article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "BACKGROUND\nMost gastric cancer patients are diagnosed at mid- to late-stage and lose the chance of radical surgery, medical treatment is especially important to prolong the survival of patients. Apatinib mesylate, which is a small molecule vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, could be used as antiangiogenesis therapy for gastric cancer.\nA 67-year-old man sought medical care for upper abdominal discomfort.\n\n\nMETHODS\nThe patient was diagnosed as mixed medullary differentiated gastric adenocarcinoma, and immunohistochemistry suggested HER-2 (2+).\n\n\nMETHODS\nThe patient received chemotherapy consisting of oxaliplatin combined with S-1 as first-line treatment, and targeted therapy with apatinib mesylate as second-line treatment.\n\n\nRESULTS\nAfter 4 months of first-line chemotherapy, the patient received apatinib treatment immediately at a dose of 500 mg/d orally and died of cardiac arrest with 8.5 months of overall survival. During this period of targeted therapy with apatinib mesylate, this male patient suffered mammary gland development besides other common adverse reactions.\n\n\nCONCLUSIONS\nThis case report is the first to report the case of male mammary gland development after oral apatinib.",
"affiliations": "Chifeng Municipal Hospital, Inner Mongolia.;Chifeng Municipal Hospital, Inner Mongolia.;Chifeng Municipal Hospital, Inner Mongolia.;Chifeng Municipal Hospital, Inner Mongolia.;Chifeng Municipal Hospital, Inner Mongolia.;Chifeng Municipal Hospital, Inner Mongolia.;Chifeng Municipal Hospital, Inner Mongolia.;Chifeng Municipal Hospital, Inner Mongolia.;Geneis Beijing Co. Ltd., Beijing, China.",
"authors": "Hui|Yan|Y|;Wang|Jingchun|J|;Han|Jianguo|J|;Guo|Zhifeng|Z|;Sun|Siqi|S|;Wu|Zifang|Z|;Wang|Yanqiu|Y|;Han|Zhimin|Z|;Chen|Xiangbin|X|",
"chemical_list": "D000970:Antineoplastic Agents; D011725:Pyridines; C553458:apatinib",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000020727",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\nMD-D-19-04405\n10.1097/MD.0000000000020727\n20727\n5700\nResearch Article\nClinical Case Report\nMale mammary gland development after apatinib therapy in advanced gastric cancer\nA case reportHui Yan MDa∗ Wang Jingchun MBa Han Jianguo MBa Guo Zhifeng MBa Sun Siqi MBa Wu Zifang MBa Wang Yanqiu MBa Han Zhimin MBa Chen Xiangbin PhDb Saranathan. Maya a Chifeng Municipal Hospital, Inner Mongolia\nb Geneis Beijing Co. Ltd., Beijing, China.\n∗ Correspondence: Yan Hui, Chifeng Municipal Hospital, Inner Mongolia 024000, China (e-mail: 15304760592@163.com).\n10 7 2020 \n10 7 2020 \n99 28 e2072719 7 2019 4 4 2020 11 5 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nMost gastric cancer patients are diagnosed at mid- to late-stage and lose the chance of radical surgery, medical treatment is especially important to prolong the survival of patients. Apatinib mesylate, which is a small molecule vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, could be used as antiangiogenesis therapy for gastric cancer.\n\nPatient concerns:\nA 67-year-old man sought medical care for upper abdominal discomfort.\n\nDiagnosis:\nThe patient was diagnosed as mixed medullary differentiated gastric adenocarcinoma, and immunohistochemistry suggested HER-2 (2+).\n\nInterventions:\nThe patient received chemotherapy consisting of oxaliplatin combined with S-1 as first-line treatment, and targeted therapy with apatinib mesylate as second-line treatment.\n\nOutcomes:\nAfter 4 months of first-line chemotherapy, the patient received apatinib treatment immediately at a dose of 500 mg/d orally and died of cardiac arrest with 8.5 months of overall survival. During this period of targeted therapy with apatinib mesylate, this male patient suffered mammary gland development besides other common adverse reactions.\n\nLessons:\nThis case report is the first to report the case of male mammary gland development after oral apatinib.\n\nKeywords\nadverse reactionsapatinibgastric cancermale mammary gland developmentOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nSince most gastric cancer patients lose the chance of radical surgery when diagnosed at middle or late stage, medical treatment plays crucial roles in prolonged survival of patients.[1,2] Apatinib mesylate blocks signal transduction by binding of vascular endothelial growth factor (VEGF) to its receptor, and could be used as antiangiogenesis therapy for multiple cancers.[3] Although common adverse reactions of apatinib include hypertension, proteinuria, hand-foot syndrome, gastrointestinal bleeding, etc, so far there has been no reported case of male mammary gland development after oral apatinib. Here we report a case of a male gastric cancer patient suffered mammary gland development besides above-mentioned common adverse reactions of apatinib after 1month of treatment. To our knowledge, this is the first report on male mammary gland development caused by apatinib.\n\n2 Case presentation\nA 67-year-old man sought medical care for upper abdominal discomfort in December 2016. Gastroscopy revealed gastric-to-gastric antrum lesions. Pathological examination suggested mixed medullary differentiated adenocarcinoma, and immunohistochemistry suggested HER-2(2+). On February 20, 2017, radical gastrectomy was performed. The tumor had invaded the main body of the pancreas, so palliative gastrojejunostomy was selected. Cancer cells were suspected in the postoperative peritoneal lavage fluid.\n\n2.1 First-line treatment\nThe patient was given systemic chemotherapy (March 30, 2017) consisting of oxaliplatin combined with S-1, and he declined detection of HER-2 FISH for personal reasons; III-degree myelosuppression occurred during treatment, manifesting as a decrease in white blood cells and platelet count. Oral S-1 was ceased 12 days later. On April 28, May 23, and June 19, 2017, the chemotherapeutic dose was decreased to 75%, II-degree myelosuppression occurred, and bone marrow suppression recovered slowly. On September 9, abdominal computed tomography was performed: the right posterior lobe of the liver showed a low-density lesion 4.5×2.1 cm in size, and the enhanced scan showed a ring-shaped enhancement, suggesting a metastatic tumor. The assessment was for progressive disease (liver metastasis) with a progression-free survival of 4 months.\n\n2.2 Second-line treatment\nConsidering it is still difficult to recover bone marrow suppression after reducing the dose of chemotherapy this patient previously received, targeted therapy was selected for the second-line treatment. The targeted therapy was apatinib mesylate tablets at an initial dose of 500 mg/d (August 10 through October 20, 2017); 1 month after the beginning of treatment (September 13, 2017), a review of abdominal computed tomography findings showed gastric cancer, the range of postoperative gastrojejunostomy was relative stable, and the range of low density lesion of the right-posterior lobe of the liver was reduced to 3.9 × 1.5 cm; the efficacy was classified as partial remission according to the RESIST 1.0 standard. The patient's conscious bilateral breast pain was obvious on September 10, and the bilateral mammary gland was palpable, hard lumps, and tenderness. Male mammary gland development was diagnosed according to the breast ultrasound and breast magnetic resonance imaging results (Fig. 1), and the left and right ranges were 2.3 × 0.9 cm, 1.5 × 0.7 cm, respectively. The patient reported skin itching; urine routine prompts urine protein (3+); blood routine tips for white blood cells 2.0 × 109/L, platelets 74 × 109/L; and thickening of the stratum corneum at the finger joints with mild pain, though he had no trouble with normal physical activity. The patient's blood pressure was 150/100 mm Hg; apatinib was stopped. The patient was given auxiliary hematopoietic and antihypertensive symptomatic treatment and then reexamined. Urine routine analysis showed urine protein (–), blood routine results returned to normal, and blood pressure was controlled under 130/80 mm Hg. The breast ultrasound result showed male mammary gland development. Oral apatinib was continued, and the dose was kept at 500 mg/d because the patient continued to tolerate it. On October 20, routine urine analysis showed urinary protein 2+, and the patient produced black stool, suggesting upper gastrointestinal bleeding. Oral apatinib tablets were ceased. On November 2, the patient suddenly had a cardiac arrest and could not be resuscitated. As of the patient's death, second-line treatment progression-free survival had lasted 2.3 months, and his overall survival was 8.5 months.\n\nFigure 1 Magnetic resonance imaging T1 and T2 weighted images show developmental mammary gland images.\n\n3 Discussion\nApatinib mesylate is a small molecule vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitor that blocks signal transduction by binding of vascular endothelial growth factor (VEGF) to its receptor, potently inhibits tumor angiogenesis, and plays an anti-tumor therapeutic role.[3,4]\n\nDue to his history of high blood pressure, the patient showed hand-foot syndrome, proteinuria, itchy skin, and continued high blood pressure after 1 month of apatinib treatment. During this period, proteinuria 3+ occurred, and recovered after 10 days of stopping apatinib treatment; the patient's skin was itchy, and no drug intervention was given because the side effects were mild. Unlike other patients, this patient developed the above-mentioned adverse reactions and developed male mammary gland development. Previous studies have shown that targeted anti-tumor drugs such as imatinib could induce male mammary gland development,[5,6] specifically, 18% (7/38) of patients who received imatinib treatment had developed male mammary gland development in that study.[6] Moreover, it was suggested the mechanism of imatinib inducing male mammary gland development was blocking testosterone synthesis involved in tyrosine kinases.[5,6] Another case reported that kidney cancer patients who developed male gynecomastia under treatment of sunitinib, which is a multi-target receptor tyrosine kinase inhibitor, including VEGF.[7] An experimental study used mice suggested that neutralizing VEGF bioactivity also reduced the testosterone-stimulated growth of the glandular epithelial tissue. This effect, as the previously demonstrated effect of anti-VEGF treatment on corpus luteum growth, is secondary to inhibition of vascular growth.[8] However, we did not check the patient's testosterone levels which may provide more clues to our study. Since apatinib mesylate is also a tyrosine kinase inhibitor, it is speculated the use of this drug could be the cause of male mammary gland development in our study. As there has been few study reported in this area yet, more research would be need to verify.\n\n4 Consent\nWe have obtained written informed consent from the patient's daughter for publication of the patient's details.\n\nAuthor contributions\nConceptualization: Yan Hui.\n\nData curation: Jingchun Wang, Jianguo Han, Zhifeng Guo, Siqi Sun, Zifang Wu, Yanqiu Wang, Zhimin Han.\n\nWriting – original draft: Xiangbin Chen.\n\nAbbreviations: VEFG = vascular endothelial growth factor, VEGFR-2 = vascular endothelial growth factor receptor 2.\n\nHow to cite this article: Hui Y, Wang J, Han J, Guo Z, Sun S, Wu Z, Wang Y, Han Z, Chen X. Male mammary gland development after apatinib therapy in advanced gastric cancer: a case report. Medicine. 2020;99:28(e20727).\n\nThe authors have no funding and conflicts of interest to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Jemal A Siegel R Ward E \nCancer statistics, 2007\n. CA Cancer J Clin \n2007 ;57 :43 –66\n.17237035 \n[2] Wang F Shen L Li J \nThe Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer\n. Cancer Commun \n2019 ;39 :10 .\n[3] Li J Qin S Xu J \nApatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial\n. J Clin Oncol \n2013 ;31 :3219 –25\n.23918952 \n[4] Fontanella C Ongaro E Bolzonello S \nClinical advances in the development of novel VEGFR2 inhibitors\n. Ann Transl Med \n2014 ;2 :123 .25568876 \n[5] Gambacorti-Passerini C Tornaghi L Cavagnini F \nGynaecomastia in men with chronic myeloid leukaemia after imatinib\n. Lancet \n2003 ;361 :1954 –6\n.12801741 \n[6] Kim H Chang HM Ryu MH \nConcurrent male gynecomastia and testicular hydrocele after imatinib mesylate treatment of a gastrointestinal stromal tumor\n. J Korean Med Sci \n2005 ;20 :512 –5\n.15953881 \n[7] Pierluigi B Guido M Camillo A \nOnset of male gynaecomastia in a patient treated with sunitinib for metastatic renal cell carcinoma\n. Clin Drug Invest \n2009 ;29 :487 –90\n.\n[8] Ingela F Peter H Erik L \nNeutralizing VEGF bioactivity with a soluble chimeric VEGF-receptor protein flt (1-3) IgG inhibits testosterone-stimulated prostate growth in castrated mice\n. Prostate \n2004 ;58 :57 –65\n.14673953\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(28)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D018276:Carcinoma, Medullary; D006801:Humans; D008297:Male; D042361:Mammary Glands, Human; D011725:Pyridines; D013274:Stomach Neoplasms",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e20727",
"pmc": null,
"pmid": "32664067",
"pubdate": "2020-07-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Male mammary gland development after apatinib therapy in advanced gastric cancer: A case report.",
"title_normalized": "male mammary gland development after apatinib therapy in advanced gastric cancer a case report"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-257296",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"dru... |
{
"abstract": "Palmoplantar erythrodysesthesia syndrome (PPES) and nail changes are common presentations of cutaneous toxicity of docetaxel chemotherapy, which deteriorate the quality of life of patients. Herein, we describe a female patient who developed PPES and multiple nail changes due to docetaxel treatment for infiltrative ductal carcinoma. Cold application and elevation of extremities during docetaxel infusion, potent topical steroids and oral pyridoxine increased the tolerance to chemotherapy and provided regression of painful cutaneous lesions without cessation of the treatment.",
"affiliations": "Dermatology Clinic, Ankara Halil Sivgin Cubuk State Hospital, Ankara, Turkey.",
"authors": "Akoglu|Gulsen|G|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.129326",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-46-22510.4103/0253-7613.129326Drug WatchDocetaxel-induced palmoplantar erythrodysesthesia syndrome and long-lasting multiple nail changes Akoglu Gulsen Dermatology Clinic, Ankara Halil Sivgin Cubuk State Hospital, Ankara, TurkeyCorrespondence to: Dr. Gulsen Akoglu, E-mail: gusemd@yahoo.comMar-Apr 2014 46 2 225 227 28 7 2013 10 8 2013 12 1 2014 Copyright: © Indian Journal of Pharmacology2014This 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.Palmoplantar erythrodysesthesia syndrome (PPES) and nail changes are common presentations of cutaneous toxicity of docetaxel chemotherapy, which deteriorate the quality of life of patients. Herein, we describe a female patient who developed PPES and multiple nail changes due to docetaxel treatment for infiltrative ductal carcinoma. Cold application and elevation of extremities during docetaxel infusion, potent topical steroids and oral pyridoxine increased the tolerance to chemotherapy and provided regression of painful cutaneous lesions without cessation of the treatment.\n\nKEY WORDS\nChemotherapydocetaxelnailpalmoplantar erythrodysesthesia syndrome\n==== Body\nIntroduction\nPalmoplantar erythrodysesthesia syndrome (PPES) and nail changes are common adverse effects of certain chemotherapeutic agents which may deteriorate the quality of life of patients. Doxorubucin, cytarabine, 5 fluorouracil and docetaxel are the most frequently responsible chemotheraupeutic drugs for PPES.[1] Herein, we describe a female patient with PPES and nail changes due to docetaxel treatment for infiltrative ductal breast carcinoma.\n\nCase Report\nA 52-year-old female patient had undergone left radical mastectomy with axillary lymph node dissection for invasive ductal breast carcinoma. She had completed the third cycle of docetaxel chemotherapy (CT) with the dose of 100 mg/m2 and a cumulative dose of 480 mg. One week after the cycle, she presented to the out-patient department with palmoplantar redness, pain, tingling and burning sensation which had started 3 weeks back. In her medical history, the patient was on insulin and atorvastatin for diabetes mellitus and hyperlipidemia.\n\nExamination of the patient revealed palmoplantar erythema, tenderness, desquamation and onycholysis of the second fingernail of the right hand [Figure 1a and b]. The patient had noticed onycholysis after the first cycle; palmoplantar erythema had emerged 1 week after the second cycle of docetaxel CT. Examination of the feet for fungal infection was negative. The laboratory examinations including complete blood count, liver and kidney functions tests were within normal limits except higher total cholesterol and low density lipoprotein levels (270 mg/dl and 199 mg/dl, respectively). Whole-body bone scintigraphy, abdominal ultrasonography and electromyography were normal.\n\nFigure 1 (a and b) Palmoplantar erythema, desquamation and fissuring\n\nThe clinical findings of the patient were compatible with a diagnosis of palmoplantar erythrodysesthesia (PPES) and nail toxicity due to docetaxel CT. The severity of PPES was grade 2 according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Potent topical steroids, oral pyridoxine (250 mg/day), elevation of extremities during infusion and cold pack application were recommended. PPES regressed completely after 1 week and the patient tolerated the next CT infusions more comfortably. However, the dysesthesia symptoms did not lessen. After completion of CT treatment, the patient was put on radiotherapy of the operated region for 25 days. During the follow ups, the nail changes began to worsen 2 months after docetaxel CT. All fingernails of hands and feet had onycholysis; some of them had subungal hyperkeratosis, nail pain, brown discoloration and four consecutive Beau's lines [Figure 2]. Examination for fungal infection was negative. According to NCI scale, nail changes were compatible with grade 2 nail toxicity. About 6 months after CT, all fingernails of both hands completely recovered while toe nails had still minimal distal subungal hyperkeratosis and brown-yellow discoloration. The severity of dysesthesia symptoms regressed by more than 50%. The relationship between docetaxel and PPES and nail changes was considered ‘certain/definite’ using the WHO-UMC scale[2] and Naranjo's algorithm.[3]\n\nFigure 2 Onycholysis and Beau's lines in the fingernails of hands\n\nDiscussion\nDocetaxel, a semi-synthetic chemotherapeutic agent belonging to taxane group, has been successfully used for the treatment of various malignancies such as ovarian, breast, lung, head and neck cancers. However, many cutaneous adverse effects including erythematous pruritic maculopapular eruption, PPES, hyperpigmentation, photolichenoid eruption, and nail changes have been observed in 50-70% of the treated patients.[45] Since the skin toxicity is self-limiting and usually resolves in 1-2 weeks, cessation of docetaxel treatment is rarely required.\n\nThe symptoms of PPES usually start 24-48 hours after CT cycle and begin to regress within 2 weeks after cessation of the treatment. The suggested mechanism is direct cytotoxic effect of the chemotherapeutic agent on the acral epidermis. Since a correlation between dose and severity of the lesions is observed, symptoms may regress by reducing the dosage of the drug or cessation of the therapy. PPES may be graded according to NCI scale as follows: grade 1 (erythema, peeling; no pain), grade 2 (erythema, peeling, pain, not interfering with function), and grade 3 (erythema, peeling, pain, interfering with function).[1] The dysesthesia due to peripheral neuropathy is dose dependent and may cause severe sensorineural and even motor dysfunction in patients using high dosages of drugs.[6] In our case, the drug was not stopped and local treatments and oral pyridoxine were administered. The management resulted in an increase in the tolerance to CT and regression of painful cutaneous lesions. However, some dysesthesia symptoms remained.\n\nDocetaxel-induced nail changes are reported to develop in 0-44% of patients. These changes include paronychia, onycholysis, pyogenic granuloma, nail bed color changes, Beau lines, subungual hemorrhage, and abscess formation. Nail changes were considered to be linked to cumulative dosages or CT cycles.[4] On the other hand, some observers suggest that frequent exposure and long-term use of the drug are important risk factors.[7] In a recent study, body mass index, breast or ovarian cancer diagnosis and the number of cycles administered were determined to be the independent factors for docetaxel-induced nail toxicity.[8] Due to immunosuppression during CT, such nail changes are prone to secondary bacterial and fungal infections. Nail changes are usually asymptomatic and totally disappear after cessation of the drug while permanent changes may be observed in some patients.[7] The multiple nail changes of our patient (discoloration, subungual hyperkeratosis, Beau lines, and onycholysis) have not been commonly reported previously.[4] Our patient developed a number of Beau's lines which corresponded to the number of CT cycles received. The regression of hand nail changes required 6 months; however, the period was much longer for foot nails.\n\nMany causality methods have been proposed to establish a casual relationship between the drug and the adverse event. In this case, a temporal relationship was established with the symptoms regressing after completion of each chemotherapy cycle. The PPES and nail changes were definitive pharmacological phenomenon and every CT cycle served as a rechallenge. Hence, a certain or definite casual relationship was established. In conclusion, docetaxel may cause PPES and long-lasting multiple nail changes. Local treatments and oral pyridoxine may increase its tolerance and provide remarkable relief during and after CT cycles without cessation of the treatment. The physicians should be well aware of these reactions and the possible treatment.\n\nSource of Support: Nil\n\nConflict of Interest: No\n==== Refs\n1 Hueso L Sanmartin O Nagore E Botella-Estrada C Requena C Llombart B Chemotherapy-induced acral erythema: A clinical and histopathologic study of 44 cases Actas Dermosifiliogr 2008 99 281 90 18394404 \n2 The Uppsala Monitoring Centre Last accessed on 2014 Feb 02 Available from: http://www.Who-umc.org Available from: http://who-umc.org/Graphics/24734.pdf \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 Rafi L Friedrich M Tilgen W Reichrath J Severe nail changes due to docetaxel treatment Eur J Dermatol 2003 13 610 1 14721789 \n5 Vasudevan B Sawhney MP Sharma N Docetaxel-induced photolichenoid eruption Indian J Pharmacol 2009 41 203 4 20523876 \n6 Hilkens PH Pronk LC Verweij J Vecht CJ van Putten WL van den Bent MJ Peripheral neuropathy induced combination chemotherapy of docetaxel and cisplatin Br J Cancer 1997 75 417 22 9020489 \n7 Hong J Park SH Choi SJ Lee SH Lee KC Lee JI Nail toxicity after treatment with docetaxel: A prospective analysis in patients with advanced non-small cell lung cancer Jpn J Clin Oncol 2007 37 424 8 17584826 \n8 Can G Aydiner A Cavdar I Taxane-induced nail changes: Predictors and efficacy of the use of frozen gloves and socks in the prevention of nail toxicity Eur J Oncol Nurs 2012 16 270 5 21784705\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "46(2)",
"journal": "Indian journal of pharmacology",
"keywords": "Chemotherapy; docetaxel; nail; palmoplantar erythrodysesthesia syndrome",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D000077143:Docetaxel; D005260:Female; D060831:Hand-Foot Syndrome; D006801:Humans; D008875:Middle Aged; D054039:Onycholysis; D043823:Taxoids; D013997:Time Factors",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "225-7",
"pmc": null,
"pmid": "24741199",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21784705;7249508;20523876;18394404;17584826;14721789;9020489",
"title": "Docetaxel-induced palmoplantar erythrodysesthesia syndrome and long-lasting multiple nail changes.",
"title_normalized": "docetaxel induced palmoplantar erythrodysesthesia syndrome and long lasting multiple nail changes"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-110155",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"druga... |
{
"abstract": "We report the case of a 62-year-old woman who developed a withdrawal syndrome after using a standard 1.5-mg transdermal scopolamine (TDS) patch behind the ear to prevent motion sickness during sailing. The patient, who had used TDS occasionally for years without significant adverse effects, more recently, having worn a patch continuously for 7 days, approximately 24 to 36 hours after removing the patch developed dizziness, nausea, sweating, fatigue, and drowsiness. All symptoms disappeared without therapy in about 2 days. Approximately 1 year after the first episode, though, a very similar, more severe disabling reaction developed on 2 occasions. Drowsiness and malaise were accompanied by severe asthenia, orthostatic sweating, inability to stand, and hypotension. All clinical tests (electrocardiogram; spirometry; blood cell count; plasma levels of cortisol, sodium, and potassium; and liver and kidney function tests) were negative, and symptoms disappeared slowly, after several days. Although we are certain that scopolamine was responsible for the symptoms, we are less clear as to the nature of the disorder. The effects being more severe after a more prolonged use of the TDS patch, the increase in severity each successive time, and the time lag between removing the patch and appearance of symptoms all indicated a withdrawal syndrome for which several mechanisms may be suggested.",
"affiliations": "Departments of *Public Health and †Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy; and ‡School of Biological and Chemical Sciences, Birkbeck College, University of London, London, United Kingdom.",
"authors": "Manno|Maurizio|M|;Di Renzo|Gianfranco|G|;Bianco|Pasquale|P|;Sbordone|Carmine|C|;De Matteis|Francesco|F|",
"chemical_list": "D012601:Scopolamine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000099",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "38(5)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D005260:Female; D006801:Humans; D008875:Middle Aged; D012601:Scopolamine; D013375:Substance Withdrawal Syndrome; D057968:Transdermal Patch",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "204-5",
"pmc": null,
"pmid": "26366965",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unique Scopolamine Withdrawal Syndrome After Standard Transdermal Use.",
"title_normalized": "unique scopolamine withdrawal syndrome after standard transdermal use"
} | [
{
"companynumb": "IT-CONCORDIA PHARMACEUTICALS INC.-GSH201606-003300",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATROPINE SULFATE\\HYOSCYAMINE SULFATE\\... |
{
"abstract": "Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71·6% [90% confidence interval (CI) 61·2-80·6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88·1% (90% CI 79·5-93·9%) and 90·8% (90% CI 82·6-95·9%). With longer median follow-up for D-VMP and D-Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease-negativity (10-5 ) rates were 16·4% and 15·4%. Infusion-related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard-of-care regimens demonstrated comparable clinical activity to DARA IV-containing regimens, with low infusion-related reaction rates and reduced administration time.",
"affiliations": "Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Clínica Universidad de Navarra-CIMA, IDISNA, CIBERONC, Pamplona, Spain.;Royal Bournemouth Hospital, Bournemouth, UK.;Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.;Clinica Medica São Germano, São Paulo, Brazil.;Hematology Department, Institut Català d'Oncologia - Hospitalet, IDIBELL, University of Barcelona, Barcelona, Spain.;CHU de Toulouse, IUCT-O, Université de Toulouse, UPS, Service d'Hématologie, Toulouse, France.;Department of Hematology, Hôpital Haut Lévêque, University Hospital, Pessac, France.;Department of Hematology Chaim Sheba Medical Center, Ramat-Gan, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;4th Department of Medicine - Haematology, Charles University Hospital, Hradec Králové, Czech Republic.;Department of Hematology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;University Hospital Brno, Brno, Czech Republic.;Janssen Research & Development, LLC, Spring House, PA, USA.;Janssen Research & Development, LLC, Spring House, PA, USA.;Janssen Research & Development, LLC, Spring House, PA, USA.;Janssen Research & Development, LLC, Spring House, PA, USA.;Janssen Research & Development, LLC, Spring House, PA, USA.;Janssen Research & Development, LLC, Spring House, PA, USA.;Janssen Research & Development, LLC, Spring House, PA, USA.;Hematology Department, University Hospital Hôtel-Dieu, Nantes, France.",
"authors": "Chari|Ajai|A|0000-0002-0405-7480;Rodriguez-Otero|Paula|P|;McCarthy|Helen|H|;Suzuki|Kenshi|K|;Hungria|Vania|V|;Sureda Balari|Anna|A|0000-0002-1238-6970;Perrot|Aurore|A|;Hulin|Cyrille|C|;Magen|Hila|H|0000-0002-3990-394X;Iida|Shinsuke|S|;Maisnar|Vladimir|V|;Karlin|Lionel|L|;Pour|Ludek|L|;Parasrampuria|Dolly A|DA|0000-0003-3072-1784;Masterson|Tara|T|;Kosh|Michele|M|;Yang|Shiyi|S|;Delioukina|Maria|M|;Qi|Ming|M|;Carson|Robin|R|;Touzeau|Cyrille|C|0000-0003-0275-2575",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; C556306:daratumumab; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide; D008558:Melphalan; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.16980",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "192(5)",
"journal": "British journal of haematology",
"keywords": "NDMM; RRMM; combination therapy; daratumumab; subcutaneous",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003131:Combined Modality Therapy; D003907:Dexamethasone; D005260:Female; D005500:Follow-Up Studies; D006402:Hematologic Diseases; D006801:Humans; D007167:Immunotherapy; D000077269:Lenalidomide; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D011241:Prednisone; D059039:Standard of Care; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "869-878",
"pmc": null,
"pmid": "33216361",
"pubdate": "2021-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label Phase II study.",
"title_normalized": "subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy pleiades an open label phase ii study"
} | [
{
"companynumb": "GB-CELGENEUS-GBR-20190106537",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DARATUMUMAB"
},
"drugadditional": "2",
... |
{
"abstract": "BACKGROUND\nMortality due to septic shock is relatively high. The dynamic monitoring of plasma cell-free DNA (cfDNA) can guide the treatment of septic shock.\n\n\nMETHODS\nHerein, we present a typical case of septic shock syndrome caused by the bacilli Acinetobacter baumannii and Pantoea. The patient complained of abdominal pain, fever and chills upon admission to the Emergency Department. Marked decreases in white blood cells and procalcitonin (PCT) were observed after the patient received continuous renal replacement and extracorporeal membrane oxygenation. Plasma cfDNA levels were consistently high, peaking at 1366.40 ng/mL, as measured by a duplex real-time PCR assay with an internal control, which was developed as a novel method for the accurate quantification of cfDNA. The patient died of septic shock on HD 8, suggesting that cfDNA could be used to monitor disease progression more effectively than PCT and the other inflammatory factors measured in this case.\n\n\nCONCLUSIONS\nCfDNA may be a promising marker that complements other inflammatory factors to monitor disease progression in patients with septic shock.",
"affiliations": "Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.;Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.;Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. sypan@njmu.edu.cn.",
"authors": "Liu|Jing-Ping|JP|;Zhang|Shi-Chang|SC|;Pan|Shi-Yang|SY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v8.i1.200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2307-8960",
"issue": "8(1)",
"journal": "World journal of clinical cases",
"keywords": "Acinetobacter baumannii; Case report; Cell-free DNA; Septic shock",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "200-207",
"pmc": null,
"pmid": "31970188",
"pubdate": "2020-01-06",
"publication_types": "D002363:Case Reports",
"references": "10984072;26903338;27834061;27317895;12794413;18182792;28164563;18875018;26550041;18670422;22809118;28098591;30005596;22401927;23984731;22440322;12813013;23140420;15639681;31413532;27088084",
"title": "Value of dynamic plasma cell-free DNA monitoring in septic shock syndrome: A case report.",
"title_normalized": "value of dynamic plasma cell free dna monitoring in septic shock syndrome a case report"
} | [
{
"companynumb": "CN-PFIZER INC-2020044385",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
},
"drugadditional": null,
... |
{
"abstract": "Presented herein is the case of a heavily pretreated patient with high-grade neuroendocrine prostate cancer that achieved a complete metabolic response on platinum-based chemotherapy after treatment with the dual CD-47 and SIRP-α inhibitor, RRx-001, in a Phase II clinical trial.",
"affiliations": "Walter Reed National Military Medical Center Bethesda Maryland.;Walter Reed National Military Medical Center Bethesda Maryland.;Virginia Cancer Specialists (VCS) Fairfax Virginia.;EpicentRx San Diego California.;St. Francis Hospital & Medical Center Hartford Connecticut.;Developmental Therapeutics Branch National Cancer Institute, NIH Bethesda Maryland.;Developmental Therapeutics Branch National Cancer Institute, NIH Bethesda Maryland.;VA Connecticut Health Care System West Haven Connecticut.;Walter Reed National Military Medical Center Bethesda Maryland.",
"authors": "Ojemuyiwa|Michelle|M|;Zeman|Karen|K|;Spira|Alexander|A|;Oronsky|Bryan|B|0000-0002-3940-6329;Ray|Carolyn|C|;Trepel|Jane B|JB|;Lee|Min-Jung|MJ|;Onyiuke|Ifeyinwa|I|;Brzezniak|Christina|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1880",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1880CCR31880Case ReportCase ReportsComplete metabolic response of metastatic castration‐resistant neuroendocrine carcinoma of the prostate after treatment with RRx‐001 and reintroduced platinum doublets OJEMUYIWA et al.Ojemuyiwa Michelle \n1\nZeman Karen \n1\nSpira Alexander \n2\nOronsky Bryan http://orcid.org/0000-0002-3940-6329info@epicentrx.com \n3\nRay Carolyn \n4\nTrepel Jane B. \n5\nLee Min‐Jung \n5\nOnyiuke Ifeyinwa \n6\nBrzezniak Christina \n1\n\n1 \nWalter Reed National Military Medical Center\nBethesda\nMaryland\n\n2 \nVirginia Cancer Specialists (VCS)\nFairfax\nVirginia\n\n3 \nEpicentRx\nSan Diego\nCalifornia\n\n4 \nSt. Francis Hospital & Medical Center\nHartford\nConnecticut\n\n5 \nDevelopmental Therapeutics Branch\nNational Cancer Institute, NIH\nBethesda\nMaryland\n\n6 \nVA Connecticut Health Care System\nWest Haven\nConnecticut\n* Correspondence\n\nBryan Oronsky, EpicentRx, San Diego, CA.\n\nEmail: info@epicentrx.com\n05 11 2018 12 2018 6 12 10.1002/ccr3.2018.6.issue-122478 2481 08 5 2018 29 6 2018 17 7 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-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.Key Clinical Message\nPresented herein is the case of a heavily pretreated patient with high‐grade neuroendocrine prostate cancer that achieved a complete metabolic response on platinum‐based chemotherapy after treatment with the dual CD‐47 and SIRP‐α inhibitor, RRx‐001, in a Phase II clinical trial.\n\nmacrophage repolarizationneuroendocrine cancerplatinum doubletsprimingprostate cancerRRx‐001 source-schema-version-number2.0component-idccr31880cover-dateDecember 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:14.12.2018\n\n\nOjemuyiwa \nM \n, \nZeman \nK \n, \nSpira \nA \n, et al. Complete metabolic response of metastatic castration‐resistant neuroendocrine carcinoma of the prostate after treatment with RRx‐001 and reintroduced platinum doublets . Clin Case Rep . 2018 ;6 :2478 –2481 . 10.1002/ccr3.1880\n==== Body\n1 INTRODUCTION\nProstate cancer (PC) is the most common malignancy in US men (excluding nonmelanoma skin cancer) and the second leading cause of death after non‐small‐cell lung cancer (NSCLC).1 The mainstays of treatment for metastatic and locally advanced prostate cancer are androgen deprivation therapies (ADT), such as bicalutamide and/or leuprolide. These ultimately fail due to castrate resistance, which may be treated with sequential use of abiraterone, enzalutamide and followed by docetaxel, cabazitaxel, or sipuleucel‐T. Regretfully, all of these therapies eventually and inevitably engender resistance, which is uniformly fatal, due to the development and proliferation of androgen‐resistant cells.2 The neuroendocrine (NE) cell, initially a minor and widely interspersed cell population in normal human prostate glands, may proportionally increase with the progression to the advanced, hormone‐resistant state3 following long‐term androgen deprivation therapy (Figure 1). Since NE cells are negative for prostate‐specific antigen (PSA) and androgen receptor (AR), progression of ADT‐treated prostate cancer in the setting of negative or low levels of PSA suggests the possibility of neuroendocrine transformation.\n\nFigure 1 In normal prostatic parenchyma, the neuroendocrine (NE) cells are rare and widely interspersed. Neuroendocrine cells may “take over” after androgen deprivation therapy (ADT) eliminates the androgen‐sensitive cells\n\nConsistent with the hypothesis that ADT is responsible for or induces NE conversion, (a) overtde novo disease is extremely rare (<0.1% of all diagnosed PCs),4 (b) a higher proliferation index of tumor cells that are located in close proximity to the NE cell foci has been observed, and (c) the secretory products of NE cells have been shown to inhibit apoptosis,5 suggesting that the neuroendocrine cells actively aid and abet carcinogenesis.6\n\n\nTreatment‐emergent or secondary neuroendocrine prostate cancer (t‐NEPC) is thought to occur in up to 25% of patients with advanced PC.7, 8 Prostate‐specific antigen (PSA) is an unreliable marker of disease activity since neuroendocrine cells do not express it, contributing to late‐stage recognition of t‐NEPC during ADT and its overall poor prognosis. Symptoms are generally related to obstruction, with episodes of urinary retention and hematuria.9 Based on the treatment paradigm for small‐cell lung cancer, as the prototype of aggressive neuroendocrine tumors, patients are often treated with platinum‐based chemotherapy and radiation as appropriate. However, despite initial responses, rapid progression is the rule and no standard second line or curative therapy is available.10 This report presents a case of a complete metabolic regression of t‐NEPC after sequential treatment with the experimental macrophage M1 repolarizing agent, RRx‐001, dosed intravenously once weekly until progression, followed by reintroduced carboplatin and etoposide on a multi‐arm, multi‐center clinical trial called QUADRUPLE THREAT (NCT02489903).\n\n2 CASE PRESENTATION\nThe subject of this case report is a 65‐year‐old male diagnosed with pT3a, N0, Mx, Gleason score 9 (4 + 5) adenocarcinoma of the prostate diagnosed in 2008, for which he received radical retropubic prostatectomy (RRP) followed by external beam radiation therapy (EBRT). Due to a prostate‐specific antigen doubling time of <3 months in 2012, he was started on combined upfront androgen deprivation therapy with bicalutamide and goserelin. Subsequent therapies included enzalutamide plus an experimental prostate‐specific antigen (PSA)‐TRICOM viral vaccine (PROSTVAC), and docetaxel. Neuroendocrine differentiation was diagnosed by needle biopsy and the patient was treated with six cycles of carboplatin plus etoposide from April 2016 to September 2016.\n\nOn 09 November 2016, with progressive disease in the pelvis (enlargement of retroperitoneal lymphadenopathy), the patient enrolled on the Phase II QUADRUPLE THREAT clinical trial in which RRx‐001 is dosed weekly intravenously until progression followed by rechallenge with platinum and etoposide.\n\nThe patient began weekly RRx‐001 infusions on 23 November 2016. He received a second dose on 29 November and a third on 6 December 2016. On 7 December after three doses of RRx‐001, the patient presented to the hospital with lower back pain. Magnetic resonance imaging (MRI) of the brain done at that time demonstrated lesions that had not been imaged previously (because baseline cranial imaging had not been required) and, the patient immediately received two weeks of whole brain radiation therapy.\n\nThe patient was reimaged with positron emission tomography/computed tomography (PET/CT) on 28 December 2016 and this scan showed RECIST evidence of progression in the previously documented retroperitoneal lymphadenopathy. There was significant enlargement and increased fluorodeoxyglucose (FDG) avidity of the retroperitoneal mass that was confluent with the left kidney, causing obstruction at the ureteropelvic junction. In addition, new liver lesions were discovered (Figure 2). RRx‐001 was discontinued and the patient was transitioned back to carboplatin and etoposide rechallenge on 4 January 2017.\n\nFigure 2 A, Axial fused positron emission tomography/computed tomography (PET/CT) enrollment scan: liver on left shows diffuse background parenchymal activity with no discrete lesions. Image on the right shows large, highly fluorodeoxyglucose (FDG) avid nodal conglomerate at left ureteropelvic junction. B, Images after three doses of RRx001: Multiple discrete, highly FDG avid lesions in both the left and right lobes of the liver with significant increase in size and FDG avidity of retroperitoneal nodal mass. Note the mass effect on the kidney. C, Scan after two cycles of platinum doublets: extensive regression of liver lesions and complete metabolic response with activity approximating tissue background levels. Significant decrease in size with a complete metabolic response in retroperitoneal nodal mass\n\nOn 19 January, day 15 of his first cycle, the patient developed hematuria with urinary clotting, anemia (hemoglobin 7.1 g/dL), renal insufficiency (creatinine 1.42 mg/dL), and symptoms of obstruction. Over the month of January, 2017, these symptoms recurred, requiring two separate hospitalizations. Treatment for the hematuria, clotting, and anemia involved continuous bladder irrigation and red blood cell transfusion. After two cycles of platinum doublets, reimaging demonstrated a complete metabolic response on qualitative evaluation of FDG PET, even though his tumors were morphologically stable.\n\nIn addition, the hematuria and clotting subsided, the patient's quality of life drastically improved and the creatinine decreased from 1.42 to 1.2 mg/dL.\n\n3 DISCUSSION\nAn under‐recognized diagnosis, treatment‐emergent t‐NEPC, which may result from androgen deprivation therapy, due to the preferential selection and outgrowth of NE clones, is an incurable and highly lethal disease subtype with no available standard options in the second line after treatment with platinum doublets. High rates of initial responses to platinum doublets are followed inevitably by the development of intractable resistance. RRx‐001, a minimally toxic macrophage repolarizing agent with epigenetic properties, has been demonstrated to resensitize to previously tried and failed standard chemotherapies.11\n\n\nIn the Phase II QUADRUPLE THREAT trial, RRx‐001 is administered as a pretreatment or primer until progression in patients with four tumor types, SCLC, ovarian cancer, neuroendocrine, andepidermal growth factor receptor (EGFR) mutated NSCLC, prior to rechallenge with platinum doublets. RRx‐001 is an epigenetic inhibitor and dual checkpoint inhibitor of CD47‐SIRPα inhibition, which repolarizes M2‐like tumor‐associated macrophages to M1‐like macrophages. RRx‐001, which has been associated with pseudoprogression12 due to biopsy‐proven immune cell infiltration,13 edema, necrosis, and inflammation, appears to have elicited a similar pseudoprogressive enlargement of the tumors of this patient, (although in the absence of a biopsy, differentiating between true progressive disease and pseudoprogression is impossible), which might have suggested that he was in the throes of a death spiral rather than on the cusp of a complete metabolic response with platinum doublets.\n\nThese cases serve as an object lesson that marked clinical deterioration and radiographic worsening do not necessarily equal treatment failure in RRx‐001 patients, given the activity of RRx‐001 as primer, which enhances responses to subsequent chemotherapies.14, 15 Therefore, despite initial appearances of rapidly progressive disease after only three doses of RRx‐001, which might otherwise and in another context have warranted a referral to hospice, the best decision for this patient was not to withdraw treatment but to continue it per protocol with reintroduced platinum doublets. In another patient on the QUADRUPLE THREAT trial with high‐grade extrapulmonary neuroendocrine disease and a durable partial response to single agent RRx‐001, documented elsewhere,16 an increase in the size of his tumors preceded significant regression. Serial biopsies of his lesions demonstrated an influx of CD8+ lymphocytes, which appeared after 12 weeks.\n\nIn summary, given the absence of secondary salvage treatment options in t‐NEPC, it is hoped that resensitization to initially highly effective platinum doublets after “priming” with RRx‐001 will provide significant clinical benefit, even if as in the case of this patient rapid clinical worsening preceded it, and markedly change the bleak prognosis of this disease.\n\nINFORMED CONSENT\nHuman Subjects: Informed consent was obtained by all participants in this study.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nMO: treated the patient. MO, KZ, AS, BO, CR, JT, ML, IO, and CB: wrote and edited the manuscript.\n\nACKNOWLEDGMENTS\nThe authors gratefully acknowledge the invaluable assistance of Dr. Corey A. Carter in the writing of this case report.\n==== Refs\nREFERENCES\n1 \n\nSiegel \nR \n, \nNaishadham \nD \n, \nJemal \nA \n. Cancer statistics 2012 . CA Cancer J Clin . 2012 ;62 :10 ‐29 .22237781 \n2 \n\nKarantanos \nT \n, \nCorn \nPG \n, \nThompson \nTC \n. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches . Oncogene . 2013 ;32 (49 ):5501 ‐5511 .23752182 \n3 \n\nWeinstein \nMH \n, \nPartin \nAW \n, \nVeltri \nRW \n, \nEpstein \nJI \n. Neuroendocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy . Hum Pathol . 1996 ;27 :683 ‐687 .8698312 \n4 \n\nHumphrey \nPA \n. Histological variants of prostatic carcinoma and their significance . Histopathology . 2012 ;60 :59 ‐7410 .22212078 \n5 \n\nAbrahamsson \nPA \n. Neuroendocrine cells in tumour growth of the prostate . Endocr Relat Cancer . 1999 ;6 :503 ‐1910 .10730904 \n6 \n\nBonkhoff \nH \n, \nWernert \nN \n, \nDhom \nG \n, \nRemberger \nK \n. Relation of endocrine‐paracrine cells to cell proliferation in normal, hyperplastic, and neoplastic human prostate . Prostate . 1991 ;19 :91 ‐98 .1717965 \n7 \n\nBeltran \nH \n, \nTagawa \nST \n, \nPark \nK \n, et al. Challenges in recognizing treatment‐related neuroendocrine prostate cancer . J Clin Oncol . 2012 ;30 :e386 –e910 .23169519 \n8 \n\nLotan \nTL \n, \nGupta \nNS \n, \nWang \nW \n, et al. ERG gene rearrangements are common in prostatic small cell carcinomas . Mod Pathol . 2011 ;24 :820 ‐828 .21336263 \n9 \n\nStein \nME \n, \nBernstein \nZ \n, \nAbacioglu \nU \n, et al. Small cell (neuroendocrine) carcinoma of the prostate: Etiology, diagnosis, prognosis, and therapeutic implications – A retrospective study of 30 patients from the rare cancer network . Am J Med Sci . 2008 ;336 :478 ‐488 .19092321 \n10 \n\nTerry \nS \n, \nBeltran \nH \n. The many faces of neuroendocrine differentiation in prostate cancer progression . Front Oncol . 2014 ;4 :60 .24724054 \n11 \n\nOronsky \nB \n, \nPaulmurugan \nR \n, \nFoygel \nK \n, et al. RRx‐001: a systemically non‐toxic M2‐to‐M1 macrophage stimulating and prosensitizing agent in Phase II clinical trials . Expert Opin Investig Drugs . 2017 ;26 (1 ):109 ‐119 .\n12 \n\nReid \nT \n, \nOronsky \nB \n, \nScicinski \nJ \n, et al. Safety and activity of RRx‐001 in patients with advanced cancer: a first‐in‐human, open‐label, dose‐escalation phase 1 study . Lancet Oncol . 2015 ;16 (9 ):1133 ‐1142 .26296952 \n13 \n\nZhao \nH \n, \nNing \nS \n, \nNolley \nR, \n et al. The immunomodulatory anticancer agent, RRx‐001, induces an interferon 4 through epigenetic induction of viral mimicry . Clin Epigenetics . 2017 ;9 :4 .28149332 \n14 \n\nCarter \nCA \n, \nOronsky \nB \n, \nCaroen \nS \n, et al. Partial response in an RRx‐001‐primed patient with refractory small‐cell lung cancer after a third introduction of platinum doublets . Case Rep Oncol . 2016 ;9 (2 ):285 ‐289 .27403127 \n15 \n\nCarter \nCA \n, \nOronsky \nB \n, \nCaroen \nS \n, et al. Partial response to carboplatin in an RRx‐001 pretreated patient with EGFR‐inhibitor‐resistance and T790M‐negative NSCLC . Respir Med Case Rep . 2016 ;18 :62 ‐65 .27330954 \n16 \n\nCarter \nCA \n, \nSchmitz \nB \n, \nPeterson \nPG \n, et al. Immune reactivity and pseudoprogression or tumor flare in a serially biopsied neuroendocrine patient treated with the epigenetic agent RRx‐001 . Case Rep Oncol . 2016 ;9 (1 ):164 ‐170 .27065848\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "6(12)",
"journal": "Clinical case reports",
"keywords": "RRx‐001; macrophage repolarization; neuroendocrine cancer; platinum doublets; priming; prostate cancer",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2478-2481",
"pmc": null,
"pmid": "30564353",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "10730904;1717965;19092321;21336263;22212078;22237781;23169519;23752182;24724054;26296952;27065848;27330954;27403127;27935336;28149332;28943185;8698312",
"title": "Complete metabolic response of metastatic castration-resistant neuroendocrine carcinoma of the prostate after treatment with RRx-001 and reintroduced platinum doublets.",
"title_normalized": "complete metabolic response of metastatic castration resistant neuroendocrine carcinoma of the prostate after treatment with rrx 001 and reintroduced platinum doublets"
} | [
{
"companynumb": "US-ACCORD-100982",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Invasive mold disease in thoracic organ transplant recipients is a well-recognized complication, but the long-term persistence of molds within the human body and evasion of host defenses has not been well-described. We present 2 cases of invasive mold disease (Verruconis gallopava and Aspergillus fumigatus) in thoracic transplant recipients who had the same mold cultured years prior to the invasive disease presentation. The paired isolates from the index and recurrent infections in both patients were compared using whole-genome sequencing to determine if the same strain of mold caused both the index and recurrent infections. In Case 1, the isolates were found to be of the same strain indicating that the initial colonizing isolate identified pre-transplant eventually caused invasive mold disease post-transplant while in Case 2, the 2 isolates were not of the same strain. These results demonstrate the distinct possibility of molds both persisting within the human body for years prior to invasive mold disease or the long-term risk of recurrent, persistent infection with more than one strain. Further studies of long-term molecular epidemiology of IMD and risk factors for mold persistence in transplant recipients are encouraged.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA.;Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA.;Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA.;Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University, Durham, NC, USA.;Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Duke University, Durham, NC, USA.;Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Duke University, Durham, NC, USA.;Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA.;Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA.;Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.;Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA.",
"authors": "Messina|Julia A|JA|http://orcid.org/0000-0001-6411-198X;Wolfe|Cameron R|CR|;Hemmersbach-Miller|Marion|M|http://orcid.org/0000-0001-6041-6815;Milano|Carmelo|C|;Todd|Jamie L|JL|;Reynolds|John|J|;Alexander|Barbara D|BD|;Schell|Wiley A|WA|;Cuomo|Christina A|CA|;Perfect|John R|JR|",
"chemical_list": "D000935:Antifungal Agents; D004271:DNA, Fungal",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12935",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nAspergillus fumigatus\n; \nVerruconis gallopava\n; Whole-genome sequencing; invasive mold disease; solid organ transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D001232:Aspergillus fumigatus; D001706:Biopsy; D004271:DNA, Fungal; D017809:Fatal Outcome; D016027:Heart Transplantation; D006801:Humans; D000072742:Invasive Fungal Infections; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D004718:Saccharomycetales; D066027:Transplant Recipients; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12935",
"pmc": null,
"pmid": "29851203",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19624922;24803380;28053851;11565080;21955216;24559945;26250569;24726020;26496602;18710910;27638360;20070679;15065620;28120932;24847077;25232160;27812511;28270580",
"title": "Genomic characterization of recurrent mold infections in thoracic transplant recipients.",
"title_normalized": "genomic characterization of recurrent mold infections in thoracic transplant recipients"
} | [
{
"companynumb": "US-SA-2018SA302981",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Objectives: This study aimed to evaluate the efficacy of long-term weekly prophylactic heme arginate (HA) infusions in reducing attack frequency and severity in female AIP patients. Methods: We report the results of five female AIP patients with frequent recurrent attacks (>9/year) before and after institution of weekly prophylaxis with heme arginate (3 mg/kg body weight). All five cases had confirmed disease-associated mutations in the porphobilinogen deaminase gene, and all had received genetic and clinical counseling about AIP. Results: In the five included patients, average annual attack rate (AAR) in the year prior to HA prophylaxis was 11.82 (range 9.03-17.06), and average total HA usage was 32.60 doses (range: 13.71-53.13). After 2.58-14.64 years of HA prophylaxis, average AAR was reduced to 2.23 (range 0.00-5.58), and attack severity (i.e., doses required per attack) was reduced from 2.81 to 1.39 doses/attack. Liver and renal function remained stable during weekly administration of HA prophylaxis. The most common complications were port-A catheter-related events. No other complications or safety concerns occurred with long-term use of HA prophylaxis. Conclusion: Our study demonstrated women with AIP receiving weekly prophylactic HA infusions resulted in fewer episodes that required acute HA treatment while maintaining stable renal and liver function. Weekly prophylactic HA infusions effectively prevent frequent porphyric attacks and reduce attack severity.",
"affiliations": "Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Chang Gung Memorial Hospital and College of Medicine, Taoyuan, Taiwan.;Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.;Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.",
"authors": "Kuo|Hung-Chou|HC|;Lin|Chia-Ni|CN|;Tang|Yi-Fen|YF|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2021.712305",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812\nFrontiers Media S.A.\n\n712305\n10.3389/fphar.2021.712305\nPharmacology\nOriginal Research\nProphylactic Heme Arginate Infusion for Acute Intermittent Porphyria\nKuo et al.\nProphylaxis for Acute Intermittent Porphyria\nKuo Hung-Chou 1 *\n\nLin Chia-Ni 2 3\nTang Yi-Fen 4\n1 Department of Neurology, Chang Gung Memorial Hospital-Linkou Medical Center, Chang Gung Memorial Hospital and College of Medicine, Taoyuan, Taiwan\n2 Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan\n3 Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan\n4 Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan\nEdited by: Herbert Bonkovsky, Wake Forest Baptist Medical Center, United States\n\nReviewed by: Bruce Mao Zheng Wang, University of California, San Francisco, United States\n\nManish Thapar, Thomas Jefferson University, United States\n\n*Correspondence: Hung-Chou Kuo, kuo0426@adm.cgmh.org.tw\nThis article was submitted to Drugs Outcomes Research and Policies, a section of the journal Frontiers in Pharmacology\n\n06 10 2021\n2021\n12 71230505 6 2021\n24 9 2021\nCopyright © 2021 Kuo, Lin and Tang.\n2021\nKuo, Lin and Tang\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.\nObjectives: This study aimed to evaluate the efficacy of long-term weekly prophylactic heme arginate (HA) infusions in reducing attack frequency and severity in female AIP patients.\n\nMethods: We report the results of five female AIP patients with frequent recurrent attacks (>9/year) before and after institution of weekly prophylaxis with heme arginate (3 mg/kg body weight). All five cases had confirmed disease-associated mutations in the porphobilinogen deaminase gene, and all had received genetic and clinical counseling about AIP.\n\nResults: In the five included patients, average annual attack rate (AAR) in the year prior to HA prophylaxis was 11.82 (range 9.03–17.06), and average total HA usage was 32.60 doses (range: 13.71–53.13). After 2.58–14.64 years of HA prophylaxis, average AAR was reduced to 2.23 (range 0.00–5.58), and attack severity (i.e., doses required per attack) was reduced from 2.81 to 1.39 doses/attack. Liver and renal function remained stable during weekly administration of HA prophylaxis. The most common complications were port-A catheter-related events. No other complications or safety concerns occurred with long-term use of HA prophylaxis.\n\nConclusion: Our study demonstrated women with AIP receiving weekly prophylactic HA infusions resulted in fewer episodes that required acute HA treatment while maintaining stable renal and liver function. Weekly prophylactic HA infusions effectively prevent frequent porphyric attacks and reduce attack severity.\n\nmenopause\nporphyric attack\nannual attack rate\nheme arginate\nheme prophylaxis\nacute intermittent porphyria\nHealth Promotion Administration, Ministry of Health and Welfare 10.13039/100013227 KMRPB3J008\n==== Body\npmcIntroduction\n\nAcute intermittent porphyria (AIP) is an autosomal hereditary disease caused by dominant negative mutation in the porphobilinogen deaminase (PBGD) gene and resulting accumulation of potentially neurotoxic porphyrin precursors of heme biosynthesis. AIP patients experience periodic severe abdominal pain and sympathetic nervous system over-activity (e.g., hypertension, palpitation, tachycardia), often requiring emergency hospitalization. Other neurological symptoms may include delirium, seizures, motor paresis, and hysteria, often leading to a neuropsychiatric misdiagnosis and subsequent mistreatment (Jain et al., 2011). AIP attacks are more commonly observed in females after puberty, and sex hormones are considered to be a precipitating factor in disease onset. Cyclic acute AIP attacks in females are closely associated with the luteal phase of the menstrual cycle (Andersson et al., 2003; Pischik and Kauppinen, 2006). In some female patients, acute flares are predictable and recur regularly 7–10 days prior to menses every one or 2 months. Other triggers of AIP clinical symptoms include infection, fasting, and medications, although activating factors often remain unidentified (Siegesmund et al., 2010).\n\nTreatment of acute AIP attacks involves symptomatic treatment and suppression of hepatic rate-limiting enzymes of heme biosynthesis (i.e., 5-aminolevulinic acid synthase 1, or ALAS-1). Glucose, which inhibits ALAS1 by affecting peroxisome proliferator-activated receptor gamma coactivator1-alpha (Handschin et al., 2005), could be considered in situation of mild attacks. For severe acute attacks, intravenous heme is the most effective therapy as it provides exogenous heme and down-regulates ALAS1 transcription which in turn, results in a rapid reduction in the overproduction of ALA and PBG. Typically, acute porphyric attacks last no longer than 1–2 weeks and can be treated efficiently with 3–5 days of intravenous heme therapy. In Taiwan, intravenous heme therapy is only available in the form of heme arginate (HA), while hematin is available in the United States. HA has been recommended as the initial treatment for acute porphyric attacks because of its increased stability and safety over hematin (Mustajoki and Nordmann, 1993; Anderson, 2019).\n\nSevere AIP attacks can be frequent, potentially life-threatening, and lead to chronic deterioration in neurological, liver and kidney function, reducing patients’ quality of life as well as increasing financial burden (Neeleman et al., 2018). Recently, an exciting RNA interference (RNAi) therapy, givosiran, was FDA-approved for reducing the severity and frequency of porphyric attacks in acute hepatic porphyria (Balwani et al., 2020; Honor et al., 2021; Thapar et al., 2021). but its accessibility and pricing may remain limiting issues for use (Massachi et al., 2020; Thapar et al., 2021). Other prevention strategies for AIP attacks include hormone-suppression therapy (Anderson et al., 1990; Herrick et al., 1990; Kauppinen and Mustajoki, 1992), prophylactic heme therapy (Kauppinen, 2005; Yarra et al., 2019), and in extreme cases, liver transplantation (Soonawalla et al., 2004; Dowman et al., 2012; Balwani et al., 2017; Stein et al., 2017). Prophylactic administration of human heme could also be considered for childbearing age woman who experienced an acute porphyria flare during her first pregnancy and wish to conceive for second pregnancy (Vassiliou et al., 2020).\n\nRecurrent severe attacks affect about 3–8% of patients with acute porphyria (Schmitt et al., 2018), however, reports on the use of prophylactic HA therapy were limited. In our medical center, prophylactic HA therapy has been offered to carefully selected AIP patients, approximately 5% of AIP patients are receiving scheduled prophylactic HA infusion. This study aimed to demonstrate the safety and efficacy of long-term weekly prophylactic HA infusions in preventing frequent porphyric attacks in patients with AIP.\n\nMaterials and Methods\n\nStudy Design\n\nRetrospective review of medical records was conducted. The hospital historical records that were evaluated was from the first available record of each case patient to July 2020. Demographics, treatment history (since their initial presentation to the hospital), and clinical outcomes of interest were extracted from patients’ medical records in the emergency room, inpatient ward, and outpatient clinic.\n\nStudy Subjects\n\nFemale patients receiving weekly prophylactic HA (Normosang®, Orphan Europe) infusions at Chang Gung Memorial Hospital (CGMH), Linkou Medical Center, Taiwan, and who met the following criteria were included: 1) confirmed mutation in the PBGD gene and diagnosed with AIP; 2) Patients with frequent porphyric attacks, defined as having at least 9 attacks in the year prior and receiving more than one HA infusion for the attacks (The data for ALA and PBG level associated with reported attacks is presented in Supplementary Table S1); 3) received genetic counseling and were educated to avoid potential triggering factors of AIP acute attacks; and 4) had been receiving weekly infusions of HA (3 mg/kg body weight) prophylactically to prevent AIP attacks. Electrophysiological findings of the patients with neurologic porphyria have been reported in our prior studies (Kuo et al., 2011; Wu et al., 2015; Kuo et al., 2016; Lin et al., 2018).\n\nEthical Considerations\n\nThe study protocol was approved by the institutional review board of CGMH (202000914B0), and the study was conducted in accordance with the Declaration of Helsinki. Written informed consent of included patients was waived by the same committee because of the retrospective nature of the study, data analysis were performed using only the de-identified data.\n\nMain Outcome Measures\n\nThe main efficacy outcomes include the frequency and the severity of porphyric attacks. An acute attack is defined as an attack requiring hospitalization, urgent healthcare visits, and treatment with at least one heme arginate infusion. The frequency of attacks is defined as the annual rate of attacks (annualized attack rate, or AAR). Attack severity is represented by the number of heme infusions (equivalent to days of receiving heme therapy) during an attack, with HA administered at 3 mg/kg body weight/day. Safety evaluation included estimated glomerular filtration rate (eGFR), serum aspartate transaminase (AST) levels, serum alanine transaminase (ALT) levels, and renal and liver ultrasound findings. Thrombophlebitis, port A infection and replacement, and transferrin saturation index (% of serum iron related to TIBC) are included as complications associated with HA infusions.\n\nStatistical Analysis\n\nPatients’ demographic and clinical characteristics for the period before HA treatment were summarized for each patient. Changes in attack severity after initiating HA treatment, including number of attacks and AAR, total doses of HA required for attacks, and duration of treatment was also summarized for each patient. Treatment duration in years is represented as the total number of treatment days/365.25. Personal dose usage per year was calculated as total doses of HA used divided by duration, and AAR was calculated as total number of porphyric attacks divided by duration. Averages were calculated for the number of porphyric attacks, total doses of HA required for porphyric attacks, duration of treatment period, doses per year, and overall AAR for all five patients. All data were arranged and graphed using Microsoft Excel (Microsoft, Redmond, WA, United States).\n\nRole of the funding source: The funding agency had no role in study design, data collection and data analysis, decision to publish, or preparation of the manuscript.\n\nResults\n\nA total of five female patients who met the study criteria were included. Patient demographics, clinical characteristics and brief medical history are summarized in Table 1. ALA and PBG data for all 5 patients are summarized in Supplementary Table S1, biochemical elevation of ALA and PBG are evident. AARs for each patient individually and averages for overall patients are listed in Table 2. Average AARs decreased from 11.82 at 1 year prior to prophylaxis to 2.25 during/after prophylactic HA treatment. Reduced attack rates were sustained throughout the follow-up period (average 8.57 years) with continued use of weekly prophylactic HA infusions.\n\nTABLE 1 Selected demographic and clinical characteristics of AIP patients for period before heme arginate prophylaxis.\n\nCase No.\t#1\t#2\t#3\t#4\t#5\t\nSex\tF\tF\tF\tF\tF\t\nCurrent Age (years)\t51–55\t51–55\t21–25\t31–35\t51–55\t\nAge of onset (years)\t36\t33\t16\t20\t30\t\nPBGD gene mutation\tc.652G > A exon 11\tc.77G > A exon 2\tc.652G > A exon 11\tc.33+5G > A at IVS1\tc.973C> T exon 14\t\nPredicted change in protein\tp. Gly218Arg\tp. Arg26His\tp. Gly218Arg\tSplicing aberration\tp. Arg325X\t\nNeurological manifestations except for visceral symptoms before diagnosis, CNS\tNone\tneuropsychologic symptoms\tNone\tConvulsion and resulted in rhabdomyolysis\tConscious impairment\t\nNeurological manifestations except for visceral symptoms before diagnosis, PNS\tNone\tSensorimotor polyneuropathy\tNone\tNone\tMotor paresis, severe neuralgia, dysarthria\t\nClinical characteristics\t\n Severity of disease ((1-year prior to prophylaxis)\t9 attacks, total of 25 hemin doses\t13 attacks, total of 56 hemin doses\t17 attacks, total of 30 hemin doses\t10 attacks, total of 33 hemin doses\t10 attacks, total of 19 hemin doses\t\n eGFR prior to prophylaxis, (ml/min/1.73m2)\t65.6\t24\t144\t74.4\t16\t\n ALT prior to prophylaxis, (U/L)\t27\t18\t20\t24\t27\t\n AST prior to prophylaxis, (U/L)\t27\t25\t20\t33\t28\t\n Years of receiving weekly prophylaxis (Year of initiation)\t14.64 (2005 Nov)\t7.34 (2013 Feb)\t4.36 (2014 Jan–2018 Jun a )\t13.91 (2006 Aug)\t2.58 (2017 Nov)\t\na Case #3 was recruited to a phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria (ENVISION trial), discontinued heme arginate prophylactic treatment during 2018 June. AIP, acute intermittent porphyria; CNS, central nervous system; PNS, peripheral nervous system.\n\nTABLE 2 Summary of changes in attack severity after initiating heme arginate prophylactic treatment.\n\n\tHA for acute attack 1-year before prophylactic treatment\tHA prophylactic treatment from initiation to menopause\tHA prophylactic treatment from menopause to present (2020 June)\tHA prophylactic treatment from initiation to present (2020 June)\t\nCase #\tAttacks (n)\tHA use (dose)\tDoses/year\tAAR b\tDuration a (years)\tAttacks (n)\tHA use (dose)\tDoses/year\tAAR b\tDuration a (years)\tAttacks (n)\tHA use (dose)\tDoses/year\tAAR b\tDuration a (years)\tAttacks (n)\tHA use (dose)\tDoses/year\tAAR b\t\n#1\t9\t25\t13.71\t9.03\t11.64\t26\t40\t3.44\t2.23\t3.00\t5\t2\t0.67\t1.67\t14.64\t31\t42\t2.87\t2.12\t\n#2\t13\t56\t53.13\t13.01\t5.59\t40\t119\t21.27\t7.15\t1.75\t1\t3\t1.71\t0.57\t7.34\t41\t122\t16.61\t5.58\t\n#3\t17\t30\t25.25\t17.06\t—\t—\t—\t—\t—\t—\t—\t—\t—\t—\t4.36 d\t7 d\t9 d\t2.07 d\t1.61 d\t\n#4\t10\t33\t33.11\t10.03\t—\t—\t—\t—\t—\t—\t—\t—\t—\t—\t13.91\t27\t36\t2.59\t1.94\t\n#5\t10\t19\t19.12\t10.06\t—\t—\t—\t—\t—\t3.58 c\t10 c\t19 c\t5.30 c\t2.79 c\t2.58\t0\t0\t0.00\t0.00\t\nAverage\t11.8\t32.6\t32.60\t11.82\t9.22\t33.0\t79.5\t12.36\t4.7\t2.78\t5.3\t8.0\t2.56\t1.7\t8.57\t21.2\t41.8\t4.83\t2.25\t\na Duration, total number of days receiving treatment/365.25.\n\nb AAR, annualized attack rate (=total number of porphyria attacks/duration).\n\nc For case #5, duration, attacks, and doses of heme arginate given for porphyric attacks after menopause to starting observation 1-year for frequent and severe attack were not included.\n\nd For Case #3, duration was set as date of starting heme arginate prophylactic treatment until date of screening for the clinical trial (2018/Jun./8).\n\nTime Course Description of Treatments Prior to Prophylaxis\n\nTime course descriptions of individual cases are illustrated in Figures 1, 2; Supplementary Figures S1–S3). To illustrate the safety and efficacy of HA prophylaxis, two cases (#3 and #5) are described in detail below (Figures 1, 2).\n\nFIGURE 1 The tracked information of AIP severity, adverse events, kidney and liver function for patient #3. AIP severity is identified by numbers of attacks and total heme arginate doses for porphyric attacks treated. Black dots indicate the most severe attack in the past, which was treated using heme arginate. Red dots indicate AIP severity status within 1-year before receiving prophylactic heme arginate. A dotted frame marks the initiation date of initial prophylactic heme arginate infusion. Port A insertion and adverse events of heme arginate infusion are shown as red triangle with given examined date, Port A-related infection is shown as a green oval. Serum ferritin is indicated as yellow square. Transferrin saturation index (% of serum iron relative to TIBC) is shown as blue triangle. Kidney function is recorded as eGFR level, and sizes of left (L) and right (R) side of kidney along with examined date. Liver function is recorded as ALT and AST levels, and parenchymal liver disease score along with examined date.\n\nFIGURE 2 The tracked information of AIP severity, adverse events, kidney and liver function for patient #5. AIP severity is identified by numbers of attacks and total heme arginate doses for porphyric attacks treated. Black dots indicate the most severe attack in the past, which was treated using heme arginate. Red dots indicate AIP severity status within 1-year before receiving prophylactic heme arginate. A dotted frame marks the initiation date of initial prophylactic heme arginate infusion. Port A insertion and adverse events of heme arginate infusion are shown as red triangle with given examined date, Port A-related infection is shown as a green oval. Serum ferritin is indicated as yellow square. Transferrin saturation index (% of serum iron relative to TIBC) is shown as blue triangle. Kidney function is recorded as eGFR level, and sizes of left (L) and right (R) side of kidney along with examined date. Liver function is recorded as ALT and AST levels, and parenchymal liver disease score along with examined date.\n\n(Case #3) A 21–25-year-old female with disease onset in 2011 at age 16 years, initially presented with persistent sharp pain at the sacral region accompanied by postprandial vomiting and epigastric pain radiating to the back. Hepatic porphyria was suspected due to her AIP family history (daughter of patient 1), and AIP was confirmed after measuring relevant enzyme activity and undergoing genetic testing 3 weeks later. After experiencing 17 recurrent attacks requiring 30 doses of HA treatment within 1 year between 2013 and 2014, weekly prophylactic HA was initiated in January 29, 2014 (Figure 1).\n\n(Case #5) A 51–55-year-old female was first admitted to CGMH in 2005 for intermittent lower abdominal pain, lethargy, general malaise and pricking pain for 1 month. She was first diagnosed with AIP at age 38 and has been receiving HA treatment for porphyric attacks since. Her first severe acute attack occurred in 2005 and she was hospitalized for 14 doses of HA treatment (Figure 2). Frequent attacks persisted during menopause (2015), and AARs were similar before and during the first year of menopause (6.04 and 6.46, respectively) (Supplementary Table S2). In 2017, her AAR was 10.06 and both the frequency (10 attacks, 19 HA doses in total) and duration of each attack increased, requiring HA for consecutive days. The patient was hospitalized for 8 days in November 2017. The treating physician recommended prophylactic HA treatment and regular weekly infusions began in December 2017, lasting until now (Figure 2).\n\nProphylactic Treatment\n\n(Case #3) HA prophylaxis reduced AAR in this patient from 17.06 before prophylaxis to 1.61 afterwards, and annual HA doses decreased from 25.25 to 2.07 doses/year (Table 2). Her kidney function by eGFR was good at disease onset and remained relatively normal over 4.36 years HA prophylactic course (Figure 1; Supplementary Table S3). Aminotransferase levels were higher than the upper limit at disease onset in 2011, but returned to normal from 2012 to date (Figure 1; Supplementary Table S3). Her first port-A was inserted in 2011 for HA treatment, and was replaced twice in 2015 and 2017 due to infections (Figure 1). On June 13, 2018, this patient was recruited to participate in a Phase 3 clinical trial (ENVISION trial of givosiran), and consequently discontinued HA prophylaxis (see discontinuance protocol below).\n\n(Case #5) Prophylactic HA treatment effectively prevented porphyric attacks in this patient. No episodes of porphyric attacks occurred after initiation of HA prophylaxis in 2018. AAR was reduced from 10.06 to 0.00, and was sustained throughout 2.58 years of follow-up (Table 2). Renal and kidney function remained stable after HA prophylaxis (Supplementary Tables S3, S4). She received Port-A-cath insertion for HA infusions in 2012 and one Port A replacement was done in 2018. There was an incidence of secondary iron overload, however no signs of end-organ effects were observed after clinical investigation. No other adverse events or infection occurred during the follow-up period (Figure 2).\n\nProphylaxis Discontinuation\n\n(Case #3) Upon discontinuing HA prophylaxis to participate in a Phase 3 clinical trial for givosiran, this patient was subjected to a 4-week washout period and randomized double-blinded treatment (placebo) for 24 weeks according to the trial protocol (Balwani et al., 2020). During this time, the patient had 18 attacks requiring 30 HA doses (Figure 1). Per trial protocol, an open-label treatment period succeeded the randomized treatment phase, and the patient received givosiran from Jan 16, 2019 to her most recent mid-2020 visit (Figure 1). The clinical results of the trial open-label period are summarized in Figure 1, Supplementary Table S5. In short, 13 porphyric attacks occurred during the open-label period, and only 13 doses of HA were required.\n\nDiscussion\n\nAcute porphyric attacks of AIP are devastating, disruptive, and can lead to long-term complications that reduce patients’ quality of life. In the present study, prophylactic HA infusions given regularly and managed properly provided substantial and long-term clinical benefit to carefully-selected patients. Both the frequency and the severity of porphyric attacks were reduced by prophylactic HA infusions. The safety of HA prophylaxis was demonstrated through the absence of complications and the stability of organ function throughout long-term treatment. Common complications during the course of treatment were venous access issues (infection, thrombosis) that were managed easily. Patients’ liver and kidney function remained stable throughout 2.6–14.6 years of prophylactic HA therapy and no patients developed end-stage renal disease, liver failure or hepatocellular carcinoma. In two patients (cases 1 and 2; Supplementary Figures S3, S4), the frequency and severity of porphyric attacks by prophylactic HA was further reduced during and after menopause, showing that prophylactic HA therapy is effective in both pre- and postmenopausal women.\n\nAn audit of prophylactic heme use in England reported that patients had a median of 12 acute attacks requiring hospital admission prior to initiation of heme prophylaxis (Marsden et al., 2015). However, the candidate selection criteria for prophylactic hematin or HA therapy vary between 3-6 attacks per year in previous studies and are determined by clinician discretion. A 40-year retrospective review of a medical records database in the Netherlands indicated that prophylactic heme therapy was initiated in recurrent patients having more than 4 porphyric attacks per year (Neeleman et al., 2018). A recent prospective case series enrolled patients who had at least 3 acute porphyric attacks within the year prior to prophylactic heme treatment (Yarra et al., 2019). A review advised physicians to consider prophylactic heme therapy for recurrent patients with more than 4 attacks per year or female patients with menstrual-associated cyclic attacks (Balwani et al., 2017). In the present study, scheduled prophylactic HA doses was considered for female AIP patients with at least 9 acute attacks in the year prior. This was because we wanted to focus on patients with true refractory and menstrual cycle-related acute attacks, and whose frequent admission to hospital have significantly disrupt home-life, and work (more than 9 porphyric attacks in the year prior is roughly one hospitalization every 1.5 months on average). We trust that our candidate survey and selection mechanism helped to facilitate the satisfactory outcomes reported herein.\n\nResults of the present study demonstrated that HA prophylaxis reduced AAR and the need for acute HA therapy by 50–100%. While there has been one study which reported use of heme arginate increased the frequency of recurrent porphyric attacks (Schmitt et al., 2018), effectiveness were reported by other authors. Marsden et al. (2015) observed a range of 0–75 heme doses for acute porphyric attacks in 22 patients with AIP before prophylactic heme treatment, which decreased to 0–20 during HA prophylaxis (Marsden et al., 2015). AIP patients receiving prophylactic heme therapy in a real-world study using the MarketScan claims database had significantly lower AAR and attack duration than those receiving acute HA treatments only (Blaylock et al., 2020). Another case series reported decreases of 75–100% in acute attacks and inpatient admissions during an 11-month weekly prophylactic heme infusion treatment (Yarra et al., 2019). The present study is in support of the view that HA prophylaxis effectively prevent frequent porphyric attacks and reduce attack severity.\n\nVenous access devices represent an area of concern for regular heme infusions. In a small patient cohort undergoing prophylactic heme regimens for porphyria, the median number of venous access devices used per patient was 2 (range: 1–15 devices over 1–150 months) with mean life-span 1.2 years per device (Marsden et al., 2015). A separate study involving 11 AIP patients with recurrent attacks found that 73% required placement of Port-A catheters to secure venous access, but this was not an absolute limitation for heme therapy (Neeleman et al., 2018). The multinational study EXPLORE demonstrated that of 50% of patients received prophylactic heme, 40% received central venous catheter placement (Gouya et al., 2020); of these, 3 and 4% experienced infectious and thrombotic events, respectively, associated with the central venous catheter. In the present study, Port-A Catheters were placed in all 5 patients, and related infection and thrombosis involved port-A catheter replacement. One patient received 11 port-A catheters over a course of 8 years (Supplementary Figure S4), showing that while venous access-related complications do occur, they are manageable and tolerable.\n\nPuberty, the luteal phase, and hormone replacement are well-recognized precipitating factors for acute porphyric attacks (Andersson et al., 2003; Balwani et al., 2017). and affected patients may either recover spontaneously or enter remission during menopause. A population-based study investigating AIP in women in Sweden found that 50% of women reported reduced symptoms after menopause (Andersson et al., 2003; Balwani et al., 2017). In another Swedish population-based study, 7% of women still experienced post-menopausal attacks (Bylesjo et al., 2009). These findings resonate with the effectiveness of gonadorelin (GnRH) prophylaxis in preventing AIP, for which an audit reported that in 50% of patients (11/22) who considered the treatment ineffective and intolerable, the main complaint was estrogen deficiency (Schulenburg-Brand et al., 2017). In contrast, AAR decreased in almost all patients (19/22) in a UK audit of prophylactic heme therapy, and three patients were being weaned off the drug during remission (Marsden et al., 2015). While 68% (15/22) of patients who received prophylactic heme in the UK audit had tried GnRH previously but discontinued it due to ineffectiveness and adverse events, only one patient (4.5%) in the study of Schulenburg-Brand et al. (2017) found the prophylactic hemin regimen unsatisfactory (Schulenburg-Brand et al., 2017). In the present study, case #5 continued to experience frequent attacks after menopause, and was later treated successfully with prophylactic HA; notably, two other patients (cases 1 and 2) who continued prophylactic HA treatment after menopause experienced reduced attack frequency and severity, suggesting that prophylactic HA may have greater clinical potential in preventing porphyric attacks than GnRH therapy.\n\nThe recently approved ALAS-1 RNAi strategy has shown promise, reducing up to 74% of acute attacks in a phase III placebo-controlled trial (Balwani et al., 2020). The adverse events associated with ALAS-1 RNAi include elevation of serum aminotransferase levels, changes in serum creatinine and eGFR suggesting kidney function issues, and injection-site reactions (Balwani et al., 2020). More recently, there have been rare instances concerning severe adverse events including pancreatitis, and homocysteinemia in givosiran-treated porphyria patients (Ventura et al., 2020). A recent study by To-Figueras et al. (2021) showed that while dysregulation of homocysteine homeostasis was also observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation. Incidences of secondary iron overload occurred during prophylactic HA treatment in our patients, however, there were only subjective complaints of skin pigmentation from young AIP patients, and no other remarkable end-organ effects of secondary iron overload were noted. In the present study, comparable reductions in AAR were observed in a single patient (case #3) who participated in a clinical trial of givosiran and no remarkable changes were noted in liver and kidney function, no severe adverse event was reported during prophylactic HA treatment nor givosiran treatment period.\n\nThe financial burden of treatment for patients with AIP has been the focus of several recent studies (Gouya et al., 2018; Blaylock et al., 2020; Massachi et al., 2020). While FDA-approved givosiran has been shown to reduce the severity and frequency of porphyric attacks in acute hepatic porphyria (Balwani et al., 2020), hemin was found to be the less costly option compared to givosiran for AIP patients due accessibility and current cost for use (Massachi et al., 2020). Based on the published study by Massachi et al., 2020, the total cost of care with hemin for patients with single/multiple attacks per year, and hemin prophylaxis was between 46 and 92% lower compared to givosiran treatment in (Massachi et al., 2020). The information provided in their study may help inform economic decision making. Note however, the cost of complications, side effects, adverse events for either treatments were not accounted for. In addition, the indirect burden on time and travel required to receive weekly HA prophylaxis were also not considered.\n\nThis study has a few limitations, including its retrospective nature and small sample size. Not all patients were followed to post-menopausal status and one patient experienced discontinuance of the prophylactic HA infusions. We acknowledge the potential increase in the elimination half-life of heme arginate after repeated infusion, and for this reason weekly prophylactic HA infusions is not a current standard protocol for the frequent and repetitive menstrual cycle-associated porphyric attacks in AIP patients. Prospective evaluation of a larger number of patients with AIP receiving prophylactic HA therapy is needed to confirm results of the present study and add further insight into the potential for preventing porphyric attacks in pre- and post-menopausal women.\n\nConclusion\n\nRegular weekly HA infusions demonstrate long-term clinical benefits in reducing the severity and frequency of porphyric attacks in women with AIP. Patients had fewer episodes that required healthcare visits or acute HA treatment and had stable renal and liver function during the follow up period. HA prophylaxis provides a safe and effective strategy for managing patients with AIP.\n\nThe author wish to thank the patients who participated in this study.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by institutional review board of Chang Gung Memorial Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\n\nH-CK contributed to study design, data acquisition, data analysis and interpretation, and writing the manuscript. C-NL and Y-FT contributed to data acquisition and data analysis.\n\nFunding\n\nThis research was supported in part by grant from the Health Promotion Administration, Ministry of Health and Welfare, Taiwan (2019 Rare Disease Control Program: KMRPB3J008).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2021.712305/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\nAnderson K. E. (2019). Acute hepatic porphyrias: Current diagnosis & management. Mol. Genet. Metab. 128 , 219–227. 10.1016/j.ymgme.2019.07.002 31311713\nAnderson K. E. Spitz I. M. Bardin C. W. Kappas A. (1990). A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria. Arch. Intern. Med. 150 , 1469–1474. 10.1001/archinte.1990.00390190115018 2196028\nAndersson C. Innala E. Bäckström T. (2003). Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J. Intern. Med. 254 , 176–183. 10.1046/j.1365-2796.2003.01172.x 12859699\nBalwani M. Sardh E. Ventura P. Peiró P. A. Rees D. C. Stölzel U. (2020). Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N. Engl. J. Med. 382 , 2289–2301. 10.1056/NEJMoa1913147 32521132\nBalwani M. Wang B. Anderson K. E. Bloomer J. R. Bissell D. M. Bonkovsky H. L. (2017). Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology 66 , 1314–1322. 10.1002/hep.29313 28605040\nBlaylock B. Epstein J. Stickler P. (2020). Real-world annualized healthcare utilization and expenditures among insured US patients with acute intermittent porphyria (AIP) treated with hemin. J. Med. Econ. 23 , 537–545. 10.1080/13696998.2020.1724118 31999204\nBylesjö I. Wikberg A. Andersson C. (2009). Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. Scand. J. Clin. Lab. Invest. 69 , 612–618. 10.1080/00365510902935979 19401933\nDowman J. K. Gunson B. K. Mirza D. F. Bramhall S. R. Badminton M. N. Newsome P. N. (2012). Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis. Liver Transpl. 18 , 195–200. 10.1002/lt.22345 21618697\nGouya L. Ventura P. Balwani M. Bissell D. M. Rees D. C. Stölzel U. (2020). EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks. Hepatology 71 , 1546–1558. 10.1002/hep.30936 31512765\nGouya L. Bloomer J. Balwani M. Bissell D. Rees D. Stölzel U. (2018). An analysis of healthcare utilization and costs associated with patients with acute hepatic porphyrias (AHPS) with recurrent attacks in explore: a prospective, multinational natural history study of patients with ahp. Value in Health 21 , S125. 10.1016/j.jval.2018.04.856\nHandschin C. Lin J. Rhee J. Peyer A. K. Chin S. Wu P. H. (2005). Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell 122 , 505–515. 10.1016/j.cell.2005.06.040 16122419\nHerrick A. L. McColl K. E. Wallace A. M. Moore M. R. Goldberg A. (1990). LHRH analogue treatment for the prevention of premenstrual attacks of acute porphyria. Q. J. Med. 75 , 355–363. 10.1093/oxfordjournals.qjmed.a068444 2117297\nHonor A. Rudnick S. R. Bonkovsky H. L. (2021). Givosiran to treat acute porphyria. Drugs Today (Barc) 57 , 47–59. 10.1358/dot.2021.57.1.3230207 33594389\nJain G. Bennett J. I. Resch D. S. Godwin J. E. (2011). Schizoaffective disorder with missed diagnosis of acute porphyria: a case report and overview. Prim. Care Companion CNS Disord. 13 , 11br01234. 10.4088/PCC.11br01234\nKauppinen R. Mustajoki P. (1992). Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore) 71 , 1–13. 10.1097/00005792-199201000-00001 1549056\nKauppinen R. (2005). Porphyrias. The Lancet 365 , 241–252. 10.1016/S0140-6736(05)17744-710.1016/s0140-6736(05)70154-9\nKuo H. C. Huang C. C. Chu C. C. Lee M. J. Chuang W. L. Wu C. L. (2011). Neurological complications of acute intermittent porphyria. Eur. Neurol. 66 , 247–252. 10.1159/000330683 21986212\nKuo H. C. Ro L. S. Jung S. M. Huang C. C. Chu C. C. (2016). Porphyric neuropathies in an acute intermittent porphyria family. Neuropathology 36 , 290–294. 10.1111/neup.12272 26582343\nLin C. N. Huang Y. C. Ro L. S. Liao M. F. Ning H. C. Kuo H. C. (2018). Validation and evaluation of two porphobilinogen deaminase activity assays for diagnosis of acute intermittent porphyria. Clin. Chim. Acta 479 , 1–6. 10.1016/j.cca.2018.01.009 29317194\nMarsden J. T. Guppy S. Stein P. Cox T. M. Badminton M. Gardiner T. (2015). Audit of the Use of Regular Haem Arginate Infusions in Patients with Acute Porphyria to Prevent Recurrent Symptoms. JIMD Rep. 22 , 57–65. 10.1007/8904_2015_411 25762493\nMassachi S. Epstein J. Hurd J. Bonkovsky H. L. (2020). Cost savings with hemin versus givosiran for the treatment of patients with acute intermittent porphyria (AIP). J. Med. Econ. 23 , 1–9. 10.1080/13696998.2020.1835306 31589081\nMustajoki P. Nordmann Y. (1993). Early administration of heme arginate for acute porphyric attacks. Arch. Intern. Med. 153 , 2004–2008. 10.1001/archinte.1993.00410170078008 8357285\nNeeleman R. A. Wagenmakers M. A. E. M. Koole-Lesuis R. H. Mijnhout G. S. Wilson J. H. P. Friesema E. C. H. (2018). Medical and financial burden of acute intermittent porphyria. J. Inherit. Metab. Dis. 41 , 809–817. 10.1007/s10545-018-0178-z 29675607\nPischik E. Kauppinen R. (2006). Can pregnancy stop cyclical attacks of porphyria. Am. J. Med. 119 , 88–90. 10.1016/j.amjmed.2005.08.032 16431203\nSchmitt C. Lenglet H. Yu A. Delaby C. Benecke A. Lefebvre T. (2018). Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver. J. Intern. Med. 284 , 78–91. 10.1111/joim.12750 29498764\nSchulenburg-Brand D. Gardiner T. Guppy S. Rees D. C. Stein P. Barth J. (2017). An Audit of the Use of Gonadorelin Analogues to Prevent Recurrent Acute Symptoms in Patients with Acute Porphyria in the United Kingdom. JIMD Rep. 36 , 99–107. 10.1007/8904_2017_2 28220410\nSiegesmund M. van Tuyll van Serooskerken A. M. Poblete-Gutiérrez P. Frank J. (2010). The acute hepatic porphyrias: current status and future challenges. Best Pract. Res. Clin. Gastroenterol. 24 , 593–605. 10.1016/j.bpg.2010.08.010 20955962\nSoonawalla Z. F. Orug T. Badminton M. N. Elder G. H. Rhodes J. M. Bramhall S. R. (2004). Liver transplantation as a cure for acute intermittent porphyria. Lancet 363 , 705–706. 10.1016/S0140-6736(04)15646-8 15001330\nStein P. E. Badminton M. N. Rees D. C. (2017). Update review of the acute porphyrias. Br. J. Haematol. 176 , 527–538. 10.1111/bjh.14459 27982422\nThapar M. Rudnick S. Bonkovsky H. L. (2021). Givosiran, a novel treatment for acute hepatic porphyrias. Expert Rev. Precision Med. Drug Dev. 6 , 9–18. 10.1080/23808993.2021.1838275\nTo-Figueras J. Wijngaard R. García-Villoria J. Aarsand A. K. Aguilera P. Deulofeu R. (2021). Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran. J. Inherit. Metab. Dis. 44 , 961–971. 10.1002/jimd.12391 33861472\nVassiliou D. Lempessi C. Harper P. Sardh E. (2020). Challenges in the management of acute intermittent porphyria with recurrent attacks during pregnancy: A case report. Clin. Case Rep. 8 , 2483–2487. 10.1002/ccr3.3185 33363763\nVentura P. Corradini E. Di Pierro E. Marchini S. Marcacci M. Cuoghi C. (2020). Hyperhomocysteinemia in patients with acute porphyrias: A potentially dangerous metabolic crossroad. Eur. J. Intern. Med. 79 , 101–107. 10.1016/j.ejim.2020.04.002 32487371\nWu C. L. Ro L. S. Jung S. M. Tsai T. C. Chu C. C. Lyu R. K. (2015). Clinical presentation and electrophysiological findings of porphyric neuropathies: a follow-up study. Muscle Nerve 51 , 363–369. 10.1002/mus.24327 24985076\nYarra P. Faust D. Bennett M. Rudnick S. Bonkovsky H. L. (2019). Benefits of prophylactic heme therapy in severe acute intermittent porphyria. Mol. Genet. Metab. Rep. 19 , 100450. 10.1016/j.ymgmr.2019.01.002 30733921\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "12()",
