review of the previously biopsied pleural tumor revealed that the pleural tumor cells were positive for Wilms' tumor-1 and calretinin, and negative for mouse monoclonal epithelial cell adhesion molecule antibody and thyroid transcription factor-1, consistent with malignant epithelioid mesothelioma, invading fibro-adipose tissue. At the time of consultation, he reported increasing shortness of breath, dyspnea on exertion, intermittent cough productive of clear sputum, 40 pounds of weight loss, drenching sweats, and chest wall numbness near his incision site, although he was still able to perform rigorous exercise on a daily basis. His past medical and surgical histories were otherwise only remarkable for hypertension and inguinal hernia repair surgery, respectively. His family history was notable for mesothelioma in a maternal uncle and breast cancer in a maternal aunt. His exam revealed diffusely decreased right-sided breath sounds, right-sided dullness to percussion, a well-healed right chest wall incision, and an Eastern Cooperative Oncology Group (ECOG) performance status of one. His forced vital capacity (FVC) was 1.88 L (41% of predicted) and forced expiratory volume in one second (FEV1) was 1.54 L (46% of predicted).\n\nHe was seen by pulmonology, medical oncology, radiation oncology, and thoracic surgery, with further staging recommended. Fluoro-deoxyglucose positron-emission tomography (FDG-PET) CT was performed and showed extensive mass-like circumferential pleural thickening throughout the right hemithorax which was diffusely fluoro-deoxyglucose (FDG) avid (SUVmax 16.1) and invaded the left hilum with mass effect on the left atrium. It also showed diffuse metastatic nodularity of the pericardium and associated small pericardial effusion. Magnetic resonance imaging (MRI) of the brain was negative for metastatic disease. A repeat chest CT with intravenous contrast re-demonstrating the known disease burden but was concerning for vascular invasion (Figure 1A). An MRI of the chest showed a 19.4 x 20.8 x 21.5-cm mass in the right pleural space with mediastinal and diaphragmatic invasion. The tumor extended across the midline at the level of the carina, with vascular encasement, segmental esophageal encasement, the involvement of the azygoesophageal recess, and invasion into the superficial right hemidiaphragm. As a result of his clinical American Joint Committee on Cancer primary tumor stage T4 disease due to the mediastinal invasion, he was not a surgical candidate. He opted to enroll in phase I/II clinical trial of front-line pemetrexed/cisplatin chemotherapy in combination with repeated dose intrapleural interferon-alpha gene therapy [14].\n\nFigure 1 Pre and post-treatment chest CT scans\nAxial (from left to right, at the levels of the diaphragm, great vessels, and inferior clavicular heads), coronal, and sagittal IV contrast-enhanced CT images obtained (A) prior to immuno-gene therapy, and at (B) three months and (C) six months following immuno-gene therapy, revealing a sustained dramatic decrease in burden of pleural tumor. Representative regions of the tumor prior to immuno-gene therapy are indicated by red arrows, with representative regions of tumor response to therapy at three months and six months following immuno-gene therapy indicated by blue arrows and green arrows, respectively.\n\nCT, computed tomography; IV, intravenous\n\nIntrapleural interferon-alpha immuno-gene therapy details\n\nThe patient went to the operating room for surgical creation of a small pleural space in which a pleural catheter was placed, approximately 5 cm below the tip of the right scapula in the lateral chest wall, to facilitate intrapleural infusion of the adenoviral vector for immuno-gene therapy, as per study protocol. The following week, he received his first intrapleural interferon-alpha gene therapy treatment, which he tolerated without complication. Five days later, he presented for his second treatment, at which time he developed sudden tachycardia and electrocardiogram revealed supraventricular tachycardia (SVT) requiring treatment with adenosine. As a result, his second intrapleural treatment was held. The following day, he experienced another episode of SVT with hypotension, for which he again responded to adenosine. He was admitted to the hospital, where a chest CT revealed significant compression of the pulmonary veins and left atrium and transthoracic echocardiogram demonstrated increasing pulmonary hypertension, with mild right ventricular dilation. Cardiology was consulted, who attributed the cardiac symptoms to vascular compression. The options of urgent chemotherapy or radiotherapy were discussed, and radiotherapy was recommended in an attempt to quickly improve symptoms and relieve vascular compression.\n\nRadiotherapy setup and treatment planning details\n\nThe patient underwent CT simulation in the supine position with his arms above his head, with a full body vac-lock bag used for immobilization. The isocenter was set at the carina. The primary tumor was contoured using the simulation CT dataset, with the gross tumor volume (GTV) defined as all visible tumor on the simulation CT images. A 0.8-mm expansion to account for the microscopic disease was added to the GTV to generate the clinical target volume (CTV). The planning target volume (PTV) was generated as a 0.5-cm uniform expansion on the GTV. The plan was designed to treat the PTV to a dose of 30 Gy in 10 daily fractions using a forward-planned, field-in-field, three-dimensional conformal radiotherapy (3D-CRT) technique. A two-field technique was used with 15-MV anterior-posterior and posterior-anterior beams and multi-leaf collimation (MLC) to spare dose to bone, heart, liver, and kidney. Image-guided radiotherapy, with daily pre-treatment kV-kV scans, was used to optimize patient alignment and target localization. The treatment volumes and plan are depicted in Figure 2.\n\nFigure 2 Radiation treatment plan\nRepresentative axial (A) and coronal (B) simulation CT images depicting the radiotherapy fields used for treatment, with the GTV outlined in red. Digitally reconstructed radiograph of an anterior-posterior field with multi-leaf collimators used for treatment, with the GTV outlined in red (C). Representative axial (D), coronal (E), and sagittal (F) simulation CT images depicting radiotherapy dose distribution for the treated plan. A dose of 30 Gy was delivered in 10 fractions using forward-planned, field-in-field three-dimensional conformal radiotherapy.\n\nCT, computed tomography; GTV, gross tumor volume\n\nRadiotherapy course\n\nHis treatment was tolerated well overall, without any unplanned breaks. His pre-radiotherapy dyspnea improved rapidly during treatment, such that he no longer required supplemental oxygen by the second week of treatment. He developed acute grade two dyspepsia, managed with omeprazole, as well as grade two dysphagia, cough, fatigue, and constipation. His ECOG performance status improved from three at the start of radiotherapy to two at the end of radiotherapy.\n\nPost-radiotherapy course\n\nTwo days after completion of radiotherapy, he was started on systemic therapy with intravenous pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). Six days after cycle one day one of chemotherapy, he noted severe radiation esophagitis and weight loss, prompting hospitalization, during which time he required nasogastric tube (NGT) feeds and opioid analgesia. His symptoms improved over that week, and his NGT was removed. He received cycles two and three of chemotherapy, 21 days apart, with post-cycle three chest CT showing dramatic interval response to therapy, with a representative mass in the right paratracheal region measuring 1.2 x 8.5 cm, previously 3.9 x 9.1 cm two months prior (Figure 1B). He continued with another three cycles of chemotherapy, with repeat chest CT after cycle six showing ongoing interval improvement of multiple pleural masses, with profound response in the ipsilateral treated hemi-thorax, and no evidence of contralateral pericardial disease. Overall, he tolerated these six cycles of systemic therapy well and reported improvements in energy level, appetite, breathing, and odynophagia.\n\nThe patient then opted to enroll on a randomized trial of maintenance pemetrexed versus observation following completion of six cycles of first-line therapy [NCT01085630], and he was randomized to the pemetrexed arm. He continued on pemetrexed monotherapy (500 mg/m2) for a total of eight cycles, every 21 days, over the next seven months. Following maintenance cycle two, his chest CT showed ongoing stable disease (Figure 1C). He tolerated this well initially, with occasional fatigue, anemia, ankle edema, and cough. During cycle four, he reported some productive cough and worsening dyspnea on exertion with subsequent chest CT scan revealing increasing multifocal opacities involving nearly all lobes of the lung. These imaging findings were favored to represent infection versus delayed radiation pneumonitis versus chemotherapy-induced pneumonitis, for which he was managed with levofloxacin and prednisone, with significant improvement of symptoms. He initially clinically improved on this therapy, however ultimately required admission to the intensive care unit following cycle six for septic shock attributed to right-sided pneumonia, which improved with volume resuscitation, antibiotics, and steroids. His CT chest at the time of admission demonstrated a stable burden of mesothelioma. After discharge home, the patient continued with cycles seven and eight of pemetrexed but was admitted about one month after his final cycle for worsening lower extremity edema, dyspnea, and orthopnea that was only partially responsive to intravenous diuretics. His chest CT at this time showed increasing consolidation in the right lung, with stable pleural thickening, but with an increasing left-sided pleural effusion without pleural thickening. Given a negative workup by cardiology, and a lack of other clear explanations for his symptoms and contralateral effusion, this clinical worsening of symptoms was favored to represent disease progression, and he was switched to treatment with gemcitabine (1000 mg/m2), of which he received two cycles of therapy.\n\nUnfortunately, in the first few weeks following gemcitabine therapy, he developed progressive shortness of breath and performance status decline. Reimaging confirmed that he had further progressive disease. Systemic therapy was stopped, and he was transitioned to outpatient hospice. He passed away comfortably three months later.\n\nDiscussion\nTo date, this is the first published report of an abscopal effect in a patient with MPM, as well as the first report of abscopal effect following radiotherapy and immuno-gene therapy for MPM. While this was not the initially planned treatment regimen for the patient, it is noteworthy to report the findings given the novelty of immuno-gene therapy, low radiotherapy dose, and substantial, durable local response to therapy for this aggressive disease.\n\nIn this patient’s case, the initial plan was to proceed with two infusions of immuno-gene therapy, as per the study protocol [14]. However, given that he developed SVT requiring adenosine infusion prior to the second planned infusion, the remainder of his immuno-gene therapy course was discontinued. Per the study protocol, should he have completed his two infusions, the next therapy would have been standard chemotherapy. However, he developed critical findings concerning for superior vena cava syndrome, and given his worsening illness, he was emergently started on a course of palliative radiotherapy, with the hope that this would prevent further immediate progression of disease, and potentially also regression of disease. As can be seen in Figure 1, the patient’s response to immuno-gene therapy, palliative radiotherapy, and subsequent chemotherapy, both in-field and out-of-field was dramatic, and notably more pronounced than what is generally achievable for even well-responding MPM patients. In fact, his exaggerated response was far greater than would be expected based upon the volume of disease irradiated and radiation dose employed, potentially by eliciting an abscopal effect.\n\nThe hypothesis for the mechanism of action for the abscopal effect is that tumor cell injury by radiation therapy generates the release of tumor cell neoantigens which are then taken up by antigen-presenting cells and brought to lymph nodes to activate T-cells. There, T-cells become primed to identify and attack tumor-specific antigens, allowing them to attack tumor that expresses these antigens, which includes both the treated primary and out-of-field tumor, leading to tumor regression both in-field and out-of-field. In the last few decades, there has been increasing recognition of the abscopal effect, such that 46 case reports of this type of tumor response from radiotherapy alone have been published between 1969 and 2014. The tumor types in which an abscopal response has been described include hepatocellular carcinoma, melanoma, and renal cell carcinoma, among others [17]. To our knowledge, this case represents the first reported case of an abscopal effect in MPM.\n\nGiven the dismal prognosis of MPM, even with the best available standard modern therapies, there is interest in using novel therapies, such as immunotherapy, or immuno-gene therapy, in its treatment. Given the efficacy of therapies directed against cytotoxic T-lymphocyte-associated protein 4 (CLTA-4) in other cancers, tremelimumab, an anti-CTLA-4 antibody, was studied in a randomized phase III trial against placebo in MPM, but it unfortunately did not show a significant improvement in overall survival (7.7 vs. 7.3 months) [10]. Therapies directed against programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have also been studied in MPM [18]. Pembrolizumab, an anti-PD-1 antibody, was used in a phase I study of 25 PD-L1-positive patients with MPM and yielded an overall response rate of 20%, with more than half of the patients having stable disease for over six months [11]. Nivolumab, also an anti-PD-1 antibody, was used in a phase II study of 34 patients with MPM and showed a 50% disease control rate at 12 weeks [12]. Avelumab, an anti-PD-L1 antibody, was used in a phase I study of patients with 53 patients who received prior treatment for unresectable MPM or malignant peritoneal mesothelioma, and it was found to have nearly a 10% partial response rate, with a and median progression-free survival of 17.1 weeks, and a safe toxicity profile [13]. In addition, immuno-gene therapy for MPM with intrapleural Ad.IFN therapy, followed by systemic chemotherapy, has been studied, as in this patient, with a median overall survival of 21 months for the whole epithelial cohort [14]. While recognizing that this was not a randomized trial and should be compared to other survival data with caution, it is worth noting that an overall survival of 21.5 months among second-line patients with this novel combination compares favorably to that of standard of care definitive chemotherapy with pemetrexed, cisplatin, and bevacizumab for unresectable MPM among even first-line patients, which yielded a median overall survival of 18.8 months [8]. As these relatively new data emerge demonstrating safety and some degree of efficacy for immunotherapy and immuno-gene therapy, increasing interest is emerging in understanding how these therapies interact with radiotherapy.\n\nThe possibility exists that radiotherapy could be combined with these systemic treatments to produce an augmented radiotherapy effect, and possibly, an out-of-field abscopal effect. Preclinical data exist that suggest that radiation can act synergistically with immune checkpoint inhibitors by increasing tumor antigen production and presentation, increasing cytotoxic T-lymphocyte activity, and decreasing myeloid immune suppressor cells. It has also been suggested that radiation-associated immune activation could lead to a more thorough regression of the irradiated tumor, as well as microscopic metastatic disease that was not appreciated at the time of initial therapy [19]. In a murine study of localized radiotherapy and anti-CTLA-4 therapy in an MPM model, the growth of the primary tumor as well as the non-irradiated tumor was delayed. Further analysis of the mice showed increased Treg and cytotoxic T-cell infiltration in the primary and non-irradiated tumor, with subsequent decreases in Treg cells and increases in cytotoxic T-cells after anti-CTLA-4 therapy was administered, suggesting the feasibility of the abscopal effect in MPM [18]. In humans, the data for combining immunotherapy with radiotherapy are more limited but appear promising in thoracic malignancies like non-small cell lung cancer [20], as well as extra-thoracic malignancies [19]. That said, this is an active area of interest, with ongoing clinical trials studying the combination of immunotherapy with radiotherapy in non-small cell lung cancer, small cell lung cancer, esophageal cancer, and MPM, among others [20]. Herein, we provide evidence that immuno-gene therapy combined with radiotherapy in MPM was feasible and capable of producing durable locoregional and distant disease control, as well as abscopal effect, for this highly aggressive malignancy.\n\nWhile effective, the toxicity of therapy in this patient warrants discussion. The patient received his first immuno-gene therapy infusion without issue, but within a few days developed two episodes of SVT with hypotension. Following evaluation by the cardiology team, it was favored that tumor burden with resultant vascular compression was the most likely etiology of his symptoms, but given the temporal relation to his infusion, the relationship to the immunotherapy cannot be definitively excluded. It is possible that the SVT may have been a result of an intra-tumoral inflammatory response in the setting of recent immuno-gene therapy infusion, with bulky tumor adjacent to the pericardium. As such, there may need to be additional caution in the future with Ad.IFN administration in similar settings of bulky disease adjacent to vital structures. Furthermore, while he tolerated radiotherapy without issue during treatment, he went on to develop severe radiation esophagitis with weight loss, requiring NGT placement and hospitalization. While radiation esophagitis is an expected side effect of thoracic radiotherapy, even with a relatively low dose of 30 Gy in 10 fractions, severity to the point of NGT placement from radiotherapy alone is greater than expected. As such, it is possible that having received recent immuno-gene therapy may have made him more susceptible to the development of inflammatory side effects. It is also possible that his innately being susceptible to radiation-induced inflammatory toxicities also immunologically allowed for him to respond better to immunotherapy and/or be more likely to develop an abscopal effect from the combination of radiation therapy and systemic therapy. While the development of these adverse effects should not preclude therapy in appropriately selected patients, it is worthwhile to know that these effects can happen and to counsel patients and providers to be aware of such symptoms, such that appropriate surveillance and early intervention can be administered. Further study of immunotherapy and immuno-gene therapy with radiotherapy, with differing dose and fractionation schemas, both in MPM and other disease sites is warranted.\n\nConclusions\nMPM is a highly aggressive disease with few, if any, curative interventions, and thus a need exists for improved therapies, including immunotherapy and immuno-gene therapy. With this case report, we provide evidence that immuno-gene therapy combined with radiotherapy in MPM is feasible and capable of producing durable locoregional and distant disease control, as well as abscopal effect.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Malignant pleural mesothelioma: an epidemiological perspective Ann Cardiothoracic Surg Robinson BM 491 496 1 2012 \n2 Radiation-induced malignant mesothelioma: frequency and prognosis Int J Radiat Oncol Biol Phys Barsky AR Friedberg JS Culligan M 715 716 90 2014 \n3 Germline BAP1 mutations predispose to malignant mesothelioma Nat Genet Testa JR Cheung M Pei J 1022 1025 43 2011 21874000 \n4 Survival by histologic subtype of malignant pleural mesothelioma and the impact of surgical resection on overall survival Clin Lung Cancer Verma V Ahern CA Berlind CG 901 912 19 2018 \n5 Pathology of mesothelioma Environ Health Prev Med Inai K 60 64 13 2008 19568882 \n6 Treatment of malignant pleural mesothelioma with chemotherapy preceding versus after surgical resection J Thorac Cardiovasc Surg Verma V Ahern CA Berlind CG 32793 32794 ahead of print [PubMed 18 2018 http://PMID: \n7 Malignant Pleural Mesothelioma (Version 2.2018) 12 2018 National Comprehensive Cancer Network 2018 http://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf \n8 Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-lab, phase 3 trial Lancet Zalcman G Mazieres J Margery J 1405 1414 387 2016 26719230 \n9 Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: results of a phase II study on 31 consecutive patients Lung Cancer Castagneto B Zai S Mutti L 303 310 31 2001 11165411 \n10 Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): results from the global, double-blind, placebo-controlled DETERMINE study J Clin Oncol Kindler HL Scherpereel A Calabro L 8502 34 2016 \n11 Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE- 028): preliminary results from a non-randomised, open-label, phase 1b trial Lancet Oncol Alley EW Lopez L Santoro A 623 630 18 2017 28291584 \n12 OA13.01 A phase II study of nivolumab in malignant pleural mesothelioma (NivoMes): with translational research (TR) biopsies J Thorac Oncol Quispel-Janssen J Zago G Schouten R 292 293 12 2017 \n13 Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase 1b trial: safety, clinical activity and PD-L1 expression J Clin Oncol Hassan R Thomas A Patel MR 8503 34 2016 \n14 Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNα combined with chemotherapy Clin Cancer Res Sterman DH Alley E Stevenson JP 3791 3800 22 2016 26968202 \n15 Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor J Immunol Lugade AA Moran JP Gerber SA 7516 7523 174 2005 15944250 \n16 Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumors: a proof-of-principle trial Lancet Oncol Golden EB Chhabra A Chachoua A 795 803 16 2015 26095785 \n17 Using immunotherapy to boost the abscopal effect Nature Reviews Cancer Ngwa W Irabor OC Schoenfeld JD 313 322 18 2018 29449659 \n18 Immunotherapy and radiation therapy for malignant pleural mesothelioma Transl Lung Cancer Res Alley EW Katz SI Cengel KA 212 219 6 2017 28529903 \n19 Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies Transl Lung Cancer Res Simone CB 2nd Burri SH Heinzerling JH 545 552 4 2015 26629423 \n20 Combining immunotherapy with radiation therapy in thoracic oncology J Thorac Dis Badiyan SN Roach MC Chuong MD 2492 2507 10 2018\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(2)",
"journal": "Cureus",
"keywords": "abscopal effect; gene therapy; immunotherapy; mesothelioma; radiation therapy",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e4102",
"pmc": null,
"pmid": "31057996",
"pubdate": "2019-02-20",
"publication_types": "D002363:Case Reports",
"references": "26719230;28291584;29449659;30206494;11165411;21874000;26095785;23977542;26968202;19568882;28529903;30224273;30454981;26629423;15944250",
"title": "First-ever Abscopal Effect after Palliative Radiotherapy and Immuno-gene Therapy for Malignant Pleural Mesothelioma.",
"title_normalized": "first ever abscopal effect after palliative radiotherapy and immuno gene therapy for malignant pleural mesothelioma"
} | [
{
"companynumb": "US-ACCORD-129193",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Factor V (FV) deficiency may be inherited as an autosomal recessive disease or acquired as a result of autoantibody formation, either spontaneously or secondary to exposure to bovine thrombin or medications. Congenital FV deficiency has traditionally been treated with plasma transfusions. However, recent evidence has suggested that platelet (PLT) transfusions may be a better alternative as FV stored within PLT alpha granules has greater procoagulant potential and is released locally at sites of vascular injury. We report three cases of FV deficiency, one congenital and two acquired, and emphasize the different management approaches.\n\n\n\nPatient 1 was a 30-year-old man with congenital FV deficiency who presented with a trauma-induced hematoma of his lower extremity. He was treated with 5 PLT units over 48 hours. Patient 2 was a 64-year-old woman who presented with an upper-extremity thrombus and was discovered to have a FV inhibitor, likely secondary to antibiotics. Patient 3 was a 75-year-old woman with hepatitis C virus (HCV) who presented with minor ecchymosis and was found to have a FV inhibitor secondary to either HCV or antibiotic exposure. Corticosteroids alone were able to eradicate the inhibitors in both patients with acquired inhibitors.\n\n\n\nFV deficiency can present with a diverse range of symptoms. For bleeding patients, PLT transfusions should be the initial therapy. In patients with thrombosis, the risks and benefits of anticoagulation must be carefully assessed before treatment. For patients with minor bleeds, transfusions may be withheld, and elimination of the inhibitor should be the primary objective.",
"affiliations": "Division of Transfusion Medicine and Hemostasis, Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.;Division of Transfusion Medicine and Hemostasis, Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.;Division of Hematology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.;Division of Transfusion Medicine and Hemostasis, Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.",
"authors": "Gavva|Chakri|C|;Yates|Sean G|SG|;Rambally|Siayareh|S|;Sarode|Ravi|R|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D001323:Autoantibodies; D005165:Factor V",
"country": "United States",
"delete": false,
"doi": "10.1111/trf.13623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "56(7)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D001323:Autoantibodies; D019468:Disease Management; D005165:Factor V; D005166:Factor V Deficiency; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D017713:Platelet Transfusion; D013927:Thrombosis",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "1745-9",
"pmc": null,
"pmid": "27125565",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Transfusion management of factor V deficiency: three case reports and review of the literature.",
"title_normalized": "transfusion management of factor v deficiency three case reports and review of the literature"
} | [
{
"companynumb": "US-INFO-000725",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "METHODS\nA 69-year-old woman with small cell lung cancer presented in the emergency ward because of severe back pain. She had received tolvaptan treatment in hospital for paraneoplastic SIADH but had discontinued the drug after discharge from hospital 3 days ago. Restriction of fluid intake was not tolerated.\n\n\nMETHODS\nConsistent with SIADH, there were profound hyponatraemia, elevated urine osmolality and urine sodium.\n\n\nMETHODS\nAfter a generalized seizure triggered by hyponatraemia, tolvaptan was reintroduced in addition to radiochemotherapy. Serum sodium concentration increased and finally returned to normal.\n\n\nCONCLUSIONS\nIf restriction of fluid intake is not tolerated by the patients the vasopressin antagonist tolvaptan provides an alternative symptomatic treatment of paraneoplastic SIADH.",
"affiliations": "Medizinische Klinik und Poliklinik III, Klinikum der Universität München.;Medizinische Klinik und Poliklinik III, Klinikum der Universität München.",
"authors": "Schnaiter|A|A|;Hiddemann|W|W|",
"chemical_list": "D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0034-1387289",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "139(41)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000368:Aged; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D005260:Female; D006801:Humans; D007177:Inappropriate ADH Syndrome; D008175:Lung Neoplasms; D010257:Paraneoplastic Syndromes; D055752:Small Cell Lung Carcinoma; D000077602:Tolvaptan; D016896:Treatment Outcome",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "2077-9",
"pmc": null,
"pmid": "25268207",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Symptomatic therapy of SIADH in small cell lung cancer by tolvaptan.",
"title_normalized": "symptomatic therapy of siadh in small cell lung cancer by tolvaptan"
} | [
{
"companynumb": "DE-OTSUKA-EU-2014-10537",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Thrombus incidence is higher among neonates, especially in preterm infants, due to the associated additional risk factors.\nThe medical recordings of premature infants who had been diagnosed as having intracardiac thrombus between January 2016 and January 2019 were evaluated retrospectively. We use recombinant tissue plasminogen activator when the thrombus is relatively large compared to left atrium, pedunculated, mobile, or snake shaped.\nA total of 13 premature patients were diagnosed as having intracardiac thrombus during the 3-year period. All were diagnosed during echocardiographic studies. Low molecular weight heparin was administered in four patients. In three, recombinant tissue plasminogen activator was started with low dose (0.01 mg/kg/h) and increased gradually to 0.06 mg/kg/h. In three, recombinant tissue plasminogen activators were started with standard dose (0.5 mg/kg/h). In one recombinant tissue, plasminogen activator was started with low dose (0.01 mg/kg/h) and increased to standard dose. Two patients died before treatment, three patients died during treatment, follow-up was not available for two patients, and thrombus completely resolved in six patients.\nIn preterm babies with risk factors, intracardiac thrombus should be kept in mind during all echocardiographic studies. In our patients, low and standard dose regimens were used, and the treatment results were similar.",
"affiliations": "Faculty of Medicine, Ataturk University, Erzurum, Turkey.;Faculty of Medicine, Ataturk University, Erzurum, Turkey.;Faculty of Medicine, Ataturk University, Erzurum, Turkey.;Faculty of Medicine, Ataturk University, Erzurum, Turkey.;Erzurum Nenehatun Obstetrics and Gynecology Hospital, Erzurum, Turkey.;Faculty of Medicine, Ataturk University, Erzurum, Turkey.",
"authors": "Kara|Mustafa|M|https://orcid.org/0000-0001-6568-1538;Güler|Muhlike|M|https://orcid.org/0000-0002-7513-2193;Keskin Yildirim|Zühal|Z|https://orcid.org/0000-0001-8689-4014;Tekgunduz|Kadir|K|https://orcid.org/0000-0001-6375-5644;Laloglu|Fuat|F|https://orcid.org/0000-0003-1595-4723;Ceviz|Naci|N|https://orcid.org/0000-0002-2911-6483",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": "10.1080/14767058.2019.1647530",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": "34(11)",
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": "Intracardiac thrombus; preterm infants; recombinant tissue plasminogen activator",
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": "D005343:Fibrinolytic Agents; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D012189:Retrospective Studies; D013927:Thrombosis; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "1763-1767",
"pmc": null,
"pmid": "31366253",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical features and treatment results in preterm infants with intracardiac thrombus.",
"title_normalized": "clinical features and treatment results in preterm infants with intracardiac thrombus"
} | [
{
"companynumb": "TR-ROCHE-2377091",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "A 37-year-old woman presented with chest pain and shortness of breath in the third trimester of pregnancy. Diagnostic imaging demonstrated a saddle pulmonary embolism, severe impairment of right ventricular function, and an extensive deep venous thrombus. She underwent catheter-directed thrombolysis with tissue plasminogen activator and delivered a healthy infant at term. (Level of Difficulty: Intermediate.).",
"affiliations": "Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California-San Francisco, School of Medicine, San Francisco, California.;Division of Vascular and Interventional Radiology, Department of Radiology and Biomedical Imaging, University of California-San Francisco, School of Medicine, San Francisco, California.;Division of Vascular and Interventional Radiology, Department of Radiology and Biomedical Imaging, University of California-San Francisco, School of Medicine, San Francisco, California.;Division of Cardiology, Department of Internal Medicine, University of California-San Francisco, School of Medicine, San Francisco, California.;Division of Cardiology, Department of Internal Medicine, University of California-San Francisco, School of Medicine, San Francisco, California.;Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California-San Francisco, School of Medicine, San Francisco, California.;Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California-San Francisco, School of Medicine, San Francisco, California.;Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California-San Francisco, School of Medicine, San Francisco, California.",
"authors": "Compadre|Amanda J|AJ|;Kohi|Maureen|M|;Lokken|R Peter|RP|;Blissett|Sarah|S|;Harris|Ian S|IS|;Lucero|Jennifer|J|;Rosenstein|Melissa G|MG|;Sobhani|Nasim C|NC|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2020.08.022",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)31087-1\n10.1016/j.jaccas.2020.08.022\nMini-Focus Issue: Interventional Cardiology\nCase Report: Clinical Case\nCatheter-Directed Thrombolysis for Submassive Pulmonary Embolism in the Third Trimester of Pregnancy\nCompadre Amanda J. MD Amanda.compadre@uscf.edu\na∗\nKohi Maureen MD b\nLokken R. Peter MD, MPH b\nBlissett Sarah MD c\nHarris Ian S. MD c\nLucero Jennifer MD ad\nRosenstein Melissa G. MD, MAS a\nSobhani Nasim C. MD a\na Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California-San Francisco, School of Medicine, San Francisco, California\nb Division of Vascular and Interventional Radiology, Department of Radiology and Biomedical Imaging, University of California-San Francisco, School of Medicine, San Francisco, California\nc Division of Cardiology, Department of Internal Medicine, University of California-San Francisco, School of Medicine, San Francisco, California\nd Department of Anesthesia and Perioperative Care, University of California-San Francisco, School of Medicine, San Francisco, California\n∗ Address for correspondence: Dr. Amanda J. Compadre, University of California at San Francisco, 550 16th Street, 7th Floor, OBGYN, Mailstop 0132, San Francisco, California 94143. Amanda.compadre@uscf.edu\n21 10 2020\n10 2020\n21 10 2020\n2 12 18991904\n30 3 2020\n16 7 2020\n13 8 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 37-year-old woman presented with chest pain and shortness of breath in the third trimester of pregnancy. Diagnostic imaging demonstrated a saddle pulmonary embolism, severe impairment of right ventricular function, and an extensive deep venous thrombus. She underwent catheter-directed thrombolysis with tissue plasminogen activator and delivered a healthy infant at term. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nKeywords\n\ncatheter-directed thrombolysis\npregnancy\nthromboembolism\nAbbreviations and Acronyms\n\nCDT, catheter-directed thrombolysis\nCTA, computed tomography angiography\nIV, intravenous\nPA, pulmonary artery\nPE, pulmonary embolism\nPOD, post-operative day\nRV, right ventricle\nUFH, unfractionated heparin\n==== Body\nPresentation\n\nA 37-year-old nullipara presented to the emergency department at 33 weeks 2 days gestational age with several hours of shortness of breath and chest pain. Initial evaluation was notable for tachycardia to 120 beats/min, tachypnea with a respiratory rate of 30 breaths/min, and oxygen desaturation requiring 4 liters of supplemental oxygen through high-flow nasal cannula to maintain saturations above 94%. Blood pressure was normal at 112/70 mm Hg. She was dyspneic at rest and became increasingly dyspneic with speaking. On examination, jugular venous pressure was elevated to 6 cm above the sternal angle, and a right ventricle (RV) heave was palpated. Heart sounds S1 and S2 were normal, without accentuation of S2. S2 was not palpable. Breath sounds were decreased bilaterally, and asymmetrical swelling of the right lower extremity was present.Learning Objectives\n\n• To describe unique considerations for treatment of a pulmonary embolism in pregnancy.\n\n• To illustrate a novel way of treating a submassive pulmonary embolism in pregnancy.\n\n• To review the published medical literature surrounding the use of catheter-directed thrombolysis for treatment of pulmonary embolism in pregnancy.\n\nMedical history\n\nThe patient had been found to be heterozygous for the prothrombin gene mutation G20210A 2 years prior on elective carrier screening. She also had a recent history of immobility after a soft tissue injury of the right knee 2 weeks prior to presentation. She denied any other medical history.\n\nDifferential diagnosis\n\nGiven her history, symptoms, and vital sign abnormalities, differential diagnosis included pulmonary embolism, cardiac arrhythmia, undiagnosed cardiac structural abnormality, pregnancy-related cardiomyopathy, and infectious causes such as pneumonia with pleurisy or pleural effusion and pericarditis.\n\nInvestigations\n\nThe patient’s laboratory results were notable for a hemoglobin of 11.1 g/dl, white blood cell count of 10.1 × 109 l; and platelet count of 175 × 109 l. Her serum lactate was 0.9 mmol/l. Her initial troponin was 0.48 ng/ml (reference range: <0.05 ng/l). Electrocardiography showed sinus tachycardia. There was high suspicion for pulmonary embolism with concern for impending hemodynamic instability based on vital signs and physical examination findings. Thus, the decision was made to forego lower extremity Doppler ultrasonography as the initial study and to proceed directly to computed tomography angiography (CTA). The benefit of reaching a prompt diagnosis and rapid initiation of treatment was thought to outweigh the minimal risks of radiation to the fetus, and the patient was amenable to this treatment. Of note, the fetal radiation exposure associated with CTA is estimated at a maximum of 0.66 mGy, which is well below the 50-mGy threshold of increased risk of intrauterine fetal demise, fetal growth restriction, and significant adverse neurodevelopmental outcomes (1).\n\nCTA with intravenous (IV) iohexol (Omnipaque 350, GE Healthcare, Chicago, Illinois) in a solution of 100 ml with abdominal shielding was performed and demonstrated a saddle pulmonary embolism (PE) (Figure 1). Transthoracic echocardiography demonstrated a flattened interventricular septum in diastole, consistent with RV volume overload, an elevated estimated systolic pulmonary artery (PA) pressure of 46 mm Hg and thrombus in the main PA and PA branches (Figure 2). Lower extremity Doppler ultrasonography demonstrated an extensive, occlusive, right-sided deep venous thrombosis extending from the popliteal vein up to the femoral vein.Figure 1 Chest Computed Tomography\n\nChest computed tomography shows (A) axial image of saddle pulmonary embolus and (B) right ventricular dilation with right-to-left ventricle diameter (RV/LV) ratio >1.\n\nFigure 2 Transthoracic Echocardiogram\n\nTransthoracic echocardiogram shows (A) flattening of interventricular septum (arrowheads) during diastole, consistent with right ventricular volume overload, and (B) visible thrombus in the main pulmonary artery (solid arrow) and pulmonary artery branches (dashed arrows).\n\nManagement\n\nFollowing the results of the CTA, IV unfractionated heparin (UFH) was initiated. The patient’s clinical status was reviewed by a multidisciplinary team including specialists in maternal fetal medicine, cardiology, obstetric anesthesia, interventional radiology, and critical care. Based on the patient’s worsening tachycardia, tachypnea, and oxygen requirement and increasing troponin concentrations (to 0.51 μg/l) over 18 h of IV UFH treatment, the multidisciplinary team expressed concern for impending hemodynamic instability. Re-evaluation for clinical improvement after 24 to 48 h of IV UFH was deemed imprudent due to the potential for rapid deterioration in maternal status that would prompt emergent delivery and resuscitation, which would be catastrophic in the setting of RV dysfunction.\n\nIn the setting of the large clot in the main PA, evidence of severe RV dysfunction, and concern for worsening cardiac status during 6 additional weeks of pregnancy, followed by delivery, catheter-directed thrombolysis (CDT) using tissue plasminogen activator was recommended. The recommendation was also made for an inferior vena cava filter placement, due to the significant lower extremity clot burden and the need to discontinue anticoagulation during delivery. The multidisciplinary members shared their decisions with the patient, with careful consideration of the risks, benefits, and alternatives to this therapy, included continuing UFH for at least 24 to 48 h. The team discussed the fact that CDT could help remove clot burden and allow for improvement in RV function before her anticipated delivery in 6 weeks.\n\nThe team also discussed the fact that the maternal and fetal risks associated with this intervention were hard to calculate, given the limited available medical literature regarding use of CDT in pregnancy but that the few case reports in pregnancy had favorable outcomes. The fetal risk of radiation exposure with CDT and inferior vena cava filter placement were also reviewed, which is considered low in the third trimester and outweighed by the maternal benefits (1).\n\nFollowing appropriate patient counseling and informed consent, bilateral ultrasonography-assisted thrombolysis catheters and suprarenal inferior vena cava filter were placed in the interventional radiology suite (Figure 3). IV iohexol 350 in a solution of 50 ml was used during fluoroscopy. Tissue plasminogen activator was infused at a rate of 1.0 mg/h along with UFH through the ultrasonography-assisted thrombolysis catheters for 24 h while the patient remained in the intensive care unit for close monitoring and continuation of IV UFH. Continuous electronic fetal heart rate monitoring was performed during this time.Figure 3 Pulmonary Angiogram\n\nPulmonary angiogram demonstrates (A) saddle pulmonary embolus with bilateral peripheral filling defects and (B) bilateral ultrasonography-assisted thrombolysis catheters in the lower lobe of the pulmonary arteries.\n\nOn post-operative day (POD) 1, ultrasonography-assisted thrombolysis catheters were removed, with improvement in RV size and function and troponin decrease to 0.35 ng/ml. By POD 2, the patient was able to maintain saturations ≥99% on room air. Subcutaneous low-molecular-weight heparin was initiated on POD 2, with a target peak concentration of 0.8 to 1.2 U/ml and a trough concentration >0.6 U/ml to avoid supratherapeutic and subtherapeutic effects, respectively. On POD 3, transthoracic echocardiography demonstrated a 12-mm Hg decrease in estimated PA systolic pressure, further indicating hemodynamic improvement. The patient was discharged at 34 weeks 2 days gestation with a plan for close outpatient follow-up. Fetal monitoring throughout her hospital admission was reassuring.\n\nDiscussion\n\nPE is one of the leading causes of maternal morbidity and mortality in the United States, accounting for 9.5% of pregnancy-related deaths from 2008 to 2017 (2). The hypercoagulable state of pregnancy increases the risk of venous thromboembolism 4-fold above the general population, for an overall venous thromboembolism incidence of 0.5 to 2 per 1,000 pregnancies (3). Inherited thrombophilias increase the risk of venous thromboembolism in pregnancy; for example, the prothrombin G20210A mutation is associated with a 2- to 3-fold increased risk of venous thromboembolism (4). However, the overall risk of venous thromboembolism in pregnancy remains <1% for a prothrombin gene heterozygote with no history of venous thromboembolism, thus, the standard practice is to not initiate anticoagulation in these patients in pregnancy.\n\nWhen a pregnant patient does receive a diagnosis of venous thromboembolism, the standard treatment for PE in pregnancy is systemic anticoagulation, regardless of PE classification (3). In the nonpregnant population, however, treatment varies based on PE classification (5). Despite the lack of high-quality data to support its use, thrombolytic therapy for PE in pregnancy has been documented in a handful of case reports and observational studies.\n\nIn the present case, CDT is described as the first-line treatment for a submassive PE in the third trimester of pregnancy. Because there are currently no guidelines regarding thrombolysis for PE in pregnancy, providers interested in using this treatment must extrapolate from data in the nonpregnant population. According to the 2016 guidelines from the American College of Chest physicians, systemic thrombolytic therapy is recommended only for patients with a massive PE and for patients with a submassive PE who clinically deteriorate despite systemic anticoagulation (6). There is currently no consensus surrounding the use of systemic or catheter direct thrombolysis as a primary treatment for patients who present with a submassive PE, due to controversy regarding risk-benefit ratio. Compared to systemic thrombolysis, CDT has the potential to lower the risk of bleeding by localizing drug delivery directly to the area of interest, allowing for a two-thirds reduction in the required dose (7). Numerous studies have demonstrated the efficacy and safety of CDT for PE in the general population. For example, 2 prospective observational studies each with 100 patients demonstrated significant reduction in right ventricle-to-left ventricle (RV/LV) ratios, significant improvement in PA pressures, and 80% clinical success rate when using CDT for massive and submassive PEs (5). A third prospective study was a randomized controlled trial that demonstrated more rapid normalization of the RV/LV ratio with CDT compared to UFH in patients with a submassive PE (5). The overall bleeding rates in these 3 studies were low, with only 1 severe incidence of bleeding and 16 moderate incidences of bleeding in a total of 280 cases. Although these studies demonstrate the efficacy and safety of CDT, there have been no direct comparisons of CDT to systemic thrombolysis. As such, the most recent CHEST guidelines recommend reserving CDT for cases with a particularly high risk of bleeding (6).\n\nWhether thrombolysis should be used in pregnancy, whether thrombolysis should be used in submassive PEs in all subjects, and whether thrombolysis should be given systemically or in a catheter-directed fashion are all topics of ongoing debate. Thus, the use of CDT as first-line treatment for a submassive PE in pregnancy makes the present case a unique situation. In this case, the decision was made based on multidisciplinary discussion among specialty providers and shared with the patient, with careful consideration of the risks, benefits, and alternatives to this therapy, as outlined above. Particular emphasis was given to the interaction between ongoing RV dysfunction and the cardiovascular burden of 6 additional weeks of pregnancy followed by labor and delivery. Pregnancy is a state of increased cardiac output and blood volume, and the normal physiologic changes of pregnancy, labor, and delivery often worsen underlying cardiac dysfunction. The primary concern for this patient was that without thrombolysis, cardiac dysfunction would worsen with ongoing pregnancy, with the potential for catastrophic urgent preterm delivery or decompensation during term delivery. CDT was chosen over systemic thrombolysis to minimize the dose of tissue plasminogen activator, given concerns regarding risk of bleeding and possible fetal effects (7).\n\nThis case adds to the limited studies regarding use of CDT in pregnancy. In the review, 5 case reports of CDT were identified for PE in pregnancy (Table 1) (8, 9, 10, 11, 12). In 1 case of submassive PE, CDT was used only after the patient developed severe RV dysfunction despite therapeutic anticoagulation. There were no maternal complications in any of the cases. In 1 case, an intrauterine fetal demise occurred 1 day after CDT; however, this fetal death was attributed to maternal acuity. None of the prior cases report long-term maternal outcomes.Table 1 5 Previous Case Reports Describing the Use of CDT for PE in Pregnancy\n\nFirst Author, Year (Ref. #)\tGA at Diagnosis\tType of PE\tMaternal Outcome\tFetal/Neonatal Outcome\t\nComplications\tLength of Follow-Up\tComplications\tLength of Follow-Up\t\nGowda et al., 2019 (8)\t9 weeks\tMassive\tPulmonary infarct\tThrough delivery\tNone\tThrough delivery\t\nSofocleous et al., 2001 (10)\t15 weeks\tMassive\tMajor bleeding∗\tThrough delivery\tFetal demise\tN/A\t\nPick et al., 2015 (11)\t33 weeks\tSubmassive\tPre-eclampsia\tThrough delivery\tPTB\tThrough delivery\t\nKrishnamurthy et al., 1999 (9)\t26 weeks\tMassive\tNone\tThrough delivery\tNone\tThrough delivery\t\nBechtel et al., 2005 (12)\t30 weeks\tMassive\tNone\tThrough delivery\tNone\tThrough delivery\t\nCDT = catheter-directed thrombolysis; GA = gestational age; PE = pulmonary embolus; PTB = preterm birth.\n\n∗ Source of bleeding was not identified, but the patient became hypotensive and anemic (drop in hemoglobin by 2 g/dl) 24 h after the procedure.