"journal": "Frontiers in pharmacology",
"keywords": "acute intermittent porphyria; annual attack rate; heme arginate; heme prophylaxis; menopause; porphyric attack",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "712305",
"pmc": null,
"pmid": "34690757",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "29675607;20955962;16431203;33043761;31512765;31999204;30733921;28220410;15652607;2196028;29317194;15001330;24985076;33363763;27982422;12859699;1549056;8357285;25762493;2117297;32521132;32487371;19401933;33594389;31311713;26582343;21618697;16122419;22454794;28605040;33861472;21986212;29498764",
"title": "Prophylactic Heme Arginate Infusion for Acute Intermittent Porphyria.",
"title_normalized": "prophylactic heme arginate infusion for acute intermittent porphyria"
} | [
{
"companynumb": "TW-SAMOHPHARM-2021004666",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "HEME"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo report the first histopathologic description of optic nerve demyelination from tacrolimus (FK 506) toxicity in the absence of toxic levels of tacrolimus in a patient presenting with asymmetric bilateral visual loss after 5 years of tacrolimus therapy.\n\n\nMETHODS\nWe report a patient status post cardiac and renal transplantation who developed severe, progressive and asynchronous bilateral visual loss after prolonged treatment with tacrolimus. Orbital MRI showed an enlarged left optic nerve that enhanced with gadolinium.\n\n\nCONCLUSIONS\nAfter extensive negative work up, biopsy of one optic nerve was performed. Microscopic analysis showed extensive demyelination in the absence of vasculitis, neoplastic or infectious etiologies. Our patient illustrates that demyelination of the optic nerve causing asynchronous vision loss can be associated with tacrolimus toxicity in the absence of toxic drug levels.",
"affiliations": "Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.",
"authors": "Venneti|Sriram|S|;Moss|Heather E|HE|;Levin|Marc H|MH|;Vagefi|M Reza|MR|;Brozena|Susan C|SC|;Pruitt|Amy A|AA|;Mourelatos|Zissimos|Z|;Trojanowski|John Q|JQ|;Galetta|Steven L|SL|;Balcer|Laura J|LJ|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jns.2010.10.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-510X",
"issue": "301(1-2)",
"journal": "Journal of the neurological sciences",
"keywords": null,
"medline_ta": "J Neurol Sci",
"mesh_terms": "D001706:Biopsy; D003711:Demyelinating Diseases; D048909:Diabetes Complications; D018450:Disease Progression; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009900:Optic Nerve; D009901:Optic Nerve Diseases; D011183:Postoperative Complications; D012307:Risk Factors; D016559:Tacrolimus; D014792:Visual Acuity",
"nlm_unique_id": "0375403",
"other_id": null,
"pages": "112-5",
"pmc": null,
"pmid": "21112060",
"pubdate": "2011-02-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Asymmetric bilateral demyelinating optic neuropathy from tacrolimus toxicity.",
"title_normalized": "asymmetric bilateral demyelinating optic neuropathy from tacrolimus toxicity"
} | [
{
"companynumb": "US-PFIZER INC-2018079372",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nWhen treated for childhood cancers, at least 50% of children exposed to platinum agents have permanent hearing loss. We determined the relative risk of childhood hearing loss after in utero exposure to platinum chemotherapy in our registry cohort.\n\n\nMETHODS\nAfter exposure to platinum chemotherapy in utero, all children undergo routine newborn hearing screening. This consists of Otoacoustic Emissions. Children who failed this screen were evaluated by audiologists. For those children with hearing loss by Automated Auditory Brainstem Response, prenatal and postnatal treatment details were compared to platinum exposed children without hearing loss.\n\n\nRESULTS\nThree hundred and seven children were exposed to chemotherapy in utero. Four children were diagnosed with hearing loss, all exposed to platinum agents. Chemotherapy exposures included: Cisplatin/Paclitaxel (2), Etoposide/Cisplatin/Bleomycin (1), Carboplatin/Paclitaxel (1) to treat ovarian (2), or cervical cancer (2). Of the 39 platinum exposed without hearing loss: 11 children were exposed to oxaliplatin, 16 were exposed to cisplatin and 12 to carboplatin in utero. Two hundred and sixty four women received non-platinum based chemotherapy for various cancers during pregnancy. Among these, there were no cases of hearing loss. There was a significant difference in hearing loss based on exposure to platinum agents in utero compared to non-platinum-containing chemotherapy regimens, 4/43 versus 0/264, p = 0.0003. There were no statistical differences in prenatal and postnatal treatment details, including: gestational age at diagnosis, at first chemotherapy treatment, at first platinum treatment, at delivery (<32 weeks, <35 weeks, <37 weeks), gender, birthweight, birthweight percentile, rates of intrauterine growth restriction, neonatal complications or use of postnatal antibiotics between the platinum exposed children with and without hearing loss.\n\n\nCONCLUSIONS\nThe only children in the registry exposed to chemotherapy who were diagnosed with hearing loss had been exposed to cisplatin or carboplatin in utero. No hearing loss occurred in children exposed to oxaliplatin, or non-platinum agents. Due to a concern for cisplatin ototoxicity, carboplatin is the preferred platinum agent for use in pregnancy when equivalent maternal survival can be expected for the particular cancer type. For newborns exposed to platinum agents in utero, newborn screening with an auditory emissions test at birth (OES) may not detect sensorineural hearing loss and auditory brainstem response testing is recommended, regardless of the newborn screening result.",
"affiliations": "Cooper Medical School of Rowan University, Camden, New Jersey, USA.;Maternal Fetal Medicine Department, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey, USA.",
"authors": "Finch|Lauren E|LE|https://orcid.org/0000-0001-9723-5313;Cardonick|Elyce H|EH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/pd.6035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0197-3851",
"issue": "41(11)",
"journal": "Prenatal diagnosis",
"keywords": null,
"medline_ta": "Prenat Diagn",
"mesh_terms": null,
"nlm_unique_id": "8106540",
"other_id": null,
"pages": "1467-1474",
"pmc": null,
"pmid": "34462927",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence of childhood hearing loss after in utero exposure to platinum agents.",
"title_normalized": "incidence of childhood hearing loss after in utero exposure to platinum agents"
} | [
{
"companynumb": "US-PFIZER INC-2019036439",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Background: There is no clear consensus regarding the potential of denosumab for increasing the risk of infection in patients who concurrently receive biologic disease-modifying anti-rheumatic drugs (bDMARDs). In this study, we compared the rate of infection in postmenopausal women with rheumatoid arthritis who received concurrent bDMARDs and denosumab with those who received bDMARDs alone. Methods: In a case-control study, postmenopausal patients with a confirmed diagnosis of rheumatoid arthritis who received concurrent bDMARDs and denosumab for at least one year were identified and included as the case group (n=40). A total of 44 age-matched postmenopausal rheumatoid arthritis women who received bDMARDs alone were included as the control group of the study. Using a chi-squared test, the incidence of bacterial or viral infections was extracted from the patients' profiles and compared between the two study groups. Statistical analyses were performed by SPSS for Windows, version 16 (Chicago, Illinois, USA). A p-value of fewer than 0.05 was regarded as significant. Results: The clinical and demographic characteristics of the patients of the two study groups were not significantly different. In total, four infections were recorded in the present series, two infections in each group. Accordingly, the rate of infection was 4.5% in the bDMARDs alone group and 5% in bDMARDs + denosumab group. This difference was not statistically significant (p=0.655, 95% CI: 0.121-6.742). Three out of four infections were herpes zoster infection. The other one was osteomyelitis of the first metatarsal bone, which occurred in the bDMARDs+denosumab group. None of the infections needed a hospitalization of IV antibiotics. Conclusion: The risk of infection is comparable between postmenopausal osteoporotic women with rheumatoid arthritis who receive bDMARDS alone and those who receive bDMARDS in combination with denosumab.",
"affiliations": "Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran.;Diabetes Advisory Committee, Gabric Diabetes Education Association, Tehran, Iran.;Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of medical sciences, Tehran, Iran.;Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran.",
"authors": "Mirzaei|Alireza|A|;Jahed|Seyed Adel|SA|;Amini Kadijani|Azade|A|;Zabihiyeganeh|Mozhdeh|M|https://orcid.org/0000-0003-4505-4929",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.47176/mjiri.35.12",
"fulltext": "\n==== Front\nMed J Islam Repub Iran\nMed J Islam Repub Iran\nMed J Islam Repub Iran\nMJIRI\nMedical Journal of the Islamic Republic of Iran\n1016-1430\n2251-6840\nIran University of Medical Sciences\n\n10.47176/mjiri.35.12\nOriginal Article\nRisk of infection in postmenopausal women with rheumatoid arthritis and osteoporosis taking denosumab and bDMARDS\nMirzaei Alireza 1\nJahed Seyed Adel 2\nAmini Kadijani Azade 3\nhttps://orcid.org/0000-0003-4505-4929\nZabihiyeganeh Mozhdeh 1 *\n1Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran\n2Diabetes Advisory Committee, Gabric Diabetes Education Association, Tehran, Iran\n3Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of medical sciences, Tehran, Iran\n* Corresponding author: Dr Mozhdeh Zabihiyeganeh, zabihiyeganeh.m@iums.ac.ir\n2021\n21 1 2021\n35 1212\n04 3 2020\n© 2021 Iran University of Medical Sciences\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/1.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial-ShareAlike 1.0 License (CC BY-NC-SA 1.0), which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.\nhttp://mjiri.iums.ac.ir\nBackground: There is no clear consensus regarding the potential of denosumab for increasing the risk of infection in patients who concurrently receive biologic disease-modifying anti-rheumatic drugs (bDMARDs). In this study, we compared the rate of infection in postmenopausal women with rheumatoid arthritis who received concurrent bDMARDs and denosumab with those who received bDMARDs alone.\n\nMethods: In a case-control study, postmenopausal patients with a confirmed diagnosis of rheumatoid arthritis who received concurrent bDMARDs and denosumab for at least one year were identified and included as the case group (n=40). A total of 44 age-matched postmenopausal rheumatoid arthritis women who received bDMARDs alone were included as the control group of the study. Using a chi-squared test, the incidence of bacterial or viral infections was extracted from the patients’ profiles and compared between the two study groups. Statistical analyses were performed by SPSS for Windows, version 16 (Chicago, Illinois, USA). A p-value of fewer than 0.05 was regarded as significant.\n\nResults: The clinical and demographic characteristics of the patients of the two study groups were not significantly different. In total, four infections were recorded in the present series, two infections in each group. Accordingly, the rate of infection was 4.5% in the bDMARDs alone group and 5% in bDMARDs + denosumab group. This difference was not statistically significant (p=0.655, 95% CI: 0.121-6.742). Three out of four infections were herpes zoster infection. The other one was osteomyelitis of the first metatarsal bone, which occurred in the bDMARDs+denosumab group. None of the infections needed a hospitalization of IV antibiotics.\n\nConclusion: The risk of infection is comparable between postmenopausal osteoporotic women with rheumatoid arthritis who receive bDMARDS alone and those who receive bDMARDS in combination with denosumab.\n\nRheumatoid arthritis\nPostmenopausal osteoporosis\nDenosumab\nbDMARDs\nCite this article as: Mirzaei A, Jahed SA, Amini Kadijani A, Zabihiyeganeh M. Risk of infection in postmenopausal women with rheumatoid arthritis and osteoporosis taking denosumab and bDMARDS. Med J Islam Repub Iran. 2021 (21 Jan);35:12. https://doi.org/10.47176/mjiri.35.12\n==== Body\n↑ What is “already known” in this topic:\n\nWhile denosumab administration in postmenopausal osteoporotic women raised some concerns regarding the increased risk of infection, later investigations revealed the safety of denosumab in this group of patients. Even so, there is still no consensus regarding the potential of denosumab for increasing the risk of infection in postmenopausal osteoporotic women who are concurrently receiving immunosuppressive medications such as biologic disease-modifying anti-rheumatic drugs (bDMARDs).\n\n→ What this article adds:\n\nIn this study, we compared the risk of infection in postmenopausal osteoporotic women with rheumatoid arthritis who were receiving concurrent bDMARDs and denosumab with the same population who were receiving bDMARDs alone. Based on the results of this study, the rate of infection was not different between the two groups of the study. Therefore, denosumab can be safely used for the treatment of osteoporosis in postmenopausal patients with rheumatoid arthritis who are receiving bDMARDs.\n\nIntroduction\n\nThe risk of osteoporosis is high in rheumatoid arthritis (RA) patients for several underling reasons including increased production of pro-inflammatory cytokines, hormone mediated mechanisms, physical disability, and cumulative effect of glucocorticoid . Accordingly, the prevalence of osteoporosis in RA patients is almost twice in comparison with the general population .\n\nPostmenopausal women are also at a high risk of osteoporotic fracture for several reasons, mainly a sharp reduction in estrogen, which protects bone from the resorptive effects of parathyroid hormone . According to the Agency for Healthcare Research and Quality (AHRQ) report, approximately 5% of 50-year-old white women, as well as 25% of 80-year-old women have experienced at least one osteoporotic vertebral fracture . Considering the health and economic burden of osteoporotic fractures , effective treatment of osteoporosis in postmenopausal RA women is of considerable importance.\n\nDenosumab, a human monoclonal antibody to Receptor activator of nuclear factor-kappa-Β ligand (RANKL), proved to be highly effective in declining the risk of osteoporotic vertebral, nonvertebral, and hip fractures in postmenopausal females. For these benefits, it received international approval for the treatment of postmenopausal osteoporosis in 2010 . Moreover, recent studies provide strong evidence considering the efficacy of denosumab for the treatment of RA, so that its implication inhibited the joint structural damages without increasing adverse events .\n\nIn spite of the detrimental effects of RANKL on the bone quality of postmenopausal women, RANKL signaling contains several critical roles in the immune system, including its role in development of lymph-nodes, lymphocyte differentiation and tolerance, dendritic cell survival, and T-cell activation . These beneficial effects of RANKL raised some concerns regarding the increased risk of infection in patients treated with RANKL inhibitors such as denosumab. Subsequently, several studies aimed to investigate if denosumab administration in postmenopausal osteoporotic women may impose a higher risk of infection on this population. As a result of these investigations, no significant increase was observed in the risk of infection, as well as the risk of cancer, delayed fracture healing, and hypocalcemia . However, there is no clear consensus on the potential of denosumab for increasing the risk of infection in patients who are receiving immunosuppressive medications such as biologic disease-modifying anti-rheumatic drugs (bDMARDs) .\n\nIn this study, we aimed to evaluate the potential of denosumab for increasing the risk of infection in RA patients with postmenopausal osteoporosis who were receiving bDMARDs.\n\nTable 1 Comparison of the demographic and clinical characteristics of the two study groups\n\nVariable\tbDMARDs alone\n(n=44)\tbDMARDs ± denosumab\n(n=40)\tp\t\nAge (year)\t62.6±11.7 \t63.1±12\t0.421\t\nBMI (kg/m2)\t26.9±4.5\t27.1±4.8\t0.643\t\nType 2 Diabetes\t5 (11.4)\t4 (10)\t0.515\t\nMean disease duration (year)\t7.1±1.6\t7.2±1.9 \t0.392\t\nMean duration of bDMARDs use (month)\t15.8±4.6\t15.4±3.2\t0.284\t\nType of bDMARDS\nEtanercept\n\nRituximab\n\nAdalimumab\n\n\t\n28 (63.6)\n7 (15.9)\n9 (20.5)\t\n29 (72.5)\n4 (10)\n7 (17.5)\t\n\n0.263\t\nBMI: body mass index; bDMARDs: Biologic disease-modifying anti-rheumatic drugs.\n\nData are show as mean± standard deviation or number (%). A p value of <0.05 is considered significant.\n\nTable 2 The demographic and clinical characteristics of patients who were presented with a serious infection\n\nVariable\tbDMARDs alone\tbDMARDs ± denosumab\t\n\tPatient 1\tPatient 2\tPatient 1\tPatient 2\t\nType of infection\tHerpes zoster\tHerpes zoster\tOsteomyelitis\tHerpes zoster\t\nAge (Year)\t59\t64\t65\t62\t\nSex\tFemale\tFemale\tFemale\tFemale\t\nBMI (kg/m2)\t26.8\t25.9\t27\t25.5\t\nDisease duration (year)\t6\t8\t7\t5\t\nDuration of bDMARDs use (month)\t17\t12\t16\t22\t\nType of bDMARDs\tAdalimumab\tAdalimumab\tEtanercept\tAdalimumab\t\nHistory of Diabetes\tNo\tNo\tyes\tNo\t\nBMI: body mass index; bDMARDs: Biologic disease-modifying anti-rheumatic drugs.\n\nMethods\n\nThe protocol of this case-control study was approved by the review board of our institute under the code of IR.IUMS.REC.1396.32412 and written informed consent was obtained from the patients to use their medical profile for publication. The medical profiles of postmenopausal patients with a confirmed diagnosis of RA based on the 2010-ACR/EULAR–classification criteria who received bDMARDs and denosumab were reviewed, and eligible patients were included in the study. The inclusion criteria were postmenopausal women, treatment with bDMARDs for the management of RA, treatment with denosumab (60 mg) injections every six months for osteoporosis, current therapeutic regimen for at least one year, absence of any local and systemic infection before the initiation of bDMARDs. Patients who were receiving immunosuppressive therapies for conditions other than RA, such as cancer and organ transplantation, were excluded from the study.\n\nA total of 40 patients who received concurrent bDMARDs and denosumab were identified as eligible for the study. A total of 44 age -matched RA patients who received bDMARDs alone were included as the control group of the study. The type of administered bDMARDs was etanercept (50 mg per week), rituximab (2 gr per six months), or adalimumab (40 mg per two weeks). All patients concurrently received a daily dose of prednisolone (2.5–7.5 mg) plus folic acid and a weekly dose of methotrexate (10 mg per week). The incidence of serious infections (requiring hospitalization or IV antibiotics) was extracted from the patients’ profiles. We also called the patients and asked about hospitalization in other centers for serious infection.\n\nStatistical analysis\n\nStatistical analyses were performed by SPSS for Windows, version 16 (Chicago, Illinois, USA). The descriptive data were presented as mean ± standard deviation or number & percentage. A comparison of mean values between the two study groups was performed with an independent t-test or its nonparametric counterpart (Mann–Whitney U test). A comparison of qualitative variables was made using a chi-squared test. A p-value of fewer than 0.05 was regarded as significant.\n\nResults\n\nWe compared the risk of infection in RA patients who received either bDMARDs alone (n=40) or concurrent with denosumab (n=44). The mean age of the patients was 62.6±11.7 years in patients who received bDMARDs alone and 63.1±12 years in patients who received concurrent denosumab (p=0.421, 95% CI: -2.270-0.3.351). The mean disease duration was 7.1±1.6 years in patients who received bDMARDs alone and 7.2±1.9 in patients who received concurrent denosumab (p=0.392, 95% CI:-1.301-1.152). The mean duration of biologic use was 15.8±4.6 months in patients who received bDMARDs alone and 15.4±3.2 months in patients who received concurrent denosumab (p=0.284, 95% CI: -4.580-2.607). Type 2 diabetes mellitus was present in five patients (11.4%) who received bDMARDs alone and four (10%) patients who received concurrent denosumab (p=0.515, 95% CI: 0.287-4.635). No significant difference was found between the clinical and demographic characteristics of the two study groups as well (Table 1).\n\nA number of two infections occurred in each group. Accordingly, the rate of infection was 4.5% in the bDMARDs alone group and 5% in the bDMARDs+denosumab group. This difference was not statistically significant (p=0.655, 95% CI: 0.121-6.742). .\n\nIn the bDMARDs alone group, two cases of herpes zoster were recorded in two patients receiving adalimumab. In the bDMARDs+denosumab group, the first one was an osteomyelitis of the first metatarsal bone in a diabetic patient receiving etanercept+denosumab. The duration of denosumab use was 18 months in this patient. The other one was a herpes zoster infection in a patient receiving adalimumab. The duration of denosumab use was 12 months in this patient.\n\nThe demographic and clinical characteristics of the patients with an infection are demonstrated in detail in Table 2.\n\nDiscussion\n\nIn this study, we investigated if the risk of infection is higher in postmenopausal osteoporotic RA patients who received concurrent bDMARDs and denosumab in comparison with those who received bDMARDs alone. According to our results, the risk of infection was 5% in the bDMARDs+ denosumab group and 4.5% in bDMARDs alone group. This difference was not statistically and clinically significant.\n\nIn a retrospective study, Hasegawa et al. aimed to compare RA patients treated with denosumab (60 mg injections every six months) plus bDMARDs (n=40) to those treated with bDMARDs alone (n=40). The types of bDMARDs in their study included infliximab, adalimumab, etanercept, abatacept, and tocilizumab. Based on their report, rates of adverse events, including infection, were comparable between the two study groups . Similarly, we found a comparable rate of infection between the bDMARDs+ denosumab group and the denosumab alone group. Though, the types of administered bDMARDs were different in two studies.\n\nLau et al. investigated the risk of serious infection in RA patients treated with bDMARDs plus denosumab in comparison with those who received bDMARDs alone. In total, 308 patients (102 in the concurrent group and 206 in bDMARDs alone group) met the eligibility criteria to include in the study. Three serious infections occurred in the bDMARDs+ denosumab group, which all were cases of pneumonia. Four serious infections occurred in the bDMARDs-alone group, which included three cases of pneumonia, and one case of upper respiratory tract infection. Moreover, one case of opportunistic infection occurred in the bDMARDs -alone group. Based on the results of this study, the risk of serious infection following the concurrent use of bDMARDs denosumab group was negligible and comparable with bDMARDs -alone group .\n\nBray et al. aimed to identify the rate of infection among patients with RA and psoriatic arthritis who concurrently received denosumab. In total, 96 patients (90 RA patients and 6 psoriatic arthritis patients) met the eligibility criteria for this study. Based on their results, the infection rate seemed to be low among patients who receive concurrent denosumab and bDMARDs (3 cases, 3.1%). However, prednisone administration found to be associated with an increased rate of infection .\n\nCurtis et al. aimed to investigate whether the rate of hospitalized infection in patients with RA who concurrently receive bDMARDs and denosumab (n=1354) is higher than those who concurrently receive bDMARDs and zoledronic acid (n=4460). According to their results, the crude rate of hospitalized infections for bDMARDs + denosumab was comparable to that for ZA (14.9/100 person-years versus 13.9/100 person-years) .\n\nAccording to our findings, joint with the results of earlier investigations, concurrent use of bDMARDs, and denosumab in postmenopausal patients with RA does not increase the rate of infection in these patients. Therefore, denosumab can be used for the treatment of osteoporosis in postmenopausal RA patients, with no concern.\n\nThe limitations of our study were the retrospective identity of research, as well as small patients' numbers, which did not allow the subgroup analysis, such as evaluating the risk of infection with different types of bDMARDs. Small number of patients might have also affected the power of statistical tests. Therefore, future complementary studies are warranted to confirm the results of present study.\n\nConclusion\n\nAccording to the results of this study, the risk of infection in postmenopausal osteoporotic RA patients was not significantly different between the denosumab and bDMARDs concurrent therapy compared with the bDMARDs alone. This finding suggests that denosumab could be used as a safe medication in the treatment of osteoporosis in RA patients receiving bDMARDs.\n\nConflict of Interests\n\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n\n1 Heidari B Hassanjani Roushan MR Rheumatoid arthritis and osteoporosis Caspian J Int Med 2012 3 3 445 6\n2 Haugeberg G Uhlig T Falch JA Halse JI Kvien TK Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register Arthritis Rheum 2000 43 3 522 30 10728744\n3 Ji M-X Yu Q Primary osteoporosis in postmenopausal women Chronic Dis Translat Med 2015 1 1 9\n4 Mirzaei A Jahed SA Nojomi M Rajaei A Zabihiyeganeh M A study of the value of trabecular bone score in fracture risk assessment of postmenopausal women Taiwan J Obstet Gynecol 2018 57 3 389 93 29880171\n5 Nelson HD Morris CD Kraemer DF Mahon S Carney N Nygren PM Osteoporosis in postmenopausal women: diagnosis and monitoring Evid Rep Technol Assess 2001 28 1 2\n6 Harvey N Dennison E Cooper C Osteoporosis: impact on health and economics Nat Rev Rheumatol 2010 6 2 99 20125177\n7 Cummings SR Martin JS McClung MR Siris ES Eastell R Reid IR Denosumab for prevention of fractures in postmenopausal women with osteoporosis New Eng J Med 2009 361 8 756 65 19671655\n8 Iwamoto N Sato S Sumiyoshi R Chiba K Miyamoto N Arinaga K Comparative study of the inhibitory effect on bone erosion progression with denosumab treatment and conventional treatment in rheumatoid arthritis patients: study protocol for an open-label randomized controlled trial by HR-pQCT Trials 2019 20 1 1 8 30606236\n9 Hasegawa T Kaneko Y Izumi K Takeuchi T Efficacy of denosumab combined with bDMARDs on radiographic progression in rheumatoid arthritis Joint Bone Spine 2017 84 3 379 27369650\n10 Cheng ML Fong L Effects of RANKL-targeted therapy in immunity and cancer Front Oncol 2014 3 329 24432249\n11 Miller PD A review of the efficacy and safety of denosumab in postmenopausal women with osteoporosis Ther Adv Musculoskelet Dis 2011 3 6 271 82 22870485\n12 Le Loët X Nicolau J Boumier P Daragon A Mejjad O Pouplin S Validation of the 2010-ACR/EULAR–classification criteria using newly EULAR-defined erosion for rheumatoid arthritis on the very early arthritis community-based (VErA) cohort Joint Bone Spine 2015 82 1 38 41 25304188\n13 Lau AN Wong-Pack M Rodjanapiches R Ioannidis G Wade S Spangler L Occurrence of serious infection in patients with rheumatoid arthritis treated with biologics and denosumab observed in a clinical setting J Rheumatol 2018 45 2 170 6 29142041\n14 Bray V Bagley A West S Etzel C Kremer J Kolfenbach J Infection Risk Among Patients Receiving Concurrent Denosumab and Biologic Or Non-Biologic DMARD Therapy: An Analysis Of The Consortium Of Rheumatology Researchers Of North America (CORRONA) Registry Arthritis Rheum 2013 65\n15 Curtis JR Xie F Yun H Saag KG Chen L Delzell E Risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab Arthritis Rheumatol 2015 67 6 1456 64 25708920\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1016-1430",
"issue": "35()",
"journal": "Medical journal of the Islamic Republic of Iran",
"keywords": "Denosumab; Postmenopausal osteoporosis; Rheumatoid arthritis; bDMARDs",
"medline_ta": "Med J Islam Repub Iran",
"mesh_terms": null,
"nlm_unique_id": "8910777",
"other_id": null,
"pages": "12",
"pmc": null,
"pmid": "33996663",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "10728744;31409388;27369650;11677787;29880171;19671655;22870485;29142041;29062981;25202438;20125177;25304188;24432249;25708920",
"title": "Risk of infection in postmenopausal women with rheumatoid arthritis and osteoporosis taking denosumab and bDMARDS.",
"title_normalized": "risk of infection in postmenopausal women with rheumatoid arthritis and osteoporosis taking denosumab and bdmards"
} | [
{
"companynumb": "IR-AMGEN-IRNNI2018140116",
"fulfillexpeditecriteria": "2",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nAortic disease is a known complication of HLA-B27-associated spondyloarthritis. We present the case of a 52-year-old HLA-B27-positive woman with aortitis of the abdominal aorta and spondyloarthritis.\n\n\nMETHODS\nIn addition to the case reported, a literature search (MEDLINE) for articles published between 1946 and September 2013 was performed using combinations of the MEDLINE subject headings keywords \"spondylarthritis,\" \"ankylosing spondylitis,\" \"reactive arthritis,\" \"psoriatic arthritis,\" \"aortitis,\" and \"abdominal aorta.\" Relevant references were retrieved.\n\n\nRESULTS\n\n\n\nMETHODS\nOur patient presented to the ER in June 2008 with a 3-week history of worsening of severe cramping lower abdominal pain. Her history also included recurrent acute episodes of iritis, which eventually led to enucleation of her left eye despite treatment with corticosteroids. CT of the abdomen showed findings suggesting aortitis of the abdominal aorta. She responded to therapy with prednisone, and follow-up imaging showed eventual resolution of the aortitis. She later went on to be diagnosed with psoriatic arthritis with spondylitis.\n\n\nMETHODS\nSix previously reported cases of abdominal aortitis in spondyloarthritis were found. Four of these were reported in patients with ankylosing spondylitis, one in reactive arthritis, and one in psoriatic arthritis. The first case reported was in 1958 and the most recent in 2012.\n\n\nCONCLUSIONS\nRheumatologists should be aware of the possibility of abdominal aortitis occurring in their patients with SpA and should consider it as part of the differential diagnosis in a SpA patient with unexplained visceral pain or systemic features out of proportion to clinically apparent disease.",
"affiliations": "University of British Columbia, Vancouver, Canada. Electronic address: gsgrewal@alumni.ubc.ca.;Department of Radiology, University of British Columbia, Vancouver, Canada.;Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, Canada.",
"authors": "Grewal|Gurinder S|GS|;Leipsic|Jonathon|J|;Klinkhoff|Alice V|AV|",
"chemical_list": "D015796:HLA-B27 Antigen; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-0172",
"issue": "44(3)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Abdominal aorta; Ankylosing spondylitis; Aortitis; HLA-B27; Large vessel; Psoriatic arthritis; Reactive arthritis; Spondyloarthritis; Vasculitis",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D001012:Aorta, Abdominal; D001025:Aortitis; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D015796:HLA-B27 Antigen; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D011241:Prednisone; D025241:Spondylarthritis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D059265:Visceral Pain",
"nlm_unique_id": "1306053",
"other_id": null,
"pages": "305-8",
"pmc": null,
"pmid": "24935530",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Abdominal aortitis in HLA-B27+ spondyloarthritis: case report with 5-year follow-up and literature review.",
"title_normalized": "abdominal aortitis in hla b27 spondyloarthritis case report with 5 year follow up and literature review"
} | [
{
"companynumb": "CA-JNJFOC-20150108562",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe regrowth of a tumor after complete clinical response and the development of keratinocytic neoplasms while patients are still undergoing continuous vismodegib have stressed the importance of the accurate monitoring to detect recurrences earlier and ensure the best possible outcome.\n\n\nOBJECTIVE\nThe objective of this study was to determine the role of reflectance confocal microscopy (RCM) in monitoring the response of locally advanced basal cell carcinoma (laBCC) to vismodegib and to discard secondary resistance.\n\n\nMETHODS\nSeven patients presenting with nine laBCC, were prospectively included and their response to this drug was assessed by means of clinical examination, dermoscopy, and RCM. The study was conducted at the Melanoma Unit in Hospital Clinic of Barcelona, between June 2012 and March 2013.\n\n\nRESULTS\nHistologically confirmed lesion 10 mm or larger in diameter for which surgery was contraindicated and radiation therapy was inappropriate. The median patient age was 73 years and the most common histological type was infiltrating BCC. RCM allowed the identification of residual tumor in two lesions and to confirm complete response in the other four cases. Two patients developed new lesions within the tumor bed, they were assessed by RCM showing features of actinic keratosis which were confirmed by histopathology.\n\n\nCONCLUSIONS\nThe use of in vivo RCM allowed the characterization of the dynamic morphologic changes in tumor response helping to better define partial response and to differentiate it from secondary resistance. Another interesting observation was the recognition of a phenomenon characterized by the development of keratinocytic neoplasms within the tumor bed.",
"affiliations": "Melanoma Unit, Dermatology Department, Hospital Clinic, Barcelona, Spain.;Department of Dermatology, Pius Hospital de Valls, Valls, Spain.;Melanoma Unit, Dermatology Department, Hospital Clinic, Barcelona, Spain.;Melanoma Unit, Dermatology Department, Hospital Clinic, Barcelona, Spain.",
"authors": "Alarcon|I|I|http://orcid.org/0000-0002-6738-2651;Pasquali|P|P|;Malvehy|J|J|;Puig|S|S|",
"chemical_list": "D000813:Anilides; C538724:HhAntag691; D011725:Pyridines",
"country": "England",
"delete": false,
"doi": "10.1111/srt.12332",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0909-752X",
"issue": "23(3)",
"journal": "Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)",
"keywords": "actinic keratosis; basal cell carcinoma; reflectance confocal microscopy; secondary resistance; vismodegib",
"medline_ta": "Skin Res Technol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides; D002280:Carcinoma, Basal Cell; D046169:Dermoscopy; D005260:Female; D006801:Humans; D000069416:Intravital Microscopy; D015603:Keratinocytes; D055623:Keratosis, Actinic; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D011725:Pyridines; D012878:Skin Neoplasms; D013030:Spain",
"nlm_unique_id": "9504453",
"other_id": null,
"pages": "283-288",
"pmc": null,
"pmid": "27785832",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tumor regrowth and development of keratinocytic neoplasms in patients under smoothened inhibition: in vivo assessment with reflectance confocal microscopy.",
"title_normalized": "tumor regrowth and development of keratinocytic neoplasms in patients under smoothened inhibition in vivo assessment with reflectance confocal microscopy"
} | [
{
"companynumb": "ES-ROCHE-1970957",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VISMODEGIB"
},
"drugadditional": "3",
"druga... |
{
"abstract": "After sedation with midazolam, induction of anesthesia with propofol was attempted in a patient taking modafinil. However, even after administration of a total of 6 mg/kg propofol IV, the patient continued to respond to tactile stimulation. Concurrently, the bispectral index was 72. Subsequent administration of low concentration sevoflurane by facemask induced an anesthetic depth that allowed unproblematic insertion of a laryngeal mask airway. Anesthesia for ophthalmologic surgery was maintained with sevoflurane. Modafinil may have caused resistance to propofol because of its effect on neural pathways that activate consciousness. The concentration of sevoflurane required to induce or maintain anesthesia remained unaltered.",
"affiliations": "From the Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina.",
"authors": "Harwood|Timothy N|TN|",
"chemical_list": "D018686:Anesthetics, Intravenous; D001559:Benzhydryl Compounds; D008738:Methyl Ethers; D064690:Wakefulness-Promoting Agents; D000077149:Sevoflurane; D000077408:Modafinil; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000606",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "9(11)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D018686:Anesthetics, Intravenous; D001559:Benzhydryl Compounds; D056805:Consciousness Monitors; D004347:Drug Interactions; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008738:Methyl Ethers; D008875:Middle Aged; D000077408:Modafinil; D015742:Propofol; D000077149:Sevoflurane; D064690:Wakefulness-Promoting Agents",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "322-323",
"pmc": null,
"pmid": "28767479",
"pubdate": "2017-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Resistance to Propofol Induction in a Patient Taking Modafinil: A Case Report.",
"title_normalized": "resistance to propofol induction in a patient taking modafinil a case report"
} | [
{
"companynumb": "US-TEVA-2018-US-846847",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MODAFINIL"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nPeripheral ulcerative keratitis (PUK) is a severe corneal condition associated with uncontrolled RA. Tocilizumab (TCZ) is used to control RA, however, episodes of paradoxical ocular inflammation have been reported in TCZ-treated patients. We report a case series of PUK in TCZ-treated RA patients with ophthalmological and systemic findings and discuss the potential underlying mechanisms.\n\n\nMETHODS\nFour patients (six eyes), 47-62 years of age, were included. At the onset of PUK, the median duration of RA was 13 years [interquartile range (IQR) 3-13] and the median treatment with TCZ was 9 months (IQR 3-14). Two patients had active disease [28-joint DAS (DAS28) >3.2] and the disease was controlled in two patients (DAS28 ≤3.2).\n\n\nRESULTS\nTCZ was initially replaced by another immunomodulatory treatment in all patients and later reintroduced in two patients without PUK recurrence. Corneal inflammation was controlled in all cases with local and systemic treatments, with severe visual loss in one eye.\n\n\nCONCLUSIONS\nPUK may occur in patients with long-standing RA after a switch to TCZ and can be interpreted, depending on the context, as insufficient efficacy or a paradoxical manifestation. These cases highlight the urgent need for reliable biomarkers of the efficacy and paradoxical reactions of biologics.",
"affiliations": "Service d'Ophtalmologie, Assistance Publique - Hôpitaux de Paris, Université Paris-Saclay, Centre de Référence Maladies Rares en Ophtalmologie, OPHTARA, Le Kremlin-Bicêtre.;Service d'Ophtalmologie, Assistance Publique - Hôpitaux de Paris, Hôpital Bichat et Fondation Ophtalmologique Rothschild, Centre de Référence Maladies Rares en Ophtalmologie, OPHTARA, Paris.;Service d'Ophtalmologie, Assistance Publique - Hôpitaux de Paris, Hôpital Bichat et Fondation Ophtalmologique Rothschild, Centre de Référence Maladies Rares en Ophtalmologie, OPHTARA, Paris.;Department of Rheumatology, Assistance Publique - Hôpitaux de Paris, Hôpitaux universitaires Paris-Saclay-Hôpital Bicêtre, Le Kremlin Bicêtre.;Department of Rheumatology, Assistance Publique - Hôpitaux de Paris, Hôpitaux universitaires Paris-Saclay-Hôpital Bicêtre, Le Kremlin Bicêtre.;Service d'Ophtalmologie, Assistance Publique - Hôpitaux de Paris, Université Paris-Saclay, Centre de Référence Maladies Rares en Ophtalmologie, OPHTARA, Le Kremlin-Bicêtre.;Department of Immunology of Viral and Auto-Immune Disease, UMR1184, CEA, Fontenay-aux-Roses, France.;Service d'Ophtalmologie, Assistance Publique - Hôpitaux de Paris, Université Paris-Saclay, Centre de Référence Maladies Rares en Ophtalmologie, OPHTARA, Le Kremlin-Bicêtre.;Service d'Ophtalmologie, Assistance Publique - Hôpitaux de Paris, Université Paris-Saclay, Centre de Référence Maladies Rares en Ophtalmologie, OPHTARA, Le Kremlin-Bicêtre.;Department of Rheumatology, Assistance Publique - Hôpitaux de Paris, Hôpitaux universitaires Paris-Saclay-Hôpital Bicêtre, Le Kremlin Bicêtre.;Service d'Ophtalmologie, Assistance Publique - Hôpitaux de Paris, Université Paris-Saclay, Centre de Référence Maladies Rares en Ophtalmologie, OPHTARA, Le Kremlin-Bicêtre.",
"authors": "Cohen|Florian|F|;Gabison|Eric Ernest|EE|;Stéphan|Sophie|S|;Belkhir|Rakiba|R|;Nocturne|Gaetane|G|;Best|Anne-Laurence|AL|;Haigh|Oscar|O|;Barreau|Emmanuel|E|;Labetoulle|Marc|M|;Seror|Raphaele|R|;Rousseau|Antoine|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keab093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "60(11)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "paradoxical manifestations; peripheral ulcerative keratitis; rheumatoid arthritis; tocilizumab",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": null,
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "5413-5418",
"pmc": null,
"pmid": "33528012",
"pubdate": "2021-11-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Peripheral ulcerative keratitis in rheumatoid arthritis patients taking tocilizumab: paradoxical manifestation or insufficient efficacy?",
"title_normalized": "peripheral ulcerative keratitis in rheumatoid arthritis patients taking tocilizumab paradoxical manifestation or insufficient efficacy"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1050074",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIntravenous thrombolysis with tissue plasminogen activator (tPA) improves patient outcomes in acute ischaemic stroke. Because its benefit is time-dependant, treatment delays must be minimised. The aim of the present study was to review patient characteristics, timeliness of tPA delivery and clinical outcome in patients receiving t-PA in a tertiary hospital stroke unit in Queensland, and to compare the findings with those of other Australian studies.\n\n\nMETHODS\nThe present study was a retrospective study conducted between 1 January 2010 and 31 December 2012. Information was collected regarding demographics, stroke characteristics, timeliness of tPA delivery, clinical outcome, safety outcome and protocol deviation.\n\n\nRESULTS\nOf 490 patients admitted with ischaemic stroke, 57 (11.6%) received tPA. Compared with other studies, the patients in the present study had more severe stroke (median National Institutes of Health Stroke Scale (NIH SS) score), more cardioembolic strokes and more patients receiving tPA between 3 and 4.5 h of symptoms onset. Median symptom onset to treatment time was 175 min and median door to needle time was 97 min. At 3 months, 21.1% of patients had died and 41.5% had a favourable outcome (modified Rankin scale ≤ 2). Symptomatic intracerebral haemorrhage occurred in 5.3% of patients and protocol deviations occurred in 21.1%. Overall, delivery and outcomes of tPA at the Princess Alexandra Hospital were comparable to those reported in other Australian studies of usual care. Several challenges and strategies for optimal thrombolysis were identified, with supporting evidence from selected Australian sites.\n\n\nCONCLUSIONS\nThe proportion of eligible stroke patients who receive tPA in a timely manner remains less than ideal at our centre. More accurate patient selection and reductions in treatment delays serve as targets for quality improvement efforts that have broad applicability.",
"affiliations": "Department of Internal Medicine, Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, Qld 4102, Australia. Email: ; xxx.;Department of Internal Medicine, Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, Qld 4102, Australia. Email: ; xxx.;Department of Internal Medicine, Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, Qld 4102, Australia. Email: ; xxx.;Department of Internal Medicine, Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, Qld 4102, Australia. Email: ; xxx.",
"authors": "Lau|Alex H T|AHT|;Hall|Graham|G|;Scott|Ian A|IA|;Williams|Marie|M|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Australia",
"delete": false,
"doi": "10.1071/AH14167",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0156-5788",
"issue": "40(1)",
"journal": "Australian health review : a publication of the Australian Hospital Association",
"keywords": null,
"medline_ta": "Aust Health Rev",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D011793:Queensland; D012189:Retrospective Studies; D020521:Stroke; D062606:Tertiary Care Centers; D015912:Thrombolytic Therapy; D013997:Time Factors; D014481:United States",
"nlm_unique_id": "8214381",
"other_id": null,
"pages": "43-53",
"pmc": null,
"pmid": "26117176",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thrombolysis in acute stroke: ongoing challenges based on a tertiary hospital audit and comparisons with other Australian studies.",
"title_normalized": "thrombolysis in acute stroke ongoing challenges based on a tertiary hospital audit and comparisons with other australian studies"
} | [
{
"companynumb": "AU-ROCHE-1611711",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"drug... |
{
"abstract": "We report two patients with diabetes in whom acute renal failure requiring hemodialysis occurred while on treatment with glucagon-like peptide-1 receptor agonists. We discuss the mechanisms of this complication and the potential for its prevention.",
"affiliations": "Department of Immunology and Diabetology, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: daniele.dubois@cch.aphp.fr.;Department of Immunology and Diabetology, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.;Department of Immunology and Diabetology, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.;Department of Nephrology, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.;Department of Immunology and Diabetology, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.",
"authors": "Dubois-Laforgue|D|D|;Boutboul|D|D|;Lévy|D J|DJ|;Joly|D|D|;Timsit|J|J|",
"chemical_list": "C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0168-8227",
"issue": "103(3)",
"journal": "Diabetes research and clinical practice",
"keywords": "Acute interstitial nephritis; Acute renal failure; Exenatide; Glucagon-like peptide-1 receptor agonists; Liraglutide; Type 2 diabetes mellitus",
"medline_ta": "Diabetes Res Clin Pract",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D005260:Female; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018027:Receptors, Glucagon; D006435:Renal Dialysis",
"nlm_unique_id": "8508335",
"other_id": null,
"pages": "e53-5",
"pmc": null,
"pmid": "24447807",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe acute renal failure in patients treated with glucagon-like peptide-1 receptor agonists.",
"title_normalized": "severe acute renal failure in patients treated with glucagon like peptide 1 receptor agonists"
} | [
{
"companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2015-03129",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditional"... |
{
"abstract": "Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approximately 900 natural and synthetic substances, which have shown hepatotoxicity. Areas covered: This review will focus on fibrates - PPARα agonists and their implication in causing liver injury. Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been varying because several large randomized clinical trials have reported similar elevations of plasma transaminase levels in fibrate or placebo treated groups. On the other hand, one meta-analysis has reported an increased risk of hepatotoxicity when fibrates are combined with statins. Fibrate induced clinically apparent liver damage has been demonstrated in case reports. However, there is a wide spectrum of clinical phenotypic presentations of these cases (onset of injury, pattern of enzyme elevation and resolution of the symptoms), which reduces the ability to identify specific cause and effect of any putative fibrate-induced hepatotoxicity. Thus, the current recommendations for using fibrates include monitoring of aminotransferase levels especially if combined with statins and discontinuation of the treatment only if the levels persist above three times the upper limit of normal.",
"affiliations": "a Department of Medicine , University of Maryland School of Medicine , Baltimore , Maryland , USA.;a Department of Medicine , University of Maryland School of Medicine , Baltimore , Maryland , USA.",
"authors": "Hedrington|Maka S|MS|;Davis|Stephen N|SN|",
"chemical_list": "D058607:Fibric Acids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D000637:Transaminases",
"country": "England",
"delete": false,
"doi": "10.1080/17425255.2018.1483337",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-5255",
"issue": "14(7)",
"journal": "Expert opinion on drug metabolism & toxicology",
"keywords": "PPARα; fenofibrate; fibrates; gemfibrozil; hepatotoxicity",
"medline_ta": "Expert Opin Drug Metab Toxicol",
"mesh_terms": "D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D016903:Drug Monitoring; D058607:Fibric Acids; D006801:Humans; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D016032:Randomized Controlled Trials as Topic; D000637:Transaminases",
"nlm_unique_id": "101228422",
"other_id": null,
"pages": "671-677",
"pmc": null,
"pmid": "29847748",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver.",
"title_normalized": "peroxisome proliferator activated receptor alpha mediated drug toxicity in the liver"
} | [
{
"companynumb": "US-SA-2018SA198171",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESOMEPRAZOLE"
},
"drugadditional": "3",
"d... |
{
"abstract": "Post-transplant ES, which is often resistant to therapies, has seldom been described. This report describes a case of ES after UBMT for RCC. A five-yr-old boy developed RCC with no evidence of monosomy 7. Because no matching family donors were available for SCT and immunosuppressive therapy was ineffective, UBMT was performed when he was six yr old. The conditioning regimen included TAI (3 Gy) and administration of FLU, CY, and rabbit antithymocyte globulin. The recovery of blood cells was good. He displayed grade II acute GVHD involving only the skin. ES developed on day 66, with positive results for Epstein-Barr virus DNA and HHV 6. Cytopenia was resolved with treatment with RTX, GCV, an escalated dose of steroids, high-dose gammaglobulin, and romiplostim. No relapse has occurred since discontinuing steroids on day 177 and romiplostim on day 268. Post-SCT ES after UBMT is rare, and the risk factors and therapies are unclear. Prospective analysis and collection of cases from multiple centers are required for clarification.",
"affiliations": "Department of Pediatrics, Japanese Red Cross Narita Hospital, Narita, Japan.",
"authors": "Ueki|Hideaki|H|;Igarashi|Shunji|S|;Kimura|Shunsuke|S|;Tsuchimochi|Taichiro|T|;Furudate|Kazuki|K|;Sakurai|Ayako|A|;Noguchi|Yasushi|Y|;Sunami|Shosuke|S|",
"chemical_list": "D004279:DNA, Viral; D007166:Immunosuppressive Agents; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013256:Steroids; D005719:gamma-Globulins; D004247:DNA; D013926:Thrombopoietin; C488777:romiplostim",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12323",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "18(7)",
"journal": "Pediatric transplantation",
"keywords": "Evans syndrome; bone marrow transplantation; refractory cytopenia of childhood; rituximab; romiplostim",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D004247:DNA; D004279:DNA, Viral; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D011446:Prospective Studies; D016553:Purpura, Thrombocytopenic, Idiopathic; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D012307:Risk Factors; D013256:Steroids; D013921:Thrombocytopenia; D013926:Thrombopoietin; D013997:Time Factors; D016896:Treatment Outcome; D005719:gamma-Globulins",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E246-51",
"pmc": null,
"pmid": "25074497",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Evans syndrome after unrelated bone marrow transplantation for refractory cytopenia of childhood.",
"title_normalized": "evans syndrome after unrelated bone marrow transplantation for refractory cytopenia of childhood"
} | [
{
"companynumb": "JP-ASTELLAS-2013JP000226",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS\\TACROLIMUS ANHYDROUS"
},
"drugaddi... |
{
"abstract": "Acute neurologic deficits in the postoperative period after carotid endarterectomy (CEA) can prompt extensive diagnostic evaluation. Reversible cerebral vasoconstriction syndrome (RCVS) is an underrecognized cause of acute neurologic deficit after CEA. We present the case of RCVS in an 84-year-old male patient who had experienced left limb weakness after CEA, prompting multiple code stroke activations. The present case is novel because the obtained computed tomography perfusion imaging studies demonstrated abnormalities that have not been previously described in patients with RCVS. These findings, combined with the cerebral angiography findings, led to the rapid diagnosis and delivery of intra-arterial vasodilator therapy. He experienced subsequent resolution of his symptoms and radiologic abnormalities.",
"affiliations": "Department of Radiology and Biomedical Imaging, University of California, San Francisco, School of Medicine, San Francisco, Calif.;Department of Radiology and Biomedical Imaging, University of California, San Francisco, School of Medicine, San Francisco, Calif.;Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, Calif.;Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, Calif.;Department of Radiology and Biomedical Imaging, University of California, San Francisco, School of Medicine, San Francisco, Calif.;Department of Radiology and Biomedical Imaging, University of California, San Francisco, School of Medicine, San Francisco, Calif.;Department of Radiology and Biomedical Imaging, University of California, San Francisco, School of Medicine, San Francisco, Calif.",
"authors": "Isikbay|Masis|M|;Narsinh|Kazim H|KH|;Arroyo|Sergio|S|;Smith|Wade S|WS|;Cooke|Daniel L|DL|;Higashida|Randall T|RT|;Amans|Matthew R|MR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvscit.2020.10.010",
"fulltext": "\n==== Front\nJ Vasc Surg Cases Innov Tech\nJ Vasc Surg Cases Innov Tech\nJournal of Vascular Surgery Cases and Innovative Techniques\n2468-4287\nElsevier\n\nS2468-4287(20)30185-4\n10.1016/j.jvscit.2020.10.010\nCase report\nComputed tomography perfusion abnormalities after carotid endarterectomy help in the diagnosis of reversible cerebral vasoconstriction syndrome\nIsikbay Masis MD a\nNarsinh Kazim H. MD a\nArroyo Sergio MD, PhD b\nSmith Wade S. MD, PhD b\nCooke Daniel L. MD a\nHigashida Randall T. MD a\nAmans Matthew R. MD Matthew.Amans@ucsf.edu\na∗\na Department of Radiology and Biomedical Imaging, University of California, San Francisco, School of Medicine, San Francisco, Calif\nb Department of Neurology, University of California, San Francisco, School of Medicine, San Francisco, Calif\n∗ Correspondence: Matthew R. Amans, MD, Department of Radiology and Biomedical Imaging, University of California, San Francisco, School of Medicine, 505 Parnassus Ave, Rm M391, Box 0628, San Francisco, CA 94143 Matthew.Amans@ucsf.edu\n27 10 2020\n3 2021\n27 10 2020\n7 1 171175\n2 9 2020\n14 10 2020\n© 2020 The Author(s)\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAcute neurologic deficits in the postoperative period after carotid endarterectomy (CEA) can prompt extensive diagnostic evaluation. Reversible cerebral vasoconstriction syndrome (RCVS) is an underrecognized cause of acute neurologic deficit after CEA. We present the case of RCVS in an 84-year-old male patient who had experienced left limb weakness after CEA, prompting multiple code stroke activations. The present case is novel because the obtained computed tomography perfusion imaging studies demonstrated abnormalities that have not been previously described in patients with RCVS. These findings, combined with the cerebral angiography findings, led to the rapid diagnosis and delivery of intra-arterial vasodilator therapy. He experienced subsequent resolution of his symptoms and radiologic abnormalities.\n\nKeywords\n\nCarotid endarterectomy\nCT perfusion\nNeurological deficits\nReversible cerebral vasoconstriction syndrome\nSurgical complications\n==== Body\nReversible cerebral vasoconstriction syndrome (RCVS) is a rare, yet serious, complication that can occur after recent carotid endarterectomy (CEA).1 Although the exact cause of RCVS remains unknown, the condition itself is characterized by multifocal narrowing of the cerebral arteries in a pattern that mimics the vasospasm and/or vasoconstriction caused by other etiologies (eg, subarachnoid hemorrhage). Although RCVS can be treated effectively with a combination of intra-arterial and systemic calcium channel blockers,2 a missed diagnosis or significant delay in the diagnosis can result in cerebral ischemia, cerebral infarction, and permanent neurologic deficits. We present a case that, to the best of our knowledge, is the first report of RCVS after CEA with computed tomography (CT) perfusion imaging studies that demonstrated a perfusion deficit. The patient provided written informed consent for the report of his case and is available on request.\n\nCase report\n\nAn 84-year-old man had presented to his vascular surgeon for performance of an elective right CEA for high-grade stenosis of the right internal carotid artery. His medical history was significant for coronary artery disease treated by angioplasty and stenting to the left anterior descending artery, right coronary artery, and left circumflex artery. He also had a history of non–small-cell lung cancer treated by right lower lobe lobectomy. His other surgical history included remote appendectomy, right knee replacement, laparoscopic cholecystectomy, and left-sided CEA 13 years previously. His medications included aspirin and clopidogrel. His social history was notable for an ~8 pack-year history of smoking, although he had quit >30 years before the current presentation. After carotid ultrasonography (performed as part of a syncope evaluation) had demonstrated ≥70% stenosis of the proximal right internal carotid artery and <50% stenosis of the left internal carotid artery, he was referred to vascular surgery for right CEA.\n\nThe patient's procedure was performed 6 weeks after the carotid artery Doppler ultrasound study. His operative course was uneventful. A collagen-impregnated Dacron graft (8 mm × 75 mm; Hemacarotid Patch Ultrathin; Getinge, Gothenburg, Sweden) was used to perform patch angioplasty.3 No periprocedural hypotension was observed, and no shunt was used during the procedure owing to the patient's recorded “excellent pulsatile backbleeding.” A “negligible” amount of estimated blood loss was documented. Postoperatively, the patient was stable, with no episodes of hypotension and no neurologic deficits. The remainder of the patient's immediate postoperative course was unremarkable.\n\nAt 10 days after his right CEA, when the patient had sat down in the evening to have dinner, he noted sudden left arm and leg weakness and numbness. Acutely, he was unable to lift either extremity against gravity for several hours, with a subsequent rapid resolution of his symptoms. During the next 2 days, he had experienced several additional neurologic episodes, each resulting in left arm and/or leg weakness and each self-resolving during a span of several hours. On postoperative day 12, the patient had experienced left arm weakness, headache, and vision changes, including the perception of abnormal clouds and colorful smoke. He described his headache as an episodic sharp pain centered only behind his right eye.\n\nOn the same day (12 days postoperatively), he presented to the local emergency department for the first time, at which point, his preprocedure CT angiogram of the head was reviewed (Fig 1, A), and magnetic resonance angiography and magnetic resonance imaging (MRI) of the neck and head were performed (Fig 1, B-E). The imaging findings were notable for patent vessels within the head and neck and no areas of acute infarct or abnormal T2-weighted fluid-attenuated inversion recovery (FLAIR) signal. Furthermore, the patient's vessel anatomy was unremarkable, with an intact circle of Willis and no variant intracranial anatomy present. He was subsequently discharged.Fig 1 Before the patient's right carotid endarterectomy (CEA), computed tomography angiography of the head showed no evidence of intracranial arterial pathology with a symmetric appearance of the middle cerebral artery branch vessels in the Sylvian fissures bilaterally on axial thick slice reformats (A). On initial presentation to the emergency room on postoperative day 12 after carotid endarterectomy, magnetic resonance angiography of the patient's neck revealed a patent right carotid bifurcation as shown on time-of-flight coronal reformats (B). Magnetic resonance angiography of the brain was also performed, and axial thick slice reformats did not show a noticeable asymmetry in the middle cerebral artery branch vessels in the Sylvian fissures (C). Magnetic resonance imaging (MRI) of the brain conducted as a part of the study does not show any abnormal T2-weighted/fluid-attenuated inversion recovery (FLAIR) signal (D) or areas of acute infarct on diffusion imaging (E). When the patient presented again on postoperative day 14, magnetic resonance imaging of the brain was repeated and again showed no evidence of infarct (F).\n\nOn postoperative day 14, he experienced another episode of left arm weakness that made it difficult to hold a mug, again associated with a similar headache and colorful visual percepts. He presented once more to his local emergency department. However, his symptoms had resolved before evaluation. A repeat MRI scan of the brain was obtained, with negative findings for acute infarct (Fig 1, F). Given the ongoing, recurrent nature of these events without a clear diagnosis, he was ultimately referred to a tertiary care center for further diagnostic evaluation.\n\nOn admission, a carotid ultrasound scan was repeated, which demonstrated a patent right internal carotid artery with <50% stenosis. A few hours after the ultrasound scan, the patient experienced another episode of left-sided weakness, which prompted an emergent neurologic evaluation and code stroke activation. His blood pressure was 116/40 mm Hg, the glucose level was 183 mg/dL, and his National Institutes of Health Stroke Scale score was 4, with points assigned for left arm/left leg weakness, sensory loss, and left facial droop. Although transcranial Doppler ultrasonography had been ordered to evaluate for possible vasospasm, it was never performed because the patient had first undergone a stroke protocol CT scan. A non–contrast-enhanced head CT scan revealed left caudate hypodensity, likely reflecting an age-indeterminate infarct, but was negative for acute abnormalities. CT angiography of the head and neck showed a patent right common and internal carotid artery with expected postoperative changes, consistent with the findings from the ultrasound study performed earlier that day (Fig 2, A). A subtle paucity of middle cerebral artery branch vessels in the right Sylvian fissure (Fig 2, B) was also noted. CT perfusion imaging demonstrated elevated mean transit times in the right cerebral hemisphere in a watershed pattern, with preserved and symmetric cerebral blood volume (Fig 2, C and D). Given this pattern of perfusion abnormality, a brain MRI study was obtained. T2-weighted FLAIR imaging did not demonstrate any evidence of edema (Fig 2, E). Consistent with the CT perfusion data, multiple foci of restricted diffusion were seen in the right frontal and parietal lobes in a watershed pattern (Fig 2, F), suggestive of low-flow and/or thromboembolic ischemia.Fig 2 Computed tomography (CT) angiography performed after the patient was transferred to a tertiary care center for further evaluation revealed a patent carotid bifurcation with no evidence of local postprocedural complications (A). Computed tomography angiography of the head was notable for the absence of middle cerebral artery branch vessels in the right Sylvian fissure (B). CT perfusion imaging revealed elevated mean transit times in a watershed territory of the right middle cerebral artery (C) with preserved symmetrical cerebral blood volume (D). Follow-up magnetic resonance imaging showed no abnormal T2-weighted/fluid-attenuated inversion recovery (FLAIR) signal in the absence of cerebral edema (E). Diffusion imaging revealed areas of focal small infarcts in watershed territories (F).\n\nFrom the patient's workup findings, the primary team (neurology) and consulting services (vascular surgery, neurointerventional radiology) decided to proceed with catheter-directed cerebral angiography to evaluate the perfusion deficits identified. The possibility of delivering intra-arterial calcium channel blockers was discussed with the patient and team, as were the potential risks (systemic hypotension and intracranial hypertension). After the patient had provided written informed consent for this procedure, angiography was performed, which again confirmed patency of the right common and internal carotid artery (Fig 3, A). The study demonstrated subtle multifocal luminal narrowing in the right anterior intracranial circulation. Specifically, the angiogram demonstrated narrowing in the right ophthalmic artery and in the branches of the M2 and M3 middle cerebral artery (Fig 3, B).Fig 3 Cerebral angiography was performed because of a suspected diagnosis of reversible cerebral vasoconstriction syndrome (RCVS). At the start of the procedure, a patent right carotid artery bifurcation was visualized (A). A cerebral angiogram revealed narrowing of multiple M2/M3 middle cerebral artery branch vessels (B; dark gray and white arrows), with narrowing of the ophthalmic artery (black arrow) and its branch vessels, which resolved with verapamil administration (C). Postprocedure computed tomography (CT) perfusion imaging showed symmetric mean transit times (D) and cerebral blood volume (E).\n\nIntra-arterial verapamil was administered (15 mg into the right internal carotid artery and 5 mg into the right external carotid artery), and the luminal caliber of the previously affected vessels improved significantly (Fig 3, C). A follow-up CT perfusion study of the head was performed, which revealed restoration of symmetric cerebral perfusion (Fig 3, D and E). The patient was monitored in the intensive care unit for 2 days after the procedure with close blood pressure monitoring using an intra-arterial line. Nimodipine (60 mg every 4 hours) was administered for the first 4 days after the procedure, at which point the patient was discharged with verapamil at 40 mg three times daily. The patient's remaining hospital course was uneventful. After the procedure, the patient no longer experienced any episodes of transient weakness or other neurologic abnormalities.\n\nDiscussion\n\nIn the present report, we have discussed a patient who had recently undergone CEA and had presented with acute neurologic deficits. The differential diagnosis for acute neurologic deficit after CEA includes intracranial hemorrhage,4 cerebral hyperperfusion syndrome,5 thromboembolic stroke,6 reversible cerebral vasoconstriction syndrome,1,7 myocardial infarction,8 cervical hematoma,9 postoperative neck infection,10 and iatrogenic nerve injury.11 Given this broad differential diagnosis, the evaluation of these patients will benefit initially from a thorough history, physical examination, laboratory analysis, and diagnostic imaging studies.\n\nBrain perfusion imaging (eg, CT perfusion imaging, which is a component of a CT stroke protocol study) might be required as a part of the diagnostic evaluation and can complement vessel imaging and MRI. The results from our present patient have highlighted the value of CT perfusion imaging to demonstrate asymmetric increases in the mean transit time resulting from small cerebral vessel vasoconstriction (despite the patency of the large vessels at the circle of Willis). The perfusion abnormalities seen in the present case served to be the most striking and obvious findings on diagnostic imaging. These findings in the setting of no cerebral edema (shown by an absence of T2/FLAIR signal on MRI) can help to exclude the possibility of cerebral hyperperfusion or autoregulatory failure as the diagnosis.5 Cerebral angiography can identify these subtle small vessel abnormalities, as in the present case, which will enable the diagnosis of RCVS and also allow for its treatment with intra-arterial vasodilator therapy.\n\nConclusions\n\nAcute neurologic deficits after recent CEA should prompt a thorough diagnostic evaluation with consideration of a broad range of etiologies. Diagnostic imaging studies, specifically perfusion studies, can have an important role in this evaluation. CT perfusion imaging can help identify areas of reversible ischemia, which can be caused by RCVS, shown for the first time in the present case. The prompt identification of perfusion abnormalities is critical to the delivery of timely intervention and avoiding clinically significant cerebral infarction. Without the performance of catheter-directed angiography and the observed response to calcium channel blockers, cases of RCVS can easily be missed, with the assumption that a cardioembolic etiology is responsible for the patient's symptoms.\n\nAuthor conflict of interest: none.\n\nThe editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.\n==== Refs\nReferences\n\n1 Causey M.W. Amans M.R. Han S. Higashida R.T. Conte M. Reversible cerebral vasoconstriction syndrome is a rare cause of stroke after carotid endarterectomy J Vasc Surg 64 2016 1847 1850 26924717\n2 Nowak D.A. Rodiek S.O. Henneken S. Zinner J. Schreiner R. Fuchs H.-H. Reversible segmental cerebral vasoconstriction (Call-Fleming syndrome): are calcium channel inhibitors a potential treatment option? Cephalalgia 23 2003 218 222 12662190\n3 Hemacarotid Patch Ultrathin n.d Available at: https://www.getinge.com/int/product-catalog/hemacarotid-patch-ultrathin/\n4 Wu T.Y. Anderson N.E. Barber P.A. Neurological complications of carotid revascularisation J Neurol Neurosurg Psychiatry 83 2012 543 550 22193563\n5 Huibers A.E. Westerink J. de Vries E.E. Hoskam A. den Ruijter H.M. Moll F.L. Editor’s choice – cerebral hyperperfusion syndrome after carotid artery stenting: a systematic review and meta-analysis Eur J Vasc Endovasc Surg 56 2018 322 333 30196814\n6 Radak D. Popovic A.D. Radicević S. Nesković A.N. Bojić M. Immediate reoperation for perioperative stroke after 2250 carotid endarterectomies: differences between intraoperative and early postoperative stroke J Vasc Surg 30 1999 245 251 10436443\n7 Asuzu D.T. Kumar J. Capek S. Park M.S. Fulminant reversible cerebral vasoconstriction syndrome after carotid endarterectomy for asymptomatic stenosis World Neurosurg 134 2020 423 426 31733386\n8 Boulanger M. Camelière L. Felgueiras R. Berger L. Rerkasem K. Rothwell P.M. Periprocedural myocardial infarction after carotid endarterectomy and stenting Stroke 46 2015 2843 2848 26286540\n9 Doig D. Turner E.L. Dobson J. Featherstone R.L. de Borst G.J. Brown M.M. Incidence, impact, and predictors of cranial nerve palsy and haematoma following carotid endarterectomy in the international carotid stenting study Eur J Vasc Endovasc Surg 48 2014 498 504 25344019\n10 Singh A. Wyatt M. Clarke M. Wales L. Late sterile abscess formation in carotid endarterectomy following use of BioGlue: a word of caution EJVES Short Rep 37 2017 12 13 29234733\n11 Cunningham E.J. Bond R. Mayberg M.R. Warlow C.P. Rothwell P.M. Risk of persistent cranial nerve injury after carotid endarterectomy J Neurosurg 101 2004 445 448 15352602\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-4287",
"issue": "7(1)",
"journal": "Journal of vascular surgery cases and innovative techniques",
"keywords": "CT perfusion; Carotid endarterectomy; Neurological deficits; Reversible cerebral vasoconstriction syndrome; Surgical complications",
"medline_ta": "J Vasc Surg Cases Innov Tech",
"mesh_terms": null,
"nlm_unique_id": "101701125",
"other_id": null,
"pages": "171-175",
"pmc": null,
"pmid": "33748556",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "31733386;26924717;22193563;15352602;12662190;26286540;10436443;30196814;29234733;25344019",
"title": "Computed tomography perfusion abnormalities after carotid endarterectomy help in the diagnosis of reversible cerebral vasoconstriction syndrome.",
"title_normalized": "computed tomography perfusion abnormalities after carotid endarterectomy help in the diagnosis of reversible cerebral vasoconstriction syndrome"
} | [
{
"companynumb": "US-BAYER-2021-156851",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "We present the clinical case of a patient who developed a toxic optic neuropathy due to ethambutol in the context of a tuberculosis reactivation and who also had a personal history of multiple sclerosis. The objective is to highlight the importance of making a good differential diagnosis of this adverse effect and of knowing its main clinical, campimetric and tomographic manifestations and characteristics. Furthermore, since the reversibility of damage is still discussed in the literature, early diagnosis is essential. For this purpose, it is important to inform the patient of the possible symptoms and to carry out an ophthalmological examination and colour tests before starting treatment to assess whether there is progression.",
"affiliations": "Unidad de Neurooftalmología, Servicio de Oftalmología, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, España. Electronic address: v.gomezcalle@gmail.com.;Unidad de Neurooftalmología, Servicio de Oftalmología, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, España.;Unidad de Neurooftalmología, Servicio de Oftalmología, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, España.;Unidad de Neurooftalmología, Servicio de Oftalmología, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, España.",
"authors": "Gómez-Calleja|V|V|;Pérez-García|P|P|;Ly-Yang|F|F|;Santos-Bueso|E|E|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.oftal.2020.12.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5794",
"issue": null,
"journal": "Archivos de la Sociedad Espanola de Oftalmologia",
"keywords": "Esclerosis múltiple; Etambutol; Ethambutol; Multiple sclerosis; Neuropatía óptica; Optic neuropathy; Optical coherence tomography; Tomografía de coherencia óptica",
"medline_ta": "Arch Soc Esp Oftalmol (Engl Ed)",
"mesh_terms": null,
"nlm_unique_id": "101715860",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33632567",
"pubdate": "2021-02-22",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Optic neuropathy by ethambutol in a patient with multiple sclerosis.",
"title_normalized": "optic neuropathy by ethambutol in a patient with multiple sclerosis"
} | [
{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2022-01647",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"... |
{
"abstract": "The incidence of cytomegalovirus (CMV) reactivations in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT) is relatively low. However, the recent increased use of novel agents, such as bortezomib and/or immunomodulators, before transplant, has led to an increasing incidence of Herpesviridae family virus infections. The aim of the study was to establish the incidence of post-engraftment symptomatic CMV reactivations in MM patients receiving ASCT, and to compare this incidence with that of patients treated with novel agents or with conventional chemotherapy before transplant. The study was a survey of 80 consecutive patients who underwent ASCT after treatment with novel agents (Group A). These patients were compared with a cohort of 89 patients treated with VAD regimen (vincristine, doxorubicin, and dexamethasone) before ASCT (Group B). Overall, 7 patients (4.1%) received an antiviral treatment for a symptomatic CMV reactivation and 1 died. The incidence of CMV reactivations was significantly higher in Group A than in Group B (7.5% vs. 1.1%; P = 0.048). When compared with Group B, the CMV reactivations observed in Group A were significantly more frequent in patients who received bortezomib, whether or not associated with immunomodulators (9.4% vs. 1.1%; P = 0.019), but not in those treated with immunomodulators only (3.7% vs. 1.1%; P = 0.396). These results suggest that MM patients treated with bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after ASCT.",
"affiliations": "Hematology Unit, Campus Bio-Medico University Hospital, Rome, Italy.",
"authors": "Marchesi|F|F|;Mengarelli|A|A|;Giannotti|F|F|;Tendas|A|A|;Anaclerico|B|B|;Porrini|R|R|;Picardi|A|A|;Cerchiara|E|E|;Dentamaro|T|T|;Chierichini|A|A|;Romeo|A|A|;Cudillo|L|L|;Montefusco|E|E|;Tirindelli|M C|MC|;De Fabritiis|P|P|;Annino|L|L|;Petti|M C|MC|;Monarca|B|B|;Arcese|W|W|;Avvisati|G|G|;|||",
"chemical_list": "D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "16(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "autologous stem cell transplantation; bortezomib; bortezomib-based therapy; cytomegalovirus; multiple myeloma; novel agents",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D016022:Case-Control Studies; D015331:Cohort Studies; D003586:Cytomegalovirus Infections; D003907:Dexamethasone; D004317:Doxorubicin; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D060828:Induction Chemotherapy; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012189:Retrospective Studies; D012307:Risk Factors; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D014750:Vincristine",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "158-64",
"pmc": null,
"pmid": "24215479",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High incidence of post-transplant cytomegalovirus reactivations in myeloma patients undergoing autologous stem cell transplantation after treatment with bortezomib-based regimens: a survey from the Rome transplant network.",
"title_normalized": "high incidence of post transplant cytomegalovirus reactivations in myeloma patients undergoing autologous stem cell transplantation after treatment with bortezomib based regimens a survey from the rome transplant network"
} | [
{
"companynumb": "IT-JNJFOC-20131111928",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report the long-term anatomical and functional outcomes of patients with choroidal neovascularization secondary to age-related macular degeneration treated with intravitreal bevacizumab (IVB).\n\n\nMETHODS\nRetrospective case series. Patients diagnosed with subfoveal choroidal neovascularization secondary to age-related macular degeneration that were treated with at least 1 intravitreal injection of 1.25 mg of IVB and had a minimum follow-up of 60 months. Patients underwent best-corrected Snellen visual acuity testing, optical coherence tomography, and ophthalmoscopic examination at baseline and follow-up visits.\n\n\nRESULTS\nTwo hundred and forty-seven consecutive patients (292 eyes) were included. The mean number of IVB injections per eye was 10.9 ± 6.4. At 5 years, the BCVA decreased from 20/150 (logMAR 0.9 ± 0.6) at baseline to 20/250 (logMAR 1.1 ± 0.7) (P = <0.0001). The mean CMT decreased from 343.1+ 122.3 μm at baseline to 314.7 ± 128.8 μm at 60 months of follow-up (P = 0.009). Geographic atrophy (GA) was observed at baseline in 47 (16%) of 292 eyes. By 5 years, GA developed or progressed in 124 (42.5%) of 292 eyes (P < 0.0001).\n\n\nCONCLUSIONS\nThe early visual gains obtained from IVB were not maintained at 5 years of follow-up. In addition, IVB may play a role in the development or progression of GA.",
"affiliations": "*Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD; †The Vitreoretinal and Uveitis Division, King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia; ‡The Retina and Vitreous Service, Clínica Privada de Ojos, Mar del Plata, Argentina; § Instituto de Cirugia Ocular, San Jose, Costa Rica; ¶University of Puerto Rico, San Juan, Puerto Rico; **Hospital La Fe, Universidad de Valencia, Spain; ††Clinica Oftalmologica Centro Caracas and the Arevalo-Coutinho Foundation for Research in Ophthalmology, Caracas, Venezuela; ‡‡OFTALMOS, Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina; §§Fundación Hospital Nuestra Señora de la Luz, Mexico City, Mexico; ¶¶Retina Division, Department of Ophthalmology and Visual Sciences, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil; and ***MACULA D&T Diagnóstico, Tratamiento & Rehabilitación Visual, Lima, Peru.",
"authors": "Arevalo|J Fernando|JF|;Lasave|Andres F|AF|;Wu|Lihteh|L|;Acón|Dhariana|D|;Berrocal|María H|MH|;Diaz-Llopis|Manuel|M|;Gallego-Pinazo|Roberto|R|;Serrano|Martin A|MA|;Alezzandrini|Arturo A|AA|;Rojas|Sergio|S|;Maia|Mauricio|M|;Lujan|Silvio|S|;|||",
"chemical_list": "D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000000827",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-004X",
"issue": "36(5)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D020256:Choroidal Neovascularization; D005260:Female; D005451:Fluorescein Angiography; D057092:Geographic Atrophy; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration; D008297:Male; D008875:Middle Aged; D009887:Ophthalmoscopy; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "859-67",
"pmc": null,
"pmid": "26529555",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "INTRAVITREAL BEVACIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION: 5-Year Results of The Pan-American Collaborative Retina Study Group.",
"title_normalized": "intravitreal bevacizumab for choroidal neovascularization in age related macular degeneration 5 year results of the pan american collaborative retina study group"
} | [
{
"companynumb": "US-ROCHE-1661609",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 34-year-old patient, gravida 7, para 0, with three consecutive spontaneous abortions followed by four recurrent molar pregnancies is described. The patient conceived only with clomiphene citrate or human gonadotropin treatment. The occurrence of molar pregnancies succeeded spontaneous abortions with one remaining pregnancy progressing to gestational trophoblastic disease. The role of clomiphene citrate and human gonadotropins in the pathogenesis of this disease is discussed.",
"affiliations": null,
"authors": "Mor-Joseph|S|S|;Anteby|S O|SO|;Granat|M|M|;Brzezinsky|A|A|;Evron|S|S|",
"chemical_list": "D006063:Chorionic Gonadotropin; D002996:Clomiphene; D008596:Menotropins",
"country": "United States",
"delete": false,
"doi": "10.1016/0002-9378(85)90389-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "151(8)",
"journal": "American journal of obstetrics and gynecology",
"keywords": null,
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D006063:Chorionic Gonadotropin; D002996:Clomiphene; D005260:Female; D006801:Humans; D006828:Hydatidiform Mole; D008596:Menotropins; D010062:Ovulation Induction; D011247:Pregnancy; D012008:Recurrence; D014594:Uterine Neoplasms",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "1085-6",
"pmc": null,
"pmid": "3920913",
"pubdate": "1985-04-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Recurrent molar pregnancies associated with clomiphene citrate and human gonadotropins.",
"title_normalized": "recurrent molar pregnancies associated with clomiphene citrate and human gonadotropins"
} | [
{
"companynumb": "IL-SA-2019SA006317",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOMIPHENE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Purpose: To determine the efficacy of pegylated interferon alfa-2A in the treatment of refractory inflammatory cystoid macular edema (CME)Methods: Retrospective chart reviewResults: Treatment with pegylated interferon alfa-2A led to an improvement in CME in all eyes of seven included patients, with a mean decrease in CMT from 478 µm to 310 µm (p < .05). The vision in one patient did not improve due to preexisting retinal atrophy. All other eyes showed improvement in vision, with a mean improvement in best LogMAR visual acuity from +0.59 to +0.28 (p < .05). The treatment effect was sustained with low-dose treatment every 2 weeks or less in the majority of patients. Two patients who stopped interferon treatment given flu-like symptoms and intolerable rash, respectively, showed rapid recurrence of CME.Conclusions: Weekly administration of pegylated interferon alfa-2A is an effective treatment for refractory inflammatory CME, though side effects may limit tolerability in some patients.",
"affiliations": "Department of Ophthalmology, Portland VA Health Care System, Portland, OR, USA.;Department of Ophthalmology, Portland VA Health Care System, Portland, OR, USA.;Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.;Department of Ophthalmology, Portland VA Health Care System, Portland, OR, USA.;Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.;Department of Ophthalmology, Portland VA Health Care System, Portland, OR, USA.",
"authors": "Stiefel|Hillary C|HC|;Kopplin|Laura J|LJ|;Albini|Thomas|T|;Chang|Michael|M|;Vegunta|Sravanthi|S|;Suhler|Eric B|EB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2019.1687729",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "29(3)",
"journal": "Ocular immunology and inflammation",
"keywords": "Pegylated interferon (peginterferon alfa-2A); cystoid macular edema; uveitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "566-571",
"pmc": null,
"pmid": "31743052",
"pubdate": "2021-04-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of Refractory Cystoid Macular Edema with Pegylated Interferon Alfa-2A: A Retrospective Chart Review.",
"title_normalized": "treatment of refractory cystoid macular edema with pegylated interferon alfa 2a a retrospective chart review"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-328837",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Herein we share, to our knowledge for the first time, a a case of valproic acid use complicated by symptomatic atrio-ventricular conduction block episodes on Holter monitoring. Symptomatic atrio-ventricular block episodes should be considered as an unusual side effect of valproic acid despite normal blood therapeutic level. Before consideration of pacemaker implantation in such cases, valproic acid usage should be investigated, and dose reduction should be attempted.",
"affiliations": "Gaziantep University, Department of Cardiology.;Gaziantep University, Department of Neurology.;Gaziantep University, Department of Cardiology.",
"authors": "Davutoglu|Vedat|V|;Neyal|Munife|M|;Altunbas|Gokhan|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4022/jafib.1520",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-6911",
"issue": "9(5)",
"journal": "Journal of atrial fibrillation",
"keywords": "Valproic acid; atrio-ventricular block; drug",
"medline_ta": "J Atr Fibrillation",
"mesh_terms": null,
"nlm_unique_id": "101514767",
"other_id": null,
"pages": "1520",
"pmc": null,
"pmid": "29250271",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "16650140;22126214;8822697",
"title": "Valproic Acid as a Cause of Transient Atrio-Ventricular Conduction Block Episodes.",
"title_normalized": "valproic acid as a cause of transient atrio ventricular conduction block episodes"
} | [
{
"companynumb": "TR-VISTAPHARM, INC.-VER201801-000104",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional"... |
{
"abstract": "Recurrent malignant gliomas (RMGs) are difficult to control, and no standard protocol has been established for their treatment. At our institute, we have often treated RMGs by tumor-selective particle radiation called boron neutron capture therapy (BNCT). However, despite the cell-selectivity of BNCT, brain radiation necrosis (BRN) may develop and cause severe neurological complications and sometimes death. This is partly due to the full-dose X-ray treatments usually given earlier in the treatment course. To overcome BRN following BNCT, recent studies have used bevacizumab (BV). We herein used extended BV treatment beginning just after BNCT to confer protection against or ameliorate BRN, and evaluated; the feasibility, efficacy, and BRN control of this combination treatment. Seven patients with RMGs (grade 3 and 4 cases) were treated with BNCT between June 2013 and May 2014, followed by successive BV treatments. They were followed-up to December 2017. Median overall survival (OS) and progression-free survival (PFS) after combination treatment were 15.1 and 5.4 months, respectively. In one case, uncontrollable brain edema occurred and ultimately led to death after BV was interrupted due to meningitis. In two other cases, symptomatic aggravation of BRN occurred after interruption of BV treatment. No BRN was observed during the observation period in the other cases. Common terminology criteria for adverse events grade 2 and 3 proteinuria occurred in two cases and necessitated the interruption of BV treatments. Boron neutron capture therapy followed by BV treatments well-prevented or well-controlled BRN with prolonged OS and acceptable incidence of adverse events in our patients with RMG.",
"affiliations": "Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.;Kyoto University Research Reactor Institute.;Kyoto University Research Reactor Institute.;Kyoto University Research Reactor Institute.;Kyoto University Research Reactor Institute.;Department of Neurosurgery, Ehime Prefectural Central Hospital.;Department of Neurosurgery, Tsukuba University.;Neutron Therapy Research Center, Okayama University.;Section for Advanced Medical Development, Cancer Center, Osaka Medical College.",
"authors": "Shiba|Hiroyuki|H|;Takeuchi|Koji|K|;Hiramatsu|Ryo|R|;Furuse|Motomasa|M|;Nonoguchi|Naosuke|N|;Kawabata|Shinji|S|;Kuroiwa|Toshihiko|T|;Kondo|Natsuko|N|;Sakurai|Yoshinori|Y|;Suzuki|Minoru|M|;Ono|Koji|K|;Oue|Shiro|S|;Ishikawa|Eiichi|E|;Michiue|Hiroyuki|H|;Miyatake|Shin-Ichi|SI|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab",
"country": "Japan",
"delete": false,
"doi": "10.2176/nmc.oa.2018-0111",
"fulltext": "\n==== Front\nNeurol Med Chir (Tokyo)Neurol. Med. Chir. (Tokyo)NMCNeurologia medico-chirurgica0470-81051349-8029The Japan Neurosurgical Society 3046415010.2176/nmc.oa.2018-0111nmc-58-487Original ArticleBoron Neutron Capture Therapy Combined with Early Successive Bevacizumab Treatments for Recurrent Malignant Gliomas – A Pilot Study SHIBA Hiroyuki 1TAKEUCHI Koji 1HIRAMATSU Ryo 1FURUSE Motomasa 1NONOGUCHI Naosuke 1KAWABATA Shinji 1KUROIWA Toshihiko 1KONDO Natsuko 2SAKURAI Yoshinori 2SUZUKI Minoru 2ONO Koji 2OUE Shiro 3ISHIKAWA Eiichi 4MICHIUE Hiroyuki 5MIYATAKE Shin-Ichi 61 Department of Neurosurgery, Osaka Medical College, Takatsuki, Osaka, Japan;2 Kyoto University Research Reactor Institute, Kumatori, Osaka, Japan;3 Department of Neurosurgery, Ehime Prefectural Central Hospital, Matsuyama, Ehime, Japan;4 Department of Neurosurgery, Tsukuba University, Tsukuba, Ibaraki, Japan;5 Neutron Therapy Research Center, Okayama University, Okayama, Okayama, Japan;6 Section for Advanced Medical Development, Cancer Center, Osaka Medical College, Takatsuki, Osaka, JapanAddress reprint requests to: Shin-Ichi Miyatake, MD, PhD, Section for Advanced Medical Development, Cancer Center, Osaka Medical College, 2–7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan. e-mail: neu070@osaka-med.ac.jp12 2018 21 11 2018 58 12 487 494 23 4 2018 27 9 2018 © 2018 The Japan Neurosurgical Society2018This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Recurrent malignant gliomas (RMGs) are difficult to control, and no standard protocol has been established for their treatment. At our institute, we have often treated RMGs by tumor-selective particle radiation called boron neutron capture therapy (BNCT). However, despite the cell-selectivity of BNCT, brain radiation necrosis (BRN) may develop and cause severe neurological complications and sometimes death. This is partly due to the full-dose X-ray treatments usually given earlier in the treatment course. To overcome BRN following BNCT, recent studies have used bevacizumab (BV). We herein used extended BV treatment beginning just after BNCT to confer protection against or ameliorate BRN, and evaluated; the feasibility, efficacy, and BRN control of this combination treatment. Seven patients with RMGs (grade 3 and 4 cases) were treated with BNCT between June 2013 and May 2014, followed by successive BV treatments. They were followed-up to December 2017. Median overall survival (OS) and progression-free survival (PFS) after combination treatment were 15.1 and 5.4 months, respectively. In one case, uncontrollable brain edema occurred and ultimately led to death after BV was interrupted due to meningitis. In two other cases, symptomatic aggravation of BRN occurred after interruption of BV treatment. No BRN was observed during the observation period in the other cases. Common terminology criteria for adverse events grade 2 and 3 proteinuria occurred in two cases and necessitated the interruption of BV treatments. Boron neutron capture therapy followed by BV treatments well-prevented or well-controlled BRN with prolonged OS and acceptable incidence of adverse events in our patients with RMG.\n\nbevacizumabboron neutron capture therapybrain radiation necrosisrecurrent malignant glioma\n==== Body\nIntroduction\nThe prognosis of recurrent malignant gliomas (RMGs) is poor, and no standard treatment has been established.1) Since 2002 at our institute, we have applied a form of tumor-selective particle radiation called, boron neutron capture therapy (BNCT), for patients with RMGs and observed favorable survival outcomes.2,3) BNCT is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low-energy thermal neutrons to yield high-linear-energy transfer alpha particles and recoiling lithium-7 nuclei. These particles are released within a very short range such as 9 μm, and therefore the cytotoxic effects are confined to within boron-10-containing cells.4)\n\nBoron-10-containing compounds can be accumulated selectively in tumor cells by several mechanisms. For example, boronophenylalanine (BPA) is selectively and preferentially accumulated in tumor cells by amino acid transporters through their increased metabolism of amino acids compared to normal cells. Even with this novel and selective particle radiation therapy, radiation damage—chiefly brain radiation necrosis (BRN) and symptomatic pseudoprogression (psPD)—often occurs.5,6) Radiation damage is especially likely in RMG cases, because full-dose X-ray treatment (XRT) is generally part of the treatment history in such cases.\n\nIn a previous study analyzing human BRN surgical specimens, we discovered that the edema in BRN is caused by overexpression of vascular endothelial growth factor (VEGF) in reactive astrocytes.7) Bevacizumab (BV), an anti-VEGF antibody, has recently been used for the treatment of symptomatic BRN.8–10) Based on these findings, we have recently used BV in an attempt to control the symptomatic BRN and the psPD encountered after BNCT for RMGs.5,11)\n\nRecently, several reports have examined the use of re-irradiation for RMG with addition of BV to confer protection against radiation injury12,13) and to enhance the efficacy of irradiation by overcoming the hypoxia-mediated mechanisms of radio-resistance.14) Here, we introduce the preliminary results of our use of BNCT for re-irradiation of RMG with BV added just after BNCT and continued for as long as possible. In this study, we estimate the feasibility and efficacy of this treatment.\n\nMaterials and Methods\nPatient background\nFrom June 2013 to May 2014, we treated seven cases of RMG using reactor-based BNCT. All patients had undergone full-dose XRT at the initial treatment. Patients’ demographics are documented in Table 1; these included WHO grade (histology), age, class of recursive portioning analysis (RPA) for RMG as advocated by Carson et al. in a 2007 article in the Journal of Clinical Oncology.1) Patients were followed-up until the end of December 2017.\n\nClinical regimen of BNCT\nThis protocol was approved by the Ethical Committee of Osaka Medical College with the authorization number 1386. After confirmation of the recurrence of the original lesions on magnetic resonance imaging (MRI), the patients underwent BPA–positron emission tomography (PET) analysis to assess the distribution of BPA.15,16) The lesion/normal brain (L/N) ratio of BPA uptake can be estimated from this BPA–PET, and dose planning was performed according to the L/N ratio, as described previously.2,17) BPA was purchased from Interpharma Praha, a.s., (Prague, Czech Republic) and administered over a 2-h period (200 mg/kg/h) just prior to and during the neutron irradiation (100 mg/kg/h), as described previously.18) Based on the PET-based simulation described above and blood boron concentration in each patient, we selected a neutron irradiation time that would keep the peak brain dose below 11.0 Gy-equiv. (Gray-equivalent) in cases 1–4. After confirmation of the safety of this approach in these four cases, the neutron irradiation time was increased to keep the peak brain dose below 13.0 Gy-equiv. in cases 5–7. Here, Gy-equiv. corresponds to the biologically equivalent X-ray dose that would have equivalent effects on tumors and on the normal brain.\n\nBV treatments\nThe BV treatments were initiated at 2–6 weeks after BNCT and continued until the tumor progression or occurrence of several adverse events (AE) such as continuous grade 3 proteinuria (common terminology criteria for adverse events: CTCAE ver. 4.0), or until discontinuation at the wish of the patient. The dose of BV was principally 10 mg/kg biweekly, but was decreased as appropriate due to AE.\n\nPatient follow-up and study endpoints\nPatients were followed-up by bimonthly Gd-enhanced and fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI). When the lesions became enlarged or new lesions appeared on the follow-up MRI, we applied BPA–PET to evaluate the tumor activity in selected cases,11) if the PET machine time was available, to distinguish the pathology as tumor progression or BRN or psPD, as shown in Table 1. BRN was judged by repetitive PET or transient aggravation on MRI during interruption of BV treatment, together with recovery of the aggravation by resumption of BV treatment. Worsening of the FLAIR and/or T1-Gd image on MRI even with the continuation of BV treatments was judged as tumor progression. If the follow-up PET showed the increased L/N ratio in comparison with the baseline PET, the lesion was judged as tumor recurrence. If the L/N ratio in follow-up PET showed decreased activity in comparison with baseline L/N ratio, the lesion was judged as BRN.19)\n\nThe feasibility (occurrence of any AE), efficacy (overall survival (OS)) and progression free survival (PFS), and control of BRN were evaluated.\n\nRPA classification\nTo objectively evaluate the survival benefit of this treatment, we classified our BNCT cases according to Carson’s RPA classification as follows1): RPA class 1, not GBM (initial histology), KPS ≥ 80, frontal only (tumor location); RPA class 2, not GBM, KPS ≥ 80, not frontal only; RPA class 3, not GBM, 60 ≤ KPS ≤ 70; RPA class 4, GBM, age < 50, KPS ≥ 90; RPA class 5, GBM, age < 50, 60 ≤ KPS ≤ 80; RPA class 6, GBM, age ≥ 50, no steroid use; RPA class 7, GBM, age ≥ 50, steroid use. Table 1 shows the RPA classification for each of our cases treated by BNCT.\n\nResults\nEach of the endpoints (OS, PFS, AE and control of BRN), the corresponding median OS (mOS) described in Carson’s RPA classification, the BNCT-related minimum and maximum dose for tumor and maximum dose for normal brain tissue, and the courses of BV treatments and causes of death are summarized in Table 1.\n\nOverall and progression free survival\nTwo of the seven patients were still alive at the end of the observation period (December 2017). mOS and PFS after the BNCT and BV treatments were 15.1 and 5.4 months, respectively. With regard to OS, only one case (Case 6) showed a shorter survival time in comparison with the reported mOS classified with the corresponding Carson’s RPA. The other six cases showed longer survival times than those in the classification. Even with the application of RANO criteria, it is rather difficult to assess PFS due to the modification of MRI made to account for the influence of BV.20) We lost four cases due to tumor progression and one case (Case 6) due to uncontrollable brain edema.\n\nControl of BRN\nBrain radiation necrosis may have been present in three cases (Cases 4, 6 and 7). In cases 4 and 6, BV treatments were discontinued due to severe meningitis (Table 1) and financial difficulties, respectively. Case 7 showed the aggravation of brain edema and slight enhancement during the discontinuance of BV treatments, which seemed to be BRN (see the detail in the case presentation below). Another case (Case 1) experienced transient aggravation suggestive of psPD on MRI, 1 month after BNCT. In the other three cases, there was no incidence of BRN or psPD, as judged by follow-up PET imaging or the clinical course, as defined above.\n\nAdverse events\nAll cases showed CTCAE grade 2 alopecia which is usually observed in BNCT alone. As shown in Table 1, proteinuria was the most commonly observed AE during BV treatment. In the present study, CTCAE grade 2 and 3 proteinuria were observed in two individual cases (Cases 3 and 7) and grade 1 proteinuria was observed in two cases (Cases 1 and 4).\n\nInstructive case presentations\nCase 3:\nA 36-year-old male with recurrent anaplastic oligo-astrocytoma. RPA was classified as class 2. Prior to BNCT and BV treatment, he complained of intractable seizure. After the treatment the seizure could be well-controlled and the patient exhibited improvement on MRI. Repeated BPA–PET analysis yielded L/N ratios of 5.0, 1.9 and 2.1 just prior to, 7 months after, and 13 months after BNCT, respectively, as shown in Fig. 1.21–23) Unfortunately, MRI was aggravated as shown in the Fig. 1A-4 and B-4, and the patient died of tumor progression 38 months after BNCT. The patient received a total of 55 courses of BV. The prominent AE were general fatigue and proteinuria (CTCAE grade 2).\n\nCase 7:\nA 57-year-old male with re-recurrent anaplastic oligo-astrocytoma. RPA was classified as class 3, because he lost his job as a carpenter due to disease progression. He underwent 60 Gy XRT at the first recurrence, but unfortunately this had no effect on the recurrent tumor. The L/N ratios of BPA–PET prior to XRT and BNCT were 2.9 and 3.7, respectively. BNCT was administered at 6 months after XRT. BNCT and subsequent BV well-controlled his tumor. The L/N ratios of BPA–PET studies at 1, 3.5, and 12 months after BNCT were 2.2, 2.1 and 1.8, respectively, as shown in Fig. 2. He returned to his job 3 months after BNCT. He underwent 58 courses of BV. The prominent AE was proteinuria (CTCAE grade 3), which necessitated an occasional interruption of BV. When 5 months had passed after discontinuance of BV administration (38 months after BNCT) because of proteinuria, his right hemiparesis and dysarthria worsened and his convulsions increased. Based on MRI studies, we attributed these developments to symptomatic BRN (Fig. 3).\n\nDiscussion\nMalignant gliomas still represent one of the most aggressive and devastating tumors in neuro-oncology. In spite of extensive research, the treatment outcome is still not satisfying. At primary diagnosis, treatment commonly consists of neurosurgical resection, as radical as possible without resulting in marked morbidity, followed by post-operative radiotherapy. With this combination, overall survival rates of 9–12 months have been obtained.24,25) Recently, novel chemotherapy regimens have been added to this treatment combination. Radiochemotherapy with temozolomide has achieved a significant increase in overall survival times up to 14.6 months.26) Concomitant administration of ACNU/VM26 to radiotherapy could extend overall survival to 16.5 months.27) However, almost all GBM recur, with local failure being the most common pattern of recurrence.28) Therefore, local control is the most critical issue to help improve overall survival for patients with GBM.\n\nIn most patients, treatment options at the time of recurrence are limited. Chemotherapy is the most frequently applied treatment for recurrent gliomas. Radiotherapy as a treatment for recurrent gliomas is controversial. Commonly, full doses of irradiation have been applied post-operatively after primary diagnosis, and re-irradiation is associated with a higher risk of BRN, with toxicity outweighing its benefits.29) Even with tumor-selective particle radiation BNCT, BRN or symptomatic psPD are inevitable due to not only the preceding XRT but also BNCT which gives the peak dose of approximately 10–13 Gy-equiv. to the normal brain by single fraction irradiation, as in the present series.\n\nIn this small-scale preliminary clinical study, only one case (Case 6) showed an OS shorter than the corresponding mOS in Carson’s RPA classification. Two patients (Cases 4 and 7) are still alive without tumor progression. In these patients a rather high tumor minimum dose was prescribed (>60 Gy-equiv., as shown in Table 1), which may have been the reason for the excellent OS. The other six cases showed good control of BRN by this treatment protocol and showed an OS longer than the corresponding mOS in Carson’s RPA classification.\n\nWith regard to newly diagnosed GBM, BV was not found to contribute to the prolongation of OS in two large-scale phase 3 clinical trials.30,31) Also for recurrent GBM, BV showed no contribution to the prolongation of OS in the phase 3 EORTC 26101 trial,32) although promising results were obtained in a phase 2 clinical trial.33) In comparison with these clinical results, our preliminary study showed several potentially conflicting findings in regard to OS prolongation. Based on our study, BV was expected to contribute to the prolongation of OS through its synergy with BNCT. However, although there have been several retrospective reports of the role of BV in re-irradiation for RMG,34–37) none of them showed any apparent benefit of BV in the prolongation of OS for RMG in a re-irradiation setting. Further clarification is expected to come from the RTOG 1205/NCT01730950 trial, which was conducted to compare re-irradiation/BV with BV alone. As discussed above, BRN was well-controlled in the present study, with only one patient dying from severe brain edema because he could not be kept on BV treatments. Therefore, the prolonged OS in this series should be attributed to the synergy of BNCT and the control of BRN by BV.\n\nThe most common and prominent additional AE in this treatment regimen, compared to BNCT alone, was proteinuria. In this series, the occurrence rate and the severity of proteinuria may have been related to the total BV dose. In the literature, there are only two reports about the relationship of the incidence of proteinuria to the total dose of BV. Hayman SR reported an apparent relationship between proteinuria and the cumulative dose of BV,38) while Slusarz39) did not recognize any relationship. There have been several reports concerning the distinctive relationship between a single dose of BV and proteinuria.40–43) We and other investigators reported that a regimen with smaller doses of BV (5 mg/kg, biweekly) still exhibited potent effects for BRN.9,10) Further clinical trials will thus be needed to examine the potential of such smaller doses to reduce the risk of proteinuria. In addition, the timing of the first BV treatment should start within a month, and hopefully within 2 weeks, after BNCT, because Case 1 showed symptomatic psPD at 1 month after BNCT, which was recovered with subsequent addition of BV.\n\nBoron neutron capture therapy followed by BV treatments well-prevented or well-controlled BRN with prolonged OS and acceptable incidence of AE in our cohort of patients with RMG. Most interesting issue in this clinical study not only for authors but also for readers is BNCT with early administration of BV can show the superior clinical results for RMG especially in OS in comparison with BNCT alone or not. In the previous work,3) we showed BNCT without early BV intervention showed mOS as 10.8M (95% confidence interval (CI): 7.3–12.8M) and 9.1M (95% CI: 4.4–11.0M) for all RMG (n = 22) and poor risk RMG (RPA class 3 and 7) (n = 11), respectively. While in this current study we showed BNCT with early BV administration showed mOS as 15.1M (95% CI: 6.5–42.7M) and 11.1M (95% CI: −3.0–35.5M) for all RMG (n = 7) and for poor risk RMG (RPA class 3 and 7) (n = 5), respectively. At a glance, there are differences in OS both in all RMG and in poor risk RMG cases between BNCT with and without early BV treatments. However, there is no statistical significance between them with statistical analyses. Possibly small patient numbers and large variations in OS in this current study may be the cause of the lack of statistical significance. Based on these preliminary results, now we are performing a prospective clinical trial using BNCT and simultaneous BV treatments for poor prognosis patients with recurrent malignant glioma.\n\nFunding\n\nThis work was partly supported by “Kenzo Suzuki Memorial Medical Science Applications Foundation”.\n\nConflicts of Interest Disclosure\n\nThe author declares that there are no conflicts of interest.\n\nFig. 1. Periodic change of MRI and BPA–PET in Case 3. The upper panel (A-1 to A-5) shows FLAIR MRI studies. The middle panel (B-1 to B-5) shows Gd-T1 MRI studies. The lower panel (C-1 to C-3) shows F-BPA–PET studies. The lesion to normal brain (L/N) ratio of the enhanced tumor is 5.0 (C-1), 2.2 (C-2), and 1.7 (C-3). A-1, B-1, and C-1; prior to BNCT. A-2, B-2, and C-2; 7 months after BNCT. A-3, B-3, and C-3; 13 months after BNCT. A-4 and B-4; 26.5 months after BNCT. A-5 and B-5; 33 months after BNCT. This is the representative tumor recurrence appeared in this treatment regimen. BV treatment can control the BRN but even after BNCT some tumor recurred. The tumor recurrence with the maintenance BV treatments seems to be aggressive as reported.41–43)\n\nFig. 2. Periodic change of MRI in Case 7. The upper panel (A-1 to A-4) shows FLAIR MRI studies. The middle panel (B-1 to B-4) shows Gd-T1 MRI studies. The lower panel (C-1 to C-5) shows time course of BPA–PET imaging. A-1 and B-1 are prior to BNCT. A-2 and B-2 are 1 week after BNCT. A-3 and B-3 are 1 month after BNCT. A-4 and B-4 are 24 months after BNCT. Each time of point and L/N ratio of PET imaging are stated in case presentation in the text of Results. This is the illustrative case that BNCT can control tumor activity, while BV can control BRN successively and successfully for long time.\n\nFig. 3. Aggravation of BRN in case 7 due to BV discontinuance. Five months after discontinuance of BV administration because of proteinuria (38 months after BNCT) in case 7. His right hemiparesis and dysarthria got worse and convulsions increased. We considered them as due to symptomatic BRN by follow-up MRI studies and clinical course.\n\nTable 1 Clinical data of individual patients in this series\n\n\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\tCase 7\t\nAge at BNCT\t68\t66\t36\t37\t62\t57\t57\t\nGender\tMale\tMale\tMale\tMale\tMale\tMale\tMale\t\nWHO grade (histology)\tIV (GBM)\tIV (GBM)\tIII (AOA)\tIII (AO)\tIV (GBM)\tIV (GBM)\tIII (AOA)\t\nRPA class\t7\t3\t2\t1\t7\t7\t3\t\nBRN while BV treatment\tNo\tNo\tNo\tNo\tNo\tNo\tNo\t\nCause of death\tTumor progression\tTumor progression\tTumor progression\tAlive\tTumor progression\tMeningitis\tAlive\t\nmOS in JCO# (Month)\t4.9\t3.8\t17.2\t25.7\t4.9\t4.9\t3.8\t\nOS (Month)\t15.1\t7.5\t38\t53 (Censored)\t11.1\t4.4\t43 (Censored)\t\nPFS (Month)\t3.6\t5.4\t19.5\t53 (No progression)\t5\tNot applicable\t43 (No progression)\t\nBNCT dose (Gy-equiv.)\t\t\t\t\t\t\t\t\n Tumor mini\t36.8\t29.9\t42.6\t60.4\t27.6\t43.8\t63.9\t\n Tumor max\t56.3\t69.2\t97.5\t96.5\t54.4\t96.2\t151\t\n Normal max\t8.92\t10.5\t9.68\t10.1\t11.2\t13\t12\t\nCourses of BV\t19\t9\t55\t32\t20\t2\t65\t\nAdverse events\tProteinuria grade 1\tNo\tProteinuria grade 2\tProteinuria grade 1\tNo\tMeningitis\tProteinuria grade 3\t\nBRN: brain radiation necrosis, BV: bevacizumab, OS: overall survival, PFS: progression free survival is determined by RANO criteria appeared in J Clin Oncol,20) RPA class: recursive portioning analysis class is determined by the criteria advocated by Carson et al.,1)\n\n# Median overall survival for the corresponding RPA class, described in J Clin Oncol 2007. See the detail in the text and reference number 1.\n==== Refs\nReferences\n1) Carson KA Grossman SA Fisher JD Shaw EG : Prognostic factors for survival in adult patients with recurrent glioma enrolled onto the new approaches to brain tumor therapy CNS consortium phase I and II clinical trials . J Clin Oncol \n25 : 2601 –2606 , 2007 17577040 \n2) Miyatake S Kawabata S Kajimoto Y : Modified boron neutron capture therapy for malignant gliomas performed using epithermal neutron and two boron compounds with different accumulation mechanisms: an efficacy study based on findings on neuroimages . J Neurosurg \n103 : 1000 –1009 , 2005 16381186 \n3) Miyatake S Kawabata S Yokoyama K : Survival benefit of boron neutron capture therapy for recurrent malignant gliomas . J Neurooncol \n91 : 199 –206 , 2009 18813875 \n4) Barth RF Vicente MG Harling OK : Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer . Radiat Oncol \n7 : 146 , 2012 22929110 \n5) Miyatake S Furuse M Kawabata S : Bevacizumab treatment of symptomatic pseudoprogression after boron neutron capture therapy for recurrent malignant gliomas. Report of 2 cases . Neuro-oncology \n15 : 650 –655 , 2013 23460324 \n6) Miyatake S Kawabata S Nonoguchi N : Pseudoprogression in boron neutron capture therapy for malignant gliomas and meningiomas . Neuro-oncology \n11 : 430 –436 , 2009 19289492 \n7) Nonoguchi N Miyatake S Fukumoto M : The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles . J Neurooncol \n105 : 423 –431 , 2011 21688077 \n8) Furuse M Kawabata S Kuroiwa T Miyatake S : Repeated treatments with bevacizumab for recurrent radiation necrosis in patients with malignant brain tumors: a report of 2 cases . J Neurooncol \n102 : 471 –475 , 2011 20694573 \n9) Furuse M Nonoguchi N Kuroiwa T : A prospective, multicentre, single-arm clinical trial of bevacizumab for patients with surgically untreatable, symptomatic brain radiation necrosis† . Neurooncol Pract \n3 : 272 –280 , 2016 27833757 \n10) Levin VA Bidaut L Hou P : Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system . Int J Radiat Oncol Biol Phys \n79 : 1487 –1495 , 2011 20399573 \n11) Miyatake S Kawabata S Hiramatsu R Furuse M Kuroiwa T Suzuki M : Boron neutron capture therapy with bevacizumab may prolong the survival of recurrent malignant glioma patients: four cases . Radiat Oncol \n9 : 6 , 2014 24387301 \n12) Perez-Torres CJ Yuan L Schmidt RE : Specificity of vascular endothelial growth factor treatment for radiation necrosis . Radiother Oncol \n117 : 382 –385 , 2015 26376163 \n13) Schnell O Thorsteinsdottir J Fleischmann DF : Re-irradiation strategies in combination with bevacizumab for recurrent malignant glioma . J Neurooncol \n130 : 591 –599 , 2016 27599828 \n14) Anderson JC Duarte CW Welaya K : Kinomic exploration of temozolomide and radiation resistance in glioblastoma multiforme xenolines . Radiother Oncol \n111 : 468 –474 , 2014 24813092 \n15) Imahori Y Ueda S Ohmori Y : Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high-grade gliomas: part I . Clin Cancer Res \n4 : 1825 –1832 , 1998 9717808 \n16) Imahori Y Ueda S Ohmori Y : Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high-grade gliomas: part II . Clin Cancer Res \n4 : 1833 –1841 , 1998 9717809 \n17) Kawabata S Miyatake S Kajimoto Y : The early successful treatment of glioblastoma patients with modified boron neutron capture therapy. Report of two cases . J Neurooncol \n65 : 159 –165 , 2003 14686736 \n18) Kawabata S Hiramatsu R Kuroiwa T Ono K Miyatake S : Boron neutron capture therapy for recurrent high-grade meningiomas . J Neurosurg \n119 : 837 –844 , 2013 23808536 \n19) Miyashita M Miyatake S Imahori Y : Evaluation of fluoride-labeled boronophenylalanine-PET imaging for the study of radiation effects in patients with glioblastomas . J Neurooncol \n89 : 239 –246 , 2008 18566749 \n20) Wen PY Macdonald DR Reardon DA : Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group . J Clin Oncol \n28 : 1963 –1972 , 2010 20231676 \n21) Han SJ Rolston JD Molinaro AM : Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma . Neuro-oncology \n16 : 1255 –1262 , 2014 24670608 \n22) Omuro A Chan TA Abrey LE : Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma . Neuro-oncology \n15 : 242 –250 , 2013 23243055 \n23) Mrugala MM Engelhard HH Dinh Tran D : Clinical practice experience with NovoTTF-100ATM system for glioblastoma: The Patient Registry Dataset (PRiDe) . Semin Oncol \n41 \nSuppl 6 : S4 –S13 , 2014 25213869 \n24) Walker MD Gehan EA : Clinical studies in malignant gliomas and their treatment with the nitrosoureas . Cancer Treat Rep \n60 : 713 –716 , 1976 782695 \n25) Combs SE Gutwein S Schulz-Ertner D : Temozolomide combined with irradiation as postoperative treatment of primary glioblastoma multiforme. Phase I/II study . Strahlenther Onkol \n181 : 372 –377 , 2005 15925979 \n26) Stupp R Mason WP van den Bent MJ : Concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM). Conclusive results of a randomized phase III trial by the EORTC Brain & RT Groups and NCIC Clinical Trials Group. 2004 \n27) Weller M Müller B Koch R Bamberg M Krauseneck P Neuro-Oncology Working Group of the German Cancer Society : Neuro-oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma . J Clin Oncol \n21 : 3276 –3284 , 2003 12947063 \n28) Sneed PK Gutin PH Larson DA : Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost . Int J Radiat Oncol Biol Phys \n29 : 719 –727 , 1994 8040017 \n29) Brandes AA Pasetto LM Monfardini S : New drugs in recurrent high grade gliomas . Anticancer Res \n20 : 1913 –1920 , 2000 10928126 \n30) Chinot OL Wick W Mason W : Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma . N Engl J Med \n370 : 709 –722 , 2014 24552318 \n31) Gilbert MR Dignam JJ Armstrong TS : A randomized trial of bevacizumab for newly diagnosed glioblastoma . N Engl J Med \n370 : 699 –708 , 2014 24552317 \n32) Wick W Gorlia T Bendszus M : Lomustine and bevacizumab in progressive glioblastoma . N Engl J Med \n377 : 1954 –1963 , 2017 29141164 \n33) Taal W Oosterkamp HM Walenkamp AM : Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial . Lancet Oncol \n15 : 943 –953 , 2014 25035291 \n34) Flieger M Ganswindt U Schwarz SB : Re-irradiation and bevacizumab in recurrent high-grade glioma: an effective treatment option . J Neurooncol \n117 : 337 –345 , 2014 24504501 \n35) Gutin PH Iwamoto FM Beal K : Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas . Int J Radiat Oncol Biol Phys \n75 : 156 –163 , 2009 19167838 \n36) Hundsberger T Brügge D Putora PM Weder P Weber J Plasswilm L : Re-irradiation with and without bevacizumab as salvage therapy for recurrent or progressive high-grade gliomas . J Neurooncol \n112 : 133 –139 , 2013 23314822 \n37) Niyazi M Ganswindt U Schwarz SB : Irradiation and bevacizumab in high-grade glioma retreatment settings . Int J Radiat Oncol Biol Phys \n82 : 67 –76 , 2012 21030162 \n38) Hayman SR Calle JC Jatoi A : Urinary podocyte excretion and proteinuria in patients treated with antivascular endothelial growth factor therapy for solid tumor malignancies . Oncology \n86 : 271 –278 , 2014 24902997 \n39) Slusarz KM Merker VL Muzikansky A Francis SA Plotkin SR : Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients . Cancer Chemother Pharmacol \n73 : 1197 –1204 , 2014 24710627 \n40) Izzedine H Massard C Spano JP Goldwasser F Khayat D Soria JC : VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management . Eur J Cancer \n46 : 439 –448 , 2010 20006922 \n41) Johnson DH Fehrenbacher L Novotny WF : Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer . J Clin Oncol \n22 : 2184 –2191 , 2004 15169807 \n42) Yang JC Haworth L Sherry RM : A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer . N Engl J Med \n349 : 427 –434 , 2003 12890841 \n43) Zhu X Wu S Dahut WL Parikh CR : Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis . Am J Kidney Dis \n49 : 186 –193 , 2007 17261421\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0470-8105",
"issue": "58(12)",
"journal": "Neurologia medico-chirurgica",
"keywords": "bevacizumab; boron neutron capture therapy; brain radiation necrosis; recurrent malignant glioma",
"medline_ta": "Neurol Med Chir (Tokyo)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D016754:Boron Neutron Capture Therapy; D001932:Brain Neoplasms; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005240:Feasibility Studies; D005260:Female; D005910:Glioma; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010865:Pilot Projects; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "0400775",
"other_id": null,
"pages": "487-494",
"pmc": null,
"pmid": "30464150",
"pubdate": "2018-12-15",
"publication_types": "D016428:Journal Article",
"references": "10928126;12890841;12947063;14686736;15169807;15925979;16381186;17261421;17577040;18566749;18813875;19167838;19289492;20006922;20231676;20399573;20694573;21030162;21688077;22929110;23243055;23314822;23460324;23808536;24387301;24504501;24552317;24552318;24670608;24710627;24813092;24902997;25035291;25213869;26376163;27599828;27833757;29141164;782695;8040017;9717808;9717809",
"title": "Boron Neutron Capture Therapy Combined with Early Successive Bevacizumab Treatments for Recurrent Malignant Gliomas - A Pilot Study.",
"title_normalized": "boron neutron capture therapy combined with early successive bevacizumab treatments for recurrent malignant gliomas a pilot study"
} | [
{
"companynumb": "JP-ROCHE-2080372",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Erythromelalgia is a rare neurovascular disorder characterized by erythema, warmth, and episodic burning pain, often felt in the face, hands, and feet. Symptoms are typically worse with heat, exercise, stress, and during the overnight hours. Management often requires a multidisciplinary approach, including pain trigger avoidance, cool water baths, and topical and oral neuropathic medications. The use of spinal cord stimulation has been described in multiple case reports with success reported out to 24 months. To our knowledge, the use of dorsal root ganglion (DRG) stimulation for erythromelalgia-related pain has not been described. Herein, we present a case of erythromelalgia-related pain at the bilateral plantar surfaces of the feet, which was treated successfully with bilateral sacral S1 nerve root DRG stimulation.",
"affiliations": "Division of Pain Medicine, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Pain Medicine, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Pain Medicine, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Hagedorn|Jonathan M|JM|0000-0003-1039-8166;Canzanello|Nicholas|N|;Lamer|Tim J|TJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/papr.12998",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7085",
"issue": "21(6)",
"journal": "Pain practice : the official journal of World Institute of Pain",
"keywords": "chronic pain; dorsal root ganglion (DRG) stimulation; erythromelalgia; neuromodulation",
"medline_ta": "Pain Pract",
"mesh_terms": "D004916:Erythromelalgia; D005528:Foot; D005727:Ganglia, Spinal; D006801:Humans; D010146:Pain; D062187:Spinal Cord Stimulation",
"nlm_unique_id": "101130835",
"other_id": null,
"pages": "698-702",
"pmc": null,
"pmid": "33508884",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016454:Review",
"references": null,
"title": "Dorsal Root Ganglion Stimulation for Erythromelalgia Related Foot Pain: A Case Report and Review of the Literature.",
"title_normalized": "dorsal root ganglion stimulation for erythromelalgia related foot pain a case report and review of the literature"
} | [
{
"companynumb": "US-ORGANON-O2108USA000525",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Antiphospholipid syndrome (APS) is characterised by recurrent arterial and/or venous thromboses and recurrent late miscarriages in the presence of antiphospholipid antibodies, and can be a hugely debilitating disorder. While the commonest thrombotic manifestations of this condition such as deep vein thrombosis and stroke are well documented, there has been increasing recognition of numerous less common complications in most organ systems. We present a female patient with APS and a lupus-like illness who had atraumatic sacral fractures as well as multiple spontaneous fractures affecting her ribs and the metatarsals in both her feet.",
"affiliations": "Department of Rheumatology, Worthing Hospital, Worthing, UK.",
"authors": "Villiers|Joseph|J|;Khamashta|Munther|M|;Hepburn|Alastair|A|",
"chemical_list": "D017152:Antibodies, Antiphospholipid; D005938:Glucocorticoids",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D005260:Female; D005500:Follow-Up Studies; D017102:Fracture Healing; D015775:Fractures, Stress; D005938:Glucocorticoids; D006801:Humans; D008279:Magnetic Resonance Imaging; D008682:Metatarsal Bones; D008875:Middle Aged; D049268:Positron-Emission Tomography; D012008:Recurrence; D012272:Ribs; D018570:Risk Assessment; D012447:Sacrum; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24172778",
"pubdate": "2013-10-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "16432096;17549257;20842676;16935844;9664068;6414579;15361379;19591965;12632427",
"title": "Recurrent atraumatic metatarsal, rib and sacral insufficiency fractures in a woman with the antiphospholipid syndrome.",
"title_normalized": "recurrent atraumatic metatarsal rib and sacral insufficiency fractures in a woman with the antiphospholipid syndrome"
} | [
{
"companynumb": "PHHY2015GB008223",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy.",
"affiliations": "Renal and Transplantation Unit, St. George's University Hospital National Health Service Foundation Trust, London, UK; Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK. Electronic address: debasish.banerjee@stgeorges.nhs.uk.;Renal and Transplantation Unit, St. George's University Hospital National Health Service Foundation Trust, London, UK; Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.;Renal Unit, King's College Hospital, London, UK.;Infection and Immunity Research Institute, St. George's, University of London, London, UK.;Renal Unit, Epsom and St. Helier University Hospitals National Health Service Trust, London, UK.;Renal Unit, Epsom and St. Helier University Hospitals National Health Service Trust, London, UK; South West Thames Institute for Renal Research, St. Helier Hospital, London, UK.",
"authors": "Banerjee|Debasish|D|;Popoola|Joyce|J|;Shah|Sapna|S|;Ster|Irina Chis|IC|;Quan|Virginia|V|;Phanish|Mysore|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.kint.2020.03.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0085-2538",
"issue": "97(6)",
"journal": "Kidney international",
"keywords": "COVID-19; SARS-CoV-2 infection; immunosuppression; kidney transplantation",
"medline_ta": "Kidney Int",
"mesh_terms": "D000368:Aged; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D005334:Fever; D005500:Follow-Up Studies; D006084:Graft Rejection; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D012720:Severity of Illness Index; D066027:Transplant Recipients",
"nlm_unique_id": "0323470",
"other_id": null,
"pages": "1076-1082",
"pmc": null,
"pmid": "32354637",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "32007145;12859532;32171076;14647384;14663579;21752960;23698397;32160893;32105632;25716741;32015508;32181990;23486063",
"title": "COVID-19 infection in kidney transplant recipients.",
"title_normalized": "covid 19 infection in kidney transplant recipients"
} | [
{
"companynumb": "GB-BAUSCH-BL-2020-018532",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": nu... |
{
"abstract": "A 55-year-old male on long-term amiodarone therapy presented with ischaemic chest pain and recurrent unwitnessed syncope. Interrogation of his internal cardiac defibrillator, which had been inserted 4 years earlier, revealed two episodes of ventricular fibrillation, the timing of which corresponded to his syncopal events. Severe spontaneous coronary artery vasospasm was observed on coronary angiogram. Thyroid function testing revealed severe hyperthyroidism with a diagnosis of type 2 amiodarone-induced thyrotoxicosis (AIT) subsequently made. Treatment with prednisolone therapy was commenced and thyroid function rapidly normalized. Prednisolone was weaned without recurrence of hyperthyroidism and on last review, 6 months after initial presentation, he remains free from further chest pain and arrhythmias. Our patient's presentation is a very rare case of AIT-associated coronary artery spasm and documented ischaemic ventricular fibrillation with fortunate survival.",
"affiliations": "Department of Cardiology, The Royal Melbourne Hospital, Melbourne, Vic., Australia.;Department of Endocrinology, The Royal Melbourne Hospital, Melbourne, Vic., Australia.;Department of Cardiology, The Royal Melbourne Hospital, Melbourne, Vic., Australia.;Department of Endocrinology, The Royal Melbourne Hospital, Melbourne, Vic., Australia.;Department of Cardiology, The Royal Melbourne Hospital, Melbourne, Vic., Australia.",
"authors": "Brooks|Matthew J|MJ|;Pattison|David A|DA|;Teo|Eliza P|EP|;Price|Sarah|S|;Gurvitch|Ronen|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000345528",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2235-0640",
"issue": "2(1)",
"journal": "European thyroid journal",
"keywords": "Amiodarone-induced thyrotoxicosis; Coronary artery spasm; Ventricular fibrillation",
"medline_ta": "Eur Thyroid J",
"mesh_terms": null,
"nlm_unique_id": "101604579",
"other_id": null,
"pages": "65-7",
"pmc": null,
"pmid": "24783040",
"pubdate": "2013-03",
"publication_types": "D016428:Journal Article",
"references": "17148557;7092449;6797752;11172193;21865355;12957773;22007100;18279027;20181115;15255432;21875344;22130792;8541184",
"title": "Amiodarone-induced destructive thyroiditis associated with coronary artery vasospasm and recurrent ventricular fibrillation.",
"title_normalized": "amiodarone induced destructive thyroiditis associated with coronary artery vasospasm and recurrent ventricular fibrillation"
} | [
{
"companynumb": "PHHY2015AU062552",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Lidocaine acts as a local anesthetic by blocking transmembrane sodium channel permeability, but also induces the synthesis of heat shock proteins and sensitizes cells to hyperthermia. A previous study reported two cases of deep focal skin ulceration at points corresponding to depot local lidocaine injection sites after treatment with non-ablative fractional resurfacing and it was hypothesized that lidocaine had focally sensitized keratinocytes to the thermal damage of laser treatment. The objective of this study was to investigate whether lidocaine potentiates hyperthermia damage to both normal and cancerous skin cells using an in vitro model.\n\n\n\nNormal skin cell lines (fibroblasts, keratinocytes), skin cancer cell lines (melanoma, basal cell carcinoma), and a mucosal cancer cell line (cervical carcinoma) were exposed to various concentrations of lidocaine (0-0.3%) with or without hyperthermia (37°C, 42°C).\n\n\n\nCompared to normal skin cells, we demonstrate that cancer cell lines show significantly increased cell toxicity when a moderate temperature (42°C) and low lidocaine concentrations (0.1-0.2%) are combined. The toxicity directly correlates with a higher percentage of cells in S-phase (28-57%) in the cancer cell lines compared to normal skin cell lines (13-19%; R-square 0.6752).\n\n\n\nThese results suggest that lidocaine potentiates thermal sensitivity of cell cycle active skin cells. The direct correlation between cell toxicity and S-phase cells could be harnessed to selectively treat skin and mucosal cancer cells while sparing the surrounding normal tissue. Additional research pre-clinically and clinically using several different heat sources (e.g., lasers, ultrasound, etc.) and lidocaine concentrations is needed to confirm and optimize these results. Lidocaine-enhanced hyperthermia may provide a non-invasive, alterative treatment option for highly proliferating, superficial skin, and mucosal lesions such as cancer or warts. Lasers Surg. Med. 51:88-94, 2019. © 2018 Wiley Periodicals, Inc.",
"affiliations": "Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.;Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.;Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.;Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.;Commonwealth Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.;Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.;Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts.",
"authors": "Raff|Adam B|AB|;Thomas|Carina N|CN|;Chuang|Gary S|GS|;Avram|Mathew M|MM|;Le|Monica H|MH|;Anderson|R Rox|RR|;Purschke|Martin|M|",
"chemical_list": "D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1002/lsm.23027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-8092",
"issue": "51(1)",
"journal": "Lasers in surgery and medicine",
"keywords": "cancer treatment; heat; hyperthermia; lidocaine; local anaesthetics; moderate temperatures; skin cell lines",
"medline_ta": "Lasers Surg Med",
"mesh_terms": "D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D006979:Hyperthermia, Induced; D008012:Lidocaine; D012867:Skin; D012878:Skin Neoplasms",
"nlm_unique_id": "8007168",
"other_id": null,
"pages": "88-94",
"pmc": null,
"pmid": "30320907",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lidocaine-induced potentiation of thermal damage in skin and carcinoma cells.",
"title_normalized": "lidocaine induced potentiation of thermal damage in skin and carcinoma cells"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-09603",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugad... |
{
"abstract": "The coronavirus disease 2019 (COVID-19) pandemic has increased concern regarding SARS-CoV-2 infection in inflammatory bowel disease (IBD) patients, especially those on immunosuppressive therapies or with active disease. There are limited reports describing the clinical features of COVID-19 in an IBD population, and the impact of immunosuppression on the severity of the infection remains unclear.\nA 33-year-old female patient with a long history of ulcerative colitis, poorly controlled, was admitted with COVID-19 a few days after being discharged from the hospital for treatment of acute severe ulcerative colitis. High-risk factors for COVID-19 complications, i.e., high-dose steroids (40 mg prednisone) and severe active disease, were present at admission. Despite the development of extensive pulmonary involvement, the patient had a favorable outcome.\nManagement of IBD patients during the COVID-19 pandemic has been challenging. Measures to minimize the potential risk of SARS-CoV-2 infection, including strict social distancing and self-isolation, in the IBD population have been recommended, especially for high-risk patients. Although steroid tapering and persistence of biologics are advised by professional groups, the best treatment strategy for IBD patients presenting a flare during the outbreak has yet to be defined.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.;Division of Gastroenterology and Hepatology, Department of Gastroenterology, Hospital das Clínicas, School of Medicine, University of São Paulo, São Paulo, Brazil.",
"authors": "Garcia|Karoline Soares|KS|;Moutinho|Bruna Damásio|BD|;de Azevedo|Matheus Freitas Cardoso|MFC|;Queiroz|Natalia Sousa Freitas|NSF|;Milani|Luciane Reis|LR|;Sanches|Lucas Navarro|LN|;Barros|Luisa Leite|LL|;Oba|Jane|J|;Carlos|Alexandre de Sousa|AS|;Damião|Aderson Omar Mourão Cintra|AOMC|;Sipahi|Aytan Miranda|AM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000508161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-9365",
"issue": "5(2)",
"journal": "Inflammatory intestinal diseases",
"keywords": "COVID-19; Colitis; Coronavirus infections; Inflammatory bowel disease; Ulcerative colitis",
"medline_ta": "Inflamm Intest Dis",
"mesh_terms": null,
"nlm_unique_id": "101677990",
"other_id": null,
"pages": "93-97",
"pmc": null,
"pmid": "32984404",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "32529821;32109013;30668662;32245909;32214232;32171057;32169119;16968120;32171076;32211765;32272113;32073213;32220112;32247695",
"title": "Recovery from COVID-19 Pneumonia in a Patient with Acute Severe Colitis.",
"title_normalized": "recovery from covid 19 pneumonia in a patient with acute severe colitis"
} | [
{
"companynumb": "BR-GYP-000007",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "Breast cancer in men is rare and only about 390 men in the UK are diagnosed with breast cancer each year with an incidence rate in the UK of 1.5 cases per 100 000 men. In addition, the increased use of radiotherapy for management of breast cancer has led to a reported increase of radiation induced angiosarcomas (RIAS) with an incidence of 0.05-0.3%. Here we report a unique and extremely rare case of RIAS of breast in a male patient. To our knowledge this is the only case in the literature of a radiation induced angiosarcoma of the breast in a male.",
"affiliations": "Department of Reconstructive and Plastic Surgery, The Christie NHS Foundation Trust, Manchester M204BX, UK.;Department of Reconstructive and Plastic Surgery, The Christie NHS Foundation Trust, Manchester M204BX, UK.;Department of Reconstructive and Plastic Surgery, The Christie NHS Foundation Trust, Manchester M204BX, UK.;Department of Reconstructive and Plastic Surgery, The Christie NHS Foundation Trust, Manchester M204BX, UK.",
"authors": "Tsapralis|Nikolaos|N|0000-0002-1210-6609;Vlachogiorgos|Apostolos|A|;Pham|Hien|H|;Mowatt|David|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jscr/rjz158",
"fulltext": "\n==== Front\nJ Surg Case RepJ Surg Case RepjscrJournal of Surgical Case Reports2042-8812Oxford University Press 10.1093/jscr/rjz158rjz158Case ReportNothing is impossible: radiation induced angiosarcoma of breast in a male patient http://orcid.org/0000-0002-1210-6609Tsapralis Nikolaos Vlachogiorgos Apostolos Pham Hien Mowatt David Department of Reconstructive and Plastic Surgery, The Christie NHS Foundation Trust, Manchester M204BX, UKCorrespondence address. Tel: +07842314752; E-mail: Nikolaos.tsapralis@christie.nhs.uk5 2019 23 5 2019 23 5 2019 2019 5 rjz15802 1 2019 22 3 2019 07 5 2019 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2019.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBreast cancer in men is rare and only about 390 men in the UK are diagnosed with breast cancer each year with an incidence rate in the UK of 1.5 cases per 100 000 men. In addition, the increased use of radiotherapy for management of breast cancer has led to a reported increase of radiation induced angiosarcomas (RIAS) with an incidence of 0.05–0.3%. Here we report a unique and extremely rare case of RIAS of breast in a male patient. To our knowledge this is the only case in the literature of a radiation induced angiosarcoma of the breast in a male.\n==== Body\nINTRODUCTION\nBreast cancer in men is rare and only about 390 men in the UK are diagnosed with breast cancer each year with an incidence rate in the UK of 1.5 cases per 100 000 men [1, 2].\n\nThe management of breast cancer in male patients is the same as the one in females and therefore adjuvant radiotherapy is very commonly used. Unfortunately, the increased use of radiotherapy for management of breast cancer has led to a reported increase of radiation induced angiosarcomas (RIAS) with an incidence of 0.05–0.3% [3–5]. Here we report a unique and extremely rare case of RIAS of breast in a male patient.\n\nCASE REPORT\nA 72-year-old male was diagnosed with left breast invasive ductal carcinoma (tumor of 11 mm, stage I (T1N0M0), grade3, estrogen receptor (ER) and progesterone receptor (PR) positive, Ki-67 8%, EGFR and Her-2 negative) and underwent left breast mastectomy and lymph node axillary dissection.\n\nHis past medical history included atrial fibrillation, hypertension, hypercholesterolemia, glaucoma and he had a strong family history of breast carcinoma.\n\nHe received 20 days of adjuvant radiotherapy treatment and five years of endocrine adjuvant treatment of his chest wall with single field modality technique and a total dose of 4005 cGy D-Max in 15 fractions.\n\nSix years after completion of adjuvant radiotherapy treatment for his breast cancer, the patient developed multiple purpuric nodules below and very close to the mastectomy scar and a punch biopsy revealed radiation induced angiosarcoma. A CT scan of his chest, abdomen and pelvis had shown no evidence of distant metastases. He underwent a wide resection of the mastectomy scar down to the ribs and the defect was reconstructed with pedicled latissimus dorsi flap in combination with a V-Y fashion adipocutaneous advancement flap from his abdomen (Fig. 1).\n\nFigure 1: Patient in upright position. Left chest wall reconstruction with pedicled latissimus dorsi flap in combination with a V-Y fashion adipocutaneous advancement flap from his abdomen after resection of RIAS of his breast.\n\nThe histology report showed a multifocal grade 3 angiosarcoma (pT2a, pN0) involving the dermis and subcutaneous tissue composed of inter-anastomosing vascular channels lined by atypical endothelial cells. The nearest peripheral margin appeared to be approximately 10 mm and the deep margin from the tumor was documented as very close but free of tumor infiltration.\n\nThe patient had three more surgical treatments and one treatment with electrochemotherapy (Bleomycin 34 000 IU) with partial response to control local disease recurrence. The local disease-free interval was 8,5,7 and 3 months period between these treatments.\n\nUnfortunately, he rapidly developed widespread disease over his chest wall that was not amenable to surgical treatment, nor further session of electrochemotherapy (Fig. 2).\n\nFigure 2: Patient in upright left lateral position. Rapidly developed wide spread disease over his left anterior and lateral chest wall not amenable to surgical treatment and electrochemotherapy. At this point chemotherapy treatment commenced with Paclitaxel.\n\nAfter a long discussion with the patient and a multidisciplinary team consensus, a decision was made for further management with adjuvant chemotherapy. The proposed treatment by the medical oncology team was full dose Paclitaxel on a weekly basis which was started 3 months after his last electrochemotherapy session. The full dose had seemed to show significant improvement in his chest wall disease but unfortunately this was too toxic for the patient to tolerate and therefore on week 4 the dose was decreased (Fig. 3). This reduced the side effects of Paclitaxel in full dose, including severe neutropenia and excessive fatigue. Disease progression was noted on the reduced dose of Paclitaxel treatment and therefore the further treatment was changed to Pazopanib 600 mg per day. However, soon after commencement, the development of hypertension and confusion necessitated cessation of treatment.\n\nFigure 3: Patient in upright left lateral position. Significant control of his chest wall local disease progression with administration of full dose of Paclitaxel.\n\nIn the meantime, a chest X-ray revealed progressive interstitial thickening in the right mid and upper zone, confirming our clinical suspicion of rapid progression of disease on the patient’s chest wall.\n\nAt that stage, a decision was taken with the patient and his family to focus on symptom relief and best supportive care at home. The patient died 32 months after his first surgical treatment for the radiation induced breast angiosarcoma and eight years and five months following completing the adjuvant radiotherapy treatment for his breast cancer.\n\nDISCUSSION\nRIAS is relatively rare, with an estimated incidence at between 0.05 and 0.3% in women treated with radiotherapy. It is a well recognized late complication of adjuvant radiotherapy, with a latency period that varies from approximately five to ten years [6].\n\nThe incidence of RIAS does not appear to be influenced by the type of surgery performed (mastectomy or wide local excision) but there might be a potential interaction of radiotherapy and lymphoedema following treatment [4].\n\nThere may also be a dose response relationship between the dose of radiotherapy administrated and the incidence of RIAS with a minimum of 10 Gy associated with the development of the condition but usually associated with higher doses [4].\n\nThe 5-year survival rate of RIAS patients is reported in the literature in the range of 25–50% [7, 8]. The patient in our case died 32 months after his diagnosis for RIAS.\n\nFurthermore, tumor grade is considered to be an important prognostic factor for RIAS. Patients with high grade tumor as in our case, have worse survival rate. Our patient had multiple episodes of local recurrences treated surgically and with electrochemotherapy but ultimately his disease progressed rapidly such that active treatment with curative intent was ceased.\n\nHe was subsequently referred to our medical oncology colleagues knowing that the role of chemotherapy for RIAS remains uncertain. An agent such as Paclitaxel has shown encouraging results in unresectable angiosarcomas but its dose-limiting toxic effects does not allow prolonged treatment for more than 6 months in most cases [9].\n\nIn our case the dose of paclitaxel initially had to be reduced and eventually stopped due to its toxic effect after four months of treatment. Subsequent attempts at disease control with a tyrosine kinase inhibitor, Pazopanib, had to be abandoned as well due to toxicities. His disease rapidly progressed, infiltrating deeper structures of his chest wall and the patient entered the supportive care pathway in order to ensure that he received the best possible care in the last period of his life.\n\nWide surgical resection with adequate clear histological margins remains the first line treatment for radiation-induced angiosarcoma.\n\nTo our knowledge this is the only case in the literature of a radiation induced angiosarcoma of the breast in a male.\n\nCONFLICT OF INTEREST STATEMENT\nNone Declared.\n==== Refs\nREFERENCES\n1 https://www.breastcanceruk.org.uk/science-and-research/background-briefings/male-breast-cancer/ \n2 https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-types-grades/types/male-breast-cancer \n3 \nMonroe AT , Feigenberg SJ , Mendenhall NP \nAngiosarcoma after breast-conserving therapy . Cancer 2003 ;97 :1832 –40 .12673708 \n4 \nSheth GR , Cranmer LD , Smith BD , Grasso-Lebeau L , Lang JE \nRadiation-induced sarcoma of the breast: a systematic review . Oncologist 2012 ;17 :405 –18 .22334455 \n5 \nTorres KE , Ravi V , Kin K , Yi M , Guadagnolo BA , May CD , et al \nLong-term outcomes in patients with radiation-associated angiosarcomas of the breast following surgery and radiotherapy for breast cancer . Ann Surg Oncol 2013 ;20 :1267 –74 .23224828 \n6 \nAlves I , Marques JC \nRadiation-induced angiosarcoma of the breast: a retrospective analysis of 15 years’ experience at an oncology center . Radiol Bras 2018 ;51 :281 –6 .30369653 \n7 \nMery CM , George S , Bertagnolli MM , Raut CP \nSecondary sarcomas after radiotherapy for breast cancer: sustained risk and poor survival . Cancer 2009 ;115 :4055 –63 .19526590 \n8 \nD’Angelo SP , Antonescu CR , Kuk D , Qin L , Moraco N , Carvajal RC , et al \nHigh-risk features in radiation-associated breast angiosarcomas . Br J Cancer 2013 ;109 :2340 –6 .24104962 \n9 \nZemanova M \nClinical management of secondary angiosarcoma after breast conservation therapy . Rep Pract Oncol Radiother 2013 ;19 :37 –46 .24936318\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2042-8812",
"issue": "2019(5)",
"journal": "Journal of surgical case reports",
"keywords": null,
"medline_ta": "J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101560169",
"other_id": null,
"pages": "rjz158",
"pmc": null,
"pmid": "31139339",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports",
"references": "12673708;19526590;22334455;23224828;24104962;24936318;30369653",
"title": "Nothing is impossible: radiation induced angiosarcoma of breast in a male patient.",
"title_normalized": "nothing is impossible radiation induced angiosarcoma of breast in a male patient"
} | [
{
"companynumb": "GB-TEVA-2019-GB-1093665",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": "1",
... |
{
"abstract": "Overdose with calcium channel blockers is uncommon, but is associated with high mortality. The management includes fluid resuscitation, calcium gluconate, glucagon, vasopressors, and high-dose insulin-euglycemia therapy. We describe a rare case of massive overdose of lercanidipine with shock, refractory to conventional therapies and multi-organ failure. Charcoal hemoperfusion with continuous venovenous hemodiafiltration was then used successfully and the patient showed remarkable recovery.",
"affiliations": "Department of Critical Care Medicine, Max Superspeciality Hospital, New Delhi, India.",
"authors": "Nasa|Prashant|P|;Singh|Akhilesh|A|;Juneja|Deven|D|;Singh|Omender|O|;Javeri|Yash|Y|",
"chemical_list": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D002606:Charcoal; D017311:Amlodipine; C060343:lercanidipine",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.4103/1319-2442.144262",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1319-2442",
"issue": "25(6)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D002606:Charcoal; D004095:Dihydropyridines; D062787:Drug Overdose; D017583:Hemodiafiltration; D006464:Hemoperfusion; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure; D012769:Shock; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9436968",
"other_id": null,
"pages": "1255-8",
"pmc": null,
"pmid": "25394445",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Continuous venovenous hemodiafiltration along with charcoal hemoperfusion for the management of life-threatening lercanidipine and amlodipine overdose.",
"title_normalized": "continuous venovenous hemodiafiltration along with charcoal hemoperfusion for the management of life threatening lercanidipine and amlodipine overdose"
} | [
{
"companynumb": "IN-ENDO PHARMACEUTICALS INC-2015-000903",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LERCANIDIPINE"
},
"drugaddition... |
{
"abstract": "Since 2011, telaprevir (TVR)-based triple therapy is the new treatment standard for hepatitis C genotype 1 virus infection. The aim of our retrospective interim analysis encompassing the first 24 weeks on TVR-based triple therapy was to assess 'real-life' antiviral efficacy and side effects in a large single-centre cohort, both in comparison with the data obtained in large prospective clinical trials. In total, we treated 102 patients: 24 treatment-naïve patients, 58 patients pretreated with PEG-IFN/RBV (thereof: 28 with nonresponse, 25 with relapse, five unknown) and 20 patients who previously had received nonpegylated interferon. 74 of 102 patients were assigned with HCV genotype 1b; 34 of 102 patients were treated in the context of liver cirrhosis. 72 of 102 patients have reached treatment week 24 (mean treatment duration 31 weeks). In the ITT analysis, overall response rates were at: week 4: 66%; week 12: 85%; and week 24: 78%. So far, 24 patients discontinued treatment prematurely, of those, 10 patients were due to virological failure. Haematological side effects were frequent (40% anaemia), as were 'flu-like' symptoms (94%), rash (65%) and pruritus (79%). According to our interim ITT analysis encompassing up to 24 weeks of TVR-based triple therapy, our 'real-life' antiviral effects are comparable to the results of large multicentric clinical trials. However, TVR-based triple therapy exhibited a high frequency of side effects requiring multiple therapeutic interventions. Notably, in our 'real-life' cohort, no lethal case was observed so far.",
"affiliations": "Department of Gastroenterology, Hepatology, and Infectiology, University Hospital Tuebingen, Tuebingen, Germany.",
"authors": "Werner|C R|CR|;Franz|C|C|;Egetemeyr|D P|DP|;Janke-Maier|P|P|;Malek|N P|NP|;Lauer|U M|UM|;Berg|C P|CP|",
"chemical_list": "D000998:Antiviral Agents; D009842:Oligopeptides; D012254:Ribavirin; C486464:telaprevir; D007372:Interferons",
"country": "England",
"delete": false,
"doi": "10.1111/jvh.12145",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-0504",
"issue": "21(5)",
"journal": "Journal of viral hepatitis",
"keywords": "hepatitis C; rash; real life; side effects; telaprevir",
"medline_ta": "J Viral Hepat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006801:Humans; D007372:Interferons; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D012189:Retrospective Studies; D012254:Ribavirin; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "9435672",
"other_id": null,
"pages": "333-40",
"pmc": null,
"pmid": "24716636",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of telaprevir (TVR) triple therapy in a 'real-life' cohort of 102 patients with HCV genotype 1: interim analysis after 24 weeks of treatment.",
"title_normalized": "efficacy and safety of telaprevir tvr triple therapy in a real life cohort of 102 patients with hcv genotype 1 interim analysis after 24 weeks of treatment"
} | [
{
"companynumb": "DE-VERTEX PHARMACEUTICALS-2014-004937",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INTERFERON ALFA-2A OR INTERFERON ALFA-2B"
}... |
{
"abstract": "BACKGROUND It is still challenging to remove an epidural catheter in a postoperative patient receiving urgent antiplatelet and anticoagulation therapy for acute coronary syndrome. CASE REPORT While under general anesthesia combined with thoracic epidural anesthesia, a 72-year-old male patient underwent right radical nephrectomy for renal cell carcinoma. On postoperative day 1 (POD1), the patient experienced bradycardia and a decrease in blood pressure, and he was diagnosed acute myocardial infarction. Intra-aortic balloon pumping (IABP) was induced for cardiogenic shock, and urgent thrombus aspiration and coronary balloon angioplasty were performed. On POD3, the surgeon removed the epidural catheter under both antiplatelet and anticoagulation therapy. At that time, the platelet count was 45×10⁹/L and the activated partial thromboplastin time (APTT) was 72.2 seconds. Four hours after the epidural catheter was removed, the patient complained of bilateral fatigue in legs and developed a loss of sensation. Six hours after the epidural catheter was removed, he developed motor paralysis and became completely paralyzed in both limbs after 9 hours. At 19 hours after the epidural catheter was removed, emergency magnetic resonance imaging detected a spinal epidural hematoma at the level of Th9-11 with compression of the spinal cord. Emergency laminectomy was performed to decompress and remove the spinal epidural hematoma at 18 hours after the onset of sensorimotor symptoms. After surgery and rehabilitation, these symptoms had only slightly improved. CONCLUSIONS In patients with urgent antithrombotic therapy for urgent percutaneous coronary intervention (PCI) with an IABP for acute coronary syndrome, the epidural catheter should not be removed until the IABP and heparin are discontinued, and platelet counts have recovered.",
"affiliations": "Department of Anesthesiology, Fukuoka University Hospital, Fukuoka City, Fukuoka, Japan.;Department of Anesthesiology, Fukuoka University Hospital, Fukuoka City, Fukuoka, Japan.;Department of Anesthesiology, Fukuoka University Hospital, Fukuoka City, Fukuoka, Japan.;Department of Anesthesiology, Fukuoka University Hospital, Fukuoka City, Fukuoka, Japan.;Department of Anesthesiology, Fukuoka University Hospital, Fukuoka City, Fukuoka, Japan.",
"authors": "Mimata|Ryosuke|R|;Higashi|Midoriko|M|;Yasui|Madoka|M|;Hirai|Takanao|T|;Yamaura|Ken|K|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.917716",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3151546510.12659/AJCR.917716917716ArticlesSpinal Epidural Hematoma Following Epidural Catheter Removal in a Patient with Postoperative Urgent Coronary Intervention and Intra-Aortic Balloon Pumping (IABP): A Case Report Mimata Ryosuke ABCDEFHigashi Midoriko ABCDEFYasui Madoka BCHirai Takanao BCYamaura Ken ABCDEFDepartment of Anesthesiology, Fukuoka University Hospital, Fukuoka City, Fukuoka, JapanAuthors’ 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: Midoriko Higashi, e-mail: midoriko@fukuoka-u.ac.jp2019 13 9 2019 20 1356 1359 23 5 2019 17 7 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 72\n\nFinal Diagnosis: Spinal epidural hematoma\n\nSymptoms: Paralysis\n\nMedication: Heparin\n\nClinical Procedure: Laminectomy\n\nSpecialty: Anesthesiology\n\nObjective:\nRare disease\n\nBackground:\nIt is still challenging to remove an epidural catheter in a postoperative patient receiving urgent antiplatelet and anticoagulation therapy for acute coronary syndrome.\n\nCase Report:\nWhile under general anesthesia combined with thoracic epidural anesthesia, a 72-year-old male patient underwent right radical nephrectomy for renal cell carcinoma. On postoperative day 1 (POD1), the patient experienced bradycardia and a decrease in blood pressure, and he was diagnosed acute myocardial infarction. Intraaortic balloon pumping (IABP) was induced for cardiogenic shock, and urgent thrombus aspiration and coronary balloon angioplasty were performed. On POD3, the surgeon removed the epidural catheter under both anti-platelet and anticoagulation therapy. At that time, the platelet count was 45×109/L and the activated partial thromboplastin time (APTT) was 72.2 seconds. Four hours after the epidural catheter was removed, the patient complained of bilateral fatigue in legs and developed a loss of sensation. Six hours after the epidural catheter was removed, he developed motor paralysis and became completely paralyzed in both limbs after 9 hours. At 19 hours after the epidural catheter was removed, emergency magnetic resonance imaging detected a spinal epidural hematoma at the level of Th9-11 with compression of the spinal cord. Emergency laminectomy was performed to decompress and remove the spinal epidural hematoma at 18 hours after the onset of sensorimotor symptoms. After surgery and rehabilitation, these symptoms had only slightly improved.\n\nConclusions:\nIn patients with urgent antithrombotic therapy for urgent percutaneous coronary intervention (PCI) with an IABP for acute coronary syndrome, the epidural catheter should not be removed until the IABP and heparin are discontinued, and platelet counts have recovered.\n\nMeSH Keywords:\nAnesthesia, EpiduralAnticoagulantsHematoma, Epidural, SpinalPlatelet Aggregation Inhibitors\n==== Body\nBackground\nIn patients with anti-thrombotic therapy, the removal of the epidural catheter is associated with a high risk of spinal epidural hematoma, and it is recommended that anticoagulation therapy should be transiently stopped during this procedure [1]. However, in postoperative urgent anti-thrombotic therapy for acute coronary syndrome, it is difficult to stop therapy. It therefore remains challenging to remove an epidural catheter in a postoperative patient receiving urgent anti-platelet and anticoagulation therapy.\n\nCase Report\nA 72-year-old male patient underwent right radical nephrectomy for renal cell carcinoma. He had a medical history of hypertension, type 2 diabetes mellitus, chronic renal disease, and bronchial asthma. In addition, he was prescribed an angiotensin 2 receptor antagonist, a calcium antagonist, a dipeptidyl peptidase-4 (DPP-4) inhibitor, insulin therapy, and a beta-2 stimulant inhalation drug.\n\nSurgery was performed under general and epidural anesthesia. The epidural anesthesia was performed at the Th11-12 level with the patient in the lateral position using an epidural catheter inserted 5 cm toward the head. During the procedure, there were no complications, such as bleeding or aspiration of cerebral spinal fluid. After administration of a test dose of 3 mL of 0.75% ropivacaine, the epidural catheter was fixed. General anesthesia was induced with intravenous fentanyl (100 µg), propofol (100 mg), and rocuronium (36 mg) and maintained with 1.5–2% sevoflurane with intermittent injections (every 2 hours) of an epidural bolus of 5 mL of 0.75% ropivacaine with 50 µg of fentanyl. After surgery, the patient was continuously infused with local anesthetic (200 mL of 0.2% ropivacaine containing 500 µg of fentanyl) at a rate of 5 mL/hour. The platelet count was 118×109/L before surgery and 86×109/L after surgery.\n\nOn postoperative day 1 (POD1), the patient experienced bradycardia and a decrease in blood pressure and was diagnosed with acute myocardial infarction. Intra-aortic balloon pumping (IABP) was induced for cardiogenic shock, and urgent thrombus aspiration and coronary balloon angioplasty were performed for the right coronary artery (segment 2). Anti-platelet therapy aspirin (100 mg/day) and anti-coagulant therapy (heparin 300 units/hour) were immediately started. The dose of heparin was adjusted to an activated clotting time (ACT) of 160 seconds.\n\nOn POD3, the surgeon removed the epidural catheter while both antiplatelet agent and anticoagulation therapy were ongoing. At that time, the platelet count was 45×109/L and activated partial thromboplastin time (APTT) was 72.2 seconds. Four hours after the epidural catheter was removed, the patient complained of bilateral fatigue in the legs and was developing loss of sensation. Six hours after the epidural catheter was removed, he developed motor paralysis, and after 9 hours, he had become completely paralyzed in both limbs. Because of concern about spinal epidural hematoma, the heparin and IABP were immediately stopped, and an emergency computed tomography (CT) scan was performed and examined. The CT and magnetic resonance imaging (MRI) performed at 19 hours after the epidural catheter was removed showed a spinal epidural hematoma at the level of Th9-11 with compression of the spinal cord (Figures 1, 2). An emergency laminectomy was performed under general anesthesia to decompress and remove the spinal epidural hematoma at 21 hours after the epidural catheter was removed and 17 hours after the onset of sensorimotor symptoms. Manual muscle testing (MMT) was 0, and his sensory defect was below Th12 before surgery. After surgery and rehabilitation, the patient’s symptoms slightly improved from MMT 0 to 2 in the right anterior tibialis muscle and the long toe long stretch muscle, but other lower limb muscles were not improved and remained at MMT 0. Sensory symptoms were lost below the right L5 and left L2 level, and the bladder rectal disorder remained.\n\nDiscussion\nSpinal hematoma related to epidural anesthesia is rare, occurring at a rate of 1/168 000 [2]. Anticoagulants increase the risk of spinal epidural hematoma to a rate of 1/6600 [3]. Epidural catheter insertion with low-molecular-weight heparins is a risk factor for this event and increases it to a rate of 1/3100 [3], with most such cases occurring after the removal of the epidural catheter [4].\n\nCardiac complications are not rare, occurring at a rate of 0.5–9.1% [5]. However, urgent PCI and hemodynamic mechanical support, such as IABP after surgery, are not simple procedures. They require urgent anti-thrombotic therapy, such as anti-platelet and/or anticoagulant therapy, and these situations are especially challenging in postoperative patients with an epidural catheter. Anti-platelet therapy is recommended following urgent PCI. It prevents the procedure from increasing the risk for recurrence of myocardial ischemia. However, the risk of spinal epidural hematoma is increased in patients with anticoagulant therapy.\n\nCurrent guidelines recommend that clopidogrel should be discontinued more than 7 days before a patient undergoes epidural anesthesia and the removal of an epidural catheter [1,6]. However, low-dose isolated aspirin (acetylsalicylic acid) does not increase the risk of spinal hematoma and does not need to be stopped before neuraxial blockade [1,6]. However, this remains controversial, and there is no consensus regarding whether anti-platelet therapy should be stopped or not used during urgent PCI when the epidural catheter is removed [7]. In some case reports, following urgent PCI, the removal of an epidural catheter during anti-platelet therapy was successful when transiently discontinued with aspirin and platelet transfusion [8]. However, in another case report, the removal of the epidural catheter was also successful when performed with monitoring of platelet aggregation and rotational thromboelastometry with continued anti-platelet therapy [9,10]. In the latter case, the patient underwent coronary artery balloon angioplasty because of postoperative periods of acute coronary syndrome. The patient received only aspirin and was not treated with clopidogrel. However, because the patient’s hemodynamic status was unstable, the patient needed IABP with anticoagulation therapy (heparin). The risk of spinal hematoma with both antiplatelet and heparin is 7.34 higher than that associated with heparin alone [11]. In the current case, the patient needed heparin because of IABP. If intravenous heparin alone is administered, the guidelines recommend that it should be stopped 4 hours before the removal of the epidural catheter.\n\nThe platelet count is also a risk factor for spinal hematoma. It is recommended that it should be above 70×109/L before performing spinal or epidural anesthesia in obstetric patients [12]. In the current case, the platelet count was lower, at 45×109/L, because of IABP. Therefore, the recovery of the platelet count, platelet transfusion, or coagulation testing, such as a platelet aggregation or rotational thromboelastometry, should be performed before removing the epidural catheter.\n\nEarly surgical removal of a spinal epidural hematoma is critical, and surgical removal of the hematoma should be performed less than 8 hours after motor symptom appear, but only 38% of patients have a full recovery [13]. On the other hand, despite such a recommendation, it has been reported that good recovery can be achieved even if removal of an epidural hematoma is delayed 80 hours after the onset of sensorimotor symptoms [14]. However, the onset of complete paralysis before the removal of the hematoma, as occurred in this case, has a poor prognosis [15]. In this case, there were 2reasons why the laminectomy was delayed. First, the laminectomy took a long time because paralysis developed in another hospital and the patient was urgently transported to our hospital. Second, the surgery had to be performed after IABP was removed. If the surgery was done a little earlier, the prognosis might be improved. Therefore, early diagnosis and surgical removal of the hematoma remains important.\n\nConclusions\nIn a patient undergoing urgent antithrombotic therapy for urgent PCI with IABP for acute coronary syndrome, the removal of the epidural catheter should be delayed until IABP with heparin is discontinued and the platelet count recovers.\n\nThe authors are grateful to The SNAS Team Springer Nature Author Services.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Magnetic resonance images in T2 sagittal images revealed a hyper-acute epidural hematoma over the T10 vertebra extending to the T12 vertebra.\n\nFigure 2. Magnetic resonance images in T1 axial cuts showing epidural hematoma compressing the spinal cord.\n==== Refs\nReferences:\n1. Horlocker TT Wedel DJ Rowlingson JC Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition) Reg Anesth Pain Med 2010 35 64 101 20052816 \n2. Ruppen W Derry S McQuay H Moore RA Incidence of epidural hematoma, infection, and neurologic injury in obstetric patients with epidural analgesia/anesthesia Anesthesiology 2006 105 394 99 16871074 \n3. Schroeder DR Statistics: Detecting a rare adverse drug reaction using spontaneous reports Reg Anesth Pain Med 1998 23 183 89 9845392 \n4. Vandermeulen EP Van Aken H Vermylen J Anticoagulants and spinal-epidural anesthesia Anesth Analg 1994 79 1165 77 7978443 \n5. Lee TH Marcantonio ER Mangione CM Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery Circulation 1999 100 1043 49 10477528 \n6. Narouze S Benzon HT Provenzano D Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications (Second Edition): Guidelines From the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain Reg Anesth Pain Med 2018 43 225 62 29278603 \n7. Vela Vásquez RS Peláez Romero R Aspirin and spinal haematoma after neuraxial anaesthesia: Myth or reality? Br J Anaesth 2015 115 688 98 26475800 \n8. Burad J Kausalya R Ismaili M Safe removal of epidural catheter – a dilemma, in patients who are started on dual anti platelet therapy postoperatively for acute coronary syndrome – a case report Middle East J Anaesthesiol 2012 21 905 8 23634578 \n9. Bergmann L Kienbaum P Görlinger K Peters J Uneventful removal of an epidural catheter guided by impedance aggregometry in a patient with recent coronary stenting and treated with clopidogrel and acetylsalicylic acid Reg Anesth Pain Med 2007 32 354 57 17720122 \n10. Young AC Shah S Buvanendran A Use of a quantitative platelet function test to guide epidural catheter removal in a patient who inadvertently received clopidogrel Pain Med 2015 16 1029 30 25585659 \n11. Stafford-Smith M Impaired haemostasis and regional anaesthesia Can J Anaesth 1996 43 R129 41 8706215 \n12. ACOG Practice Bulletin No. 209: Obstetric analgesia and anesthesia Obstet Gynecol 2019 133 e208 25 30801474 \n13. Horlocker TT Wedel DJ Benzon H Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation) Reg Anesth Pain Med 2003 28 172 97 12772135 \n14. Yao YX Li MX Sun LJ Good outcomes after the delayed removal of an epidural hematoma: a case report Medicine (Baltimore) 2018 97 e0341 29620662 \n15. Lawton MT Porter RW Heiserman JE Surgical management of spinal epidural hematoma: Relationship between surgical timing and neurological outcome J Neurosurg 1995 83 1 7 7782824\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "20()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D000767:Anesthesia, Epidural; D000768:Anesthesia, General; D015906:Angioplasty, Balloon, Coronary; D000925:Anticoagulants; D001919:Bradycardia; D003328:Coronary Thrombosis; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D007796:Laminectomy; D008279:Magnetic Resonance Imaging; D008297:Male; D009203:Myocardial Infarction; D010243:Paralysis; D011183:Postoperative Complications; D012770:Shock, Cardiogenic; D013117:Spinal Cord Compression; D017131:Thrombectomy",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "1356-1359",
"pmc": null,
"pmid": "31515465",
"pubdate": "2019-09-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7782824;12772135;20052816;26475800;10477528;23634578;29278603;17720122;29620662;16871074;30801474;25585659;8706215;9845392;7978443",
"title": "Spinal Epidural Hematoma Following Epidural Catheter Removal in a Patient with Postoperative Urgent Coronary Intervention and Intra-Aortic Balloon Pumping (IABP): A Case Report.",
"title_normalized": "spinal epidural hematoma following epidural catheter removal in a patient with postoperative urgent coronary intervention and intra aortic balloon pumping iabp a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-239099",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"... |
{