\n\nThis is the third case report to describe CDT as treatment for a PE in the third trimester of pregnancy. In any trimester of pregnancy, CDT for massive or submassive PE can be considered for patients with current or impending hemodynamic instability. In the third trimester, special consideration should be given to CDT as the first-line treatment for any submissive PE due to the potential catastrophic events that acute decompensation could prompt, including the need for premature delivery with the myriad of short- and long-term complications of prematurity and the further deterioration of maternal status when the hemodynamic burden of an emergency delivery is superimposed on significant cardiopulmonary dysfunction. Furthermore, given the inherent limitations of gestation, patients in the third trimester have less time for cardiac function to improve before the intense cardiovascular stress of labor and delivery.\n\nFollow-up\n\nThe patient presented at 38 weeks 5 days gestation for a scheduled induction of labor. Low-molecular-weight heparin was discontinued, and IV UFH was initiated, with monitoring of activated partial thromboplastin time. The patient delivered a healthy infant weighing 3,735 g at 39 weeks 0 days gestation. On postpartum day 1, she was transitioned back to weight-based therapeutic low-molecular-weight heparin, with the plan to continue this for 6 months. The remainder of her postpartum course was unremarkable, and she and the infant were discharged home on postpartum day 4. The inferior vena cava filter was removed 2 months postpartum. The filter was kept in place longer than the standard 4-week period due to the unique hypercoagulability of the postpartum state and the patient’s extensive lower extremity clot burden. At a follow-up visit 6 months after CDT, the patient was doing well and reported a healthy infant who was meeting all pediatric milestones.\n\nConclusions\n\nIn summary, this paper describes the case with excellent maternal and neonatal outcome following CDT as first-line treatment for a submassive PE in the third trimester of pregnancy. Further research should explore the efficacy and safety of this treatment in pregnancy. Due to the complex physiologic changes in pregnancy and the cardiovascular strain associated with delivery, pregnant patients in the third trimester with submassive PE may derive the most benefit from expeditious thrombolysis and associated resolution right ventricular strain.\n\nAuthor Relationship With Industry\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n==== Refs\nReferences\n\n1 American College of Obstetricians and Gynecologists Guidelines for diagnostic imaging during pregnancy and lactation. ACOG committee opinion No. 723 Obstet Gynecol 130 2017 e210 28937575\n2 U.S. Centers for Disease Control and Prevention Enhancing Reviews and Surveillance to Eliminate Maternal Mortality Available at: https://www.cdc.gov/reproductivehealth/maternal-mortality/erase-mm/index.html\n3 Greer I.A. Pregnancy complicated by venous thrombosis N Engl J Med 373 2015 540 547 26244307\n4 American College of Obstetricians and Gynecologists Inherited thrombophilias in pregnancy. ACOG practice bulletin No. 197 Obstet Gynecol 132 2018 e18 29939939\n5 Sista A.K. Kuo W.T. Schiebler M. Madoff D.C. Stratification, imaging, and management of acute massive and submassive pulmonary embolism Radiology 284 2017 5 24 28628412\n6 Kearon C. Akl E.A. Ornelas J. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report Chest 149 2016 315 322 26867832\n7 Heavner M.S. Zhang M. Bast C.E. Parker L. Eyler R.F. Thrombolysis for massive pulmonary embolism in pregnancy Pharmacother J Hum Pharmacol Drug Ther 37 2017 1449 1457\n8 Gowda N. Nwabuobi C.K. Louis J.M. Catheter-directed thrombolytic therapy in the management of massive pulmonary embolism in pregnancy Obstet Gynecol 134 2019 1002 1004 31599843\n9 Krishnamurthy P. Martin C.B. Kay H.H. Catheter-directed thrombolysis for thromboembolic disease during pregnancy: a viable option J Matern Fetal Med 8 1999 24 27 10052842\n10 Sofocleous C.T. Hinrichs C. Bahramipour P. Barone A. Abujudeh H. Contractor D. Percutaneous management of life-threatening pulmonary embolism complicating early pregnancy J Vasc Interv Radiol 12 2001 1355 1356 11698639\n11 Pick J. Berlin D. Horowitz J. Winokur R. Sista A.K. Lichtman A.D. Massive pulmonary embolism in pregnancy treated with catheter-directed tissue plasminogen activator Case Rep 4 2015 91 94\n12 Bechtel J. Mountford M. Ellinwood W. Massive pulmonary embolism in pregnancy treated with catheter fragmentation and local thrombolysis Obstet Gynecol 105 2005 1158 1160\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "2(12)",
"journal": "JACC. Case reports",
"keywords": "CDT, catheter-directed thrombolysis; CTA, computed tomography angiography; IV, intravenous; PA, pulmonary artery; PE, pulmonary embolism; POD, post-operative day; RV, right ventricle; UFH, unfractionated heparin; catheter-directed thrombolysis; pregnancy; thromboembolism",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "1899-1904",
"pmc": null,
"pmid": "34317077",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports",
"references": "28937575;26867832;29939939;26244307;16260553;28628412;25827861;10052842;31599843;11698639",
"title": "Catheter-Directed Thrombolysis for Submassive Pulmonary Embolism in the Third Trimester of Pregnancy.",
"title_normalized": "catheter directed thrombolysis for submassive pulmonary embolism in the third trimester of pregnancy"
} | [
{
"companynumb": "US-BoehringerIngelheim-2020-BI-073346",
"fulfillexpeditecriteria": "1",
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"abstract": "Long QT interval is an important finding that is often missed by electrocardiogram interpreters. Long QT syndrome (inherited and acquired) is a potentially lethal cardiac channelopathy that is frequently mistaken for epilepsy. We present a case of long QT syndrome with multiple cardiac arrests presenting as syncope and seizures. The long QTc interval was aggravated by hypomagnesaemia and drugs, including clarithromycin and levofloxacin. Multiple drugs can cause prolongation of the QT interval, and all physicians should bear this in mind when prescribing these drugs.",
"affiliations": "Department of Cardiology, National University Heart Centre, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore 119228. kian_keong_poh@nuhs.edu.sg.",
"authors": "Ambhore|Anand|A|;Teo|Swee-Guan|SG|;Bin Omar|Abdul Razakjr|AR|;Poh|Kian-Keong|KK|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.11622/smedj.2014172",
"fulltext": null,
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"issn_linking": "0037-5675",
"issue": "55(12)",
"journal": "Singapore medical journal",
"keywords": null,
"medline_ta": "Singapore Med J",
"mesh_terms": "D000328:Adult; D017147:Defibrillators, Implantable; D004562:Electrocardiography; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D012307:Risk Factors; D012640:Seizures",
"nlm_unique_id": "0404516",
"other_id": null,
"pages": "607-11; quiz 612",
"pmc": null,
"pmid": "25630313",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10973849;16949478;11136691;11332559;11773906;12109926;12534433;12709470;12736279;14516292;14594906;15367556;463773;6630761;4085514;3731424;3338130;1519533;8256751;13435203;14136838;14158288;16414944;11104743",
"title": "Importance of QT interval in clinical practice.",
"title_normalized": "importance of qt interval in clinical practice"
} | [
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"companynumb": "SG-LUPIN PHARMACEUTICALS INC.-2015-03897",
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"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
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{
"abstract": "A 28-yr-old African American man with a history of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome, tobacco use, and sickle cell trait was referred to a physiatrist at a multidisciplinary spine center with a 1-yr history of nontraumatic thoracic back pain that had significantly worsened over the previous 4 wks. In the context of recurrent infections requiring hospital admissions and the patient's immunosuppressed status, magnetic resonance imaging of his thoracic spine was obtained, showing an acute or subacute anterior compression deformity of the T7 vertebral body. He was subsequently provided with a hyperextension brace, physical therapy referral, and a trial of intranasal calcitonin. The patient reported significant improvement in pain at his 3-mo follow-up appointment and continued to show pain and functional improvement in physical therapy sessions up to 6 mos later.",
"affiliations": "From the Department of Physical Medicine and Rehabilitation, Medical College of Wisconsin, Milwaukee, Wisconsin.",
"authors": "Donohue|Nicholas K|NK|;Braza|Diane W|DW|",
"chemical_list": "D050071:Bone Density Conservation Agents; D002116:Calcitonin",
"country": "United States",
"delete": false,
"doi": "10.1097/PHM.0000000000001513",
"fulltext": null,
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"issn_linking": "0894-9115",
"issue": "100(3)",
"journal": "American journal of physical medicine & rehabilitation",
"keywords": null,
"medline_ta": "Am J Phys Med Rehabil",
"mesh_terms": "D020083:Acquired Hyperostosis Syndrome; D000328:Adult; D050071:Bone Density Conservation Agents; D001915:Braces; D002116:Calcitonin; D003131:Combined Modality Therapy; D050815:Fractures, Compression; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D010147:Pain Measurement; D026741:Physical Therapy Modalities; D013904:Thoracic Vertebrae",
"nlm_unique_id": "8803677",
"other_id": null,
"pages": "e29-e31",
"pmc": null,
"pmid": "32618750",
"pubdate": "2021-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Rare Case of Nontraumatic Thoracic Compression Fracture in a 28-Year-Old Man.",
"title_normalized": "a rare case of nontraumatic thoracic compression fracture in a 28 year old man"
} | [
{
"companynumb": "US-MYLANLABS-2021M1028129",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstancename": "NAPROXEN"
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"abstract": "BACKGROUND\nGastrointestinal (GI) disorders are one of the main adverse events in patients treated by mycophenolic acid (MPA). The aim of our prospective questionnaire-based study was to assess GI side-effects in de novo renal-transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).\n\n\nMETHODS\nBetween January 2002 and April 2003, all patients receiving MPA with a functioning allograft at 1 month post-transplantation were enrolled in this study (n = 130). Ninety-three of them received MMF (group I), and 37 patients received EC-MPS (group II). Each month, every patient completed a questionnaire regarding GI disorders.\n\n\nRESULTS\nDuring the first year post-transplantation, GI disorders occurred in 31 patients from the MMF group (33.3%) and 12 patients from the EC-MPS group (32.4%) (not significant). The incidence of upper GI disorders was also similar in both groups. Diarrhoea was observed in 18 patients (19.3%) from group I, and in five patients from group II (13.5%) (not significant). Its frequency and severity were similar in both groups. Weight loss was observed in three patients receiving MMF. Diarrhoea resolved spontaneously in 10 patients from group I and in all patients from group II. For the other eight patients in group I, the diarrhoea required MMF discontinuation in three patients and dose reduction in five patients.\n\n\nCONCLUSIONS\nIn conclusion, in this questionnaire-based evaluation, the incidence of GI disorders was similar in patients receiving either MMF or EC-MPS during the first year post-transplantation.",
"affiliations": "Department of Nephrology, Dialysis and Transplantation, CHU Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France. nassim.kamar@free.fr",
"authors": "Kamar|Nassim|N|;Oufroukhi|Loubna|L|;Faure|Patrick|P|;Ribes|David|D|;Cointault|Olivier|O|;Lavayssiere|Laurence|L|;Nogier|Marie Béatrice|MB|;Esposito|Laure|L|;Durand|Dominique|D|;Rostaing|Lionel|L|",
"chemical_list": "D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1093/ndt/gfi009",
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"issn_linking": "0931-0509",
"issue": "20(10)",
"journal": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association",
"keywords": null,
"medline_ta": "Nephrol Dial Transplant",
"mesh_terms": "D000328:Adult; D003967:Diarrhea; D005260:Female; D005767:Gastrointestinal Diseases; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011446:Prospective Studies; D011795:Surveys and Questionnaires; D013608:Tablets, Enteric-Coated; D013997:Time Factors",
"nlm_unique_id": "8706402",
"other_id": null,
"pages": "2231-6",
"pmc": null,
"pmid": "16046517",
"pubdate": "2005-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Questionnaire-based evaluation of gastrointestinal disorders in de novo renal-transplant patients receiving either mycophenolate mofetil or enteric-coated mycophenolate sodium.",
"title_normalized": "questionnaire based evaluation of gastrointestinal disorders in de novo renal transplant patients receiving either mycophenolate mofetil or enteric coated mycophenolate sodium"
} | [
{
"companynumb": "FR-ROCHE-1946312",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Epidermal growth factor receptor inhibitors (EGFRI), EGFR tyrosine kinase inhibitors (TKI) and anti-EGFR antibodies commonly develop skin toxicities including acneiform eruption (AfE). However, precise skin changes and risk factors for severe AfE are still unclear. The objective of the current study was elucidation of the useful parameters for early and sensitive detection of the skin changes by EGFRI. Transepidermal water loss (TEWL), skin surface hydration, skin surface lipid levels and erythema/melanin index were serially measured for 2 weeks in 19 EGFR-TKI afatinib/erlotinib-treated patients and for 8 weeks in 20 anti-EGFR antibody cetuximab-treated patients. The TEWL levels of the cheek in the patients who developed AfE of grade 2 and more (AfE ≥ Gr2) were already elevated at 7 days after the initiation of afatinib/erlotinib therapy compared with those before therapy as well as in patients with grade 1 or less (AfE ≤ Gr1). In patients treated with cetuximab, the skin surface hydration on the cheek in AfE ≥ Gr2 patients significantly decreased compared with that of AfE ≤ Gr1 patients at the 2nd and 6th week. Baseline skin surface lipid levels and erythema index on the cheek of patients with AfE ≥ Gr2 were significantly higher than those with AfE ≤ Gr1. The small sample size of the present study, especially for logistic regression analysis, is a limitation. In conclusion, instrumental evaluation declared rapid inflammatory changes of the skin by EGFRI and elucidated oily skin as a risk for severe AfE.",
"affiliations": "Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.;Appearance Support Center, National Cancer Center Hospital, Tokyo, Japan.;Appearance Support Center, National Cancer Center Hospital, Tokyo, Japan.;Department of Dermatology, Mie University Graduate School of Medicine, Tsu, Japan.;Department of Dermatology, Mie University Graduate School of Medicine, Tsu, Japan.;Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Palliative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.;Community Cancer Centers Program, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Japan.;Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan.;Department of Dermatology, Mie University Graduate School of Medicine, Tsu, Japan.",
"authors": "Kikuchi|Katsuko|K|http://orcid.org/0000-0002-0457-9262;Nozawa|Keiko|K|;Yamazaki|Naoya|N|http://orcid.org/0000-0002-9638-0428;Nakai|Yasuo|Y|;Higashiyama|Ayaka|A|;Asano|Masayuki|M|;Fujiwara|Yutaka|Y|;Kanda|Shintaro|S|;Ohe|Yuichiro|Y|;Takashima|Atsuo|A|;Boku|Narikazu|N|;Inoue|Akira|A|;Takahashi|Masanobu|M|;Mori|Takahiro|T|;Taguchi|Osamu|O|;Inoue|Yasuhiro|Y|;Mizutani|Hitoshi|H|",
"chemical_list": "D000970:Antineoplastic Agents; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.14691",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "46(1)",
"journal": "The Journal of dermatology",
"keywords": "acneiform eruption; epidermal growth factor receptor inhibitor; sebum; skin toxicities; transepidermal water loss",
"medline_ta": "J Dermatol",
"mesh_terms": "D017486:Acneiform Eruptions; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011379:Prognosis; D012307:Risk Factors; D012867:Skin; D014870:Water Loss, Insensible",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "18-25",
"pmc": null,
"pmid": "30402978",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Instrumental evaluation sensitively detects subclinical skin changes by the epidermal growth factor receptor inhibitors and risk factors for severe acneiform eruption.",
"title_normalized": "instrumental evaluation sensitively detects subclinical skin changes by the epidermal growth factor receptor inhibitors and risk factors for severe acneiform eruption"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-055610",
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "Coronavirus pneumonia (COVID-19) is a novel infectious disease with a high mortality rate due to severe acute respiratory syndrome. A 57-year-old woman was admitted to the emergency department (ED) with fever, cough, atypical chest pain, and dyspnea. She remained in the ED for about 48 h while waiting for the result of the COVID-19 oropharyngeal swab. Once she tested positive, she was hospitalized in the pneumological department with a diagnosis of pneumonia based on a chest X-ray and biochemical tests. Although azithromycin and hydroxychloroquine were promptly administered, she had a worsening of dyspnea even with a high-flow oxygen mask. D-dimer was increased, and a computed tomography scan with pulmonary and leg angiogram was positive for bilateral pulmonary embolism, deep-venous thrombosis, and multiple consolidated opacities in the lung parenchyma. This case highlights the fact that, in a pandemic situation, there is a potentially fatal risk of overlooking an alternative diagnosis in a COVID-19 patient who is generally considered as suffering only from pneumonia.",
"affiliations": "Department of Cardiology, Ospedale Civile di Dolo, AULSS 3 Serenissima, Venice, Italy.;Department of Cardiology, Ospedale Civile di Dolo, AULSS 3 Serenissima, Venice, Italy.;Department of Cardiology, Ospedale Civile di Dolo, AULSS 3 Serenissima, Venice, Italy.",
"authors": "Secco|Eleonora|E|;Pasqualetto|Maria Cristina|MC|;Rigo|Fausto|F|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jcecho.jcecho_43_20",
"fulltext": "\n==== Front\nJ Cardiovasc Echogr\nJ Cardiovasc Echogr\nJCE\nJournal of Cardiovascular Echography\n2211-4122 2347-193X Wolters Kluwer - Medknow India \n\nJCE-30-110\n10.4103/jcecho.jcecho_43_20\nCase Report\nPulmonary Embolism in COVID-19 Pneumonia: An Overlapping Diagnosis or a Misdiagnosis?\nSecco Eleonora Pasqualetto Maria Cristina Rigo Fausto Department of Cardiology, Ospedale Civile di Dolo, AULSS 3 Serenissima, Venice, Italy\nAddress for correspondence: Dr. Eleonora Secco, Via Riviera 29 Aprile, 2, 30031 Dolo VE, Italy. E-mail: eleonora.secco@aulss3.veneto.it\nApr-Jun 2020 \n17 8 2020 \n30 2 110 112\n27 4 2020 26 5 2020 06 6 2020 Copyright: © 2020 Journal of Cardiovascular Echography2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Coronavirus pneumonia (COVID-19) is a novel infectious disease with a high mortality rate due to severe acute respiratory syndrome. A 57-year-old woman was admitted to the emergency department (ED) with fever, cough, atypical chest pain, and dyspnea. She remained in the ED for about 48 h while waiting for the result of the COVID-19 oropharyngeal swab. Once she tested positive, she was hospitalized in the pneumological department with a diagnosis of pneumonia based on a chest X-ray and biochemical tests. Although azithromycin and hydroxychloroquine were promptly administered, she had a worsening of dyspnea even with a high-flow oxygen mask. D-dimer was increased, and a computed tomography scan with pulmonary and leg angiogram was positive for bilateral pulmonary embolism, deep-venous thrombosis, and multiple consolidated opacities in the lung parenchyma. This case highlights the fact that, in a pandemic situation, there is a potentially fatal risk of overlooking an alternative diagnosis in a COVID-19 patient who is generally considered as suffering only from pneumonia.\n\nCOVID-19D-dimerpneumoniapulmonary embolism\n==== Body\nINTRODUCTION\nCoronavirus pneumonia (COVID-19) is a novel infectious disease with high mortality due to severe acute respiratory syndrome (SARS), and recent observations suggest that a hypercoagulative status induced by an inflammatory response could be a potential risk factor for pulmonary embolism.\n\nCASE REPORT\nWe present the case of a 57-year-old Caucasian woman who was admitted to the emergency department (ED) with fever, dyspnea, cough, and atypical chest pain on the left hemithorax following a week at home in isolation for fever during the COVID-19 outbreak. She had a history of varicose vein surgery 2 years previously, had autoimmune hypothyroidism in substitutive hormonal therapy, and was mildly overweight (body mass index 27.6); no cardiovascular risk factors such as smoking, diabetes, arterial hypertension, dyslipidemia, or family history were declared. An oropharyngeal swab for COVID-19 was performed in the ED. The patient was placed in an isolation room while waiting for the result and remained there for about 48 h. While she was in the ED, her blood pressure (BP) was 120/80 mmHg with mild sinus tachycardia (heart rate [HR] 95–113 bpm), her body temperature was 35.4°C, respiratory rate was 28 breaths/min, peripheral oxygen saturation was 92%, and a blood gas analysis (BGA) confirmed blood saturation of 91% without supplemental oxygen, with PaO2 of 60.7 mmHg, PaCO2 of 26.3 mmHg, and lactate of 3.3 mmol/L. A high-flow oxygen mask with reservoir was applied (10 L/min), and saturation was progressively raised to 98%. Blood chemistry tests showed increased inflammatory parameters with neutrophilic leukocytosis (white blood cell count 15.59 × 109/L, neutrophil count 12.13 × 109/L) and elevated C-reactive protein (174.7 mg/L). In addition, troponin I (280.8 ng/mL), brain natriuretic peptide (312.9 pg/ml), liver enzymes (aspartate aminotransferase 217 UI/L and alanine aminotransferase 326 UI/L), lactate dehydrogenase (479 UI/L), and ferritin (1335.2 ug/L) were increased. Procalcitonin was negative (0.3 ng/ml). A chest X-ray showed bilateral basal infiltrate opacities, and these findings were confirmed by a lung ultrasound which identified basal bilateral B lines and rare subpleural consolidations. Electrocardiogram (EKG) showed mild sinus tachycardia with HR of 113 bpm in the presence of negative T waves in the inferior and V1–V3 leads, S wave in DI, and RSr' in V1 as incomplete right branch block [Figure 1]. Diagnosis of COVID-19 pneumonia was made considering the positive results of the oropharyngeal swab and imaging exams; the patient was transferred to the pneumology ward, where medical therapy with hydroxychloroquine and azithromycin was administered. Prophylactic anticoagulation was not prescribed because the woman was considered low risk (Padua prediction score for risk venous thromboembolism = 2). However, a few hours later, she suffered a sudden worsening of dyspnea and chest pain. BP mildly decreased to 100/70 mmHg. BGA with high-flow oxygen supplement revealed the following: PO287 mmHg, PCO228 mmHg, saturation 96%, and lactate 1.33 mmol/L. A new EKG was performed which confirmed the same findings of the previous EKG with initial signs of right ventricle overload. A very abnormal pathological value of D-dimer was found (>128,000 ng/mL), and a focus echocardiography revealed a right ventricle dilatation with increased systolic pulmonary artery pressure of around 40 mmHg [Figures 2 and 3]. Due to the suspicion of pulmonary embolism, an urgent computed tomography scan with pulmonary angiography (CTPA) extended to the legs was performed. The CTPA was positive for bilateral filling defects of the principal pulmonary arteries [Figures 4 and 5], with multiple bilateral consolidation particularly in the inferior lobes and a deep thrombosis of the left popliteal vein. Prompt intravenous unfractionated heparin was administered, and the woman was immediately transferred to the intensive cardiology department where she underwent thrombolytic treatment, resulting in rapid clinical improvement. The patient was discharged 8 days later in good health and with two negative oropharyngeal swabs.\n\nFigure 1 Electrocardiogram performed in the emergency department\n\nFigure 2 Right ventricle dilatation\n\nFigure 3 Pulmonary artery systolic pressure\n\nFigure 4 Filling defect in the principal pulmonary right artery\n\nFigure 5 Filling defect in the main branch of the left pulmonary artery\n\nDISCUSSION\nFrom the beginning of the COVID-19 pandemic, the association between pulmonary embolism and pneumonia has been extensively described. The current gold standard for the etiological diagnosis of SARS-coronavirus-2 infection is real-time reverse transcription-polymerase chain reaction on respiratory tract specimens, with 95% sensitivity.[12] Considering the high level of accuracy of this test, the medical approach is often entirely focused on interstitial pneumonia and respiratory management, leading to the potential risk of a missed or overlapping diagnosis, with associated prognostic implications. On the other hand, clinicians may consider the role of COVID-19 infection in an abnormal activation of the coagulation system with thrombotic complications.[34] Although the exact cause remains unclear, it is well documented in the literature that any kind of pneumonia results in a more pronounced relative risk of pulmonary embolism,[5] and two important retrospective cohort studies have already highlighted that patients with pneumonia have a 2–3-fold increased risk of acute venous thrombosis.[67] Current case reports[89] have also described this phenomenon and have reinforced the association. However, we consider it important not to forget other possible diagnostic hypotheses in the context of respiratory failure, especially regarding COVID-19-positive patients. Clinicians should make a diagnosis of pneumonia only after correct evaluation of other possible causes of respiratory distress. This is vital because misdiagnosis could not only be potentially life-threatening for patients but also have medicolegal implications for clinicians. Finally, we suggest the prompt provision of prophylactic anticoagulant measures with low-molecular-weight heparin also in low-risk patients with COVID-19 infection to avoid pulmonary thromboembolism. This consideration is based on recently published evidence[10] but also on day-to-day clinical practice in a COVID hospital.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Corman VM Landt O Kaiser M Molenkamp R Meijer A Chu DK Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR Euro Surveill 2020 25 2000045 \n2 Lippi G Simundic A Plebani M Potential preanalytical and analytical vulnerabilities in the laboratory diagnosis of coronavirus disease 2019 (COVID-19) Clin Chem Lab Med 2020 pii: 20200285 \n3 Dimitrios G Ziogas IA Panagiota G Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past J Clin Virol 2020 127 104362 32305883 \n4 Tang N Li D Wang X Sun Z Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia J Thromb Haemost 2020 18 844 7 32073213 \n5 Ribeiro DD Lijfering WM Van Hylckama Vlieg A Rosendaal FR Cannegieter SC Pneumonia and risk of venous thrombosis: Results from the MEGA study J Thromb Haemost 2012 10 1179 82 22487204 \n6 Smeeth L Cook C Thomas S Hall AJ Hubbard R Vallance P Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting Lancet 2006 367 1075 9 16581406 \n7 Samama M For the Sirius Study Group An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: The Sirius study Arch Intern Med 2000 160 3415 20 11112234 \n8 Danzi GB Loffi M Galeazzi G Gherbesi E Acute pulmonary embolism and COVID-19 pneumonia: A random association? Eur Heart J 2020 41 1858 32227120 \n9 Yuanliang X Xiang W Pei Y Shutong Z COVID-19 complicated by acute pulmonary embolism Radiology 2020 2 2 \n10 Tang N Bai H Chen X Gong J Li D Sun Z Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy J Thromb Haemost 2020 18 844 7 32073213\n\n",