"abstract": "Numerous cases of Cushing syndrome have been reported as a result of the interaction between ritonavir (RTV) and exogenous steroid medications. Another complication that frequently occurs is secondary adrenal insufficiency, which can be profound and has not been well described. Here, we report 6 cases of adrenal suppression caused by RTV and exogenous steroids, all of which required corticosteroid replacement therapy and 2 of which were severe enough to require hospitalization. These cases add to the body of literature on the dangerous interaction between RTV and corticosteroids and highlight the risk of secondary adrenal suppression. We also review the literature on this complication and make a recommendation for managing and monitoring such cases.",
"affiliations": "Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA bwood2@uw.edu.;Department of Pathology, University of Washington, Seattle, WA, USA.;Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA.;Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA.;Division of Allergy and Infectious Disease, University of Washington, Seattle, WA, USA.",
"authors": "Wood|Brian R|BR|;Lacy|John Matthew|JM|;Johnston|Christine|C|;Weigle|David S|DS|;Dhanireddy|Shireesha|S|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D017320:HIV Protease Inhibitors; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1177/2325957414567681",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-9574",
"issue": "14(4)",
"journal": "Journal of the International Association of Providers of AIDS Care",
"keywords": "Cushing syndrome; HIV; adrenal insufficiency; glucocorticoids; ritonavir",
"medline_ta": "J Int Assoc Provid AIDS Care",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000309:Adrenal Insufficiency; D000328:Adult; D000368:Aged; D005260:Female; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D019438:Ritonavir",
"nlm_unique_id": "101603896",
"other_id": null,
"pages": "300-5",
"pmc": null,
"pmid": "25589302",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adrenal Insufficiency as a Result of Ritonavir and Exogenous Steroid Exposure: Report of 6 Cases and Recommendation for Management.",
"title_normalized": "adrenal insufficiency as a result of ritonavir and exogenous steroid exposure report of 6 cases and recommendation for management"
} | [
{
"companynumb": "PHHY2015US171780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "After pulmonary resection for non-small-cell lung cancer, some patients with postoperative recurrence and mutated epidermal growth factor receptor (EGFR) subsequently receive EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib may be efficacious if those patients become resistant to the 1st-line EGFR-TKI because of the T790M mutation. We recently performed thoracoscopic rebiopsy to detect the T790M mutation in 4 patients who became resistant to the 1st-line EGFR-TKI treatment for postoperative recurrence. Our limited experience suggests that thoracoscopic biopsy is associated with limited morbidity, can help detect the T790M mutation and may improve the management of select patients with acquired resistance to the 1st-line EGFR-TKIs.",
"affiliations": "Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.;Department of Respiratory Medicine, Kyoto University, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.",
"authors": "Hamaji|Masatsugu|M|;Motoyama|Hideki|H|;Menju|Toshi|T|;Chen-Yoshikawa|Toyofumi-Fengshi|TF|;Sonobe|Makoto|M|;Kim|Young Hak|YH|;Date|Hiroshi|H|",
"chemical_list": "D004273:DNA, Neoplasm; D066246:ErbB Receptors",
"country": "England",
"delete": false,
"doi": "10.1093/icvts/ivy107",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1569-9285",
"issue": "27(4)",
"journal": "Interactive cardiovascular and thoracic surgery",
"keywords": null,
"medline_ta": "Interact Cardiovasc Thorac Surg",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D011013:Pneumonectomy; D011184:Postoperative Period; D013906:Thoracoscopy",
"nlm_unique_id": "101158399",
"other_id": null,
"pages": "606-608",
"pmc": null,
"pmid": "29618075",
"pubdate": "2018-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Thoracoscopic rebiopsy to detect the T790M mutation after postoperative recurrence.",
"title_normalized": "thoracoscopic rebiopsy to detect the t790m mutation after postoperative recurrence"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1089046",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Tacrolimus is a common immunosuppressant used in solid organ transplant recipients. Although most patients develop diarrheal symptoms, data regarding patterns of injury in patients taking tacrolimus are limited. We performed this study to characterize tacrolimus-related features of colonic injury. We retrospectively identified colonic samples from 20 patients receiving tacrolimus monotherapy. Records were reviewed for symptoms, endoscopic findings, other medications, and infections. None of the patients had gastrointestinal infections or used other drugs known to cause colonic injury; none had received mycophenolate within 6 months of presentation. Cases were evaluated for the nature and distribution of inflammation and crypt abnormalities, including distortion, destruction, and apoptosis. Eighteen (90%) patients were solid organ transplant recipients. Seventeen (85%) had gastrointestinal symptoms, particularly diarrhea (75%). More than 50% had endoscopic colitis and 15% had ulcers and/or erosions. Most (90%) cases showed regenerative epithelial changes; apoptotic crypt cells were present in 55% and numerous in 10% of cases. Neutrophilic cryptitis was present in 60% of cases; 35% showed crypt destruction. Plasma cell-rich lamina propria inflammation and crypt distortion were observed in 40% and 25% of cases, respectively. There was no correlation between therapy duration and features of chronic injury. We conclude that tacrolimus can cause symptomatic colitis. Histologic abnormalities are often mild, featuring regenerative crypts and scattered apoptotic debris. However, 40% of symptomatic patients have chronic colitis, most likely reflecting drug-induced immune dysregulation. Pathologists should be aware of these associations because colitis often resolves with decreasing drug dosage rather than treatment directed toward inflammatory bowel disease.",
"affiliations": "Department of Pathology, University of Michigan, Ann Arbor, MI.;Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.;Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.",
"authors": "Hissong|Erika|E|;Mostyka|Maria|M|;Yantiss|Rhonda K|RK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PAS.0000000000001761",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-5185",
"issue": "46(1)",
"journal": "The American journal of surgical pathology",
"keywords": null,
"medline_ta": "Am J Surg Pathol",
"mesh_terms": null,
"nlm_unique_id": "7707904",
"other_id": null,
"pages": "118-123",
"pmc": null,
"pmid": "34138798",
"pubdate": "2022-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Histologic Features of Tacrolimus-induced Colonic Injury.",
"title_normalized": "histologic features of tacrolimus induced colonic injury"
} | [
{
"companynumb": "US-MYLANLABS-2022M1027051",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Carotid cavernous fistulas (CCF) are vascular communications between the carotid artery and the cavernous sinus. Ophthalmologists are called to diagnose and manage the condition in cases that present with ocular features. A 73-year-old female was referred to our glaucoma center clinic. Eight years before, she had started receiving medication for glaucoma and had undergone laser iridotomy, but a satisfactory management of intraocular pressure (IOP) had not been achieved. The patient was complaining of intermittent diplopia, bilateral proptosis, and conjunctival chemosis over the past 6 months. Best-corrected visual acuity in the right (OD) and left eye (OS) was 9/10 and 10/10, respectively. Visual field testing showed slight paracentral field defects mostly in OS. IOP was 20 mm Hg in OD and 34 mm Hg in OS. We referred the patient to neuroradiology, and MRI angiography revealed a CCF with angiographic classification of Cognard grade 2. Closure of the CCF by transarterial embolization was performed in the neuroradiology department. One week following the procedure, the clinical signs of diplopia, proptosis, and conjunctival chemosis had greatly improved, and IOP was reduced to 12 mm Hg OD and 19 mm Hg in OS. Glaucoma treatment was maintained with topical brimatoprost, brinzolamide, and timolol. Owing to the risk of vision loss associated with vascular stasis, retinal ischemia, and high IOP, ophthalmologists must be aware of the clinical features of CCF and should request appropriate imaging studies such as MRI angiography in order to confirm the diagnosis and plan multidisciplinary treatment.",
"affiliations": "Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.;Ophthalmology Unit, Azienda Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.",
"authors": "Calafiore|Silvia|S|;Perdicchi|Andrea|A|;Scuderi|Gianluca|G|;Contestabile|Maria Teresa|MT|;Abdolrahimzadeh|Solmaz|S|;Recupero|Santi Maria|SM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000446151",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. 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 10.1159/000446151cop-0007-0296Case ReportGlaucoma Management in Carotid Cavernous Fistula Calafiore Silvia a*Perdicchi Andrea aScuderi Gianluca aContestabile Maria Teresa aAbdolrahimzadeh Solmaz bRecupero Santi Maria aaOphthalmology Unit, NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Rome, ItalybOphthalmology Unit, Azienda Policlinico Umberto I, Sapienza University of Rome, Rome, Italy*Silvia Calafiore, Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Vicolo del convento 74, IT-00015 Monterotondo, Rome (Italy), E-Mail silviacalafiore@live.itMay-Aug 2016 2 6 2016 2 6 2016 7 2 296 302 17 2 2016 12 4 2016 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.Carotid cavernous fistulas (CCF) are vascular communications between the carotid artery and the cavernous sinus. Ophthalmologists are called to diagnose and manage the condition in cases that present with ocular features. A 73-year-old female was referred to our glaucoma center clinic. Eight years before, she had started receiving medication for glaucoma and had undergone laser iridotomy, but a satisfactory management of intraocular pressure (IOP) had not been achieved. The patient was complaining of intermittent diplopia, bilateral proptosis, and conjunctival chemosis over the past 6 months. Best-corrected visual acuity in the right (OD) and left eye (OS) was 9/10 and 10/10, respectively. Visual field testing showed slight paracentral field defects mostly in OS. IOP was 20 mm Hg in OD and 34 mm Hg in OS. We referred the patient to neuroradiology, and MRI angiography revealed a CCF with angiographic classification of Cognard grade 2. Closure of the CCF by transarterial embolization was performed in the neuroradiology department. One week following the procedure, the clinical signs of diplopia, proptosis, and conjunctival chemosis had greatly improved, and IOP was reduced to 12 mm Hg OD and 19 mm Hg in OS. Glaucoma treatment was maintained with topical brimatoprost, brinzolamide, and timolol. Owing to the risk of vision loss associated with vascular stasis, retinal ischemia, and high IOP, ophthalmologists must be aware of the clinical features of CCF and should request appropriate imaging studies such as MRI angiography in order to confirm the diagnosis and plan multidisciplinary treatment.\n\nKeywords\nCarotid cavernous fistulaGlaucomaManagementOcular hypertensionMultidisciplinary treatment\n==== Body\nIntroduction\nCarotid cavernous fistulas (CCF) are vascular communications between the carotid artery and the cavernous sinus [1, 2]. Although CCF management is formally in the area of interest of neuroradiology and neurosurgery, ophthalmologists are frequently called to diagnose and manage the condition in cases first presenting with ocular features. In fistulas draining directly into the ophthalmic veins, the diagnosis may be straightforward, presenting with symptoms of pulsatile proptosis, diplopia, marked episcleral congestion and chemosis, and a red eye [3]. However, in posterior dural draining CCF (through the superior/inferior petrous sinuses), symptoms may be mild and difficult to interpret (white-eye syndrome). In both cases, an orbital bruit may be audible with careful auscultation [2].\n\nOther features of CCF include venous and arterial stasis that may cause retinal and choroidal changes such as conjunctiva arterialization, anterior segment ischemia with neovascular changes, papilledema, retinal venous dilatation, retinal hemorrhage, and central retinal vein occlusion, which require appropriate treatment [4]. Orbital venous stasis and extraocular muscle engorgement may cause restricted ocular motility associated with diplopia. Alternatively, ophthalmoplegia/diplopia may also be caused by decreased perfusion and ischemia of cranial nerves in the intracavernous sinus [1, 3]. The involvement of both eyes (OU; or in rare cases only the fellow eye in isolation) is explained by the communication of the cavernous sinuses [1, 3].\n\nIn this report, glaucoma management in a 73-year-oldfemale with a CCF is presented.\n\nCase Presentation\nA 73-year-old female was referred to our glaucoma center clinic for management of glaucoma and to undergo evaluation for selective laser trabeculoplasty, Argon laser trabeculoplasty, and/or cataract surgery. Eight years before, she had started receiving medication for ocular hypertension that included a combination of topical bimatoprost, dorzolamide, brimonidine, and oral acetazolamide (250 mg) with unsatisfactory results and had undergone laser iridotomy 2 months before. Past medical history was significant for chronic obstructive pulmonary disease, depressive mood disorder, and treatment for breast cancer.\n\nOn presentation, the patient was complaining of intermittent diplopia, bilateral proptosis, and conjunctival chemosis over the past 6 months. Best-corrected visual acuity in the right eye (OD) was 9/10 (corrected with −1.5 cyl/100 axis) and uncorrected visual acuity in the left eye (OS) was 10/10. Clinical examination revealed the following: proptosis of OU, respectively 20 and 22 mm in OD and OS, diplopia, conjunctival chemosis in OU but more severe in OD (fig. 1a), diffuse corneal epithelial abrasion due to proptosis in OU, narrow iridocorneal angle in OU (Shaffer grade 2), initial lens nuclear sclerosis OU, and two viable laser iridotomies in OS. Intraocular pressure (IOP) measured with Icare tonometry was 20 mm Hg in OD and 34 mm Hg in OS [5]. Fundus examination with optic nerve head evaluation was normal with no signs of venous or arterial congestion and absence of hemorrhages or exudates in OU. Optical coherence tomography (OCT) of the optic discs showed normal peripapillary retinal nerve fiber thicknesses in OU (fig. 2a). Visual-field testing showed slight paracentral field defects mostly in OS, but with substantially normal glaucoma hemifield test in OU (fig. 2b).\n\nBased on the clinical signs (proptosis, diplopia, and conjunctival chemosis), examination results (substantially normal optic nerve heads and visual fields in OU), and the patient history (8 years of ocular hypertension that was well controlled with medical therapy in the past), the clinical presentation was considered to be atypical and consistent with a secondary glaucoma of unknown etiology, so we decided to perform further investigations before considering treatment. As the first step an orbital auscultation was performed in OU in order to look for any bruit that is typical of CCF, but the results were doubtful and uncertain. We then referred the patient to neuroradiological consultation and investigation of the cerebral vasculature. MRI angiography revealed a CCF with angiographic classification of Cognard grade 2 (fig. 3a).\n\nClosure of the CCF by transarterial embolization was performed in the neuroradiology department, using detachable balloon embolization by introducing an intravascular microcatheter into the intracavernous portion of the internal carotid artery and placing a stent in the fistula. Finally, a postoperative control arteriography was performed, showing considerable reduction of the flow at the fistula (fig. 3b).\n\nOne week following the procedure, the patient was seen at our clinic. The clinical signs of diplopia, proptosis, and conjunctival chemosis were greatly reduced (fig. 1b). IOP was reduced to 12 mm Hg OD and 19 mm Hg in OS on topical treatment with brimatoprost, brinzolamide, and timolol. The values of IOP remained stable for the following 6 months.\n\nDiscussion\nThe increase of IOP in CCF is mainly caused by increased episcleral and vortex vein pressure. In such cases, closure of the fistula and normalization of circulation has a favorable result in reducing IOP. In other cases, glaucoma may be caused by iris neovascularization due to decreased retinal perfusion or vascular engorgement and edema of the choroid and ciliary body, causing a forward movement of the iris/lens resulting in pupil block glaucoma [6, 7]. IOP measurement, visual field testing, and optic nerve head evaluation are of paramount importance, and the patient must be closely followed up in this manner [8, 9, 10]. OCT, other than being used in macular pathology, is also helpful for the early diagnosis of peripapillary and macular retinal nerve fiber changes [11]. Furthermore, the ophthalmologist should request appropriate imaging studies such as MRI angiography in order to confirm the diagnosis and to plan appropriate multidisciplinary treatment. Therapy options depend on the gravity of the conditions as in CCF, ocular symptoms put the involved eyes at great risk. In patients with dural draining CCF and without ocular or cerebral signs, close observation may be adopted [12]. Occasionally, dural draining fistulas may favorably evolve to spontaneous closure, and this may especially occur after diagnostic angiography. In patients with dural CCF with low ocular or cerebral risk, a manual carotid-jugular manipulation/compression technique has also been adopted [12]. Although surgical treatment and/or radiotherapy have been used in the past, the current treatment of choice for direct or dural fistulas is transarterial or transvenous embolization of the fistula [13]. When possible, the best approach is through the inferior petrous sinus. If not accessible, the superior ophthalmic vein approach is adopted.\n\nConclusions\nOwing to the risk of vision loss in involved eyes, the ophthalmologist must be aware of the various clinical features of CCF. Diagnosis may be straightforward in cases with direct CCF draining directly into the ophthalmic veins or may be difficult, especially in cases of dural draining CCF where symptoms are subtle. Treatment options must be carefully considered and adopted in a timely manner, owing to the risks of vision loss associated with high IOP, vascular stasis, and ischemia of the retina and other ocular structures. A multidisciplinary approach of neuroradiologists, neurosurgeons, and ophthalmologists is advisable in complex cases.\n\nStatement of Ethics\nThe study was conducted in accordance with the Tenets of the Declaration of Helsinki, and the patient provided consent to the publication of her case.\n\nDisclosure Statement\nThe authors report no conflicts of interests.\n\nFig. 1 a Frontal view of the patient showing bilateral axial proptosis, orbital edema, and injected chemotic conjunctiva with dilated corkscrew vessels, which is more severe in OD. b Postoperative appearance showing significant objective improvement of the proptosis and conjunctival chemosis.\n\nFig. 2 a OCT scans showing normal peripapillary retinal nerve fiber thickness in OU. b Visual field analysis showing slight field defects mostly in OS with the bilateral normal glaucoma hemifield test.\n\nFig. 3 a Angiogram of the left carotid artery demonstrates a carotid-cavernous fistula classified as Cognard grade 2. White arrow = internal carotid artery segment; black arrow = arterialized superior ophthalmic vein. b Postoperative angiography showing exclusion of the CCF where the superior ophthalmic vein cannot be visualized.\n==== Refs\nReferences\n1 De Keizer R Carotid-cavernous and orbital arteriovenous fistulas: ocular features, diagnostic and hemodynamic considerations in relation to visual impairment and morbidity Orbit 2003 22 121 142 12789591 \n2 Barrow DL Spector RH Braun IF Landman JA Tindall SC Classification and treatment of spontaneous carotid-cavernous sinus fistulas J Neurosurg 1985 62 248 256 3968564 \n3 Phelps CD Thompson HS Ossoinig KC The diagnosis and prognosis of atypical carotid-cavernous fistula (red-eyed shunt syndrome) Am J Ophthalmol 1982 93 423 436 7072809 \n4 Lambiase A Abdolrahimzadeh S Recupero SM An update on intravitreal implants in use for eye disorders Drugs Today (Barc) 2014 50 239 249 24696869 \n5 Scuderi GL Cascone NC Regine F Validity and limits of the rebound tonometer (Icare 5): clinical study Eur J Ophthalmol 2011 21 251 257 20853257 \n6 Jorgensen JS Guthoff R The role of episcleral venous pressure in the development of secondary glaucoma Klin Monatsbl Augenheikd 1988 193 471 475 \n7 Cruciani F Lorenzatti M Nazzaro V Abdolrahimzadeh S Bilateral acute angle closure glaucoma and myopia induced by topiramate Clin Ter 2009 160 215 216 19756324 \n8 Scuderi GL Cesareo M Perdicchi A Recupero SM Standard automated perimetry and algorithms for monitoring glaucoma progression Prog Brain Res 2008 77 99 \n9 Iester M Perdicci A Capris E Comparison between discriminant analysis models and glaucoma probability score for the detection of glaucomatous optic nerve head changes J Glaucoma 2008 17 535 540 18854729 \n10 Recupero SM Contestabile MT Taverniti L Open-angle glaucoma: variations in the intraocular pressure after visual field examination J Glaucoma 2003 12 114 118 12671465 \n11 Michelessi M Lucenteforte E Oddone F Optic nerve head and fibre layer imaging for diagnosing glaucoma Cochrane Database Syst Rev 2015 11 CD008803 26618332 \n12 Higashida RT Hieshima GB Halbach VV Bentson JR Godo K Closure of carotid cavernous sinus fistulae by external compression of the carotid artery and jugular vein Acta Radiol Suppl 1986 369 580 583 2980563 \n13 Thèaudin M Saint-Maurice JP Chapot R Vahedi K Mazighi M Vignal C Diagnosis and treatment of dural carotid-cavernous fistulas: a consecutive series of 27 patients J Neurol Neurosurg Psychiatry 2007 78 174 179 17028116\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "7(2)",
"journal": "Case reports in ophthalmology",
"keywords": "Carotid cavernous fistula; Glaucoma; Management; Multidisciplinary treatment; Ocular hypertension",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "296-302",
"pmc": null,
"pmid": "27462258",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "20853257;18854729;12789591;3968564;7072809;3210642;18929103;12671465;2980563;26618332;19756324;17028116;24696869",
"title": "Glaucoma Management in Carotid Cavernous Fistula.",
"title_normalized": "glaucoma management in carotid cavernous fistula"
} | [
{
"companynumb": "IT-ALLERGAN-1669886US",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DORZOLAMIDE HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nTo investigate real-world haematological toxicity, overall survival (OS) and the treatment characteristics of docetaxel and cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC).\n\n\nMETHODS\nThis retrospective claims data study followed patients with mCRPC receiving cabazitaxel or docetaxel from their first chemotherapy infusion. Haematological toxicities were measured using treatment codes and inpatient diagnoses. OS was estimated using the Kaplan-Meier method. A multivariable Cox regression analysis was used to identify OS predictors.\n\n\nRESULTS\nData from 539 patients administered docetaxel and 240 administered cabazitaxel were analysed. Regarding adverse events, within 8 months of treatment initiation, some kind of treatment for haematological toxicity was documented in 31% of patients given docetaxel and in 61% of patients given cabazitaxel. In the same period, hospitalization associated with haematological toxicity was documented in 11% of the patients in the docetaxel cohort and in 15% of the patients in the cabazitaxel cohort. In the docetaxel cohort, 9.9% of patients required reverse isolation and 13% were diagnosed with sepsis during hospitalization. In the cabazitaxel cohort, the cumulative incidence was 7.9% and 15%, respectively. The median OS was reached at 21.9 months in the docetaxel cohort and, because of a later line of therapy, at 11.3 months in the cabazitaxel cohort. A multivariate Cox regression revealed that indicators of locally advanced and metastatic disease, severe comorbidities, and prior hormonal/cytotoxic therapies were independent predictors of early death.\n\n\nCONCLUSIONS\nCabazitaxel patients face an increased risk of haematological toxicities during treatment. Together with their short survival time, this calls for a strict indication when using cabazitaxel in patients with mCRPC.",
"affiliations": "Center for Health Economics Research Hannover (CHERH), Leibniz Universität Hannover, Hannover, Germany.;Techniker Krankenkasse, Versorgungsmanagement, Hamburg, Germany.;Techniker Krankenkasse, Versorgungsmanagement, Hamburg, Germany.;Center for Health Economics Research Hannover (CHERH), Leibniz Universität Hannover, Hannover, Germany.;Forschungszentrum Ungleichheit und Sozialpolitik, Universität Bremen - SOCIUM, Bremen, Germany.;Gesundheitsforschung für Männer gGmbH, Berlin, Germany.",
"authors": "Kreis|Kristine|K|;Horenkamp-Sonntag|Dirk|D|;Schneider|Udo|U|;Zeidler|Jan|J|;Glaeske|Gerd|G|;Weissbach|Lothar|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bju.15542",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1464-4096",
"issue": null,
"journal": "BJU international",
"keywords": "cabazitaxel; claims data; docetaxel; metastatic castration-resistant prostate cancer; survival; toxicity",
"medline_ta": "BJU Int",
"mesh_terms": null,
"nlm_unique_id": "100886721",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34242474",
"pubdate": "2021-07-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and survival of docetaxel and cabazitaxel in metastatic castration-resistant prostate cancer.",
"title_normalized": "safety and survival of docetaxel and cabazitaxel in metastatic castration resistant prostate cancer"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2022069790",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "4",
... |
{
"abstract": "Several studies on opiates demonstrated that selected brain areas as cerebellum and limbic system have the greatest density of opioid receptors. Recently, few cases of severe cerebellitis following methadone poisoning have been reported in children. We present the case of a 30-month-old girl who developed a delayed encephalopathy after methadone intoxication. She was admitted to our emergency department in coma, and after naloxone infusion, she completely recovered. Five days after intoxication, she developed psychomotor agitation, slurred speech, abnormal movements, and ataxia despite a negative neuroimaging finding. A repeat magnetic resonance imaging (MRI) performed 19 days after the intoxication for persistent symptoms showed signal abnormalities in the temporomesial regions, basal ganglia, and substantia nigra. To our knowledge, this is the first report of these delayed MRI findings associated with synthetic opioid intoxication.",
"affiliations": "Paediatric Emergency Unit, Paediatric Department, University of Padua, 35100 Padua, Italy. anna.zanin@unipd.it",
"authors": "Zanin|Anna|A|;Masiero|Susanna|S|;Severino|Maria Savina|MS|;Calderone|Milena|M|;Da Dalt|Liviana|L|;Laverda|Anna Maria|AM|",
"chemical_list": "D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1177/0883073809343318",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "25(6)",
"journal": "Journal of child neurology",
"keywords": null,
"medline_ta": "J Child Neurol",
"mesh_terms": "D001921:Brain; D002675:Child, Preschool; D004660:Encephalitis; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008691:Methadone; D009460:Neurologic Examination; D020258:Neurotoxicity Syndromes; D012008:Recurrence",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "748-51",
"pmc": null,
"pmid": "19808992",
"pubdate": "2010-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A delayed methadone encephalopathy: clinical and neuroradiological findings.",
"title_normalized": "a delayed methadone encephalopathy clinical and neuroradiological findings"
} | [
{
"companynumb": "IT-VISTAPHARM, INC.-VER201801-000243",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"druga... |
{
"abstract": "We report the case of a 67-year-old female with hypertension and rheumatoid arthritis who had 5 unprovoked episodes of anaphylaxis in an 18-month period of time. We review idiopathic anaphylaxis, including its definition, diagnostic work-up, and differential diagnosis.",
"affiliations": "Medical College of Wisconsin, Milwaukee, WI, USA.;Medical College of Wisconsin, Milwaukee, WI, USA.",
"authors": "Mendez|Anjeanette|A|;Pelz|Barry J|BJ|https://orcid.org/0000-0002-3195-5577",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/21526567211041925",
"fulltext": "\n==== Front\nAllergy Rhinol (Providence)\nAllergy Rhinol (Providence)\nAAR\nspaar\nAllergy & Rhinology\n2152-6575\n2152-6567\nSAGE Publications Sage CA: Los Angeles, CA\n\n10.1177/21526567211041925\n10.1177_21526567211041925\nCase Report\nIdiopathic Anaphylaxis: A Diagnosis of Exclusion\nMendez Anjeanette MD\nhttps://orcid.org/0000-0002-3195-5577\nPelz Barry J. MD\n5506 Medical College of Wisconsin , Milwaukee, WI, USA\nBarry J. Pelz, Division of Asthma, Allergy, and Immunology, 9000 W Wisconsin Ave, Suite 440, Milwaukee, WI 53226, USA. Email: bpelz@mcw.edu\n13 9 2021\nJan-Dec 2021\n12 21526567211041925© The Author(s) 2021\n2021\nSAGE Publications Inc. unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nWe report the case of a 67-year-old female with hypertension and rheumatoid arthritis who had 5 unprovoked episodes of anaphylaxis in an 18-month period of time. We review idiopathic anaphylaxis, including its definition, diagnostic work-up, and differential diagnosis.\n\nidiopathic anaphylaxis\ncase report\ndiagnosis of exclusion\nanaphylaxis\ntypesetterts19\ncover-dateJanuary-December 2021\n==== Body\npmcAnaphylaxis is a severe allergic reaction that can present with involvement of the gastrointestinal (GI), cardiovascular, dermatological, and/or respiratory systems. It typically occurs after exposure to an allergen though in rare cases it can happen without any trigger; this is known as idiopathic anaphylaxis (IA). IA is a diagnosis of exclusion made after a comprehensive clinical evaluation is performed and potential allergens are excluded. We report a case of multiple anaphylactic events with no identifiable trigger and negative work-up suspicious for IA.\n\nThe patient was a 67-year-old female with hypertension and rheumatoid arthritis who presented for evaluation of recurrent episodes of anaphylaxis. She experienced 5 episodes within an 18-month span. Her initial event occurred the morning after eating a chicken salad from a restaurant. She awoke with generalized pruritus, urticaria, oral swelling, and an isolated episode of nonbloody diarrhea. She was seen at an immediate care clinic and managed with oral corticosteroids and diphenhydramine. This episode escalated rapidly over a period of several minutes and resolved completely within 4 h. Her next episode occurred 10 to 15 m after she ate a vanilla-flavored waffle for breakfast and started to experience pruritus of her hands and feet, swelling of her lips and tongue, and acute onset of a single episode of nonbloody diarrhea. The symptoms developed over a 5-min time period. She did not experience any flushing with this event. There was no visible rash. She was treated in an emergency department (ED) with intravenous solumedrol and intravenous diphenhydramine, with a resolution of symptoms within 4 h. The patient had an additional episode 1 month later while she was walking outside. She had sudden onset of lip and tongue swelling, generalized pruritus, and an isolated episode of nonbloody diarrhea that improved with diphenhydramine and rest. Again, there was no visible rash. She returned to baseline within 2 h of symptom onset. She had a similar event while working at a sewing machine in her basement when she suddenly developed swelling of the lips and tongue, generalized pruritus, and nonbloody diarrhea. She managed this herself with diphenhydramine and prednisone at home. Her most recent event occurred 2 months prior to her initial presentation. She was a passenger in her husband’s car when symptoms suddenly occurred. Although this event began with swelling of the lips and tongue and generalized pruritus, she also developed chest tightness and shortness of breath. She was not eating or drinking any substances. She also recalls that the car windows were closed. She was not sick or taking any new medications. Symptoms were not alleviated with 50 mg diphenhydramine, and she was taken to a nearby urgent care where she was found to be hypotensive to 82/49. She was transferred by Emergency Medical Services to the ED and was treated with intramuscular (IM) epinephrine and supplemental oxygen en route. A review of the ED records indicates that her presenting blood pressure at the ED was 112/57. Due to persistent wheezing and lip and tongue swelling, she was administered a second dose of IM epinephrine and a bolus of intravenous fluids and subsequently treated with antihistamines and steroids. She did not have a rash. She returned to baseline within 4 h.\n\nOn our initial evaluation, we obtained a detailed history and performed a thorough physical exam which was unremarkable. The patient denies any previous history of asthma, rhinitis symptoms, atopic dermatitis, food allergy, or urticaria. Additionally, she denies any allergies to stinging insects or medications. The patient's home medications included omeprazole 20 mg daily, aspirin 81 mg daily, amlodipine 5 mg daily, atorvastatin 20 mg daily, metoprolol succinate 50 mg daily, nabumetone 750 mg daily, and a daily probiotic. She has been on these medications without any dose changes for several years and has remained on each of these over the ensuing 14 months of follow-up care in our clinic without any additional anaphylactic events. Percutaneous testing for environmental allergies was positive to cat dander and negative to tree pollens, grass pollens, weed pollens, ragweed pollens, molds, dust mites, dogs, cockroaches, and mice. The patient has not been around cats for several years, but previously experienced pruritic and watery eyes with cat exposure. Serum testing for environmental allergies corroborated the percutaneous testing by showing sensitization to cats and none of the other allergens tested. Serologic testing for galactose-α-1,3-galactose (alpha-gal) was also negative. Additionally, no hidden agents or cofactors including exercise, alcohol, latex, nonsteroidal antiinflammatory drugs (NSAIDs), or spices were identified in the episodes.\n\nAnaphylaxis varies in duration and severity. Symptoms are usually rapid in onset and in severe cases may be life-threatening.1 Patients can present with a combination of symptoms that may involve the skin, respiratory, GI, and cardiovascular systems.1–4 When investigating an anaphylactic event, it is important to obtain an extensive history of each episode. Work-up should include details leading up to the event such as ingestion of any foods or drugs, activities prior to and during the episode, and history of exposure to stinging insects.2,4 Excluding other possible diagnoses such as mastocytosis is important as well.2 If no precipitating factor can be identified, IA becomes the diagnosis of exclusion.\n\nIA can be categorized into either frequent or infrequent based on the number of episodes per year.2,4 Frequent IA involves 6 or more episodes per year or 2 episodes in the last 2 months.2,4 IA can be further categorized into generalized or angioedema-predominant, depending on the nature of the symptoms.2 Additionally, when episodes of IA are difficult to control without prednisone, it is further classified as corticosteroid-dependent IA.2\n\nThe pathogenesis of IA remains unclear, though several theories have been proposed. One theory is that patients with IA have an increased number of mast cells, but studies have only found a modest to no increase at all in the number of mast cells in affected patients.4 Another theory that has been explored is increased lymphocyte activation in IA patients.1,3–5 In 1 study, Grammer et al6 used flow cytometry to evaluate the immunological differences between IA patients during acute episodes versus those in remission and healthy controls. It was noted that IA patients in an acute event had statistically significant increases in T-cell activation markers when compared to those in remission and controls.4,6 Additionally, B-cell activation markers were elevated in both groups of IA patients.4,6 Other theories include the potential effects of estrogen or progesterone on basophil activation, as IA is noted to have a higher incidence in women.5,7 A study performed by the US National Institutes of Health involving 8 symptomatic women and 10 control subjects showed no difference in basophil activation in response to progesterone or estrogen.7 Despite the multitude of proposed theories, the pathogenesis of IA remains elusive.\n\nIA is a steroid-responsive disease that clinically presents no differently than other forms of anaphylaxis. In acute attacks, treatment consists of epinephrine, antihistamines, and corticosteroids if indicated.1,3,5 Long-term treatments are considered based on the frequency and the severity of episodes.4 Corticosteroids and antihistamines are used in patients with frequent or severe episodes though long-term adverse effects of steroids may limit therapy.4 Additionally, there are isolated case reports documenting success with therapies such as omalizumab and ketotifen.4,8\n\nIn our patient's case, she experienced 5 anaphylactic episodes where no foods, medications, hidden allergens, or cofactors (including exercise, alcohol, latex, NSAIDs, spices, or mammalian meats) triggering the events could be identified. As such, the working diagnosis was thought to be IA, which was further categorized as generalized and infrequent. The patient was prescribed an emergency kit that included autoinjectable epinephrine, prednisone, and cetirizine to always carry on her person. Dust mite anaphylaxis was considered, but since the patient is not allergic to dust mites, this possibility was ruled out.9 Additionally, although clinical suspicion for hereditary or acquired angioedema was extremely low, since many of the episodes involved lip and tongue swelling, labs obtained as part of our additional work-up included quantitative C1 esterase, C1 esterase function, C4 complement level, and C1q; all of which were found to be normal. A baseline tryptase level was also obtained at the time of initial consultation (when the patient was well) and was noted to be within normal limits at 5.3 μg/L (reference range <11). Due to this finding, no further testing for mast cell disease including additional blood tests or bone marrow biopsy was pursued. Additional tryptase levels have not been obtained, since the patient has not had any additional events. Given her history of rheumatoid arthritis, we considered evaluating markers of B-cell activation, including B cell activating factor (BAFF), but these studies have not been performed to date. The patient has been followed closely for the past 14 months and has not had any recurrence of episodes.\n\nDeclaration of Conflicting Interests: 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 iD: Barry J. Pelz https://orcid.org/0000-0002-3195-5577\n\nStatement of Human and Animal Rights: This article does not contain any studies with human or animal subjects.\n\nStatement of Informed Consent: There are no human subjects in this article and informed consent is not applicable.\n\nTrial Registration: Not applicable, because this article does not contain any clinical trials.\n==== Refs\nReferences\n\n1 Carter MC Akin C Castells MC Scott EP Lieberman P . Idiopathic anaphylaxis yardstick: practical recommendations for clinical practice. Ann Allergy Asthma Immunol. 2020;124 (1 ):16–27.31513910\n2 Greenberger PA . Idiopathic anaphylaxis. Immunol Allergy Clin North Am. 2007;27 (2 ):273–293. PMID 17493503.17493503\n3 Giannetti MP Akin C Castells M . Idiopathic anaphylaxis: a form of mast cell activation syndrome. J Allergy Clin Immunol Pract. 2020;8 (4 ):1196–1201.32276688\n4 Fenny N Grammer LC . Idiopathic anaphylaxis. Immunol Allergy Clin North Am. 2015;35 (2 ):349–362. PMID 25841556.25841556\n5 Kuhlen JL Yamini VV . Pathogenesis, newly recognized etiologies, and management of idiopathic anaphylaxis. Discov Med. 2015;19 (103 ):137–144.25725228\n6 Grammer LC Shaughnessay MA Harris KE , et al. Lymphocyte subsets and activation markers in patients with acute episodes of idiopathic anaphylaxis. Ann Allergy Asthma Immunol. 2000;85 (5 ):368–371.11101177\n7 Slater JE Kaliner M . Effects of sex hormones on basophil histamine release in recurrent idiopathic anaphylaxis. J Allergy Clin Immunol. 1987;80 (3 Pt 1 ):285–290.2442235\n8 Sanchez-Valenzuela MC Garcia-Saucedo JC Motoa G Carrillo-Martin I Gonzalez-Estrada A . Treatment of idiopathic anaphylaxis with omalizumab. Ann Allergy Asthma Immunol. 2019;123 (6 ):612–613.31568858\n9 Sompornrattanaphan M Jitvanitchakul Y Malainual N , et al. Dust mite ingestion-associated, exercise-induced anaphylaxis: a case report and literature review. Allergy Asthma Clin Immunol. 2020;16 (2 ):1–5. doi: 10.1186/s13223-019-0399-1. PMID: 31911805; PMCID: PMC6945635.31911804\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2152-6567",
"issue": "12()",
"journal": "Allergy & rhinology (Providence, R.I.)",
"keywords": "anaphylaxis; case report; diagnosis of exclusion; idiopathic anaphylaxis",
"medline_ta": "Allergy Rhinol (Providence)",
"mesh_terms": null,
"nlm_unique_id": "101570968",
"other_id": null,
"pages": "21526567211041925",
"pmc": null,
"pmid": "34540335",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "11101177;32276688;25841556;31513910;2442235;17493503;31568858;31911805;25725228",
"title": "Idiopathic Anaphylaxis: A Diagnosis of Exclusion.",
"title_normalized": "idiopathic anaphylaxis a diagnosis of exclusion"
} | [
{
"companynumb": "2021A800602",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL SUCCINATE"
},
"drugadditional": "3",
"... |
{
"abstract": "Loperamide is an inexpensive, over-the-counter antidiarrheal agent with emerging reports of overdose due to its opioid properties. Although it is considered by many patients to be safe, cardiotoxicity has been reported, prompting the United States Food and Drug Administration to release a warning regarding the arrhythmogenic potential of loperamide. We present a case of a 32-year-old male presenting in acute loperamide overdose and subsequent cardiac dysrhythmia with focal wall motion abnormalities on echocardiogram. This finding has not been previously reported in the literature and is unique in this clinical presentation. We also highlight the potential mechanisms for loperamide cardiotoxicity and its challenging management.",
"affiliations": "University of Miami Miller School of Medicine, Miami, Florida.;Jackson Memorial Hospital, Department of Emergency Medicine, Miami, Florida.;Jackson Memorial Hospital, Department of Emergency Medicine, Miami, Florida.",
"authors": "Bornstein|Kasha|K|;Montrief|Timothy|T|;Parris|Mehruba Anwar|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5811/cpcem.2019.4.42510",
"fulltext": "\n==== Front\nClin Pract Cases Emerg MedClin Pract Cases Emerg MedClinical Practice and Cases in Emergency Medicine2474-252XUniversity of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine 3140310010.5811/cpcem.2019.4.42510cpcem-3-262Case ReportLeft Ventricular Regional Wall Motion Abnormality in the Setting of Acute Loperamide Overdose Bornstein Kasha MSc*Montrief Timothy MD, MPH†Parris Mehruba Anwar MD†\n* University of Miami Miller School of Medicine, Miami, Florida\n† Jackson Memorial Hospital, Department of Emergency Medicine, Miami, FloridaAddress for Correspondence: Kasha Bornstein, MSc, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136. Email: kashabornstein@med.miami.edu.8 2019 01 7 2019 3 3 262 266 23 1 2019 08 4 2019 22 4 2019 Copyright: © 2019 Bornstein et al2019This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Loperamide is an inexpensive, over-the-counter antidiarrheal agent with emerging reports of overdose due to its opioid properties. Although it is considered by many patients to be safe, cardiotoxicity has been reported, prompting the United States Food and Drug Administration to release a warning regarding the arrhythmogenic potential of loperamide. We present a case of a 32-year-old male presenting in acute loperamide overdose and subsequent cardiac dysrhythmia with focal wall motion abnormalities on echocardiogram. This finding has not been previously reported in the literature and is unique in this clinical presentation. We also highlight the potential mechanisms for loperamide cardiotoxicity and its challenging management.\n==== Body\nINTRODUCTION\nLoperamide is an inexpensive, widely used, nonprescription antidiarrheal. Its mechanism of action involves inhibition of intestinal peristalsis through μ-opioid receptor agonism, calcium channel blockade, calmodulin inhibition, and by decreasing paracellular permeability.1 Loperamide is sold under the trade name Imodium in the United States (U.S.). When initially introduced in the 1970s, loperamide was listed as a Schedule II drug, due to concerns over its opioid properties. Loperamide was transferred to Schedule V in 1977, and then decontrolled in 1982 following multiple volunteer studies showing low risk of dependence at therapeutic doses secondary to its poor oral systemic bioavailability and limited central nervous system penetration.2–4 However, reports of loperamide misuse are increasing, more commonly at very high doses of 70–100 milligrams (mg) per day, either to attenuate the effects of opioid withdrawal or for its euphoric effects.5\n\nAs loperamide misuse has become more widespread in the past decade, descriptions of significant cardiac dysrhythmias in the overdose setting have emerged. These include ventricular tachycardia and torsades de pointes secondary to the drug’s ability to block cardiac sodium and potassium channels at high doses.6–7 The U.S. faces an increasing population of opioid-addicted patients with escalating opioid overdose mortality. In the setting of efforts to regulate prescription opioid medication misuse through new legislation, many patients are turning to loperamide as an accessible and inexpensive alternative. An added benefit is the lack of social stigma associated with its use.8 It is imperative that healthcare providers be made aware of this emerging trend of loperamide use and its under-recognized cardiac toxicity. We describe one case of loperamide overdose presenting with cardiac dysrhythmia and focal wall motion abnormalities discovered on echocardiogram.\n\nCASE REPORT\nA 32-year-old man with a history of polysubstance use including heroin was found combative and delirious in his room by staff at his sober living facility. Multiple empty boxes of loperamide were found in his backpack at the scene by emergency medical services. He was given intravenous (IV) fluids and transported to the emergency department (ED). In the ED, he was notably agitated. On physical exam, he was noted to be tachycardic with a regular pulse of 128 beats per minute and a blood pressure of 123/77 millimeters of mercury (mmHg). He was tachypneic with mild respiratory distress, diaphoretic, and oriented to person only. He was intubated for airway protection using etomidate and succinylcholine. An initial electrocardiogram (ECG) showed a regular, wide-complex tachycardia with a prolonged QTc of 473 milliseconds (ms) and QRS of 140 ms, with an RSR’ pattern in lead aVR. This was determined to be sinus tachycardia with a left bundle branch block by the consulting cardiologist and electrophysiologist (Image 1). The patient’s electrolyte levels were within normal limits.\n\nAcutely, in conjunction with poison control the decision was made to manage the patient with 0.4 milligram (mg) IV naloxone, 400 mg IV lidocaine, and one gram IV magnesium. The patient also received 50 milliequivalent (mEq) IV sodium bicarbonate for presumed sodium channel toxicity from the high-dose loperamide. An initial troponin I was elevated to 0.084 nanograms (ng) per milliliter (mL) (reference 0.000–0.045 ng/mL). A point-of-care ultrasound (POCUS) demonstrated left ventricular anterior wall hypokinesis. He underwent emergent cardiac catheterization, which revealed left ventricular anterior wall hypokinesis, angiographically normal cardiac arteries with a left ventricle ejection fraction (LVEF) of 45%, and an elevated left ventricular filling pressure of 23 mmHg.\n\nCPC-EM Capsule\nWhat do we already know about this clinical entity?\n\nLoperamide is a widely used, nonprescription opioid antidiarrheal typically understood to have low risk of dependence given its low bioavailability and limited central nervous system activity.\n\nWhat makes this presentation of disease reportable?\n\nPrior to this case, there were no reported instances of cardiac angiography confirming loperamide as a primary pharmacological cause of depressed myocardial function.\n\nWhat is the major learning point?\n\nLoperamide toxicity can present with elevated cardiac injury markers. Resuscitation should be guided by treatment of factors that may induce electrolyte abnormalities.\n\nHow might this improve emergency medicine practice?\n\nThis case contributes to awareness of the toxidrome as a unique clinical entity. Management to guide resuscitation should be based on pharmacologic principles.\n\nDuring his hospitalization, the patient’s QT peaked one day after admission to 616 ms with a QTc 573 ms and a QRS of 120 ms (Image 2). At that time the patient admitted to taking over 100 mg of loperamide as well as an unknown amount of gabapentin as an alternative to opioids on the day of admission. His dysrhythmia resolved and QTc normalized within four days of admission with no further exposure to loperamide. A subsequent transthoracic ECG showed a LVEF of 55% and no evidence of diastolic dysfunction or hypokinesis of the anterior wall. At discharge, his ECG showed a QTc of 442 ms and a QRS of 98 ms (Image 3). A loperamide serum concentration was not measured during hospitalization. Urine toxicology screen on admission was negative for opiates as loperamide is not included in the standard panel of drugs screened.\n\nDISCUSSION\nThis is a novel case of acute loperamide overdose with subsequent cardiac dysrhythmia with focal wall motion abnormalities on ECG. We do not think gabapentin contributed to his cardiac toxicity as the mechanism of action, nor would toxicity of gabapentin explain the clinical presentation or the laboratory abnormalities. Furthermore, there have been no prior reports of arrhythmias with gabapentin, although both hypertension and hypotension have been reported. The management of loperamide toxicity is largely supportive, although some recommendations can be extrapolated from case reports, pharmacologic principals, and anecdotal experience. In the setting of an acute ingestion, loperamide should adsorb to activated charcoal. Activated charcoal can be administered within two to four hours after a large overdose, provided the patient is not an aspiration risk, in contrast to our case.9\n\nFor patients with decreased responsiveness or respiratory depression, naloxone can be considered as an adjunct to appropriate airway management. This modality showed benefit in one adult case10 and a series of pediatric cases.11,12 In one pediatric case, a four-month-old girl inadvertently ingested approximately two mg/kg of loperamide liquid and subsequently became comatose with respiratory depression. She recovered after three injections of 0.01 mg IV naloxone over 24 hours.12 While naloxone should reverse the respiratory depression induced by loperamide’s μ-opioid agonism, it would not be expected to affect the cardiotoxicity associated with loperamide. However, little data exists to guide naloxone use in acute loperamide toxicity, including dosing. Given loperamide’s long half-life, repeated doses of naloxone may be warranted.12\n\nECG abnormalities are characteristic of loperamide toxicity, particularly prolonged QT and QRS intervals. Again, little data exists to guide cardiac resuscitation in the setting of loperamide ingestion. It is therefore reasonable to treat factors that may induce ECG interval prolongation such as electrolyte abnormalities and other medications. This may be attempted with antiarrhythmic medications such as amiodarone, sotalol, lidocaine, or procainamide,13–15 as well as sodium bicarbonate to overcome loperamide’s sodium channel blockade. Class 1b antiarrhythmic agents such as lidocaine may be preferable in loperamide toxicity as they have weak sodium channel blocking effects and decrease the effective refractory period in comparison to other class one agents.\n\nCONCLUSION\nWithin the literature, the majority of case reports regarding loperamide overdose describe a constellation of symptoms including decreased levels of consciousness, unheralded syncope, markedly increased QTc and QRS intervals, and dysrhythmias including ventricular tachycardia and torsades de pointes. Only one case is reported in which a long-time loperamide user presented with severely depressed global left ventricular function measured by ECG but normal coronary angiography.16 Additionally, two case reports of loperamide overdose described mild global hypokinesis of the left ventricle as measured by ECG without corresponding coronary angiography.15,17 The literature includes only one case report of acute loperamide overdose involving a patient who received both an ECG and coronary angiography. In that case, investigations revealed normal ventricular function and no angiographic abnormalities.18 This case provides an opportunity to describe a novel presentation of acute loperamide toxicity, with an elevated cardiac injury marker and confirmed focal left ventricular anterior wall hypokinesis that subsequently resolved after clearance of the drug.\n\nSection Editor: Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nDocumented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n\nImage 1 Patient’s initial electrocardiogram showing sinus tachycardia with a left bundle branch block and prolonged QT interval of 328 milliseconds (ms), QTc of 470 ms, and QRS of 140 ms.\n\nImage 2 Patient’s electrocardiogram one day after admission showing first degree atrioventricular block, and loperamide-induced QT prolongation, with a QT interval of 616 milliseconds (ms), QTc of 573 ms, and QRS of 120 ms.\n\nImage 3 Patient’s electrocardiogram upon discharge, showing a sinus rhythm with a QT interval of 434 milliseconds (ms), QTc of 442 ms, and QRS of 98 ms.\n==== Refs\nREFERENCES\n1 Baker DE Loperamide: a pharmacological review Rev Gastroenterol Disord 2007 7 suppl 3 S11 8 18192961 \n2 DEA Office of Diversion Control DEA Orange Book Lists of Scheduling Actions 2016 Available at: http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf Accessed April 6, 2019 \n3 Jaffe JH Kanzler M Green J Abuse potential of loperamide Clin Pharmacol Ther 1980 28 6 812 9 7438696 \n4 Korey A Zilm DH Sellers EM Dependence liability of two antidiarrheals, nufenoxole and loperamide Clin Pharmacol Ther 1980 27 5 659 64 7371363 \n5 Juurlink DN Activated charcoal for acute overdose: a reappraisal Br J Clin Pharmacol 2016 81 3 482 7 26409027 \n6 Kang J Compton DR Vaz RJ Proarrhythmic mechanisms of the common anti-diarrheal medication loperamide: revelations from the opioid abuse epidemic Naunyn Schmiedebergs Arch Pharmacol 2016 389 10 1133 7 27530870 \n7 Harmer AR Valentin JP Pollard CE On the relationship between block of the cardiac Na channel and drug-induced prolongation of the QRS complex Br J Pharmacol 2011 164 2 260 73 21480866 \n8 Lasoff DR Koh CH Corbett B Loperamide trends in abuse and misuse over 13 years: 2002–2015 Pharmacotherapy 2017 37 2 249 53 27995643 \n9 Daniulaityte R Carlson R Falck R ‘I just wanted to tell you that loperamide WILL WORK’: a web-based study of extra-medical use of loperamide Drug Alcohol Depend 2013 130 1–3 241 4 23201175 \n10 Bhatti Z Norsworthy J Szombathy T Loperamide metabolite-induced cardiomyopathy and QTc prolongation Clin Toxicol (Phila) 2017 55 7 659 61 28349724 \n11 Minton NA Smith PG Loperamide toxicity in a child after a single dose Br Med J (Clin Res Ed) 1987 294 6584 1383 \n12 Friedli G Haenggeli CA Loperamide overdose managed by naloxone Lancet 1980 1 8183 1413 \n13 Lasoff DR Schneir A Ventricular dysrhythmias from loperamide misuse J Emerg Med 2016 50 3 508 9 26794455 \n14 Upadhyay A Bodar V Malekzadegan M Loperamide induced life threatening ventricular arrhythmia Case Rep Cardiol 2016 5040176 \n15 Spinner HL Lonardo NW Mulamalla R Ventricular tachycardia associated with high-dose chronic loperamide use Pharmacotherapy 2015 35 2 234 8 25645123 \n16 Mirza M Attakamvelly S Dillon A Potential life threatening cardiac toxicity from an easily accessible over the counter drug J Am Coll Cardiol 2017 69 11 2375 \n17 Patel KM Shah S Subedi D Takotsubo-like cardiomyopathy after loperamide overdose Am J Ther 2018 25 5 e548 50 28639963 \n18 Salama A Levin Y Jha P Ventricular fibrillation due to overdose of loperamide, the “poor man’s methadone.” J Community Hosp Intern Med Perspect 2017 7 4 222 6 29046747\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2474-252X",
"issue": "3(3)",
"journal": "Clinical practice and cases in emergency medicine",
"keywords": null,
"medline_ta": "Clin Pract Cases Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101718968",
"other_id": null,
"pages": "262-266",
"pmc": null,
"pmid": "31403100",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": "18192961;21480866;23201175;25645123;26409027;26794455;27530870;27547470;27995643;28349724;28639963;29046747;3109665;6104193;7371363;7438696",
"title": "Left Ventricular Regional Wall Motion Abnormality in the Setting of Acute Loperamide Overdose.",
"title_normalized": "left ventricular regional wall motion abnormality in the setting of acute loperamide overdose"
} | [
{
"companynumb": "US-BION-008207",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "BACKGROUND\nGraves' orbitopathy (GO) is a potentially sight-threatening disease for which currently available medical therapy is not reliably successful. Mycophenolate mofetil (MMF) is a selective immunosuppressant used widely in many autoimmune diseases. Preliminary studies have shown that MMF is effective in the treatment of active GO.\n\n\nOBJECTIVE\nTo evaluate the efficacy and safety of MMF in patients with active moderate-to-severe GO.\n\n\nMETHODS\nOne hundred and 74 patients with active moderate-to-severe GO were randomized to receive either MMF or glucocorticoids (GC).\n\n\nMETHODS\nThe primary outcome was overall response at the 12th and 24th weeks; the outcome assessments included clinical activity score (CAS), soft tissue involvement, pain, visual acuity, proptosis, diplopia and reduction in eye movements. The secondary outcome was changes in those individual parameters. Adverse effects were recorded at each visit.\n\n\nRESULTS\nA greater overall response rate was found in the MMF group compared with the GC group at the 24th week (91·3% vs 67·9%, P = 0·000). MMF therapy showed a better CAS response than GC (92·5% vs 70·5% improved, P < 0·05). Patients treated with MMF showed a significantly improved rate of diplopia and proptosis than patients treated with GC at the 24th week (90·4% and 68·8% improved, respectively). Disease reactivation was not observed in the patients treated with MMF but was observed in five patients after GC therapy. Adverse events occurred in 4 of 80 patients treated with MMF (5%), all of which were mild to moderate. A severe adverse event was only observed in one patient treated with GC but not at all in patients treated with MMF.\n\n\nCONCLUSIONS\nCompared with GC treatment, MMF therapy is more effective and safer for patients with active moderate-to-severe GO.",
"affiliations": "Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China.;Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China.;Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China.;Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China.;Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China.;Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China.;Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China.",
"authors": "Ye|Xiaozhen|X|;Bo|Xiaoyong|X|;Hu|Xiaohao|X|;Cui|Huanhuan|H|;Lu|Bin|B|;Shao|Jiaqing|J|;Wang|Jian|J|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1111/cen.13170",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-0664",
"issue": "86(2)",
"journal": "Clinical endocrinology",
"keywords": null,
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D005938:Glucocorticoids; D049970:Graves Ophthalmopathy; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D009173:Mycophenolic Acid; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0346653",
"other_id": null,
"pages": "247-255",
"pmc": null,
"pmid": "27484048",
"pubdate": "2017-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Efficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves' orbitopathy.",
"title_normalized": "efficacy and safety of mycophenolate mofetil in patients with active moderate to severe graves orbitopathy"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1015661",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "METHODS\nPneumocystis carinii pneumonia occasionally appears in immunodeficient patients. While several reports have shown that Pneumocystis carinii pneumonia occurred in the early phase of starting infliximab treatment in patients with Crohn's disease (CD), the present case suggests for the first time that an increased dosage of infliximab may also lead to pneumonia.\n\n\nRESULTS\nA 51-year-old male had been taking 5 mg of infliximab for the treatment of CD for 10 years with no adverse events. Beginning in September 2013, the dose of infliximab had to be increased to 10 mg/kg because his status worsened. Thereafter, he complained of a fever and cough, and a CT scan revealed ground-glass opacities in the lower lobes of the bilateral lung with a crazy-paving pattern. Bronchoscopy detected swelling of the tracheal mucosa with obvious dilations of the vessels. A polymerase chain reaction using a bronchoalveolar lavage fluid sample detected specific sequences for Pneumocystis jirovecii; thus he was diagnosed with Pneumocystis carinii (jirovecii) pneumonia. After discontinuing infliximab and starting antibiotic treatment, his symptoms and CT findings were dramatically improved.\n\n\nCONCLUSIONS\nThe administration of an increased dosage of infliximab can cause Pneumocystis carinii pneumonia in CD patients.",
"affiliations": "Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.;Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan.",
"authors": "Iwama|Takuya|T|;Sakatani|Aki|A|;Fujiya|Mikihiro|M|;Tanaka|Kazuyuki|K|;Fujibayashi|Shugo|S|;Nomura|Yoshiki|Y|;Ueno|Nobuhiro|N|;Kashima|Shin|S|;Gotoh|Takuma|T|;Sasajima|Junpei|J|;Moriichi|Kentaro|K|;Ikuta|Katsuya|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13099-016-0086-4",
"fulltext": "\n==== Front\nGut PathogGut PathogGut Pathogens1757-4749BioMed Central London 8610.1186/s13099-016-0086-4Case ReportIncreased dosage of infliximab is a potential cause of Pneumocystis carinii pneumonia Iwama Takuya ganmatakuya@asahikawa-med.ac.jp Sakatani Aki sakatani@asahikawa-med.ac.jp Fujiya Mikihiro +81-166-68-2462fjym@asahikawa-med.ac.jp Tanaka Kazuyuki kazuyuki@asahikawa-med.ac.jp Fujibayashi Shugo fujishu@asahikawa-med.ac.jp Nomura Yoshiki nomuzo@asahikawa-med.ac.jp Ueno Nobuhiro u-eno@asahikawa-med.ac.jp Kashima Shin shin1014@asahikawa-med.ac.jp Gotoh Takuma t-gotti@asahikawa-med.ac.jp Sasajima Junpei junsasaji@gmail.com Moriichi Kentaro morimori@asahikawa-med.ac.jp Ikuta Katsuya ikuta@asahikawa-med.ac.jp Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, 2-1 Midorigaoka-higashi, Asahikawa, Hokkaido 078-8510 Japan 2 2 2016 2 2 2016 2016 8 213 12 2015 18 1 2016 © Iwama et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Methods\nPneumocystis carinii pneumonia occasionally appears in immunodeficient patients. While several reports have shown that Pneumocystis carinii pneumonia occurred in the early phase of starting infliximab treatment in patients with Crohn’s disease (CD), the present case suggests for the first time that an increased dosage of infliximab may also lead to pneumonia.\n\nResults\nA 51-year-old male had been taking 5 mg of infliximab for the treatment of CD for 10 years with no adverse events. Beginning in September 2013, the dose of infliximab had to be increased to 10 mg/kg because his status worsened. Thereafter, he complained of a fever and cough, and a CT scan revealed ground-glass opacities in the lower lobes of the bilateral lung with a crazy-paving pattern. Bronchoscopy detected swelling of the tracheal mucosa with obvious dilations of the vessels. A polymerase chain reaction using a bronchoalveolar lavage fluid sample detected specific sequences for Pneumocystis jirovecii; thus he was diagnosed with Pneumocystis carinii (jirovecii) pneumonia. After discontinuing infliximab and starting antibiotic treatment, his symptoms and CT findings were dramatically improved.\n\nConclusions\nThe administration of an increased dosage of infliximab can cause Pneumocystis carinii pneumonia in CD patients.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nPneumocystis carinii pneumonia occasionally appears in immunodeficient patients, particularly with the administration of chemotherapy. While several reports have shown that infliximab treatment [1–5], which is generally used for the treatment of rheumatoid arthritis and Crohn’s disease, can lead to Pneumocystis carinii pneumonia [6–12], to the best of our knowledge, no case has demonstrated the development of pneumonia due to an increased dosage of infliximab treatment. The present case suggests that an increased dosage of infliximab is a potential cause of Pneumocystis carinii pneumonia.\n\nCase\nA 51-year-old male was suffering Crohn’s disease (CD) since 1990. The patient’s weight was 67 kg. He had the inflammatory type of Crohn’s disease, and the area of his lesion was the colon and small intestine. He had no complications, including intra- or extraenteral lesions, or any other systemic disorders. He had been taking 5 mg/kg of infliximab (total 400 mg) since 2004 and 0.15 g/day of 6-mercaptopurine since 2005. However, he complained of abdominal pain, his Harvey–Bradshaw index scores increased from 5 to 13, and he subsequently began taking 10 mg/kg of infliximab (total 650 mg) from September 2013. In January 2014, he complained of a fever and cough. Laboratory tests on this admission showed high levels of C-reactive protein and anti-mycoplasma antibody while other examination items, including the white blood cell count and T-SPOT, were unremarkable. A computed tomography (CT) scan revealed ground-glass opacities in the lower lobes of the bilateral lung with a crazy-paving pattern (Fig. 1a). Bronchoscopy detected swelling of the tracheal mucosa with obvious dilations of the vessels (Fig. 2). A bronchoalveolar lavage fluid sample obtained during bronchoscopy included 255 cells/field with 80 % macrophages, 12 % lymphocytes and 8 % neutrophils. A polymerase chain reaction using the bronchoalveolar lavage fluid sample detected specific sequences for Pneumocystis jirovecii. Taken together, he was diagnosed as having pneumonia due to the combined infection of Mycoplasma and Pneumocystis carinii (jirovecii). The patient stopped infliximab administration and took 2 g/day of ceftriaxone, 500 mg/day of azithromycin and 400 mg/80 mg/day of sulfamethoxazole/trimethoprim; thereafter his symptoms including a fever and cough improved. CT after the antibiotic therapy showed a significant improvement of the ground-glass opacities in the lower lobes of the bilateral lung (Fig. 1b).Fig. 1 Computed tomography findings of the chest. Ground-glass opacities were seen in the lower lobes of the bilateral lung with a crazy-paving pattern on admission (a). Ground-glass opacities were improved after antibiotic therapy (b)\n\nFig. 2 Bronchoscopy finding. Swelling and obvious dilations of the vessels were seen in the tracheal mucosa on admission\n\n\n\nDiscussion\nThe present report demonstrated a case of Pneumocystis carinii pneumonia due to the increased dosage of infliximab. While several cases have demonstrated pneumonia due to Pneumocystis carinii after infliximab treatment, to the best of our knowledge, this is the first case in which an increased dosage of infliximab triggered pneumonia. A summary of previously reported cases and our case of Pneumocystis carinii pneumonia in CD patients is shown in Table 1.Table 1 Date on pneumocystis pneumonia during administrarion of infliximab\n\nNo.\tReference\tYear\tSex\tAge at diagnosis (years)\tCrohn’s disease duration\tIFX duration\tDose of IFX\tConcomitant drug(s)\tMedication\tClinical course\t\n1\tSeddik et al. [6]\t2004\tMale\t29\tND\t1 month\t5 mg/kg\tPSL + AZA\tST\t2 weeks alive\t\n2\tVelayos et al. [7]\t2004\tMale\t19\t2 years\t2 years 3 months\t5 mg/kg\tAZA\tST + PSL\t2 weeks alive\t\n3\tKaur et al. [8]\t2004\tMale\t59\t3 weeks\t9 weeks\tND\tPSL\tST + PM\t1 month died\t\n4\tStratakos et al. [9]\t2005\tFemale\t77\t9 months\t8 months\t5 mg/kg\tmPSL + AZA\tST\t6 month alive\t\n5\tItaba et al. [10]\t2007\tFemale\t57\t21 years\t5 weeks\t5 mg/kg\tPSL + AZA\tST + mPSL\t4 month alive\t\n6\t金井 et al. [11]\t2009\tMale\t69\t44 years\t4 weeks\t5 mg/kg\t5-ASA + PSL\tST + mPSL\t6 month alive\t\n7\tTshudy et al. [12]\t2010\tMale\t8\t6 years\t15 months\t5 mg/kg\tNone\tST\t4 weeks alive\t\n8\tPresent case\t2014\tMale\t51\t24 years\t10 years\t10 mg/kg\t6-MP (0.15 g/day)\tST\t1 year 5 month alive\t\n\nST sulfamethoxazole/trimethoprim, PSL prednisolone, mPSL methylprednisolone, PM pentamidine, AZA azathioprine, 5-ASA mesalazine, 6-MP 6mercaptopurine, ND not described\n\n\n\nOf the seven cases, five were male and two were female. The age ranged from 8 to 77 years. While Pneumocystis carinii pneumonia appeared at 4 weeks to 29 months after starting infliximab treatment in previous reports, the present case exhibited pneumonia at 120 months after starting infliximab treatment, at 102 months after starting the 6-mercaptopurine treatment, 24 weeks after starting an increased dosage of infliximab from 5 to 10 mg/kg. This suggests that an increased dosage of infliximab is a potential cause of immunodeficiency, leading to Pneumocystis carinii pneumonia. Notably, all cases developing Pneumocystis carinii pneumonia took immunomodulators and/or steroids, suggesting that the combined use of these drugs is a risk for pneumonia. Because sulfamethoxazole/trimethoprim was effective for all cases, antibiotics should be immediately administered after the diagnosis of Pneumocystis carinii pneumonia.\n\nConclusions\nThe findings of the present case suggest that the administration of an increased dosage of infliximab, as well as a general dose of infliximab, can cause Pneumocystis carinii pneumonia in CD patients, particularly in patients taking immunomodulators and/or steroids, illustrating the need for follow up, including pulmonary symptoms and CT examinations, when increasing the dosage of infliximab in CD patients.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nAuthors’ contributions\nTI and AS were equally contributed to this study. TI, AS and MF conceived the report, collected data, and wrote the first draft of the report. AS and KT followed up the patient. YN, NU and SK performed endoscopy and evaluated the disease severity. SF, TG and JS evaluated radiological images including computed tomography. KM and IK supervised the study. All authors contributed to the critical revision of the report for important intellectual content. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe would like to thank Dr. Yuhei Inaba for his excellent suggestion and Dr. Tatsuya Utsumi and Dr. Hiroki Sato for significant assistances.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Tai TL O’Rourke KP McWeeney M Burke CM Sheehan K Barry M Pneumocystis carinii pneumonia following a second infusion of infliximab Rheumatology 2002 41 951 952 10.1093/rheumatology/41.8.951 12154220 \n2. Mori S Imamura F Kiyofuji C Ito K Koga Y Honda I Sugimoto M Pneumocystis jiroveci pneumonia in a patient with rheumatoid arthritis as a complication of treatment with infliximab, anti-tumor necrosis factor alpha neutralizing antibody Mod Rheumatol 2006 16 58 62 10.3109/s10165-005-0454-2 16622728 \n3. Imaizumi K Sugishita M Usui M Kawabe T Hashimoto N Hasegawa Y Pulmonary infectious complications associated with anti-TNF alpha therapy (infliximab) for rheumatoid arthritis Intern Med 2006 45 685 688 10.2169/internalmedicine.45.1623 16778341 \n4. Kasai S Tokuda H Otsuka Y Ookohchi Y Handa H Emoto N Yoshikawa M Two cases of respiratory infection complicating treatment with infliximab Nihon Kokyuki Gakkai Zasshi. 2007 45 366 371 17491318 \n5. Mori S Tomita Y Horikawa T Cho I Sugimoto M Delayed spinal infection after laminectomy in a patient with rheumatoid arthritis interruptedly exposed to anti-tumor necrosis factor alpha agents Clin Rheumatol 2008 27 937 939 10.1007/s10067-008-0869-1 18330608 \n6. Seddik M Melliez H Seguy D Viget N Cortot A Colombel JF Pneumocystis jiroveci (carinii) pneumonia after initiation of infliximab and azathioprine therapy in a patient with Crohn’s disease Inflamm Bowel Dis 2004 11 618 620 10.1097/01.MIB.0000164002.32735.c2 15905713 \n7. Velayos FS Sandborn WJ Pneumocystis carinii pneumonia during maintenance anti-tumor necrosis factor-alpha therapy with infliximab for Crohn’s disease Inflamm Bowel Dis 2004 10 657 660 10.1097/00054725-200409000-00025 15472531 \n8. Kaur N Mahl TC Pneumocystis carinii pneumonia with oral candidiasis after infliximab therapy for Crohn’s disease Dig Dis Sci 2004 49 1458 1460 10.1023/B:DDAS.0000042246.58984.98 15481319 \n9. Stratakos G Kalomenidis I Papas V Malagari K Kollintza A Roussos C Anagnostopoulou M Paniara O Zakynthinos S Papiris SA Cough and fever in a female with Crohn’s disease receiving infliximab Eur Respir J 2005 26 354 357 10.1183/09031936.05.00005205 16055885 \n10. Itaba S Iwasa T Sadamoto Y Nasu T Misawa T Inoue K Shimokawa H Nakamura K Takayanagi R Pneumocystis pneumonia during combined therapy of infliximab, corticosteroid, and azathioprine in a patient with Crohn’s disease Dig Dis Sci 2007 52 1438 1441 10.1007/s10620-006-9575-5 17404870 \n11. Kanai H Noguchi T Koyanagi H Marubashi K Saruya S Infliximab treatment in a hemodialysis patient with relapse of Crohn’s disease after a 40-year interval Dial Ther. 2009 42 905 910 10.4009/jsdt.42.905 \n12. Tschudy J Michail S Disseminated histoplasmosis and pneumocystis pneumonia in a child with Crohn disease receiving infliximab J Pediatr Gastroenterol Nutr 2010 51 221 222 10.1097/MPG.0b013e3181c2c10d 20410844\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1757-4749",
"issue": "8()",
"journal": "Gut pathogens",
"keywords": null,
"medline_ta": "Gut Pathog",
"mesh_terms": null,
"nlm_unique_id": "101474263",
"other_id": null,
"pages": "2",
"pmc": null,
"pmid": "26839596",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "16622728;15481319;17404870;16055885;17491318;15472531;12154220;15905713;20410844;18330608;16778341",
"title": "Increased dosage of infliximab is a potential cause of Pneumocystis carinii pneumonia.",
"title_normalized": "increased dosage of infliximab is a potential cause of pneumocystis carinii pneumonia"
} | [
{
"companynumb": "JP-JNJFOC-20160208850",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Immunoglobulin A deficiency (IgAD) is the most common form of primary immunodeficiency in western countries. It can be associated with the development of autoimmune diseases both in adults and in children even though the exact pathophysiology is not fully defined.\nWe report here a case of a young patient who developed nephrotic syndrome secondary to membranoproliferative glomerulonephritis associated with the incidental finding of IgAD. We began corticosteroid therapy and angiotensin-converting enzyme inhibitor, and we observed partial remission of the nephrotic syndrome after about nine months; nonetheless, in the following follow-up visits, a progressive decline of renal function was found.\nOur case extends the spectrum of hitherto described glomerulonephritides associated with IgAD which were described until now.",
"affiliations": "Department of Medicine, Nephrology and Dialysis Unit, SS Annunziata Hospital, \"G. d'Annunzio\" University, Chieti, Italy.;Department of Medicine, Nephrology and Dialysis Unit, SS Annunziata Hospital, \"G. d'Annunzio\" University, Chieti, Italy.;Department of Medicine, Nephrology and Dialysis Unit, SS Annunziata Hospital, \"G. d'Annunzio\" University, Chieti, Italy.;Department of Experimental and Clinical Medicine-Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Ancona, Italy.;Department of Medicine, Nephrology and Dialysis Unit, SS Annunziata Hospital, \"G. d'Annunzio\" University, Chieti, Italy.",
"authors": "Pezzutto|Alessandro|A|;Sirolli|Vittorio|V|;Di Liberato|Lorenzo|L|;Morroni|Manrico|M|;Bonomini|Mario|M|0000-0002-8466-6314",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S303038",
"fulltext": "\n==== Front\nInt Med Case Rep J\nInt Med Case Rep J\nimcrj\nimcrj\nInternational Medical Case Reports Journal\n1179-142X\nDove\n\n303038\n10.2147/IMCRJ.S303038\nCase Report\nIgA Deficiency and Membranoproliferative Glomerulonephritis: A Case Report\nPezzutto et al\nPezzutto et al\nPezzutto Alessandro 1\nSirolli Vittorio 1\nDi Liberato Lorenzo 1\nMorroni Manrico 2\nhttp://orcid.org/0000-0002-8466-6314\nBonomini Mario 1\n1 Department of Medicine, Nephrology and Dialysis Unit, SS Annunziata Hospital, “G. d’Annunzio” University, Chieti, Italy\n2 Department of Experimental and Clinical Medicine-Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Ancona, Italy\nCorrespondence: Vittorio Sirolli Email vsirolli@unich.it\n03 6 2021\n2021\n14 377380\n27 2 2021\n04 5 2021\n© 2021 Pezzutto et al.\n2021\nPezzutto et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ 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).\nBackground\n\nImmunoglobulin A deficiency (IgAD) is the most common form of primary immunodeficiency in western countries. It can be associated with the development of autoimmune diseases both in adults and in children even though the exact pathophysiology is not fully defined.\n\nCase Presentation\n\nWe report here a case of a young patient who developed nephrotic syndrome secondary to membranoproliferative glomerulonephritis associated with the incidental finding of IgAD. We began corticosteroid therapy and angiotensin-converting enzyme inhibitor, and we observed partial remission of the nephrotic syndrome after about nine months; nonetheless, in the following follow-up visits, a progressive decline of renal function was found.\n\nConclusion\n\nOur case extends the spectrum of hitherto described glomerulonephritides associated with IgAD which were described until now.\n\nKeywords\n\nmembranoproliferative glomerulonephritis\nIgA deficiency\nnephrotic syndrome\n==== Body\nIntroduction\n\nSelective IgAD is the most common primary immunoglobulin deficiency in western countries. It can be associated with the development of autoimmune diseases being more prevalent among adults though the exact pathophysiology is not fully defined. In this paper, we report the case of a young patient suffering from nephrotic syndrome secondary to membranoproliferative glomerulonephritis associated with IgAD. To the best of our knowledges, this is the first report of such association in a young adult.\n\nCase Presentation\n\nOn December 2013, a 19-year-old man was referred to our Unit due to the sudden development of nephrotic syndrome manifesting with leg edema and ascites. Blood arterial pressure was 140/70 mmHg, heart rate 70 bpm, and body weight 74.5 kg. Renal ultrasound showed kidney enlargement and cortical hyperechogenicity. Laboratory tests revealed reduced renal function (serum creatinine 1.5 mg/dL, urea 38 mg/dL), hypoproteinemia (4.1 g/dl), hypoalbuminaemia (1.96 g/dL), and dyslipidemia (total cholesterol 290 mg/dL, triglycerides 250 mg/dL). Urinalysis documented heavy proteinuria (300 mg/dL) with microhematuria and leucocyturia. Immunological investigations showed an isolated reduction of complement factor (C) 3 (26.7 mg/dl) and of immunoglobulin (Ig) G (447 mg/dL) and IgA (<7.8 mg/dL); C4, IgM, IgG subclasses, and IgE in the normal range; negative search for ANA, ENA, c-ANCA, p-ANCA, thyroid peroxidase, thyroglobulin antibodies, HBV and HCV serologic analyses. We performed a percutaneous kidney biopsy that revealed membranoproliferative glomerulonephritis (Figure 1) associated with a marked immunostaining positivity for C3 in a diffuse granular manner and mild mesangial segmental focal total IgG positivity. The patient was treated with methylprednisolone, 60 mg i.v. for 1 week, followed by 64 mg per os, and with the angiotensin-converting enzyme inhibitor (ACEi) lisinopril (20 mg/day), until February 2014, when he was readmitted due to weight gain (79 kg). We resumed methylprednisolone iv therapy for 7 days, followed by methylprednisolone 32 mg per os. During hospitalization, normalization of kidney function was achieved (serum creatinine 1.1 mg/dL, serum urea 35 mg/dL) with persistence of proteinuria (dipstick 300 mg/dL). Partial remission was observed in June 2014, and methylprednisolone therapy was gradually tapered until suspension in September 2014. Molecular analyses of the complement CFH, CFI, MCP, C3, CFB genes were also performed. As regards to factor H (which is composed of 20 SCR, Short Consensus Repeat), mutation screening was carried out by next-generation sequencing: no mutations were identified in any SCRs 1–20, in the gene promoter or in the signal peptide. As regards factor B, screening for mutations by next-generation sequencing was carried out in the 18 exons that make up the CFB gene and no mutation was identified. Regarding factor I, screening was conducted in the 13 exons that make up the CFI gene and no mutation was identified, as was found for the 41 exons that make up the C3 gene.\n\nFrom December 2014 until September 2016, at follow-up checks we found normal kidney function (creatinine 1.2 mg/dL, urea 32 mg/dL), mild hypoproteinemia (6.2 g/dL), a mild C3 reduction (78.6 mg/dl), and proteinuria (30–50 mg/dL). At that time the patient was on therapy with ACEi only.\n\nIn October 2016, we again observed reduced kidney function (creatinine 1.5 mg/dL, urea 26 mg/dL) associated with an increase in proteinuria (at dipstick, 150 mg/dL), hypoproteinemia (5.9 g/dL) and C3 reduction (79 mg/dL). Thus, in the light of these data, methylprednisolone 32 mg per os was started again, and gradually tapered until August 2017. However, despite the steroid therapy, we observed a further deterioration of kidney function (creatinine values progressively increasing from 1.5 mg/dl to 2.2 mg/dl) associated with persistence of proteinuria and C3 reduction. Hence, we readmitted our patient and in January 2019 performed a second kidney biopsy (Figure 2), which disclosed disease progression with presence of sclerosis (4/14 glomeruli) and a marked diffuse immunostaining positivity for C3, like the previous biopsy. Electron microscopy confirmed the diagnosis of membranoproliferative glomerulonephritis (Figure 3). We decided to restart methylprednisolone therapy 32 mg, which the patient continued for six months before it was progressively reduced until definitive suspension. The latest kidney function values show creatinine 2.5 mg/dL, proteinuria (100 mg/dl).\n\nSince this was a retrospective case report in which the patient was not identified, the requirement for institutional approval to publish the case details was waived. Written informed consent from the patient for publication of the study was obtained. Figure 1 Kidney biopsy performed in 2013. Marked mesangial proliferation and diffuse simplification of the glomeruli. Hematoxylin eosin, x20.\n\nFigure 2 Kidney biopsy performed in 2019. Glomerular enlargement with marked mesangial proliferation and diffuse lobular simplification of the glomeruli. Compared to the first biopsy, the glomeruli showed an accentuated lobular configuration and tubulointerstitial damage (tubular atrophy and fibrosis and inflammation). Hematoxylin eosin, x10.\n\nFigure 3 Kidney biopsy performed in 2019: electron micrograph showing an extensive circumferential electron-dense deposits (asterisks), and visceral epithelial foot process effacement (arrows). Scale bar 2.7 μm.\n\nDiscussion\n\nIgAD is defined as serum IgA levels below or equal to 7 mg/dL in subjects older than 4 years after exclusion of other causes of hypogammaglobulinemia and in the presence of normal serum levels of IgG and IgM.1 IgAD can be primary or secondary to several conditions (drugs, infections, chromosopathies, monogenic diseases) which were however reasonably excluded in the case reported. IgA deficiency patients are often asymptomatic and diagnosis is incidental. However, the defect may be associated with respiratory and gastrointestinal tract infections, malignancies (particularly of gastrointestinal tract and lymphoid) and autoimmune diseases.1 Autoimmunity is more prevalent in adults (median age 29 years) and in females. There is reported to be an increased percentage of autoantibodies in children suffering from IgAD without necessarily any clinical manifestations.2 However, preexisting selective IgAD significantly contribute to the development of two different autoimmune disorders (type 1 diabetes, Guillain-Barré syndrome) complicating SARS-Cov-2 infection.3 Moreover, Naito et al observed that the frequency of selective IgAD has a strong positive correlation with the prevalence of COVID-19 per population.4\n\nOur discussion focuses on kidney diseases, especially glomerular diseases, associated with IgAD.\n\nIgAD and Glomerulonephritis in Children and Adolescents\n\nIn children and adolescents, there are few reports about glomerulonephritis and IgAD. Liu et al described a child with nephrotic syndrome secondary to diffuse and generalized mesangiopathic glomerulonephritis and a medical history of asthma, chronic otitis media and IgAD.5 Kawasaki et al described a child suffering from nephrotic syndrome secondary to diffuse membranous glomerulonephritis stage 1 and IgAD.6 Ichikawa et al reported a probably multimodal autoimmune disorder producing juvenile alopecia, autoimmune encephalitis (Rasmussen syndrome) and membranous nephropathy, based on congenital IgAD.7 Again, Martini et al reported the case of a 9-year-old girl with clinical signs and symptoms resembling Henoch-Schonlein syndrome and IgAD, the renal biopsy indicating mesangial proliferative glomerulonephritis with diffuse granular deposits of C3 on immunofluorescence without IgA. However, the authors believed that this case represented an unusual variant of acute post-streptococcal glomerulonephritis characterized by mild systemic vasculitis.8\n\nRecently, Di Genova et al reported 2 cases of children suffering from nephrotic syndrome and IgAD, not biopsied due to ethical issues associated with severe relapses during corticosteroid therapy. However, these patients obtained a positive outcome with human monoclonal anti-CD20 antibodies (rituximab and ofatumumab, respectively).9 The most recent case refers to a 5-year-old girl with selective IgAD and membranoproliferative glomerulonephritis related to streptococcal infection and treated with benefit multidrug therapy.10\n\nIgAD and Glomerulonephritis in Adults\n\nThe association between glomerulonephritis and IgAD is better documented in adults. It is supposed that IgAD, which predisposes to infections, may contribute to the onset of glomerulonephritis, especially in chronic infectious patients.11 There are also reports of elevated levels of circulating immune complexes containing IgG and IgM, which may mediate some cases of vasculitis. A review by Huang et al reported 18 cases of glomerulonephritis associated with IgAD: the most common renal pathology associated with IgAD is mesangioproliferative glomerulonephritis.12 Camilleri et al reported the case of a 59 years old woman with IgAD associated with oligoarthritis and glomerulonephritis mediated by immune complexes.13 John et al reported a case of mesangioproliferative glomerulonephritis in a 55-year-old woman with IgAD and serum antinuclear antibodies who presented with nephrotic syndrome without a diagnosis of systemic lupus erythematosus.14 Also described is a case of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis in a Japanese woman who had been diagnosed with IgAD 12 years previously; however, the patient had also been diagnosed with generalized epilepsy and received phenytoin and valproic acid for at least 15 years, which are known to cause IgAD.15\n\nThe pathogenesis of glomerular diseases in IgAD is still poorly understood. In our case, we did not find direct evidence of a pathogenic linkage between IgAD and membranoproliferative glomerulonephritis. One may only speculate on an association with circulating immune complexes, which are present in 50–60% of patients with selective IgAD.16\n\nConclusions\n\nAs far as we know, there is one sole case in the literature reporting an association between immunoglobulin deficiency and a mesangiocapillary glomerulonephritis pattern: this is a 55-year-old man presenting with a fainting attack.17 By contrast, our patient presented only IgAD, IgG reduction being related to nephrotic syndrome. Our patient has no causes of secondary IgAD; moreover, we twice sampled IgA titers, in 2013 and 2019, and we found them very low on both occasions. He had a mild response to corticosteroid therapy but no infectious diseases during this therapy, as one might expect due to IgAD.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n\n1. Yel L. Selective IgA deficiency. Clin Immunol. 2010;30 (1 ):10–16. doi:10.1007/s10875-009-9357-x\n2. Barka N, SHen GQ, Shoenfeld Y, et al. Multireactive pattern of serum autoantibodies in asymptomatic individuals with immunoglobulin a deficiency. Clin Diagn Lab Immunol. 1995;2 (4 ):469–472. doi:10.1128/CDLI.2.4.469-472.1995 7583926\n3. Pfeuffer S, Pawlowski M, Joos GS, et al. Autoimmunity complicating SARS-Cov-2 infection in selective IgA-deficiency. Neurol Neuroimmunol Neuroinflamm. 2020;7 (6 ):e 881. doi:10.1212/NXI.0000000000000881\n4. Naito Y, Takagi T, Yamamoto T, Watanabe S. Association between selective IgA deficiency and COVID-19. J Clin Biochem Nutr. 2020;67 (2 ):122–125. doi:10.3164/jcbn.20-102 33041507\n5. Liu K, Wigfall DR, Harland RC, Sanfilippo FP, Howell DN. Identification of selective immunoglobulin A deficiency by renal biopsy. Am J Kidney Dis. 1995;26 (3 ):520–526. doi:10.1016/0272-6386(95)90501-4 7645563\n6. Kawasaki Y, Suzuki J, Onishi N, Takahashi A, Isome M, Suzuki H. IgA deficiency and membranous glomerulonephritis presenting as nephrotic syndrome. Pediatr Nephrol. 2005;20 (5 ):662–664. doi:10.1007/s00467-004-1720-9 15711951\n7. Ichikawa K, Takeshita S, Ito S, Nezu A. Rasmussen syndrome combined with IgA deficiency and membranous nephropathy. Pediatr Nephrol. 2009;40 (6 ):468–470. doi:10.1016/j.pediatrneurol.2008.12.008\n8. Martini A, Ravelli A, Notarangelo LD, Burgio VL, Plebani A. Henoch-Schönlein syndrome and selective IgA deficiency. Arch Dis Child. 1985;60 (2 ):160–162. doi:10.1136/adc.60.2.160 3977390\n9. Di Genova L, Ceppi S, Stefanelli M, Esposito S. IgA deficiency and nephrotic syndrome in children. Int J Environ Res Public Health. 2018;15 (8 ):1702. doi:10.3390/ijerph15081702\n10. Sugimoto K, Enya T, Miyazaki K, Mijazawa T, Takemura T, Okada M. Membranoproliferative glomerulonephritis related to a streptococcal infection in a girl with IgA deficiency: a case report. BMC Nephrol. 2020;21 (1 ):68.32103732\n11. Sleasman JW. The association between immunodeficiency and the development of autoimmune disease. Adv Dental Res. 1996;10 (1 ):57–61. doi:10.1177/08959374960100011101\n12. Huang JB, Yang WC, Hu CC, Yang AH, Lin CC. IgA deficiency with membranous glomerulonephritis: a case report and review. J Nephrol. 2003;16 (1 ):154–158.12649548\n13. Camilleri JP, Moore RH, Griths DS, Williams BD. Selective IgA deficiency associated with glomerulonephritis and oligoarthritis. Ann Rheum Dis. 1992;51 (1 ):123–125. doi:10.1136/ard.51.1.123 1540017\n14. John M, Lam M, Latham B, Saker B, French MA. Nephrotic syndrome in a patient with IgA deficiency-associated mesangioproliferative glomerulonephritis. Pathology. 2000;32 (1 ):56–58. doi:10.1080/003130200104600 10740809\n15. Sugiyama M, Banno Y, Nozaki Y, Kinoshita K, Funauchi M. A case of selective immunoglobulin A deficiency with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. Int J Rheum Dis. 2014;17 (3 ):341–343. doi:10.1111/1756-185X.12157 24119007\n16. Kwitko AO, McKenzie PE, Shearman DJC, Gormly AA, Woodroffe AJ. Circulating immune complexes in IgA deficiency. Clin Exp Immunol. 1979;38 :45–51.527254\n17. Rashid HU, Biswas CK, Morley AR, Kerr DN. Mesangiocapillary glomerulonephritis type I associated with immunoglobulin deficiency. Br Med J (Clin Res Ed). 1981;283 (6288 ):407–408. doi:10.1136/bmj.283.6288.407\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-142X",
"issue": "14()",
"journal": "International medical case reports journal",
"keywords": "IgA deficiency; membranoproliferative glomerulonephritis; nephrotic syndrome",
"medline_ta": "Int Med Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101566269",
"other_id": null,
"pages": "377-380",
"pmc": null,
"pmid": "34113180",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "20101521;10740809;3977390;527254;7645563;7583926;15711951;8934926;24119007;19433284;6789986;12649548;33041507;1540017;32817413;30096909;32103732",
"title": "IgA Deficiency and Membranoproliferative Glomerulonephritis: A Case Report.",
"title_normalized": "iga deficiency and membranoproliferative glomerulonephritis a case report"
} | [
{
"companynumb": "IT-PFIZER INC-202100925247",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"dru... |
{
"abstract": "Although crystalluria is a frequent finding in the routine examination of urine, amoxicillin crystalluria is a rare event whose incidence remains unknown. Crystalluria caused by amoxicillin is very uncommon and may be asymptomatic or have severe renal implications. The authors describe the case of an 87-year-old female patient who presented with massive amoxicillin crystalluria due to poor hydration, low urinary pH and high intravenous amoxicillin dosage.\nAmoxicillin crystalluria is a rare event.It can range from a transient asymptomatic crystalluria without renal damage to major haematuria or acute renal failure.We should be aware of this complication because high intravenous doses of amoxicillin are frequently prescribed and measures can be adopted to prevent this complication.",
"affiliations": "Department of Internal Medicine 1, Unidade Local de Saúde do Alto Minho, EPE, Portugal.;Department of Internal Medicine 1, Unidade Local de Saúde do Alto Minho, EPE, Portugal.;Department of Internal Medicine 1, Unidade Local de Saúde do Alto Minho, EPE, Portugal.;Department of Internal Medicine 1, Unidade Local de Saúde do Alto Minho, EPE, Portugal.;Laboratory Department, Unidade Local de Saúde do Alto Minho, EPE, Portugal.",
"authors": "Couto|Joana|J|;Dos Santos|Luis Pontes|LP|;Alves|Joana Carlos|JC|;López|Raquel|R|;Maldonado|Cristina|C|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2017_000736",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2017_000736736-1-4152-1-10-20171019ArticlesAmoxicillin Crystalluria: A Rare Side-Effect of a Commonly Prescribed Antibiotic Couto Joana 1dos Santos Luis Pontes 1Alves Joana Carlos 1López Raquel 1Maldonado Cristina 2\n1 Department of Internal Medicine 1, Unidade Local de Saúde do Alto Minho, EPE, Portugal\n2 Laboratory Department, Unidade Local de Saúde do Alto Minho, EPE, Portugal2017 23 10 2017 4 10 00073611 9 2017 23 9 2017 © EFIM 20172017This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseAlthough crystalluria is a frequent finding in the routine examination of urine, amoxicillin crystalluria is a rare event whose incidence remains unknown. Crystalluria caused by amoxicillin is very uncommon and may be asymptomatic or have severe renal implications. The authors describe the case of an 87-year-old female patient who presented with massive amoxicillin crystalluria due to poor hydration, low urinary pH and high intravenous amoxicillin dosage.\n\nLEARNING POINTS\nAmoxicillin crystalluria is a rare event.\n\nIt can range from a transient asymptomatic crystalluria without renal damage to major haematuria or acute renal failure.\n\nWe should be aware of this complication because high intravenous doses of amoxicillin are frequently prescribed and measures can be adopted to prevent this complication.\n\nCrystalluriaamoxicillin‘shock wheat’ crystals‘broom like’ crystals\n==== Body\nINTRODUCTION\nCrystalluria is a frequent finding in the routine examination of sediments in urine. It was shown that crystalluria was present in 8.2% of almost 10,000 regular urine samples. In most cases, the crystals are composed of calcium oxalate, uric acid, triple phosphate, calcium phosphate and amorphous phosphate, or urates. Their precipitation is caused by transient supersaturation of the urine, the ingestion of food rich in these minerals, or by changes in urine temperature and/or pH[1].\n\nIn a minority of cases, crystalluria is associated with pathological conditions (urolithiasis, acute uric acid nephropathy, ethylene glycol poisoning or hypereosinophilic syndrome) or caused by drugs such as sulphadiazine, acyclovir, triamterene, piridoxilate or primidone, which can crystallize within the tubular lumina and cause renal damage[1,2]. Amoxicillin is excreted by the kidneys: 90% by the proximal tubules and 10% by glomerular filtration, Amoxicillin crystalluria can cause haematuria and acute renal failure due to tubular damage and medullary congestion[3, 4]. Its incidence remains unknown[5].\n\nCASE PRESENTATION\nAn 87-year-old female was admitted to our hospital with the following symptoms: fever (maximum temperature: 38.2°C), swelling, pruritus and burning of the right lower limb associated with an acute confusional state. After examination, a diagnosis of erysipelas and acute confusional state (triggered by the onset infection) was made. The patient had a previous history of hypertension, chronic venous insufficiency and dyslipidaemia, with chronic medication that consisted of hydrochlorothiazide (25 mg/day) and simvastatin (20 mg/day). At admission renal function was normal according to her age (GFR: 77 ml/min/1.73 m2) as was the urine sample with a pH of 6.5. Treatment with intravenous amoxicillin (1,000 mg) plus clavulanic acid (200 mg) three times per day was initiated. Her therapeutic regimen while hospitalized consisted of these antibiotics together with furosemide (40 mg/day), lorazepam (1 mg/day) and simvastatin (20 mg/day).\n\nOn the fourth day of treatment, the patient developed hypogastric pain and decreased urinary output, so a urine sample was taken. Macroscopically, the urine sample was normal, and the sediment contained erythrocytes (5.1 per hpf) and some leukocytes (68.1 per hpf), had a pH of 5.6 and a relative density of 1.005 and, after centrifugation, showed hyaline casts, squamous cells and massive crystalluria. Microscopically, the crystals had the appearance of isolated thin and colourless needle-shaped aggregates with random distribution and were highly birefringent under polarized light microscopy (different from the more commonly observed crystals of uric acid and calcium oxalate). This appearance is also described as ‘shocks of wheats’ and ‘broom bush-like’ crystals and suggests a drug-induced crystalluria, which in this clinical context was compatible with an amoxicillin-related crystalluria.\n\nIn addition, impairment in renal function was noted (TGF: 59 ml/min/1.73 m2; GRF at admission of 77 ml/min/1.73 m2). After amoxicillin/clavulanic acid was replaced with cefazolin, a new urine sample was collected (after 36 h) which showed normal sediment and absence of crystals on microscopy.\n\nDISCUSSION\nAmoxycillin crystalluria was first described in 1985 in a 26-year-old healthy volunteer, to whom 3.0 g of amoxicillin was administered intravenously over 20 min to investigate amoxicillin renal excretion[4,6]. Amoxicillin urinary oversaturation (high dosage, short half-life, predominant urinary excretion), insufficient hydration and low urinary pH favour crystalluria. After amoxicillin is discontinued, crystalluria disappears in 3–24 h, while gross haematuria resolves in 1–3 days and acute renal failure in 3–17 days. Renal failure can be non-oliguric or oligoanuric, and temporary dialysis is rarely necessary[2].\n\nIn the described case, our patient presented with a reversible amoxicillin crystalluria, without macroscopic haematuria and low urinary pH. The renal impairment (GFR: 77–59 ml/min/1.73 m2) was probably due to the association of massive amoxicillin crystalluria and dehydration. The crystals were not analyzed because the appearance and the clinical context were diagnostic.\n\nThe authors have emphasized this complication of amoxicillin use because high intravenous doses are frequently prescribed and some preventative measures such as increasing fluid intake and urine alkalinization can be adopted, especially in individuals with poor self-hydration capacity such our geriatric patient who showed a concomitant acute confusional state. Amoxycillin crystals differ strikingly from the more common urinary crystals, and this along with the clinical information, should lead to the diagnosis with a subsequent reduction in dose or withdrawal of the drug.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Amoxicillin crystals: large aggregated needle-shaped, ‘shocks of wheat’ and ‘broom bush-like’ crystals birefringent under polarized light microscopy\n==== Refs\nREFERENCES\n1 Fogazzi GB Crystalluria: a neglected aspect of urinary sediment analysis Nephrol Dial Transplant 1996 11 379 387 8671802 \n2 Fogazzi GB Cantù M Saglimbini L Daudon MA A rare but possible cause of crystalluria Nephrol Dial Transplant 2003 18 212 214 12480988 \n3 Jones P Gaber L Nilsson GR Acute renal failure following amoxycillin overdose Clin Pediatr 1993 32 735 739 \n4 Sjovall J Westerlund D Alvan G Renal excretion of intravenously infused amoxycillin and ampicillin Br J Clin Pharmacol 1985 19 191 201 3986077 \n5 Hentzien M Lambert D Limelette A N’Guyen Y Robbins A Lebrun D Macroscopic amoxicillin crystalluria Lancet 2015 385 9984 2296 25680270 \n6 Van Noord C Wulkan RW van den Dorpel MA Crystalluria Neth J Med 2012 70 84 87 22418755\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "4(10)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Crystalluria; amoxicillin; ‘broom like’ crystals; ‘shock wheat’ crystals",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000736",
"pmc": null,
"pmid": "30755915",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "12480988;22418755;25680270;3986077;8275607;8671802",
"title": "Amoxicillin Crystalluria: A Rare Side-Effect of a Commonly Prescribed Antibiotic.",
"title_normalized": "amoxicillin crystalluria a rare side effect of a commonly prescribed antibiotic"
} | [
{
"companynumb": "PT-WEST-WARD PHARMACEUTICALS CORP.-PT-H14001-18-00314",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
... |
{
"abstract": "Immune checkpoint inhibitors are changing the landscape of oncology treatment as they are significantly improving treatment for multiple malignancies. Nivolumab, an anti-programmed death 1 antibody, is a US Food and Drug Administration-approved treatment for melanoma, non-small cell lung cancer, and kidney cancer but can result in a spectrum of autoimmune side effects. Adverse effects can occur within any organ system in the body including the colon, lung, liver, endocrine systems, or kidneys.\n\n\n\nA 70-year-old male with clear cell kidney cancer was admitted with acute kidney injury while on nivolumab. A kidney biopsy revealed diffuse tubular injury and immune complex-mediated glomerulonephritis. Electron microscopy of the specimen showed hump-like subepithelial deposits. Nivolumab was discontinued and the patient was started on a high dose of steroids. After 5 months of systemic corticosteroids and hemodialysis, the patient's kidney function improved to his baseline level. Despite a prolonged interruption to treatment, immunosuppressive therapy did not compromise the anticancer effects of nivolumab.\n\n\n\nImmune-related adverse effects in the kidney can cause autoimmune glomerulonephritis as well as tubulointerstitial injury. In the literature, immune-related nephritis generally responded well to systemic corticosteroid treatment. Based on our experience, a prolonged course of a high dose of steroids and hemodialysis may be required to achieve an adequate treatment effect.",
"affiliations": "Department of Medicine, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA. Kyungsuk.Jung@fccc.edu.;Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, 3500N Broad St, Philadelphia, PA, 19140, USA.;Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA.",
"authors": "Jung|Kyungsuk|K|0000-0003-1306-5180;Zeng|Xu|X|;Bilusic|Marijo|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-016-0408-2",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 40810.1186/s12882-016-0408-2Case ReportNivolumab-associated acute glomerulonephritis: a case report and literature review http://orcid.org/0000-0003-1306-5180Jung Kyungsuk Kyungsuk.Jung@fccc.edu 1Zeng Xu Xu.Zeng@tuhs.temple.edu 2Bilusic Marijo mbilusic@gmail.com 31 Department of Medicine, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111 USA 2 Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, 3500N Broad St, Philadelphia, PA 19140 USA 3 Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111 USA 22 11 2016 22 11 2016 2016 17 18810 6 2016 15 11 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nImmune checkpoint inhibitors are changing the landscape of oncology treatment as they are significantly improving treatment for multiple malignancies. Nivolumab, an anti-programmed death 1 antibody, is a US Food and Drug Administration-approved treatment for melanoma, non-small cell lung cancer, and kidney cancer but can result in a spectrum of autoimmune side effects. Adverse effects can occur within any organ system in the body including the colon, lung, liver, endocrine systems, or kidneys.\n\nCase presentation\nA 70-year-old male with clear cell kidney cancer was admitted with acute kidney injury while on nivolumab. A kidney biopsy revealed diffuse tubular injury and immune complex-mediated glomerulonephritis. Electron microscopy of the specimen showed hump-like subepithelial deposits. Nivolumab was discontinued and the patient was started on a high dose of steroids. After 5 months of systemic corticosteroids and hemodialysis, the patient’s kidney function improved to his baseline level. Despite a prolonged interruption to treatment, immunosuppressive therapy did not compromise the anticancer effects of nivolumab.\n\nConclusion\nImmune-related adverse effects in the kidney can cause autoimmune glomerulonephritis as well as tubulointerstitial injury. In the literature, immune-related nephritis generally responded well to systemic corticosteroid treatment. Based on our experience, a prolonged course of a high dose of steroids and hemodialysis may be required to achieve an adequate treatment effect.\n\nKeywords\nImmunotherapyNivolumabRenal cell carcinomaAcute kidney injuryAutoimmune nephritisCase reportissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThe field of oncologic immunotherapy is expanding rapidly. Since its introduction into clinical application for the treatment of melanoma [1, 2], immunotherapy has been studied in numerous trials for other types of cancer. Although treatments appear promising, immune checkpoint inhibition is associated with a unique category of side effects, termed immune-related adverse events (irAE) [3].\n\nProgrammed death 1 (PD1) is a transmembrane protein expressed on T cells, B cells, and natural killer cells. It binds to PD ligand 1 (PDL1) on the cell surface of tumor cells, inhibits cancer cell apoptosis, and down-regulates the functions of T cells [4, 5]. Nivolumab is a human immunoglobulin (Ig)G4 anti-PD1 monoclonal antibody, designed to augment an immunologic reaction against cancer cells. The medication is currently US Food and Drug Administration-approved for patients with advanced melanoma, non-small cell lung cancer, and renal cell carcinoma. irAE caused by nivolumab can affect any organ system including the lung, colon, liver, endocrine, kidney, skin, and brain. Grade 3 or 4 kidney injury was reported in 2% of the patients with renal cell carcinoma who were treated with nivolumab (creatinine >3 times above baseline or >4.0 mg/dL, or life-threatening consequences requiring dialysis) [6].\n\nKidney injury can cause diverse sequelae and potentially limit further oncologic treatment options, necessitating close follow-up and treatment. In clinical practice, irAE has been managed by treatment interruption and systemic corticosteroids as the first line, and tumor necrosis factor inhibitors or cytotoxic immunosuppressants as the second line [6].\n\nIn this report, we present a case of nivolumab-induced glomerulonephritis successfully treated with prolonged use of a high dose of steroids and hemodialysis.\n\nCase presentation\nHistory and initial presentation\nThe patient was a 70-year-old male with a past medical history of oxygen-dependent chronic pulmonary obstructive disease, squamous cell carcinoma of the right vocal cord (treated with definitive radiation therapy in November 1998), and stage 3b chronic kidney disease who was diagnosed with metastatic clear cell renal cell carcinoma in January 2013. Other pertinent past medical history included left renal vein thrombosis for which he was taking enoxaparin. The patient had a history of smoking (120 packs/year) but had quit smoking (120 packs/year) but had quit smoking in January 2013.\n\nFor the metastatic renal cell cancer, the patient was started on pazopanib 600 mg daily in February 2013, with a good initial response. However, medication was discontinued in December 2013 because of disease progression in the lungs and rib cage. He then began treatment with nivolumab 3 mg/kg every 2 weeks in December 2013. His disease initially responded well to the treatment. During the 10-month period while the patient was on nivolumab, left and right kidney tumors decreased by 19 and 13%, respectively, and adrenal masses decreased by 23% on both sides. He continued treatment until October 27, 2014 when he was found to have acute kidney injury (AKI), with a creatinine level of 10.08 mg/dL. His serum creatinine level the month prior was 1.67 mg/dL. He was admitted for evaluation and treatment for AKI. At the time of presentation, the patient had symptoms of generalized weakness, fatigue, and loss of appetite. His temperature was 35.7 °C (tympanic), and his blood pressure and heart rate were 135/70 mmHg and 79 beats/min, respectively. He showed a 1.7 kg weight gain over 1 month and there was the suggestion of 1+ bilateral ankle edema on physical examination. There was no flank pain or costovertebral angle tenderness.\n\nHospital course\nUpon admission, a metabolic panel revealed sodium 135 mmol/L, potassium 3.8 mmol/L, chloride 95 mmol/L, CO2 28 mmol/L, total protein 6.1 g/dL, blood urea nitrogen (BUN) 58 mg/dL, and creatinine 10.08 mg/dL. Urinalysis was positive at >300 mg/dL for protein and 3+ for hemoglobin. On microscopic examination of urine, there were too-numerous-to-count red blood cells, 3–5 white blood cells, and 1–3 granular casts observed under high-power magnification. Fraction excretion of sodium was 2.2%. Serum C3 and C4 levels were within normal ranges. Hepatitis B surface antigen, hepatitis C antibody, anti-nuclear antibody, anti-double strand DNA antibody, glomerular basement membrane antibody, cytoplasmic anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody were all negative. Ultrasound revealed solid masses in the interpolar region of the right kidney and upper pole of the left kidney, representative of his known renal cell carcinoma. Otherwise, kidney sizes were within the normal range and there was no evidence of hydronephrosis.\n\nBiopsy of the right lower pole of the kidney was performed on October 29, 2014. Light microscopic examination demonstrated diffuse tubular injury with vacuoles and immune complex-mediated glomerulonephritis with cellular crescents and necrosis. There was moderate interstitial inflammation with lymphocytes observed. With immunofluorescence, there was diffuse granular mesangial staining for IgA, C3, and kappa and lambda light chains. The specimen was also sent for electron microscopic examination. One glomerulus with severe cellular crescents was selected for examination and demonstrated several hump-like subepithelial deposits and no subendothelial deposits. There was partial podocyte foot process effacement. Proximal tubules were flattened with simplified tubular epithelium and shorter microvilli. Pathologic examinations confirmed the final diagnosis of acute toxic-type tubular injury and IgA-dominant acute post-infectious glomerulonephritis. Pictures of microscopic examinations are shown in Fig. 1.Fig. 1 Microscopic examinations of kidney biopsy specimens. a and b Hematoxylin and eosin staining of the kidney biopsy specimen revealed interstitial infiltrate with tubular injury (arrows), glomerulonephritis with cellular crescents (arrowhead), and mesangial proliferation (arrow). c Immunofluorescence staining for IgA deposits. d Electron microscopic picture of subepithelial deposit (arrow)\n\n\n\n\nAlthough there was the possibility of post-infectious glomerulonephritis based on findings of glomerular deposits in the kidney biopsy, the patient did not show symptoms of streptococcal infection such as pharyngitis or a rash prior to admission. The patient’s C3 level was normal and he was not hypertensive. Based on patient’s previous exposure to nivolumab and lymphocyte infiltration observed in the biopsy, immunotherapy-induced kidney injury was taken into consideration. Nivolumab was discontinued and methylprednisolone administration 40 mg intravenously twice a day was started. The following day, serum potassium increased to 5.6 mmol/L, and creatinine and BUN were elevated at 11.01 and 63 mg/dL, respectively. Nephrology was consulted and hemodialysis was initiated. Methylprednisolone was increased to 40 mg three times a day (1 mg/kg/day). After the biopsy report, the patient was started on pulse dose steroids, methylprednisolone 1 g intravenously daily for 3 days, followed by methylprednisolone 40 mg intravenously three times a day. The creatinine level decreased after steroid treatment and hemodialysis. Four days later, steroids were changed to oral prednisone 40 mg twice a day and the patient was discharged on steroid treatment and outpatient hemodialysis. On the day of discharge, his creatinine level was 8.80 mg/dL.\n\nFollow-up and outcome\nOne month after discharge, the patient was admitted with a fever, rash, tachycardia, and leukocytosis, consistent with systemic inflammatory response syndrome (SIRS). The source of infection was unclear as blood and urine cultures were negative. The patient had generalized patchy skin lesions with desquamation, most prominent at the bilateral proximal arms and upper torso. Biopsy of skin lesions was deferred, as they were thought to be an irAE and already clinically improving with steroid treatment. The patient was discharged after a short course of intravenous antibiotics. The dose of prednisone was increased at this time. Another month after the second hospitalization, the patient was re-admitted with fever, tachycardia, and hypotension. Again, there was no compelling source of infection identified after an extensive diagnostic work up. During the third hospitalization of 9 days, he received a stress dose of hydrocortisone 100 mg three times a day. Upon discharge, he resumed a tapering course of steroids, starting with prednisone 60 mg daily. The patient tolerated the prolonged course of oral steroids well with no apparent adverse effects. Oral prednisone was stopped at the end of February 2015. In April 2015, his serum creatinine level was 1.81 mg/dL and BUN was 13 mg/dL. Hemodialysis was discontinued on April 27, 2015. The last contact with the patient was on March 30, 2016 and his kidney function remained stable at the time. Change in serum creatinine over the 6-month treatment period is shown in Fig. 2.Fig. 2 Serum creatinine changes over the 6-month treatment period\n\n\n\n\nWhile recovering from nivolumab toxicity, the patient did not receive any treatment for renal cell carcinoma. In spite of the prolonged systemic corticosteroid treatment, anti-tumor activity seemed to continue as the tumors in bilateral kidneys and adrenal glands decreased in sizes for 18 months (left adrenal gland: 3.7 to 2.4 cm, right adrenal gland: 7.0 to 5.8 cm, left kidney mass: 6.0 to 3.4 cm, right kidney mass: 7.0 to 5.8 cm; all measurements in longest diameter). In March 2016, he was started on axitinib 3 mg twice a day for symptomatic disease progression (worsening of rib lesion).\n\nConclusions\nirAE are encountered more frequently in daily oncologic practice with the increased use of immune checkpoint inhibitors. Immune checkpoint inhibition involves two major transmembrane proteins, cytotoxic T-lymphocyte antigen 4 and PD1. Nivolumab, a monoclonal anti-PD1 antibody, blocks T cell inhibition and stimulates the immunologic response towards cancer cells, but it may also impair the self-tolerance of the immune system. This potential side effect can occur in any organ of the body but is known to predominately occur in the gastrointestinal tract, lung, liver, and endocrine system [7].\n\nIn clinical trials of nivolumab or other anti-PD1 antibodies, the renal system was not affected as frequently as other organ systems. In a population of patients with non-small cell lung cancer, seven of 287 patients (2.4%) who were treated with nivolumab developed renal injury, but all events were either grade 1 or 2 [8]. Among patients with melanoma treated with pembrolizumab (anti-PD1 antibody), one of 277 patients (0.4%) experienced nephritis with renal failure [9]. Another anti-PD1 antibody, lambrolizumab, was associated with renal failure in three of 135 patients (2%) with melanoma, with two of these three patients having grade 3 or 4 adverse events [10].\n\nTable 1 summarizes case reports on irAE affecting the kidney, identified in a review of the literature. Fadel et al. reported a case of lupus nephritis that occurred after use of ipilimumab and was resolved after steroid treatment [11]. Six cases of ipilimumab-associated nephritis were reported [12–15]. The articles generally reported successful treatment of ipilimumab-associated nephritis using systemic steroids. In addition, there were three cases of AKI caused by anti-PD1 antibody, such as nivolumab or pembrolizumab. Two patients who had nivolumab-related kidney injury were successfully treated with steroids [16], and one patient who developed pembrolizumab-related kidney injury showed improvement of nephritis after steroid treatment [17].Table 1 Reports in the literature of immunotherapy-associated renal adverse events and treatment\n\nAuthor\tNo. of patients\tAge\tGender\tMedication\tCancer\tKidney biopsy\tTreatment\tOutcome\t\nFadel et al. [11] 2009\t1\t64\tM\tIpilimumab\tMelanoma\tExtra-membranous and mesangial deposits of immunoglobulin (consistent with lupus nephritis)\tSteroids\tResolved\t\nForde et al. [12] 2012\t1\t59\tM\tIpilimumab\tMelanoma\tNot available\tSteroids; no dialysis\tResolved\t\nVoskens et al. [13] 2013\t1\t53\tF\tIpilimumab\tMucosal\tNot available\tSteroids\tResolved\t\n2\t72\tF\tIpilimumab\tUnknown primary\tNot available\tSteroids\tResolved\t\nIzzedine et al. [14] 2014\t1\t72\tM\tIpilimumab\tMelanoma\tInterstitial inflammation and poly-nuclear infiltration in glomerulus\tSteroids\tResolved\t\n2\t60\tF\tIpilimumab\tMelanoma\tTubulointerstitial inflammation with necrosis and two non-necrotizing granulomas\tSteroids\tResolved\t\nThajudeen et al. [15] 2015\t1\t74\tM\tIpilimumab\tMelanoma\tInterstitial edema with infiltrate of lymphocytes and granulomas\tSteroids\tResolved; ipilimumab resumed\t\nVandiver et al. [16] 2016\t1\t58\tF\tNivolumab\tMelanoma\tNot available\tSteroids\tResolved\t\nHofmann et al. [17] 2016\t1\t52\tM\tNivolumab\tMelanoma\tNot available\tSteroids and normal saline\tResolved; nivolumab resumed\t\n2\t73\tM\tPembrolizumab\tMelanoma\tNot available\tSteroids\tImproved\t\n\n\n\nAlthough alterations in immunologic self-tolerance theoretically account for renal dysfunction, specific mechanisms among existing case reports are diverse. Biopsy results also varied. One patient was diagnosed with lupus nephritis during treatment with ipilimumab [11]. Diagnosis was made based on the patient being positive for anti-nuclear and anti-double-stranded DNA antibodies. Electron microscopy confirmed the presence of granular, electron-dense extra-membranous deposits. Izzedine et al. reported two cases of acute interstitial nephritis associated with ipilimumab [14]. In a more recent case, reported by Thajudeen et al., a biopsy revealed granulomas and interstitial infiltration with lymphocytes, eosinophils, and plasma cells [15]. In the current case, the biopsy revealed acute tubular injury and immune complex-mediated glomerulonephritis.\n\nRegardless of the etiology or biopsy results, patient’s kidney functions generally improved after steroid treatment. We found no case in our review of the literature in which tumor necrosis factor inhibitors or cytotoxic immunosuppressants were required. In some reviewed cases, immunotherapy resumed after kidney function improved. In the current case, nivolumab was permanently discontinued and the patient continued on a lengthy tapering course of steroids for approximately 4 months. Even after prolonged use of systemic corticosteroids and discontinuation of nivolumab, the immunologic anti-tumor effect appeared to persist and the tumors in his kidneys shrank in size. In the literature, there was a case of a melanoma patient who experienced continued tumor regression in spite of discontinuation of ipilimumab and daily administration of systemic corticosteroids for irAE [18]. In another case of a patient with melanoma treated with ipilimumab, both steroids and infliximab were used for grade 3 colitis, and there was no disease progression after approximately 3 years [19]. In a clinical trial, corticosteroids for treatment of irAE did not impact the clinical activity of ipilimumab in advanced melanoma patients [20].\n\nIn the current case, the possibility of post-infectious glomerulonephritis was raised based on glomerular deposits in the kidney biopsy. However, the patient did not have symptoms of pharyngitis or a skin infection prior to admission. Lack of hypertension and a normal C3 level were also not consistent with post-infectious glomerulonephritis. Autoimmune glomerular injury was determined as a major component of the etiology in our case, based on the temporal relationship between the use of nivolumab and the onset of AKI. To the best of the authors’ knowledge, this is the first case of nivolumab-associated glomerulonephritis confirmed by light and electron microscopic findings.\n\nThe patient in our case was twice admitted with unexplained SIRS. Both hospitalizations occurred while on a decreasing dose of prednisone. After extensive diagnostic testing for infection, there was no clear source of SIRS. Pyrexia has been reported as a side effect of immunotherapy in clinical trials, but our patient had severe SIRS with hypotension requiring admission to the intensive care unit. Although the potential relationship between immunotherapy and SIRS is intriguing, more evidence is required before a causal link can be established.\n\nIn summary, use of systemic corticosteroids has been generally successful in achieving an optimal treatment response for immunotherapy-associated renal dysfunction. Nivolumab manufacturer recommends 0.5–1 mg/kg/day prednisone equivalents for grade 2 or 3 renal dysfunction, and if no improvement occurs, 1–2 mg/kg/day prednisone equivalents and discontinuation of nivolumab. For life-threatening grade 4 renal dysfunction, the recommendation is to start with 1–2 mg/kg/day prednisone equivalents and permanently discontinue nivolumab [6]. Based on our experience, a pulse dose of steroids can be used for resistant renal dysfunction. Although treatment responses may not be ostensible initially, a presumptive decision of treatment failure should be avoided. As in our case, patients may require a prolonged course of systemic corticosteroids and hemodialysis, and kidney function may improve months later.\n\nAbbreviations\nAKIAcute kidney injury\n\nirAEImmune-related adverse events\n\nPD1Programmed death 1\n\nPDL1PD ligand 1\n\nSIRSSystemic inflammatory response syndrome\n\nAcknowledgements\nNo acknowledgements. There was no financial support or funding for this case report.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this article is available in the Zenodo repository, doi:10.5281/zenodo.55295; https://zenodo.org/record/55295.\n\nAuthors’ contributions\nMB managed longitudinal care of the patient. KJ contributed to inpatient care during admissions. XZ reported on light microscopy and electron microscopy examinations. KJ wrote the first draft of the manuscript. MB and XZ provided revisions and KJ wrote the final version of manuscript. All authors read and approved the final version of manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report.\n\nEthics approval and consent to participate\nThis study was exempted from institutional review board approval because it was a case review and secondary analysis.\n==== Refs\nReferences\n1. Schadendorf D Hodi FS Robert C Weber JS Margolin K Hamid O Patt D Chen TT Berman DM Wolchok JD Pooled analysis of of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma J Clin Oncol 2015 33 17 1889 94 10.1200/JCO.2014.56.2736 25667295 \n2. Wolchok JD Kluger H Callahan MK Postow MA Rizvi NA Nivolumab plus ipilimumab in advanced melanoma N Engl J Med 2013 369 2 122 33 10.1056/NEJMoa1302369 23724867 \n3. Champiat S Lambotte O Barreau E Belkhir R Berdelou A Carbonnel F Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper Ann Oncol 2016 27 4 559 74 10.1093/annonc/mdv623 26715621 \n4. Francisco LM Salinas VH Brown KE Vanguri VK Freeman GJ Kuchroo VK Sharpe AH PD-L1 regulates the development, maintenance, and function of induced regulatory T cells J Exp Med 2009 206 13 3015 29 10.1084/jem.20090847 20008522 \n5. Amarnath S Mangus CW Wang JC Wei F He A Kapoor V The PDL1-PD1 axis converts human TH1 cells into regulatory T cells Sci Transl Med 2011 3 111 111 20 10.1126/scitranslmed.3003130 \n6. Opdivo (Nivolumab). http://packageinserts.bms.com/pi/pi_opdivo.pdf. Last Accessed 27 May 2016.\n7. Spain L Diem S Larkin J Management of toxicities of immune checkpoint inhibitors Cancer Treat Rev 2016 44 51 60 10.1016/j.ctrv.2016.02.001 26874776 \n8. Borghaei H Paz-Ares L Horn L Spiegel DR Steins M Ready NE Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer N Engl J Med 2015 373 17 1627 39 10.1056/NEJMoa1507643 26412456 \n9. Robert C Schachter J Long GV Arance A Grobb JJ Mortier L Pembrolizumab versus ipilimumab in advanced melanoma N Engl J Med 2015 372 26 2512 32 10.1056/NEJMoa1503093 \n10. Hamid O Robert C Daud A Hodi FS Hwu WJ Kefford R Safety and tumor responses with lambrolizumab (Anti-PD-1) in melanoma N Engl J Med 2013 369 2 134 44 10.1056/NEJMoa1305133 23724846 \n11. Fadel F Karoui KE Knebelmann B Anti-CTLA4 antibody-induced lupus nephritis N Eng J Med 2009 361 2 211 2 10.1056/NEJMc0904283 \n12. Forde PM Rock K Wilson G O’Byrne KJ Ipilimumab-induced immune-related renal failure – A case report Anticancer Res 2012 32 10 4607 8 23060594 \n13. Voskens CJ Goldinger SM Loquai C Robert C Kaehler KC Berking C Bergmann T Bockmeyer CL The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network PLoS One 2013 8 1 e53745 10.1371/journal.pone.0053745 23341990 \n14. Izzedine H Guetin V Gharbi C Mateus C Robert C Routier E Kidney injuries related to ipilimumab Invest New Drugs 2014 32 769 73 10.1007/s10637-014-0092-7 24687600 \n15. Thajudeen B Madhrira M Bracamonte E Cranmer LD Ipilimumab granulomatous interstitial nephritis Am J Ther 2015 22 3 e84 7 10.1097/MJT.0b013e3182a32ddc 24067875 \n16. Vandiver JW, Singer Z, Harshberger C. Severe hyponatremia and immune nephritis following an initial infusion of nivolumab. Target Oncol. 2000; doi:10.1007/s11523-016-0426-9.\n17. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Urqurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016; doi: 10.1016/j.ejca.2016.02.025.\n18. Harmankaya K Erasim C Koelblinger C Ibrahim R Hoos A Pehamberger H Binder M Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy Med Oncol 2011 28 1140 4 10.1007/s12032-010-9606-0 20593249 \n19. Arriola E Wheater M Krisnan R Smart J Foria V Ottensmeier C Immunosuppression for ipilimumab-related toxicity can cause pneumocystis pneumonia but spare antitumor immune control Oncoimmunology 2015 4 1 e1040218 10.1080/2162402X.2015.1040218 26451305 \n20. Amin A Depril V Hamid O Wolchok J Maio M Neyns B Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development of maintenance of ipilimumab clinical activity J Clin Oncol 2009 27 abstr 9037 10.1200/JCO.2008.20.6235\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "17(1)",
"journal": "BMC nephrology",
"keywords": "Acute kidney injury; Autoimmune nephritis; Case report; Immunotherapy; Nivolumab; Renal cell carcinoma",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D005921:Glomerulonephritis; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D000077594:Nivolumab",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "188",
"pmc": null,
"pmid": "27876011",
"pubdate": "2016-11-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "26412456;23724867;24067875;19587352;27085692;25667295;20593249;26451305;23724846;26940583;20008522;25891173;24687600;26874776;22133721;26715621;23060594;23341990",
"title": "Nivolumab-associated acute glomerulonephritis: a case report and literature review.",
"title_normalized": "nivolumab associated acute glomerulonephritis a case report and literature review"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2016-111798",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Összefoglaló. Bár a figyelemhiányos hiperaktivitási zavar kezelése során alkalmazott metilfenidát-monoterápiával összefüggésben jelentkező gynaecomastiáról bizonyos nemkívánatos hatások adatbázisai beszámolnak, a szakirodalom áttekintése alapján ez idáig mindössze 5 esettanulmányt publikáltak a témában. Tanulmányunkban egy autizmusspektrum-zavarral és figyelemhiányos hiperaktivitási zavarral egyaránt diagnosztizált gyermek esetét mutatjuk be, akinél 6 hónapon át tartó, folyamatos metilfenidát-monoterápiájával összefüggésben kétoldali gynaecomastia kialakulását tapasztaltuk. A kezelés azonnali leállítása mellett 10 napos klomifénkezelés történt. A metilfenidát-terápia azonnali leállítását követően 14 nappal a gynaecomastia mindkét oldalon visszahúzódott. 3 hónapos, gyermekpszichiátriai szempontból gyógyszermentes időszakot követően a metilfenidát-terápia újraindítása történt, de 1 hónap elteltével a nem kívánt mellékhatás ismét jelentkezett. A metilfenidát-terápia és a gynaecomastia kialakulása közötti kapcsolat számos mechanizmussal kapcsolatban kérdéseket vet fel. Gyermekpszichiátriai szempontból érdekes kérdés, hogy releváns lehet-e a gyógyszeres terápia következményeként kialakuló nemkívánatos mellékhatás megjelenésében az autizmusspektrum-zavar és a figyelemhiányos hiperaktivitási zavar komorbid fennállása. A jelenség hátterében felmerül továbbá a neuroendokrin-immunológiai rendszer szabályozásának esetleges megváltozása. Esettanulmányunk felhívja a gyakorló orvoskollégák figyelmét a metilfenidát-terápia alkalmazása mellett potenciálisan kialakuló gynaecomastia monitorozására. Orv Hetil. 2021; 162(42): 1703-1708. Summary. Although gynecomastia associated with methylphenidate monotherapy in the treatment of attention deficit hyperactivity disorder has already been reported in some adverse event databases, based on a review of the literature it appears that only five case reports have been published. In our study, we present the case of a child diagnosed with both autism spectrum disorder and attention deficit/hyperactivity disorder, who developed bilateral gynecomastia in association with continuous methylphenidate monotherapy for 6 months. With immediate cessation of methylphenidate therapy, clomiphene treatment was given for 10 days. A total of 14 days after cessation of methylphenidate treatment gynecomastia receded on both sides. After a methylphenidate drug-free period of 3 months, methylphenidate therapy was restarted, but 1 month later the side effect reappeared. The relationship between methylphenidate and the development of gynecomastia raises questions about a number of mechanisms. From a child psychiatrist point of view, it is an interesting question whether the presence of comorbid autism spectrum disorder and attention deficit/hyperactivity disorder may be relevant in the onset of adverse events by medication. The phenomenon may also be caused by altered regulation of the neuroendocrine-immune system. Our case report draws the attention of practicing physicians to monitoring of potential gynecomastia during methylphenidate therapy. Orv Hetil. 2021; 162(42): 1703-1708.",
"affiliations": "1 Semmelweis Egyetem, Mentális Egészségtudományok Doktori Iskola, Pszichiátria Program, Gyermekpszichiátriai Kórképek Vizsgálata Munkacsoport, Budapest.;3 Bethesda Gyermekkórház, Figyelemhiányos Hiperaktivitás Zavar (ADHD) Ambulancia, Budapest.;4 Eötvös Loránd Tudományegyetem, Pedagógiai és Pszichológiai Kar, Pszichológiai Intézet, Fejlődés- és Klinikai Gyermekpszichológia Tanszék, Budapest.",
"authors": "Kollárovics|Nóra|N|;Nagy|Péter|P|;Balázs|Judit|J|",
"chemical_list": "D008774:Methylphenidate",
"country": "Hungary",
"delete": false,
"doi": "10.1556/650.2021.32198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-6002",
"issue": "162(42)",
"journal": "Orvosi hetilap",
"keywords": "attention deficit/hyperactivity disorder; autism spectrum disorder; autizmusspektrum-zavar; figyelemhiányos hiperaktivitási zavar; gynaecomastia; gynecomastia; methylphenidate; metilfenidát",
"medline_ta": "Orv Hetil",
"mesh_terms": "D000067877:Autism Spectrum Disorder; D002648:Child; D006177:Gynecomastia; D006801:Humans; D008297:Male; D008774:Methylphenidate",
"nlm_unique_id": "0376412",
"other_id": null,
"pages": "1703-1708",
"pmc": null,
"pmid": "34657003",
"pubdate": "2021-10-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Possible association between methylphenidate treatment in a child with autism spectrum disorder and subsequent gynecomastia",
"title_normalized": "possible association between methylphenidate treatment in a child with autism spectrum disorder and subsequent gynecomastia"
} | [
{
"companynumb": "HU-LUPIN PHARMACEUTICALS INC.-2021-22183",
"fulfillexpeditecriteria": "2",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE"
},
"drugaddit... |
{
"abstract": "OBJECTIVE\nRadioiodine is being used increasingly as first line therapy for hyperthyroidism. Our aim is to highlight some of the difficulties which can occur following the use of 131I to treat hyperthyroidism in fertile women.\n\n\nMETHODS\nWe present 3 cases of young women to whom radioiodine was given, only to find some weeks later that they had been pregnant at the time of treatment.\n\n\nCONCLUSIONS\nThese cases serve as a reminder of the importance of obtaining an accurate and full menstrual and contraceptive history. Guidelines advocate the application of the ten day rule with the further recommendation that pregnancy testing may be undertaken as an alternative.",
"affiliations": "Department of Endocrinology, University Hospital of Wales, Cardiff.",
"authors": "Evans|P M|PM|;Webster|J|J|;Evans|W D|WD|;Bevan|J S|JS|;Scanlon|M F|MF|",
"chemical_list": "D007457:Iodine Radioisotopes",
"country": "England",
"delete": false,
"doi": "10.1046/j.1365-2265.1998.00423.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-0664",
"issue": "48(3)",
"journal": "Clinical endocrinology",
"keywords": null,
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D000328:Adult; D000075202:Contraindications; D004622:Embryo, Mammalian; D005314:Embryonic and Fetal Development; D005260:Female; D006801:Humans; D006980:Hyperthyroidism; D007457:Iodine Radioisotopes; D001523:Mental Disorders; D009381:Neoplasms, Radiation-Induced; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D011879:Radiotherapy Dosage; D012306:Risk",
"nlm_unique_id": "0346653",
"other_id": null,
"pages": "281-3",
"pmc": null,
"pmid": "9578816",
"pubdate": "1998-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Radioiodine treatment in unsuspected pregnancy.",
"title_normalized": "radioiodine treatment in unsuspected pregnancy"
} | [
{
"companynumb": "GB-CURIUM-2021000091",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "The risk of hepatocellular cancer (HCC) after sustained virological response (SVR) with direct-acting antivirals (DAA) is unclear. Our aim was to examine the risk and determinants of HCC in patients cured with DAA.\n\n\n\nWe conducted a retrospective cohort study of hepatitis C virus patients who were treated with DAA in any of the 129 Veterans Health Administration hospitals between January 1, 2015 and December 31, 2015. We calculated the annual incidence rates of HCC by SVR. We used Cox regression models to compare the risk of HCC in patients with vs those without SVR and to identify factors associated with incident HCC among patients with SVR. We reviewed a sample of HCC patients for tumor size and stage at diagnosis.\n\n\n\nAmong 22,500 patients treated with DAA (19,518 with SVR; 2982 without SVR), the mean (standard deviation) age was 61.6 (6.1) years, and 39.0% had cirrhosis. There were 271 new cases of HCC, including 183 in patients with SVR. Compared with patients without SVR, those with SVR had a significantly reduced risk of HCC (0.90 vs 3.45 HCC/100 person-years; adjusted hazard ratio, 0.28, 95% CI=0.22-0.36). Patients with cirrhosis had the highest annual incidence of HCC after SVR (1.82 vs 0.34/100 person-years in patients without cirrhosis; adjusted hazard ratio, 4.73. 95% CI, 3.34-6.68). Most (>44.8%) HCC were classified as stage I. Maximum size of the largest lesion was ≤5 cm in over 75% of cases.\n\n\n\nAmong patients treated with DAA, SVR was associated with a considerable reduction in the risk of HCC. We did not find any evidence to suggest that DAAs promote HCC. However, in patients with SVR, the absolute risk of HCC remained high in patients with established cirrhosis. These patients should be considered for ongoing HCC surveillance.",
"affiliations": "Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address: kanwal@bcm.edu.;Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas.;Center for Innovation to Implementation (Ci2i), Palo Alto Veterans Affairs Medical Center, Palo Alto, California; Division of Primary Care and Population Health, Stanford University, Palo Alto, California.;Section of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.;Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas.;Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas.",
"authors": "Kanwal|Fasiha|F|;Kramer|Jennifer|J|;Asch|Steven M|SM|;Chayanupatkul|Maneerat|M|;Cao|Yumei|Y|;El-Serag|Hashem B|HB|",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2017.06.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "153(4)",
"journal": "Gastroenterology",
"keywords": "Liver Cancer; Outcome; Therapy; Viral Hepatitis",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D005260:Female; D006526:Hepatitis C; D006787:Hospitals, Veterans; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D065840:Protective Factors; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D000072230:Sustained Virologic Response; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden; D014481:United States",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "996-1005.e1",
"pmc": null,
"pmid": "28642197",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents.",
"title_normalized": "risk of hepatocellular cancer in hcv patients treated with direct acting antiviral agents"
} | [
{
"companynumb": "US-JNJFOC-20171208399",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
},
"drugadditional": null,
... |
{
"abstract": "Prototheca wickerhamii is a rare cause of septic prepatellar bursitis. We report a patient who had no apparent immunodeficiency developed P. wickerhamii prepatellar bursitis following intra-bursal corticosteroid injection. Clinical manifestations could not distinguish Prototheca bursitis from septic bursitis caused by other pathogens. Bursal fluid aspiration sent for direct microscopic examination and cultures could give an early diagnosis. Systemic antifungal therapy with complete surgical excision of infected bursa provided a good outcome.",
"affiliations": "Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand.;Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand. Electronic address: anupop.jit@mahidol.ac.th.",
"authors": "Katwilat|P|P|;Chongtrakool|P|P|;Muangsomboon|S|S|;Jitmuang|A|A|",
"chemical_list": "D000935:Antifungal Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2019.100901",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "29(4)",
"journal": "Journal de mycologie medicale",
"keywords": "Immunocompetent woman; Prepatellar bursitis; Prototheca wickerhamii; Protothecosis",
"medline_ta": "J Mycol Med",
"mesh_terms": "D000935:Antifungal Agents; D002062:Bursitis; D005260:Female; D006801:Humans; D007121:Immunocompetence; D007239:Infections; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D011525:Prototheca",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "361-364",
"pmc": null,
"pmid": "31570306",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prototheca wickerhamii prepatellar bursitis in an immunocompetent woman: A case report.",
"title_normalized": "prototheca wickerhamii prepatellar bursitis in an immunocompetent woman a case report"
} | [
{
"companynumb": "TH-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-231403",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"d... |
{
"abstract": "Gorham-Stout disease (GSD) is a rare condition in which spontaneous, progressive resorption of bone occurs. There are no previous reports of patients with fatal progression of GSD with skull base osteomyelitis (SBO) and lateral medullary syndrome (LMS). We present the case of a 27-year-old man diagnosed with GSD with involvement of the maxillofacial bones and skull base. The patient developed SBO; LMS resulted from progressive osteolysis, and the patient died of associated brainstem stroke. Careful follow-up with special emphasis on the early detection of intracranial complications is critical in patients presenting with progressive GSD with involvement of the skull base.",
"affiliations": "Department of Pediatrics, Gifu University Graduate School of Medicine, Japan.;Department of Pediatrics, Gifu University Graduate School of Medicine, Japan.;Department of Pediatrics, Gifu University Graduate School of Medicine, Japan.;Department of Radiology, Gifu University Graduate School of Medicine, Japan.;Department of Neurosurgery, Gifu University Graduate School of Medicine, Japan.;Department of Pediatrics, Gifu University Graduate School of Medicine, Japan.",
"authors": "Nozawa|Akifumi|A|;Ozeki|Michio|M|;Hori|Tomohiro|T|;Kato|Hiroki|H|;Ohe|Naoyuki|N|;Fukao|Toshiyuki|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.2118-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3079935210.2169/internalmedicine.2118-18Case ReportFatal Progression of Gorham-Stout Disease with Skull Base Osteomyelitis and Lateral Medullary Syndrome Nozawa Akifumi 1Ozeki Michio 1Hori Tomohiro 1Kato Hiroki 2Ohe Naoyuki 3Fukao Toshiyuki 1\n1 Department of Pediatrics, Gifu University Graduate School of Medicine, Japan\n2 Department of Radiology, Gifu University Graduate School of Medicine, Japan\n3 Department of Neurosurgery, Gifu University Graduate School of Medicine, JapanCorrespondence to Dr. Michio Ozeki, michioo@gifu-u.ac.jp\n\n25 2 2019 1 7 2019 58 13 1929 1933 11 9 2018 9 12 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Gorham-Stout disease (GSD) is a rare condition in which spontaneous, progressive resorption of bone occurs. There are no previous reports of patients with fatal progression of GSD with skull base osteomyelitis (SBO) and lateral medullary syndrome (LMS). We present the case of a 27-year-old man diagnosed with GSD with involvement of the maxillofacial bones and skull base. The patient developed SBO; LMS resulted from progressive osteolysis, and the patient died of associated brainstem stroke. Careful follow-up with special emphasis on the early detection of intracranial complications is critical in patients presenting with progressive GSD with involvement of the skull base. \n\ndenosumabsirolimussphenoiditisWallenberg syndromelateral medullary syndrome\n==== Body\nIntroduction\nGorham-Stout disease (GSD) is a form of lymphangiomatosis characterized by diffuse lymphatic vessel proliferation accompanied by progressive osteolysis. The symptoms of GSD are variable; lesions can arise in the skull, maxillofacial skeleton, arms, legs, pelvis, spine, and ribs (1). Mortality depends on the area affected. Patients with GSD of the maxillofacial bones are at a particularly high risk of death because of the possibility of disease progression to the brain and spine (2). Kim et al. reviewed 64 reports of GSD in the maxillofacial region among articles published from 1928 through 2015. In that review, there were 7 cases of disease-specific death, resulting in a mortality rate of 10.94% (3). Four patients died of lung-related problems, two of spinal involvement, and one of intracranial extension. The patient with intracranial extension suffered from osteolytic lesions of the parietal bone, zygoma, ramus, and vertebra (4). However, there are no previous reports of patients with GSD who died of cerebral infarction associated with skull base and maxillofacial lesions.\n\nWhile standard treatments for GSD are lacking, previous reports have described treatment with surgery, radiation therapy, and medications (bisphosphonates, thalidomide, and interferon) (1). Recently, the efficacy of sirolimus for various vascular anomalies including GSD has been reported, and clinical trials of sirolimus are ongoing (5).\n\nWe herein report the case of a patient with GSD involving the skull base and maxillofacial bones who presented with brainstem infarction secondary to rapid osteolysis.\n\nCase Report\nA 27-year-old man presented with painless mobility of the right maxillary incisors. He reported no history of trauma. A physical examination revealed no signs of local inflammation or systemic disease. All laboratory values were normal. Computed tomography (CT) demonstrated osteolysis of the right maxilla. A histological study of a maxillary biopsy specimen revealed the presence of abundant fibrous tissue. Six years later, the maxilla was rebiopsied because of progressive disease. Histopathology showed resorption of typical bone structures, which had been replaced with thin-walled endothelium-lined capillaries of vascular or lymphatic origin. D2-40 immunostaining delineated the endothelium of the lymphatic channels, so a diagnosis of GSD was made.\n\nThe patient was treated with localized radiotherapy (40 Gy) and bisphosphonates. However, CT revealed osteolysis spreading from the right maxilla to the frontal bone, the temporal bone, and the zygomatic bone (Fig. 1). Extraosseous soft-tissue masses compressed the right facial nerve and trigeminal nerve, leading to facial paresis and pain. One year later, the patient was transferred to Gifu University Hospital for alternative treatment. We decided to treat him with an mTOR inhibitor, sirolimus. This treatment was approved by the review board at Gifu University Hospital. Written informed consent was obtained from the patient. Sirolimus treatment (2 mg/day) was started. Six months later, the patient was hospitalized for the control of sharp pain resulting from nerve damage.\n\nFigure 1. Three-dimensional volume rendering images of computed tomography shows massive osteolysis of the right maxillofacial region in the maxilla, the frontal bone, the temporal bone, and the zygomatic bone.\n\nThe patient received a steroid and morphine for pain control. We initiated treatment with denosumab (120 mg, subcutaneous injection) in addition to sirolimus to halt the progression of the osteolysis. However, the osteolysis progressed and extended to the skull base. Axial CT one month after hospitalization showed progression of massive osteolysis in the right central skull base (Fig. 2). Magnetic resonance imaging (MRI) of the skull base after one month of hospitalization revealed extraosseous soft-tissue masses filling the sphenoid sinus (Fig. 3A). Nasal endoscopy revealed a connection between the sphenoid sinus and the oral cavity. Biopsy from the soft-tissue mass was negative for neoplasia.\n\nFigure 2. Axial CT image showing progression of bone destruction in the skull base. (A) At the time of hospitalization, there is indistinct osteolysis in the skull base. (B) One month after hospitalization, axial CT shows progression of massive osteolysis in the right central skull base.\n\nFigure 3. (A) Axial T1-weighted image after 1 month of hospitalization reveals extraosseous soft-tissue masses filling the sphenoid sinus. (B) Axial fat-suppressed contrast-enhanced T1-weighted image shows moderately enhanced bone marrow of the skull base and extraosseous soft-tissue masses.\n\nThe patient complained of sudden vertigo, dysphagia, and left-sided paresthesia after six weeks of hospitalization. Neurological examinations revealed both tactile and thermal/pain hyperesthesia on the right side of his face, and thermal/pain hyperesthesia in his left limbs. Horner’s syndrome on the right side and limb ataxia in the left upper and lower limbs were evident. Subsequently performed diffusion-weighted images demonstrated a hyperintense area in the right lateral medulla, consistent with an acute infarct (Fig. 4A). Magnetic resonance angiography failed to identify any arterial dissection. Coagulation workup and echocardiograms were all normal. The patient was diagnosed with a brainstem stroke with lateral medullary syndrome (LMS) and was started on aspirin.\n\nFigure 4. (A) Diffusion-weighted image after the onset of lateral medullary syndrome (LMS) shows a hyperintense area in the right lateral medulla. (B) A few days after the onset of LMS, fluid attenuation inversion recovery image shows hyperintense areas in the right temporal lobe, the pons, and the bilateral middle cerebellar peduncles. The hyperintense white matter of the right temporal lobe is caused by the pressure of the extraosseous soft-tissue masses.\n\nContrast-enhanced T1-weighted MRI demonstrated moderately enhanced bone marrow of the skull base and extraosseous soft-tissue masses (Fig. 3B). Laboratory data indicated high levels of inflammation, with an elevated white blood cell count (14,000/μL) and C-reactive protein level (8.72 mg/dL). Microbiological testing of a nasopharyngeal swab revealed Pseudomonas aeruginosa. Therefore, skull base osteomyelitis (SBO) was diagnosed. Antibiotic therapy was initiated empirically with meropenem. A few days after the onset of LMS, disturbance of consciousness progressed. Fluid-attenuated inversion recovery imaging demonstrated hyperintense areas in the right temporal lobe, the pons, and the bilateral middle cerebellar peduncles (Fig. 4B). The treatments were not effective; the patient’s condition progressively worsened, and he died after several weeks.\n\nDiscussion\nWe herein report a case of GSD with involvement of the maxillofacial bones and skull base. Although GSD often progresses slowly and insidiously, this patient’s osteolysis progressed more rapidly than we expected. The osteolytic lesion eventually contributed to his death. The tissue of the osteolytic skull base lesion was observed to change into densely structured, fibrous connective tissue. The replacement of bone by connective tissue is the characteristic finding in GSD, which makes the diagnosis difficult based on histological examinations (1,3). Furthermore, the soft-tissue masses were fragile, and the sphenoid sinus was connected to the oral cavity in our patient, which increased susceptibility to bacterial infection via the oral cavity.\n\nIn our patient, extensive osteolysis of the skull base caused sphenoiditis with both SBO and LMS. SBO was diagnosed based on the following findings: laboratory results showing high levels of inflammation, the presence of Pseudomonas aeruginosa in the nasopharynx, multiple cranial nerve palsies that appeared later, and abnormal bone marrow signal intensities on MRI (6). Ng et al. described a case in which a 10-year-old immunocompetent patient developed LMS secondary to SBO arising from sphenoiditis (7). SBO is rarely caused by paranasal infections (8). However, it is difficult to diagnosis the disease properly because the only clinical symptom may be headache, with cranial neuropathies occurring later. In our patient, MRI clearly revealed the abnormal bone marrow of the skull base with hyperintensity on fat-suppressed contrast-enhanced T1-weighted images, which was highly suggestive of SBO. If the diagnosis is delayed, this condition has high morbidity and mortality. Therefore, patients with GSD who have osteolytic lesions of the skull base should be monitored closely for any signs of SBO.\n\nLMS, also known as Wallenberg syndrome, is a vascular syndrome occurring in the posterior circulation of the brainstem. Although the precise pathogenesis of LMS secondary to SBO is unknown, it likely results from direct extension of SBO, with thrombophlebitis causing vascular occlusion and lateral medullary infarct, rather than a thromboembolic event, as is usually seen in LMS (7). Our patient had neurological symptoms before the diagnosis of SBO. He required prolonged antibiotic therapy for SBO but eventually experienced fatal LMS. We assumed that vascular occlusion from thrombophlebitis had already occurred when the skull base became inflamed. Therefore, the early diagnosis and treatment are important to decrease the mortality and morbidity of these conditions.\n\nIn the present case, denosumab and sirolimus were prescribed. However, these drugs were ineffective. Some studies suggest that osteoclast progenitor cells in GSD patients may be more sensitive to osteoclast-inducing factors and receptor activator of nuclear factor κ-B ligand (RANKL) than control cells (9). The inhibition of RANKL with denosumab might be useful in these patients; however, there are no reports of denosumab treatment for GSD. Recently, several studies have reported the efficacy of sirolimus, a mammalian target of rapamycin inhibitor, against complex vascular anomalies (5,10). Adams et al. reported the efficacy of sirolimus for complex vascular anomalies in a phase 2 clinical trial. In that trial, all three GSD patients had a partial response at the end of a six-month course. However, the case number is small at present, so further studies are needed to elucidate the efficacy of sirolimus for GSD. In the present case, these drugs were unable to prevent the progression of osteolysis. Sirolimus acts as an anti-angiogenic drug; however, the drug does not inhibit osteolysis or cause new bone formation. Therefore, it is difficult to control the progression of osteolysis once fatal lesions arise. Aggressive GSD, as in the present case, should be treated in the early stages of the disease. It is currently difficult to detect aggressive GSD at an early stage and therefore difficult to administer treatment early in the course of the disease. Several studies have examined whether lymphangiogenic and osteoclastogenic factors can serve as biomarkers of activity of GSD. These studies have shown that VEGF-A and IL-6 concentrations can be high in patients with active GSD and that their concentrations can fall following treatment with various therapies (1). Thus, these biomarkers may enable the early diagnosis of aggressive GSD.\n\nTo our knowledge, this is the first case report of GSD in a patient with SBO and LMS. Osteolysis of the skull base and maxillofacial region are alarming GSD lesions. Careful follow-up with special emphasis on the early detection of intracranial complications is critical.\n\n\nThe authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional guidelines on human experimentation (Akifumi Nozawa, Michio Ozeki, Tomohiro Hori, Hiroki Kato, Naoyuki Ohe, Toshiyuki Fukao) and with the Helsinki Declaration of 1975, as revised in 2008.\n\n\nThe patient has consented to the submission of the case report for submission to the journal.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinancial Support\nThe present study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (25461587); a Health and Labour Science Research Grant for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan received by M.O.; and Practical Research Project for Rare/Intractable Diseases from Japan’s Agency for Medical Research and Development, AMED (17lk0201055h0002).\n\nAcknowledgments\nThe authors thank Drs. Norio Kawamoto, Takeshi Kimura, Kaori Kanda, Shiho Yasue, and Yoriko Matsuzawa from Gifu University, and Dr. Masataka Takahashi from the University of Tokyo Hospital.\n==== Refs\n1. \nDellinger MT , Garg N , Olsen BR \nViewpoints on vessels and vanishing bones in Gorham-Stout disease . Bone \n63 : 47 -52 , 2014 .24583233 \n2. \nPerschbacher S , Perschbacher K , Pharoah M , Bradley G , Lee L , Yu E \nGorham's disease of the maxilla: a case report . Dentomaxillofac Radiol \n39 : 119 -123 , 2010 .20100925 \n3. \nKim MK , Hong JR , Kim SG , Lee SK \nFatal progression of Gorham disease: a case report and review of the literature . J Oral Maxillofac Surg \n73 : 2352 -2360 , 2015 .26169484 \n4. \nLee S , Finn L , Sze RW , Perkins JA , Sie KC \nGorham Stout syndrome (disappearing bone disease): two additional case reports and a review of the literature . Arch Otolaryngol Head Neck Surg \n129 : 1340 -1343 , 2003 .14676163 \n5. \nAdams DM , Trenor CC 3rd, Hammill AM , et al \nEfficacy and safety of sirolimus in the treatment of complicated vascular anomalies . Pediatrics \n137 : e20153257 , 2016 .26783326 \n6. \nChandler JR , Grobman L , Quencer R , Serafini A \nOsteomyelitis of the base of the skull . Laryngoscope \n96 : 245 -251 , 1986 .3485233 \n7. \nNg J , Connolly DJ , Rittey CD , Mordekar SR \nSkull base osteomyelitis leading to lateral medullary syndrome in a child . Eur J Paediatr Neurol \n11 : 111 -114 , 2007 .17258480 \n8. \nGrobman LR , Ganz W , Casiano R , Goldberg S \nAtypical osteomyelitis of the skull base . Laryngoscope \n99 : 671 -676 , 1986 .\n9. \nHirayama T , Sabokbar A , Itonaga I , Watt-Smith S , Athanasou NA \nCellular and humoral mechanisms of osteoclast formation and bone resorption in Gorham-Stout disease . J Pathol \n195 : 624 -630 , 2001 .11745700 \n10. \nNozawa A , Ozeki M , Kuze B , Asano T , Matsuoka K , Fukao T \nGorham-Stout disease of the skull base with hearing loss: dramatic recovery and antiangiogenic therapy . Pediatr Blood Cancer \n63 : 931 -934 , 2016 .26713883\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(13)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Wallenberg syndrome; denosumab; lateral medullary syndrome; sirolimus; sphenoiditis",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D001862:Bone Resorption; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D014854:Lateral Medullary Syndrome; D008297:Male; D010015:Osteolysis, Essential; D010019:Osteomyelitis; D019291:Skull Base",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1929-1933",
"pmc": null,
"pmid": "30799352",
"pubdate": "2019-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11745700;14676163;17258480;20100925;24583233;2501603;26169484;26713883;26783326;3485233",
"title": "Fatal Progression of Gorham-Stout Disease with Skull Base Osteomyelitis and Lateral Medullary Syndrome.",
"title_normalized": "fatal progression of gorham stout disease with skull base osteomyelitis and lateral medullary syndrome"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2019037266",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Thrombocytopenia is a life-threatening condition, the severity of which is exacerbated further if the patient requires anticoagulation and is refractory to platelet transfusion. This is the first report of an infant undergoing extracorporeal support with immune-mediated platelet refractoriness. A 19-month-old girl, with a complex cardiac history, required extracorporeal support because of deterioration 8 days post-cardiac surgery. The child suffered from ongoing thrombocytopenia, unresponsive to multiple platelet transfusions. An incremental rise in the platelet count was achieved following transfusion of human leukocyte antigen-matched platelets, although this was unsuccessful with subsequent transfusions of matched platelets. Following 7 days on extracorporeal membrane oxygenation (ECMO), without cardiac improvement and likely poor prognosis, treatment was withdrawn and the patient died. The management of immune-mediated platelet refractoriness, in an anticoagulated patient on ECMO, requires early diagnosis and timely intervention to achieve a good outcome for the child. An understanding of the condition and a multidisciplinary approach to its treatment will assist in effective direction of medical therapy.",
"affiliations": "The Heart Centre for Children, The Sydney Children's Hospitals Network, Sydney, Australia.",
"authors": "Gill|Martin|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1058",
"issue": "51(2)",
"journal": "The journal of extra-corporeal technology",
"keywords": "ECMO; pediatric; platelet refractoriness; transfusion",
"medline_ta": "J Extra Corpor Technol",
"mesh_terms": "D001777:Blood Coagulation; D001803:Blood Transfusion; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D007223:Infant; D010976:Platelet Count; D017713:Platelet Transfusion; D013921:Thrombocytopenia",
"nlm_unique_id": "0267637",
"other_id": null,
"pages": "83-87",
"pmc": null,
"pmid": "31239581",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "10782501;11155742;18510692;24816643;25393955;25444534;9417523",
"title": "Platelet Refractoriness in a Pediatric ECMO Patient: A Case Report.",
"title_normalized": "platelet refractoriness in a pediatric ecmo patient a case report"
} | [
{
"companynumb": "AU-BEH-2020111397",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Hereditary transthyretin amyloidosis (hATTR amyloidosis) is a multisystemic disease usually presenting in a mixed neurological and cardiological phenotype. We present a case of hATTR amyloidosis associated with Leu55Arg mutation causing a form of familial oculo-leptomeningeal amyloidosis. Two brothers and their mother presented with severe autonomic neuropathy, loss of visual acuity and lepto-meningeal involvement. One patient suffered subarachnoid hemorrhage as a possible complication of cerebral involvement. The patients suffered from treatment-refractory weight loss and recurring vitreous opacities. RNA interference-based treatment has led to stabilization of autonomic and peripheral neuropathy but has had no effect on ocular symptoms.",
"affiliations": "Amyloidosis Center Charité Berlin (ACCB), Charité-Universitätsmedizin Berlininstitution>, Charitéplatz 1, Berlin, Germany.;Amyloidosis Center Charité Berlin (ACCB), Charité-Universitätsmedizin Berlininstitution>, Charitéplatz 1, Berlin, Germany.;Amyloidosis Center Charité Berlin (ACCB), Charité-Universitätsmedizin Berlininstitution>, Charitéplatz 1, Berlin, Germany.;Amyloidosis Center Charité Berlin (ACCB), Charité-Universitätsmedizin Berlininstitution>, Charitéplatz 1, Berlin, Germany.;Amyloidosis Center Charité Berlin (ACCB), Charité-Universitätsmedizin Berlininstitution>, Charitéplatz 1, Berlin, Germany.;Amyloidosis Center Charité Berlin (ACCB), Charité-Universitätsmedizin Berlininstitution>, Charitéplatz 1, Berlin, Germany.;Amyloidosis Center Charité Berlin (ACCB), Charité-Universitätsmedizin Berlininstitution>, Charitéplatz 1, Berlin, Germany.;Amyloidosis Center Charité Berlin (ACCB), Charité-Universitätsmedizin Berlininstitution>, Charitéplatz 1, Berlin, Germany.",
"authors": "Kleefeld|Felix|F|;Knebel|Fabian|F|;Eurich|Dennis|D|;Schatka|Imke|I|;Blüthner|Elisabeth|E|;Schönfeld|Shideh|S|;Amthauer|Holger|H|;Hahn|Katrin|K|",
"chemical_list": "D011228:Prealbumin; C000630214:TTR protein, human",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/JND-200542",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "7(4)",
"journal": "Journal of neuromuscular diseases",
"keywords": "FAP; Transthyretin amyloidosis; hATTR; polyneuropathy",
"medline_ta": "J Neuromuscul Dis",
"mesh_terms": "D000328:Adult; D028227:Amyloid Neuropathies, Familial; D001342:Autonomic Nervous System Diseases; D005260:Female; D006801:Humans; D008297:Male; D008578:Meninges; D010523:Peripheral Nervous System Diseases; D011228:Prealbumin; D013345:Subarachnoid Hemorrhage; D014786:Vision Disorders",
"nlm_unique_id": "101649948",
"other_id": null,
"pages": "515-519",
"pmc": null,
"pmid": "32741838",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Familial Oculo-Leptomeningeal Transthyretin Amyloidosis Caused by Leu55Arg Mutation.",
"title_normalized": "familial oculo leptomeningeal transthyretin amyloidosis caused by leu55arg mutation"
} | [
{
"companynumb": "DE-PFIZER INC-2020372056",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SILDENAFIL CITRATE"
},
"drugadditional": "3",
... |
{
"abstract": "Cerebral edema peaks 36-72 h after moderate traumatic brain injury but thought to be uncommon after mild traumatic brain injury. Post-traumatic headache can develop 48-72 h post-injury, perhaps reflecting the developing cerebral edema. Pseudotumor cerebri can result from various causes, including cerebral edema, and is characterized by increased intracranial pressure, headache, visual, and other common symptoms. Our objective was to report a phenotypically identifiable post-traumatic headache subtype.\n\n\n\nThis case series of six pediatric patients with post-traumatic pseudotumor cerebri was assessed at 48-120 h post-primary injury with new or a change in symptoms such as headache, vision, auditory, balance, and cognition. Clinical findings included slight fever, neck/head pain, papilledema or cranial nerve deficit (6th), and lack of coordination. Elevated cerebral spinal fluid pressure was documented by lumbar puncture, with no infection. Symptoms improved with treatment specific to post-traumatic headache subtype (lumbar puncture, topiramate, or acetazolamide).\n\n\n\nRecognition of specific post-traumatic headache subtypes after mild traumatic brain injury will expedite treatment intervention to lower intracranial pressure and resolve symptoms.",
"affiliations": "Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9063, USA. tonia.sabo@utsouthwestern.edu.;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, USA. charlene.supnet@utsouthwestern.edu.;Department of Applied Physiology and Wellness, Southern Methodist University, 3101 University Boulevard, Dallas, TX, USA. spurkayastha@smu.edu.",
"authors": "Sabo|Tonia|T|;Supnet|Charlene|C|;Purkayastha|Sushmita|S|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-017-3681-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "34(4)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": "Acetazolamide; Concussion; Idiopathic intracranial hypertension; Intracranial pressure; Post-traumatic headache; Pseudotumor cerebri",
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D000293:Adolescent; D000070642:Brain Injuries, Traumatic; D002648:Child; D005260:Female; D006801:Humans; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008297:Male; D009460:Neurologic Examination; D051298:Post-Traumatic Headache; D011559:Pseudotumor Cerebri",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "681-690",
"pmc": null,
"pmid": "29230542",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Secondary intracranial hypertension (pseudotumor cerebri) presenting as post-traumatic headache in mild traumatic brain injury: a case series.",
"title_normalized": "secondary intracranial hypertension pseudotumor cerebri presenting as post traumatic headache in mild traumatic brain injury a case series"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP010875",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional... |
{
"abstract": "Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder and was incorporated into the WHO classification of Tumours of the Lung, Pleura, Thymus and Heart in 2015. LYG is known to be associated with the host's immune function, and can be caused by some immunosuppressive agents, including methotrexate. A woman in her sixties with an 18-year history of methotrexate treatment for rheumatoid arthritis visited our hospital after detection of an abnormal chest shadow on her radiograph. She had been having anemia and a slight fever. Computed tomography (CT) revealed a 2.9-cm sized nodule in her left lung and hilar adenopathy, which suggested a primary lung carcinoma or an inflammatory lesion. We performed a left upper lobectomy with lymph node dissection for the purpose of diagnosis and treatment. Pathologic findings revealed that the tumor was a grade 3 LYG based on the number of EBV-positive B cells. The patient was treated with two chemotherapy regimens including R-CHOP at another hospital, and survived for four years after resection without recurrence in the lung. It is rare to find a case resected LYG, and the clinical or pathological findings of our case are expected to be extremely helpful in studying this disease and improving the understanding of this disease.",
"affiliations": "Department of Cardiovascular and Thoracic Surgery, Hokkaido University Hospital, 0608638, Sapporo, Hokkaido, Japan.;Department of Thoracic Surgery, Hakodate National Hospital, 0418512, Hakodate, Hokkaido, Japan.;Department of Pathology, Hakodate National Hospital, 0418512, Hakodate, Hokkaido, Japan.",