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"issue": "30(2)",
"journal": "Journal of cardiovascular echography",
"keywords": "COVID-19; D-dimer; pneumonia; pulmonary embolism",
"medline_ta": "J Cardiovasc Echogr",
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"nlm_unique_id": "101562228",
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"pages": "110-112",
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"title": "Pulmonary Embolism in COVID-19 Pneumonia: An Overlapping Diagnosis or a Misdiagnosis?",
"title_normalized": "pulmonary embolism in covid 19 pneumonia an overlapping diagnosis or a misdiagnosis"
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"abstract": "Renal failure is a rare complication of neuroblastoma or its therapy. To our knowledge, no reports describe treatment of children with neuroblastoma with chemotherapy in the setting of renal failure and maintenance hemodialysis. We report a 6-year-old child with high-risk neuroblastoma who developed renal failure requiring long-term hemodialysis. She was subsequently treated with 13 cycles of intravenous irinotecan 20 mg/m(2)/day and oral temozolomide 100 mg/m(2)/day for 5 days before disease progression without any dose adjustments, transfusions, febrile neutropenia or diarrhea. This case demonstrates that irinotecan and temozolomide can be safely administered in children with renal failure requiring hemodialysis.",
"affiliations": "Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.",
"authors": "Armstrong|Amy E|AE|;Dargart|Jamie|J|;Reichek|Jennifer|J|;Walterhouse|David O|DO|;Matossian|Debora|D|;Cohn|Richard A|RA|;Gosiengfiao|Yasmin|Y|",
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"keywords": "chemotherapy; hemodialysis; irinotecan; neuroblastoma; renal failure; temozolomide",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D002648:Child; D003606:Dacarbazine; D005260:Female; D006801:Humans; D000077146:Irinotecan; D009447:Neuroblastoma; D006435:Renal Dialysis; D051437:Renal Insufficiency; D000077204:Temozolomide; D016896:Treatment Outcome",
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"title": "Irinotecan and temozolomide for treatment of neuroblastoma in a patient with renal failure on hemodialysis.",
"title_normalized": "irinotecan and temozolomide for treatment of neuroblastoma in a patient with renal failure on hemodialysis"
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"abstract": "We describe the case of a 74-year-old man who developed severe hip pain several days after an intra-articular methylprednisolone injection to his right hip. Culture of the ipsilateral iliopsoas bursa revealed a Staphylococcus lugdunensis infection, which was successfully eradicated through irrigation and debridement as well as antibiotics.\n\n\n\nInfection after hip injection is a known theoretical risk but is rarely reported in the literature. We present a case of septic bursitis after corticosteroid injection. Readers should be mindful that these complications do occur in clinical practice and portend significant morbidity.",
"affiliations": "Harvard Combined Orthopaedic Residency Program, Harvard Medical School, Boston, Massachusetts.;Harvard Combined Orthopaedic Residency Program, Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.;Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.",
"authors": "Crawford|Alexander M|AM|0000-0003-4965-6046;Grisdela|Philip T|PT|0000-0002-5325-3461;Maguire|James H|JH|;von Keudell|Arvind G|AG|",
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"pubdate": "2021-06-23",
"publication_types": "D016428:Journal Article",
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"title": "Septic Iliopsoas Bursitis After Intra-articular Methylprednisolone Injection to the Hip: A Case Report.",
"title_normalized": "septic iliopsoas bursitis after intra articular methylprednisolone injection to the hip a case report"
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"abstract": "The clinical implications of COVID-19 in pregnancy remain unknown. While preliminary reports demonstrate that pregnant patients have a similar symptomatic presentation to the general population, the appropriate management and timing of delivery in these patients is still unclear, as pregnancy may impose additional risk factors and impede recovery in gravid patients. In this brief report, we present a case of COVID-19 in a pregnant patient with severe respiratory compromise, whose clinical status significantly improved after caesarean delivery. We also address the potential benefits of experimental therapy, including tocilizumab, a monoclonal antibody that targets interleukin-6 receptors.",
"affiliations": "Obstetrics and Gynecology, Icahn School of Medicine at Mount Sinai, New York, New York, USA margeaux.oliva@mountsinai.org.;Obstetrics and Gynecology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Infectious Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Infectious Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Maternal Fetal Medicine, Obstetrics and Gynecology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.",
"authors": "Oliva|Margeaux|M|http://orcid.org/0000-0003-1442-4587;Hsu|Karen|K|;Alsamarai|Sarah|S|;Chavez|Vincent de|V|;Ferrara|Lauren|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D004791:Enzyme Inhibitors; D006886:Hydroxychloroquine; D002443:Ceftriaxone; D017963:Azithromycin; C502936:tocilizumab",
"country": "England",
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"journal": "BMJ case reports",
"keywords": "immunological products and vaccines; infectious diseases; obstetrics and gynaecology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D061067:Antibodies, Monoclonal, Humanized; D017963:Azithromycin; D000073640:Betacoronavirus; D000086382:COVID-19; D002443:Ceftriaxone; D002585:Cesarean Section; D018352:Coronavirus Infections; D018450:Disease Progression; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D058873:Pandemics; D011024:Pneumonia, Viral; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
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"pmid": "32675129",
"pubdate": "2020-07-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32217113;32145216;26873562;32220284;32186894;20177305;32196655;32278764;32180426;32350134;32105680;32154135;32119083;32229802;28321847;32151335;27346577;32248521",
"title": "Clinical improvement of severe COVID-19 pneumonia in a pregnant patient after caesarean delivery.",
"title_normalized": "clinical improvement of severe covid 19 pneumonia in a pregnant patient after caesarean delivery"
} | [
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"companynumb": "US-SLATE RUN PHARMACEUTICALS-20US000268",
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"abstract": "Geriatric psychiatrists who treat neuropsychiatric symptoms of dementia are in the unique position of offering palliation to people with terminal illness in whom neuropsychiatric symptoms may be indicators of the illness's end stage (e.g., feeding problems). Little is known, however, about the characteristics of hospice referrals from inpatient geriatric psychiatry units.\n\n\n\nThis was a retrospective chart review of patients with dementia admitted to an inpatient geriatric psychiatry unit and referred to hospice on discharge.\n\n\n\nPatients were referred to hospice because of feeding problems, with oral intake insufficient to sustain life. Most patients (78%) died within 31 days of discharge, and all patients (100%) died within 6 months of discharge.\n\n\n\nThe results from this study support a symptom-based approach to hospice referral for people with dementia, as opposed to prognostic estimation, where certain symptom clusters may indicate a more rapidly progressing course.",
"affiliations": "Division of Geriatric Psychiatry (JMW, EKG, BPF), McLean Hospital, Belmont, MA; Department of Psychiatry (JMW, BPF), Harvard Medical School, Boston. Electronic address: jwilkins1@partners.org.;Division of Geriatric Psychiatry (JMW, EKG, BPF), McLean Hospital, Belmont, MA.;Division of Geriatric Psychiatry (JMW, EKG, BPF), McLean Hospital, Belmont, MA; Department of Psychiatry (JMW, BPF), Harvard Medical School, Boston.",
"authors": "Wilkins|James M|JM|;Goldstein|Elizabeth K|EK|;Forester|Brent P|BP|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jagp.2018.11.011",
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"issn_linking": "1064-7481",
"issue": "27(2)",
"journal": "The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry",
"keywords": "Hospice; dementia; inpatient hospitalization; neuropsychiatric symptoms",
"medline_ta": "Am J Geriatr Psychiatry",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003704:Dementia; D005260:Female; D005852:Geriatric Psychiatry; D017051:Hospice Care; D006760:Hospitalization; D006801:Humans; D008297:Male; D011567:Psychiatric Department, Hospital; D012017:Referral and Consultation; D012189:Retrospective Studies",
"nlm_unique_id": "9309609",
"other_id": null,
"pages": "162-166",
"pmc": null,
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"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Characteristics of Hospice Referrals From an Inpatient Geriatric Psychiatry Unit.",
"title_normalized": "characteristics of hospice referrals from an inpatient geriatric psychiatry unit"
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"abstract": "Lidocaine has a concentration-dependent effect on seizures. Concentrations above 15 μg/mL frequently result in seizures in laboratory animals and human. We report a case of central nervous system (CNS) lidocaine toxicity and recurrent seizure after erroneous ingestion of lidocaine solution. A 4-year-old boy presented to the Emergency Department of Imam Hospital of Sari in December 2013 due to tonic-clonic generalized seizures approximately 30 min ago. 3 h before seizure, his mother gave him 2 spoons (amount 20-25 cc) lidocaine hydrochloride 2% solution instead of pediatric gripe by mistake. Seizure with generalized tonic-clonic occurred 3 times in home. Neurological examination was essentially unremarkable except for the depressed level of consciousness. Personal and medical history was unremarkable. There was no evidence of intracranial ischemic or hemorrhagic lesions in computed tomography scan. There were no further seizures, the condition of the patient remained stable, and he was discharged 2 days after admission. The use of viscous lidocaine may result in cardiovascular and CNS toxicity, particularly in children. Conservative management is the best option for treatment of lidocaine induced seizure.",
"affiliations": "Department of Emergency, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Emergency, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Emergency, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Emergency, Mazandaran University of Medical Sciences, Sari, Iran.",
"authors": "Aminiahidashti|Hamed|H|;Laali|Abolghasem|A|;Nosrati|Nazanin|N|;Jahani|Fatemeh|F|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/2231-4040.150370",
"fulltext": "\n==== Front\nJ Adv Pharm Technol ResJ Adv Pharm Technol ResJAPTRJournal of Advanced Pharmaceutical Technology & Research2231-40400976-2094Medknow Publications & Media Pvt Ltd India JAPTR-6-3510.4103/2231-4040.150370Case ReportRecurrent seizures after lidocaine ingestion Aminiahidashti Hamed Laali Abolghasem Nosrati Nazanin Jahani Fatemeh Department of Emergency, Mazandaran University of Medical Sciences, Sari, IranAddress for correspondence: Dr. Abolghasem Laali, Department of Emergency, Mazandaran University of Medical Sciences, Khazar St, Sari, Iran. E-mail: didehdar@gmail.comJan-Mar 2015 6 1 35 37 Copyright: © Journal of Advanced Pharmaceutical Technology & Research2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Lidocaine has a concentration-dependent effect on seizures. Concentrations above 15 μg/mL frequently result in seizures in laboratory animals and human. We report a case of central nervous system (CNS) lidocaine toxicity and recurrent seizure after erroneous ingestion of lidocaine solution. A 4-year-old boy presented to the Emergency Department of Imam Hospital of Sari in December 2013 due to tonic-clonic generalized seizures approximately 30 min ago. 3 h before seizure, his mother gave him 2 spoons (amount 20–25 cc) lidocaine hydrochloride 2% solution instead of pediatric gripe by mistake. Seizure with generalized tonic-clonic occurred 3 times in home. Neurological examination was essentially unremarkable except for the depressed level of consciousness. Personal and medical history was unremarkable. There was no evidence of intracranial ischemic or hemorrhagic lesions in computed tomography scan. There were no further seizures, the condition of the patient remained stable, and he was discharged 2 days after admission. The use of viscous lidocaine may result in cardiovascular and CNS toxicity, particularly in children. Conservative management is the best option for treatment of lidocaine induced seizure.\n\nLidocainelidocaine ingestionrecurrent seizures\n==== Body\nINTRODUCTION\nLidocaine belongs to the amide group of local anesthetics. It is also used as a type 1b antiarrhythmic agent. It is rapidly absorbed from the gastrointestinal tract with peak plasma level within 30–60 min. After ingestion, lidocaine undergoes extensive first-pass hepatic metabolism with a bioavailability of about 35%.[1] This may cause a false impression of the general safety of its use as an oral agent. Published reports of toxicity of lidocaine largely involved parenteral therapy.[2]\n\nLidocaine has a concentration-dependent effect on seizures. At lower concentrations, it has anticonvulsant properties, whereas concentrations above 15 μg/mL frequently result in seizures in laboratory animals and human. Seizures induced by lidocaine in experimental conditions invariably start in the amygdala. Despite the clear focal onset in these experimental models, the seizures emerging in patients given intravenous (IV) lidocaine are almost invariably generalized and without any clear signs of focality. Given the prevalence of partial seizures and the frequent use of lidocaine, a higher incidence of partial seizures would be expected with its use.[3]\n\nIt has a narrow therapeutic index, with only a slight difference between therapeutic and potentially toxic concentrations. Lidocaine toxicity is dose-related and proportional to its plasma level.[4] Although neurologic toxicity has been frequently observed with IV use, it has also been reported for topical use.[5]\n\nHere, a case of central nervous system (CNS) lidocaine toxicity and recurrent seizure after erroneous ingestion of lidocaine solution is reported.\n\nCASE REPORT\nA 4-year-old boy with 25 kg weight presented to the Emergency Department of Imam Hospital of Sari in December 2013 due to tonic-clonic generalized seizures approximately 30 min ago. 3 h before seizure, his mother mistakenly gave him 2 spoons (amount 20–25 cc) lidocaine hydrochloride 2% solution instead of pediatric gripe. Seizure with generalized tonic-clonic occurred 3 times in home. On arrival at our Emergency Department, she was agitated and had confused speech with Glasgow coma scale score of 14/15. His initial blood pressure was 90/55 mmHg with a pulse rate of 130 beats/min.\n\nHis temperature was 36.9°C axial. Respiratory rate was 20 per min with a SpO2 of 96% on 2 L of nasal oxygen. Twitching movement with muscle spasm was noticed in the limbs. The pupils were 4 mm in diameter, equal and reactive, and no focal neurological deficit was found. His skin was normal. Bowel sound was normal, and the bladder was not palpable. An electrocardiogram (ECG) showed sinus tachycardia with a heart rate of 139 beats/min, and QT interval was 0.89 s. Neurologic examination was essentially unremarkable except for the depressed level of consciousness. The personal and medical history was unremarkable; including the absence of birthing trauma or febrile seizures. He had no history of use of other drugs.\n\nLaboratory studies while the patient received supplemental oxygen included an arterial blood gas with pH 7.30; pO2104 mm Hg; pCO239 mmHg; and HCO321. A complete blood count revealed white blood cells 10,400/mm3(31% polymorphonuclear leukocytes, 64% lymphocytes, 5% monocytes); hemoglobin 12 g; and hematocrit 35%. Blood chemistry studies were unremarkable except for an elevated glucose (219 mg %) obtained while the patient was receiving an IV line with 5% glucose. One day after admission; a repeat glucose level was 89 mg%.\n\nShortly after arrival at the Emergency Department, he developed one episode of brief generalized convulsion with upward gaze and episode lasting for around 30 s, 5 mg of IV diazepam was administered and a contrast-enhanced computed tomography (CT) scan of the brain was promptly performed. The latter showed no evidence of intracranial ischemic or hemorrhagic lesions. Serum lidocaine concentration 30 min after the onset of seizures was 5.1 μg/ml. There were no further seizures; the patient remained stable and was discharged 2 days after admission.\n\nDISCUSSION\nLidocaine has a rapid onset and is effective for about 30–60 min in its plain form and up to about 90 min in combination with a vasoconstrictor. Therefore, most of the signs and symptoms of poisoning with lidocaine start about 10–25 min after administration.[6] Almost all types of local anesthetics including lidocaine are toxic to nerve cells. The first symptoms and signs of local anesthetic toxicity are usually neurological with numbness of the mouth and tongue. Shortly afterward, there is the onset of tinnitus, lightheadedness, numbness, disorientation, confusion, auditory and visual disturbances lethargy and potentially, coma, apnea, and cardiovascular collapse (CC).[7] Cardiovascular toxicity usually reveals with tachycardia and hypertension; but, with increasing toxicity, bradycardia, and hypotension occur. Ventricular arrhythmias and cardiac arrest may also occur. Local anesthetic toxicity is extremely rare in neonates, infants, and children.\n\nRecurrent seizures have been previously reported in a neonate where IV lidocaine was given in conjunction with midazolam and atropine for the preoperative intubation.[8] Therefore, it seems that prolonged and recurrent seizures after lidocaine administration for ingestion have not been previously explained. It has been reported that seizures happen when the dose of lidocaine administered exceeds 3 mg/kg.[67] However, some cases of seizure following administration of recommended doses of lidocaine have also been reported.[8] Most of these seizures are self-resolving or resolve with conventional anticonvulsants. They may be dangerous because of the acidosis and hypoxia due to a prolonged duration and resulted in hypoxic-ischemic encephalopathy.\n\nOral ingestion of 5–25 ml of 2% viscous lidocaine has resulted in the seizure in children.[9] Thus, CNS toxicity provides a warning sign to cardiac toxicity. Early recognition of potential cardiac toxicity is important because if it goes unrecognized for any interval, it is more difficult to resuscitate. The earliest signs of cardiac toxicity are ECG changes which include prolonged PR, QRS, and QT intervals. Subsequently, it may progress to bradycardia, atrioventricular and intraventricular blocks, ventricular dysrhythmia, and CC that are often refractory to treatment. The level causing CC to CNS toxicity ratio (CC/CNS) has been estimated in animal studies. Local anesthetics with higher potency and lipophilicity like bupivacaine have a lower CC/CNS ratio as compared with that of lidocaine (3 vs. 7). Therefore, bupivacaine toxicity can occur with few premonitory symptoms of CNS excitation.[10]\n\nThe mainstay of management in lidocaine or other local anesthetic toxicity is supportive treatment to prevent hypoxia, acidosis, and hyperkalemia which may enhance the toxicity, especially cardiac toxicity. Gastric decontamination is of limited value because of rapid absorption after ingestion. Benzodiazepine and barbiturates can be used to control local anesthetic-induced seizure. However, they may exacerbate circulatory and respiratory depression. Propofol was found to be as effective as thiopental in the treatment of bupivacaine-induced seizure in rats and has also been used successfully to stop the seizure in patients with lidocaine toxicity.[11] However, it should be used cautiously in patients with local anesthetic toxicity as it typically lowers blood pressure and may cause significant Bradydysrhythmias and even a systole. Therefore, it is contraindicated in local anesthetic toxicity with cardiovascular compromise. It is also proposed that propofol's effect in bupivacaine toxicity may be due to the lipid component of the propofol preparation in which 10% lipid is present.[12]\n\nCONCLUSION\nThe use of viscous lidocaine may result in cardiovascular and CNS toxicity, particularly in children. Clinicians must be aware of the potential toxicity of topical or oral lidocaine and carefully review dosage schedules and potential toxicity with parents as well as considering alternate therapeutic modalities. Seizures in a patient suffering from erroneous oral ingestion should encourage parents and physicians to consider the possibility of lidocaine use and toxicity. Lidocaine-induced seizures are a warning sign for subsequent cardiac toxicity which can be lethal. Conservative management is the best option for treatment of lidocaine-induced seizure.\n\nSource of Support: Nil\n\nConflict of Interest: Nil.\n==== Refs\nREFERENCES\n1 Boyes RN Scott DB Jebson PJ Godman MJ Julian DG Pharmacokinetics of lidocaine in man Clin Pharmacol Ther 1971 12 105 16 5099888 \n2 Kudo K Nishida N Kiyoshima A Ikeda N A fatal case of poisoning by lidocaine overdosage - Analysis of lidocaine in formalin-fixed tissues: A case report Med Sci Law 2004 44 266 71 15296252 \n3 DeToledo JC Lidocaine and seizures Ther Drug Monit 2000 22 320 2 10850400 \n4 Becker DE Reed KL Local anesthetics: Review of pharmacological considerations Anesth Prog 2012 59 90 101 22822998 \n5 Brosh-Nissimov T Ingbir M Weintal I Fried M Porat R Central nervous system toxicity following topical skin application of lidocaine Eur J Clin Pharmacol 2004 60 683 4 15568142 \n6 Donald MJ Derbyshire S Lignocaine toxicity; a complication of local anaesthesia administered in the community Emerg Med J 2004 21 249 50 14988367 \n7 Hoffman RS Nelson LS Howland MA Goldfrank's Manual of Toxicologic Emergencies 2007 8th ed New York McGraw-Hill 560 5 \n8 Moran LR Hossain T Insoft RM Neonatal seizures following lidocaine administration for elective circumcision J Perinatol 2004 24 395 6 15167881 \n9 Hess GP Walson PD Seizures secondary to oral viscous lidocaine Ann Emerg Med 1988 17 725 7 3382075 \n10 Morishima HO Pedersen H Finster M Hiraoka H Tsuji A Feldman HS Bupivacaine toxicity in pregnant and nonpregnant ewes Anesthesiology 1985 63 134 9 4025863 \n11 Heavner JE Arthur J Zou J McDaniel K Tyman-Szram B Rosenberg PH Comparison of propofol with thiopentone for treatment of bupivacaine-induced seizures in rats Br J Anaesth 1993 71 715 9 8251286 \n12 Ohmura S Ohta T Yamamoto K Kobayashi T A comparison of the effects of propofol and sevoflurane on the systemic toxicity of intravenous bupivacaine in rats Anesth Analg 1999 88 155 9 9895084\n\n",