"authors": "Fujiwara-Kuroda|Aki|A|;Iwashiro|Nozomu|N|;Kimura|Noriko|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101327",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30541-4\n10.1016/j.rmcr.2020.101327\n101327\nCase Report\nA case of resected pulmonary lymphomatoid granulomatosis\nFujiwara-Kuroda Aki a-black@wj8.so-net.ne.jpa-black@huhp.hokudai.ac.jpab∗ Iwashiro Nozomu b Kimura Noriko c a Department of Cardiovascular and Thoracic Surgery, Hokkaido University Hospital, 0608638, Sapporo, Hokkaido, Japan\nb Department of Thoracic Surgery, Hakodate National Hospital, 0418512, Hakodate, Hokkaido, Japan\nc Department of Pathology, Hakodate National Hospital, 0418512, Hakodate, Hokkaido, Japan\n∗ Corresponding author. Department of Cardiovascular and Thoracic Surgery, Hokkaido University Hospital, West-7, North-15, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. a-black@wj8.so-net.ne.jpa-black@huhp.hokudai.ac.jp\n28 12 2020 \n2021 \n28 12 2020 \n32 10132714 10 2020 25 11 2020 23 12 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder and was incorporated into the WHO classification of Tumours of the Lung, Pleura, Thymus and Heart in 2015. LYG is known to be associated with the host's immune function, and can be caused by some immunosuppressive agents, including methotrexate. A woman in her sixties with an 18-year history of methotrexate treatment for rheumatoid arthritis visited our hospital after detection of an abnormal chest shadow on her radiograph. She had been having anemia and a slight fever. Computed tomography (CT) revealed a 2.9-cm sized nodule in her left lung and hilar adenopathy, which suggested a primary lung carcinoma or an inflammatory lesion. We performed a left upper lobectomy with lymph node dissection for the purpose of diagnosis and treatment. Pathologic findings revealed that the tumor was a grade 3 LYG based on the number of EBV-positive B cells. The patient was treated with two chemotherapy regimens including R–CHOP at another hospital, and survived for four years after resection without recurrence in the lung. It is rare to find a case resected LYG, and the clinical or pathological findings of our case are expected to be extremely helpful in studying this disease and improving the understanding of this disease.\n\nKeywords\nLymphomatoid granulomatosisMethotrexateMethotrexate-associated lymphoproliferative disorders (MTX-LPD)LungEBV-Positive diffuse larger B-Cell lymphomaVideo-assisted thoracic surgery\n==== Body\n1 Introduction\nLymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disorder driven by the Epstein-Barr virus (EBV) and often develops as a methotrexate-associated lymphoproliferative disorder. LYG involves extra-nodal sites including the lungs, skin, central nervous system, liver, and kidneys. When it affects a single lung nodule, it could be difficult to distinguish from other lung nodules, including primary lung carcinoma or other granulomatous lesions in the lung on imaging. We should carefully survey patients’ symptoms or prescription history to make an accurate diagnosis of LYG.\n\n2 Case presentation\nA woman in her sixties, found out to have anemia, was referred to our hospital. She had been suffering from rheumatoid arthritis for 18 years and was on methotrexate prescribed by her doctor. No source of bleeding was identified by endoscopic examination. On a chest radiograph taken a month after her first visit, an abnormal shadow in her left lung was noted. She revisited our hospital and was admitted in the department of respiratory medicine for a detailed examination. On admission, she had a slight fever of 37 °C and complained of drenching night sweats. Physical examination revealed the following: body temperature, 36.3 °C (37.6 °C at night); heart rate, 85 beats per minute; blood pressure, 142/96 mmHg; and no rale, was noted. She had never smoked. Laboratory data included: RBC, 4.40 × 106/μL; hemoglobin, 11.3 g/dL; lactate dehydrogenase (LDH) (reference value), 251 (120–240) IU/L; C-reactive protein, 3.51 g/dL; soluble interleukin-2 (IL-2) receptor (reference value), 1320 (145–516) U/mL. Her chest X-ray and computed tomography (CT) showed a solid 2.9 × 2.7-cm sized nodule in the middle of her left upper lobe (Fig. 1). The tumor size increased within a few months. Ipsilateral hilar adenopathy was also seen. We performed bronchoscopy with both exfoliative and lavage cytology, and neither of them indicated malignant findings, lung carcinoma or other malignancies were suggested based on these imaging findings. Although it may not have been malignant, some inflammatory diseases such as mycosis or granuloma could have caused her symptoms. Given the appearance, we made a decision to perform surgery with excision on her lung and performed left upper lobectomy with lymph node dissection for the purposes of diagnosis and treatment. The resected specimen was an irregular, solid, white nodule with extensive yellow necrotic areas in the middle of the lobe (Fig. 2). Histopathological examination showed marked obstruction of vessels with extensive fibrosis around vessels. Severe angiocentric and angiodestructive infiltration of lymphocytes including reactive T-cells were also seen. There were variable numbers of larger atypical cells with large nucleoli, similar to Hodgkin cells, and some multi-nucleated giant cells around the fibrosis (Fig. 3). Immunohistochemical findings showed that the Hodgkin-like cells were positive for CD30, and also for LMP1, a marker for EBV. EBV was also confirmed by in situ hybridization (Fig. 4). Other immunohistochemical staining showed that the atypical cells were positive for CD20 and CD79a focally and negative for EML4-ALK fusion protein. The tumor was diagnosed as grade 3 lymphomatoid granulomatosis. Two of the 55 lymph nodes, one in subaortic (#5) and the other in lober (#12) lymph node, also had the same lesion with extensive necrosis and eosinophilic infiltration. Even after surgery, she had been suffering from a slight fever, loss of appetite, weight loss, and pleural/peritoneal effusion. An increase in the soluble IL-2 receptor level of 1320 U/mL was also seen. She was transferred to the hematology department of another hospital to receive chemotherapy treatment. She was administered two courses of R–CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) therapy; however, she abandoned it because of a poor response seen on the swollen lymph nodes throughout the body and soluble IL-2 receptor level, and myelosuppression caused by the agents. Alternatively, she received 20 courses of molecular-target therapy with brentuximab vedotin, an antibody-drug targeting CD30-positive Hodgkin lymphoma and systemic anaplastic large cell lymphoma, although it was not approved as a treatment of DLBCL. She has been carefully followed up at the hospital, and no recurrence in the lung has been noticed four years after the resection.Fig. 1 Chest radiography (A) and CT (B) images revealing a solid mass with the tendency to increase in the left upper lobe. The enlarged hilar lymph node is also seen.\n\nFig. 1Fig. 2 Partly lobulated white nodule observed in the resected lobe.\n\nFig. 2Fig. 3 Histopathological examination revealing central necrosis (A), a proliferation of spindle-shaped cells (B), angiocentric and angiodestructive lymphoid infiltration (C), atypical cells with an irregular nucleus, and multinucleated giant cells (D).\n\nFig. 3Fig. 4 Atypical cells positive for LMP1, a marker for EBV (A). More than fifty cells are positive for EBV, as assessed by in situ hybridization, per high-power field (B).\n\nFig. 4\n\n3 Discussion\nMethotrexate-associated lymphoproliferative disorder (MTX-LPD) is an iatrogenic immunodeficiency that mainly occurs in patients with RA who are treated with long-term methotrexate therapy [1,2]. MTX-LPD was initially reported by Ellman in 1991 [3], was increasingly reported as MTX became a common therapy for RA, and has been listed as one of the serious complications in the MTX treatment guidelines in Japan. The LPD incidence ratio of RA patients is two to four fold in the control healthy population irrespective of MTX treatment [4]. MTX-LPD is categorized as other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) according to the 2008 and WHO classification [5]. The pathological features of MTX-LPD vary; diffuse large B-cell lymphoma (DLBCL) type is most predominant (35–60%) followed by Hodgkin lymphoma (HL) type (12–25%) [4]. The positive rate for EBV is about 40%, especially high (70%) in HL type [4]. Making a diagnosis of MTX-LPD only by its histological findings is supposed to be extremely difficult considering that there are various histological types of this disease. Unlike other lymphoproliferative disorders, MTX-LPD often involves extra-nodal organs, including the lung, skin, pharynx/tonsil, and soft tissues. Approximately 40–70% of patients with MTX-LPD regress after MTX withdrawal [1], so the first step is the withdrawal of MTX [5]. Meanwhile, relapse/regrowth events (RRE) after regression are seen in some cases of MTX-LPD. Tokuhira et al. reported that MTX-LPD presents three patterns after methotrexate withdrawal to clarify the clinical management of MTX-LPD [5]. A regressive group (R-G) includes patients with LPD regression after immunosuppressive drugs (ISDs) withdrawal without RRE, a relapse/regrowth group (R/R-G) includes patients with LPD regression after ISD withdrawal with RRE, and a persistent group (P-G) includes patients with persistent LPD after ISD withdrawal. Patients in R/R-G and P-G require additional chemotherapy. They also reported that the serum C-reactive protein (CRP), serum soluble IL-2 receptor, and LDH were increased in the P-G group, whereas only CRP and soluble IL-2 receptor were increased in the R/R-G group. In our case, not only swollen lymph nodes but also the level of soluble IL-2 receptor did not regress after MTX withdrawal. This indicates that the patient belongs to the P-G group and requires chemotherapy based on diffuse large B-cell lymphoma (DLBCL), which is the commonest type of MTX-LPD [11].\n\nLymphomatoid granulomatosis (LYG) is an Epstein-Barr virus-driven lymphoproliferative disorder [6] that has unique histopathologic and clinical features [7]. LYG was initially incorporated into the World Health Organization classification of Tumours of Haematopoietic and Lymphoid Tissues in 2001 [8] and has been categorized as a distinct mature B-cell neoplasm in the revised version in 2016 [9]. LYG, characterized by angiocentric and angiodestructive features, typically affects middle-aged adults in the fourth to sixth decades of life, commonly involves the lungs (70%) and involves multiple organs, including the central nervous system (40%), skin (34%), kidney (19%), liver (17%), spleen (10%), lymph nodes (6%), and others (19%) [7,10]. The most common radiographic feature of the lung lesion of LYG is multiple nodules, occurring in approximately 80% of all cases [11,12]. Single lung nodules rarely appear in LYG patients and are used to discriminate other diseases, such as lung cancer, primary pulmonary lymphoma, and other granulomatous lung lesions such as sarcoidosis, tuberculous or non-tuberculous mycobacterial infection, and mycosis.\n\nIn our case of MTX-induced LYG, the patient had a history of long-term MTX therapy, and a growing single lung nodule and hilar lymph node were observed on preoperative CT findings. She was initially suspected to have lung cancer. Her clinical findings with slight fever or the history of methotrexate intake could help establish an accurate diagnosis of the disease. The postoperative CT findings showed multiple swollen lymph nodes. Furthermore, pathological findings also showed obvious infiltration of tumor cells in the hilar/mediastinal lymph nodes. These features were also typical for MTX-induced LYG.\n\nThe chemotherapeutic regimen for LYG, including MTX-LPG/MTX-DLBCL, has not been standardized as it is a rare disease. Chaves et al. reported that approximately three-quarters of patients with LYG (grade 3 in 45%) treated with rituximab-based therapies, mainly R–CHOP achieved a response [13]. Another study reported that the overall response rate in patients to combination chemotherapy with DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in patients with high-grade LYG was 77% with 41% complete response [2,14]. In our case, the main lung lesion and hilar/mediastinal lymph nodes were removed at the time of surgery; however, serum soluble IL-2 receptor did not respond to R–CHOP therapy. The patient consequently required another chemotherapy regimen and had survived without recurrence.\n\nIn conclusion, LYG is not a common disease to thoracic surgeons, but we should consider it as a differential diagnosis in patients with a single lung nodule or multiple lung nodules and a prescription history of immunosuppressive agents, including methotrexate. The clinical and pathological findings of our case are expected to help acquire an easier diagnosis and a deeper understanding of LYG as one of MTX-LPD.\n\nDeclaration of competing interest\nAll authors declare no potential conflict of interest.\n==== Refs\nReferences\n1 Ikeue T. Kawachi H. Yoshida H. Tanaka E. Noguchi S. Fukao A. Endobronchial manifestation of methotrexate-induced lymphoproliferative disorder Intern. Med. 58 2019 1597 1603 10.2169/internalmedicine.2109-18 30713318 \n2 Katzenstein A.L. Doxtader E. Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades Am. J. Surg. Pathol. 34 2019 435 10.1097/PAS.0b013e3181fd8781 e48 \n3 Ellman M.H. Hurwits H. Thoma C. Kozloff M. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate J. Rheumatol. 18 1991 1741 1743 1787499 \n4 Sumi T. Methotrexate-associated lymphoproliferative disorders Nihon Jibiinkoka Gakkai Kaiho 116 2013 734 735 10.3950/jibiinkoka.116.734 24024271 \n5 Tokuhira M. Tamaru J. Kizaki M. Clinical management for other iatrogenic immunodeficiency-associated lymphoproliferative disorders J. Clin. Exp. Hematop. 59 2019 72 92 10.3960/jslrt.19007 31257348 \n6 Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri A.S. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues fourth ed. 2008 \n7 Melani C. Jaffe E.S. Wilson W.H. Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder Blood 135 2020 1344 1352 10.1182/blood.2019000933 32107539 \n8 Jaffe E.S. Harris N. Stein H. Vardiman J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2001 IARC Press Lyon 185 187 \n9 Swerdlow S.H. Campo E. Pileri S.A. The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 127 2016 2375 2390 10.1182/blood-2016-01-643569 26980727 \n10 Katzenstein A.L. Carrington C.B. Liebow A.A. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases Cancer 43 1979 360 373 10.1002/1097-0142 (197901)43:1<360::aid-cncr2820430151>3.0.co;2-8 761171 \n11 Dee P.M. Arora N.S. Inners D.J. Jr. The pulmonary manifestations of lymphomatoid lymphomatoid granulomatosis Radiology 143 1982 613 618 10.1148/radiology.143.3.7079490 7079490 \n12 Hare S.S. Souza C.A. Bain G. Seely J.M. Gomes M.M. Quigley M. The radiological spectrum of pulmonary lymphoproliferative disease Br. J. Radiol. 85 2012 848 864 10.1259/bjr/16420165 22745203 \n13 Chaves J.C. Sandoval-Sus J. Horna P. Dalia S. Bello C. Chevernick P. Sotomayor E.M. Sokol L. Shah B. Lymphomatoid granulomatosis: a single institution experience and review of the literature Clin. Lymphoma, Myeloma & Leukemia 16 suppl 2016 S170 S174 10.1016/j-clml.2016.02.024 \n14 Melani C. Roschewski M. Pittaluga S. Cohen J. Lucas A.N. Steinberg S.M. Jaffe E.S. Wilson W.H. Phase II study of interferon-alpha and DA-EPOCH +/-R in lymphomatoid granulomatosis [Abstract] Blood 132 suppl 1 2018 785 10.1182/blood-2018-00-116707\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "32()",
"journal": "Respiratory medicine case reports",
"keywords": "EBV-Positive diffuse larger B-Cell lymphoma; Lung; Lymphomatoid granulomatosis; Methotrexate; Methotrexate-associated lymphoproliferative disorders (MTX-LPD); Video-assisted thoracic surgery",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101327",
"pmc": null,
"pmid": "33437613",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "7079490;30713318;22745203;21107080;24024271;32107539;31257348;1787499;27521314;26980727;761171",
"title": "A case of resected pulmonary lymphomatoid granulomatosis.",
"title_normalized": "a case of resected pulmonary lymphomatoid granulomatosis"
} | [
{
"companynumb": "JP-STRIDES ARCOLAB LIMITED-2021SP006001",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BRENTUXIMAB VEDOTIN"
},
"druga... |
{
"abstract": "BACKGROUND\nPercutaneous left atrial appendage closure (LAAC) and the role of postinterventional anticoagulation often evokes controversy in daily practice. This study aimed to evaluate LAAC in patients with non-rheumatic atrial fibrillation, high thromboembolic risk and contraindications for long-term anticoagulation in a clinical scenario.\n\n\nMETHODS\nBetween 2010-2015, LAAC was attempted in 118 patients (47 women).\n\n\nRESULTS\nDevices were successfully implanted in 95% (Watchman™ device: N.=97; Amplatzer™ Cardiac Plug/Amulet: N.=14; Amplatzer PFO Occluder: N.=1). Mean age was 75±8.35 years. Mean HAS-BLED and CHA2DS2VASc scores were 4.3 and 4.9, respectively. Median follow-up was 447 days (IQR: 183-789 days). The primary safety endpoint was defined as major bleeding according to the International Society on Thrombosis and Hemostasis. The combined efficacy endpoint included ischemic strokes, transitory ischemic attacks (TIA) and systemic embolisms. Procedural complication rate was 3.4%. After successful intervention, either a therapy with anticoagulants (N.=62) or dual antiplatelet therapy (DAPT, N.=50) was prescribed temporarily. Medication was reduced if implantation proved satisfying in a 6-week follow-up transesophageal echocardiography, which was the case in 79% of these patients. During follow-up, one patient suffered a TIA (0.6%/year). No other efficacy event was observed. Eleven major bleedings occurred (6.6%/year): one each under DAPT plus phenprocoumon, DAPT plus rivaroxaban, acetylsalicylic acid (ASA) plus rivaroxaban, two under DAPT, two under ASA plus low molecular weight heparin, and four under ASA only.\n\n\nCONCLUSIONS\nIn the present study, catheter-based LAA occlusion prevented thromboembolisms with high efficacy. Major bleedings were however common in patients with, but also without anticoagulation, independent from time course.",
"affiliations": "Department of Cardiology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany - adrian.seidel@charite.de.;Department of Cardiology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany.;Department of Cardiology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany.;Department of Cardiology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany.;Department of Cardiology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany.;Department of Cardiology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany.;Department of Cardiology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany.;Department of Cardiology, Campus Virchow-Klinikum, Charité University of Medicine, Berlin, Germany.",
"authors": "Seidel|Adrian|A|;Parwani|Abdul S|AS|;Krackhardt|Florian|F|;Huemer|Martin|M|;Attanasio|Philipp|P|;Haverkamp|Wilhelm|W|;Pieske|Burkert|B|;Boldt|Leif-Hendrik|LH|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "Italy",
"delete": false,
"doi": "10.23736/S0026-4725.17.04425-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-4725",
"issue": "65(6)",
"journal": "Minerva cardioangiologica",
"keywords": null,
"medline_ta": "Minerva Cardioangiol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D020517:Atrial Appendage; D001281:Atrial Fibrillation; D006328:Cardiac Catheterization; D000075202:Contraindications; D004359:Drug Therapy, Combination; D017548:Echocardiography, Transesophageal; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D055989:Septal Occluder Device; D020521:Stroke; D013923:Thromboembolism; D016896:Treatment Outcome",
"nlm_unique_id": "0400725",
"other_id": null,
"pages": "545-552",
"pmc": null,
"pmid": "28565887",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and efficacy of catheter-based left atrial appendage closure in patients with contraindications for long-term anticoagulation.",
"title_normalized": "safety and efficacy of catheter based left atrial appendage closure in patients with contraindications for long term anticoagulation"
} | [
{
"companynumb": "DE-BAYER-2018-034963",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "This study examined the uses of diverted methadone and buprenorphine among opiate-addicted individuals recruited from new admissions to methadone programs and from out-of-treatment individuals recruited from the streets. Self-report data regarding diversion were obtained from surveys and semi-structured qualitative interviews. Approximately 16% (n = 84) of the total sample (N = 515) reported using diverted (street) methadone two-three times per week for six months or more, and for an average of 7.8 days (SD = 10.3) within the past month. The group reporting lifetime use of diverted methadone as compared to the group that did not report such use was less likely to use heroin and cocaine in the 30 days prior to admission (ps <.01) and had lower ASI Drug Composite scores (p <.05). Participants in our qualitative sub-sample (n = 22) indicated that street methadone was more widely used than street buprenorphine and that both drugs were largely used as self-medication for detoxification and withdrawal symptoms. Participants reported using low dosages and no injection of either medication was reported.",
"affiliations": "Friends Research Institute, Inc., Social Research Center, 1040 Park Avenue, Suite 103, Baltimore, MD 21201, USA. sgmitchell@friendssocialresearch.org",
"authors": "Gwin Mitchell|Shannon|S|;Kelly|Sharon M|SM|;Brown|Barry S|BS|;Schacht Reisinger|Heather|H|;Peterson|James A|JA|;Ruhf|Adrienne|A|;Agar|Michael H|MH|;O'Grady|Kevin E|KE|;Schwartz|Robert P|RP|",
"chemical_list": "D013287:Illicit Drugs; D002047:Buprenorphine; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.3109/10550490903077820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1055-0496",
"issue": "18(5)",
"journal": "The American journal on addictions",
"keywords": null,
"medline_ta": "Am J Addict",
"mesh_terms": "D000328:Adult; D015142:Baltimore; D002047:Buprenorphine; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D008396:Maryland; D008691:Methadone; D009293:Opioid-Related Disorders; D012651:Self Medication; D012720:Severity of Illness Index",
"nlm_unique_id": "9208821",
"other_id": null,
"pages": "346-55",
"pmc": null,
"pmid": "19874152",
"pubdate": "2009",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "16869033;16389204;18479840;1115569;18799767;6619823;1578593;18161640;15679749;2265296;18612886;18428077;11343531;17506154;18679031;11064485;7485676;18584580;19999682;7351540;11147165;10334372;12653811;18770082;17305688;12609698;18559110;12189001;2491420;12738346;16793221;17913395;2265282;15204673;5009264;18552728;3833809;11058673;10795360;18018814;4009158;1737971;12388653;12555905",
"title": "Uses of diverted methadone and buprenorphine by opioid-addicted individuals in Baltimore, Maryland.",
"title_normalized": "uses of diverted methadone and buprenorphine by opioid addicted individuals in baltimore maryland"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-06301",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "The monitoring of Human Herpesvirus 6 (HHV-6) after allogeneic stem cell transplantation has proven to be useful in preventing life-threatening complications; however, the pathogenic role of HHV-6 after autologous transplantation is not well-characterized, although viral reactivation might be responsible for significant complications even after this type of transplant. Here we report, for the first time to our knowledge, the case of a patient with chromosomally integrated HHV-6 (ciHHV-6), presenting with high titers of HHV-6 DNA copies after autologous transplantation, mimicking HHV-6 reactivation. The presence of viral DNA in the follicle bulb confirmed the ciHHV-6 and allowed for the discontinuation of the antiviral treatment. Due to the increasing awareness of HHV-6 potential pathogenicity and the fact that ciHHV-6 is expected in 1-2% of the population, such a case might be helpful in recognizing ci HHV-6, thus avoiding unnecessary and potentially toxic antiviral therapy once the viral genomic integration is confirmed.",
"affiliations": "Molecular Biology Section, Clinical Investigation Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Molecular Biology Section, Clinical Investigation Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Infectious Disease Unit, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.;Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy.",
"authors": "Mineri|Rossana|R|;Mariotti|Jacopo|J|;Sarina|Barbara|B|;Morabito|Lucio|L|;Crocchiolo|Roberto|R|;Bramanti|Stefania|S|;Sarno|Tiziana|T|;Tordato|Federica|F|;Carlo-Stella|Carmelo|C|;Santoro|Armando|A|;Castagna|Luca|L|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4084/MJHID.2018.013",
"fulltext": "\n==== Front\nMediterr J Hematol Infect DisMediterr J Hematol Infect DisMediterranean Journal of Hematology and Infectious DiseasesMediterranean Journal of Hematology and Infectious Diseases2035-3006Università Cattolica del Sacro Cuore 10.4084/MJHID.2018.013mjhid-10-1-e2018013Case ReportGenomic Integration of HHV-6 Mimicking Viral Reactivation after Autologous Stem Cell Transplantation Mineri Rossana 1Mariotti Jacopo 2Sarina Barbara 2Morabito Lucio 2Crocchiolo Roberto 2Bramanti Stefania 2Sarno Tiziana 1Tordato Federica 3Carlo-Stella Carmelo 2Santoro Armando 24Castagna Luca 2\n1 Molecular Biology Section, Clinical Investigation Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy\n2 Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy\n3 Infectious Disease Unit, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano 20089, Italy\n4 Humanitas University, Via Alessandro Manzoni 113, 20089 Rozzano (Mi), ItalyCorrespondence to: Rossana Mineri, PhD. Molecular Biology Section, Clinical Investigation Laboratory, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Italy. Tel. 0039 02 28844748. E-mail: rossana.mineri@humanitas.it2018 15 2 2018 10 1 e201801303 10 2017 31 1 2018 2018This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The monitoring of Human Herpesvirus 6 (HHV-6) after allogeneic stem cell transplantation has proven to be useful in preventing life-threatening complications; however, the pathogenic role of HHV-6 after autologous transplantation is not well-characterized, although viral reactivation might be responsible for significant complications even after this type of transplant. Here we report, for the first time to our knowledge, the case of a patient with chromosomally integrated HHV-6 (ciHHV-6), presenting with high titers of HHV-6 DNA copies after autologous transplantation, mimicking HHV-6 reactivation. The presence of viral DNA in the follicle bulb confirmed the ciHHV-6 and allowed for the discontinuation of the antiviral treatment. Due to the increasing awareness of HHV-6 potential pathogenicity and the fact that ciHHV-6 is expected in 1–2% of the population, such a case might be helpful in recognizing ci HHV-6, thus avoiding unnecessary and potentially toxic antiviral therapy once the viral genomic integration is confirmed.\n\nBone marrow transplantationInfectious diseaseHHV-6 integration\n==== Body\nIntroduction\nHuman herpesvirus 6 (HHV-6) reactivation may be responsible for severe side effects after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with early post-transplant mortality.1–3 HHV-6 reactivation is typically detected 2 to 4 weeks after allo-HSCT and is associated with hepatitis, pneumonitis, CMV reactivation, fever, skin rash, myelosuppression, encephalitis, acute graft-versus-host disease; therefore, its regular monitoring is recommended after those allo-HSCTs with a higher risk of reactivation, such as cord blood or haploidentical HSCT.4–5 At our center, the control of HHV-6 is routinely performed after cord or haploidentical HSCT, whereas for all the other transplant settings (i.e., allo-HSCT from HLA-identical donor, or autologous stem cell transplantation, ASCT) the search for HHV-6 is made only in the presence of clinical conditions evoking a potential role of the virus, such as prolonged aplasia or cutaneous rash6. Recently, it has been discovered that 1% to 2% of the population have chromosomally integrated HHV-6 (ciHHV-6), that is the presence of HHV-6 in every somatic cell leading to high copy numbers of the virus in the absence of any viral reactivation or disease.7–10\n\nMethods\nHere we present a case of a patient affected by non-Hodgkin’s lymphoma undergoing high-dose chemotherapy followed by ASCT, with ciHHV-6 (detected through CMV HHV6,7,8 R-gene®, bioMérieux) mimicking viral reactivation early after transplant.\n\nResults\nA 66-years old man was diagnosed with stage IVA diffuse large B-cell lymphoma in December 2015 following the appearance of hepatomegaly, leading to the detection of a 7-cm hepatic mass by abdominal ultrasound. Complete staging showed sub- and supradiaphragmatic nodal and extranodal disease (liver, lung), with a Revised-International Prognostic Index (R-IPI) = 4 (stage, LDH higher than the average range, age> 60 years old and extranodal disease) and an NCCN IPI=5. The patient’s history disclosed myocardial infarction 25 years before and concurrent HCV positivity. He received six cycles of full-dose R-CHOP with concomitant central nervous system prophylaxis, from April to July 2016. A new disease assessment in August 2016 showed metabolic complete remission. Due to the high-risk features at diagnosis, consolidation therapy with high-dose chemotherapy followed by ASCT had been planned, and the patient was admitted to the transplantation unit at the end of August to receive ASCT, after conditioning chemotherapy with FEAM (fotemustine, etoposide, cytarabine, melphalan) regimen.11 The aplastic phase was complicated by NCI-CTC grade 3 mucositis and Aspergillus pneumonia, classified as probable, according to EORTC criteria,12 successfully treated with voriconazole (the patient has been receiving prophylaxis with fluconazole). On day +15 after ASCT, a determination of HHV-6 viral load was made because of persistent aplasia, showing 9.7 × 10e5 copies/mL, with a total leucocytes count of 1,380 × 10e6/L. Molecular analysis by PCR was negative for CMV and EBV. Then, in the hypothesis of HHV-6 reactivation, known to have an incidence of 8–15% after ASCT,13–15 antiviral therapy with foscarnet was started, and subsequent shift to ganciclovir was realized, after hematological recovery. However, the constant increase of HHV-6 load, observed in conjunction of the augmentation of the leucocyte counts (see Figure 1), led to the alternative hypothesis of ciHHV-6, soon confirmed by the analysis of patient’s follicle bulb at the beginning of October.\n\nIndeed, it is known that ciHHV-6 corresponds to the presence of one or more HHV-6 copies per white blood cell, with high HHV-6 titers persisting over time in blood, and of virus in tissues, allowing for a diagnosis made through the analysis of follicle bulb or nails.16 Nonetheless, a confirmatory test is needed in the diagnostic process, as we did in the present case. The patient was discharged in good clinical conditions at day +28 from ASCT, and the antiviral treatment was discontinued at the moment of hospital discharge. Finally, the cause of the prolonged aplasia was not identified. Three months later the patient was healthy, and a CT scan confirmed the complete remission and a favorable evolution of the fungal infection. As expected, leukocyte, neutrophil and platelet counts were normalized, while HHV-6 blood titer was 1.14 × 10e7 copies/mL with a total leucocyte count of 6,920 × 10e6/L in early January 2017.\n\nDiscussion\nThe present clinical case shows a genomic integration of HHV-6 mimicking reactivation early after autologous stem cell transplantation. Similar cases of transmission of integrated HHV-6 were described in recipients of allogeneic transplant from HLA matched or mismatched related donors;17–18 more recently, it has been described after allogeneic, combined cord blood/haplo transplantation.19 However, to our knowledge, our case is the first described after autologous stem cell transplantation. It is known from the literature that approximately 95% of the healthy adults experienced the HHV-6 infection in childhood. After primary infection, HHV-6 persists in the host and is detectable in multiple tissues, such as salivary glands, brain cells, monocytes, and early bone marrow progenitor cells in a similar way to other herpesviruses as CMV. However, ciHHV-6 represents an alternative form of viral persistence, occurring in a subgroup of individuals and characterized by very high viral loads in the blood (>1×106 HHV-6 copies/ml), in other body fluids or tissue samples. Growing evidence suggests that the integrated viral sequences are inherited through the germline and are therefore present in every nucleated cell. This phenomenon may confound the laboratory diagnosis of active HHV-6 infection because whole blood and spinal fluid from individuals with viral integration are persistently positive for HHV-6 DNA even in the absence of independent viral replication. Therefore, ciHHV-6 must be suspected every time whole blood HHV-6 DNA is detected at high load at the time of engraftment and persists at a high level after transplant, without any adverse influence on patients outcome.\n\nAlthough the frequency of HHV-6 infection is quite different between allo-HSCT and ASCT, being higher after allo-HSCT,20 the recognition of these cases may lead to the avoidance of unnecessary and potentially toxic antiviral treatments, particularly during the delicate phase of hematological recovery in the early post-transplant period. Currently, the screening for ciHHV-6 is not recommended, but we believe that the awareness of this phenomenon after ASCT is of interest for clinicians working in the field, since over 20,000 ASCTs are reported by the European Blood and Marrow Transplantation,21 with an estimated number of 200–400 such new cases every year only in Europe.\n\nAcknowledgments\nWe thank all the personnel of the Transplant Unit in the Oncology Department, at Humanitas Cancer Center, Rozzano, Italy, for patient’s assistance, clinical care and follow-up.\n\nCompeting interests: The authors have declared that no competing interests exist.\n\nFigure 1 Whole blood HHV-6 titers and total leucocyte counts are shown here. On the X axis, the days after autologous transplant are shown.\n==== Refs\nReferences\n1 http://www.eortc.org/sites/default/files/ECIL3_CMV_HHV-6_Guidelines_Update_2009.pdf\n\n\n2 Zerr DM Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplantation J Clin Virol 2006 37 Suppl 1 S52 56 https://doi.org/10.1016/S1386-6532(06)70012-9 17276370 \n3 Dulery R Salleron J Dewilde A Rossignol J Boyle EM Gay J de Berranger E Coiteux V Jouet JP Duhamel A Yakoub-Agha I Early human herpesvirus type 6 reactivation after allogeneic stem cell transplantation: a large-scale clinical study Biol Blood Marrow Transplant 2012 18 1080 1089 https://doi.org/10.1016/j.bbmt.2011.12.579 22212513 \n4 Sashihara J Tanaka-Taya K Tanaka S Amo K Miyagawa H Hosoi G Taniguchi T Fukui T Kasuga N Aono T Sako M Hara J Yamanishi K Okada S High incidence of human herpesvirus 6 infection with a high viral load in cord blood stem cell transplant recipients Blood 2002 100 2005 2511 12200359 \n5 Tormo N Solano C de la Cámara R Garcia-Noblejas A Carde-oso L Clari MA Nieto J López J Hernández-Boluda JC Remigia MJ Benet I Navarro D An assessment of the effect of human herpesvirus-6 replication on active cytomegalovirus infection after allogeneic stem cell transplantation Biol Blood Marrow Transplant 2010 16 653 661 https://doi.org/10.1016/j.bbmt.2009.12.003 20005968 \n6 Fule Robles JD Cheuk DK Ha SY Chiang AK Chan GC Human herpesvirus types 6 and 7 infection in pediatric hematopoietic stem cell transplant recipients Ann Transplant 2014 19 269 276 https://doi.org/10.12659/AOT.889995 24881673 \n7 Tanaka-Taya K Sashihara J Kurahashi H Amo K Miyagawa H Kondo K Okada S Yamanishi K Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA J Med Virol 2004 73 465 473 https://doi.org/10.1002/jmv.20113 15170644 \n8 Daibata M Taguchi T Nemoto Y Taguchi H Miyoshi I Inheritance of chromosomally integrated human herpesvirus 6 DNA Blood 1999 94 1545 1549 10477678 \n9 Hubacek P Virgili A Ward KN Pohlreich D Keslova P Goldova B Markova M Zajac M Cinek O Nacheva EP Sedlacek P Cetkovsky P HHV-6 DNA throughout the tissues of two stem cell transplant patients with chromosomally integrated HHV-6 and fatal CMV pneumonitis Br J Haematol 2009 145 394 398 https://doi.org/10.1111/j.1365-2141.2009.07622.x 19222466 \n10 Kamble RT Clark DA Leong HN Heslop HE Brenner MK Carrum G Transmission of integrated human herpesvirus-6 in allogeneic hematopoietic stem cell transplantation Bone Marrow Transplant 2007 40 563 566 https://doi.org/10.1038/sj.bmt.1705780 17637686 \n11 Musso M Scalone R Marcacci G Lanza F Di Renzo N Cascavilla N Di Bartolomeo P Crescimanno A Perrone T Pinto A Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study Bone Marrow Transplant 2010 45 1147 1153 https://doi.org/10.1038/bmt.2009.318 19898504 \n12 De Pauw B Walsh TJ Donnelly JP Stevens DA Edwards JE Calandra T Pappas PG Maertens J Lortholary O Kauffman CA Denning DW Patterson TF Maschmeyer G Bille J Dismukes WE Herbrecht R Hope WW Kibbler CC Kullberg BJ Marr KA Mu-oz P Odds FC Perfect JR Restrepo A Ruhnke M Segal BH Sobel JD Sorrell TC Viscoli C Wingard JR Zaoutis T Bennett JE European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Clin Infect Dis 2008 46 1813 1821 https://doi.org/10.1086/588660 18462102 \n13 Chapenko Trociukas I Donina S Chistyakov M Sultanova A Gravelsina S Lejniece S Murovska M Relationship between beta-herpesviruses reactivation and development of complications after autologou peripheral blood stem cell transplantation J Med Virol 2012 84 1953 1960 https://doi.org/10.1002/jmv.23412 23080502 \n14 Piukovics K Borbényi Z Rajda C Csomor A Déak J Terhes G Monitoring human herpesvirus-6 in patients with autologous stem cell transplantation In Vivo 2014 28 1113 1117 25398808 \n15 Colombier MA Amorim S Salmona M Thieblemont C Legoff J Lafaurie M HHV-6 reactivation as a cause of fever in autologous hematopoietic stem cell transplant recipients J Infect 2017 75 155 159 https://doi.org/10.1016/j.jinf.2017.05.011 28551368 \n16 Pellett PE Ablashi DV Ambros PF Agut H Caserta MT Descamps V Flamand L Gautheret-Dejean A Hall CB Kamble RT Kuehl U Lassner D Lautenschlager I Loomis KS Luppi M Lusso P Medveczky PG Montoya JG Mori Y Ogata M Pritchett JC Rogez S Seto E Ward KN Yoshikawa T Razonable RR Chromosomally integrated human herpesvirus 6: questions and answers Rev Med Virol 2012 22 144 155 https://doi.org/10.1002/rmv.715 22052666 \n17 Kamble RT Clark DA Leong HN Heslop HE Brenner MK Carrum G Transmission of integrated human herpesvirus-6 in allogeneic hematopoietic stem cell transplantation Bone Marrow Transplant 2007 40 563 566 https://doi.org/10.1038/sj.bmt.1705780 17637686 \n18 Clark DA Nacheva EP Leong HN Brazma D Li YT Tsao EH Buyck HC Atkinson CE Lawson HM Potter MN Griffiths PD Transmission of integrated human herpesvirus 6 through stem cell transplantation: implications for laboratory diagnosis J Infect Dis 2006 193 912 916 https://doi.org/10.1086/500838 16518751 \n19 Purev E Winkler T Danner RL Fahle GA Cook L Zerr DM Jerome KR Childs RW Engraftment of donor cells with germ-line integration of HHV6 mimics HHV6 reactivation following cord blood/haplo transplantation Blood 2014 124 1198 1199 https://doi.org/10.1182/blood-2014-06-577684 25124787 \n20 Quintela A Escuret V Roux S Bonnafous P Gilis L Barraco F Labussière-Wallet H Duscastelle-Leprêtre S Nicolini FE Thomas X Chidiac C Ferry T Frobert E Morisset S Poitevin-Later F Monneret G Michallet M Ader F Lyon HEMINF Study Group HHV-6 infection after allogeneic hematopoietic stem cell transplantation:from chromosomal integration to viral co-infections and T-cell reconstitution patterns J Infect 2016 72 214 222 https://doi.org/10.1016/j.jinf.2015.09.039 26518057 \n21 Passweg JR Baldomero H Bader P Bonini C Cesaro S Dreger P Duarte RF Dufour C Kuball J Farge-Bancel D Gennery A Kröger N Lanza F Nagler A Sureda A Mohty M Hematopoietic stem cell transplantation in Europe 2014: more than 40000 transplants annually Bone Marrow Transplant 2016 51 786 792 https://doi.org/10.1038/bmt.2016.20 26901709\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2035-3006",
"issue": "10(1)",
"journal": "Mediterranean journal of hematology and infectious diseases",
"keywords": "Bone marrow transplantation; HHV-6 integration; Infectious disease",
"medline_ta": "Mediterr J Hematol Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101530512",
"other_id": null,
"pages": "e2018013",
"pmc": null,
"pmid": "29531650",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19222466;18462102;23080502;26901709;10477678;17637686;24881673;22052666;28551368;25124787;26518057;17276370;22212513;12200359;19898504;15170644;25398808;16518751;20005968",
"title": "Genomic Integration of HHV-6 Mimicking Viral Reactivation after Autologous Stem Cell Transplantation.",
"title_normalized": "genomic integration of hhv 6 mimicking viral reactivation after autologous stem cell transplantation"
} | [
{
"companynumb": "IT-WEST-WARD PHARMACEUTICALS CORP.-IT-H14001-18-03937",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FOTEMUSTINE"
},
"... |
{
"abstract": "Intra abdominal drain insertion in doubtful cases has been practised since many years. It may be associated with certain minor as well as major complications like drain site haemorrhage, infection, intestinal perforation and even visceral herniation from the site. Herein, we report a case of 28-year-old unbooked G2P1L1 at 33 weeks gestation with previous caesarean, who underwent Lower Segment Caesarean Section (LSCS) in view of breech presentation in labour. On sixth postoperative day, tubular structure herniation through the drain site was observed. She was undertaken for laparotomy and fallopian tube herniation through the drain site was confirmed. Ipsilateral salpingectomy was done. Thus, drain placement lead to prolonged hospital stay and maternal morbidity.",
"affiliations": "Assistant Professor, Department of Obstetrics and Gynaecology, University College of Medical Sciences and Guru Teg Bahadur Hospital , Delhi, India .;Director and Professor, Department of Obstetrics and Gynaecology, University College of Medical Sciences and Guru Teg Bahadur Hospital , Delhi, India .;Director and Professor, Department of Obstetrics and Gynaecology, University College of Medical Sciences and Guru Teg Bahadur Hospital , Delhi, India .;Assistant Professor, Department of Obstetrics and Gynaecology, University College of Medical Sciences and Guru Teg Bahadur Hospital , Delhi, India .",
"authors": "Sharma|Richa|R|;Guleria|Kiran|K|;Suneja|Amita|A|;Bhartiya|Vishnu|V|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2017/22505.9139",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "11(1)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Postpartum morbidity; Prophylactic drain; Tubal herniation",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "QD03-QD04",
"pmc": null,
"pmid": "28274005",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports",
"references": "18836735;666956;23862093;19830090;8064711;22919523;22288027;16749960;22431833;8979207;1422770",
"title": "Post-Caesarean Drain Placement - Minor Procedure Leading to Major Complication.",
"title_normalized": "post caesarean drain placement minor procedure leading to major complication"
} | [
{
"companynumb": "IN-MYLANLABS-2017M1010126",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLDOPA"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nEfficacy and safety of nab-paclitaxel plus gemcitabine have not been clarified in Japanese patients with metastatic pancreatic cancer. No pharmacokinetic profile of co-administration of nab-paclitaxel and gemcitabine has been reported. We conducted a phase I/II study of the efficacy, safety, and pharmacokinetics in Japanese patients with metastatic pancreatic cancer.\n\n\nMETHODS\nThe patients were administered 125 mg/m(2) nab-paclitaxel followed by 1000 mg/m(2) gemcitabine on day 1, 8, and 15 every 4 weeks. Treatment was continued until disease progression, unacceptable adverse events, or withdrawal of consent, whichever occurred first. The primary endpoints were tolerability in phase I and overall response rate according to RECIST in phase II.\n\n\nRESULTS\nA total of 34 patients were enrolled. At the time of 1-year follow-up analysis since the last patient enrollment, the objective response rate by independent review committee was 58.8% (20 of 34 patients; 95% confidence interval [CI], 40.7-75.4%). The median progression-free survival and median overall survival were 6.5 months (95% CI, 5.1-8.3) and 13.5 months (95% CI, 10.6--not reached), respectively. Main adverse drug reactions of grade 3 or higher were neutropenia (70.6%), leukopenia (55.9%), anemia (14.7%), lymphocytopenia (14.7%), thrombocytopenia (14.7%), and peripheral sensory neuropathy (11.8%). There were no treatment-related deaths and no marked differences in pharmacokinetics of combined paclitaxel and gemcitabine in historical comparison between co-administration and monotherapies.\n\n\nCONCLUSIONS\nNab-paclitaxel plus gemcitabine regimen showed highly promising efficacy with manageable safety profile under careful observation and with appropriate supportive care in Japanese patients with metastatic pancreatic cancer.\n\n\nBACKGROUND\nJapicCTI-121987.",
"affiliations": "Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. hiueno@ncc.go.jp.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan.;Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.;Department of Medical Oncology, St.Marianna University School of Medicine Hospital, Kawasaki, Japan.;Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan.",
"authors": "Ueno|Hideki|H|;Ikeda|Masafumi|M|;Ueno|Makoto|M|;Mizuno|Nobumasa|N|;Ioka|Tatsuya|T|;Omuro|Yasushi|Y|;Nakajima|Takako Eguchi|TE|;Furuse|Junji|J|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-016-2972-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "77(3)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Combination chemotherapy; Gemcitabine; Nab-paclitaxel; Pancreatic cancer; Pharmacokinetics",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "595-603",
"pmc": null,
"pmid": "26842789",
"pubdate": "2016-03",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I/II study of nab-paclitaxel plus gemcitabine for chemotherapy-naive Japanese patients with metastatic pancreatic cancer.",
"title_normalized": "phase i ii study of nab paclitaxel plus gemcitabine for chemotherapy naive japanese patients with metastatic pancreatic cancer"
} | [
{
"companynumb": "JP-CIPLA LTD.-2016JP02464",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "A 55-year old man with a history of meningioma treated with LHRH-agonist plus radiotherapy for prostate cancer (PCa) experienced a meningioma growth during hormone therapy (HT). Meningioma was radically resected revealing an atypical meningioma and HT was continued due to the high risk of PCa relapse until symptomatic meningioma relapse occurred after further 10 months. Gross lesions were radically removed and histology revealed anaplastic meningioma. This is the first case of rapid meningioma evolution to an anaplastic histology during LHRH-agonist.",
"affiliations": "Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria Hospital, Cancer Care Center, via Don Sempreboni 5, 37034 Verona, Negrar, Italy. Electronic address: lucanicosia.rg@gmail.com.;Unit of Neurosurgery, Department of Neurosciences, Hospital Trust of Verona, Verona, Italy.;Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy.;Unit of Neurosurgery, Department of Neurosciences, Hospital Trust of Verona, Verona, Italy.;Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria Hospital, Cancer Care Center, via Don Sempreboni 5, 37034 Verona, Negrar, Italy.;Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy.;Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria Hospital, Cancer Care Center, via Don Sempreboni 5, 37034 Verona, Negrar, Italy.;Unit of Neurosurgery, Department of Neurosciences, Hospital Trust of Verona, Verona, Italy.;Department of Anesthesiology and Intensive Care Medicine, Fondazione Policlinico Universitario \"A. Gemelli\", IRCCS, Rome, Italy.;Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria Hospital, Cancer Care Center, via Don Sempreboni 5, 37034 Verona, Negrar, Italy.;Advanced Radiation Oncology Department, IRCCS Sacro Cuore Don Calabria Hospital, Cancer Care Center, via Don Sempreboni 5, 37034 Verona, Negrar, Italy.",
"authors": "Nicosia|L|L|;Bucpapaj|R|R|;Barresi|V|V|;Damante|R|R|;Napoli|G|G|;Ghimenton|C|C|;Giaj-Levra|N|N|;Cancedda|M|M|;Flaminio|S|S|;Figlia|V|V|;Alongi|F|F|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D007987:Gonadotropin-Releasing Hormone; D016729:Leuprolide",
"country": "France",
"delete": false,
"doi": "10.1016/j.neuchi.2020.10.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3770",
"issue": "67(2)",
"journal": "Neuro-Chirurgie",
"keywords": "LHRH agonist; Meningioma; Neurosurgery; Radiotherapy",
"medline_ta": "Neurochirurgie",
"mesh_terms": "D018931:Antineoplastic Agents, Hormonal; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D016729:Leuprolide; D008297:Male; D008577:Meningeal Neoplasms; D008579:Meningioma; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011471:Prostatic Neoplasms",
"nlm_unique_id": "0401057",
"other_id": null,
"pages": "193-197",
"pmc": null,
"pmid": "33190809",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Resected atypical meningioma relapsed to anaplastic meningioma during luteinizing hormone-releasing hormone agonist therapy.",
"title_normalized": "resected atypical meningioma relapsed to anaplastic meningioma during luteinizing hormone releasing hormone agonist therapy"
} | [
{
"companynumb": "NVSC2020IT330148",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": "1",
... |
{
"abstract": "Pyoderma gangrenosum is an intractable disease of unknown cause involving recurrent ulcerative lesions on the skin, and may accompany ulcerative colitis, rheumatoid arthritis, leukemia, systemic lupus erythematosus, and other conditions. Here, we report a rare case of pyoderma gangrenosum in the thoracic abdomen following post-mastectomy reconstructive surgery. A 39-year-old presented at the hospital with a complaint of left papilla erosion. Skin biopsy at the site revealed invasive skin cancer, with Paget-like progression in the cancerous nipple and suspected malignancy of skin appendages. After partial mastectomy including the areola, invasive ductal breast carcinoma was diagnosed. The patient underwent a subsequent full mastectomy with simultaneous sentinel lymph node biopsy and primary breast reconstructive surgery using a rectus abdominis myocutaneous flap. Two weeks post-surgery, healing of the abdominal surgical wound was found to be delayed, and suture abscess was suspected. Despite localized treatment, an ulcerative lesion developed in the thoracic region, and pyoderma gangrenosum was diagnosed following skin biopsy. After the introduction of steroid pulse therapy, no progression of the lesion was observed. This report describes the disease characteristics, diagnosis, and treatment of post-surgical pyoderma gangrenosum and discusses the case in the context of previous literature.",
"affiliations": "Division of Breast and Endocrine Surgery, Department of Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. luke-szk@is.icc.u-tokai.ac.jp.",
"authors": "Suzuki|Yasuhiro|Y|;Yokoyama|Kozue|K|;Terao|Mayako|M|;Morioka|Toru|T|;Tsuda|Banri|B|;Niikura|Naoki|N|;Okamura|Takuho|T|;Yamada|Eri|E|;Imagawa|Kotaro|K|;Akamatsu|Tadashi|T|;Tokuda|Yutaka|Y|;Kumaki|Nobue|N|",
"chemical_list": "D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0005",
"issue": "42(3)",
"journal": "The Tokai journal of experimental and clinical medicine",
"keywords": null,
"medline_ta": "Tokai J Exp Clin Med",
"mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D005260:Female; D006801:Humans; D016462:Mammaplasty; D008408:Mastectomy; D011183:Postoperative Complications; D011239:Prednisolone; D020551:Pulse Therapy, Drug; D017511:Pyoderma Gangrenosum; D017568:Rectus Abdominis; D013524:Surgical Flaps; D016896:Treatment Outcome",
"nlm_unique_id": "7704186",
"other_id": null,
"pages": "133-138",
"pmc": null,
"pmid": "28871582",
"pubdate": "2017-09-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pyoderma Gangrenosum after Breast Mastectomy and Primary Rectus Abdominis Flap Reconstruction.",
"title_normalized": "pyoderma gangrenosum after breast mastectomy and primary rectus abdominis flap reconstruction"
} | [
{
"companynumb": "JP-SA-2017SA179019",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "POVIDONE-IODINE"
},
"drugadditional": "3",
... |
{
"abstract": "Previous studies examining the use of pulmonary arterial hypertension (PAH) drugs in patients with Eisenmenger syndrome (ES) have shown that it may have beneficial effects in some patients with ES; however, experience with additional cases is necessary to confirm its efficacy and appropriate clinical use. We herein report our experience of an adult patient with ES who benefitted from treatment with PAH drugs. A 32-year-old Japanese man with severe ES induced by a ventricular septal defect associated with Down syndrome began treatment with bosentan at 62.5 mg. Eleven months later, he was admitted for tadalafil (40 mg) add-on therapy because his 6-minute walking distance and brain natriuretic peptide (BNP) level had not improved and his hepatic enzyme levels had increased. However, marked hypotension developed, and the tadalafil dose was decreased. His BNP level subsequently increased, so the bosentan dose was increased to 125 mg. The bosentan was then abruptly stopped because of a low platelet count and high liver enzyme levels. Ambrisentan was then administered for these side effects, but because severe dyspnea developed, the bosentan was started again at 62.5 mg. This resulted in immediate clinical improvement. The patient was finally switched to ambrisentan (5 mg), which was well tolerated. The findings in this particular case show that although it should be used with caution, bosentan may be beneficial in select patients with ES. In addition, ambrisentan may be considered as first-line treatment in some patients as long as liver enzymes and platelets are carefully monitored.",
"affiliations": "Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.",
"authors": "Yao|Atsushi|A|",
"chemical_list": "D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides; C467894:ambrisentan; D000077300:Bosentan",
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.14-346",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1349-2365",
"issue": "56 Suppl()",
"journal": "International heart journal",
"keywords": null,
"medline_ta": "Int Heart J",
"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D000077300:Bosentan; D004314:Down Syndrome; D004541:Eisenmenger Complex; D065128:Endothelin Receptor Antagonists; D006345:Heart Septal Defects, Ventricular; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides",
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "S8-11",
"pmc": null,
"pmid": "25787798",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Medical treatment for an adult patient with eisenmenger syndrome. A case report.",
"title_normalized": "medical treatment for an adult patient with eisenmenger syndrome a case report"
} | [
{
"companynumb": "JP-ACTELION-A-CH2018-170307",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BOSENTAN"
},
"drugadditional": "1",
... |
{
"abstract": "Abiraterone improves survival in metastatic castration-resistant prostate cancer (mCRPC) but may result in the development or worsening of comorbid conditions. We assessed the course of these conditions in patients receiving abiraterone in clinical practice and compared outcomes with those in clinical trials.\n\n\n\nMedical records of patients with mCRPC who started abiraterone at an academic institution between 2012 and 2015 were reviewed for emergency department (ED) visits, hospitalizations, and the development and/or worsening of key comorbid conditions while on abiraterone. Patient characteristics and adverse events were compared with those from clinical trials.\n\n\n\nIn a cohort of 174 patients, 28% experienced either the development or worsening of a comorbid disease; 8% required an ED visit or hospitalization owing to known adverse effects of abiraterone. Increasing age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17), higher prostate-specific antigen at initiation of treatment (OR, 1.68; 95% CI, 1.18-2.47), preexisting uncontrolled hypertension (OR, 7.61; 95% CI, 1.22-38.70), congestive heart failure (OR, 7.61; 95% CI, 1.22-38.70), and cardiac arrhythmias (OR, 4.73; 95% CI, 1.39-15.12) were associated with increased odds of an ED visit or hospitalization owing to known adverse effects of abiraterone. The rate of discontinuation (6%) was similar to 1 phase III trial that demonstrated the drug's efficacy in chemotherapy-naive patients.\n\n\n\nFew patients discontinued abiraterone owing to toxicity; however, the fact that over one-quarter of patients experienced the development or worsening of cardiovascular and metabolic diseases warrants development of team-based approaches to the management of these comorbid conditions.",
"affiliations": "Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI. Electronic address: chengpa@med.umich.edu.;Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI; Research, Pratt & Whitney, East Hartford, CT.;Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI; Department of Health Management and Policy, School of Public Health, University of Michigan, Ann Arbor, MI.;Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI; Department of Urology, University of Michigan Medical School, Ann Arbor, MI.;Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI; VA Ann Arbor Healthcare System, Ann Arbor, MI.",
"authors": "Tsao|Phoebe A|PA|;Estes|Jason P|JP|;Griggs|Jennifer J|JJ|;Smith|David C|DC|;Caram|Megan E V|MEV|",
"chemical_list": "D000069501:Abiraterone Acetate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clgc.2019.03.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "17(3)",
"journal": "Clinical genitourinary cancer",
"keywords": "Androgen blockade; Cardiovascular disease; Comorbid conditions; Health care utilization; Metastatic prostate cancer",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases; D004636:Emergency Service, Hospital; D006760:Hospitalization; D006801:Humans; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "e592-e601",
"pmc": null,
"pmid": "31023520",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Cardiovascular and Metabolic Toxicity of Abiraterone in Castration-resistant Prostate Cancer: Post-marketing Experience.",
"title_normalized": "cardiovascular and metabolic toxicity of abiraterone in castration resistant prostate cancer post marketing experience"
} | [
{
"companynumb": "US-JNJFOC-20190208405",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
},
"drugadditional": null,
... |
{
"abstract": "A case of maternal death from pulmonary hypertension secondary to pulmonary granulomatosis is presented. The granulomas are associated with a history of intravenous injection of medications (Ritalin and Talwin) intended for oral use.",
"affiliations": null,
"authors": "Lundquest|D E|DE|;Young|W K|WK|;Edland|J F|JF|",
"chemical_list": "D013627:Talc; D008774:Methylphenidate; D010423:Pentazocine; D011431:Dextropropoxyphene",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "32(3)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D011431:Dextropropoxyphene; D005260:Female; D006099:Granuloma; D006801:Humans; D008099:Liver; D008168:Lung; D008774:Methylphenidate; D009206:Myocardium; D010423:Pentazocine; D011247:Pregnancy; D011248:Pregnancy Complications; D019966:Substance-Related Disorders; D013627:Talc",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "798-801",
"pmc": null,
"pmid": "3598527",
"pubdate": "1987-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Maternal death associated with intravenous methylphenidate (Ritalin) and pentazocine (Talwin) abuse.",
"title_normalized": "maternal death associated with intravenous methylphenidate ritalin and pentazocine talwin abuse"
} | [
{
"companynumb": "US-PFIZER INC-2016334276",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "We report the case of a 35-year-old male, who was diagnosed with systemic lupus erythematosus (SLE) in 2010 based on the presence of articular, serous, renal, immune, and hematologic involvement. He also had secondary antiphospholipid syndrome (APS). He was treated with prednisone 10 mg per day, hydroxychloroquine 200 mg per day, methotrexate 12.5 mg per week, leflunomide 20 mg per day, and oral anticoagulation previous to the present event. He presented to emergency room with a 7 day disease duration characterized by pain in the left thigh, which increased with physical activity, resulting in claudication; he also had malaise and fever. The X-ray films showed periostitis of the lower half of the left femur with bone marrow narrowing; the scintigraphy showed marked increased uptake in the middle and distal thirds of the left femur, and magnetic resonance imaging (MRI) showed thickening and hyperintensity of the cortex of the diaphysis and distal epiphysis of the femur and endosteal irregularity. Empirical treatment was started with vancomycin for 3 weeks. Femur biopsy and cultures were performed, isolating Salmonella spp. group \"D\" Vi (-); treatment with cotrimoxazole and ceftazidime for 4 weeks followed by doxycycline and cotrimoxazole for 4 months were given with a favorable functional outcome. This is an unusual case of a young adult with Garre's sclerosing osteomyelitis associated to SLE and caused by salmonella. The literature is reviewed and the clinical conditions predisposing to this infection are discussed, particularly in patients with SLE.",
"affiliations": "Rheumatology Department, Hospital \"Guillermo Almenara Irigoyen\" EsSalud, Av. Grau 800. La Victoria, 13, Lima, Peru. claudiaelerafitz@gmail.com.;Rheumatology Department, Hospital \"Guillermo Almenara Irigoyen\" EsSalud, Av. Grau 800. La Victoria, 13, Lima, Peru.;Rheumatology Department, Hospital \"Guillermo Almenara Irigoyen\" EsSalud, Av. Grau 800. La Victoria, 13, Lima, Peru.",
"authors": "Elera-Fitzcarrald|Claudia|C|;Alfaro-Lozano|José L|JL|;Pastor-Asurza|César A|CA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D006886:Hydroxychloroquine; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D002442:Ceftazidime; D000077339:Leflunomide; D004318:Doxycycline; D011241:Prednisone; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-015-3092-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "34(12)",
"journal": "Clinical rheumatology",
"keywords": "Osteomyelitis; Salmonella infections; Systemic lupus erythematosus",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D016736:Antiphospholipid Syndrome; D002442:Ceftazidime; D004318:Doxycycline; D005269:Femur; D006801:Humans; D006886:Hydroxychloroquine; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D000077339:Leflunomide; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008727:Methotrexate; D010019:Osteomyelitis; D011241:Prednisone; D012480:Salmonella Infections; D012598:Sclerosis; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "2155-8",
"pmc": null,
"pmid": "26511966",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12794259;23608216;26229835;16371405;19502263;25900955;15229953;3881103;14747764;12396094;8636449;3041342;11237131;24098001;11933203;6951157;17921638;19960581;25012167",
"title": "Garre's sclerosing osteomyelitis caused by salmonella group D in a patient with systemic lupus erythematosus: an unusual complication.",
"title_normalized": "garre s sclerosing osteomyelitis caused by salmonella group d in a patient with systemic lupus erythematosus an unusual complication"
} | [
{
"companynumb": "PHHY2015PE156744",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "In contrast to intoxications in toddlers which can be due to accidental ingestions, many intoxications in infants are due to medication errors. To our knowledge, this is the first case report of a citalopram intoxication in an infant, and may offer new insight on possible screening methods for intoxication as well as pharmacokinetics of citalopram in small infants.\n\n\n\nThis case report describes an unintentional citalopram intoxication in a 4 week old infant due to a vitamin D drops 'look alike' error. The infant showed extreme jitteriness and opisthotonus at presentation, as well as prolonged signs of gastro-oesophageal reflux. No cardiac rhythm disturbances or convulsions were seen. The clinical course combined with Finnegan scores was correlated to and supported by pharmacokinetic and pharmacokinetic data of citalopram in the patient.\n\n\n\nUsing Finnegan scores in general pediatric practice could help objectify follow-up of acute intoxications in young infants with neurological symptoms.",
"affiliations": "Pediatrics, Maastricht UMC+, Maastricht, The Netherlands.;Pharmacology, Catharina Hospital, Eindhoven, The Netherlands.;Pediatrics, Catharina Hospital, Michelangelolaan 2, 5623, EJ Eindhoven, The Netherlands. marianne.eijkemans@catharinaziekenhuis.nl.;Pharmacology, Catharina Hospital, Eindhoven, The Netherlands.",
"authors": "Janson|Jo-Anne|JA|;Wasylewicz|Arthur T M|ATM|;Eijkemans|Marianne|M|0000-0003-4550-8628;Kerskes|Marieke|M|",
"chemical_list": "D015283:Citalopram",
"country": "England",
"delete": false,
"doi": "10.1186/s12887-020-02439-5",
"fulltext": "\n==== Front\nBMC Pediatr\nBMC Pediatr\nBMC Pediatrics\n1471-2431 BioMed Central London \n\n2439\n10.1186/s12887-020-02439-5\nCase Report\nCitalopram intoxication in four week old infant\nJanson Jo-Anne 1 Wasylewicz Arthur T. M. 2 http://orcid.org/0000-0003-4550-8628Eijkemans Marianne marianne.eijkemans@catharinaziekenhuis.nl 3 Kerskes Marieke 2 1 grid.412966.e0000 0004 0480 1382Pediatrics, Maastricht UMC+, Maastricht, The Netherlands \n2 grid.413532.20000 0004 0398 8384Pharmacology, Catharina Hospital, Eindhoven, The Netherlands \n3 grid.413532.20000 0004 0398 8384Pediatrics, Catharina Hospital, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands \n7 12 2020 \n7 12 2020 \n2020 \n20 55216 12 2019 19 11 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nIn contrast to intoxications in toddlers which can be due to accidental ingestions, many intoxications in infants are due to medication errors. To our knowledge, this is the first case report of a citalopram intoxication in an infant, and may offer new insight on possible screening methods for intoxication as well as pharmacokinetics of citalopram in small infants.\n\nCase presentation\nThis case report describes an unintentional citalopram intoxication in a 4 week old infant due to a vitamin D drops ‘look alike’ error. The infant showed extreme jitteriness and opisthotonus at presentation, as well as prolonged signs of gastro-oesophageal reflux. No cardiac rhythm disturbances or convulsions were seen. The clinical course combined with Finnegan scores was correlated to and supported by pharmacokinetic and pharmacokinetic data of citalopram in the patient.\n\nConclusions\nUsing Finnegan scores in general pediatric practice could help objectify follow-up of acute intoxications in young infants with neurological symptoms.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s12887-020-02439-5.\n\nKeywords\nCitalopramSSRIInfantIntoxicationFinnegan scoresissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nCitalopram is the second most commonly used antidepressant in the world [1]. Citalopram is used in treating depression in pregnant as well as postpartum women, and is the most used antidepressant in pregnancy [1–3]. Citalopram is a selective serotonin reuptake inhibitor (SSRI), it works by inhibiting the central nervous system (CNS) reuptake of serotonin (5-HT) and the potentiation of serotonergic activity. Citalopram intoxication in adults is usually mild, consisting of symptoms of nausea, dizziness, tremors and somnolence, nevertheless significant toxicity can occur [4]. In children however, it has been defined as the most hazardous intoxication of all SSRIs, with seizures occurring four times more frequent that other SSRI’s, as well as cardiotoxic effects, which occur more than three times as much [5].\n\nIn contrast to intoxications in toddlers which are often due to accidental ingestions, many intoxications in infants are due to medication errors [6]. Common medication errors which can occur in a ‘home’ situation are often due to ‘look-alike, sound-alike’ drug names and packaging [7]. In this case report, we describe an infant that was given his mother’s citalopram drops instead of its vitamin D drops, which are recommended to prevent rickets [8]. Little is known about the toxicity or kinetics of citalopram in infants [5]. To our knowledge, this is first case report of a citalopram intoxication in an infant, and may offer new insight on possible screening methods for intoxication as well as some insight into the pharmacokinetics of citalopram in small infants.\n\nCase presentation\nA previously healthy, 4 week old, Caucasian boy was brought to the emergency department by his mother because he had accidentally been given the mothers’ dose of citalopram. Instead of the vitamin D drops she intended to give him, she accidentally switched bottles of the citalopram and vitamin D. These bottles are similar, as shown in Fig. 1. The mother noticed the incorrect medication bottle around 30 min later and immediately presented the infant to the emergency department. She administered 10 drops of citalopram, corresponding to 20 mg. With a weight of 3355 g corresponding to a dose of around 6.0 mg/kg.\nFig. 1 Photo showing the citalopram (left) and vitamin D (right). (Picture provided by the parents)\n\n\n\nUpon first physical examination we saw an extremely jittery, agitated infant with an evident opisthotonos, as shown in Fig. 2. Vital signs were stable, the patient had a respiratory rate of 50/min and an oxygen saturation of 100% in room air. At presentation the patient showed an isolated systolic hypertension. Blood pressure was 110/38 mmHg (reference value p95 for systolic pressure 105 mmHg), with a regular heart rate of 190 beats per minute [9]. An electrocardiogram showed sinus tachycardia with normal intervals. A nasogastric tube was inserted to empty the stomach; activated charcoal and sodium sulfate were administered over a 2 h period to prevent any possible further absorption of the citalopram. Furthermore, an intravenous cannula was placed with maintenance fluid and secure intravenous access.\nFig. 2 The infant at presentation at the emergency department showing clear signs of opisthotonos (placed with permission of the parents)\n\n\n\nThe patient was transferred to a neonatal intensive care unit (NICU) for intensive monitoring, concerning the possible risk of cardiac rhythm disturbances and convulsions. Laboratory testing was performed including a complete blood count, infection parameters and electrolyte concentration, all results were within normal limits. Because of the risk of convulsions and intracerebral hemorrhage, amplitude-integrated electroencephalography (aEEG) and cerebral ultrasound were performed, which showed no abnormalities.\n\nAfter 16 h the patient was transferred back to the medium care neonatal ward. In the following days he continued showing signs of extreme jitteriness and increased muscle tone. After 4 days these symptoms were found to be acceptable enough to discharge the patient. Before, during and after admission the patient was only fed formula feeding, breast milk was not used.\n\nDuring several weeks, at ambulant follow-up, the patient showed persistent signs of increased muscle tone for at least 1 month after discharge. Furthermore, he showed signs of agitation and gastro-oesophageal reflux. Treatment was started with esomeprazole to counteract the effect of the gastro-oesophageal reflux. After 7 months patients symptoms disappeared completely and the patient was discharged from further ambulant follow-up.\n\nPharmacokinetic and pharmacodynamic evaluation\nTo assess pharmacokinetic parameters as well as to predict time to improvement of symptoms, citalopram and the active metabolite desmethylcitalopram concentrations were measured in the serum of the patient. Citalopram and desmethylcitalopram concentrations were analyzed using a validated UPLC-MS-MS method at the Onze Lieve Vrouwe Gasthuis hospital in Amsterdam, the Netherlands. Two hours after ingestion, the citalopram plasma concentration was 77 μg/l with no detectable desmethylcitalopram concentration. Fifty-four hours after ingestion, citalopram serum level decreased to 33 μg/l and desmethylcitalopram increased to a concentration of 43 μg/l.\n\nTo objectify the severity and clinical course, Finnegan scores were randomly measured during the course of admission (Additional file 1) [10]. Fig. 3 shows the course of the known Finnegan scores, citalopram and desmethylcitalopram serum levels. Finnegan scores were as follows: 2 h after ingestion 11, 24 h after ingestion 8, 46 h after ingestion 6, 66 h after ingestion 3, more elaborate data is shown in Additional file 1. Unfortunately during the time of admittance at the NICU, Finnegan scores were not measured.\nFig. 3 Pharmacokinetics and pharmacodynamic parameters after ingestion of 20 mg citalopram by a 4 week old infant. Legend: Figure shows Finnegan scores throughout admission taken at random times. The blue dots represent the Finneganscores. Dotted blue line represents NICU admission where no Finneganscores were recorded. Scoring is displayed on the primary Y-axis on the left side of the figure. The orange dots represent the citalopram serum levels and the green dots the desmethylcitalopram serum levels, concentration is displayed on the secondary Y-axis on the right side of the figure\n\n\n\nDiscussion and conclusions\nIn this case report we presented a 4 week old infant which was accidently given 20 mg citalopram resulting in a dose of 6.0 mg/kg, being around 30 times a ‘recommended’ dose in older children. The most prominent symptoms were an opisthotonos and persistent jitteriness.\n\nThis case report describes an unintentional citalopram intoxication due to a vitamin D drops ‘look alike’ error. It is of great importance that clinicians are aware of the fact that packaging of drops can be similar. In this case, a warning was sent to the central medication incident database, to prevent further mix-ups.\n\nAt presentation 2 h after ingestion, the serum citalopram concentration was 77 μg/l, much lower than the reported toxicity levels in adults, starting at 400 μg/l. [4] However, the measured concentration might not yet be the peak concentration, as the Tmax is about 2 h for Cipramil® drops [11, 12]. In a similar case report, a 10 month old infant ingested an unknown amount of citalopram tablets, the initial plasma level (1 h after ingestion) was 1400 μg/l. [13] In contrast to our case, this infant developed seizures requiring anti-epileptic therapy, making it impossible to administer repeated doses of activated charcoal and laxative.\n\nWhile neurological symptoms dissipated during admission, the patient kept on showing signs of increased muscle tone and gastro-oesophageal reflux during several weeks. A possible explanation for these symptoms could be high levels of the active metabolite desmethylcitalopram [14]. Around 80% of citalopram is metabolized via hepatic cytochrome P450 system, CYP2C19, CYP3A4 and CYP2D6 playing a major role. It is metabolized, into several metabolites of which only desmethylcitalopram is known to be pharmacologically active. The active metabolite desmethylcitalopram has a longer half-life than citalopram being around 50 h in adults [15] and possible playing a major role in the therapeutic effect of the treatment [16]. However, no citalopram and desmethylcitalopram plasma levels were measured at follow-up to support this hypothesis.\n\nBecause there are no scores to objectify seriousness and clinical course of intoxications in infants we chose to use the Finnegan scores (Additional file 1). The Finnegan score is an objective method used to monitor neonatal abstinence symptoms. A score of eight or higher in three measurements indicates the need for therapy. Finnegan scores measure: high pitched cries, sleep-disturbances, hyperactive reflexes, tremors, convulsions, hyperthermia, sneezing, tachydyspnea and feeding problems. Previous studies show values above eight can be considered pathological in a 4 week old infant, and can be interpreted as a sign of narcotic withdrawal [17]. While the Finnegan scores seemed to correlate to neurological course during admission, it did not adequately correlate to the gastro-intestinal symptoms that persisted like the GER and increased muscle tone. A possible explanation is that Finnegan scores mainly subjectively quantify the level of neurologic excitability, and in lesser amount gastrointestinal dysfunction [18].\n\nWe suggest using the Finnegan scores in future SSRI intoxications in infants to objectify and predict acute clinical course. Keep in mind that the Finnegan-scores can be only be used up until 4 weeks of age [10]. The symptoms that occurred could be labeled as severe serotonin syndrome, where the Hunter criteria can be useful for diagnosis [19]. We did not use these criteria during the clinical course. Further research is needed because the Hunter criteria are not validated for the pediatric population. We describe a unique case-report concerning a 4 week old infant with accidental citalopram intoxication. The patient presented with extreme jitteriness and increased muscle tone. Fortunately, no serious adverse effects were monitored. During the clinical course, we have shown Finnegan scores can be helpful in determining toxicity and half-life of citalopram.\n\nThe clinical course seems to be correlated to the Finnegan scores, this seems partly supported by pharmacokinetic data of citalopram in a young infant, previously not described in literature. We believe that using Finnegan scores in general pediatric practice could help objectify follow-up of intoxications in young infants with neurological symptoms. Moreover, by presenting this case we hope to invite researchers to validate Finnegan scores to use in intoxications of young infants.\n\nSupplementary Information\n\nAdditional file 1. Finnegan scores of patient.\n\n \n\nAbbreviations\nSSRISelective Serotonin Reuptake Inhibitor\n\nCNSCentral nervous system\n\n5-HTSerotonin\n\nNICUNeonatal intensive care unit\n\nUPLC-MS-MSUltra-performance liquid chromatography-tandem mass spectrometry\n\nCmaxMaximum (or peak) serum concentration\n\nT ½Drug elimination half-life\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nJJ MD, pediatric resident: Conceptualized and drafted the clinical part of the initial manuscript. Drafting the article critically for important intellectual content. Final approval of the version to be published. 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. AW MSc, PhD, hospital pharmacist: Conceptualized and drafted the pharmacokinetic part of the manuscript. Drafting the article critically for important intellectual content. Final approval of the version to be published. 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. ME MD, pediatrician: review and adjustment of clinical part of manuscript. Revising the article critically for important intellectual content. Final approval of the version to be published. 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. MK MSc, hospital pharmacist: review and adjustment of pharmacokinetic part of the manuscript. Revising the article critically for important intellectual content. Final approval of the version to be published. 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. All above mentioned authors approved the final manuscript as submitted and agree to be accountable for all aspects of work.\n\nFunding\nNo funding was secured for this study. The authors have no financial relationships relevant to this article to disclose.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nParents of the infant signed a consent form to use the medical data and photos of their son.\n\nConsent for publication\nParents of the infant signed a consent form to use the medical data and photos of their son and published the data and photos in a medical journal.\n\nCompeting interests\nThe authors declare that they have no competing interests. The authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1. Gaynes BN Gavin N Meltzer-Brody S Perinatal depression: prevalence, screening accuracy, and screening outcomes Evid Rep Technol Assess 2005 119 1 8 \n2. Bakker MK Kolling P van den Berg PB de Walle HE de Jong van den Berg LT Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from the Netherlands Br J Clin Pharmacol 2008 65 4 600 606 10.1111/j.1365-2125.2007.03048.x 17953715 \n3. Mitchell AA Gilboa SM Werler MM Kelley KE Louik C S H-D. National Birth Defects Prevention Study, medication use during pregnancy, with particular focus on prescription drugs: 1976-2008 Am J Obstet Gynecol 2011 1 51 e1 e8 \n4. Jimmink A Caminada K Hunfeld NG Touw DJ Clinical toxicology of citalopram after acute intoxication with the sole drug or in combination with other drugs: overview of 26 cases Ther Drug Monit 2008 30 3 365 371 10.1097/FJC.0b013e3181379ef6 18520609 \n5. Klein-Schwartz W Benson BE Lee SC Litovitz T Comparison of citalopram and other selective serotonin reuptake inhibitor ingestions in children Clin Toxicol 2012 50 5 418 423 10.3109/15563650.2012.678497 \n6. Nationaal Vergiftigingen Informatie Centrum (NVIC). Annual report of acute poisonings 2018. https://www.researchgate.net/publication/337440825_Jaaroverzicht_NVIC_Acute_vergiftigingen_bij_mens_en_dier_in_2018. Accessed 02 Dec 2020.\n7. Basco WT Garner SS Myla E Freeland Katherine D Kit S Paul N Assessment of Pediatric Look-Alike, Sound-Alike (LASA) Substitution Errors 2013 \n8. Health Council of the Netherlands. Evaluatie van de voedingsnormen voor vitamine D (Evaluation of the dietary standards of vitamin D). 2012. https://www.gezondheidsraad.nl/documenten/adviezen/2012/09/26/evaluatie-van-de-voedingsnormen-voor-vitamine-d. Accessed 02 Dec 2020.\n9. Dionne JM Abitbol CL Flynn JT Hypertension in infancy: diagnosis, management and outcome Pediatr Nephrol 2012 27 1 17 32 10.1007/s00467-010-1755-z 21258818 \n10. Levinson-Castiel R Merlob P Linder N Sirota L Klinger G Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants Arch Pediatr Adolesc Med 2006 160 2 173 176 10.1001/archpedi.160.2.173 16461873 \n11. Medicines.org.uk. Summary of product characteristics Cipramil® Drops 40 mg/ml. 2019; https://www.medicines.org.uk/emc/product/3349/smpc. Accessed 28-10-2019.\n12. Blake MJ Castro L Leeder SL Kearns GL Ontogeny of drug metabolizing enzymes in the neonate Semin Fetal Neonatal Med 2005 10 2 123 138 10.1016/j.siny.2004.11.001 15701578 \n13. Masullo LN Miller MA Baker SD Bose S Levsky M Clinical course and toxicokinetic data following isolated citalopram overdose in an infant Clin Toxicol 2006 44 2 165 168 10.1080/15563650500514525 \n14. Sangkuhl K Klein TE Altman RB PharmGKB summary: citalopram pharmacokinetics pathway Pharmacogenet Genomics 2011 21 11 769 772 10.1097/FPC.0b013e328346063f 21546862 \n15. Bezchlibnyk-Butler K Aleksic I Kennedy SH Citalopram--a review of pharmacological and clinical effects J Psychiatry Neurosci 2000 25 3 241 254 10863884 \n16. Ozbey G Yucel B Bodur NE Serum N-Desmethylcitalopram concentrations are associated with the clinical response to citalopram of patients with major depression Psychiatry Investig 2018 15 3 313 319 10.30773/pi.2017.05.22 \n17. Zimmermann-Baer U Notzli U Rentsch K Bucher HU Finnegan neonatal abstinence scoring system: normal values for first 3 days and weeks 5-6 in non-addicted infants Addiction. 2010 105 3 524 528.17 10.1111/j.1360-0443.2009.02802.x 20402996 \n18. Raffaeli G Cavallaro G Allegaert K Wildschut ED Fumagalli M Agosti M Tibboel D Mosca F Neonatal abstinence syndrome: update on diagnostic and therapeutic strategies Pharmacotherapy. 2017 37 7 814 823 10.1002/phar.1954 28519244 \n19. Dunkley EJC Isbister GK Sibbritt D Dawson AH Whyte IM The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity QJM 2003 96 9 635 642 10.1093/qjmed/hcg109 12925718\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2431",
"issue": "20(1)",
"journal": "BMC pediatrics",
"keywords": "Citalopram; Finnegan scores; Infant; Intoxication; SSRI",
"medline_ta": "BMC Pediatr",
"mesh_terms": "D002648:Child; D015283:Citalopram; D005764:Gastroesophageal Reflux; D006801:Humans; D007223:Infant; D012640:Seizures; D019966:Substance-Related Disorders",
"nlm_unique_id": "100967804",
"other_id": null,
"pages": "552",
"pmc": null,
"pmid": "33287753",
"pubdate": "2020-12-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21514558;12925718;28519244;20402996;17953715;15760246;10863884;15701578;16461873;29475241;18520609;21546862;22506805;16615673;21258818",
"title": "Citalopram intoxication in four week old infant.",
"title_normalized": "citalopram intoxication in four week old infant"
} | [
{
"companynumb": "NL-JUBILANT CADISTA PHARMACEUTICALS-2020JUB00357",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
... |
{
"abstract": "OBJECTIVE\nColonoscopy with polypectomy is associated with a reduced risk of colorectal cancer (CRC), but poor bowel cleansing limits the diagnostic yield of the procedure. Patients with spinal cord injury (SCI) frequently have suboptimal bowel cleansing with standard pre-colonoscopy bowel preparation regimens. We aimed to assess the safety, tolerability, and efficacy of a multi-day inpatient bowel preparation regimen in a population of patients with SCI.\n\n\nMETHODS\nRetrospective case series.\n\n\nMETHODS\nVA Puget Sound SCI Center.\n\n\nMETHODS\nAll patients with SCI (n = 53) who underwent inpatient colonoscopy at the VA Puget Sound from July 12, 2013 to February 12, 2015.\n\n\nMETHODS\nPatient characteristics, tolerance of full bowel preparation, pre- and post-bowel preparation electrolyte values, adverse events, and adequacy of bowel cleansing were abstracted.\n\n\nRESULTS\nSixty-eight percent of patients had a cervical level of injury and the majority were either American Spinal Injury Association Impairment Scale A (41%) or D (43%). The full bowel preparation was tolerated by 91% of inpatients. In those with pre- and post-bowel preparation laboratory testing, there were small, but statistically significant decreases in serum calcium and phosphate. No patient had symptoms associated with electrolyte abnormalities or required treatment. Five out of 53 inpatients experienced autonomic dysreflexia (AD) during bowel preparation. Eighty-nine percent of patients had adequate bowel cleansing at colonoscopy.\n\n\nCONCLUSIONS\nWe demonstrate a safe and effective inpatient bowel preparation regimen in a SCI population. The regimen was associated with mild, asymptomatic hypophosphatemia and hypocalcemia. AD was an uncommon event, predominantly occurring in patients who experienced frequent AD episodes at baseline.",
"affiliations": "a Spinal Cord Injury Service , Veterans Affairs Puget Sound Health Care System , Seattle , Washington , USA.;a Spinal Cord Injury Service , Veterans Affairs Puget Sound Health Care System , Seattle , Washington , USA.;c Department of Internal Medicine , University of Washington , Seattle , Washington , USA.;c Department of Internal Medicine , University of Washington , Seattle , Washington , USA.;a Spinal Cord Injury Service , Veterans Affairs Puget Sound Health Care System , Seattle , Washington , USA.",
"authors": "Song|Shawn H|SH|http://orcid.org/0000-0002-2894-7111;Svircev|Jelena N|JN|;Teng|Brandon J|BJ|;Dominitz|Jason A|JA|;Burns|Stephen P|SP|",
"chemical_list": "D004573:Electrolytes; D009942:Organometallic Compounds; D019343:Citric Acid; D011092:Polyethylene Glycols; C110422:magnesium citrate",
"country": "England",
"delete": false,
"doi": "10.1080/10790268.2016.1258968",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-0268",
"issue": "41(2)",
"journal": "The journal of spinal cord medicine",
"keywords": "Autonomic dysreflexia; Colonoscopy; Spinal cord injuries",
"medline_ta": "J Spinal Cord Med",
"mesh_terms": "D019343:Citric Acid; D003113:Colonoscopy; D004573:Electrolytes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009942:Organometallic Compounds; D011092:Polyethylene Glycols; D012189:Retrospective Studies; D013119:Spinal Cord Injuries; D014481:United States; D014493:United States Department of Veterans Affairs",
"nlm_unique_id": "9504452",
"other_id": null,
"pages": "149-156",
"pmc": null,
"pmid": "28366050",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "22138085;15758907;22773527;19777861;16620189;10347539;21200035;19136102;12526948;19769634;16630226;26439436;25239068;23941791;12838225;17978311;22356322;11726845;19139757;25599220;21481857;15640987;25366532;8797642;15832903",
"title": "A safe and effective multi-day colonoscopy bowel preparation for individuals with spinal cord injuries.",
"title_normalized": "a safe and effective multi day colonoscopy bowel preparation for individuals with spinal cord injuries"
} | [
{
"companynumb": "US-MYLANLABS-2019M1109241",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM CITRATE"
},
"drugadditional": null,... |
{
"abstract": "Outside the context of overdose and serotonin syndrome, seizures and myoclonic movements attributed to selective serotonin reuptake inhibitors (SSRIs) are rare and poorly documented. We present a 77-year-old man, with no history of epilepsy, presenting in the emergency department with whole body jerks since that morning. Two days earlier, due to a prescription mistake, he was started on paroxetine 20 mg instead of his usual fluoxetine 20 mg. The patient's electroencephalogram (EEG), performed in the emergency department, revealed a bilateral synchronous parieto-occipital fast spike activity pattern, which correlated consistently with negative myoclonus. Two days after stopping paroxetine, the patient presented no seizures and no abnormalities in the EEG. We present an EEG documented case of drug-induced seizures, with a bilateral parieto-occipital pattern, secondary to paroxetine intake. A hyperexcitability of the primary somatosensory cortex inhibiting primary motor cortex output could explain the electroclinical correlation.",
"affiliations": "Epilepsy Unit, Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Epilepsy Unit, Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Epilepsy Unit, Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Epilepsy Unit, Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.",
"authors": "Correia|Pedro|P|http://orcid.org/0000-0002-0720-7616;Ribeiro|Joana Afonso|JA|;Bento|Conceição|C|;Sales|Francisco|F|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine; D017374:Paroxetine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-224586",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "clinical neurophysiology; epilepsy and seizures; neurology (drugs and medicines); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D004569:Electroencephalography; D005473:Fluoxetine; D006801:Humans; D008297:Male; D019300:Medical Errors; D009207:Myoclonus; D017374:Paroxetine; D012640:Seizures; D017367:Serotonin Uptake Inhibitors; D013003:Somatosensory Cortex; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29691274",
"pubdate": "2018-04-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15784664;27236241;21532372;17486478;26650063;11436961;9169967;9409341;10746609;16272166;28276064",
"title": "Negative myoclonus secondary to paroxetine intake.",
"title_normalized": "negative myoclonus secondary to paroxetine intake"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-172633",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
... |
{
"abstract": "Cutaneous squamous cell carcinoma (CSCC) is the most frequent post-transplant tumour entity resulting from immunosuppression treatment that is needed to prevent organ rejection. Solid organ transplant (SOT) recipients are at higher risk for CSCC and vulnerable for aggressive disease or a fatal course. Here, we report on a case of post-kidney transplant metastatic CSCC, demonstrating efficacy of cemiplimab in achieving complete remission after previous disease progression under cetuximab treatment. Unfortunately, the patient developed severe pneumonia, which was only later diagnosed as cemiplimab-associated pneumonitis. Due to a rapidly evolving septic condition, intensive care treatment was required and resulted in a fatal outcome. The patient's transplant remained intact, yet first-line treatment of advanced CSCC, such as with cemiplimab, should be weighed critically in SOT recipients, as transplant rejection may occur. However, the present case underlines the feasibility of cemiplimab as a second-line treatment option in this patient collective.",
"affiliations": "Department of Dermatology and Venereology, University Skin Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Dermatology and Venereology, University Skin Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Dermatology and Venereology, University Skin Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Dermatology and Venereology, University Skin Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Geidel|G|G|;Rünger|A|A|;Schneider|S W|SW|;Gebhardt|C|C|https://orcid.org/0000-0001-7090-9584",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jdv.17732",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "36 Suppl 1()",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": null,
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "49-52",
"pmc": null,
"pmid": "34855252",
"pubdate": "2022-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Value of cemiplimab in progressive metastatic cutaneous squamous cell carcinoma after kidney transplantation: a case report.",
"title_normalized": "value of cemiplimab in progressive metastatic cutaneous squamous cell carcinoma after kidney transplantation a case report"
} | [
{
"companynumb": "DE-MLMSERVICE-20220104-3302598-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional... |
{
"abstract": "To compare clinical, diagnostic, management, and outcome factors in children with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and a history of herpes simplex encephalitis (HSE) to children with NMDAR encephalitis without a history of HSE.\n\n\n\nAll patients with anti-NMDAR antibodies in cerebrospinal fluid treated at our institution between 2012 and 2019 were identified and divided into those with a history of HSE (HSE+NMDAR group) and those without a history of HSE (NMDAR-only group). Demographic data, clinical characteristics, immunotherapy, and outcome data were collected on all patients and compared between the 2 groups.\n\n\n\nSeventeen patients were identified with anti-NMDAR antibodies in cerebrospinal fluid, 6 of whom had a history of HSE. Mean age in the HSE+NMDAR cohort was significantly younger in the HSE+NMDAR cohort, as 5 of the 6 patients were infants. Of HSE+NMDAR patients, 50% had behavioral symptoms, 67% had movement disorders, and 100% had seizures at disease nadir. In the NMDAR-only group, 100% had behavioral symptoms, 73% had movement disorders, and 73% had seizures at nadir. HSE+NMDAR patients received a median of 1 immunotherapy, compared to a median of 4.5 immunotherapies in the NMDAR-only group.\n\n\n\nBehavioral symptoms were more common in NMDAR-only patients, whereas seizures were more common in HSE+NMDAR patients. Both groups had significant disability at disease nadir, with more improvement in disability over time in the NMDAR-only group. HSE+NMDAR patients received fewer immunotherapies than NMDAR-only patients. Outcomes of infants with HSE appear to primarily reflect sequelae from HSE.",