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"medline_ta": "J Adv Pharm Technol Res",
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"title": "Recurrent seizures after lidocaine ingestion.",
"title_normalized": "recurrent seizures after lidocaine ingestion"
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"abstract": "Recent studies have demonstrated that vasopressors can be delivered safely through peripheral intravenous lines. While norepinephrine is usually delivered at a concentration of 16 to 32 μg/mL, out of concern for extravasation and interstitial necrosis, some patients receive more dilute norepinephrine solutions through peripheral intravenous catheters. We describe a case of severe hyponatremia and seizure resulting from administration of norepinephrine concentrated at 4 μg/mL in dextrose 5% in water. After the incident, the institutional policy changed to recommend normal saline as the default diluent for peripheral norepinephrine, with a more concentrated option available. The incident also informed similar guidelines at other hospitals.",
"affiliations": "From the Department of Integrated Sciences: Genetics, Physiology, Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Medicine, Sinai Health System, Toronto, Ontario, Canada.;Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.;Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Alibhai|Nafeesa|N|;Detsky|Michael|M|;Wunsch|Hannah|H|;Teja|Bijan|B|",
"chemical_list": "D014867:Water; D005947:Glucose; D009638:Norepinephrine",
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"mesh_terms": "D005947:Glucose; D006801:Humans; D007010:Hyponatremia; D009638:Norepinephrine; D012640:Seizures; D014867:Water",
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"title": "Severe Hyponatremia and Seizure From Peripheral Infusion of Norepinephrine Diluted in Dextrose 5% in Water: A Case Report.",
"title_normalized": "severe hyponatremia and seizure from peripheral infusion of norepinephrine diluted in dextrose 5 in water a case report"
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"abstract": "Restless arms syndrome (RAS) is characterized by uncomfortable aching or burning sensations in the arms. RAS is regarded as an upper limb variant of restless legs syndrome (RLS). The lack of specific diagnostic criteria makes it difficult to recognize the RAS. Therefore, RAS is usually neglected in clinical practice. Moreover, when a patient was diagnosed with RAS, the adjustment of medications was the first choice for doctors, which may make the patient's condition unstable.\n\n\n\nA 33-year-old woman was diagnosed with schizophrenia and major depressive disorder. Starting with 0.6 g/d amisulpride, 0.1 g/d quetiapine, 75 mg/d venlafaxine sustained-release tablets, the patient reported symptoms of RAS (itching arms) on the fourth day since the latest hospitalization. After ruling out other factors, her RAS was suspected to be induced by antidepressants or antipsychotics. Without medication adjustment, RAS spontaneously remitted.\n\n\n\nThis case suggests that psychiatrists should pay attention to RAS when using antipsychotics and/or antidepressants. Moreover, RAS may be transitory. When a patient manifests RAS, observation may be one choice instead of an immediate medication adjustment.",
"affiliations": "Mental Health Center, West China Hospital/West China School of Nursing, Sichuan University, Chengdu, China.;Mental Health Center, West China Hospital/West China School of Nursing, Sichuan University, Chengdu, China.;Mental Health Center, West China Hospital/West China School of Nursing, Sichuan University, Chengdu, China.;Mental Health Center, West China Hospital/West China School of Nursing, Sichuan University, Chengdu, China.;Mental Health Center, West China Hospital/West China School of Nursing, Sichuan University, Chengdu, China.;Mental Health Center, West China Hospital, Sichuan University, No.28 Dianxin South Road, Chengdu, 610041, China. jay_li@163.com.",
"authors": "Chen|Juan|J|;Meng|Na|N|;Cao|Bingrong|B|;Ye|Yinghua|Y|;Ou|Ying|Y|;Li|Zhe|Z|0000-0001-8233-7149",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
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"fulltext": "\n==== Front\nBMC Psychiatry\nBMC Psychiatry\nBMC Psychiatry\n1471-244X\nBioMed Central London\n\n3433\n10.1186/s12888-021-03433-6\nCase Report\nTransitory restless arms syndrome in a patient with antipsychotics and antidepressants: a case report\nChen Juan 1\nMeng Na 1\nCao Bingrong 1\nYe Yinghua 1\nOu Ying 1\nhttp://orcid.org/0000-0001-8233-7149\nLi Zhe jay_li@163.com\n\n23\n1 grid.13291.38 0000 0001 0807 1581 Mental Health Center, West China Hospital/West China School of Nursing, Sichuan University, Chengdu, China\n2 grid.13291.38 0000 0001 0807 1581 Mental Health Center, West China Hospital, Sichuan University, No.28 Dianxin South Road, Chengdu, 610041 China\n3 Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China\n16 9 2021\n16 9 2021\n2021\n21 4537 4 2021\n19 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nRestless arms syndrome (RAS) is characterized by uncomfortable aching or burning sensations in the arms. RAS is regarded as an upper limb variant of restless legs syndrome (RLS). The lack of specific diagnostic criteria makes it difficult to recognize the RAS. Therefore, RAS is usually neglected in clinical practice. Moreover, when a patient was diagnosed with RAS, the adjustment of medications was the first choice for doctors, which may make the patient’s condition unstable.\n\nCase presentation\n\nA 33-year-old woman was diagnosed with schizophrenia and major depressive disorder. Starting with 0.6 g/d amisulpride, 0.1 g/d quetiapine, 75 mg/d venlafaxine sustained-release tablets, the patient reported symptoms of RAS (itching arms) on the fourth day since the latest hospitalization. After ruling out other factors, her RAS was suspected to be induced by antidepressants or antipsychotics. Without medication adjustment, RAS spontaneously remitted.\n\nConclusions\n\nThis case suggests that psychiatrists should pay attention to RAS when using antipsychotics and/or antidepressants. Moreover, RAS may be transitory. When a patient manifests RAS, observation may be one choice instead of an immediate medication adjustment.\n\nKeywords\n\nRestless arms syndrome\nAntipsychotics\nAntidepressants\nCase report\nThe Science and Technology project of Health Commission of Sichuan Province20PJ027 Li Zhe Applied Psychology Research Center of Sichuan ProvinceCSXL-202A08 Li Zhe Department of Human Resources and Social Security of Sichuan Province[2020] 291-20 Li Zhe Science and Technology project of Health Commission of Sichuan Province20PJ020 Chen Juan issue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nRestless arms syndrome (RAS) is usually defined by upper limbs restlessness [1]. It is characterized by uncomfortable aching or burning sensations in the arms and an urge to move arms [1]. Those unpleasant sensations and restlessness have a negative effect on sleep [2] and even lead to suicidal thoughts [3]. RAS may be related to antipsychotics [4] and could be released by dopaminergic treatment [5] as well as complementation of iron [2]. However, a previous review showed that RAS might be an extremely rare disease with unknown prevalence and no specific diagnostic criteria [1]. Generally, RAS is regarded as an upper limb variant of Restless legs syndrome (RLS) [6]. Arm restlessness, as a late feature, was reported by nearly half of the patients diagnosed with RLS [7]. However, the lack of specific diagnostic criteria makes it difficult to recognize RAS. Therefore, RAS is usually neglected in clinical practice. In addition, the relationship between RAS and antidepressants as well as antipsychotics remains unknown. Moreover, when a patient was diagnosed with RAS, the adjustment of medication was the first choice for doctors in previous reports [1]. However, changes in medication may make the patient’s condition unstable. Here, we report a rare case of RAS that may be induced by antidepressants and/or antipsychotics. More importantly, we first reported a case of RAS with spontaneous remission without medication adjustment, which may help us to better understand and deal with RAS.\n\nCase presentation\n\nThe patient was a female aged 33 years old. Three years ago, she manifested auditory hallucinations (hearing that someone was talking about her), persecutory delusions (feeling that someone would kill her) and disorganized behaviour (talking solely, laughing solely, and saying that she was a robot). She was diagnosed with schizophrenia by The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [8]. After a short-term hospitalization, she went home with symptom remission. The treatment method was not clear. Although she did not take medications regularly after discharge, she could work and live normally. One year ago, similar symptoms recurred. She was discharged with remission of symptoms by 0.2 g/d quetiapine and 7.5 mg/d dexzopiclone. Three months ago, she felt stressed and worried that someone would kill her again. After prescribing amisulpride, quetiapine, benzhexol hydrochloride and propranolol hydrochloride, the symptoms were controlled. The exact doses were not clear. After discharge, she took those medications regularly. Ten days ago, she was depressed because she could not get a job. She felt useless and complained of palpitations. She also said that a robot appeared around her. She was diagnosed with schizophrenia and major depressive disorder by DSM-5 [8]. Except for increased prolactin (195.7 ng/ml; reference range, 6.0–29.9 ng/ml) and cortisol (659.4 nmol/l; reference range, 147.3–609.3 nmol/l), blood examination showed no abnormalities. Ferritin (88.30 ng/ml; reference range 24–336 ng/ml) and renal function (glomerular filtration rate = 104.47 ml/min/1.73m2; reference range, 56–122 ml/min/1.73m2) were in the normal range. She had no pregnancy and immune diseases. Physical examination and imaging diagnosis showed no abnormalities. She also had no family history of psychiatric or neurological illness. Treatment was started with 0.6 g/d amisulpride to control psychiatric symptoms, 0.1 g/d quetiapine to improve sleep, 75 mg/d venlafaxine sustained-release tablets to relieve depression, 4 mg/d benzhexol hydrochloride and 20 mg/d propranolol hydrochloride. After 3 days, the patient reported daytime sleepiness and itch in her arms. When she rested, the itch worsened. In contrast, the itch could be relieved when she moved her arms. There was no rash, redness, swelling or pain on the arms. She did not report any discomfort in the legs. A nocturnal polysomnogram but not electromyogram channels in the arms was conducted on the patient. The time of wakefulness were 47.5 min. The numbers of wakefulness were 14. The periodic limb movement index was 6. The results indicated poor sleep continuity (see Table 1 and Fig. 1 in detail). She was diagnosed with RAS, a variant of RLS, according to the International RLS Study Group Criteria [9]. On the second day, the patient reported remission of itch in her arms without adjusting the medication. She did not complain of itch on the arms again in the ward and the half-year follow-up period. Table 1 The results of nocturnal polysomnogram\n\nIndex\tResults\t\nTime in bed, min\t608\t\nTotal sleep time, min\t553.5\t\nNumbers of wakefulness\t14\t\nTime of wakefulness, min\t47.5\t\nNREM 1, min (%)\t69.0 (12.5%)\t\nNREM 2, min (%)\t259.5 (46.9%)\t\nNREM 3, min (%)\t66.0 (11.9%)\t\nREM, min (%)\t159.0 (28.7%)\t\nArousal index, No./h\t8.4\t\nSleep onset latency, min\t7.0\t\nREM latency, min\t108.5\t\nRespiratory disturbance index, No./h\t1.3\t\nLowest arterial oxygen saturation, %\t92\t\nLimb movement index, No./h\t9.1\t\nPeriodic limb movement index, No./h\t6.0\t\nAbbreviations: NREM, nonrapid eye movement; REM, rapid eye movement\n\nFig. 1 The Hypnogram of the case. Abbreviations: R, rapid eye movement; N1, the first stage of nonrapid eye movement; W, wakeup; N2, the second stage of nonrapid eye movement; N3, the third stage of nonrapid eye movement\n\nDiscussion and conclusions\n\nAlthough there is no diagnostic criterion specific for RAS, similar diagnostic criteria for RLS exist. RAS is regarded as an RLS variant [1]. The patient with RAS manifested paresthesias in the upper extremities. The arms were affected predominantly, and legs were affected little or not involved. Therefore, RAS is difficult to diagnose and may be easily ignored by physicians. This case reinforced physicians could consider the possibility of RAS when using antidepressants and/or antipsychotics.\n\nThe patient was, at the time of presentation, taking two antipsychotic medications, which could result in the side effect of akathisia which is a form of restlessness. However, the symptoms of akathisia could not improve by the movement of upper limbs [10]. In our case, when she rested, the itch worsened. In contrast, the itch could be relieved when she moved her arms. Moreover, sleep disturbance would not usually present in a patient with akathisia [10].\n\nThe patient’s main complaint was transitory itchiness, which has many potential causes. One possibility is a reaction to the sleeves of a garment, laundered perhaps with allergenic soap. However, the patient’s itchiness relieved from the movement of upper limbs. There was no rash, redness, swelling or pain on the arms. Therefore, the patient is more likely to be diagnosed with RAS.\n\nAnother interesting finding is that the itching symptom disappeared without any medication discontinuation or intervention. The result differentiates from previous cases in RLS. Previous studies reported that leg symptoms were usually remitted after the withdrawal of antidepressants or quetiapine [11]. There is a titration process in the treatment of antidepression or antipsychotics. The medication adjustment resulting from RAS would increase the period of medication therapy from the initial dose to the maintenance dose. The nocturnal polysomnogram indicated normal periodic limb movement in the patient, and the obvious arm symptoms disappeared spontaneously without any intervention. Therefore, we did not address RAS or periodic limb movement. Our case suggests that RLS may only feature arm symptoms. In addition, RAS may be spontaneous remission without any intervention.\n\nRAS may result from iron deficiency, pregnancy, end-stage renal disease and rheumatic diseases [1]. In our case, ferritin and glomerular filtration rate were normal, which suggested that the patient have no iron deficiency or renal diseases. In addition, the patient also had no pregnancy or immune diseases. Therefore, the possible reason for RAS is the use of medications. However, medication-induced RAS is seldomly reported. Moreover, RAS is regarded as the variant of RLS. In fact, there is no overwhelming evidence of why RLS happens in patients with antidepressants or antipsychotics. The sort of medications may be risk factors for RLS. RLS might be induced by a single antidepressant or antipsychotic. Several studies thought that RLS was a side effect of quetiapine [12]. When the patient was under monotherapy, the most common reason for RLS was quetiapine (28.5%) in the antipsychotic group and paroxetine (22.2%) in the antidepressant group [13]. However, a low concentration of amisulpride may improve RLS resulting from dopaminergic agonist effects in the spinal area [14]. Another case pointed out that RLS symptoms improved rapidly on 0.5 mg of clonazepam and 50 mg of quetiapine after adjustment from 1 mg of clonazepam [15]. In addition, combined medications may increase the risk of RLS. Ocak [16] reported that patients with anxiety or depression who received combined drug treatment, such as selective serotonin reuptake inhibitors (SSRIs) + quetiapine and SSRIs + mirtazapine, had a 4.7-fold increase in RLS. In our case, the patients used three medications, including amisulpride, quetiapine and venlafaxine sustained-release tablets. As a result of not withdrawing medication, we cannot be sure which medication induced or improved the RAS in our case.\n\nThe dose of quetiapine and combined antidepressant medications may have an impact on the occurrence of RAS. One report showed that secondary RLS was a dose-dependent side effect of quetiapine [17]. A previous study revealed that quetiapine at doses of 200–600 mg/d induced RLS [18]. Another case pointed out that quetiapine at a low dose (50 mg/d) also resulted in RLS in a 75-year-old woman with insomnia [19]. Furthermore, RLS presented at very small to moderate doses (25–250 mg) in patients with affective disorders on treatment with antidepressants and quetiapine [20]. Similar to previous conclusions, the dose of quetiapine (100 mg/d) was also small in our case, which may induce RAS.\n\nThe possible mechanisms between RAS and antidepressants or antipsychotics in our patient may be as follows. First, central dopaminergic dysfunction may play an important role in the relationship between quetiapine and RLS. RLS was induced by antagonize dopamine receptors [21]. Although the D2 receptor affinity ratio of quetiapine and amisulpride was lower than that of other antipsychotic medications, such as olanzapine and ziprasidone, a sufficient ratio of initial transient binding with D2 receptors might be the reason for RLS [22]. On the other hand, RLS induced by quetiapine might be associated with 5-hydroxytryptamine (5-HT) agonism. Quetiapine has a strong antagonistic effect on 5-HT, which can increase the inhibitory effect of dopaminergic neurotransmission by 5-HT [23]. Moreover, quetiapine, with a high affinity for histamine1 receptors, presents antihistamine action that is thought to be related to the occurrence of RLS [24]. Venlafaxine hydrochloride may lead to dopaminergic hypoactivity resulting from enhanced serotonin-mediated inhibition of dopaminergic neurotransmission [25]. In addition, the occurrence of antipsychotic-induced RLS may result from cytochrome P450 enzymes. Cytochrome P450 enzymes are related to the plasma levels of antipsychotics and antidepressants [26]. A study pointed out that the value of O-desmethylvenlafaxine, an active metabolite of venlafaxine, is higher when quetiapine is coadministered [27]. A possible reason is that CYP3A4, a sort of cytochrome P450, is the main metabolizing enzyme for quetiapine as well as the metabolizing enzyme for venlafaxine [27]. Quetiapine reduces the metabolism of venlafaxine via CYP3A4, which may lead to the side effects of RAS. Amisulpride is directly absorbed by the gastrointestinal tract and eliminated by the kidneys as an unchanged drug [28]. Therefore, amisulpride has no effect on the liver metabolizing process of quetiapine and venlafaxine. Gender may be another influencing factor of RAS. In a nationwide survey, Tison et al. [29] reported that 10% of women and 5% of men had RLS in 10,263 French adults. Another study also found that females accounted for 69% of patients with RLS [30]. In our case, the patient was female. The case pointed out that females may have a higher likelihood of suffering from RAS.\n\nIn conclusion, RAS may be present in an individual with a small to moderate dose of quetiapine or combined with antidepressants. Psychiatrists should also be aware of RAS, especially in female patients with schizophrenia. Polysomnograms could be beneficial for the diagnosis of RAS. More importantly, the case pointed out that the RAS may be transient and does not have a continuous effect on patients. Psychiatrists may not have to immediately change the medication regimen when the RAS appears. When a patient manifests RAS, observation may be a choice instead of an immediate medication adjustment. Moreover, further studies should explore the underlying mechanisms of RAS and its management strategies.\n\nAbbreviations\n\nRAS Restless arms syndrome\n\nRLS Restless legs syndrome\n\nDSM-5 The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition\n\nAcknowledgements\n\nWe are appreciated to the patient in the study.\n\nAuthors’ contributions\n\nCJ and MN were the major contributors in writing and revising the manuscript. CB and YY interpreted the patient data. OY collected the patient data. LZ made the substantial contribution to the conception and design of the work. All authors read and approved the final manuscript.\n\nFunding\n\nThe study was support by Science and Technology project of Health Commission of Sichuan Province, 20PJ027 (ZL), Science and Technology project of Health Commission of Sichuan Province, 20PJ020 (JC), Applied Psychology Research Center of Sichuan Province, CSXL-202A08 (ZL), Department of Human Resources and Social Security of Sichuan Province, [2020] 291–20 (ZL). The above funding agencies had no role in the design of the study, collection, analysis, and interpretation of the data, or in the writing of the manuscript.\n\nAvailability of data and materials\n\nThis is a single-patient case report. Data sharing is not applicable to this article as no datasets besides those mentioned in the article were generated or analyzed.\n\nDeclarations\n\nEthics approval and consent to participate\n\nWritten informed consent was obtained from the patient and her parents for the case report. West China Hospital Ethics Committee approved the study.\n\nConsent for publication\n\nThe patient and patient’s parents received a complete description of the report and provided written informed consent. A copy of the written consent is available for review by the editor of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nJuan Chen and Na Meng contributed equally to this work.\n==== Refs\nReferences\n\n1. Ruppert E Restless arms syndrome: prevalence, impact, and management strategies Neuropsychiatr Dis Treat 2019 15 1737 1750 10.2147/NDT.S161583 31308668\n2. Ruppert E Cretin B Meyer C Kilic-Huck U Bourgin P Characterization of periodic upper limb movement disorder in a patient with restless arms syndrome Mov Disord 2012 27 11 1459 1461 10.1002/mds.25154 22927037\n3. Ruppert E Tranchant C Kilic-Huck U Carpentier N Bataillard M Bourgin P Bedtime-related jerks in the upper limbs associated with restless arms syndrome Neurology 2015 84 9 959 10.1212/WNL.0000000000001306 25732362\n4. Konstantakopoulos G, Oulis P, Michalopoulou P, Papadimitriou G. \"Restless arms syndrome\" Associated with Olanzapine European Psychiatry. 2009;24:1007.\n5. Munhoz RP Arruda WO Teive HA An upper limb variant of RLS? Report of 2 cases Clin Neurol Neurosurg 2012 114 3 265 266 10.1016/j.clineuro.2011.10.016 22056005\n6. Allen RP Picchietti DL Garcia-Borreguero D Ondo WG Walters AS Winkelman JW Zucconi M Ferri R Trenkwalder C Lee HB International Restless Legs Syndrome Study Group Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated international restless legs syndrome study group (IRLSSG) consensus criteria--history, rationale, description, and significance Sleep Med 2014 15 8 860 873 10.1016/j.sleep.2014.03.025 25023924\n7. Michaud M, Chabli A, Lavigne G, Montplaisir J. Arm restlessness in patients with restless legs syndrome. Mov Disord. 2000;15(2):289–93. 10.1002/1531-8257(200003)15:2%3C289::AID-MDS1012%3E3.0.CO;2-E.\n8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Washington, DC: American Psychiatric Publishing; 2013.\n9. International Restless Legs Syndrome Study Group. Diagnostic-criteria. 2012. http://www.irlssg.org/Diagnostic-criteria. Accessed 1 Dec 2012.\n10. Walters AS Hening W Rubinstein M Chokroverty S A clinical and polysomnographic comparison of neuroleptic-induced akathisia and the idiopathic restless legs syndrome Sleep 1991 14 4 339 345 1682986\n11. Park Y-M Restless legs syndrome caused by quetiapine Chronobiology in Medicine 2020 2 1 21 24 10.33069/cim.2019.0030\n12. Soyata AZ Celebi F Yargc LI Restless legs syndrome after single low dose quetiapine administration Curr Drug Saf 2016 11 2 172 173 10.2174/1574886311207040298 26582164\n13. Semiz M Solmaz V Aksoy D Inanir S Colak B Gokbakan MA Inanir A Prevalence of restless legs syndrome among psychiatric patients who are under antidepressant or antipsychotic monotherapy Bull Clin Psychopharmacol 2016 26 2 161 168 10.5455/bcp.20150908024954\n14. Colle R Boichot F Bouteiller E Elie-Lefebvre C Hardy P David DJ Verstuyft C Corruble E Restless legs syndrome and schizophrenia: a case report J Clin Psychopharmacol 2018 38 1 91 92 10.1097/JCP.0000000000000832 29215385\n15. Boku S Hirota M Yoshida H Homma H Iwasaki S Matsubara S A case of restless legs syndrome successfully treated with quetiapine Sleep Biol Rhythms 2006 4 2 193 195 10.1111/j.1479-8425.2006.00216.x\n16. Ocak D Kotan VO Paltun SC Aydemir MÇ Is restless legs syndrome related with depression/anxiety disorders or medications used in these disorders? A cross-sectional, clinic-based study Psychiatry and Clinical Psychopharmacology 2019 29 4 832 839 10.1080/24750573.2019.1673943\n17. Pinninti NR Mago R Townsend J Doghramji K Periodic restless legs syndrome associated with quetiapine use: a case report J Clin Psychopharmacol 2005 25 6 617 618 10.1097/01.jcp.0000186870.75042.25 16282854\n18. Vohra A Quetiapine induced restless legs syndrome: a series of four cases Asian J Psychiatr 2015 16 73 74 10.1016/j.ajp.2015.05.045 26096664\n19. Buturak SV Yazici K Yazici AE Tot S Basterzi AD Restless legs syndrome in an elderly patient induced by combined use of low dose quetiapine and citalopram Bull Clin Psychopharmacol 2016 22 3 271 274 10.5455/bcp.20120729090847\n20. Rittmannsberger H Werl R Restless legs syndrome induced by quetiapine: report of seven cases and review of the literature Int J Neuropsychopharmacol 2013 16 6 1427 1431 10.1017/S1461145712001599 23331473\n21. Oliveira C Dehanov S Vieira C Maia T Restless legs syndrome induced by quetiapine: a case report and review of the literature Eur Neuropsychopharmacol 2019 29 S123 S124 10.1016/j.euroneuro.2019.09.205\n22. Kanamitsu K Arakawa R Sugiyama Y Suhara T Kusuhara H Prediction of CNS occupancy of dopamine D2 receptor based on systemic exposure and in vitro experiments Drug Metab Pharmacokinet 2016 31 6 395 404 10.1016/j.dmpk.2016.07.003 27745731\n23. Chernoloz O El Mansari M Blier P Effects of sustained administration of quetiapine alone and in combination with a serotonin reuptake inhibitor on norepinephrine and serotonin transmission Neuropsychopharmacol 2012 37 7 1717 1728 10.1038/npp.2012.18\n24. Sato H Ito C Hiraoka K Tashiro M Shibuya K Funaki Y Yoshikawa T Iwata R Matsuoka H Yanai K Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers Psychopharmacology 2015 232 19 3497 3505 10.1007/s00213-015-4002-2 26146015\n25. Michopoulos I Ferentinos P Oulis P Gournellis R Restless legs syndrome associated with the combined use of quetiapine and venlafaxine J Clin Psychopharmacol 2014 34 1 159 161 10.1097/JCP.0b013e3182a95af2 24135842\n26. Ravyn D Ravyn V Lowney R Nasrallah HA CYP450 Pharmacogenetic treatment strategies for antipsychotics: a review of the evidence Schizophr Res 2013 149 1–3 1 14 10.1016/j.schres.2013.06.035 23870808\n27. Paulzer M Schoretsanitis G Hiemke C Grunde G Haen E Augustin M Reduced clearance of venlafaxine in a combined treatment with quetiapine Prog Neuro-Psychopharmacol Biol Psychiatry 2018 85 116 121 10.1016/j.pnpbp.2018.04.014\n28. Bergemann N Kopitz J Kress KR Frick A Plasma amisulpride levels in schizophrenia or schizoaffective disorder Eur Neuropsychopharmacol 2004 14 3 245 250 10.1016/j.euroneuro.2003.09.001 15056484\n29. Tison F Crochard A Leger D Bouee S Lainey E El Hasnaoui A Epidemiology of restless legs syndrome in French adults - a nationwide survey: the INSTANT study Neurology 2005 65 2 239 246 10.1212/01.wnl.0000168910.48309.4a 16043793\n30. Holmes R Tluk S Metta V Patel P Rao R Williams A Chaudhuri KR Nature and variants of idiopathic restless legs syndrome: observations from 152 patients referred to secondary care in the UK J Neural Transm (Vienna) 2007 114 7 929 934 10.1007/s00702-006-0614-3 17238008\n\n",
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"title": "Transitory restless arms syndrome in a patient with antipsychotics and antidepressants: a case report.",
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"abstract": "An 82-year-old Japanese man, who presented with a fever and abdominal pain, was admitted to our hospital. According to enhanced computed tomography images, the probable diagnosis was abdominal aortic mycotic aneurysm. Eight sets of blood cultures obtained from the patient were negative. Despite administering treatment with vancomycin and ceftriaxone, the aneurysm progressively enlarged. He underwent open debridement surgery and in situ replacement because of an aneurysmal rupture. Bacteroides fragilis was isolated from the tissue culture of the aortic wall. Metronidazole was administered and discontinued without any infection relapse. When faced with similar cases, rare pathogens should thus be considered as possible causes of mycotic aneurysms.",
"affiliations": "Division of Internal Medicine, National Hospital Organization Minami-Wakayama Medical Center, Japan.",
"authors": "Fukuchi|Takahiko|T|;Kawasaki|Sadao|S|;Hayashi|Hiroki|H|;Koreeda|Daisuke|D|;Ashikawa|Takahiro|T|",
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"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.7090Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27904124Case ReportMycotic Aneurysm Caused by Bacteroides fragilis in an Elderly Immunosuppressed Patient Fukuchi Takahiko 12Kawasaki Sadao 2Hayashi Hiroki 3Koreeda Daisuke 2Ashikawa Takahiro 21 Division of Internal Medicine, National Hospital Organization Minami-Wakayama Medical Center, Japan2 Division of Emergency Medicine, National Hospital Organization Minami-Wakayama Medical Center, Japan3 Division of Thoracic Surgery, National Hospital Organization Minami-Wakayama Medical Center, JapanCorrespondence to Dr. Takahiko Fukuchi, chicco@f.email.ne.jp\n\n1 12 2016 55 23 3535 3538 7 1 2016 29 3 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).An 82-year-old Japanese man, who presented with a fever and abdominal pain, was admitted to our hospital. According to enhanced computed tomography images, the probable diagnosis was abdominal aortic mycotic aneurysm. Eight sets of blood cultures obtained from the patient were negative. Despite administering treatment with vancomycin and ceftriaxone, the aneurysm progressively enlarged. He underwent open debridement surgery and in situ replacement because of an aneurysmal rupture. Bacteroides fragilis was isolated from the tissue culture of the aortic wall. Metronidazole was administered and discontinued without any infection relapse. When faced with similar cases, rare pathogens should thus be considered as possible causes of mycotic aneurysms. \n\nBacteroides fragilismycotic aneurysminfected abdominal aneurysmimmunosuppressed patientmetronidazole\n==== Body\nIntroduction\nMycotic aneurysm could be a fatal infectious disease if not appropriately managed. Previous reports indicate that most of the causative pathogens are Gram-positive cocci, such as Staphylococcus aureus or Streptococcus pneumoniae, and aerobic Gram-negative bacteria, such as Salmonella spp. (1).\n\nAn 82-year-old man was diagnosed with rheumatic arthritis and underwent long-term treatment with methotrexate (during the past 2 years). He then developed a mycotic aneurysm which had been caused by an anaerobic bacterial infection with Bacteroides (B.) fragilis. As this finding is extremely rare in terms of mycotic aneurysms, we herein describe the assessment, clinical course, and management of this case.\n\nCase Report\nAn 82-year-old Japanese man was admitted to our hospital because of a 3-day history of chills and abdominal and back pain. He was diagnosed with rheumatoid arthritis, for which he had been prescribed methotrexate 4 mg/week 2 years earlier. Additionally, he had a history of hypertension and angina pectoris. He had no history of tuberculosis, syphilis, or previous abdominal surgery. He denied having any digestive symptoms such as nausea, diarrhea, or melena. There was no evidence that he had a colonic diverticulum.\n\nOn admission, he was alert, his vital signs were blood pressure of 144/84 mmHg, heart rate of 115 beats/min, body temperature of 38.3°C, respiration rate of 16 breaths/min, and SpO2 of 96% with ambient air. His physical examination revealed pain and tenderness on his right lower abdominal quadrant, but no pulsatile masses.\n\nLaboratory findings showed an elevated white blood cell count of 16,400/μL (neutrophils, 92%; lymphocytes, 2.1%) and C-reactive protein of 22.39 mg/dL. His serological tests for syphilis were negative. Enhanced computed tomography displayed an abdominal aortic aneurysm (Figure).\n\nFigure. Abdominal aortic aneurysm on enhanced computed tomography taken on admission day.\n\nAccording to a clinical suspicion of a mycotic aneurysm, three sets of blood cultures were obtained on admission, followed by a series of blood cultures taken on 3 consecutive days. Ceftriaxone 2 g intravenously (IV) every 12 h and vancomycin 1 g IV every 24 h were immediately administered for coverage of Gram-positive cocci and Gram-negative bacilli, such as Salmonella spp. We consulted a cardiovascular surgeon who recommended medical therapy as the primary therapy, but with continuous monitoring. The six sets of blood cultures obtained from the patient were negative. Then, vancomycin was discontinued because it was less likely that the infection was caused by Gram-positive bacteria.\n\nOn the seventh hospitalization day, he developed a high-grade (40°C) fever. Abdominal ultrasound revealed acalculous cholecystitis. At that time, two additional sets of blood cultures were obtained, and ceftriaxone was replaced with cefepime 2 g IV every 12 h.\n\nOn the ninth hospitalization day, the abdominal aneurysm became enlarged and finally ruptured; therefore, urgent open debridement and in situ replacement were performed. There was no evidence indicating either intestinal or colonic comorbidity or any abnormal laparoscopic findings. No serious complications occurred during the surgery. The Gram stain of the necrotic tissue of the aortic wall revealed Gram-negative bacteria suspected to be an anaerobe; thus, piperacillin/tazobactam 4.5 g IV every 6 h and metronidazole 500 mg PO (per os) three times daily were administered according to the general antimicrobiogram findings. On the 11th hospitalization day, piperacillin/tazobactam was replaced by sulbactam/ampicillin 1.5 g IV every 6 h because B. fragilis was isolated from the tissue culture. The bacterial profile indicated that the strain was sensitive to sulbactam/ampicillin and metronidazole, but resistant to clindamycin. While sulbactam/ampicillin was discontinued on the 22nd hospitalization day because of a skin eruption, metronidazole was maintained as suppressive therapy. The patient was discharged after 32 days of hospitalization without any complications. Metronidazole was discontinued after 6 months of treatment because the patient complained of dizziness. The dizziness disappeared and the patient was free of infection relapse for 3 years after the cessation of metronidazole. He ultimately died from an unrelated case of pneumonia.\n\nDiscussion\nWe experienced a case of mycotic aneurysm caused by an obligate anaerobic bacterium, B. fragilis, which was successfully treated with surgical intervention and long-term antimicrobial treatment.\n\nPhysicians should be alert when using empiric therapy against common pathogens. We selected vancomycin and ceftriaxone to provide coverage for the most common pathogens involved in mycotic aneurysms, such as staphylococci (60%) and Salmonella (20-25%) (1). Although the eight sets of blood cultures obtained during hospitalization were negative, B. fragilis was isolated from the tissue culture of the necrotic aortic wall that was obtained during surgery. This causative pathogen was not covered by the empirical therapy initially administered; however, it is practically impossible to provide antimicrobial coverage for all the microorganisms that could potentially cause some disease in a given patient. Nevertheless, if the clinical course is not progressing as expected after the beginning of antimicrobial therapy, physicians should consider that the causative pathogen may be a rare or unusual one. While antimicrobial coverage for anaerobes was not initially achieved by empirical therapy (e.g., carbapenems), no data are available regarding the effect of medical therapy alone (2). Therefore, whether the patient's clinical course was altered by the management provided remains equivocal.\n\nAdditionally, the duration of antimicrobial treatment was debated. Some experts mention that adverse drug reactions to metronidazole therapy are rare, but include central nervous system toxicity (3). A review article reported that metronidazole treatment over 6 months led to encephalopathy; however, this adverse event was resolved after the discontinuation of metronidazole (4). In the present case, we decided to continue the treatment for as long as possible until the onset of any adverse events.\n\nIt is extremely rare for an anaerobic microorganism to cause a mycotic aneurysm, and it is also difficult for such microorganisms to be cultured successfully from blood samples. To the best of our knowledge, only 22 cases of mycotic aneurysm caused by the B. fragilis group have been previously reported in both English and Japanese literature (2,5-16). Of these, only nine reports confirmed bacteremia secondary to B. fragilis infection (Table). Likewise, in our case, we failed to isolate B. fragilis from a number of blood cultures. In addition, six patients presented conditions associated with an immunosuppressive state such as diabetes mellitus, liver cirrhosis, active malignancy, or the use of immunosuppressive agents, similar to our patient. Moreover, six patients had comorbidity with either the gastrointestinal tract or genital infectious diseases.\n\nTable. Features of 23 Patients with Mycotic Aneurysm Caused by Bacteroides Fragilis Group.\n\nNumber\tculture result\tauthor\tbacteremia\timmune- \nsuppression\trelation with \nGI tract\tknown \naneurysm\tsurgical \nprocedure\tcomplication\tantibiotics\tprognosis\t\n1\tBacteroides spp.\tSheehan\t-\t-\tNA\tNA\t-\t+\tampicillin + cloxacillin\tdied\t\n2\tB. fragilis\tReddy\t+\t+\tNA\t-\t+\t+\tMNZ\tsurvived\t\n3\tB. fragilis\tSuddelson\t+\t-\t-\t+\t+\t-\tMNZ\tsurvived\t\n4\tBacteroides spp.\tTaylor\t+\tNA\t-\t+\t+\tNA\tiv+poATB\tsurvived\t\n5\tB. fragilis\tJewkes\tNA\t-\t+\t+\t+\t-\tgentamicin+MNZ\tsurvived\t\n6\tB. fragilis\tReddy\tNA\tNA\t-\tNA\t+\t-\tivATB\tsurvived\t\n7\tB. fragilis\t\tNA\tNA\t-\t-\t+\t+\tivATB\tsurvived\t\n8\tB. fragilis\tSessa\tNA\tNA\tNA\tNA\t+\t+\tATB\tdied\t\n9\tB. fragilis\t\tNA\tNA\tNA\tNA\t+\t+\tATB\tsurvived\t\n10\tB. fragilis, Peptostreptococcus prevotii\tBrook\tNA\t-\t+\t-\t+\t+\tNA\tdied\t\n11\tB. fragilis\tO'Donnell\t+\t+\tNA\tNA\t+\t+\tpiperacillin /tazobactam +gentamicin\tdied\t\n12\tB. fragilis\tDoita\t-\t-\t-\tNA\t+\t-\tNA\tsurvived\t\n13\tB. thetaiotaomicron\tHsu\tNA\tNA\tNA\tNA\t+\t+\tNA\tdied\t\n14\tB. fragilis\tMatsuyama\t-\t+\t+\tNA\t+\t-\timipenem/cilastatin\tsurvived\t\n15\tB. fragilis\tBeland\t+\t-\t+\tNA\t+\t-\tMNZ+cefepime\tsurvived\t\n16\tB. fragilis\tLee\t+\t+\t+\tNA\t+\t+\tcefotaxime +teicoplanin\tdied\t\n17\tB.thetaiotaomicron\tMaeda\t-\tNA\tNA\tNA\t+\t+\tNA\tdied\t\n18\tB. thetaiotaomicron Acinetobacter lwofii \tKim\t+\t+\tNA\tNA\t+\t-\tMNZ + ciprofloxacin\tsurvived\t\n19\tB. fragilis\tOhuchi\tNA\t-\t+\tNA\t+\t+\tcefmetazole\tdied\t\n20\tB. fragilis\tUnno\t+\t-\tNA\t-\t+\t+\tNA\tdied\t\n21\tB. fragilis\tHanada\t+\t-\t+\t+\t+\t-\tmeropenem\tsurvived\t\n22\tB. fragilis\tAizawa\t+\t-\tNA\tNA\t+\t-\tcefmetazole +clindamycin\tsurvived\t\n23\tB. fragilis\tFukuchi\t-\t+\t-\tNA\t+\t-\tMNZ\tsurvived\t\nNA: not available, ATB: antibiotics, MNZ: metronidazole\n\nWe then hypothesized that this patient's unusual infection was probably related to the immunosuppressive status or some colonic comorbidity (17). However, there was no available evidence to confirm such a hypothesis. Furthermore, as we generally recommend to our patients, we advised the patient to undergo colonoscopy, which he refused. If there had been a colonic malignancy, it is likely that he would have died from this disease. Thus, we might be able to rule out the possibility of colonic comorbidity, particularly colon cancer.\n\nPrevious research reported up to the late 1980s has referred to the relationship between mycotic aneurysms and endocarditis or a previously known atherosclerotic aneurysm; however, the tendency has become less common in recent studies. Further research is needed to elucidate this disease.\n\nIn similar cases, when the results of multiple blood cultures are negative, but the patient has progressive clinical manifestations of infection, we recommend that clinicians consider rare pathogens, such as facultative anaerobes, as causative agents.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases . 8th ed. \nBennet JE DR , Blaser MJ , Eds. Elsevier Saunders , Philadelphia, PA , 2015 : 1023 -1027 .\n2. \nBrook I \nAnaerobic bacteria as a cause of mycotic aneurysm of the aorta: microbiology and antimicrobial therapy . Current Cardiology Reviews \n5 : 36 -39 , 2009 .20066146 \n3. \nBrook I \nTreatment of anarobic infection . Expert Rev Anti Infect Ther \n5 : 991 -1005 , 2007 .18039083 \n4. \nBottenberg MM , Hegge KA , Eastman DK , Kumar R \nMetronidazole-induced encephalopathy: a case report and review of the literature . J Clin Pharmacol \n51 : 112 -116 , 2011 .20220041 \n5. \nSessa C , Farah I , Voirin L , Magne JL , Brion JP , Guidicelli H \nInfected aneurysms of the infrarenal abdominal aorta: diagnostic criteria and therapeutic strategy . Ann Vasc Surg \n11 : 453 -463 , 1997 .9302056 \n6. \nBrook I , Frazier EH \nAerobic and anerobic microbiology of mycotic aortic aneurysm . Clin Infect Dis \n28 : 928 -929 , 1999 .10825076 \n7. \nO'Donell JA , Asbel LE \nBacteroides fragilis bacteremia and infected aortic aneurysm presenting as fever of unkown origin: Diagnostic delay without routine anaerobic blood cultures . Clin Infect Dis \n29 : 1309 -1311 , 1999 .10524981 \n8. \nOuchi S , Nakajima T , Minagawa Y , Komoda K , Kawazoe K \nInfected abdominal aneurysm caused by Bacteroides . Jpn J Cardiovasc Surg \n28 : 377 -380 , 1999 (in Japanese, Abstract in Enlish).\n9. \nDoita M , Marui T , Kurosawa M , et al \nContained rupture of the aneurysm of common iliac artery associated with pyogenic vertebral spondylitis . Spine \n26 : e303 -e307 , 2001 .11458171 \n10. \nHanada T , Higami H , Inao T \nA case of infected abdominal aortic aneurysm observed its formation course on CT . J Jpn Surg Assoc \n66 : 2125 -2128 , 2005 (in Japanese, Abstract in Enlish).\n11. \nAizawa Y , Sato T , Harada T , et al \nInfrarenal mycotic aortic aneurysm: three case reports . Iwamizawashiritsu-sougoubyouin-ishi \n33 : 21 -25 , 2007 (in Japanese).\n12. \nLee HL , Liu KH , Yang YJ , Kan CD \nBacteroides fragilis aortic arch pseudoaneurysm: case report with review . J Cardiothorac Surg \n3 : 29 , 2008 .18492250 \n13. \nLopes RJ , Almeida J , Dias PJ \nInfectious thoracic aortitis: a literature review . Clin Cardiol \n32 : 488 -490 , 2009 .19743492 \n14. \nMaeda H , Umezawa H , Goshima M , et al \nPrimary infected abdominal aortic aneurysm: surgical procedures, early mortality rates, and a survey of the prevalence of infectious organisms over a 30-year period . Surg Today \n41 : 346 -351 , 2011 .21365414 \n15. \nKim MG , Jeon JW , Ryu IH , et al \nMycotic abdominal aortic aneurysm caused by bacteroides thetaiotaomicron and acinetobacter lwoffii: the first case in Korea . Infect Chemother \n46 : 54 -58 , 2014 .24693472 \n16. \nUnno H , Matsuzaki K \nA case of ruptured infected thoracic aortic aneurysm associated with preoperative paraplegia . Jpn J Vasc Sur \n14 : 675 -678 , 2015 (in Japanese, Abstract in Enlish).\n17. \nPanwalker AP \nUnusual infections associated with colorectal cancer . Rev Infect Dis \n10 : 347 -364 , 1988 .3287564\n\n",
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"title": "Mycotic Aneurysm Caused by Bacteroides fragilis in an Elderly Immunosuppressed Patient.",
"title_normalized": "mycotic aneurysm caused by bacteroides fragilis in an elderly immunosuppressed patient"
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nFew studies have so far focused on the preoperative presence of venous thromboembolism (VTE) in lung cancer patients undergoing surgery. In this study, we investigated the prevalence and risk factors for preoperative deep venous thrombosis (DVT) in patients scheduled to undergo lung cancer surgery.\n\n\nMETHODS\nBetween June 2013 and December 2018, 948 consecutive patients underwent lung cancer surgery in Kindai University Hospital. Four patients did not undergo screening for DVT; thus, 944 patients were enrolled in this study. Preoperatively, venous ultrasonography of the lower extremities was performed in patients deemed at risk for DVT, and the prevalence and risk factors for preoperative DVT were examined.\n\n\nRESULTS\nNinety-one patients (9.6%) were diagnosed with preoperative DVT, and postoperative symptomatic pulmonary thromboembolism occurred in one patient (0.11%). A multivariable logistic regression analysis demonstrated that female sex, age ≥ 72 years, history of VTE, a Wells score ≥ 2 points, chronic obstructive pulmonary disease (COPD), and lower hemoglobin levels were significantly associated with preoperative DVT.\n\n\nCONCLUSIONS\nFemale sex, age ≥ 72 years, history of VTE, Wells score ≥ 2 points, COPD, and lower hemoglobin levels were identified to be independent risk factors for preoperative DVT. Monitoring for these risk factors and management considering them should help improve the outcomes after lung cancer surgery.",
"affiliations": "Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan. takemoto@med.kindai.ac.jp.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, 589-8511, Japan.",
"authors": "Takemoto|Toshiki|T|;Soh|Junichi|J|;Ohara|Shuta|S|;Fujino|Toshio|T|;Koga|Takamasa|T|;Nishino|Masaya|M|;Hamada|Akira|A|;Chiba|Masato|M|;Shimoji|Masaki|M|;Suda|Kenichi|K|;Tomizawa|Kenji|K|;Mitsudomi|Tetsuya|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s00595-021-02243-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-1291",
"issue": "51(9)",
"journal": "Surgery today",
"keywords": "D-dimer; Deep venous thrombosis; Lung cancer",
"medline_ta": "Surg Today",
"mesh_terms": null,
"nlm_unique_id": "9204360",
"other_id": null,
"pages": "1480-1487",
"pmc": null,
"pmid": "33611651",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The prevalence and risk factors associated with preoperative deep venous thrombosis in lung cancer surgery.",
"title_normalized": "the prevalence and risk factors associated with preoperative deep venous thrombosis in lung cancer surgery"
} | [
{
"companynumb": "JP-DSJP-DSJ-2021-132907",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
"drugadditional": null,
... |
{
"abstract": "This is the first report of a complete remission in aggressive T-cell large granular lymphocytic (T-LGL) leukemia after treatment with pentostatin. The aggressive variant of the disease is rare, and traditional therapies include immunosuppressive agents, however, there is no standard consensus for treatment. Cytotoxic chemotherapy has led to remission in a few reported cases. We present this unique case as an alternative treatment for individuals refractory to chemotherapy. A 55-year-old African American male with hypertension, type II diabetes mellitus, hyperlipidemia, and gout presented with symptoms of multiple ecchymosis, fatigue, and weight loss. He was found to have splenomegaly (SM) and significant leukocytosis to 101 k/µL with 30% blasts on peripheral smear. Following bone marrow aspiration and biopsy with flow cytometry, he was diagnosed with aggressive T-LGL leukemia. The chemotherapy regimen hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) was initially chosen based on his clinical presentation but was refractory to treatment. His therapy was changed to alemtuzumab; however, patient tolerated poorly and did not respond. Pentostatin was added to alemtuzumab with improvement in clinical symptoms and laboratory parameters. The patient was transitioned to pentostatin monotherapy and achieved complete remission after 1 month. This report provides support for pentostatin as an effective treatment for patients with aggressive T-cell malignancies refractory to cytotoxic chemotherapy. Pentostatin has previously been studied to treat T-cell prolymphocytic leukemia (T-PLL), hairy cell leukemia, and marginal zone lymphoma. This case suggests an alternative, well-tolerated option that could be considered for initial therapy of aggressive T-LGL leukemia.",