"affiliations": "Division of Pediatric Neurology, Department of Pediatrics, Children's Hospital of Alabama, 9968University of Alabama at Birmingham, Birmingham, AL, USA.;Division of Pediatric Neurology, Department of Pediatrics, Children's Hospital of Alabama, 9968University of Alabama at Birmingham, Birmingham, AL, USA.",
"authors": "Marcus|Lydia|L|0000-0003-2725-2825;Ness|Jayne M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/08830738211002679",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "36(9)",
"journal": "Journal of child neurology",
"keywords": "NMDA receptor antibody; encephalitis; herpes; pediatric",
"medline_ta": "J Child Neurol",
"mesh_terms": null,
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "743-751",
"pmc": null,
"pmid": "33818179",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pediatric N-Methyl-d-Aspartate (NMDA) Receptor Encephalitis, With and Without Herpes Encephalitis.",
"title_normalized": "pediatric n methyl d aspartate nmda receptor encephalitis with and without herpes encephalitis"
} | [
{
"companynumb": "US-UCBSA-2021044022",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nThe impact of deep cerebral veins on neurologic outcome after intravenous thrombolysis in patients with acute ischemic stroke is unclear. We investigated the relationship between the appearance of deep cerebral veins on susceptibility-weighted imaging and neurologic outcome in patients who underwent thrombolysis.\n\n\nMETHODS\nWe retrospectively analyzed 109 consecutive patients with acute ischemic stroke who had pretreatment SWI and received intravenous thrombolysis within 6 hours. We calculated the signal difference ratio (defined as the relative difference in signal intensity between the ipsilateral and contralateral veins) of the thalamostriate vein, septal vein, and internal cerebral vein on pretreatment SWI.\n\n\nRESULTS\nOnly the signal difference ratio of the thalamostriate vein was significantly associated with poor outcome (3-month modified Rankin Scale score > 2, P = .008). The optimal threshold was relative hypointensity of the ipsilateral vein of >4.8% (sensitivity of 53.7% and specificity of 80.9%). We defined a signal difference ratio of the thalamostriate vein of ≥5% as an ipsilateral prominent thalamostriate vein. Patients with an ipsilateral prominent thalamostriate vein were more likely to have poor outcome (OR = 3.66; 95% CI, 1.25-10.68; P = .02) and a lower rate of successful reperfusion (reperfusion rate of ≥70%; OR = 0.35; 95% CI, 0.13-0.92; P = .03), compared with those without an ipsilateral prominent thalamostriate vein. However, patients with an ipsilateral prominent thalamostriate vein were still less likely to experience poor outcome when reperfusion was achieved compared with when reperfusion did not occur (80.0% versus 44.4%, P = .04).\n\n\nCONCLUSIONS\nA pretreatment ipsilateral prominent thalamostriate vein was associated with reduced reperfusion after thrombolysis and poor outcome. More intensive reperfusion approaches may be required for patients with an ipsilateral prominent thalamostriate vein.",
"affiliations": "From the Departments of Neurology (X.Z., S.Z., Q.C., M.L.).;From the Departments of Neurology (X.Z., S.Z., Q.C., M.L.).;From the Departments of Neurology (X.Z., S.Z., Q.C., M.L.).;Radiology (W.D.), the Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China.;Department of Neurology (B.C.V.C.), Royal Melbourne Hospital, Grattan St, Parkville, Victoria, Australia.;From the Departments of Neurology (X.Z., S.Z., Q.C., M.L.) loumingxc@vip.sina.com.",
"authors": "Zhang|X|X|http://orcid.org/0000-0002-6393-6725;Zhang|S|S|http://orcid.org/0000-0003-0644-7930;Chen|Q|Q|http://orcid.org/0000-0002-5702-0331;Ding|W|W|http://orcid.org/0000-0001-8082-4154;Campbell|B C V|BCV|http://orcid.org/0000-0003-3632-9433;Lou|M|M|http://orcid.org/0000-0002-6627-064X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3174/ajnr.A5135",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-6108",
"issue": "38(5)",
"journal": "AJNR. American journal of neuroradiology",
"keywords": null,
"medline_ta": "AJNR Am J Neuroradiol",
"mesh_terms": "D000368:Aged; D002545:Brain Ischemia; D002550:Cerebral Veins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020521:Stroke; D015912:Thrombolytic Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "8003708",
"other_id": null,
"pages": "875-881",
"pmc": null,
"pmid": "28302608",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": "23410687;24882785;19803784;23006622;18077482;25517348;23827386;25476071;22186853;25849958;1461120;25659079;26110628;23802548;25671798;19070701;24065722;22031711;11917903;24291544;24563018;3088671;2016644;26082023;14600444;24781084;9000030;21559032;25040846",
"title": "Ipsilateral Prominent Thalamostriate Vein on Susceptibility-Weighted Imaging Predicts Poor Outcome after Intravenous Thrombolysis in Acute Ischemic Stroke.",
"title_normalized": "ipsilateral prominent thalamostriate vein on susceptibility weighted imaging predicts poor outcome after intravenous thrombolysis in acute ischemic stroke"
} | [
{
"companynumb": "CN-ROCHE-1950851",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Early conversion from a calcineurin inhibitor to belatacept has the potential to improve long-term renal allograft function; however, there remains limited experience with this strategy among African Americans and patients with preformed donor-specific antibodies (DSA). To examine these subgroups, we performed a single-center review of kidney transplant recipients converted to belatacept within 1-year of transplant between 01/2011 and 10/2017. All patients received lymphocyte-depleting induction with maintenance tacrolimus and mycophenolate +/- corticosteroids. Patients were switched to belatacept for clinical indication and followed from date of conversion until allograft failure or study conclusion. The primary endpoint at 1-year was a composite of allograft loss, biopsy proven rejection, de novo DSA formation, proteinuria, and declining renal function. Thirty-two patients were included in the review. The majority were African American, and 28.1% had DSA at transplant. Patient and allograft survival at 1-year was 96.9% and 93.8%, respectively, and estimated glomerular filtration rate improved from 41.9 to 58.4 mL/min. No African Americans or patients with pretreatment DSA developed rejection or allograft failure within 1-year. The only clinical variable correlated with suboptimal allograft function was baseline weight ≥80 kg (OR = 6.2; 95% CI, 1.2-32.3). Early conversion to belatacept appears safe for select patients with DSA and African Americans receiving lymphocyte-depleting induction.",
"affiliations": "Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.;Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.;Department of Population Health Science and Policy, Mount Sinai Hospital, New York, NY, USA.;Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.;Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.;Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.;Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York, NY, USA.",
"authors": "Santeusanio|Andrew D|AD|0000-0002-4575-5330;Bhansali|Arjun|A|;Weinberg|Alan|A|;Shapiro|Ron|R|;Delaney|Veronica|V|;Florman|Sander|S|0000-0002-1635-9136;De Boccardo|Graciela|G|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000069594:Abatacept",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.13823",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "34(4)",
"journal": "Clinical transplantation",
"keywords": "belatacept; immunosuppressive agents; kidney transplantation; transplant rejection",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000069594:Abatacept; D065095:Calcineurin Inhibitors; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "e13823",
"pmc": null,
"pmid": "32049378",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Conversion to belatacept within 1-year of renal transplantation in a diverse cohort including patients with donor-specific antibodies.",
"title_normalized": "conversion to belatacept within 1 year of renal transplantation in a diverse cohort including patients with donor specific antibodies"
} | [
{
"companynumb": "NVSC2020US077331",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "We present a case of osteomyelitis of the condyle secondary to bisphosphonate-related osteonecrosis of the jaw. A 77-year-old female was referred to our clinic with complaints of swelling in the left mandibular molar regions. The patient had been suffering from myeloperoxidase anti-neutrophil cytoplasmic antibody (MPOANCA) associated vasculitis and had been treated with glucocorticoids for 8 years, and oral bisphosphonates had been prescribed to prevent osteopenia secondary to glucocorticoids. Imaging examinations showed radiolucency of the left mandibular body. Based on the diagnosis of osteomyelitis of the mandibular body secondary to bisphosphonate-related osteonecrosis, the patient received antimicrobial therapy and was well-healed. However, the patient returned 8 weeks later complaining of acute left preauricular swelling. Computed tomography showed the destructive changes in the mandibular condyle. We speculated that the infection was caused by the local spread from osteomyelitis of the left mandibular body. The risk of jaw necrosis related to antiresorptive therapy is well known. In recent years, the number of older patients being administered glucocorticoids with bisphosphonates has increased; therefore, we must be attentive to the signs of infectious diseases of the jawbone in the aging because it can easily shift to osteomyelitis or osteonecrosis and spread infection through the marrow.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. hisashi@tokai-u.jp.",
"authors": "Kato|Hisashi|H|;Uchibori|Masahiro|M|;Nakanishi|Yasuhiro|Y|;Kaneko|Akihiro|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005938:Glucocorticoids",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0005",
"issue": "45(3)",
"journal": "The Tokai journal of experimental and clinical medicine",
"keywords": null,
"medline_ta": "Tokai J Exp Clin Med",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007568:Jaw; D008279:Magnetic Resonance Imaging; D008335:Mandibular Condyle; D010019:Osteomyelitis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "7704186",
"other_id": null,
"pages": "126-130",
"pmc": null,
"pmid": "32901900",
"pubdate": "2020-09-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Osteomyelitis of the Mandibular Condyle Secondary to Bisphosphonate-related Osteonecrosis of the Jaw.",
"title_normalized": "a case of osteomyelitis of the mandibular condyle secondary to bisphosphonate related osteonecrosis of the jaw"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-260924",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"d... |
{
"abstract": "The pathophysiology of atypical haemolytic-uraemic syndrome (aHUS) occurring de novo after renal transplantation may include genetic mutations of regulators of complement activation, but they are still rarely determined. A 41-year-old female renal transplant recipient presented two very different episodes of thrombotic microangiopathy. The first episode was associated with antibody-mediated rejection and the second was an isolated, acute aHUS, successfully treated with eculizumab. The diagnosis included a genetic analysis and we found a synonymous variant in the Complement Factor H (CFH) gene, c2634C>T (p.His878=) and low factor H (FH) activity during both events. In conclusion, the diagnosis of aHUS should be considered when TMA is associated with an AMR episode. In this setting, a silent polymorphism of factor H may be responsible for these rare cases of \"de novo\" aHUS after transplantation.",
"affiliations": "Département de Néphrologie, Dialyse et Transplantation Rénale, Cliniques Universitaires de Bruxelles, ULB-Hôpital Erasme, Brussels, Belgium.;Clinique d'Immunobiologie, ULB-Hôpital Erasme, Brussels, Belgium.;Laboratoire d'Anatomie Pathologique, ULB-Hôpital Erasme, Brussels, Belgium.;Département de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium.",
"authors": "Broeders|Emine N|EN|http://orcid.org/0000-0001-5377-9335;Stordeur|Patrick|P|;Rorive|Sandrine|S|;Dahan|Karin|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D017242:Complement Factor H; C481642:eculizumab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D065766:Atypical Hemolytic Uremic Syndrome; D017242:Complement Factor H; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25538218",
"pubdate": "2014-12-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19343177;19179328;19846853;17391126;19775316;14582050;23738544;17716239;20530529;23026949;16338962;18557729;10820178;23141475;17185560;15696434;14978182;22768050;11752044;21102542",
"title": "A 'silent', new polymorphism of factor H and apparent de novo atypical haemolytic uraemic syndrome after kidney transplantation.",
"title_normalized": "a silent new polymorphism of factor h and apparent de novo atypical haemolytic uraemic syndrome after kidney transplantation"
} | [
{
"companynumb": "BE-SA-2019SA220427",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "We report the case of a patient with major depression treated with high-dose bupropion due to prior detected subtherapeutic blood concentrations at standard dosing. Pharmacogenetic panel testing identified the patient as a carrier of the CYP2B6*6 allele, which has been associated with reduced bupropion metabolism and decreased concentrations of the pharmacologically active metabolite hydroxybupropion. Interestingly, we also found the patient to be homozygous for the CYP2C19*17 allele, predicting an ultra rapid metabolizer phenotype. We propose a combined effect of the detected CYP2C19 and CYP2B6 genetic variants on bupropion metabolism. This case underlines the potential benefit of pre-emptive pharmacogenotyping but also the yet still fragmentary evidence making precise pharmacogenotype guided antidepressant selection and dosing challenging.",
"affiliations": "Biopharmacy, Department of Pharmaceutical Sciences, University of Basel, 4056, Basel, Switzerland.;Pharmaceutical Care, Department of Pharmaceutical Sciences, University of Basel, 4001, Basel, Switzerland.;Psychiatric Services Solothurn, Solothurner Spitäler, 4503, Solothurn, Switzerland.;Psychiatric Services Solothurn, Solothurner Spitäler, 4503, Solothurn, Switzerland.;Pharmaceutical Care, Department of Pharmaceutical Sciences, University of Basel, 4001, Basel, Switzerland.;Biopharmacy, Department of Pharmaceutical Sciences, University of Basel, 4056, Basel, Switzerland.",
"authors": "Stäuble|Céline K|CK|0000-0002-2437-4803;Lampert|Markus L|ML|0000-0001-7037-2799;Mikoteit|Thorsten|T|;Hatzinger|Martin|M|;Hersberger|Kurt E|KE|0000-0001-8678-697X;Meyer Zu Schwabedissen|Henriette E|HE|0000-0003-0458-4579",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19",
"country": "England",
"delete": false,
"doi": "10.2217/pgs-2020-0087",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "21(16)",
"journal": "Pharmacogenomics",
"keywords": "CYP2B6; CYP2C19; CYP450; antidepressant; bupropion; depression; pharmacogenomics; psychiatry",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000328:Adult; D000483:Alleles; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D003866:Depressive Disorder; D014644:Genetic Variation; D006760:Hospitalization; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D017211:Treatment Failure",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "1145-1150",
"pmc": null,
"pmid": "33124517",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Nonresponse to high-dose bupropion for depression in a patient carrying CYP2B6*6 and CYP2C19*17 variants: a case report.",
"title_normalized": "nonresponse to high dose bupropion for depression in a patient carrying cyp2b6 6 and cyp2c19 17 variants a case report"
} | [
{
"companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-313999",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"druga... |
{
"abstract": "To report a case of syphilitic interstitial keratitis successfully managed with topical tacrolimus after the development of steroid-induced intraocular pressure elevation in a pediatric patient.\nA 4-year-old female with a history of congenital syphilis that was reportedly treated after birth presented with bilateral conjunctival redness, tearing, and photosensitivity. Initial ophthalmic examination revealed corneal vascularization with diffuse haze of the right eye and circumferential vascularization with stromal infiltrates of the left eye. She was diagnosed with bilateral syphilitic interstitial keratitis and initially managed with topical steroids but developed steroid-induced elevation of her intraocular pressure. She experienced several recurrences of keratitis as steroids were tapered. After a recurrence in her right eye, she was treated with topical tacrolimus. Since then, she has remained recurrence-free for almost three years with normal intraocular pressure.\nTacrolimus represents a novel alternative for the treatment of syphilitic interstitial keratitis, which is particularly useful in patients that develop elevated intraocular pressures in response to long-term treatment with steroid eye drops.",
"affiliations": "Medical College of Wisconsin, 925 N 87th St, Milwaukee, WI, 53226, USA.;University of Wisconsin-Madison, 600 Highland Ave, Madison, WI, 53792, USA.;Medical College of Wisconsin, 925 N 87th St, Milwaukee, WI, 53226, USA.",
"authors": "Martin|Jacob|J|;Kopplin|Laura|L|;Costakos|Deborah|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2021.101175",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00184-5\n10.1016/j.ajoc.2021.101175\n101175\nCase Report\nSyphilitic interstitial keratitis treated with topical tacrolimus\nMartin Jacob jsmartin@mcw.edu\na∗\nKopplin Laura b\nCostakos Deborah a\na Medical College of Wisconsin, 925 N 87th St, Milwaukee, WI, 53226, USA\nb University of Wisconsin-Madison, 600 Highland Ave, Madison, WI, 53792, USA\n∗ Corresponding author. 925 N 87th St, Milwaukee, WI, 53226, USA. jsmartin@mcw.edu\n22 7 2021\n9 2021\n22 7 2021\n23 10117529 8 2020\n15 3 2021\n19 7 2021\n© 2021 Published by Elsevier Inc.\n2021\n\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/).\nPurpose\n\nTo report a case of syphilitic interstitial keratitis successfully managed with topical tacrolimus after the development of steroid-induced intraocular pressure elevation in a pediatric patient.\n\nObservations\n\nA 4-year-old female with a history of congenital syphilis that was reportedly treated after birth presented with bilateral conjunctival redness, tearing, and photosensitivity. Initial ophthalmic examination revealed corneal vascularization with diffuse haze of the right eye and circumferential vascularization with stromal infiltrates of the left eye. She was diagnosed with bilateral syphilitic interstitial keratitis and initially managed with topical steroids but developed steroid-induced elevation of her intraocular pressure. She experienced several recurrences of keratitis as steroids were tapered. After a recurrence in her right eye, she was treated with topical tacrolimus. Since then, she has remained recurrence-free for almost three years with normal intraocular pressure.\n\nConclusion and importance\n\nTacrolimus represents a novel alternative for the treatment of syphilitic interstitial keratitis, which is particularly useful in patients that develop elevated intraocular pressures in response to long-term treatment with steroid eye drops.\n\nKeywords\n\nInterstitial keratitis\nSyphilis\nTacrolimus\nSteroid response\n==== Body\n1 Introduction\n\nInterstitial keratitis is a chronic, stromal inflammation mediated by an autoimmune reaction that may lead to permanent corneal scarring. Typical etiologies of interstitial keratitis include herpes simplex virus, varicella zoster virus, syphilis, and idiopathic.1 Though the mechanism is poorly understood, laboratory studies have revealed changes to the corneal anatomy including vascularization of deep stromal lamellae, thickening of the Descemet membrane with an altered collagen profile, and retrocorneal scrolls.2\n\nCases are typically managed by treatment of the underlying condition, topical or systemic immunosuppression, and management of the side effects of treatments. Complications of management include recurrences of interstitial keratitis, corneal scarring, and glaucoma. Our case is an example of the common management and complications of management of this disease. We present a novel therapeutic modality for syphilitic interstitial keratitis, tacrolimus, which may avoid common treatment complications.\n\n2 Case report\n\nA 4-year-old female adopted at 15-months-old from South Korea presented with a six-week history of bilateral eyelid swelling associated with conjunctival redness, tearing, and photosensitivity. Her medical history included premature birth at 31 weeks and congenital syphilis, reportedly treated although the exact therapeutic regimen was unknown. After being adopted, RPR testing and skeletal X-rays were found to be negative and a Treponema particle agglutination (TP-PA) test was reactive, consistent with successfully treated congenital syphilis. However given the unknown therapeutic regimen, a course of IV penicillin was administered.\n\nOn presentation, the patient was noted to have a visual acuity of 20/60 in the right eye (OD) and 20/25 in the left eye (OS). Given difficulty with the office exam due to photosensitivity, an exam under anesthesia was performed. On portable slit lamp exam, there was extensive right corneal vascularization with diffuse haze and a dense S-shaped haze along the superior pupillary border. The left eye had circumferential vascularization with stromal infiltrates at the border of the vessels; however, the central portion of the left cornea was clear. Aside from 2+ bilateral conjunctival injection, the remainder of the ocular exam was normal. Her refractive error was noted to be +4.25 sphere OD and +3.25 sphere OS. Intraocular pressures were 20 mmHg OD and 15 mmHg OS.\n\nIn light of her history, her findings were consistent with bilateral interstitial keratitis secondary to congenital syphilis. She was treated with topical prednisolone acetate 1 % and cyclopentolate in both eyes (OU). Both her photosensitivity and conjunctival injection improved markedly on this therapy. Her refractive error was noted to decrease to +0.75 + 0.50 × 087 OD and +0.50 sphere OS. After one month of therapy, she was noted to have a visual acuity of 20/20 OU with stromal haze sparing the visual axis OD and resolution of corneal haze OS. Her drops were weaned over a period of one month.\n\nOver the following three years, she developed several episodes of recurrent keratitis in both eyes, although this was typically asymmetric, with keratitis more often needing treatment in the right eye than the left eye. At her nadir, her visual acuity worsened to 20/80 in the right eye and 20/30 in the left eye. Additionally after a recurrence OD, she was noted to develop a large refractive shift over six months to −4.50 + 6.00 × 100 OD, while the left eye refraction remained relatively stable.\n\nThe keratitis required treatment with multiple rounds of topical prednisolone acetate 1 % which remained effective in controlling the inflammation; however, the patient developed steroid-induced intraocular pressure (IOP) elevation, with eye pressure maximally elevated to 32 mmHg OD and 45 mmHg OS (Baseline IOP was 13 mmHg OU). Elevated IOP was lowered with the addition of topical dorzolamide, latanoprost and timolol. While elevation of IOP was not marked with prednisolone 0.12 % or the subsequent use of loteprednol, these medications were not adequate to maintain disease quiescence.\n\nAfter the patient developed a severe recurrence of keratitis with extension into the visual axis in her left eye, treatment with oral systemic prednisone 0.5 mg/kg/day was initiated with resolution of keratitis. Following a two-month taper of systemic corticosteroids, the patient stayed in remission for several months with daily loteprednol; however, she then developed a keratitis relapse in her right eye with decrease of vision to 20/80 (Fig. 1). Treatment with systemic prednisone again restored quiescence and the patient was started on topical cyclosporine 0.05 % twice daily in the right eye one month into her oral steroid taper; however, cyclosporine also proved inadequate to maintain quiescence, with her exam exhibiting worsened stromal haze, vascularization of the cornea, and decline in best corrected visual acuity to 20/60.Fig. 1 Diffuse (1A) and slit beam (1B) photos of the right eye exhibiting recurrent interstitial keratitis with paracentral infiltrates with central haze.\n\nFig. 1\n\nTopical Tacrolimus ointment 0.03 % twice daily was then started in the right eye. Only Cosopt BID was concurrently used for treatment of the right eye. Within one month of instituting tacrolimus, her keratitis markedly improved with decrease in vascular precipitations without elevation of IOP. She was initially maintained on loteprednol daily OS but was transitioned to tacrolimus after one year of therapy OD. Over the following three years, she had no episodes of recurrence in either eye. On last exam, she was noted to have sustained improvement in corneal haze (Fig. 2), normal IOP, visual acuities of 20/25 OD and 20/20 OS, and refractive error measuring −2.75 + 3.25 × 118 OD and +0.50 + 0.50 × 135 OS.Fig. 2 Slit lamp photo of the right eye taken 9 months after starting treatment with topical tacrolimus. Corneal exudates have resolved with some residual patent vasculature and haze.\n\nFig. 2\n\n3 Discussion\n\nInterstitial keratitis is an autoimmune-mediated stromal inflammation that can lead to permanent, visually-significant scarring of the cornea.1 In our patient, interstitial keratitis was secondary to congenital syphilis which developed despite having been treated with IV penicillin years prior to the development of ophthalmic complications. Her chronic, relapsing inflammation was initially managed with topical steroids, but this treatment resulted in the complication of steroid-induced IOP elevation that is often encountered when managing ocular inflammatory conditions. Low-dose topical steroids, oral prednisone, IOP lowering medications, and topical cyclosporine were tried without success. Prior to the consideration of glaucoma filtering surgery or systemic immunosuppression with steroid sparing agents, all of which have significant morbidity in the pediatric population, we attempted treatment with tacrolimus.\n\nTacrolimus is a macrolide produced from soil samples containing the bacteria Streptomyces tsukubaensis that inhibits calcineurin activity, leading to inhibition of T lymphocytes.3 Tacrolimus has been used for the treatment of other inflammatory ocular diseases including vernal conjunctivitis,4 acute graft rejection after penetrating keratoplasty,5 anterior uveitis, scleritis, and graft versus host disease.3 Side effects of topical tacrolimus are reportedly minimal, but include transient ocular irritation on administration and increased risk of corneal infection with prolonged use.3,4 Systemic adverse effects from tacrolimus are unlikely to occur, as a study examining the blood concentrations of patients after topical administration of tacrolimus showed systemic exposure was minimal and transient.6\n\nTo our knowledge, topical tacrolimus has been used for the treatment of interstitial keratitis in two other reports.1,7 The first paper involved the treatment of a 12 year-old-boy with a 3-year history of interstitial keratitis suspected to be secondary to zoster sine herpete. After failure of topical and systemic steroids, topical cyclosporine 0.5 % was initially instituted; however, this was abandoned in favor of topical tacrolimus 0.1 % after continued recurrence was noted. The improved response between the two topical therapies was thought to be secondary to tacrolimus’ comparatively increased potency. Similarly, we observed a better therapeutic response to topical tacrolimus compared to topical cyclosporine.\n\nThe second paper details a randomized control trial in which patients diagnosed with suspected HSV stromal keratitis received either systemic acyclovir with topical prednisolone or 0.05 % tacrolimus eye drops four times daily in addition to systemic acyclovir and topical prednisolone. Throughout one month of therapy, the group receiving tacrolimus exhibited significantly faster improvement in best corrected visual acuity and faster resolution of both corneal edema and vascularization (as determined by masked observers using a grading scale designed for this study). There was no data following one month of therapy; so, it is unknown if these effects were sustained or how the investigators planned to manage patients’ treatment regimens (i.e. tapering drops).\n\nDespite the successful treatment of the patient's recurrent keratitis with tacrolimus, several questions remain regarding her future management. Presently, topical tacrolimus is prepared for dermatologic use but can be compounded through specialty pharmacies for ocular administration by dilution with balanced salt solution and repackaging for easier administration; however, the ideal dosage for the treatment of corneal disease has not been determined. Additionally, we do not have long term studies describing the effect of tacrolimus on the cornea, a particular concern in pediatric patients who may have to deal with complications of treatment throughout their lives. Additional questions include the length of proposed treatment with tacrolimus, the benefits of treatment of the patient's fellow eye despite current control with low dose steroids, and the future management of her marked refractive changes in her right eye.\n\n4 Conclusions\n\nTopical tacrolimus is an effective therapy for syphilitic interstitial keratitis.\n\nPatient consent\n\nThe patient's legal guardian consented to publication of the case.\n\nFunding\n\nNo funding was received for this work.\n\nAuthorship\n\nJacob Martin: Writing-Original Draft; Laura Kopplin: Writing-Review & Editing, investigation, conceptualization; Deborah Costakos: Writing-Review & Editing, investigation, conceptualization.\n\nDeclaration of competing interest\n\nNo conflict of interest exists.\n\nAcknowledgements and Disclosures\n\nNo funding or grant support was used for the writing of this article. JM, LJK and DMC have no financial disclosures. All authors attest that they meet the current ICMJE criteria for Authorship.\n==== Refs\nReferences\n\n1 Joko Therapeutic effect of 0.1% topical tacrolimus for childhood interstitial keratitis refractory to cyclosporine J Nippon Med Sch 83 1 2016 31 34 26960587\n2 Dogru Immunohistochemistry and electron microscopy of retrocorneal scrolls in syphilitic interstitial keratitis Curr Eye Res 32 10 2007 863 870 17963106\n3 Shoughy S. Topical tacrolimus in anterior segment inflammatory disorders Eye Vis 4 2017 7\n4 Samyukta Monotherapy of topical tacrolimus 0.03% in the treatment of vernal keratoconjunctivitis in the pediatric population J AAPOS 23 1 2019 36.e1 36.e5 30664932\n5 Hashemian Topical tacrolimus as adjuvant therapy to corticosteroids in acute endothelial graft rejection after penetrating keratoplasty: a randomized control trial Cornea 37 3 2018 307 312 29215395\n6 Ebihara Blood level of tacrolimus in patients with severe allergic conjunctivitis treated by 0.1% tacrolimus ophthalmic suspension Allergol Int 61 2 2012 275 282 22361511\n7 Akbari Topical tacrolimus as an adjunct to conventional therapy for stromal herpetic keratitis: a randomized clinical trial J Ophthalmic Vis Res 14 4 2019 400 411 31875094\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "23()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Interstitial keratitis; Steroid response; Syphilis; Tacrolimus",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "101175",
"pmc": null,
"pmid": "34368498",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "26960587;29215395;17963106;31875094;30664932;28286787;22361511",
"title": "Syphilitic interstitial keratitis treated with topical tacrolimus.",
"title_normalized": "syphilitic interstitial keratitis treated with topical tacrolimus"
} | [
{
"companynumb": "US-LEO PHARMA-338352",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "4",
"d... |
{
"abstract": ": Background: Kidney function in preterm newborns may be impaired by many factors.\n\n\nMETHODS\n71 newborns with gestational age (GA) < 32 weeks were enrolled. Serum creatinine (sCr), cystatin C (CysC), beta-trace protein (BTP) and urea were measured at T0 (3rd day of life) and T36 (GA 36 weeks), and estimated glomerular filtration rate (eGFR) was calculated according to different formulas at T36. Pre-natal and post-natal kidney injury risk scores were calculated.\n\n\nRESULTS\nNewborns with GA ≤ 28 weeks had higher sCr at T0, and lower sCr, BTP and higher urea levels at T36 (p = 0.007, p = 0.005 and p = 0.029, respectively). eGFR values were not different according to GA when calculated by the formulas using only CysC, but were higher in subjects with GA ≤ 28 weeks according to the other formulas. The post-natal score was positively correlated with eGFR according to sCr-based formulas, but the correlations did not persist when adjusted for urea levels and GA.\n\n\nCONCLUSIONS\nCysC-based eGFR values are not influenced by GA. Post-natal score shows a direct correlation with eGFR according to sCr-based formulas, not persisting after adjustment for GA and urea levels, implying the importance of the nutritional status, since more premature subjects receive a more aggressive nutritional regimen, testified by higher urea levels.",
"affiliations": "Division of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy.;Clinical Chemistry Laboratory, Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy.;Pediatric and Neonatal Intensive Care Unit, Maggiore della Carità University Hospital, 28100 Novara, Italy.;Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, 20122 Milan, Italy.;Clinical Chemistry Laboratory, Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy.;Pediatric and Neonatal Intensive Care Unit, Maggiore della Carità University Hospital, 28100 Novara, Italy.;Division of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy.;Interdisciplinary Research Center of Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy.",
"authors": "Monzani|Alice|A|;Crespi|Ilaria|I|;Genoni|Giulia|G|;Edefonti|Alberto|A|;Montini|Giovanni|G|;Bellomo|Giorgio|G|;Ferrero|Federica|F|;Bellone|Simonetta|S|;Prodam|Flavia|F|",
"chemical_list": "D055316:Cystatin C; D054834:Lipocalins; D014508:Urea; D003404:Creatinine; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/nu12030651",
"fulltext": "\n==== Front\nNutrients\nNutrients\nnutrients\nNutrients\n2072-6643 MDPI \n\n10.3390/nu12030651\nnutrients-12-00651\nArticle\nKidney-Detrimental Factors and Estimated Glomerular Filtration Rate in Preterm Newborns: The Role of Nutrition\nhttps://orcid.org/0000-0002-6676-5773Monzani Alice 1 https://orcid.org/0000-0002-7533-5548Crespi Ilaria 2 Genoni Giulia 3* Edefonti Alberto 4 https://orcid.org/0000-0002-7350-4475Montini Giovanni 45 Bellomo Giorgio 2 Ferrero Federica 3 Bellone Simonetta 16 https://orcid.org/0000-0001-9660-5335Prodam Flavia 67 1 Division of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; alice.monzani@gmail.com (A.M.); simonetta.bellone@med.uniupo.it (S.B.)\n2 Clinical Chemistry Laboratory, Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; ilaria.crespi@maggioreosp.novara.it (I.C.); bellomo.giorgio@gmail.com (G.B.)\n3 Pediatric and Neonatal Intensive Care Unit, Maggiore della Carità University Hospital, 28100 Novara, Italy; federicaferrero@libero.it\n4 Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Ca’ Granda IRCCS, Ospedale Maggiore Policlinico, 20122 Milan, Italy; aedefonti@hotmail.com (A.E.); giovanni.montini@unimi.it (G.M.)\n5 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy\n6 Interdisciplinary Research Center of Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; flavia.prodam@med.uniupo.it\n7 Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy\n* Correspondence: genonigiulia@gmail.com; Tel.: +39-03213732150; Fax: +39-03213733598\n28 2 2020 \n3 2020 \n12 3 65102 2 2020 25 2 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/).Background: Kidney function in preterm newborns may be impaired by many factors. Methods: 71 newborns with gestational age (GA) < 32 weeks were enrolled. Serum creatinine (sCr), cystatin C (CysC), beta-trace protein (BTP) and urea were measured at T0 (3rd day of life) and T36 (GA 36 weeks), and estimated glomerular filtration rate (eGFR) was calculated according to different formulas at T36. Pre-natal and post-natal kidney injury risk scores were calculated. Results: Newborns with GA ≤ 28 weeks had higher sCr at T0, and lower sCr, BTP and higher urea levels at T36 (p = 0.007, p = 0.005 and p = 0.029, respectively). eGFR values were not different according to GA when calculated by the formulas using only CysC, but were higher in subjects with GA ≤ 28 weeks according to the other formulas. The post-natal score was positively correlated with eGFR according to sCr-based formulas, but the correlations did not persist when adjusted for urea levels and GA. Conclusions: CysC-based eGFR values are not influenced by GA. Post-natal score shows a direct correlation with eGFR according to sCr-based formulas, not persisting after adjustment for GA and urea levels, implying the importance of the nutritional status, since more premature subjects receive a more aggressive nutritional regimen, testified by higher urea levels.\n\npreterm newbornkidney functionCystatin CBeta-trace proteinchronic kidney diseaseparenteral nutrition\n==== Body\n1. Introduction\nThe survival of preterm newborns has dramatically improved in the recent decades, with babies born as young as 25-week gestation having up to the 80% chance of survival [1]. Preterm birth has a potential detrimental influence on kidneys developmental programming. Nephrogenesis is completed between 32 and 36 weeks of gestation, with most nephrons being formed during the third trimester of pregnancy [2]. Therefore, preterm birth may negatively impact on nephron endowment. Additionally, any further impact on nephron number and function at the very beginning of life (nephrotoxic medications, mechanical ventilation with possible hyperoxia or hypoxia, hemodynamic instability) increases the risk of adverse consequences for life-long renal health [3].\n\nIn clinical routine, the most used endogenous biomarker for the assessment of neonatal kidney function is serum creatinine (sCr). However, in childhood it is dependent on age, gender and muscle mass. Furthermore, in premature newborns sCr shows a great variability in the first week of life in part due to the passage of maternal Cr through the placenta and in part to its reabsorption in the proximal tubules caused by tubular membrane immaturity, thus it is quite insensitive to detecting mild to moderate reductions in glomerular filtration rate. In the last years, new potential endogenous biomarkers have been proposed, such as cystatin C (CysC) [4] and beta-trace protein (BTP) [5]. CysC is a low molecular weight protein (13,343 Da, 120 amino acids) belonging to the cystatin superfamily of reversible inhibitors of cysteine proteases of the papain and legumain families [6]. In contrast with sCr, CysC does not seem to be affected by body muscle mass, age, gender, inflammatory state, or nutritional conditions [7]. As for creatinine, CysC is freely filtered through glomeruli. There are limited studies of CysC use to assess renal function in neonates [8,9,10], but it could be a promising biomarker as only minimal amounts cross the placenta, thereby reflecting mostly neonatal function [11]. Also BTP, a 23- to 29-kD enzyme consisting of 168 amino acids, may be a good marker of neonatal renal function because it is freely filtered at glomerular level and it does not cross the placenta at all [12].\n\nIn the present study we aim to evaluate CysC and BTP levels in preterm newborns, and to compare different formulas for estimating glomerular filtration rate (eGFR) based on CysC, BTP or sCr. Moreover, we aim to assess the impact of pre-natal and post-natal potentially kidney-detrimental factors on kidney function of preterm newborns.\n\n2. Methods\nWe performed an observational longitudinal study in the Neonatal Intensive Care Unit (NICU) of Maggiore della Carità University Hospital, Novara, a tertiary level perinatal center. We enrolled all the preterm babies with a gestational age (GA) ≤ 32 weeks born between September 2015 and December 2017. Exclusion criteria were the presence of prenatally detected kidney anomalies and complex syndromes or congenital anomalies. The protocol was conducted in accordance with the declaration of Helsinki and was approved by the Local Ethic Committee of Maggiore della Carità University Hospital of Novara (CE 79/18). Written informed consent was obtained by the newborns’ parents.\n\nPreterm babies were enrolled at birth and assessments were performed at two time points: T0, on the 3rd day of life, and T36, when they reached a GA of 36 weeks. The T0 timing was chosen on the basis that neonatal sCr values are influenced by maternal ones in the first 48–72 h after birth; the T36 timing because nephrogenesis is supposed to be completed at 36 weeks GA. Babies who were discharged or transferred to other hospitals or died before 36 weeks GA performed only the T0 assessment. \n\n2.1. Anamnestic and Clinical Course Data\nFrom medical records, we collected for each subject the following data: gender, GA, birth weight, single/multiple gestation, delivery mode, use of nephrotoxic drugs during pregnancy, positive family history for arterial hypertension (within the second degree of kinship), history of intrauterine growth restriction (IUGR) or maternal pre-eclampsia/eclampsia. GA was determined by fetal ultrasound and last menstrual period. INeS charts [13] were used to evaluate birth weight categories. Nephrotoxic drugs administered to the mothers included betamethasone [14], non-steroidal anti-inflammatory drugs [15], anti-hypertensive drugs [16], and anti-microbial agents [17].\n\nFrom our NICU dataset, we collected for each subject the following data: invasive and non-invasive ventilation and their duration, length of O2-support, bronchopulmonary dysplasia (BPD), sepsis, use and duration of antibiotic therapy especially nephrotoxic drugs (gentamicin, vancomycin), patent ductus arteriosus (PDA), pharmacological (ibuprofen) or surgical treatment for hemodynamic significant PDA, necrotizing enterocolitis (NEC), intra-ventricular hemorrhage (IVH), length of stay in the NICU, administration of parenteral nutrition and its duration.\n\nThe durations were expressed as number of days. The Yes/No items were used to create one prenatal and one postnatal kidney injury risk score (Yes = 1 point; No = 0), given by the sum of all the “Yes” answers to the presence of potential risk factors for kidney injury [16,17] (Table 1).\n\n2.2. Nutritional Regimen\nIn the subjects receiving parenteral nutrition, the protocol was as follows: (i) total parenteral nutrition with a high level of amino acids (3 g/kg/day) from the first hours of life, (ii) lipids from the first 24 h of life at 1.5–2.5 g/kg/day increasing to 3.5 g/kg/day and (iii) minimal enteral feeding at 10–20 mL/kg/day from the first one to two days of life [18]. The parenteral solutions supplied a minimum of 51 kcal/kg/day with 3 g/kg/day of proteins on the first day of life, up to a minimum of 100 kcal/kg/day and 4 g/kg/day of proteins in the first week. Enteral feeding was initiated within 48 h of postnatal life using breastmilk or preterm formula when breastmilk was not available, and this provided 83 kcal/100 mL of energy. Enteral feeding stages were based on corrected age and on the clinical conditions of each infant. When the infants tolerated an enteral intake of ≥100 mL/kg, parenteral nutrition was discontinued.\n\n2.3. Anthropometric Measurements\nWeight and length were measured at T0 and T36. Birth weight was measured using an electronic weighting scale integrated into the incubator until the babies were taken in the incubators, and then by an electronic infant weighting scale. The crown-heel length measurement was carried out with a Harpenden neonatometer with the baby lying supine and with the body, hips, and knees straightened; measurements were taken twice and then averaged. Body surface area (BSA) was calculated according to Haycock formula: BSA (m2) = 0.024265 × L (cm) 0.3964 × weight (kg) 0.5378 \n\n2.4. Biochemical Parameters\nVenous or arterial blood samples were collected at T0 and T36, and sCr, CysC, BTP and urea were measured.\n\nsCr: was measured on an ADVIA Chemistry 1800 or ADVIA Chemistry XPT with an enzymatic assay. This method is considered more specific and reliable than all the Jaffé modified methods. The analytical variability coefficient was <3%.\n\nCys C: was measured with BN II/ BN ProSpec® by amplified latex immunophelometry. \n\nBTP: was measured on serum sample with N Latex BTP system. N Latex BTP is BTP specific. \n\nUrea: was measured on ADVIA Chemistry 1800 or ADVIA Chemistry XPT using the glutamate dehydrogenase lined enzyme assay system. The analytical variability coefficient was <2.5%.\n\neGFR was calculated according to 9 existing formulas, including sCr in 2 cases, CysC in 5 cases, BTP in 1 case and combining sCr and CysC in 1 case. The applied formulas were: (1) eGFR Schwartz 2009: 0.413 × lenght/sCr [19]; (2) eGFR Brion: 0.33 × lenght/sCr [20]; (3) eGFR Schwartz 2012: 70.69 × (CysC) −0.931 [21]; (4) eGFR Zappitelli: 75.94 × (CysC) −1.170 [22]; (5) eGFR Filler: 91.62 × (CysC) −1.123 [23]; (6) eGFR Dorum: 74.835 × (CysC) −0.750 [24]; (7) eGFR Treiber: [(TKV/BSA)/CysC]/1.73 [25]; (8) eGFR Benlamri: 10 (1.902+(0.9515 × LOG(1/BTP))) [26]; (9) eGFR Zappitelli-combined: (43.82 × e\n0.003 × L)/(CysC 0.635 × sCr 0.547) [22].\n\n2.5. Kidney Ultrasonography\nAt T0 and T36 a kidney ultrasonography (US) was performed by a 5–8 MHz sector transducer (Philips HD7XE Ultrasound System). To avoid inter-observer bias during scanning and measuring, all US scans of the kidneys were performed by a single neonatologist, skilled in renal US. Renal length, anteroposterior diameter (width), and transverse diameter (depth) were measured for both kidneys. Kidney volume (KV; ml) was calculated by the equation for an ellipsoid: volume = length × width × depth × π/6. \n\nTotal kidney volume (TKV) was calculated by the sum of left and right kidney volumes, and its ratio to BSA was calculated too.\n\n2.6. Statistical Analysis\nData were expressed as mean ± standard deviation (SD), for continuous variables, and as number and percentage (%), for categorical variables. \n\nFor some analyses, subjects were divided into two subgroups according to GA (≤ and >28 weeks). Comparisons between groups were performed using Kruskal–Wallis analysis of variance (ANOVA) and the Mann–Whitney U test, as appropriate. Comparisons between paired data (T0 vs. T36) were performed by Wilcoxon signed rank test. Correlations between continuous variables were evaluated by Spearman rank order correlation. A p value of < 0.05 was considered statistically significant. All analyses were performed using SPSS version 21.0 (IBM, New York, NY, USA).\n\n3. Results\nAt T0, we enrolled 71 newborns (M:F = 37:34), born between 24 and 32 weeks of GA (mean GA 28.5 ± 2.16). Out of them, 31 (43.7%) had a GA ≤ 28 weeks. At T36, data could be collected for 53 patients, since 5 newborns (7%) were dead and 13 (18.3%) were back-transferred before 36 weeks GA to other second-level neonatology units.\n\n3.1. Anamnestic and Clinical Course Data\nThe delivery mode was vaginal eutocic in 13 newborns (19.4%), vaginal dystocic in 1 (1.5%), and caesarean section in 53 (79.1%). Sixty-one neonates were singletons (85.9%) and 10 were twins (14.1%). A history of IUGR was reported in 12 neonates (16.9%), of pre-eclampsia in 20 (28.2%), administration of at least one potential nephrotoxic drug in 54 mothers (76.1%). In 25 newborns (35.2%) a positive family history for arterial hypertension was reported. Seven newborns (9.9%) were classified as small for gestational age. \n\nClinical course data are shown in Table 2. In the overall group, the mean prenatal and postnatal scores were 1.5 ± 0.9 and 3.6 ± 1.6, respectively. Comparing the groups of subjects with a GA ≤ 28 weeks and >28 weeks, the prenatal score was similar (1.4 ± 0.9 vs. 1.6 ± 0.9, NS), whereas the postnatal score was significantly higher in the subjects with a lower GA (4.5 ± 1.6 vs. 2.9 ± 1.3, p < 0.0001).\n\nAll the infants with a GA ≤ 28 weeks received parenteral nutrition, whereas 53.6% of those with a GA > 28 weeks did (p < 0.0001). Also duration of parenteral nutrition was significantly higher in newborns with a GA ≤ 28 weeks (24.6 ± 13.4 days vs. 15.7 ± 4.2, p = 0.02).\n\n3.2. Anthropometric Data\nAnthropometric data at T0 and T36 are shown in Table 3. At T0, all anthropometric parameters were significantly lower in newborns with a GA ≤ 28 weeks (p < 0.0001 for each), whereas at T36 they were not different in the two groups. No differences were found in any of the anthropometric measures according to gender at T0, whereas at T36 males had higher weight, length and BSA (p = 0.03 for each).\n\n3.3. Biochemical and Ultrasonography (US) Data\nMean sCr, CysC, BPT, and urea values in the overall group and according to GA at T0 and T36 are reported in Table 4. \n\nNo differences were found for any of the biochemical and US data according to gender at T0 and T36. At T0, newborns with a GA ≤ 28 weeks had higher sCr levels than those with a GA > 28 weeks (Figure 1). At T36, newborns with a GA ≤ 28 weeks had lower sCr and BTP, and higher urea levels than those with a GA > 28 weeks (Figure 1). No difference was found for CysC values at T0 and T36 according to GA.\n\nsCr levels decreased over time both in subjects with a GA ≤ 28 weeks and >28 weeks, CysC decreased only in subjects with a GA ≤ 28 weeks, urea levels decreased in both groups, whereas BTP did not significantly vary over time. CysC ranged between 0.44–2.67 mg/L at T0 and between 0.75–2.1 mg/L at T36, with values higher than 2 mg/L in 5 subjects at T0, remaining higher than this cut–off only in 1 subject at T36. eGFR values are shown in Table 5. No differences were found in newborns with a GA ≤ 28 weeks and >28 weeks calculating eGFR by the four formulas using only CysC. Conversely, eGFR values estimated by other formulas were higher in subjects born at a lower GA. \n\nTKV/BSA increased overtime in both groups, without differences according to GA (in subjects with a GA ≤ 28 weeks 114.44 ± 42.85 mL/m2 at T0 vs. 355.04 ± 156.66 mL/m2 at T36, p = 0.001; in subjects with a GA > 28 weeks 105.87 ± 26.69 mL/m2 at T0 vs. 330.24 ± 81.4 mL/m2 at T36, p < 0.0001).\n\n3.4. Correlation Analyses\nAt T0, sCr values were positively correlated with CysC and BPT levels (R = 0.415, p = 0.01 and R = 0.274, p = 0.04, respectively). At T0, sCr was negatively correlated with GA (R = −0.315, p = 0.009), whereas both CysC and BTP were not influenced by GA. T0 levels of sCr, CysC and BTP did not correlate with anthropometric parameters, even when adjusted for GA. At T36, sCr values were positively correlated with CysC and BPT levels (R = 0.527, p = 0.001 and R = 0.494, p = 0.003, respectively). CysC and BTP were directly correlated (R = 0.531, p = 0.001). Neither sCr nor CysC nor BTP correlated with urea at T36. Levels of sCr, CysC, BTP and urea did not correlate with anthropometric measures at T36. The T36 levels of sCr, CysC and BTP were all directly correlated with GA (R = 0.469, p = 0.001; R = 0.317, p = 0.046; and R = 0.482, p = 0.002, respectively).\n\neGFR was negatively correlated with GA according to all formulas (p < 0.05), but the correlation did not persist when adjusted for weight, length, and urea levels at T36. No correlation was found between kidney volume and eGFR according to all formulas.\n\nPostnatal kidney injury risk scores were negatively correlated with GA (R = −0.552, p < 0.0001).\n\nAll the anthropometric measures at T36 were inversely correlated with kidney injury risk scores. Weight at T36 was negatively correlated with both prenatal and postnatal scores (R= −0.533, p < 0.0001, and R = −0.337, p = 0.02, respectively), also when adjusted for GA. Likewise, length at T36 was negatively correlated with prenatal score (R = −0.422, p = 0.003), also when adjusted for GA. No correlation was found between the kidney injury risk scores and kidney volumes.\n\nThe prenatal score did not correlate with eGFR calculated with any formulas. We found a direct correlation between the postnatal score and eGFR estimated according to Schwartz 2009 (R = 0.345, p = 0.027) and Brion’s formulas (R = 0.312, p = 0.044). However, these correlations did not persist when adjusted for weight, length and BSA at T36. The correlations did not persist also when adjusted for urea levels at T36 and GA. Conversely, no significant correlations were found between the scores and eGFR according to the other formulas.\n\n4. Discussion\nIn our study, we firstly aimed to compare the performance of CysC and BPT to traditional sCr in preterm newborns. At the 3rd day of life, CysC and BTP levels in our NICU population were comparable to the reference ranges previously reported for premature infants of similar GA [9,26], with only sCr values negatively correlated with GA. None of the biomarkers were influenced by gender or anthropometric parameters at T0. Our results are consistent with previous data by Armangil et al. in a cohort of preterm newborns with a mean GA of 32 weeks [27]. Similarly, Elmas et al. reported that CysC values measured at the 3rd day of life were independent of GA, birth weight and gender [28]. The lack of correlation we found between BTP and GA in our cohort was previously described by Filler et al. both in preterm and term newborns [29]. \n\nNotably, in our cohort 5 out of 71 subjects showed at T0 CysC levels higher than 2 mg/L, reported to correspond to an inulin clearance < 0.5 mL/min per kg according to Montini G et al. [30]. At T36, CysC persisted higher than this cut–off only in one infant, suggesting that the kidney function of preterm subjects tends to improve in most cases, despite potentially kidney–detrimental events during NICU staying. \n\nAt T36, sCr and BTP levels decreased in subjects with lower GA. One could hypothesize that the lower sCr values may be the hallmark of a worse nutritional state and of a reduced muscle mass. The higher urea levels in infants with a GA ≤ 28 weeks seem to contradict this hypothesis. Therefore, it could be argued that the reduced levels of sCr and BTP found in subjects with a lower GA may indicate a better kidney function. In our cohort CysC values were independent of GA at T36. All the three biomarkers were not influenced by anthropometric measures at T36. Intuitively, because of the lower sCr and BTP levels, in the group of infants born before 28 weeks GA also the eGFR calculated by formulas using sCr or BTP (Schwartz 2009, Brion, Treiber, Benlarmi and Zappitelli–combined) were significantly higher. Interestingly, we found the unexpected result that eGFR was negatively correlated with GA, apparently indicating that subjects born at a lower GA have a better renal function at T36. However, the correlations did not persist when adjusted for weight, length, and urea levels at T36. Therefore, we may hypothesize that the confounder underlying this association is the nutritional status of preterm newborns. Indeed, in subjects born before the 28 weeks of GA, anthropometric measures at T0 were significantly lower than in those with a GA > 28 weeks, but these differences did not persist at T36. This may be probably since more premature subjects received a more aggressive and careful nutritional regimen, as suggested by the higher urea levels found in newborn with a GA ≤ 28 weeks at T36. This hypothesis may also be supported by the significantly higher percentages of subjects receiving parenteral nutrition in this group. Indeed, all newborns with GA ≤ 28 weeks received parenteral nutrition, whereas only half of the subjects with GA > 28 weeks did. \n\nFurthermore, we must highlight the high variability in eGFR calculated according to the nine formulas. Abitbol et al. showed in preterm and term infants that Cr–based equations consistently underestimated GFR, whereas CysC and combined equations were more consistent with reference inulin clearance studies [31].\n\nSecondly, we aimed to assess the possible impact of pre–natal and post–natal potentially kidney-detrimental factors on kidney function of preterm newborns. In our cohort, the post–natal injury risk score was higher in newborns with lower GA, as intuitively foreseeable in more premature babies with a longer NICU stay. Therefore, we expected that subjects born at a lower GA and facing more potentially kidney-detrimental events would have an impaired kidney function at T36, as estimated by eGFR. Surprisingly, we found a direct correlation between post–natal score and eGFR estimated according to the formulas of Schwartz 2009 and Brion. However, these correlations did not persist when adjusted for weight, length and BSA. Conversely, no significant correlations were found between the score and eGFR according to the other formulas. Indeed, the Schwartz 2009 and Brion formulas rely on sCr values, that are known to be influenced by nutritional status and muscle mass. In our cohort, sCr at T36 was significantly lower in subjects with lower GA. Moreover, such correlations did not persist also when adjusted for urea levels at T36, probably for the same reasons already explained for the inverse correlation between eGFR and GA. eGFR at T36 does not seem to be influenced by prenatal factors. Moreover, neither prenatal nor post–natal factors influence kidney volumes at T36 in our cohort. \n\n5. Limitations\nThe post–natal variables considered as potentially kidney-detrimental are basically hallmarks of a rougher and more troubled NICU course. Therefore, they probably impair other functions of the preterm organism, and it would be difficult to disentangle the additive or synergic effects of these alterations. Moreover, due to the limited sample number, we could not assess the single contribution of all the considered risk factors on renal function. Another limit of our study is the lack of a gold standard for renal function, as it was not assessed by direct methods. Finally, we did not perform either the assessment of lean mass (for example, by bioimpedentiometry), or US and biochemical evaluation of liver function, that could have an impact on sCr production and metabolism, potentially leading to an under- or– over-estimate of its levels in preterm newborns.\n\n6. Conclusions \nAs almost 13 million infants worldwide are born prematurely each year, it is important to identify those at higher risk for developing chronic kidney disease due to congenital or acquired low nephron number. \n\nCysC seems to be a promising biomarker of renal function, as it is not influenced by GA, gender or anthropometric parameters soon after birth and by gender, anthropometric parameters and nutritional status at 36 weeks of post–menstrual age. In preterm infants, the chance to precociously detect kidney damage could allow prompt interventions that might prevent future and more serious/irreversible damages. However, its measurement is quite expensive and not widespread.\n\nIn the perspective of the best care for the preterm newborn, the potentially damaging events occurring in prenatal life have little if no impact on future kidney health. Conversely, postnatal clinical course may influence kidney function, mainly the nutritional status of preterm infants. Indeed, subjects born at a lower GA but receiving more intensive and targeted nutritional interventions may have a better renal function.\n\nTo our knowledge, this is the first study reporting a kidney-sparing effect of nutritional strategies in preterm newborns. From a clinical point of view, our findings should raise the awareness of the crucial role of nutrition, starting from the very beginning of life. \n\nFuture studies are needed to understand which practices during the stay in NICU need to be changed to preserve future kidney function, and to evaluate which nutritional strategies would be more protective of renal health.\n\nAuthor Contributions\nConceptualization, A.M., A.E. and G.M.; Methodology, A.M., G.G., A.E. and G.M.; Validation, G.B., F.F., S.B. and F.P.; Formal Analysis, I.C. and G.B.; Investigation, A.M., G.G., F.F.; Data Curation, A.M. and I.C.; Writing—Original Draft Preparation, A.M., I.C. and G.G.; Writing—Review and Editing, S.B. and F.P.; Supervision, G.M., G.B., F.F., S.B. and F.P. All the authors have approved the submitted version and agree to be personally accountable for their own contributions and for ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated, resolved, and documented in the literature. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThe study was funded by the Università del Piemonte Orientale, FAR–2016.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Serum Creatinine (sCr), Cystatine C (CysC), Beta-Trace Protein (BTP) and urea levels at T0 and T36, according to gestational age.\n\nnutrients-12-00651-t001_Table 1Table 1 Items considered in prenatal (range 0–4 points) and postnatal (range 0–10 points) kidney injury risk scores (each ‘Yes’ answer accounts for 1 point).\n\nPrenatal Kidney Injury Risk Score\tPostnatal Kidney Injury Risk Score\t\nIUGR\tBorn SGA \t\nMaternal pre-eclampsia\tNeed for invasive ventilation\t\nNephrotoxic medications during pregnancy\tNeed for non-invasive ventilation\t\nPositive family history for arterial hypertension\tBPD\t\n\n\tSepsis\t\n\n\tUse of nephrotoxic antimicrobic agents\t\n\n\tIbuprofen for PDA\t\n\n\tSurgery for PDA\t\n\n\tNEC\t\n\n\tIVH\t\nIUGR: intrauterine growth restriction, SGA: small for gestational age; BPD: bronchopulmonary dysplasia; PDA: patent ductus arteriosus; NEC: necrotizing enterocolitis; IVH: intra-ventricular hemorrhage.\n\nnutrients-12-00651-t002_Table 2Table 2 Clinical course data at T36, in the overall group and according to gestational age (GA).\n\n\n\tOverall\n(n = 53)\tGA ≤ 28 w\n(n = 25)\tGA > 28 w\n(n = 28)\t\np\n\t\nNeed for invasive ventilation (n, %)\t30 (56.6%)\t17 (68%)\t13 (46.4%)\tNS\t\nDuration of invasive ventilation\n(days, mean ± standard deviation (SD))\t8.1 ± 13.9\t12.4 ± 15.9\t4.4 ± 10.8\t0.02\t\nNeed for non-invasive ventilation (n, %)\t48 (90.6%)\t25 (100%)\t23 (82.1%)\t0.02\t\nDuration of non-invasive ventilation (days, mean ± SD)\t17.5 ± 15.9\t29.1 ± 15.4\t7.2 ± 6.6\t<0.0001\t\nDuration of need for O2-support\n(days, mean ± SD)\t22.8 ± 44\t37.3 ± 51.7\t9.9 ± 31.4\t0.007\t\nBPD (n, %)\t14 (26.4%)\t12 (48%)\t2 (7.1%)\t0.001\t\nSepsis (n, %)\t9 (17%)\t6 (24%)\t3 (10.7%)\tNS\t\nDuration of antimicrobial therapy\n(days, mean ± SD)\t17.7 ± 14.6\t24.3 ± 17.2\t11.8 ± 8.6\t0.002\t\nUse of nephrotoxic antibiotics (n, %)\t50 (94.3%)\t24 (96%)\t26 (92.9%)\tNS\t\nPDA treated with ibuprofen (n, %)\t19 (35.8%)\t13 (52%)\t6 (21.4%)\t0.02\t\nPDA treated with surgery (n, %)\t5 (9.4%)\t4 (16%)\t1 (3.6%)\tNS\t\nNEC (n, %)\t5 (9.4%)\t4 (16%)\t1 (3.6%)\tNS\t\nIVH (n, %)\t12 (22.6%)\t9 (36%)\t3 (10.7%)\t0.03\t\nLength of NICU stay\n(days, mean ± SD)\t65.2 ± 34.5\t83 ± 35\t50.7 ± 26.7\t<0.0001\t\nParenteral nutrition (n, %)\t40 (75.5%)\t25 (100%)\t15 (53.6%)\t<0.0001\t\nDuration of parenteral nutrition (days, mean ± SD)\t21.2 ± 11.4\t24.6 ± 13.4\t15.7 ± 4.2\t0.02\t\nPrenatal kidney injury risk score\t1.5 ± 0.9 \t1.4 ± 0.9\t1.6 ± 0.9\tNS\t\nPostnatal kidney injury risk score\t3.6 ± 1.6\t4.5 ± 1.6\t2.9 ± 1.3\t<0.0001\t\nn: number; BPD: bronchopulmonary dysplasia; NEC: necrotizing enterocolitis; IVH: intra-ventricular hemorrhage; NICU: neonatal intensive care unit.\n\nnutrients-12-00651-t003_Table 3Table 3 Anthropometric data in the overall population and in subjects with a GA≤ or >28 weeks, at T0 (3rd day of life) and T36 (gestational age 36 weeks). Data are expressed as mean ± SD (ranges).\n\n\n\tT0\tT36\t\nOverall\n(n = 71)\tGA ≤ 28 w\n(n = 31)\tGA > 28 w\n(n = 40)\tOverall\n(n = 53)\tGA ≤ 28 w\n(n = 25)\tGA > 28 w\n(n = 28)\t\nWeight (g)\t1084 ± 380\n(490–2236)\t829 ± 215 *\n(490–1450)\t1281 ± 363 *\n(580–2236)\t1863.7 ± 358.3\n(950–2795)\t1861 ± 373\n(1360–2795)\t1866 ± 350\n(950–2460)\t\nLength (cm)\t36.4 ± 4.1\n(28–46)\t33.5 ± 3.2 **\n(28–40)\t38.6 ± 3.4 **\n(30–46)\t41.8 ± 2.7\n(36–48)\t41.8 ± 2.5\n(37–48)\t41.8 ± 2.8\n(36–47)\t\nBSA (m2)\t0.104 ± 0.024\n(0.062–0.169)\t0.088 ± 0.015 §\n(0.062–0.128)\t0.117 ± 0.216 §\n(0.069–0.169)\t0.149 ± 0.018\n(0.097–0.196)\t0.149 ± 0.018\n(0.126–1.196)\t0.148 ± 0.019\n(0.097–0.180)\t\n*, **, §\np < 0.0001. BSA: body surface area.\n\nnutrients-12-00651-t004_Table 4Table 4 Biochemical data in the overall population and in subjects with GA≤ or >28 weeks, at T0 and T36.\n\n\n\tOverall\tGA ≤ 28 w\tGA > 28 w\t\n\n\tT0\n(n = 71)\tT36\n(n = 53)\t\np\n\tT0\n(n = 31)\tT36\n(n = 25)\t\np\n\tT0\n(n = 40)\tT36\n(n = 28)\t\np\n\t\nsCr (mg/dL)\t0.83 ± 0.22\t0.30 ± 0.07\t<0.0001\t0.88 ± 0.22\t0.27 ± 0.07\t<0.0001\t0.79 ± 0.22\t0.33 ± 0.05\t<0.0001\t\nCysC (mg/L)\t1.57 ± 0.33\t1.46 ± 0.29\tNS\t1.62 ± 0.41\t1.38 ± 0.35\t0.008\t1.54 ± 0.25\t1.55 ± 0.19\tNS\t\nBTP (mg/L)\t1.484 ± 0.464\t1.299 ± 0.381\tNS\t1.339 ± 0.418\t1.128 ± 0.306\tNS\t1.583 ± 0.474\t1.48 ± 0.374\tNS\t\nUrea (mg/dL)\t22.3 ± 1.4\t9.8 ± 6.9\t<0.0001\t25 ± 12.9\t12.5 ± 7.9\t<0.0001\t21.3 ± 11.3\t7.36 ± 4.84\t<0.0001\t\nsCr: serum Cretinine; CysC: Cystatin C; BTP: Beta-Trace Protein.\n\nnutrients-12-00651-t005_Table 5Table 5 Estimated glomerular filtration rate (eGFR) values at T36 calculated by nine different formulas, in the overall population and according to GA. All eGFR are expressed in ml/min/1.73 m2.\n\n\n\tT36\t\nOverall\n(n = 53)\tGA ≤ 28 w\n(n = 25)\tGA > 28 w\n(n = 28)\t\np\n\t\neGFR Schwartz 2009 *\t59.5 ± 15.1\t65.7 ± 17.1\t53.2 ± 9.5\t0.012\t\neGFR Brion *\t47.5 ± 12\t52.5 ± 13.6\t42.5 ± 7.6\t0.012\t\neGFR Schwartz 2012 **\t51.8 ± 12\t55.7 ± 15\t47.6 ± 5.3\tNS\t\neGFR Zappitelli **\t51.9 ± 15.7\t56.9 ± 19.6\t46.3 ± 6.5\tNS\t\neGFR Filler **\t63.5 ± 18.3\t69.3 ± 22.9\t56.9 ± 7.6\tNS\t\neGFR Dorum **\t48.8 ± 17.2\t54.3 ± 21.6\t42.6 ± 6.8\tNS\t\neGFR Treiber **\t45.2 ± 16.5\t51.1 ± 19.7\t37.9 ± 6.4\t0.04\t\neGFR Benlarmi ***\t66.9 ± 18\t75.3 ± 18\t58 ± 13.4\t0.005\t\neGFR Zappitelli–combined §\t80.1 ± 20.9\t88.7 ± 23.8\t69.4 ± 9.5\t0.009\t\n* Formulas using sCr; ** Formulas using CysC; *** Formula using BTP; § Formula combining sCr and CysC.\n==== Refs\nReferences\n1. Kutz P. Horsch S. Kuhn L. Roll C. Single–centre vs. population based outcome data of extremely preterm infants at the limits of viability Acta Paediatr. 2009 98 1451 1455 10.1111/j.1651-2227.2009.01393.x 19575767 \n2. Minuth W.W. Key features of the nephrogenic zone in the fetal human kidney–hardly known but relevant for the detection of first traces impairing nephrogenesis Cell Tissue Res. 2019 375 589 603 10.1007/s00441-018-2937-4 30338377 \n3. Gubhaju L. Sutherland M.R. Black M.J. Preterm birth and the kidney: Implications for long–term renal health Reprod. Sci. 2011 18 322 333 10.1177/1933719111401659 21427457 \n4. Filler G. Bökenkamp A. Hofmann W. Le Bricon T. Martínez–Brú C. Grubb A. Cystatin C as a marker of GFR: History, indications, and future research Clin. Biochem. 2005 38 1 8 10.1016/j.clinbiochem.2004.09.025 15607309 \n5. Filler G. Kusserow C. Lopes L. Kobrzynski M. Beta–trace protein as a marker of GFR: History, indications, and future research Clin. Biochem. 2014 47 1188 1194 10.1016/j.clinbiochem.2014.04.027 24833359 \n6. Nilsson M. Wang X. Rodziewicz–Motowidlo S. Janowski R. Lindström V. Onnerfjord P. Westermark G. Grzonka Z. Jaskolski M. Grubb A. Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C: Use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C J. Biol. Chem. 2004 279 24236 24245 10.1074/jbc.M402621200 15028721 \n7. Dharnidharka V.R. Kwon C. Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: A meta–analysis Am. J. Kidney Dis. 2002 40 221 226 10.1053/ajkd.2002.34487 12148093 \n8. Finney H. Newman D.J. Thakkar H. Fell J.M. Price C.P. Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children Arch. Dis. Child. 2000 82 71 75 10.1136/adc.82.1.71 10630919 \n9. Lee J.H. Hahn W.H. Ahn J. Chang J.Y. Bae C.W. Serum cystatin C during 30 postnatal days is dependent on the postconceptional age in neonates Pediatr. Nephrol. 2013 28 1073 1078 10.1007/s00467-013-2429-4 23429977 \n10. Treiber M. Pecovnik–Balon B. Gorenjak M. Cystatin C versus creatinine as a marker of glomerular filtration rate in the newborn Wien Klin. Wochenschr. 2006 118 66 70 10.1007/s00508-006-0555-8 16817048 \n11. Filler G. Lopes L. Awuku M. The importance of accurately assessing renal function in the neonate and infant Adv. Clin. Chem. 2015 71 141 156 26411413 \n12. Zwiers A.J. Cransberg K. de Rijke Y.B. Willemsen S.P. de Mol A.C. Tibboel D. de Wildt S.N. Reference ranges for serum β–trace protein in neonates and children younger than 1 year of age Clin. Chem. Lab. Med. 2014 52 1815 1821 10.1515/cclm-2014-0371 24940717 \n13. Bertino E. Spada E. Occhi L. Coscia A. Giuliani F. Gagliardi L. Gilli G. Bona G. Fabris C. De Curtis M. Neonatal anthropometric charts: The Italian neonatal study compared with other European studies J. Pediatr. Gastroenterol. Nutr. 2010 51 353 361 10.1097/MPG.0b013e3181da213e 20601901 \n14. Zhang J. Massmann G.A. Rose J.C. Figueroa J.P. Differential effects of clinical doses of antenatal betamethasone on nephron endowment and glomerular filtration rate in adult sheep Reprod. Sci. 2010 17 186 195 10.1177/1933719109351098 19897787 \n15. Antonucci R. Zaffanello M. Puxeddu E. Porcella A. Cuzzolin L. Pilloni M.D. Fanos V. Use of non–steroidal anti–inflammatory drugs in pregnancy: Impact on the fetus and newborn Curr. Drug. Metab. 2012 13 474 490 10.2174/138920012800166607 22299823 \n16. Boubred F. Vendemmia M. Garcia–Meric P. Buffat C. Millet V. Simeoni U. Effects of maternally administered drugs on the fetal and neonatal kidney Drug Saf. 2006 29 397 419 10.2165/00002018-200629050-00004 16689556 \n17. Fryer H. Welsh G.I. Renal consequences of therapeutic interventions in premature neonates Nephron 2019 142 117 124 10.1159/000497162 30726854 \n18. Genoni G. Binotti M. Monzani A. Bernascone E. Stasi I. Bona G. Ferrero F. Nonrandomised interventional study showed that early aggressive nutrition was effective in reducing postnatal growth restriction in preterm infants Acta Paediatr. 2017 106 1589 1595 10.1111/apa.13958 28632972 \n19. Schwartz G.J. Muñoz A. Schneider M.F. Mak R.H. Kaskel F. Warady B.A. Furth S.L. New equations to estimate GFR in children with CKD J. Am. Soc. Nephrol. 2009 20 629 637 10.1681/ASN.2008030287 19158356 \n20. Brion L.P. Fleischman A.R. McCarton C. Schwartz G.J. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: Noninvasive assessment of body composition and growth J. Pediatr. 1986 109 698 707 10.1016/S0022-3476(86)80245-1 3761090 \n21. Schwartz G.J. Schneider M.F. Maier P.S. Moxey–Mims M. Dharnidharka V.R. Warady B.A. Furth S.L. Muñoz A. Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C Kidney Int. 2012 82 445 453 10.1038/ki.2012.169 22622496 \n22. Zappitelli M. Parvex P. Joseph L. Paradis G. Grey V. Lau S. Bell L. Derivation and validation of cystatin C–based prediction equations for GFR in children Am. J. Kidney Dis. 2006 48 221 230 10.1053/j.ajkd.2006.04.085 16860187 \n23. Filler G. Lepage N. Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr. Nephrol. 2003 18 981 985 10.1007/s00467-003-1271-5 12920638 \n24. Dorum S. Silfeler I. Dorum B.A. Silfeler D.B. Canbak Y. Say A. Reference values of serum cystatin–C for full–term and preterm neonates in Istanbul Indian J. Pediatr. 2012 79 1037 1042 10.1007/s12098-011-0655-y 22180301 \n25. Treiber M. Pečovnik Balon B. Gorenjak M. A new serum cystatin C formula for estimating glomerular filtration rate in newborns Pediatr. Nephrol. 2015 30 1297 1305 10.1007/s00467-014-3029-7 25956698 \n26. Benlamri A. Nadarajah R. Yasin A. Lepage N. Sharma A.P. Filler G. Development of a beta–trace protein based formula for estimation of glomerular filtration rate Pediatr. Nephrol. 2010 25 485 490 10.1007/s00467-009-1355-y 19949816 \n27. Armangil D. Yurdakök M. Canpolat F.E. Korkmaz A. Yiğit S. Tekinalp G. Determination of reference values for plasma cystatin C and comparison with creatinine in premature infants Pediatr. Nephrol. 2008 23 2081 2083 10.1007/s00467-008-0867-1 18536938 \n28. Elmas A.T. Tabel Y. Elmas O.N. Reference intervals of serum cystatin C for determining cystatin C–based glomerular filtration rates in preterm neonates J. Matern. Fetal. Neonatal. Med. 2013 26 1474 1478 10.3109/14767058.2013.789844 23528044 \n29. Filler G. Lopes L. Harrold J. Bariciak E. β–trace protein may be a more suitable marker of neonatal renal function Clin. Nephrol. 2014 81 269 276 10.5414/CN108089 24548934 \n30. Montini G. Cosmo L. Amici G. Mussap M. Zacchello G. Plasma cystatin C values and inulin clearances in premature neonates Pediatr. Nephrol. 2001 16 463 465 10.1007/s004670100592 11405123 \n31. Abitbol C.L. Seeherunvong W. Galarza M.G. Katsoufis C. Francoeur D. Defreitas M. Edwards–Richards A. Sankar Raj V.M. Chandar J. Duara S. Neonatal kidney size and function in preterm infants: What is a true estimate of glomerular filtration rate? J. Pediatr. 2014 164 1026 1031 10.1016/j.jpeds.2014.01.044 24607244\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6643",
"issue": "12(3)",
"journal": "Nutrients",
"keywords": "Beta-trace protein; Cystatin C; chronic kidney disease; kidney function; parenteral nutrition; preterm newborn",
"medline_ta": "Nutrients",
"mesh_terms": "D003404:Creatinine; D055316:Cystatin C; D005260:Female; D005865:Gestational Age; D005919:Glomerular Filtration Rate; D006801:Humans; D007231:Infant, Newborn; D019746:Intramolecular Oxidoreductases; D007668:Kidney; D054834:Lipocalins; D008297:Male; D009752:Nutritional Status; D047928:Premature Birth; D014508:Urea",
"nlm_unique_id": "101521595",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32121201",
"pubdate": "2020-02-28",
"publication_types": "D016428:Journal Article",
"references": "30726854;24548934;24607244;15607309;20601901;11405123;21427457;10630919;23528044;16689556;25956698;16860187;16817048;24833359;28632972;30338377;12920638;19949816;15028721;3761090;19897787;23429977;22299823;18536938;12148093;26411413;19158356;22180301;19575767;22622496;24940717",
"title": "Kidney-Detrimental Factors and Estimated Glomerular Filtration Rate in Preterm Newborns: The Role of Nutrition.",
"title_normalized": "kidney detrimental factors and estimated glomerular filtration rate in preterm newborns the role of nutrition"
} | [
{
"companynumb": "IT-JNJFOC-20200808593",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "Intra-abdominal or visceral obesity is associated with insulin resistance and an increased risk for cardiovascular disease. This study aimed to compare the effects of semaglutide 1.0 mg and canagliflozin 300 mg on body composition in a subset of participants from the SUSTAIN 8 Phase IIIB, randomised double-blind trial who underwent whole-body dual-energy x-ray absorptiometry (DXA) scanning.\n\n\n\nAdults (age ≥18 years) with type 2 diabetes, HbA1c 53-91 mmol/mol (7.0-10.5%), on a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) and with an eGFR ≥60 ml min-1 [1.73 m]-2 were randomised 1:1 to semaglutide 1.0 mg once weekly and canagliflozin placebo once daily, or canagliflozin 300 mg once daily and semaglutide placebo once weekly. Body composition was assessed using whole-body DXA scans. The study participants and investigator remained blinded throughout the trial, and quality of DXA scans was evaluated in a blinded manner. Change from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint.\n\n\n\nA subset of 178 participants (semaglutide, n = 88; canagliflozin, n = 90) underwent DXA scanning at screening and were randomised into the substudy. Of these, 114 (semaglutide, n = 53; canagliflozin, n = 61) participants had observed end-of-treatment data included in the confirmatory efficacy analysis. Of the 178 participants in the substudy, numerical improvements in body composition (including fat mass, lean mass and visceral fat mass) were observed after 52 weeks with both treatments. Total fat mass (baseline 33.2 kg) was reduced by 3.4 kg and 2.6 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: -0.79 [95% CI -2.10, 0.51]). Although total lean mass (baseline 51.3 kg) was also reduced by 2.3 kg and 1.5 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: -0.78 [-1.61, 0.04]), the proportion of lean mass (baseline 59.4%) increased by 1.2%- and 1.1%-point, respectively (estimated treatment difference 0.14 [-0.89, 1.17]). Changes in visceral fat mass and overall changes in body composition (assessed by the fat to lean mass ratio) were comparable between the two treatment groups.\n\n\n\nIn individuals with uncontrolled type 2 diabetes on stable-dose metformin therapy, the changes in body composition with semaglutide and canagliflozin were not significantly different. Although numerical improvements in body composition were observed following treatment in both treatment arms, the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage.\n\n\n\nClinicalTrials.gov NCT03136484.\n\n\n\nThis trial was supported by Novo Nordisk A/S, Denmark.",
"affiliations": "School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. r.mccrimmon@dundee.ac.uk.;Novo Nordisk A/S, Vandtårnsvej, Søborg, Denmark.;National Research Institute, Los Angeles, CA, USA.;Novo Nordisk A/S, Vandtårnsvej, Søborg, Denmark.;Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland.;Novo Nordisk A/S, Vandtårnsvej, Søborg, Denmark.;Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.",
"authors": "McCrimmon|Rory J|RJ|;Catarig|Andrei-Mircea|AM|;Frias|Juan P|JP|;Lausvig|Nanna L|NL|;le Roux|Carel W|CW|;Thielke|Desirée|D|;Lingvay|Ildiko|I|",
"chemical_list": "D001786:Blood Glucose; D006442:Glycated Hemoglobin A; C517652:hemoglobin A1c protein, human; D000068896:Canagliflozin; C000591245:semaglutide; D004763:Glucagon-Like Peptides; D008687:Metformin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00125-019-05065-8",