"affiliations": "Georgetown University School of Medicine, Washington, DC, USA.;Medstar Georgetown University Hospital, Lombardi Cancer Center, Washington, DC, USA.;Medstar Georgetown University Hospital, Lombardi Cancer Center, Washington, DC, USA.",
"authors": "Krackeler|Margaret Li|ML|;Broome|Catherine|C|;Lai|Catherine|C|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/sci-2020-035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2306-9759",
"issue": "7()",
"journal": "Stem cell investigation",
"keywords": "T-cell large granular lymphocytic leukemia (T-LGL leukemia); aggressive; pentostatin; refractory; treatment",
"medline_ta": "Stem Cell Investig",
"mesh_terms": null,
"nlm_unique_id": "101672113",
"other_id": null,
"pages": "24",
"pmc": null,
"pmid": "33437844",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26765645;30820940;26811014;8608238;7522625;28115367;11154985;31520704;17205534;27486175;21190991;27408372;19805674;28427176;8751472;7989933;29685423",
"title": "Complete remission of aggressive T-cell LGL leukemia with pentostatin therapy: first case report.",
"title_normalized": "complete remission of aggressive t cell lgl leukemia with pentostatin therapy first case report"
} | [
{
"companynumb": "US-TEVA-2021-US-1963850",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "4",
... |
{
"abstract": "Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive mature T-cell malignancy caused by the human T lymphoma virus I (HTLV-I) affecting 3-5% of HTLV-1 carriers and is usually diagnosed in endemic regions. Romania is a region with high prevalence of HTLV-1 infection and ATLL and with low median age at diagnosis for aggressive types. We performed a retrospective analysis of post-transplant outcome in the first Romanian patients with ATLL receiving hematopoietic stem cell allotransplant. The study population included eight patients (three males, five females), with median age of 39.5 (range 26-57), with acute (one case) and lymphoma type (seven cases) that received peripheral stem cells (PBSC) from matched related (MRD) and unrelated donors (MUD) after reduced intensity conditioning. Graft versus host disease (GVHD) developed in six patients. Relapse occurred in four cases (50%) at a median time of 5-months post-transplant. Six patients died: four cases with disease-related deaths and two patients with GVHD-related deaths. The median survival post-transplant was 19.5 months (range 2.3-44.2 months). The post-transplant survival at 1-year was 62.5%, at 2-years 50%, and at 3-years 37.5%. In our opinion allogeneic transplant improves outcome in aggressive type ATLL.",
"affiliations": "Department of Stem Cell Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Department of Hematology, Colțea Hospital, 030171 Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj Napoca, Romania.;Department of Hematology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Department of Hematology, Colentina Hospital, 020125 Bucharest, Romania.;Department of Hematology, Colentina Hospital, 020125 Bucharest, Romania.;Department of Hematology, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Department of Hematology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.;Department of Hematology, Colțea Hospital, 030171 Bucharest, Romania.;Department of Hematology, Ion Chiricuta Clinical Cancer Center, 400015 Cluj Napoca, Romania.;Department of Stem Cell Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania.;Service d'Hématologie Adultes, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, 75015 Paris, France.",
"authors": "Tanase|Alina D|AD|0000-0003-3075-499X;Colita|Andrei|A|;Craciun|Oana G|OG|;Lipan|Lavinia|L|;Varady|Zsofia|Z|;Stefan|Laura|L|;Ranete|Adela|A|;Pasca|Sergiu|S|;Bumbea|Horia|H|;Andreescu|Mihaela|M|;Popov|Viola|V|0000-0002-1200-379X;Bardas|Alexandru|A|;Coriu|Daniel|D|;Lupu|Anca Roxana|AR|;Tomuleasa|Ciprian|C|0000-0001-5500-1519;Colita|Anca|A|;Hermine|Olivier|O|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm9082417",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383 MDPI \n\n10.3390/jcm9082417\njcm-09-02417\nArticle\nAllogeneic Stem Cell Transplantation for Adult T-Cell Leukemia/Lymphoma—Romanian Experience\nhttps://orcid.org/0000-0003-3075-499XTanase Alina D. 12 Colita Andrei 34* Craciun Oana G. 1 Lipan Lavinia 1 Varady Zsofia 1 Stefan Laura 1 Ranete Adela 1 Pasca Sergiu 5 Bumbea Horia 46 Andreescu Mihaela 7 https://orcid.org/0000-0002-1200-379XPopov Viola 7 Bardas Alexandru 8 Coriu Daniel 48 Lupu Anca Roxana 34 https://orcid.org/0000-0001-5500-1519Tomuleasa Ciprian 910 Colita Anca 111 Hermine Olivier 1213 1 Department of Stem Cell Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania; alinadanielatanase@yahoo.com (A.D.T.); oanagabrielacraciun@yahoo.com (O.G.C.); lipan.lavinia@yahoo.com (L.L.); varadyzsofia@gmail.com (Z.V.); laura.stefan@icfundeni.ro (L.S.); adela_carciumaru@yahoo.com (A.R.); ancacolita@yahoo.com (A.C.)\n2 Department of Hematology, Titu Maiorescu University of Medicine, 040441 Bucharest, Romania\n3 Department of Hematology, Colțea Hospital, 030171 Bucharest, Romania; anca.lupu@yahoo.com\n4 Department of Hematology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania; horiabum@gmail.com (H.B.); daniel.coriu@umfcd.ro (D.C.)\n5 Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj Napoca, Romania; pasca.sergiu123@gmail.com\n6 Department of Hematology, University Hospital, 050098 Bucharest, Romania\n7 Department of Hematology, Colentina Hospital, 020125 Bucharest, Romania; tevetmihaela@gmail.com (M.A.); violamariap@gmail.com (V.P.)\n8 Department of Hematology, Fundeni Clinical Institute, 022328 Bucharest, Romania; bardas.alexandru@yahoo.com\n9 Department of Hematology, Ion Chiricuta Clinical Cancer Center, 400015 Cluj Napoca, Romania; ciprian.tomuleasa@umfcluj.ro\n10 Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj Napoca, Romania\n11 Department of Petriatics, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania\n12 Service d’Hématologie Adultes, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, 75015 Paris, France; ohermine@gmail.com\n13 Institut Imagine, INSERM U1163, 75015 Paris, France\n* Correspondence: andreicolita@yahoo.com\n28 7 2020 \n8 2020 \n9 8 241704 6 2020 23 7 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive mature T-cell malignancy caused by the human T lymphoma virus I (HTLV-I) affecting 3–5% of HTLV-1 carriers and is usually diagnosed in endemic regions. Romania is a region with high prevalence of HTLV-1 infection and ATLL and with low median age at diagnosis for aggressive types. We performed a retrospective analysis of post-transplant outcome in the first Romanian patients with ATLL receiving hematopoietic stem cell allotransplant. The study population included eight patients (three males, five females), with median age of 39.5 (range 26–57), with acute (one case) and lymphoma type (seven cases) that received peripheral stem cells (PBSC) from matched related (MRD) and unrelated donors (MUD) after reduced intensity conditioning. Graft versus host disease (GVHD) developed in six patients. Relapse occurred in four cases (50%) at a median time of 5-months post-transplant. Six patients died: four cases with disease-related deaths and two patients with GVHD-related deaths. The median survival post-transplant was 19.5 months (range 2.3–44.2 months). The post-transplant survival at 1-year was 62.5%, at 2-years 50%, and at 3-years 37.5%. In our opinion allogeneic transplant improves outcome in aggressive type ATLL.\n\nallogeneic stem cell transplantationadult T-cell leukemia/lymphomaRomanian experiencecase-seriesEuropean cohort\n==== Body\n1. Introduction\nAdult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive mature T-cell malignancy caused by the human T lymphoma virus I (HTLV-I). ATLL develops in approximately 3–5% of HTLV-1 carriers and is usually diagnosed in endemic regions that include the south-west region of Japan, Central and South America, central Africa, the Middle East, Far East, central Australia, and Romania [1,2,3]. ATLL diagnosis is based on clinical features, serum anti-HTLV-1 antibody and ATLL cell morphology, and immunophenotype [4,5]. The current disease classification (Shimoyama classification) defines four clinical subtypes based on the presence of organ involvement, leukemic manifestation, high lactate dehydrogenase (LDH) and hypercalcemia: acute, lymphoma, chronic (favorable and unfavorable), and smoldering [6]. The treatment strategy is based on the aforementioned classification. Thus smoldering and favorable chronic types are defined as indolent-type ATLL and are managed by active monitoring or zidovudine/interferon (AZT/IFN-α) with or without arsenic trioxide (ATO), while acute, lymphoma and unfavorable chronic types are defined as aggressive-type ATLL and may benefit from the association of chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), and newer therapeutic agents [1,4,7]. The outcome of aggressive ATLL is poor in most patients not receiving allo-HSCT with 16–42% complete remission (CR) rate, followed by early relapses after a median progression-free survival time of 5- to 7-months and 4-year overall survival below 10% [1,5,8]. Several retrospective analyses of allo-HSCT in Japan and Europe reported long-term survival (at 3-years) in 27–45% of allo-HSCT recipients after chemotherapy but with significant associated morbidity and mortality [8,9,10,11,12]. As responses to intensive chemotherapy are not durable and the progressive disease has a poor outcome even after allo-HSCT, it is recommended that patients with aggressive ATLL should be referred as soon as possible to a transplantation center in order to receive up-front allo-HSCT, preferably from a HTLV-1 seronegative donor [1].\n\nRomania is one of the regions with the highest prevalence of HTLV-1 infection in Europe (5.33 at 10,000 blood donors in 2003–2008) [3], therefore the prevalence of ATLL is also higher with lower median age at diagnosis (42.5 years) of aggressive types [13].\n\nThe aim of this study was to evaluate the post-transplant survival, relapse rate (RR) and treatment-related mortality (TRM) in a cohort of eight patients with ATLL that received allo-HSCT in a single transplant center.\n\n2. Case-Series\nThe current study is a retrospective analysis of the ATLL cases that received allo-HSCT at the Fundeni Clinical Institute between January 2016 to July 2019. The current study was performed in accordance with the Declaration of Helsinki and with the approval of the Fundeni Clinical Institute ethics committee (24908/07.05.2020).\n\nA total of eight patients (three males, five females) were included in the current case-series. The patients were diagnosed and initially treated in several centers across Romania before their referral to the transplant center. The median age at diagnosis was 39.5 years (range 26–57). According to Shimoyama classification, one case (12.5%) had acute type, while the rest had lymphomatous type. Five patients (62.5%) presented extranodal involvement, with three of those showing skin and bone marrow involvement as well, while one patient had multiple organ involvement (lung, kidney, parotid) and the fifth had meningeal involvement.\n\nThe primary end point of the study was post-transplant survival, defined as the time from the date of allo-HSCT until date of death from any cause or date of last follow-up. Causes of death were categorized into disease-related or treatment-related deaths. Disease-related deaths were defined as deaths caused by relapse or progression of ATLL among patients who survived for at least 30 days after transplantation. Treatment-related mortality (TRM) was defined as any death other than disease-associated deaths. Neutrophil recovery was considered for an absolute neutrophil count >0.5 × 109/L for three consecutive days after transplantation. Acute and chronic graft versus host disease (GVHD) were assessed using traditional criteria [14,15]. Data were analyzed using summary descriptive statistics (medians and ranges) for continuous variables and numbers and percentages for discrete variables. Response criteria was assessed as described by Cheson et al. [16].\n\nThe clinical characteristics of patients are shown in Table 1.\n\nAll patients received initial chemotherapy as follows: six patients received CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and two cases received a modified version of LSG15 protocol (VCAP: vincristine, cyclophosphamide, doxorubicin, prednisolone; AMP-doxorubicin, ranimustine, prednisolone; and VECP: vindesine, etoposide, carboplatin, prednisolone) without ranimustine and with vincristine instead of vindesine [1,5,17]. In five cases antiretroviral therapy was added to chemotherapy. This was represented in three cases by interferon-α (IFN-α)/zidovudine (AZT) and in two cases by AZT. After first line treatment, three of the eight patients who were eligible for transplant had achieved complete remission (CR). The other five patients received second line therapy DHAP combination chemotherapy protocol (dexamethasone, high-dose cytarabine, cisplatin) two cases; modified LSG15 two cases; IFN one case) with achievement of CR in three case and stable disease (SD) in the other two. Median time from diagnosis to transplantation was 11.25 months (range 4.5–17.5 months). At time of transplantation six patients were in CR and two in SD. All patients received peripheral stem cells (PBSC) from matched related (MRD) as well as matched unrelated donors (MUD) after reduced intensity conditioning (RIC) with Fludarabine 30 mg/m2/day × 6 days-Busulfan iv 3.2 mg/kg/day × 2 days (Flu/Bu) or Thiotepa 5 mg/kg/day × 2 days-Fludarabine 40 mg/m2/day × 4 days-Busulfan iv 3.2 mg/kg/day × 2 days (TT/Flu/Bu), with four 4 cases in each as shown in Table 2. All donors had negative HTLV-1 serology. In one case (no. 5) a second haploidentical transplant was performed after early relapse following MUD transplant with progressive disease. Conditioning used for this procedure was Fludarabine 30 mg/m2/day × 4 days-Cyclophosphamide 14.5 mg/kg/day × 2 days-Total body irradiation 2Gy (Flu/Cy/TBI). Graft versus host disease (GVHD) prophylaxis consisted in cyclosporine A (3–5 mg/kg with threshold value 150–200 ng/mL) and methotrexate (15 mg/m2 on day +1, 10 mg/m2 on day +3, +6) +/− in all eight patients and post-transplant cyclophosphamide (PT-Cy; 50 mg/kg on day +3 and +4) associated with tacrolimus (0.015 mg/kg starting on day +5 to day +180) and mycophenolate mofetil (15 mg/kg from day +5 to day +100) following the procedure of haploidentical stem cell transplantation. Our GVHD prophylaxis protocol for ATLL with MUD transplants, did not include anti-thymocyte globulin (ATG). The GVHD prophylaxis was the same as sibling transplants. We assume that, in this extremely aggressive disease, the GVHD can be associated with a better survival. The median number of infused peripheral hematopoietic cells was 7.0678 × 106 CD 34/kg (range 2.47–10.63 × 106 CD 34/kg). All patients achieved engraftment with median time to neutrophil recovery of 17.87 days (range 15–21 days). Graft versus host disease (GVHD) developed in six patients (75%), three (50%) of which were acute GVHD and three (50%), chronic GVHD. All patients presented 100% donor chimerism at Day +30. Five patients were tested for HTLV-1 at 6-months post allogeneic HSCT and three of them (60%) presented a positive HTLV-1 viral load.\n\nRelapse occurred in four cases (relapse rate of 50%) at a median time of 5-months post-transplant (range 2–25 months). In our cohort, six patients died during follow-up, the most frequent cause of death (four cases) was represented by relapsed/refractory disease (66.6%), one patient (16.6%) died because of metabolic imbalances and sepsis caused by chronic GVHD, and one (16.6%) because of refractory acute GVHD. The median survival post-transplant was 19.5 months (range 2.3–44.2 months). The post allo-HSCT survival at 1-year was 62.5%, at 2-years of 50%, and at 3-years of 37.5%.\n\n3. Discussions\nThis retrospective study reports the outcome of first allo-HSCT performed for ATLL patients in our country. Romania is one of the regions with the highest prevalence of HTLV1 infection (5.33 at 10,000 donors in 2003–2008) [3]. Moreover, our group’s analysis on ATLL cases showed a lower median age at diagnosis in aggressive type ATLL (42.5 years) [13] compared to Japanese [6,11] as well as European studies [12]. This might reflect an origin of infection in the 1980s in Romania, where other outbreaks occurred by horizontal transmission in that period, including an outbreak of HIV-1 [18]. Our study group of patients receiving allo-HSCT was even younger with median age at diagnosis of 39.5 years (range 26–57). This emphasizes the need for efficient therapeutic approaches in a young population affected by a disease with poor outcome.\n\nPatients with aggressive types of ATLL not receiving HSCT have CR rates of only 25–40%, median survival less than 1-year [17,19,20,21], and usually die of tumor progression. In our experience, in patients treated by chemotherapy between 2010–2019, CR rate was 16% and median overall survival (OS) was 6.5 months (5.1 for acute type, 8.0 for lymphomatous type) [13], compared to 3.5 months in acute type and 9.5 months in lymphomatous type in historical data reported by our group (oral presentation, data not published).\n\nIn the past two decades, several studies have shown improved OS in ATLL after allo-HSCT. Most publications are from Japan and present retrospective analyses of Japanese Registry Data. The largest retrospective analysis was performed on 578 patients with ATLL transplanted between February 1992 and December 2009 showing a 3-year OS of 36% with a median OS of 9–10 months and treatment-related mortality (TRM) of 34% [22]. The European Group for Blood and Marrow Transplantation’s Lymphoma Working Party (EBMT-LWP) published a retrospective EBMT Registry data analysis of ATLL cases with allo-HSCT and reported 3-year OS rate of 34.3% in a cohort of 17 patients [12]. There are no randomized studies comparing chemotherapy alone versus allo-HSCT consolidation published so far. Kawada et al. published a single center retrospective comparison of treatment outcomes in 29 patients with allo-HSCT versus 37 cases with chemotherapy showing a significative improved 3-year OS in transplant recipients (44.9 vs. 27.7%, p < 0.05) [23]. In our cohort the overall post allo-HSCT survival at 1-year was 62.5%, at 2-years 50%, and at 3-years 37.5%. The median post-transplant survival was 19.5 months (range 2.3–44.2 months).\n\nVarious studies have described a series of patient-related factors that could influence post-transplant outcome. Gender (male), age (>50 years), reduced performance status, and failure to achieve CR before allo-HSCT have been corelated with inferior outcomes [8,21,22,24]. Patients transplanted in first clinical remission and early, during the first 100 days after diagnosis (for related donors) are reported to have better outcome [21,25]. In a Japanese registry study on 386 patients, Hishizawa et al. reported a better survival probability for those transplanted in first CR (51%) compared to 26% in patients failing to achieve CR [8]. The report of The Revised ATLL International Consensus Meeting states that up-front allo-HSCT should be considered for suitable patients [1]. There are no data supporting the influence of ATLL subtype on post-transplant outcome [21,24].\n\nOur patient population had a median age of 39.5 years (range 26–57). The only patient older than 50 years had a post allo-HSCT survival of 37.7 months. Two out of three male patients survived longer than 2-years. In our cohort, 6/8 patients were in CR prior to HSCT. Three of these patients achieved CR after first line chemotherapy and two of them survived for more than 44 and 37 months, respectively after HSCT. The other three patients were in CR after salvage chemotherapy, two of them having long term survival of 26.7 and 41 months, respectively. Both patients with SD at HSCT relapsed early after 2- and 7-months. Transplants were performed after a median time of 11.25 months (range 5–23.5 months) from diagnosis. It is remarkable that in our study all patient with post allo-HSCT survival longer than 2-years were transplanted after more than 11-months from diagnosis. All of them were in CR, emphasizing the importance of disease control before performing allo-HSCT.\n\nInitial studies from Japan reported allo-HSCT performed mainly from MRD using bone marrow cells [26,27]. Sibling donors are available only for 1/3 of patients and a large proportion are HTLV-1 carriers, condition associated with higher disease-related mortality and donor derived ATLL, leading to the recommendation to preferably use HTLV-1 seronegative donors [1,8,21]. Despite initial data of inferior outcome in MUD allo-HSCT, more recent studies demonstrated the efficacy of MUD transplants in ATLL [8,28,29]. Since availability of unrelated donors is also limited, alternative donor sources like cord blood and haploidentical siblings have been used [8,12,17,22,27,30]. In the report of the Lymphoma Working Party of the European Bone Marrow Transplant Society (EBMT) on the pan-European experience during six years (2011–2016) on 17 patients, HSCT were performed from MRD (six cases), MUD (seven cases), haploidentical relative (three cases) and one unknown donor; no outcome data associated to donor source were reported [12]. In our cohort, two patients (25%) were transplanted from MRD and the other six (75%) from MUD. In one patient (no. 5) a second haploidentical transplant (haplo-HSCT) was performed after early relapse following the first MUD transplant. Four patients had survival longer than 2-years, three of them received transplant from MUD and one from MRD. The two patients that are still alive at the end of follow-up, at 41-months and 44-months, were transplanted from MUD and MRD, respectively. The haploidentical transplant using PT-Cy was performed as second transplant in a patient with uncontrolled disease with unfavorable outcome (death caused by disease progression). There are few data on the use of haploidentical donors in ATLL.\n\nYoshimitsu et al. published a retrospective analysis on outcome of haploidentical allo-HSCT without PT-Cy in patients with ATLL from the Japan Society for Hematopoietic Cell Transplantation database between 1985 and 2015. Forty-six patients were identified with an estimated 1- and 5-year overall survival rates of the entire cohort of 34.5% and 17.7%, respectively, but with high cumulative 1- and 5-year treatment-related mortality rates of 41.3% and 55.8%, respectively [30]. In the ATLL setting, more data on haploidentical transplants with PT-Cy are still needed. Considering the results obtained in other malignant hemopathies, we could expect that performing haplo-HSCT with PT-Cy earlier after diagnosis and in cases with controlled disease to achieve outcomes comparable to MUD transplantation procedures.\n\nThe role of a graft versus lymphoma (GVL) effect was highlighted by studies from Japan and Europe that have reported several aspects: superior OS after allo-HSCT compared to autologous transplants, and improved OS and reduced relapse rate in patients with limited acute and chronic GVHD, successful management of relapse by withdrawal of immunosuppression or by donor lymphocyte infusion (DLI) [12,21,24,26,27,28,31,32,33,34,35]. In our cohort, six patients (75%) developed GVHD: three (50%) acute GVHD and three (50%) chronic GVHD. Interestingly, out of the four patients that relapsed, all had GVHD (two presented acute GVHD and the other two presented chronic GvHD). Relapse occurred later in patients with chronic GVHD (7 and 25-months, respectively) compared to those with acute GVHD (2-months). The other two patients with GVHD (one acute and one chronic) died after complications associated to this condition. It is worth mentioning that the patient with chronic GVHD survived over three years without relapse. Moreover, both patients that are still alive after 41 and 44.2-months of follow-up did not develop any form of GVHD. This shows that the GVL effect is observed to a lesser extend in our cohort despite the results showing a similar incidence of GvHD in our patients compared to other studies [12,26].\n\nIn our cohort, the most frequent cause of death was represented by relapse; of the six patients who died during follow-up, four (66.6%) were disease-related deaths, whereas the other two (33.3%) deaths were related to treatment complications (one caused by metabolic imbalances and sepsis associated to chronic GvHD and one because of refractory acute GvHD). Compared to other studies, in our patient population the disease-related mortality was higher (66.6% vs. <48%) [8,12,22,26]. We analyzed if the high relapse rate could by associated to a lesser disease control determined by the conditioning type RIC or conditioning regimen used. In recent reports of Japanese and European groups RIC is used in most patients. The EBMT-LWP study reported the use of RIC in 13 patients (76%) and myeloablative conditioning (MAC) in three patients [12]. Ishida et al. published a retrospective study on 586 patients with allo-HSCT and demonstrated no difference in OS between MAC and RIC, with slightly higher TRM with MAC, but significantly higher disease-related mortality in RIC cases (p = 0.019) [22]. Although there are no prospective studies comparing different conditioning regimen, the same study published by Ishida et al. reported the superiority of fludarabine-based regimen combined with melphalan versus busulfan-based regimens in RIC setting [22]. The regimen we used, Flu/BU and TT/Flu/Bu are extensively used in lymphoid malignancies [36,37].\n\nAnother noticeable observation is the fact that three (60%) out of the five patients tested for HTLV-1 at 6-months post allo-HSCT presented a positive HTLV-1 viral load. This event occurred, although, at 30-days, all patients presented 100% donor chimerism and the donor samples were negative for HTLV-1. A possible pattern of viral load kinetic in transplanted patients is that it becomes initially undetectable but returns to detectable levels at 6 to 12-months post allo-HSCT [31]. Recurrence of HTLV-1 could predict relapse [32], but may also represent reinfection of donor lymphocytes, considering the high prevalence of HTLV-1 in Romanian population, with some patients maintaining remission and full donor chimerism despite reemergence of HTLV-1 [20,31,32]. In our study population, in the three patients with post-transplant HTLV-1 positivity, we registered a heterogenous evolution: one case had a post-transplant survival of more than 3-years without relapse and GHVD-related death; the second case had early relapse followed by a second haploidentical stem cell transplantation with unfavorable outcome (death caused by disease progression); in the third case relapsed occurred after 25-months leading to death through disease progression.\n\nThe limitations of the current study reside especially in the low number of included patients. This is due to the low incidence of the disease even in an endemic context and the low number of these patients that are eligible for HSCT. Another limitation of the study is represented by the context in which the HSCT was performed, as there are several treatment options that are not available in Romania. The strength of the current paper stands in the fact that it is the first paper to present the outcomes of ATLL HSCT patients in Romania, an endemic country for this disease.\n\n4. Conclusions\nThe EBMT pan-European report published the results of allogeneic stem cell transplantation on 17 patients. Our case series is interesting as it presents the largest non-Asian cohort of ATLL transplanted patients outside the EBMT cohort. Overall, our results suggest that allo-HSCT improves survival in a subset of ATLL patients, particularly those with aggressive types. Allogeneic HSCT with RIC conditioning regimen represents a viable and potentially curative approach especially when performed in CR. Nonetheless, it must be considered that this therapeutic approach has its associated morbidities and mortality and further steps are needed to improve survival.\n\nAcknowledgments\nThe elaboration of this study is in part the result of a cooperative project between hematology departments from several hospitals in Bucharest and the Hematology Department of Necker Hospital in Paris, supported by the Romanian Society of Hematology and ARIL (the Romanian Association against Leukemia).\n\nAuthor Contributions\nConceptualization A.D.T. and O.H. Formal analysis, A.C. (Andrei Colita) and S.P. Investigation O.G.C., Z.V., L.S., A.R., S.P., M.A., V.P. and A.B. Methodology, A.D.T. and A.C. (Andrei Colita). Resources, O.G.C., L.L., Z.V., L.S., A.R., H.B., M.A., V.P. and A.B. Supervision, A.D.T. and O.H. Validation, D.C., A.R.L. and A.C. (Anca Colita); Visualization A.C. (Andrei Colita), Z.V., L.S., A.R., S.P., H.B., M.A., V.P., D.C., A.R.P., C.T., A.C. (Anca Colita) and O.H.; Writing—original draft, L.L. Writing—review & editing, A.C. (Andrei Colita), C.T. and A.C. (Anca Colita). All authors have read and agreed to the published version of the manuscript.\n\nFunding\nFinancial support from the Romanian Society of Hematology and ARIL (the Romanian Association against Leukemia).\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\njcm-09-02417-t001_Table 1Table 1 Clinical characteristics of patients.\n\nSex (Male/Female)\t3/5\t\nMedian Age at Transplantation (Range)\t39.5 (26–57)\t\nSubtypes of ATLL\nAcute\nLymphoma\t\n1\n7\t\nExtranodal Involvement\nSkin\nMeningeal\nMultiple Organ\nBone Marrow\t7\n3\n1\n1\n5\t\nSerum Calcium Levels (mg/dL)\n≥11\n<11\t\n1\n7\t\nECOG\n0\n1\n2\t\n3\n3\n2\t\nComorbidity\nChronic Hepatitis\nTuberculosis\t3\n1\n2\t\nATLL—Adult T-cell leukemia/lymphoma; ECOG—Eastern Cooperative Oncology Group Performance Status.\n\njcm-09-02417-t002_Table 2Table 2 Patient treatment and outcome.\n\n\n\tAge\tSex\tATLL Type\tResponse to 1st Line Chemotherapy\tTime Diagnosis HSCT (Month)\tDisease Status at HSCT\tDonor Type\tConditioning\tGVHD Prophylaxis\tGVHD\tRelapse (Month after HSCT)\tStatus (Cause of Death)\tSurvival Post HSCT (Month)\t\n1.\t41\tF\tLymphoma\tNo\t23.5\tCR\tMUD\tFlu/Bu\tCsA + MTX\tNo\tNo\tAlive\t41\t\n2.\t40\tF\tAcute\tNo\t15.5\tSD\tMUD\tTT/Flu/Bu\tCsA + MTX\tChronic\t7\tDead (relapse)\t12.3\t\n3.\t26\tM\tLymphoma\tYes\t11.5\tCR (PET neg)\tMSD\tFlu/Bu\tCsA + MTX\tNo\tNo\tAlive\t44.2\t\n4.\t57\tF\tLymphoma\tYes\t11\tCR (PET neg)\tMUD\tFlu/Bu\tCsA + MTX\tChronic\tNo\tDead\n(GVHD)\t37.7\t\n5.\t37\tF\tLymphoma\tNo\t5.5\t1: CR (PET neg)\n2: PD\t1: MUD\n2: Haplo\t1:TT/Flu/Bu\n2: Flu/Cy/TBI\t1: CsA + MTX\n2:PT-Cy, Tacro, MMF\tAcute, Grade 1\nNo\t2\n-\tDead\n(PD)\t8.6\t\n6.\t33\tM\tLymphoma\tNo\t17.5\tCR\tMUD\tFlu/Bu\tCsA + MTX\tChronic\t25\tDead\n(relapse)\t26.7\t\n7.\t40\tF\tLymphoma\tYes\t5.5\tCR (PET neg)\tMUD\tTT/Flu/Bu\tCsA + MTX\tAcute, Grade 4\tNo\tDead\n(GVHD)\t2.3\t\n8.\t48\tM\tLymphoma\tNo\t5\tSD\tMSD\tTT/Flu/Bu\tCsA + MTX\tAcute, Grade 1\t2\tDead\n(relapse)\t3.5\t\nCR, complete remission; SD, stable disease; PD, progressive disease; MUD, matched unrelated donor; MSD, matched sibling donor; Haplo, haploidentical donor; Flu, fludarabine; Bu, Busulfan; TT, Thiotepa; Cy, Cyclophosphamide; TBI, total body irradiation; CsA, Cyclosporine A; MTX, Methotrexate; PT-Cy, post-transplant cyclophosphamide; Tacro, Tacrolimus; MMF, Mycophenolate mofetil; GVHD graft versus host disease; HSCT hematopoietic stem cell transplant; PET positron emission tomography.\n==== Refs\nReferences\n1. 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A Retrospective Analysis of treatment outcomes in adult T cell leukemia/lymphoma patients with aggressive disease treated with or without allogeneic stem cell transplantation: A single-center experience Biol. Blood Marrow Transpl. 2015 21 696 700 10.1016/j.bbmt.2014.12.020 \n24. Ishida T. Hishizawa M. Kato K. Tanosaki R. Fukuda T. Takatsuka Y. Eto T. Miyazaki Y. Hidaka M. Uike N. Impact of graft-versus-host disease on allogeneic hematopoietic cell transplantation for adult T cell leukemia-lymphoma focusing on preconditioning regimens: Nationwide retrospective study Biol. Blood Marrow Transpl. 2013 19 1731 1739 10.1016/j.bbmt.2013.09.014 24090597 \n25. Fuji S. Fujiwara H. Nakano N. Wake A. Inoue Y. Fukuda T. Hidaka M. Moriuchi Y. Miyamoto T. Uikeet N. Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma Bone Marrow Transpl. 2016 51 205 211 10.1038/bmt.2015.265 \n26. Utsunomiya A. Miyazaki Y. Takatsuka Y. Hanada S. Uozumi K. Yashiki S. Tara M. Kawano F. Saburi Y. Kikuchi H. Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation Bone Marrow Transpl. 2001 27 15 20 10.1038/sj.bmt.1702731 \n27. Okamura J. Utsunomiya A. Tanosaki R. Uike N. Sonoda S. Kannagi M. Tomonaga M. Harada M. Kimura N. Masuda M. Allogeneic stem-cell transplantation with reduced conditioning intensity as a novel immunotherapy and antiviral therapy for adult T-cell leukemia/lymphoma Blood 2005 105 4143 4145 10.1182/blood-2004-11-4193 15665110 \n28. Nakase K. Hara M. Kozuka T. Tanimoto K. Nawa Y. Bone marrow transplantation from unrelated donors for patients with adult T-cell leukaemia/lymphoma Bone Marrow Transpl. 2006 37 41 44 10.1038/sj.bmt.1705197 \n29. Kato K. Kanda Y. Eto T. Muta T. Gondo H. Taniguchi S. Shibuya T. Utsunomiya A. Kawase T. Kato S. 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Shigematsu A. Yamamoto S. Nishio M. Hashino S. Morita R. Takahata M. Onozawa M. A retrospective analysis of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia/lymphoma (ATL): Clinical impact of graft-versus-leukemia/lymphoma effect Biol. Blood Marrow Transpl. 2008 14 817 823 10.1016/j.bbmt.2008.04.014 \n33. Yonekura K. Utsunomiya A. Takatsuka Y. Takeuchi S. Tashiro Y. Kanzaki T. Kanekura T. Graft-versus-adult T-cell leukemia/lymphoma effect following allogeneic hematopoietic stem cell transplantation Bone Marrow Transpl. 2008 41 1029 1035 10.1038/bmt.2008.39 18332910 \n34. Itonaga H. Tsushima H. Taguchi J. Fukushima T. Taniguchi H. Sato S. Ando K. Sawayama Y. Matsuo E. Yamasaki R. Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: The Nagasaki Transplant Group experience Blood 2013 121 219 225 10.1182/blood-2012-07-444372 23100309 \n35. Kamimura T. Miyamoto T. Kawano N. Numata A. Ito Y. Chong Y. Nagafuji K. Teshima T. Hayashi S. Akashi K. Successful treatment by donor lymphocyte infusion of adult T-cell leukemia/lymphoma relapse following allogeneic hematopoietic stem cell transplantation Int. J. Hematol. 2012 95 725 730 10.1007/s12185-012-1056-3 22481502 \n36. Nagler A. Shimoni A. Conditioning The EBMT Handbook. Hematopoietic Stem Cell Transplantation and Cellular Therapies Carreras E. Dufour C. Mohty M. Kroger N. Springer Nature Cham, Switzerland 2019 99 107 \n37. Parody R. Sureda A. Outcome of Haploidentical Stem Cell Transplantation in Patients with Lymphoma Haploidentical Stem Cell Transplantation: An Emerging Treatment Modality Demirer T. Springer Nature Cham, Switzerland 2019 119 138\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "9(8)",
"journal": "Journal of clinical medicine",
"keywords": "European cohort; Romanian experience; adult T-cell leukemia/lymphoma; allogeneic stem cell transplantation; case-series",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32731502",
"pubdate": "2020-07-28",
"publication_types": "D016428:Journal Article",
"references": "29545256;20400987;1969055;16247419;26694446;30546068;18332910;25542158;18541202;20479287;1751370;25029232;26524263;7760890;19076337;22689862;20348391;15665110;2899140;15744352;27618683;17222757;17242396;30657736;24090597;28341734;8119382;30117169;23100309;21673346;22481502;11244433",
"title": "Allogeneic Stem Cell Transplantation for Adult T-Cell Leukemia/Lymphoma-Romanian Experience.",
"title_normalized": "allogeneic stem cell transplantation for adult t cell leukemia lymphoma romanian experience"
} | [
{
"companynumb": "NVSC2020RO231145",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
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"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nTuberous sclerosis complex (TSC) is an inherited disorder caused by mutations of TSC1 or TSC2 genes, resulting in constitutive activation of the mammalian target of rapamycin (mTOR) and impairment of the cell cycle. As a consequence, hamartomatous tumors of multiple organs may develop, but generally skin, brain, kidneys, and lungs are involved. mTOR inhibitors (mTOR-I, rapamycin/everolimus) may correct underlying defects in TSC. Previous data prove benefits and safety of mTOR-I on a wide spectrum of disease manifestations and effectiveness of rapamycin in TSC patients after kidney transplantation (KT).\n\n\nMETHODS\nWe report the first case of a patient with TSC receiving everolimus initiated in immunosuppressive treatment at the time of KT. In April 2012, the 34-year-old female TSC patient, after bilateral nephrectomy due to polycystic kidneys and skin lesions related to TSC, was transplanted with a renal graft from a deceased donor (PRA, 0%; MM A/B/DR,1/2/0). Initial immunosuppressive treatment consisted of basiliximab, methylprednisolone, tacrolimus, and everolimus.\n\n\nRESULTS\nThe early postoperative period was complicated by delayed graft function. Creatinine level at discharge was 1.39 mg/dL, with stable graft function in subsequent months. Nine months after KT, inflammatory infiltration of the nephrectomy site (performed in 2011) with persistent effusion was observed. After 2 months of unsuccessful conservative treatment, the patient was converted from everolimus to mycophenolate mofetil with healing of local state. During 11 months of everolimus treatment, no improvement of skin presentation of TSC was noticed.\n\n\nCONCLUSIONS\nmTOR-I appear to be a treatment of choice in transplanted patients with TSC, although some complications precluding continuous mTOR-I therapy allowing its potential benefits, may appear.",
"affiliations": "Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Gdańsk, Poland. Electronic address: ataras@gumed.edu.pl.;Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Gdańsk, Poland.;Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland.;Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland.;Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Gdańsk, Poland.",
"authors": "Tarasewicz|A|A|;Dębska-Ślizień|A|A|;Bułanowski|M|M|;Więcek|A|A|;Rutkowski|B|B|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D003404:Creatinine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D003404:Creatinine; D051799:Delayed Graft Function; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008775:Methylprednisolone; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2912-5",
"pmc": null,
"pmid": "25380949",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Everolimus in immunosuppressive treatment after kidney transplantation in a patient with tuberous sclerosis: case report.",
"title_normalized": "everolimus in immunosuppressive treatment after kidney transplantation in a patient with tuberous sclerosis case report"
} | [
{
"companynumb": "PL-MYLANLABS-2021M1045189",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "HBL is the most common malignant liver neoplasm in children. The etiology of HBL is largely unknown but there are certain syndromes, such as Beckwith-Wiedemann syndrome, that have been clearly associated with an increased incidence of this malignancy. EBS, also known as prune belly syndrome, is a congenital anomaly characterized by lax abdominal musculature, bilateral cryptorchidism requiring, in some cases, hemodialysis due to significant kidney and urinary tract dysfunctions. Despite an improvement on the survival rates of patients with advanced-stage HBL, the presence of concomitant end-stage renal disease that occurs in patients with EBS constitutes a therapeutic challenge for the clinician not only due to the use of nephrotoxic chemotherapy but also due to the potential need for multi-organ transplant. We report case of a 2-year-old male patient with EBS diagnosed with stage IV, metastatic HBL successfully treated with multi-agent chemotherapy while on dialysis whom then underwent a simultaneous liver-kidney transplant followed by adjuvant chemotherapy. Ultimately, the patient achieved cancer remission with normalization of his renal function. Our report emphasizes that patients with HBL in the setting of EBS will not only require careful kidney function monitoring while receiving chemotherapy, but they might also need to undergo multi-organ transplantation in order to achieve adequate cancer control and also normalization of their kidney function. Awareness of this unusual association calls for further investigation to potentially establish a genetic association between these two disease processes.",
"affiliations": "Department of Pediatrics, University of Miami-Holtz Children's Hospital, Miami, FL, USA.;Department of Pediatrics, University of Miami-Holtz Children's Hospital, Miami, FL, USA.;Department of Pediatrics, University of Miami-Holtz Children's Hospital, Miami, FL, USA.;Section of Pediatric Radiology, Department of Radiology, University of Miami, Miami, FL, USA.;Division of Liver/GI Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami, Miami, FL, USA.;Department of Pediatrics, University of Miami-Holtz Children's Hospital, Miami, FL, USA.",
"authors": "Ortiz|Daniel|D|0000-0001-9466-4438;Harden|Avis|A|;Corrales-Medina|Fernando F|FF|;Saigal|Gaurav|G|;Tekin|Akin|A|;Garcia|Jennifer|J|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "22(2)",
"journal": "Pediatric transplantation",
"keywords": "ESKD; Eagle-Barrett syndrome; chemotherapy; dialysis; hepatoblastoma; multivisceral transplant",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002675:Child, Preschool; D018197:Hepatoblastoma; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008175:Lung Neoplasms; D008297:Male; D020360:Neoadjuvant Therapy; D011535:Prune Belly Syndrome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29356335",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pediatric patient with end-stage kidney disease secondary to Eagle-Barrett syndrome and metastatic unresectable hepatoblastoma treated successfully with chemotherapy and liver-kidney transplant.",
"title_normalized": "pediatric patient with end stage kidney disease secondary to eagle barrett syndrome and metastatic unresectable hepatoblastoma treated successfully with chemotherapy and liver kidney transplant"
} | [
{
"companynumb": "US-TEVA-2018-US-877644",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nThe clinical-epidemiological characteristics and course of bullous pemphigoid in the general population is not clear. Few studies have been performed to date, and only one in the Italian population more than ten years ago. We decided to evaluate the characteristics and outcome of patients admitted for a bullous pemphigoid at our Hospital in the last 4 years.\n\n\nMETHODS\nWe retrospectively reviewed the last 4 years' medical records of the Department of Dermatology of the University of Bologna, identifying all patients with histological and immunological data typical for bullous pemphigoid. The patients were contacted and, whenever possible, re-evaluated clinically and serologically. Finally, we made a reviews of therapies administered in these cases.\n\n\nRESULTS\nWe identified 53 patients with a diagnosis of sub-epidermal autoimmune blistering disease. At re-evaluation, resolution of the disease was observed in 13 cases (24.52%) while the disease persisted in 32 cases. An improvement was observed in 35 (66.03%) patients, a worsening was observed in 3 (5.66%) patients, while the class did not change in 5 (9.43%) patients. All patients received systemic steroids as first line therapy, although most patients underwent more than one therapy. Fifteen patients received systemic steroid therapy alone, 22 patients received azathioprin, 16 patients received methotrexate, all patients received a prescription of topical steroid. Twenty-eight patients had abnormal values of eosinophilia, extremely susceptible to systemic steroid therapy.\n\n\nCONCLUSIONS\nThe findings of our study differ slightly from data collected by other authors in literature. Methotrexate is the drug of choice in terms of efficacy, practicality, cost and tolerability, particularly in the elderly population.",
"affiliations": "Unit of Dermatology, Department of Specialist Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy.;Unit of Dermatology, Department of Specialist Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy - giulai87@hotmail.com.;Unit of Dermatology, Department of Specialist Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy.;Unit of Dermatology, Department of Specialist Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy.;Unit of Dermatology, Department of Specialist Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy.;Unit of Dermatology, Department of Specialist Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy.",
"authors": "Balestri|Riccardo|R|;Odorici|Giulia|G|;Patrizi|Annalisa|A|;Infusino|Salvatore D|SD|;Magnano|Michela|M|;Bardazzi|Federico|F|",
"chemical_list": "D003879:Dermatologic Agents; D005938:Glucocorticoids; D008727:Methotrexate",
"country": "Italy",
"delete": false,
"doi": "10.23736/S0392-0488.17.05481-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-0488",
"issue": "153(5)",
"journal": "Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia",
"keywords": null,
"medline_ta": "G Ital Dermatol Venereol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003879:Dermatologic Agents; D004802:Eosinophilia; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006785:Hospitals, University; D006801:Humans; D007558:Italy; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010391:Pemphigoid, Bullous; D012189:Retrospective Studies; D011795:Surveys and Questionnaires",
"nlm_unique_id": "8102852",
"other_id": null,
"pages": "613-618",
"pmc": null,
"pmid": "28079339",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Survey of bullous pemphigoid in an Italian university hospital: clinical-epidemiological characteristics and follow-up.",
"title_normalized": "survey of bullous pemphigoid in an italian university hospital clinical epidemiological characteristics and follow up"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1082907",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Spinal epidural lipomatosis (SEL) of the thoracic and lumbar spine is a rare entity, which leads to compression of the spinal canal. The exact pathogenesis is still unknown. It most commonly occurs in patients with long-term exogenous or endogenous glucocorticoid excess or morbid obesity but there are also idiopathic forms. The symptoms depend on the severity of the SEL and can manifest as clinically asymptomatic, non-specific back pain, radiculopathy up to spinal cord compression. The diagnosis is usually achieved by magnetic resonance imaging (MRI) of the affected spinal segments. The treatment varies between discontinuation of glucocorticoids, weight reduction up to multisegmental decompressive laminectomy. The following case report presents the findings of SEL in a patient with steroid-dependent Jo-1 antibody syndrome and provides a current literature review on this rare disease.",
"affiliations": "Klinik für Rheumatologie und klinische Immunologie, Immanuel Krankenhaus Berlin, Lindenberger Weg 19, 13125, Berlin, Deutschland. v.schaefer@immanuel.de.;Klinik für Rheumatologie und klinische Immunologie, Immanuel Krankenhaus Berlin, Lindenberger Weg 19, 13125, Berlin, Deutschland.;Radiologisches Institut, Evangelische Lungenklinik Berlin, Lindenberger Weg 27, 13125, Berlin, Deutschland.;Klinik für Rheumatologie und klinische Immunologie, Immanuel Krankenhaus Berlin, Lindenberger Weg 19, 13125, Berlin, Deutschland.;Klinik für Rheumatologie und klinische Immunologie, Immanuel Krankenhaus Berlin, Lindenberger Weg 19, 13125, Berlin, Deutschland.",
"authors": "Schäfer|V S|VS|;Schmidt|W A|WA|;Meybaum|C|C|;Rosenkranz|V|V|;Krause|A|A|",
"chemical_list": "D000974:Antibodies, Antinuclear; D005938:Glucocorticoids; C046750:Jo-1 antibody",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00393-016-0173-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-1855",
"issue": "75(9)",
"journal": "Zeitschrift fur Rheumatologie",
"keywords": "Glucocorticoids; Jo-1 antibody syndrome; Side effect; Spinal epidural lipomatosis",
"medline_ta": "Z Rheumatol",
"mesh_terms": "D000974:Antibodies, Antinuclear; D003937:Diagnosis, Differential; D005938:Glucocorticoids; D006801:Humans; D008068:Lipomatosis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017285:Polymyositis; D013117:Spinal Cord Compression; D013577:Syndrome",
"nlm_unique_id": "0414162",
"other_id": null,
"pages": "939-942",
"pmc": null,
"pmid": "27581001",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10414580;11229864;20859631;7954313;20213089;1553589;7949703;2183369;1984504;22772944;12748893;7586816;15795966;7279161;16490695;9218297;11224868;21284882;15191340;9297724;3585426",
"title": "Spinal epidural lipomatosis as a rare side effect in steroid-dependent Jo-1 antibody syndrome.",
"title_normalized": "spinal epidural lipomatosis as a rare side effect in steroid dependent jo 1 antibody syndrome"
} | [
{
"companynumb": "DE-TEVA-791369GER",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
"dr... |
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