"fulltext": "\n==== Front\nDiabetologiaDiabetologiaDiabetologia0012-186X1432-0428Springer Berlin Heidelberg Berlin/Heidelberg 506510.1007/s00125-019-05065-8ArticleEffects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial McCrimmon Rory J. r.mccrimmon@dundee.ac.uk 1Catarig Andrei-Mircea 2Frias Juan P. 3Lausvig Nanna L. 2le Roux Carel W. 4Thielke Desirée 2Lingvay Ildiko 51 School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY UK 2 grid.425956.9Novo Nordisk A/S, Vandtårnsvej, Søborg, Denmark 3 grid.489090.cNational Research Institute, Los Angeles, CA USA 4 grid.7886.10000 0001 0768 2743Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland 5 grid.267313.20000 0000 9482 7121Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX USA 2 1 2020 2 1 2020 2020 63 3 473 485 5 9 2019 6 11 2019 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Aims/hypothesis\nIntra-abdominal or visceral obesity is associated with insulin resistance and an increased risk for cardiovascular disease. This study aimed to compare the effects of semaglutide 1.0 mg and canagliflozin 300 mg on body composition in a subset of participants from the SUSTAIN 8 Phase IIIB, randomised double-blind trial who underwent whole-body dual-energy x-ray absorptiometry (DXA) scanning.\n\nMethods\nAdults (age ≥18 years) with type 2 diabetes, HbA1c 53–91 mmol/mol (7.0–10.5%), on a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) and with an eGFR ≥60 ml min−1 [1.73 m]−2 were randomised 1:1 to semaglutide 1.0 mg once weekly and canagliflozin placebo once daily, or canagliflozin 300 mg once daily and semaglutide placebo once weekly. Body composition was assessed using whole-body DXA scans. The study participants and investigator remained blinded throughout the trial, and quality of DXA scans was evaluated in a blinded manner. Change from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint.\n\nResults\nA subset of 178 participants (semaglutide, n = 88; canagliflozin, n = 90) underwent DXA scanning at screening and were randomised into the substudy. Of these, 114 (semaglutide, n = 53; canagliflozin, n = 61) participants had observed end-of-treatment data included in the confirmatory efficacy analysis. Of the 178 participants in the substudy, numerical improvements in body composition (including fat mass, lean mass and visceral fat mass) were observed after 52 weeks with both treatments. Total fat mass (baseline 33.2 kg) was reduced by 3.4 kg and 2.6 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: –0.79 [95% CI −2.10, 0.51]). Although total lean mass (baseline 51.3 kg) was also reduced by 2.3 kg and 1.5 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: −0.78 [−1.61, 0.04]), the proportion of lean mass (baseline 59.4%) increased by 1.2%- and 1.1%-point, respectively (estimated treatment difference 0.14 [−0.89, 1.17]). Changes in visceral fat mass and overall changes in body composition (assessed by the fat to lean mass ratio) were comparable between the two treatment groups.\n\nConclusions/interpretation\nIn individuals with uncontrolled type 2 diabetes on stable-dose metformin therapy, the changes in body composition with semaglutide and canagliflozin were not significantly different. Although numerical improvements in body composition were observed following treatment in both treatment arms, the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage.\n\nTrial registration\nClinicalTrials.gov NCT03136484.\n\nFunding\nThis trial was supported by Novo Nordisk A/S, Denmark.\n\nKeywords\nBody compositionCanagliflozinFat massGlucagon-like peptide receptor agonistsRandomised controlled trialSemaglutideType 2 diabetesWeighthttp://dx.doi.org/10.13039/501100004191Novo Nordiskissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nThe association between obesity and type 2 diabetes is well established [1, 2]. Intra-abdominal or visceral obesity in particular is associated with insulin resistance [3, 4] and an increased risk for developing cardiovascular disease [4, 5]. In addition to providing recommendations for achieving glycaemic control, current type 2 diabetes guidelines emphasise the importance of weight loss through lifestyle changes, surgical interventions or medications [6, 7]. While some conventional glucose-lowering medications contribute to weight gain [2], newer agents – including those from the glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium–glucose co-transporter-2 inhibitor (SGLT-2i) classes – have favourable effects on body weight [2]. This is an important feature, because weight gain can lead to non-compliance with therapy [8].\n\nSemaglutide is a GLP-1RA approved for the subcutaneous, once-weekly treatment of type 2 diabetes [9, 10]. The efficacy and safety of once-weekly semaglutide have been established in the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) clinical trial programme across the continuum of care in individuals with type 2 diabetes vs placebo and a range of comparators (SUSTAIN 1–5 and 7–10) [11–19] and in a cardiovascular outcomes trial (SUSTAIN 6) [20]. Canagliflozin is an SGLT-2i approved for the oral, once-daily treatment of type 2 diabetes [21]. The efficacy and safety of canagliflozin 100 mg and 300 mg have been demonstrated in an extensive clinical development programme that included cardiovascular and renal outcomes trials (CANVAS, CANVAS-R and CREDENCE) [22, 23]. Both semaglutide and canagliflozin are associated with substantial reductions in body weight. Across the SUSTAIN 1–10 trials, semaglutide has demonstrated significantly greater weight loss vs all comparators, with absolute change in body weight ranging from −3.8 to −6.5 kg with semaglutide 1.0 mg [11–20]. Canagliflozin has consistently demonstrated weight reductions of 2.5 to 4.7 kg in clinical trials [24].\n\nRecently, a Phase IIIB randomised double-blind trial (SUSTAIN 8) compared the effects of once-weekly semaglutide 1.0 mg vs once-daily canagliflozin 300 mg on glycaemic control and weight management in participants with uncontrolled type 2 diabetes on a background of metformin therapy [17]. Treatment with semaglutide resulted in a mean change in HbA1c from baseline to week 52 of −16.2 mmol/mol (−1.5%-point) compared with −10.4 mmol/mol (−1.0%-point) for canagliflozin (p < 0.0001), and a weight loss of −5.3 kg vs −4.2 kg, respectively (p = 0.003).\n\nThe magnitude of weight loss demonstrated in the SUSTAIN 8 trial would be expected to result in positive changes in body composition; however, as with any glucose-lowering agent, it is important to evaluate whether this weight loss has an adverse impact on the ratio of fat to lean mass.\n\nTo date, whether the effects on weight loss associated with the GLP-1RA semaglutide, and the SGLT-2i canagliflozin, are comparable in terms of total, lean and visceral fat have not yet been evaluated. This study compared body composition components in a subset of participants from SUSTAIN 8 who received semaglutide 1.0 mg or canagliflozin 300 mg using whole-body dual-energy x-ray absorptiometry (DXA).\n\nMethods\nSUSTAIN 8 study design\nTrial design and participants\nThe trial design for SUSTAIN 8 (ClinicalTrials.gov registration no. NCT03136484) has been described previously [17]. Briefly, SUSTAIN 8 was a 52-week, Phase IIIB randomised double-blind, double-dummy, parallel-group trial of once-weekly semaglutide 1.0 mg vs once-daily canagliflozin 300 mg in 788 adults with type 2 diabetes on stable treatment with metformin. The trial was conducted at 111 centres in 11 countries. Adults (age ≥18 years) with uncontrolled type 2 diabetes, HbA1c levels of 53–91 mmol/mol (7.0–10.5% [inclusive]) on a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) for at least 90 days prior to screening and an eGFR ≥60 ml min−1 [1.73 m]−2 were eligible. Individuals with a history or presence of pancreatitis (acute or chronic), history of diabetic ketoacidosis, myocardial infarction, stroke, hospitalisation for unstable angina or transient ischaemic attack within 180 days prior to screening, and New York Heart Association class IV heart failure were excluded.\n\nRandomisation and treatment\nParticipants were randomised in a 1:1 manner to receive either once-weekly semaglutide 1.0 mg subcutaneous injections and once-daily canagliflozin placebo oral tablets, or once-daily canagliflozin 300 mg oral tablets and once-weekly subcutaneous semaglutide placebo. Randomisation was stratified according to participation in the substudy (yes/no) to ensure balanced treatment allocation. Dosing for semaglutide began at 0.25 mg and doubled every 4 weeks until the maintenance dose of 1.0 mg was achieved at 8 weeks. Participants randomised to canagliflozin received 100 mg for 8 weeks, followed by an increase to the maintenance dose of 300 mg. The only background medication permitted was metformin (≥1500 mg or maximum tolerated dose). Participants continued on their pre-trial dose throughout the treatment period unless rescue medication was required. After a treatment period of 52 weeks, participants entered a 5-week follow-up period.\n\nOutcomes\nThe primary and confirmatory secondary endpoints were change from baseline to week 52 in HbA1c (%-point) and body weight (kg), respectively.\n\nEthics and consent\nSUSTAIN 8 was conducted in compliance with the International Conference on Harmonisation Good Clinical Practice guidelines [25] and the Declaration of Helsinki [26]. The trial protocol was approved by the institutional review board and ethics committee at each participating centre, and participants provided written informed consent before trial-related activities commenced.\n\nDXA substudy\nA planned subset of participants from the overall SUSTAIN 8 population received a DXA whole-body scan at baseline and were randomised for inclusion in the body composition substudy if the imaging laboratory deemed the quality of the scan to be acceptable.\n\nAssessments and outcomes\nThe process of DXA scan image acquisition, transfer, central analysis, reporting of results and arching followed the charter prepared by one imaging laboratory (PAREXEL Informatics Medical Imaging, Waltham, MA, USA) where scans were analysed. GE Lunar iDXA (GE Healthcare, Madison, WI, USA) and the Hologic Discovery DXA system (Hologic, Marlborough, MA, USA) were used with Prodigy and APEX software, respectively. Each participant received one scan 5 days after the screening (visit 1) and a second, final scan 5 days after the end-of-treatment visit (planned study end or premature treatment discontinuation). The quality of the DXA scans was evaluated by the same imaging laboratory in a blinded manner.\n\nChange from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint in the DXA substudy. Changes from baseline to week 52 in total fat mass (%-point), total lean mass (kg and %-point), visceral fat mass (kg and %-point) and ratio of total fat mass to total lean mass (muscle mass in this study) were additional efficacy endpoints. A comparison of change in body weight within the substudy vs the primary study was performed post hoc in order to confirm that weight loss in individuals undergoing a DXA scan in the substudy was representative of the weight loss in the primary study.\n\nStatistical analyses\nThe primary estimand was defined as the treatment difference between semaglutide and canagliflozin at week 52 for all randomised participants if all participants completed treatment and did not start rescue medication. The primary estimand was used to estimate the expected benefit from the initiation and continuation of semaglutide compared with canagliflozin, drawing inferences only from data collected before discontinuation of trial product or initiation of rescue medication. The estimand was based on the full analysis set of all randomised participants using post-baseline measurements up to and including week 52 from the ‘on-treatment without rescue medication’ observation period to support an efficacy evaluation. The analysis of all endpoints in the substudy was based on the subset of full analysis set participants who participated in the substudy (DXA analysis set); however, participants had only two DXA scans each, and not all of these were performed within the ‘on-treatment without rescue medication’ observation period (used for the confirmatory analysis). In individuals for whom DXA data were collected outside of this period, only baseline data were included in the analysis, and the corresponding end-of-treatment data were multiple imputed, as described below.\n\nAn ANCOVA with treatment and region as categorical effects and baseline measurements as a covariate was used to analyse values at week 52, and change from baseline estimates were adjusted according to the pooled baseline value to allow for comparison between treatment arms. Before analysis, missing data were imputed using observed data from participants within the same treatment group, using a regression model including region as categorical effect and baseline value as covariate. Rubin’s rules were used to combine the analysis results to draw inference [27]. Regions were defined as North America (USA and Canada); Region Europe (UK, Ireland and Sweden); or International Operations (Lebanon, Malaysia, Argentina, Mexico, Brazil and India).\n\nAs a confirmatory endpoint, change in total fat mass (kg) was tested for superiority of semaglutide 1.0 mg vs canagliflozin 300 mg. The overall type I error for the confirmatory hypotheses in SUSTAIN 8 and the substudy were controlled at a 5% level (two-sided) using a closed testing procedure (Fig. 1) [28]. Assuming a treatment difference of 1.8 kg and SD of 3.5 kg, it was estimated that 174 participants (87 per arm) would provide a 92% marginal power to establish a significant difference, resulting in 91% power for confirming superiority in the testing strategy for total fat mass loss (kg) at week 52.Fig. 1 Graphical illustration of the closed testing procedure. The overall significance level of α = 0.05 (two-sided) is initially allocated to the HbA1c non-inferiority test. The local significance level (αlocal) will be reallocated if a hypothesis is confirmed according to the weight given by the directed edges between nodes (hypotheses). The total fat-mass superiority test will receive the overall significance of α = 0.05 (two-sided) if, and only if, both HbA1c and body weight superiority are confirmed at their respective local significance levels\n\n\n\nSensitivity analyses to evaluate the robustness of the conclusions from the confirmatory analysis (change in total fat mass [kg]) included a pre-specified in-trial analysis using all post-baseline measurements up to and including week 52 from the in-trial observation period, in which participants were considered to be in the trial after randomisation regardless of discontinuation of trial product or initiation of rescue medication. Scans that did not meet the criteria for inclusion in the confirmatory analysis (performed >7 days after last dose of trial product and thus considered out-of-window, or taken after initiation of rescue medication) were included in the in-trial supplementary analysis. Data from missing scans were multiple imputed.\n\nIn post hoc analyses, possible correlations between fat loss and changes in body weight, HbA1c and BP were investigated. Correlations were calculated for each of the 500 complete multiple imputed datasets for body weight, HbA1c and systolic and diastolic BP and combined using Rubin’s rules [27].\n\nResults\nBetween 15 March 2017 and 16 November 2018, 788 individuals were randomised to receive semaglutide 1.0 mg or canagliflozin 300 mg (each n = 394). A subset of 178 participants (semaglutide, n = 88; canagliflozin, n = 90) underwent DXA scanning at screening and were also randomised into the SUSTAIN 8 substudy. Of these, 177 (99.4%) participants (semaglutide, n = 87; canagliflozin, n = 90) were exposed to treatment. In total, 25 (14.0%) participants discontinued treatment prematurely, primarily because of adverse events (n = 8 [4.5%]). Overall, 165 of 178 participants (92.7%) had a post-baseline DXA scan available (Table 1; Fig. 2). Of these, data on 114 (64%: semaglutide, n = 53 [60.2%]; canagliflozin, n = 61 [67.8%]) were within the on-treatment without rescue medication period and used in the confirmatory efficacy analysis (Table 1; Fig. 2). The remaining post-baseline DXA scan results were excluded from the confirmatory analysis because scans at discontinuation were performed >7 days after the last dose of trial product (i.e. out-of-window; n = 38) or participants were on rescue medication at the time of the scan (n = 13). The pre-specified in-trial analysis used all post-baseline measurements up to and including week 52 from the in-trial observation period, i.e. all 165 available post-baseline scans (including out-of-window scans and scans of participants on rescue medication).Table 1 Body composition substudy participant disposition and baseline characteristics\n\nVariable\tSemaglutide 1.0 mg (n = 88)\tCanagliflozin 300 mg (n = 90)\tTotal (n = 178)\t\nParticipant disposition, n (%)\t\n Randomised, DXA\t88 (100)\t90 (100)\t178 (100)\t\n Exposed\t87 (98.9)\t90 (100)\t177 (99.4)\t\n Observed EOT scan in in-trial analysisa\t82 (93.2)\t83 (92.2)\t165 (92.7)\t\n Observed EOT scan in confirmatory analysisb\t53 (60.2)\t61 (67.8)\t114 (64.0)\t\n Treatment completersc\t76 (86.4)\t76 (84.4)\t152 (85.4)\t\nWithout rescue medication\t63 (71.6)\t69 (76.7)\t132 (74.2)\t\n Premature treatment discontinuationd\t11 (12.5)\t14 (15.6)\t25 (14.0)\t\n Adverse events\t6 (6.8)\t2 (2.2)\t8 (4.5)\t\n Lost to follow-up\t1 (1.1)\t2 (2.2)\t3 (1.7)\t\n Other\t4 (4.5)\t10 (11.1)\t14 (7.9)\t\n Trial completerse\t80 (90.9)\t81 (90.0)\t161 (90.4)\t\nDemographics and baseline characteristics, mean (SD)\t\n Age, years\t57.8 (9.9)\t58.6 (10.1)\t58.2 (10.0)\t\n HbA1c, mmol/mol\t69.4 (11.9)\t66.7 (10.9)\t68.0 (11.5)\t\n HbA1c, %\t8.5 (1.1)\t8.3 (1.0)\t8.4 (1.0)\t\n Diabetes duration, years\t8.8 (5.8)\t8.5 (5.2)\t8.7 (5.5)\t\n Body weight, kg\t89.0 (18.2)\t87.6 (18.2)\t88.3 (18.2)\t\n BMI, kg/m2\t32.6 (6.4)\t32.3 (5.5)\t32.4 (6.0)\t\n Waist circumference, cm\t104.0 (13.5)\t105.9 (13.1)\t105.0 (13.3)\t\n Total fat mass,\t\n kg\n\n %\n\n\t33.9 (11.9)\n\n38.0 (8.4)\n\n\t32.5 (10.0)\n\n37.3 (7.3)\n\n\t33.2 (11.0)\n\n37.6 (7.8)\n\n\t\n Total lean mass,\t\n kg\n\n %\n\n\t51.3 (10.1)\n\n59.1 (8.0)\n\n\t51.3 (10.7)\n\n59.7 (6.9)\n\n\t51.3 (10.4)\n\n59.4 (7.5)\n\n\t\n Visceral fat mass,\t\n kg\n\n %\n\n\t1.5 (0.8)\n\n43.7 (16.2)\n\n\t1.5 (0.8)\n\n44.0 (15.3)\n\n\t1.5 (0.8)\n\n43.9 (15.7)\n\n\t\n Total fat mass:total lean mass ratio\t0.67 (0.23)\t0.65 (0.20)\t0.66 (0.22)\t\nThe baseline value is defined as the latest pre-dosing value\n\naParticipants with end-of-treatment data included in the pre-specified supplementary analysis\n\nbParticipants with end-of-treatment data included in the pre-specified confirmatory analyses\n\ncParticipants who completed treatment according to the end-of-treatment form\n\ndIncludes only exposed participants\n\neParticipants who completed the trial according to the end-of-trial form\n\nEOT, end-of-treatment (planned or premature)\n\nFig. 2 Participant disposition. aParticipants could meet more than one exclusion criterion. b‘Not assigned’ includes individuals who withdrew consent before randomisation. cParticipants in the substudy were a subset of the overall SUSTAIN 8 trial population. dIn participants for whom data were outside the relevant observation period, only baseline participant data were included in the analysis, and the corresponding end-of-treatment data were multiple imputed. eThe in-trial analysis included all available post-baseline data. Missing data were multiple imputed\n\n\n\nBaseline characteristics\nBaseline characteristics were comparable between treatment arms (Table 1). Participants had an overall mean (SD) baseline HbA1c value of 68.0 mmol/mol (11.5) [8.4% (1.0)] and body weight of 88.3 kg (18.2). Overall mean (SD) baseline body composition values were 33.2 kg (11.0) and 37.6% (7.8) for total fat mass, 51.3 kg (10.4) and 59.4% (7.5) for total lean mass, and 1.5 kg (0.8) (representing 43.9% [15.7] of abdominal fat) for visceral fat mass. The overall mean (SD) baseline total fat mass to total lean mass ratio was 0.7 (0.2).\n\nChange in total fat mass\nNumerical reductions in fat mass (kg and %-point) were observed with both treatments. Estimated reductions were numerically greater for semaglutide vs canagliflozin, but the differences were not statistically significant (Fig. 3a, b). Total fat mass (SE) was reduced with semaglutide and canagliflozin from an overall baseline of 33.2 kg: 3.4 kg (0.51) vs 2.6 kg (0.45), respectively (Fig. 3a), with an estimated treatment difference (ETD; 95% CI) of −0.79 (−2.10, 0.51). The supplementary in-trial analysis of all available data demonstrated similar, non-significant results for total fat mass with reductions of 3.0 kg (0.37) and 2.3 kg (0.36) for semaglutide and canagliflozin, respectively (ETD –0.71 [95% CI –1.72, 0.31]).Fig. 3 Body composition outcomes after 52 weeks of treatment. Change from baseline in total fat mass: kg (a) and % (b); total lean mass: kg (c) and % (d); visceral fat mass: kg (e) and % (f); ratio of total fat mass to total lean mass (g); and cumulative change in total fat mass (h). ‘On-treatment without rescue medication’ data ( n =114 [semaglutide, n = 53; canagliflozin, n = 61]). Missing data were multiple imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including region as categorical effect and data from baseline as covariate. (a–g) Responses were analysed using an ANCOVA with treatment and region as fixed factors and baseline value as covariate. Regions were defined as North America (USA and Canada); Region Europe (UK, Ireland and Sweden); or International Operations (Lebanon, Malaysia, Argentina, Mexico, Brazil and India). Numbers on the bars may not match the numbers on the scale due to rounding. (h) The dashed line on the y-axis shows the 50th percentile, while the dashed line on the x-axis shows the reference value for no change\n\n\n\nThe proportion of total fat mass (SE) was reduced from an overall baseline of 37.6% by 1.4%-point (0.39) and 1.2%-point (0.35) with semaglutide and canagliflozin, respectively (ETD –0.21 [95% CI –1.26, 0.84]) (Fig. 3b). Cumulative changes in total fat mass were comparable between semaglutide and canagliflozin; over 52 weeks, approximately 80% of participants experienced reduced total fat mass with both treatments (Fig. 3h).\n\nPost hoc correlation coefficient analysis\nA moderate correlation was observed between change in total fat mass and change in body weight between baseline and week 52 for semaglutide (r = 0.61 [95% CI 0.40, 0.76]) and canagliflozin (r = 0.54 [0.32, 0.70]) (Fig. 4a). There were no correlations between change in total fat mass and change in HbA1c, systolic BP or diastolic BP over the same period with either semaglutide or canagliflozin (r = 0.01–0.20) (Fig. 4b–d).Fig. 4 Correlation of absolute change in total fat mass (kg) with change in body weight (a), HbA1c (b), SBP (c) and DBP (d) after 52 weeks of treatment. Each point represents data (observed or imputed) from one participant. ‘On-treatment without rescue medication’ data for all randomised participants (n = 178 [semaglutide, n = 88; canagliflozin, n = 90]). Missing data were multiple imputed using data from participants within the same group defined by randomised treatment. Data are plotted for the first ten out of 500 imputations. DBP, diastolic BP; SBP, systolic BP\n\n\n\nChange in total lean mass\nTotal lean mass (SE) was reduced from an overall baseline of 51.3 kg by 2.3 kg (0.30) vs 1.5 kg (0.28) in the semaglutide and canagliflozin treatment groups, respectively (ETD –0.78 [95% CI –1.61, 0.04]) (Fig. 3c). In contrast, lean mass as a proportion of the whole (SE) increased from an overall baseline of 59.4% by 1.2%-point (0.39) with semaglutide vs 1.1%-point (0.34) with canagliflozin (ETD 0.14 [−0.89, 1.17]) (Fig. 3d).\n\nChange in visceral fat mass\nThe decreases in visceral fat mass (SE) were 0.2 kg (0.05) and 0.1 kg (0.04) with semaglutide and canagliflozin, respectively (ETD –0.07 [95% CI –0.20, 0.06]) (Fig. 3e). The percentage of visceral fat mass (SE) decreased from an overall baseline mean of 43.9% by 0.9%-point (0.94) with semaglutide vs an increase of 0.4%-point (0.69) with canagliflozin (ETD –1.38 [−3.65, 0.88]) (Fig. 3f).\n\nRatio between total fat mass and total lean mass\nBody composition changes, as assessed by the fat to lean mass ratio (SE), were favourable for both treatment groups: −0.04 (0.01) and −0.03 (0.01) with semaglutide and canagliflozin, respectively (ETD –0.01 [95% CI –0.04, 0.02]) (Fig. 3g).\n\nChange in body weight\nIn a post hoc calculation of the substudy cohort (n = 178), which served to illustrate consistency between weight loss in participants undergoing a DXA scan in the substudy and in the primary study, reduction in total fat plus lean mass was 5.7 kg with semaglutide vs 4.1 kg with canagliflozin in the substudy, suggesting a weight-loss pattern similar to that observed between treatments in the whole SUSTAIN 8 population (Table 2). Moreover, the distribution of body weight loss was similar in the SUSTAIN 8 substudy compared with the main SUSTAIN 8 trial in participants receiving both semaglutide and canagliflozin (Fig. 5a, b, respectively).Table 2 Body composition outcomes at week 52 (‘On-treatment without rescue medication’ data)\n\n\tSemaglutide 1.0 mg (n = 88)\tCanagliflozin 300 mg (n = 90)\tETD (95% CI)\t\nTotal fat massa\t\n Change at week 52, kg\t−3.41 (0.51)\t−2.62 (0.45)\t−0.79 (−2.10, 0.51)\t\n Change at week 52, %-point\t−1.43 (0.39)\t−1.21 (0.35)\t−0.21 (−1.26, 0.84)\t\nTotal lean mass\t\n Change at week 52, kg\t−2.26 (0.30)\t−1.48 (0.28)\t−0.78 (−1.61, 0.04)\t\n Change at week 52, %-point\t1.24 (0.39)\t1.10 (0.34)\t0.14 (−0.89, 1.17)\t\nTotal fat plus lean mass\n\n(post hoc assessment)b\n\n\t\n Change at week 52, kg\t−5.7\t−4.1\t\t\nTotal fat mass:total lean mass, kg\t\n Change at week 52\t−0.04 (0.01)\t−0.03 (0.01)\t−0.01 (−0.04, 0.02)\t\nVisceral fat mass\t\n Change at week 52, kg\t−0.18 (0.05)\t−0.11 (0.04)\t−0.07 (−0.20, 0.06)\t\n Change at week 52, %-point\t−0.94 (0.94)\t0.44 (0.69)\t−1.38 (−3.65, 0.88)\t\nWaist circumference, cm\t\n Change at week 52c\t−3.9 (5.6)\t−2.5 (5.5)\t\t\nData are mean (SE) unless otherwise specified and represent estimates from an ANCOVA with treatment, region and baseline value as fixed effects\n\nMultiple imputation was used where missing data were imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including region and stratification factor as categorical effects and data from baseline and all previous visits as covariates\n\nRegions were defined as North America (USA and Canada); Region Europe (UK, Ireland and Sweden); or International Operations (Lebanon, Malaysia, Argentina, Mexico, Brazil and India)\n\naFor total fat mass, responses were analysed with an ANCOVA with treatment and region as fixed factors and baseline value as covariate. Before analysis, missing data were multiple imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including region as categorical effect and data from baseline as covariate\n\nbNot pre-specified for the substudy; data are calculated as the sum of the estimated change (mean [SD])\n\ncNot pre-specified for the substudy; data are mean (SD)\n\nFig. 5 Proportion of participants achieving weight loss ≥3%, 5%, 10% or 15% of body weight from baseline after 52 weeks of treatment with semaglutide 1.0 mg (a) and canagliflozin 300 mg (b) in SUSTAIN 8 (n = 788) and the SUSTAIN 8 substudy (n = 178). ‘On-treatment without rescue medication’ data. Missing data were multiple imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including region and stratification factor as categorical effects and data from baseline and all previous visits as covariates. Regions were defined as North America (USA and Canada); Region Europe (UK, Ireland and Sweden); or International Operations (Lebanon, Malaysia, Argentina, Mexico, Brazil and India). This post hoc comparison of change in body weight within the substudy vs the primary study was performed in order to confirm that weight loss in participants undergoing a DXA scan in the substudy was representative of the weight loss in the primary study\n\n\n\nDiscussion\nIn the SUSTAIN 8 substudy, numerical reductions in absolute and proportion of total fat mass were observed for treatment with both semaglutide 1.0 mg and canagliflozin 300 mg. Although fat loss was numerically greater with semaglutide vs canagliflozin after 52 weeks of treatment, the difference was not statistically significant. Overall, 36% of participants were missing DXA scans for the end-of-treatment confirmatory analysis, mainly because scans were taken out-of-window (>7 days after the last dose of trial product). However, the supplementary in-trial analysis of all available scans demonstrated similar results, supporting the robustness of the conclusion for this endpoint. Numerical reductions were observed in both treatment groups in absolute lean mass (kg), although an increase in the proportion of total lean mass (%-point) was observed. However, the change in ratio between total fat mass and total lean mass was minimal in both treatment groups, and was not significantly different between groups. A marginal decrease in absolute visceral fat mass was observed with both treatments, whereas the proportion of visceral fat decreased slightly with semaglutide and increased slightly with canagliflozin, although differences between treatment arms were not significant. Importantly, in this substudy, there was no evidence of deleterious body composition changes, such as reductions in proportion of total lean mass; although the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage.\n\nDXA, a two-compartment method of body composition analysis that separates body components into fat mass and fat-free mass, is one of the most popular and widely used non-invasive techniques for estimating whole-body and regional body composition [29]. When used in relation to body composition, the term ‘lean mass’ usually refers to muscle mass; however, lean mass comprises the combined weight of internal organs, muscle, connective tissue and water. It is important to consider the influence of these non-muscle components in DXA measurements of lean mass, and particularly the inability of DXA to calculate variable amounts of water [29], making it difficult to distinguish between loss of muscle and reduction in extracellular volume.\n\nThe link between obesity and type 2 diabetes is well known [1, 2]. Abdominal obesity is a key factor in the development of diabetes and cardiovascular disease [30] and is a risk factor for several chronic diseases with cardiometabolic homeostasis [31]. Recent studies showing reduction in visceral fat in normal-weight [31] and overweight individuals [32] may have implications with regard to improving cardiometabolic profile. Although many conventional glucose-lowering therapies may contribute to weight gain, treatment with GLP-1RAs and SGLT-2is has been associated with clinically meaningful weight loss [2]. In SUSTAIN 8, treatment with semaglutide and canagliflozin resulted in substantial weight loss of −5.3 kg and −4.2 kg, respectively (ETD –1.06 [95% CI –1.76, −0.36]; p = 0.003 favouring semaglutide), with more participants in the semaglutide arm achieving weight loss ≥10% than those in the canagliflozin arm (22.3% vs 8.9%; OR 2.99 [95% CI 1.89, 4.75]; p < 0.0001). A post hoc calculation of reduction in overall mass (fat mass plus lean body mass) in the DXA substudy indicated reductions of 5.7 kg vs 4.1 kg for semaglutide and canagliflozin, respectively. The distribution of body weight loss in participants in the SUSTAIN 8 substudy receiving semaglutide and canagliflozin was similar compared with all participants in the primary SUSTAIN 8 trial.\n\nThe magnitude of weight loss may have implications for the effect of treatment on lean muscle mass. Regular diet-induced weight loss is associated with corresponding changes in both body fat and fat-free mass, including muscle [33]. In individuals with type 2 diabetes, it is preferable to reduce fat without significant loss of lean mass [32], although this can occur during weight loss in those who are obese [34]. Because skeletal muscle is the major site of postprandial glucose uptake [35], a decrease in lean mass may be associated with impaired glucose metabolism in individuals with type 2 diabetes. However, this is a complex process for which there are various contributing factors. A recent trial examining the effect of the SGLT-2i ipragliflozin in Japanese people with obesity revealed similar mean reductions of fat mass and total lean mass of 1.8 kg and 1.7 kg, respectively, including a small but significant 0.6 kg loss in appendicular lean mass (a good marker of skeletal muscle mass), suggesting that SGLT-2is may induce catabolism of both body fat and muscle secondary to glycosuria [36]. However, the use of DXA for the estimation of changes in body composition in SGLT-2i trials has demonstrated greater reductions in fat mass (2.2 to 2.4 kg) vs lean mass (1.1 to 1.2 kg) [37, 38]. These reductions occurred in the context of a sustained elevation in spot urinary glucose excretion, which is associated with decreased total body weight and fat mass. Thus, the caloric loss from glucosuria, and not fluid loss, was responsible for the reductions [38]. This is supported by results from a small study finding that changes in extracellular water volume with SGLT-2is are transient, and not responsible for long-term weight loss with this drug class [39].\n\nSimilar results were observed in trials assessing body composition with other GLP-1RAs [32, 40, 41]. In a substudy of the LEAD-2 trial, liraglutide 1.8 mg led to changes from baseline in fat mass and lean mass of −2.4 kg and −1.5 kg, respectively, over 26 weeks in 37 participants with type 2 diabetes [40]. In a separate prospective case-series study investigating liraglutide in nine overweight or obese elderly individuals with uncontrolled type 2 diabetes on metformin, DXA demonstrated that mean fat mass was reduced by 1.5 kg, but skeletal muscle index (a measure of muscle mass) improved [41]. A second prospective case-series study evaluated liraglutide 0.9 mg once daily in obese Japanese individuals over 24 weeks [32]. In that study (n = 9), body weight was reduced by 11.7%. Body composition analysis from DXA scans showed that this was mostly caused by decreases in visceral fat mass (mean reduction: 11.9%) and intrahepatic lipid content (mean reduction: 49.2%) with no change in subcutaneous fat. Fat mass index also decreased (mean reduction: 10.9%) whereas skeletal muscle mass remained unchanged [32]. While indirect comparisons across clinical trials should be interpreted with caution, given the heterogeneity of the study populations, these findings suggest that body composition changes with semaglutide are consistent with those in previous studies of other GLP-1RAs. These changes are supported by the proposed mechanisms of weight loss with GLP-1RAs through appetite modulation via the central nervous system with minimal effect on energy expenditure [42, 43], as well as through the increase of natriuresis caused by inhibition of the sodium–hydrogen ion transporter in the proximal tubule, which subsequently reduces sodium retention and extracellular fluid volume expansion [44]. An additional mechanism may be nausea/vomiting, which was shown to have a minimal effect on weight loss in a post hoc mediation analysis of semaglutide vs exenatide extended release and dulaglutide in the SUSTAIN 3 and 7 trials [45].\n\nThe positive effects of both treatments on weight loss demonstrated previously [11–20, 24] highlight the importance of newer agents among current pharmacological options, compared with older, standard approaches for type 2 diabetes that may increase or have little effect on weight [46]. However, the greater reduction of weight loss with semaglutide vs canagliflozin in the primary SUSTAIN 8 trial [17], when also taking into account the lack of statistical difference in body composition changes between treatments in this substudy, highlights the potential value of semaglutide in terms of weight management in individuals with uncontrolled type 2 diabetes on stable-dose metformin therapy.\n\nStrengths and weaknesses\nThe strengths of this substudy include the methods and design of SUSTAIN 8, a double-blind randomised clinical trial with a global population, relatively long treatment period of 52 weeks, and relevant head-to-head comparison with a glucose-lowering medication with demonstrated efficacy in type 2 diabetes. In addition, analysis and quality assessments of the DXA scans were performed by one central imaging laboratory using one brand of scanner, reducing the likelihood of inconsistencies in bone and soft-tissue measurements that can occur due to variability of hardware and software packages between DXA equipment manufacturers [47].\n\nDXA is one of the most popular and widely used non-invasive techniques for estimation of whole-body and regional body composition [47–49]. However, body thickness and hydration status can affect results [49], and lean muscle mass may also include non-muscle components, such as blood or interstitial fluid, leading to measurement error [50]. Moreover, the inability of DXA to distinguish different types of fat (visceral, subcutaneous, intramuscular) and lean soft tissues (muscle, organs) represents a practical limitation [49]. The lack of systematic collection of off-treatment DXA scans is a weakness of this substudy. Some participants only received baseline scans, and approximately a third did not have scans available for the confirmatory analysis, mostly due to these being taken out-of-window. However, results from the supplementary in-trial analysis, which included all available data, were similar to those observed in the confirmatory analysis and confirm the robustness of data. Finally, the SUSTAIN 8 trial did not include a placebo arm, meaning that all changes in body weight and composition reported here are comparisons between active treatments, and it cannot be concluded that all observed changes were entirely attributable to either treatment.\n\nConclusion\nIn the SUSTAIN 8 substudy, the changes in body composition between semaglutide and canagliflozin were not significantly different in participants with uncontrolled type 2 diabetes on stable-dose metformin therapy. Although numerical improvements in body composition were observed following treatment in both treatment arms, the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage.\n\nAbbreviations\nDXADual-energy x-ray absorptiometry\n\nETDEstimated treatment difference\n\nGLP-1RAGlucagon-like peptide-1 receptor agonist\n\nSGLT-2iSodium–glucose co-transporter-2 inhibitor\n\nSUSTAINSemaglutide Unabated Sustainability in Treatment of Type 2 Diabetes \n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank all the participants, investigators and trial-site staff members who were involved in the conduct of the trial; E. Yildirim (Novo Nordisk A/S, Søborg, Denmark) for review and suggestions for revising the manuscript; and S. Vanderveen and F. Harris, MRes at AXON Communications, for medical writing and editorial assistance (funded by Novo Nordisk A/S, Denmark). Some of the data were presented at the 55th EASD Annual Meeting, Barcelona, 2019 (McCrimmon R et al. Oral presentation: presentation number 54).\n\nContribution statement\nIL, A-MC, CWlR, DT and RJM participated in the design of this analysis. IL, A-MC, JF, CWlR, DT and RJM contributed to the conduct and data collection of the primary trial. NLL contributed to the data analysis. All authors interpreted the data and participated in writing the report, with the support of medical writing services provided by the funder. All authors read and approved the submitted version of the report. RJM is responsible for the integrity of this work as a whole.\n\nFunding\nThis trial was supported by Novo Nordisk A/S, Denmark. The funding sources contributed to the design and conduct of the trials, the analysis and interpretation of the data, and the preparation, review and approval of the manuscript.\n\nData availability\nIndividual participant data will be shared in datasets in a de-identified/anonymised format. Datasets from Novo Nordisk-sponsored clinical research completed after 2001 for product indications approved in both the EU and US will be shared. The study protocol and redacted Clinical Study Report (CSR) will be available according to Novo Nordisk data sharing commitments. The data will be available permanently after research completion and approval of product and product use in both EU and US. There is no end date. Data will be shared with bona fide researchers submitting a research proposal and requesting access to data, for use as approved by the Independent Review Board (IRB) according to the IRB Charter (see www.novonordisk-trials.com). The access request proposal form and the access criteria can be found at www.novonordisk-trials.com. The data will be made available on a specialised SAS data platform.\n\nDuality of interest\nRJM reports grants from the Helmsley Trust, EU IMI, MRC, Diabetes UK and the JDRF during the conduct of the study and fees from Eli Lilly, Novo Nordisk and Sanofi outside the submitted work. JPF reports grants and personal fees from Novo Nordisk during the conduct of the study and grants and personal fees from Boehringer Ingelheim, BMS Eli Lilly, Merck, Pfizer and Sanofi outside the submitted work. CWlR reports grants and other support from the Health Research Board and the Science Foundation Ireland during the conduct of the study. Outside the submitted work, he reports grants, personal fees and other support from AnaBio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GI Dynamics, Janssen, Johnson & Johnson, Keyron, Novo Nordisk and Sanofi. IL received research grants to her institution and consulting fees from Novo Nordisk during the conduct of the study. Outside the submitted work, she has received grants and/or personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GI Dynamics, Intarcia, Mannkind, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, TARGET PharmaSolutions and Valeritas. A-MC, NLL and DT are employees of Novo Nordisk A/S.\n==== Refs\nReferences\n1. Gatineau M, Hancock C, Holman N et al (2014) Adult obesity and type 2 diabetes. Available from https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/338934/Adult_obesity_and_type_2_diabetes_.pdf. Accessed 25 November 2019\n2. Van Gaal L Scheen A Weight management in type 2 diabetes: current and emerging approaches to treatment Diabetes Care 2015 38 6 1161 1172 10.2337/dc14-1630 25998297 \n3. Castro AV Kolka CM Kim SP Bergman RN Obesity, insulin resistance and comorbidities? Mechanisms of association Arq Bras Endocrinol Metabol 2014 58 6 600 609 10.1590/0004-2730000003223 25211442 \n4. Ormazabal V Nair S Elfeky O Aguayo C Salomon C Zuniga FA Association between insulin resistance and the development of cardiovascular disease Cardiovasc Diabetol 2018 17 1 122 10.1186/s12933-018-0762-4 30170598 \n5. Hubert HB Feinleib M McNamara PM Castelli WP Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study Circulation 1983 67 5 968 977 10.1161/01.cir.67.5.968 6219830 \n6. Davies MJ, D’Alessio DA, Fradkin J et al (2018) Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 61(12):2461–2498. 10.1007/s00125-018-4729-5\n7. American Diabetes Association 8. Obesity management for the treatment of type 2 diabetes: standards of medical care in diabetes-2019 Diabetes Care 2019 41 Suppl 1 S81 S89 10.2337/dc19-S008 \n8. Pi-Sunyer FX (2009) The impact of weight gain on motivation, compliance, and metabolic control in patients with type 2 diabetes mellitus. Postgrad Med 121(5):94–107. 10.3810/pgm.2009.09.2056\n9. European Medicines Agency (2017) Ozempic (semaglutide) summary of product characteristics. Available from https://www.ema.europa.eu/en/documents/product-information/ozempic-epar-product-information_en.pdf. Accessed 25 November 2019\n10. Novo Nordisk (2017) Ozempic (semaglutide). Prescribing information. Available from https://www.novo-pi.com/ozempic.pdf. Accessed 25 November 2019\n11. Sorli C Harashima SI Tsoukas GM Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial Lancet Diabetes Endocrinol 2017 5 4 251 260 10.1016/S2213-8587(17)30013-X 28110911 \n12. Ahrén B Masmiquel L Kumar H Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial Lancet Diabetes Endocrinol 2017 5 5 341 354 10.1016/s2213-8587(17)30092-x 28385659 \n13. Ahmann AJ Capehorn M Charpentier G Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial Diabetes Care 2018 41 2 258 266 10.2337/dc17-0417 29246950 \n14. Aroda VR Bain SC Cariou B Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial Lancet Diabetes Endocrinol 2017 5 5 355 366 10.1016/s2213-8587(17)30085-2 28344112 \n15. Rodbard HW Lingvay I Reed J Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial J Clin Endocrinol Metab 2018 103 6 2291 2301 10.1210/jc.2018-00070 29688502 \n16. Pratley RE Aroda VR Lingvay I Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial Lancet Diabetes Endocrinol 2018 6 4 275 286 10.1016/s2213-8587(18)30024-x 29397376 \n17. Lingvay I Catarig AM Frias JP Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial Lancet Diabetes Endocrinol 2019 7 11 834 844 10.1016/s2213-8587(19)30311-0 31540867 \n18. Zinman B Bhosekar V Busch R Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial Lancet Diabetes Endocrinol 2019 7 5 356 367 10.1016/s2213-8587(19)30066-x 30833170 \n19. Capehorn MS, Catarig AM, Furberg JK et al (2019) Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab. 10.1016/j.diabet.2019.101117\n20. Marso SP Bain SC Consoli A Semaglutide and cardiovascular outcomes in patients with type 2 diabetes N Engl J Med 2016 375 19 1834 1844 10.1056/NEJMoa1607141 27633186 \n21. Janssen Pharmaceuticals, Inc (2019) Invokana (canagliflozin) tablets. Prescribing information. Available from www.invokana.com/prescribing-information.pdf. Accessed 25 November 2019\n22. Jakher H Chang TI Tan M Mahaffey KW Canagliflozin review - safety and efficacy profile in patients with T2DM Diabetes Metab Syndr Obes 2019 12 209 215 10.2147/dmso.s184437 30787627 \n23. Perkovic V Jardine MJ Neal B Canagliflozin and renal outcomes in type 2 diabetes and nephropathy N Engl J Med 2019 380 24 2295 2306 10.1056/NEJMoa1811744 30990260 \n24. Seufert J SGLT2 inhibitors – an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin Diabetes Metab Syndr Obes 2015 8 543 554 10.2147/dmso.s90662 26609242 \n25. International Conference on Harmonisation–World Health Organization Guideline for Good Clinical Practice (1996) ICH harmonised tripartite guideline good clinical practice. Available from https://apps.who.int/medicinedocs/en/m/abstract/Js22154en/. Accessed 25 November 2019\n26. World Medical Association World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects JAMA 2013 310 20 2191 2194 10.1001/jama.2013.281053 24141714 \n27. Little RJA Rubin DB Statistical analysis with missing data 1987 New York John Wiley & Sons \n28. Bretz F Posch M Glimm E Klinglmueller F Maurer W Rohmeyer K Graphical approaches for multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests Biom J 2011 53 6 894 913 10.1002/bimj.201000239 21837623 \n29. Brownbill RA Ilich JZ Measuring body composition in overweight individuals by dual energy x-ray absorptiometry BMC Med Imaging 2005 5 1 1 10.1186/1471-2342-5-1 15748279 \n30. Van Gaal LF Mertens IL De Block CE Mechanisms linking obesity with cardiovascular disease Nature 2006 444 7121 875 880 10.1038/nature05487 17167476 \n31. Sarin HV Lee JH Jauhiainen M Substantial fat mass loss reduces low-grade inflammation and induces positive alteration in cardiometabolic factors in normal-weight individuals Sci Rep 2019 9 1 3450 10.1038/s41598-019-40107-6 30837600 \n32. Ishii S Nagai Y Sada Y Liraglutide reduces visceral and intrahepatic fat without significant loss of muscle mass in obese patients with type 2 diabetes: a prospective case series J Clin Med Res 2019 11 3 219 224 10.14740/jocmr3647 30834046 \n33. Gill LE Bartels SJ Batsis JA Weight management in older adults Curr Obes Rep 2015 4 3 379 388 10.1007/s13679-015-0161-z 26627496 \n34. Kim B Tsujimoto T So R Zhao X Oh S Tanaka K Changes in muscle strength after diet-induced weight reduction in adult men with obesity: a prospective study Diabetes Metab Syndr Obes 2017 10 187 194 10.2147/dmso.s132707 28533692 \n35. DeFronzo RA Tripathy D Skeletal muscle insulin resistance is the primary defect in type 2 diabetes Diabetes Care 2009 32 Suppl 2 S157 S163 10.2337/dc09-S302 19875544 \n36. Ohta A Kato H Ishii S Ipragliflozin, a sodium glucose co-transporter 2 inhibitor, reduces intrahepatic lipid content and abdominal visceral fat volume in patients with type 2 diabetes Expert Opin Pharmacother 2017 18 14 1433 1438 10.1080/14656566.2017.1363888 28770629 \n37. Blonde L Stenlof K Fung A Xie J Canovatchel W Meininger G Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks Postgrad Med 2016 128 4 371 380 10.1080/00325481.2016.1169894 27002421 \n38. Bolinder J Ljunggren Ö Kullberg J Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin J Clin Endocrinol Metab 2012 97 3 1020 1031 10.1210/jc.2011-2260 22238392 \n39. Schork A, Saynisch J, Vosseler A et al (2019) Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol 18(1):46. 10.1186/s12933-019-0852-y\n40. Jendle J Nauck MA Matthews DR Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue Diabetes Obes Metab 2009 11 12 1163 1172 10.1111/j.1463-1326.2009.01158.x 19930006 \n41. Perna S Guido D Bologna C Liraglutide and obesity in elderly: efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study Aging Clin Exp Res 2016 28 6 1251 1257 10.1007/s40520-015-0525-y 26749118 \n42. Brown E Wilding JPH Barber TM Alam U Cuthbertson DJ Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: mechanistic possibilities Obes Rev 2019 20 6 816 828 10.1111/obr.12841 30972878 \n43. Ryan D Acosta A GLP-1 receptor agonists: nonglycemic clinical effects in weight loss and beyond Obesity (Silver Spring) 2015 23 6 1119 1129 10.1002/oby.21107 25959380 \n44. Baretić M Kušec V Pavlić-Renar I Glucagon-like peptide-1 infusion suppresses aldosterone levels in healthy normal-weight individuals: double-blind, placebo-controlled crossover study Diabetes Ther 2018 9 6 2315 2324 10.1007/s13300-018-0517-y 30298444 \n45. Lingvay I de la Rosa R Marre M Minimal contribution of nausea or vomiting to superior semaglutide-mediated weight loss vs exenatide and dulaglutide in type 2 diabetes Diabetologia 2018 61 Suppl 1 765 \n46. Hermansen K Mortensen LS Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus Drug Saf 2007 30 12 1127 1142 10.2165/00002018-200730120-00005 18035865 \n47. Tosato M Marzetti E Cesari M Measurement of muscle mass in sarcopenia: from imaging to biochemical markers Aging Clin Exp Res 2017 29 1 19 27 10.1007/s40520-016-0717-0 28176249 \n48. Lee SY Gallagher D Assessment methods in human body composition Curr Opin Clin Nutr Metab Care 2008 11 5 566 572 10.1097/MCO.0b013e32830b5f23 18685451 \n49. Prado CM Heymsfield SB Lean tissue imaging: a new era for nutritional assessment and intervention J Parenter Enter Nutr 2014 38 8 940 953 10.1177/0148607114550189 \n50. Weiss EP, Jordan RC, Frese EM, Albert SG, Villareal DT (2017) Effects of weight loss on lean mass, strength, bone, and aerobic capacity. Med Sci Sports Exerc 49(1):206–217. 10.1249/mss.0000000000001074\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0012-186X",
"issue": "63(3)",
"journal": "Diabetologia",
"keywords": "Body composition; Canagliflozin; Fat mass; Glucagon-like peptide receptor agonists; Randomised controlled trial; Semaglutide; Type 2 diabetes; Weight",
"medline_ta": "Diabetologia",
"mesh_terms": "D000368:Aged; D001786:Blood Glucose; D001823:Body Composition; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2; D004311:Double-Blind Method; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D004763:Glucagon-Like Peptides; D006442:Glycated Hemoglobin A; D006801:Humans; D008297:Male; D008687:Metformin; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "0006777",
"other_id": null,
"pages": "473-485",
"pmc": null,
"pmid": "31897524",
"pubdate": "2020-03",
"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": "30833170;15748279;19875544;18035865;29688502;28110911;30972878;30288571;27002421;26627496;30787627;25998297;29246950;29397376;30298444;19820278;22238392;17167476;28533692;25239112;27633186;28770629;28385659;30834046;27580151;30953516;30990260;30559234;19930006;26749118;28344112;24141714;25959380;30837600;30170598;6219830;21837623;26609242;25211442;31539622;18685451;28176249;31540867",
"title": "Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial.",
"title_normalized": "effects of once weekly semaglutide vs once daily canagliflozin on body composition in type 2 diabetes a substudy of the sustain 8 randomised controlled clinical trial"
} | [
{
"companynumb": "US-JNJFOC-20191102869",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
},
"drugadditional": null,
... |
{
"abstract": "The new psychoactive substance 3,4-methylenedioxypyrovalerone (MDPV) belongs to the group of synthetic cathinones and is purchased mainly as \"research chemical\" or \"bath salt\" on the illegal drug market, also in South Bavaria. MDPV was detected in blood and urine samples from 2010 on in 50 authentic routine cases in a forensic setting. Plasma concentrations in 46 cases with available blood specimens ranged from approximately 1.0 to 301μg/L (median 23.7; mean 47.9μg/L), detected by a fully validated LC-MS/MS method. Subjects aged between 16 and 54 years (median 36; mean 35 years) and reflected experienced chronic drug users. Accused offences were mainly violent crimes such as bodily harm, robberies, homicides and acts of resistance. A lot of subjects showed highly aggressive and violent behavior with endangerment of self and others and/or psychotic symptoms as confusion, hallucinations or paranoia. The risk for such behavior rises with MDPV plasma concentrations above as low as 30μg/L, whereby a time interval of 1.5h on average between incident and/or observation of impairment and blood sampling has to be taken into account. Comprehensive toxicological analysis proved poly-drug use in almost all cases including opiates/opioids, benzodiazepines and other sedatives, antidepressants and other stimulants, also other new psychoactive substances. Alcohol was detected only in three cases. Co-consumed benzodiazepines seem not be able to completely prevent psychotic effects despite their use as first-line treatment for patients with synthetic cathinone poisonings. The study demonstrates that relatively low plasma concentrations of MDPV could be associated with mental impairment which is relevant in the assessment of forensic cases.",
"affiliations": "Department of Forensic Toxicology, Institute of Forensic Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.;Department of Forensic Toxicology, Institute of Forensic Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.;Department of Forensic Toxicology, Institute of Forensic Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.;Department of Forensic Toxicology, Institute of Forensic Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.;Institute of Forensic Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany.;Department of Forensic Toxicology, Institute of Forensic Medicine, Ludwig-Maximilians-University Munich, Nussbaumstraße 26, 80336 Munich, Germany. Electronic address: liane.paul@med.uni-muenchen.de.",
"authors": "Diestelmann|Marco|M|;Zangl|Anna|A|;Herrle|Inge|I|;Koch|Eva|E|;Graw|Matthias|M|;Paul|Liane D|LD|",
"chemical_list": "D052117:Benzodioxoles; D015198:Designer Drugs; D011759:Pyrrolidines; C554666:3,4-methylenedioxypyrovalerone",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2017.12.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "283()",
"journal": "Forensic science international",
"keywords": "Bath salts; LC–MS/MS; MDPV; New psychoactive substances; Plasma concentrations; Psychotic behavior",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000374:Aggression; D052117:Benzodioxoles; D002853:Chromatography, Liquid; D003221:Confusion; D015198:Designer Drugs; D005260:Female; D006212:Hallucinations; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010258:Paranoid Behavior; D011759:Pyrrolidines; D019966:Substance-Related Disorders; D014754:Violence; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "72-84",
"pmc": null,
"pmid": "29275216",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "MDPV in forensic routine cases: Psychotic and aggressive behavior in relation to plasma concentrations.",
"title_normalized": "mdpv in forensic routine cases psychotic and aggressive behavior in relation to plasma concentrations"
} | [
{
"companynumb": "DE-PFIZER INC-2018031946",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": "3",
... |
{
"abstract": "Patient falls represent a significant burden on healthcare facilities, particularly by prolonging hospitalization and increasing the cost of subsequent healthcare. In most cases, fall is caused by a combination of several modifiable and unmodifiable risk factors. The pharmacotherapy, which is often unreasonably administered in relation to patient health condition and drug combination, belongs among the modifiable risk factors. In this case report, the potential effect of pharmacotherapy on the patient fall-related risk as well as clinical pharmacy service that can contribute to reducing the risk of falls by engaging of clinical pharmacist in a multidisciplinary team with focus on the risks of pharmacotherapy and their management are shown.",
"affiliations": null,
"authors": "Doseděl|Martin|M|;Malý|Josef|J|;Vosátka|Jan|J|;Mikolášek|Petr|P|;Brabcová|Iva|I|;Hajduchová|Hana|H|;Bártlová|Sylva|S|;Tóthová|Valérie|V|;Vlček|Jiří|J|",
"chemical_list": null,
"country": "Czech Republic",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1210-7816",
"issue": "67(5-6)",
"journal": "Ceska a Slovenska farmacie : casopis Ceske farmaceuticke spolecnosti a Slovenske farmaceuticke spolecnosti",
"keywords": "clinical pharmacist; fall; fall risk increasing drugs (FRIDs)",
"medline_ta": "Ceska Slov Farm",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D004358:Drug Therapy; D006760:Hospitalization; D006801:Humans; D010595:Pharmacists; D012307:Risk Factors",
"nlm_unique_id": "9433765",
"other_id": null,
"pages": "205-211",
"pmc": null,
"pmid": "30871326",
"pubdate": "2018-12-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical pharmacist involvement in fall management in a polymorbid geriatric patient with a history of recurrent falls.",
"title_normalized": "clinical pharmacist involvement in fall management in a polymorbid geriatric patient with a history of recurrent falls"
} | [
{
"companynumb": "CZ-ORION CORPORATION ORION PHARMA-19_00006043",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugad... |
{
"abstract": "BACKGROUND\nNUT midline carcinoma is a rare and aggressive subset of squamous cell carcinoma, which is characterized by the translocation of nuclear protein in testis gene that is mostly fused with bromodomain and extraterminal family proteins. We describe here the first Brazilian case of NUT midline carcinoma with BRD4-NUT fusion detected in a next-generation sequencing panel and we present the clinical evolution of this patient.\n\n\nMETHODS\nA 42-year-old Caucasian man was diagnosed with poorly differentiated squamous cell carcinoma of the left maxillary sinus, with negative in situ hybridization for Epstein-Barr encoding region and human papillomavirus genotyping. He received induction therapy, chemoradiotherapy with weekly systemic chemotherapy, and, concurrently, weekly intra-arterial chemotherapy. New imaging evaluation, 1 month after the end of the last treatment, revealed a good partial response in the primary lesion. However, positron emission tomography-computed tomography showed multiple suspicious lesions in his bones and lungs, which were histologically confirmed. He died exactly 2 months after metastatic disease was diagnosed.\n\n\nCONCLUSIONS\nNUT midline carcinoma is usually very aggressive. Currently, there is no standard of care for treatment of NUT midline carcinoma. The definitive diagnosis must be by demonstration of NUTM1 rearrangement. Immunohistochemical staining of greater than 50% of tumor nuclei on formalin-fixed paraffin-embedded tissue using the monoclonal rabbit antibody to NUT (clone C52B1), has a specificity of 100%, and sensitivity of 87% for the diagnosis of NUT midline carcinoma. Our case is the first Brazilian case of NUT midline carcinoma with BRD4-NUT fusion.",
"affiliations": "Centro de Oncologia, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, São Paulo, 01308-050, Brazil. leandrojco1986@gmail.com.;Centro de Oncologia, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, São Paulo, 01308-050, Brazil.;Instituto de Ensino e Pesquisa, Hospital Sírio Libanês, São Paulo, Brazil.;Serviço de Medicina Nuclear, Hospital Sírio Libanês, São Paulo, Brazil.;Centro de Oncologia, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, São Paulo, 01308-050, Brazil.;Serviço de Anatomia Patológica, Hospital Sírio Libanês, São Paulo, Brazil.;Instituto de Ensino e Pesquisa, Hospital Sírio Libanês, São Paulo, Brazil.;Centro de Oncologia, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, São Paulo, 01308-050, Brazil.",
"authors": "Oliveira|Leandro J C|LJC|;Gongora|Aline B L|ABL|;Latancia|Marcela T|MT|;Barbosa|Felipe G|FG|;Gregorio|João Vitor A M|JVAM|;Testagrossa|Leonardo A|LA|;Amano|Mariane T|MT|;Feher|Olavo|O|",
"chemical_list": "C471990:BRD4-NUT fusion oncogene protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2213-6",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 221310.1186/s13256-019-2213-6Case ReportThe first report of molecular characterized BRD4-NUT carcinoma in Brazil: a case report Oliveira Leandro J. C. leandrojco1986@gmail.com 1Gongora Aline B. L. alineblara@yahoo.com.br 1Latancia Marcela T. marcela.latancia@gmail.com 2Barbosa Felipe G. felipe.gbarbosa@hsl.org.br 3Gregorio João Vitor A. M. jvamgregorio@gmail.com 14Testagrossa Leonardo A. Leonardo.atestagrossa@hsl.org.br 5Amano Mariane T. mtamano@mochsl.org.br 2Feher Olavo omfeher@gmail.com 141 0000 0000 9080 8521grid.413471.4Centro de Oncologia, Hospital Sírio Libanês, Rua Dona Adma Jafet, 91. 2nd floor. Building A, São Paulo, 01308-050 Brazil 2 0000 0000 9080 8521grid.413471.4Instituto de Ensino e Pesquisa, Hospital Sírio Libanês, São Paulo, Brazil 3 0000 0000 9080 8521grid.413471.4Serviço de Medicina Nuclear, Hospital Sírio Libanês, São Paulo, Brazil 4 0000 0004 1937 0722grid.11899.38Serviço de Oncologia, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil 5 0000 0000 9080 8521grid.413471.4Serviço de Anatomia Patológica, Hospital Sírio Libanês, São Paulo, Brazil 7 9 2019 7 9 2019 2019 13 27926 3 2019 30 7 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nNUT midline carcinoma is a rare and aggressive subset of squamous cell carcinoma, which is characterized by the translocation of nuclear protein in testis gene that is mostly fused with bromodomain and extraterminal family proteins. We describe here the first Brazilian case of NUT midline carcinoma with BRD4-NUT fusion detected in a next-generation sequencing panel and we present the clinical evolution of this patient.\n\nCase presentation\nA 42-year-old Caucasian man was diagnosed with poorly differentiated squamous cell carcinoma of the left maxillary sinus, with negative in situ hybridization for Epstein–Barr encoding region and human papillomavirus genotyping. He received induction therapy, chemoradiotherapy with weekly systemic chemotherapy, and, concurrently, weekly intra-arterial chemotherapy. New imaging evaluation, 1 month after the end of the last treatment, revealed a good partial response in the primary lesion. However, positron emission tomography-computed tomography showed multiple suspicious lesions in his bones and lungs, which were histologically confirmed. He died exactly 2 months after metastatic disease was diagnosed.\n\nConclusions\nNUT midline carcinoma is usually very aggressive. Currently, there is no standard of care for treatment of NUT midline carcinoma. The definitive diagnosis must be by demonstration of NUTM1 rearrangement. Immunohistochemical staining of greater than 50% of tumor nuclei on formalin-fixed paraffin-embedded tissue using the monoclonal rabbit antibody to NUT (clone C52B1), has a specificity of 100%, and sensitivity of 87% for the diagnosis of NUT midline carcinoma. Our case is the first Brazilian case of NUT midline carcinoma with BRD4-NUT fusion.\n\nKeywords\nNUT midline carcinomaPoorly differentiated squamous cell carcinomaMolecular pathologyTargeted therapyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nNUT midline carcinoma (NMC) is a rare and aggressive subset of squamous cell carcinoma, which is characterized by the translocation of nuclear protein in testis (NUT) gene that is mostly fused with bromodomain and extraterminal (BET) family proteins, such as BRD3 and BRD4 [1], generating BRD3-NUT and BRD4-NUT, respectively. A non-BET member, nuclear receptor binding SET domain 3 (NSD3), was also seen to be fused with NUT (NSD3-NUT) [2, 3], but this seems to be less frequent than BRD3-NUT and BRD4-NUT. The majority of the cases occur in the head, neck, and mediastinum, although there are reports involving the bladder, pancreas, adrenal gland, kidney, and salivary gland [4]. NMC differs from other carcinomas, which usually have complex karyotypes, because it is characterized by a few or a single translocation, most often the BRD4-NUT: t(15;19)(q14;p13.1) [4].\n\nUntil 2011, NMC was considered an extremely rare carcinoma, with only 28 reported cases worldwide [5]. Since 2012, the number of diagnosed cases increased enormously; this was identified in a review in the International NUT Midline Carcinoma Registry, which detected 48 cases of NMC from 2011 to 2014, of which 86% were BRD4-NUT positive [6]. This review suggests that NMC is probably underdiagnosed.\n\nWe describe here the first Brazilian case of NMC with BRD4-NUT fusion detected in next-generation sequencing (NGS) panel and we present the clinical evolution of this patient. Until recently, to the best of our knowledge, no cases of NMC had been reported in Latin America [4, 7]. Salles et al. described four patients with typical NMC histopathology and NUT positivity in the nucleus [8]. However, the fusion was not molecularly described. Since there is a clear failure in detecting NMC in patients, and further studies are required to provide better chances for these patients, we understand that there is a need to report and better characterize cases of NMC.\n\nCase presentation\nA 42-year-old Caucasian man presented in December 2016 with productive cough, facial pain, and rhinorrhea. He is an engineer, who does not smoke tobacco, and he had no significant premorbid conditions. There was no history of prescription drug use, and no significant family history. Neurological, cardiovascular, respiratory, and abdominal examinations were normal, except for tenderness of the face elicited by palpation. He was first diagnosed as having acute rhinosinusitis and treated with antibiotics (details were not available), without improvement. Due to symptoms persistence, magnetic resonance imaging (MRI) of his face was ordered. This study revealed an expansive irregular heterogeneous lesion (4.5 × 3.5 × 4.0 cm), with its central portion located on the interface between the left maxillary sinus and the pterygopalatine fossa. This lesion invaded medially the nasal cavity and posterosuperiorly the left orbit apex with an intracranial extension through the inferior orbital fissure (Fig. 1a–d). There was no lymphadenopathy and no perineural invasion. A biopsy demonstrated poorly differentiated squamous cell carcinoma with negative in situ hybridization for Epstein–Barr encoding region (EBER). Human papillomavirus (HPV) genotyping test was negative as well. Positron emission tomography-computed tomography (PET-CT) was negative for nodal and systemic metastases. His total leukocyte and platelet counts, as well as hemoglobin levels, were all within normal limits. His biochemical parameters, including serum electrolytes, renal function test, and liver function test, were also normal.\nFig. 1 Local tumor response seen in head and neck magnetic resonance images. Magnetic resonance images from baseline before second-line chemotherapy (a–d) showing locally advanced left maxillary sinus mass (arrows), infiltrating adjacent sinuses and skull base foramina. Follow-up magnetic resonance images (e–h) showing significant tumor shrinkage (arrows) with areas of necrosis, representing local morphological partial response\n\n\n\nHe received, from January 2017 to April 2017, induction therapy with docetaxel 75 mg/m2 at day 1, cisplatin 100 mg/m2 at day 1, and fluorouracil (5-FU) 1000 mg/m2 per day at day 1 to day 4 (DCF) for six cycles every 3 weeks, with clinical benefit and stable disease by MRI and PET-CT (Figs. 1 and 2). Chemoradiotherapy (radiotherapy 35 fractions – 70 Gy) with weekly systemic chemotherapy based on carboplatin 1.5 area under the curve (AUC), paclitaxel 45 mg/m2, and cetuximab 400 mg/m2 was administered for 7 weeks from May 2017 to July 2017. Concurrently, weekly intra-arterial chemotherapy with cisplatin 150 mg/m2 was performed for 5 weeks with grade 2 myelotoxicity and nausea.\nFig. 2 Local complete metabolic response seen in 18F-fluorodeoxyglucose positron emission tomography-computed tomography. Fluorodeoxyglucose-positron emission tomography-computed tomography head and neck images from baseline before second-line chemotherapy (a) showing locally advanced left maxillary sinus enhanced mass (arrows) with fluorodeoxyglucose avidity. Positron emission tomography-computed tomography of 1 month after end of treatment (b) confirming morphological shrinkage of the left maxillary sinus with extensive necrosis (arrows) without any fluorodeoxyglucose uptake, representing local complete metabolic response\n\n\n\nNew imaging evaluation, 1 month after the end of the last treatment, revealed a good partial response in the primary lesion (Figs. 1e–h and 2). However, PET-CT showed multiple suspicious lesions in his bones and lungs (Fig. 3), which were histologically confirmed (Fig. 4a, b). Programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) was negative (SP263 Ventana). In order to look for other therapeutic possibilities, a formalin-fixed paraffin-embedded (FFPE) tumor biopsy was sent to the Foundation Medicine with patient consent. Deoxyribonucleic acid (DNA) extracted from FFPE and hybrid capture-based NGS was applied to perform the FoundationOne™ test, which comprises a panel of 315 genes known to carry somatic mutations in human solid tumors, as well as introns of 28 genes involved in rearrangements. The test showed a rearrangement of BRD4-NUT characterizing NMC. No other mutations were found; microsatellite stability and low mutational burden were reported. The IHC for NUT protein was performed and stained positively in neoplastic nuclei (Fig. 5).\nFig. 3 Systemic disease progression evidenced in 18F-fluorodeoxyglucose positron emission tomography-computed tomography maximum intensity projection images. Maximum intensity projection fluorodeoxyglucose-positron emission tomography-computed tomography whole-body images from baseline before second-line chemotherapy (a) and 1 month after end of treatment (b). Image a shows no evidence of systemic disease. Image b shows disease progression with new bone and pulmonary fluorodeoxyglucose-avid metastasis (arrows)\n\n\nFig. 4 a Bone metastasis of poorly differentiated carcinoma showing neoplastic epithelioid clusters with small cells (hematoxylin and eosin, × 200). b Higher magnification of the neoplastic clusters (hematoxylin and eosin, × 400)\n\n\nFig. 5 NUT immunohistochemistry staining positively in neoplastic nuclei\n\n\n\nDue to the lack of available clinical trials in the country for this highly aggressive tumor, our patient received two more cycles of chemotherapy, but, unfortunately, without any response. He died exactly 2 months after metastatic disease was diagnosed.\n\nDiscussion\nWe describe the first report of a molecular characterized BRD4-NUT carcinoma in Brazil and Latin America. Our patient showed a significant partial response in the primary lesion but progressed with multiple metastatic lesions in bone and lungs.\n\nReports of NMC have been increasing since it was originally described as a genetically defined entity in 2004 [9]. It can affect individuals of all ages, despite the initial thought that it only affected children and young adults. The median age of diagnosis is 24 years. The most common primary sites are thorax, in 50% of the patients, and head and neck, in 39% of patients. There are other primary sites (non-midline, non-thoracic, or head and neck) described in reports of NMCs, such as soft tissue or bone, which can account for 11% of all cases [10]. In Brazil, lung and head and neck cancers are among the ten most frequent cancers, especially in men [11]. However, until now, there were no cases of NUT-BRD4 NMC confirmed in Brazil, probably due to underdiagnosis.\n\nNMC is usually very aggressive. Not rarely, it is metastatic at diagnosis and has poor survival rates. An analysis of a clinical database with 63 patients with NMC and outcome data of 54 patients showed a median overall survival (OS) of 6.7 months. The 2-year OS was 19% [12]. A systematic review and individual patient data analysis of 119 cases showed median OS of only 5 months. Radiotherapy and chemotherapy had a significant impact on OS, while surgery, BET inhibitors, and histone deacetylase inhibitors (HDACi) did not affect survival significantly [13].\n\nAs previously discussed, the karyotypes of NMC are not complex; they frequently have a clonal translocation of the NUTM1 gene, classically t(15;19)(q14;p13.1), which places NUT in the frame with BRD4. This feature differs from other carcinomas because the latter develop over years due to an accumulation of mutations and genetic aberrations [14]. The BRD4-NUT fusion oncoproteins drive a series of disruptions of gene expression through chromatin remodeling [15], overexpression of MYC [16], and sequestration of the activated form of p53 [17]. Another possibility is the fusion of NUT with BRD3 or NSD3, which are functionally related to BRD4. Therefore, recruitment of NUT to the chromatin through the BET family proteins is probably necessary for the oncogenesis of NMC [17].\n\nOn histological examination, NMC can have a broad morphologic range, in many cases resembling squamous cell carcinoma, in others showing small undifferentiated cells with or without areas of abrupt keratinization. Therefore, diagnosis should not be assumed just based on histological aspect [18].\n\nThe definitive diagnosis must be by demonstration of the NUTM1 rearrangement. There is no consensus on which pathology material of the patient should be submitted to molecular tests. Some authors suggested performing IHC or molecular tests in all poorly differentiated non-cutaneous carcinomas, with or without squamous differentiation, with a monomorphic appearance. Glandular tumors do not need to be tested. Viral etiology, such as HPV or Epstein–Barr virus (EBV), is not associated with NMC and can be used to rule this diagnosis out. However, NMC can be strongly positive for p16, despite its negativity for HPV; therefore, it should not be used for excluding NMC [14].\n\nIHC staining of greater than 50% of tumor nuclei on FFPE tissue using the monoclonal rabbit antibody to NUT (clone C52B1) has a specificity of 100%, and sensitivity of 87% for the diagnosis of NMC. Some germ cells tumors can also stain, but usually focally (< 10%) [19]. Confirmatory molecular tests are not mandatory. However, they can be used if the C52B1 antibody is not available or to identify the fusion partner to NUT, which may have clinical and prognostic relevance. For example, NSD3 or BRD3-NUT-positive NMC was associated with a better OS than those with BRD4-NUT, especially in non-thoracic NMC [14]. The assays that can be used for this purpose are fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), cytogenetics, and NGS-based approaches. Molecular diagnostic methods have limitations, such as the cost and access to quality services [14].\n\nCurrently, there is no standard of care for treatment of NMC. Incomplete or no surgical resection and no initial radiotherapy have been associated with shorter progression-free survival and OS. However, no chemotherapeutic regimen has been associated with better outcomes [12].\n\nTargeted therapies are in development encompassing different strategies (Table 1). A first-in-class BET inhibitor, birabresib, a selective inhibitor of BRD2, BRD3, and BRD4 was evaluated in a recently published phase Ib trial. In this trial with 43 patients, 10 of them with NMC, partial response was observed in 3 out of these 10 patients with NMC.\nTable 1 NUT midline carcinoma clinical trials available at Clinicaltrials.gov\n\nTrial\tType of study/ population\tRegimen\tMechanism of action\tStatus\t\nNCT01587703\tPhase I/II – Diagnosis of NMC determined by IHC and/or detection of NUT gene translocation by FISH, treatment naïve or with prior therapy\tGSK525762\tBET protein inhibitor\tActive, not recruiting\t\nNCT03702036\tCompassionate use – Diagnosis of NMC determined by IHC and/or detection of NUT gene translocation by FISH, with no other satisfactory alternative treatment\tGSK525762 (molibresib)\tInhibitor of the binding of BET proteins to acetylated histones\tAvailable\t\nNCT02307240\tPhase I – Diagnosis of an advanced solid tumor such as breast cancer or NMC, that has progressed despite standard therapy, or for which no standard therapy exists\tCUDC-907\tHDAC and PI3K Inhibitor\tActive, not recruiting\t\nNCT02698176\tPhase IB – Diagnosis of one of the following advanced solid tumors for which standard therapy either does not exist or has proven ineffective, intolerable, or inacceptable for the participant: NMC;TNBC; NSCLC; or CRPC\tMK-8628\tBET protein inhibitor\tTerminated due to limited efficacy\t\nNCT02516553\tPhase I – Diagnosis of advanced unresectable and/or metastatic solid tumor, refractory to conventional treatment or for whom no therapy of proven efficacy exists, or who are not amenable to standard therapies.\n\nPart Ib includes patients with SCLC, CRPC, CRC or NMC\n\n\tBI 894999\tBET protein inhibitor\tRecruiting\t\nNCT02259114\tPhase I – Advanced or metastatic: TNBC, NSCLC, CRPC, pancreatic ductal adenocarcinoma, NMC, for which standard therapy either does not exist or has proven ineffective, intolerable or inacceptable for the patient\tOTX015/MK-8628 (birabresib)\tBET protein inhibitor\t3/10 patients with NMC with PR with duration of 1.4 to 8.4 months\t\nNCT02711137\tPhase 1/2 – Histologically or cytologically confirmed diagnosis of relapsed or refractory advanced or metastatic malignancies (solid or hematologic)\tINCB057643\tBET protein inhibitor\tTerminated due to safety issues\t\nNCT02431260\tPhase 1/2 – Any advanced solid tumor or lymphoma; acute leukemia, myelodysplastic syndrome, myelodysplastic /myeloproliferative neoplasms, myelofibrosis, and multiple myeloma\tINCB054329\tBET protein inhibitor\tTerminated by the sponsor due to pharmacokinetics variability [20]\t\nNCT02369029\tPhase 1 – Patients with advanced tumors refractory to any standard treatment, with no standard therapy available or in whom standard therapy is not a therapeutic option\tBAY1238097\tBET protein inhibitor\tTerminated because of dose-limiting toxicities at a dose below targeted drug exposure [21]\t\nBET bromodomain and extraterminal, CRPC castration-resistant prostate cancer, CRC colorectal cancer, FISH fluorescence in situ hybridization, HDAC histone deacetylase, IHC immunohistochemistry, NMC NUT midline carcinoma, NSCLC non-small cell lung cancer, PI3K phosphoinositide 3-kinase, PR partial response, SCLC small cell lung cancer, TNBC triple negative breast cancer\n\n\n\nIn addition, other targets have been studied. A dual histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K) inhibitor, CUDC-907, was tested in a preclinical trial and showed some positive results. The rational was that inhibition of HDAC and PI3K, upstream regulators of MYC, could reduce MYC protein levels, a key oncogenic target in NMC, and ultimately lead to growth suppression and cell death [22]. Activity of these drugs in NMC was shown in vivo and in vitro, associated with decreased MYC protein levels. This activity should be further studied in clinical studies.\n\nThis is the first Brazilian case of NMC with BRD4-NUT fusion. Because of this diagnosis, the routine in our Pathology department has changed and the IHC for NUT protein is now validated and performed in all cases of poorly differentiated carcinomas, with or without keratinization, especially those occurring in young patients, never smokers, with unusual IHC patterns, atypical morphology and/or occurring in midline sites.\n\nConclusion\nOur case is the first Brazilian case of NMC with BRD4-NUT fusion detected in a NGS panel. The diagnosis of NMC holds importance for prognostic value as well as for clinical trials with targeted therapy. This report reinforces the need for definitive diagnosis of this subtype of low differentiated carcinoma, and highlights the IHC evaluation, the most available and accessible method, as an important diagnostic tool.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNo funding received.\n\nAuthors’ contributions\nLJCO, ABLG, MTL, MTA, and LAT described the case and wrote the initial article. OF was the patient’s personal doctor and was a reviewer of the article, together with JVAMG. FGB analyzed, selected, and wrote the subtitles for the images. All authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. French C NUT midline carcinoma Nat Rev Cancer 2014 14 3 149 150 10.1038/nrc3659 25688404 \n2. French CA NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism Cancer Discov 2014 4 8 928 941 10.1158/2159-8290.CD-14-0014 24875858 \n3. Suzuki S NSD3-NUT-expressing midline carcinoma of the lung: first characterization of primary cancer tissue Pathol Res Pract 2015 211 5 404 408 10.1016/j.prp.2014.10.013 25466466 \n4. French CA Pathogenesis of NUT midline carcinoma Annu Rev Pathol 2012 7 247 265 10.1146/annurev-pathol-011811-132438 22017582 \n5. Stelow EB A review of NUT midline carcinoma Head Neck Pathol 2011 5 1 31 35 10.1007/s12105-010-0235-x 21221870 \n6. Chau NG Intensive treatment and survival outcomes in NUT midline carcinoma of the head and neck Cancer 2016 122 23 3632 3640 10.1002/cncr.30242 27509377 \n7. French CA The importance of diagnosing NUT midline carcinoma Head Neck Pathol 2013 7 1 11 16 10.1007/s12105-013-0428-1 23463074 \n8. Salles PG Expression of P16 in NUT carcinomas with no association with human papillomavirus (HPV) Appl Immunohistochem Mol Morphol 2014 22 4 262 265 10.1097/PAI.0b013e3182a4ef2e 24185123 \n9. French CA Kutok JL Faquin WC Midline carcinoma of children and young adults with NUT rearrangement J Clin Oncol 2004 22 4135 4139 10.1200/JCO.2004.02.107 15483023 \n10. Chau NG Ma C Danga K A novel prognostic risk classification model for NUT midline carcinoma: A largest cohort analysis from the NMC registry J Clin Oncol 2018 36 suppl 6085 10.1200/JCO.2018.36.15_suppl.6085 \n11. Ministério da Saude, Instituto Nacional de Câncer José Alencar Gomes da Silva Estimate/2018 – Cancer Incidence in Brazil (Rio de Janeiro) 2017 \n12. Bauer DE Clinicopathologic features and long-term outcomes of NUT midline carcinoma Clin Cancer Res 2012 18 20 5773 5779 10.1158/1078-0432.CCR-12-1153 22896655 \n13. Giridhar Prashanth Mallick Supriya Kashyap Lakhan Rath Goura Kishor Patterns of care and impact of prognostic factors in the outcome of NUT midline carcinoma: a systematic review and individual patient data analysis of 119 cases European Archives of Oto-Rhino-Laryngology 2018 275 3 815 821 10.1007/s00405-018-4882-y 29356890 \n14. French CA NUT Carcinoma: Clinicopathologic features, pathogenesis, and treatment Pathol Int 2018 68 11 583 595 10.1111/pin.12727 30362654 \n15. Alekseyenko AA Walsh EM Wang X The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains Genes Dev 2015 29 1507 1523 10.1101/gad.267583.115 26220994 \n16. Grayson AR Walsh EM Cameron MJ MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma Oncogene 2014 33 1736 1742 10.1038/onc.2013.126 23604113 \n17. Reynoird N Schwartz BE Delvecchio M Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains EMBOJ 2010 29 2943 2952 10.1038/emboj.2010.176 \n18. Evans AG French CA Cameron MJ Pathologic characteristics of NUT midline carcinoma arising in the mediastinum Am J Surg Pathol 2012 36 1222 1227 10.1097/PAS.0b013e318258f03b 22790861 \n19. Haack H Johnson LA Fry CJ Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody Am J Surg Pathol 2009 33 984 991 10.1097/PAS.0b013e318198d666 19363441 \n20. Lewin J Soria JC Stathis A Phase Ib trial with birabresib, a small molecule inhibitor of bromodomain and extraterminal proteins, in patients with selected advanced solid tumors J Clin Oncol 2018 36 30 3007 3014 10.1200/JCO.2018.78.2292 29733771 \n21. Postel-Vinay S Herbschleb K Massard C First-in-human phase I dose escalation study of the Bromodomain and Extra-Terminal motif (BET) inhibitor BAY 1238097 in subjects with advanced malignancies Eur J Cancer 2016 69 S7 S8 10.1016/S0959-8049(16)32620-X \n22. Sun K Atoyan R Borek MA Dual HDAC and PI3K inhibitor CUDC-907 downregulates MYC and suppresses growth of MYC-dependent cancers Mol Cancer Ther 2017 16 2 285 299 10.1158/1535-7163.MCT-16-0390 27980108\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Molecular pathology; NUT midline carcinoma; Poorly differentiated squamous cell carcinoma; Targeted therapy",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D001859:Bone Neoplasms; D001938:Brazil; D002294:Carcinoma, Squamous Cell; D017809:Fatal Outcome; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008444:Maxillary Sinus Neoplasms; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000072078:Positron Emission Tomography Computed Tomography",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "279",
"pmc": null,
"pmid": "31492174",
"pubdate": "2019-09-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15483023;19363441;20676058;21221870;22017582;22790861;22896655;23463074;23604113;24185123;24875858;25466466;25688404;26220994;27509377;27980108;29356890;29733771;30362654",
"title": "The first report of molecular characterized BRD4-NUT carcinoma in Brazil: a case report.",
"title_normalized": "the first report of molecular characterized brd4 nut carcinoma in brazil a case report"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-224973",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drug... |
{
"abstract": "Intramural hematoma of the esophagus (IHE) represents a rare condition on the spectrum of esophageal injuries. The most common symptoms are hematemesis, epigastric pain or retrosternal chest pains, odynophagia, and dysphagia. Early recognition of IHE is important as it may mimic other diseases such as myocardial infarction, pulmonary embolism, Mallory-Weiss tears, Boerhaave's syndrome, ruptured aortic aneurysms, and aortic dissection. Computed tomography is the preferred investigation method, and treatment is usually conservative. We herein present 2 cases of IHE associated with catheter-directed thrombolysis in the setting of pulmonary embolism.",
"affiliations": "Cardiovascular Intervention Research Center, 158776Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.;158776Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.;158776Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.;Cardiovascular Intervention Research Center, 158776Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.;Cardiovascular Intervention Research Center, 158776Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.;Cardiovascular Intervention Research Center, 158776Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.;Cardiovascular Intervention Research Center, 158776Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.",
"authors": "Taghavyan|Nina Jalily|NJ|;Mashayekh|Arshide|A|;Pouraliakbar|Hamid Reza|HR|;Moosavi|Jamal|J|;Shafe|Omid|O|;Mohebbi|Bahram|B|;Sadeghipour|Parham|P|https://orcid.org/0000-0001-9602-0513",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1538574421989863",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-5744",
"issue": "55(5)",
"journal": "Vascular and endovascular surgery",
"keywords": "catheter directed thrombolysis; intramural esophageal hematoma; pulmonary embolism",
"medline_ta": "Vasc Endovascular Surg",
"mesh_terms": "D000368:Aged; D002404:Catheterization; D006471:Gastrointestinal Hemorrhage; D006396:Hematemesis; D006406:Hematoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D015912:Thrombolytic Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101136421",
"other_id": null,
"pages": "510-514",
"pmc": null,
"pmid": "33550927",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Spontaneous Intramural Esophageal Hematoma Secondary to Thrombolysis in the Setting of Pulmonary Embolism.",
"title_normalized": "spontaneous intramural esophageal hematoma secondary to thrombolysis in the setting of pulmonary embolism"
} | [
{
"companynumb": "IR-ROCHE-2901846",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Here we report first 2 cases of patients with nonvalvular atrial fibrillation with acute cardioembolic stroke in whom thrombi in the left atrial appendage (LAA) were resolved by edoxaban administration. Case 1 reports an 86-year-old woman who suddenly showed right hemiparesis and aphasia due to occlusion of the left middle cerebral artery. She received mechanical thrombectomy and recovered neurologically. Transesophageal echocardiography (TEE) performed on day 1 demonstrated thrombus in the LAA. The thrombus was resolved on day 13 after initiation of edoxaban (30 mg once daily) instead of warfarin, which was administered before stroke onset. Case 2 reports a 49-year-old man who was admitted because of the sudden onset of left hemiparesis and aphasia. TEE demonstrated thrombus in the LAA on day 4, and edoxaban therapy (60 mg once daily) was initiated. The thrombus resolution was observed on day 16, and no embolic stroke occurred.",
"affiliations": "Neurosurgery, Hyogo Collage of Medicine, Nishinomiya, Japan.;Neurosurgery, Hyogo Collage of Medicine, Nishinomiya, Japan.;Neurosurgery, Hyogo Collage of Medicine, Nishinomiya, Japan.;Neurosurgery, Hyogo Collage of Medicine, Nishinomiya, Japan.;Neurosurgery, Hyogo Collage of Medicine, Nishinomiya, Japan.;Neurosurgery, Hyogo Collage of Medicine, Nishinomiya, Japan. Electronic address: s-yoshi@hyo-med.ac.jp.",
"authors": "Saito|Shin|S|;Shindo|Seigo|S|;Tsudaka|Shun|S|;Uchida|Kazutaka|K|;Shirakawa|Manabu|M|;Yoshimura|Shinichi|S|",
"chemical_list": "D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C552171:edoxaban",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "25(10)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Edoxaban; atrial fibrillation; left atrial appendage thrombus; resolution",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000369:Aged, 80 and over; D015901:Angiography, Digital Subtraction; D020517:Atrial Appendage; D001281:Atrial Fibrillation; D002545:Brain Ischemia; D002533:Cerebral Angiography; D017548:Echocardiography, Transesophageal; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D011725:Pyridines; D020521:Stroke; D013844:Thiazoles; D017131:Thrombectomy; D013927:Thrombosis; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "e188-91",
"pmc": null,
"pmid": "27562709",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Resolving Thrombus in the Left Atrial Appendage by Edoxaban Treatment after Acute Ischemic Stroke: Report of 2 Cases.",
"title_normalized": "resolving thrombus in the left atrial appendage by edoxaban treatment after acute ischemic stroke report of 2 cases"
} | [
{
"companynumb": "US-DSJP-DSU-2016-133154",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
"drugadditional": null,
... |
{
"abstract": "Isavuconazole is a new azole approved for adults with invasive aspergillosis and mucormycosis, with a favorable hepatic tolerability reported in Phase III trials. Here, we report on a case of drug-induced liver failure related to isavuconazole in a pediatric patient treated for invasive aspergillosis after bone marrow transplant.",
"affiliations": "From the Pediatric Department, Ospedale San Gerardo, Fondazione MBBM, Monza, Italy.;From the Pediatric Department, Ospedale San Gerardo, Fondazione MBBM, Monza, Italy.;Infectious Disease Department.;Infectious Disease Department.;Pathology department, Ospedale S. Gerardo, Monza, Italy.;From the Pediatric Department, Ospedale San Gerardo, Fondazione MBBM, Monza, Italy.",
"authors": "Brivio|Erica|E|;Verna|Marta|M|;Migliorino|Guglielmo Marco|GM|;Foresti|Sergio|S|;Zucchini|Nicola|N|;Rovelli|Attilio|A|",
"chemical_list": "D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000002418",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "38(10)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D016026:Bone Marrow Transplantation; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D017114:Liver Failure, Acute; D008297:Male; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "1035-1037",
"pmc": null,
"pmid": "31568141",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Isavuconazole-induced Acute Liver Failure in a Pediatric Patient With Invasive Aspergillosis.",
"title_normalized": "isavuconazole induced acute liver failure in a pediatric patient with invasive aspergillosis"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1032532",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISAVUCONAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "Presented are the case history and toxicological findings of an infant fatality involving methadone. A mother found her 10-month-old infant unresponsive in a crib. The infant was taken to a hospital; however, she was cold and stiff on arrival and was pronounced dead. Few details regarding the case history were known at the time, and the autopsy findings were unremarkable. Specimens were submitted for a full toxicological analysis, including an alcohol analysis by headspace gas chromatography with flame ionization detection; a screen for drugs of abuse and several prescription drug classes using an enzyme-linked immunosorbent assay technique (ELISA); and a screen for basic compounds using gas chromatography-mass spectrometry (GC-MS). Positive findings were confirmed and quantitated using GC-MS. Methadone was detected in subclavian blood at a concentration of 0.67 mg/L. The cause of death was determined to be \"methadone intoxication\", and the manner of death was \"homicide\". A discussion of the case circumstances, the toxicology findings and methadone pharmacokinetics are presented.",
"affiliations": "Office of the Chief Medical Examiner, 1910 Massachusetts Avenue SE, Building 27, Washington, DC 20003, USA. fiona.couper@dc.gov",
"authors": "Couper|Fiona J|FJ|;Chopra|Kiran|K|;Pierre-Louis|Marie Lydie Y|ML|",
"chemical_list": "D009294:Narcotics; D008691:Methadone",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2005.04.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "153(1)",
"journal": "Forensic science international",
"keywords": null,
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D001923:Brain Chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005410:Flame Ionization; D005554:Forensic Medicine; D008401:Gas Chromatography-Mass Spectrometry; D006556:Heroin Dependence; D006708:Homicide; D006801:Humans; D007223:Infant; D008099:Liver; D008691:Methadone; D009294:Narcotics; D014822:Vitreous Body",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "71-3",
"pmc": null,
"pmid": "15941639",
"pubdate": "2005-10-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal methadone intoxication in an infant.",
"title_normalized": "fatal methadone intoxication in an infant"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-06398",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "Essentials Patients with cancer-associated VTE frequently undergo invasive procedures. Data on the perioperative interruption of anticoagulation for cancer-associated VTE are lacking. Patients with cancer-associated VTE experience high post-operative VTE and major bleeding rates. This patient population may warrant close follow-up after invasive procedures.\n\n\n\nPatients with cancer are at high risk for venous thromboembolic events. Venous thromboembolism (VTE) can lead to significant morbidity among patients with cancer, and is estimated to be one of the leading causes of death among cancer patients. Patients with cancer often require invasive procedures for biopsy or therapeutic purposes. There is a lack of data on postoperative outcomes following interruption of anticoagulation in this population.\n\n\n\nTo assess 30-day postoperative thromboembolic and major bleeding complication rates following the perioperative interruption of anticoagulation in patients with cancer-associated VTE.\n\n\n\nWe conducted a retrospective self-controlled case series study with patients with cancer-associated VTE undergoing perioperative interruption of anticoagulation at a dedicated tertiary-care anticoagulation clinic for invasive procedures between January 2013 and March 2018. The primary efficacy and safety outcomes were the 30-day postoperative rates of VTE and major bleeding, respectively. The secondary outcomes included the 30-day rates of clinically relevant non-major bleeding (CRNMB) and overall mortality. Patients undergoing multiple perioperative anticoagulation interruptions were included.\n\n\n\nOne hundred and forty-six patients undergoing 171 periprocedural interruptions were included in our cohort. The 30-day rates of VTE and major bleeding were both 4.1% (95% confidence interval [CI] 2.0-8.2). The 30-day rate of CRNMB was 2.9% (95% CI 1.3-6.7) and the 30-day overall mortality rate was 0.6% (95% CI 0.1-3.4). There were no fatal postoperative VTE or major bleeding events.\n\n\n\nThe periprocedural interruption of anticoagulation in patients with cancer-associated VTE is associated with high postoperative rates of VTE and major bleeding. Patients with cancer-associated VTE may require closer follow-up for VTE and bleeding complications after invasive procedures.",
"affiliations": "Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Canada.;Department of Medicine, Division of Hematology and Thromboembolism, McMaster University, Hamilton, Canada.;Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Canada.;Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Canada.",
"authors": "Shaw|Joseph R|JR|;Douketis|James|J|;Le Gal|Gregoire|G|;Carrier|Marc|M|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1111/jth.14468",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-7836",
"issue": "17(7)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "anticoagulants; hemorrhage; neoplasms; perioperative period; venous thromboembolism",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D001777:Blood Coagulation; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D019990:Perioperative Care; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D054556:Venous Thromboembolism",
"nlm_unique_id": "101170508",
"other_id": null,
"pages": "1171-1178",
"pmc": null,
"pmid": "31038838",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Periprocedural interruption of anticoagulation in patients with cancer-associated venous thromboembolism: An analysis of thrombotic and bleeding outcomes.",
"title_normalized": "periprocedural interruption of anticoagulation in patients with cancer associated venous thromboembolism an analysis of thrombotic and bleeding outcomes"
} | [
{
"companynumb": "CA-TEVA-2019-CA-1087254",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": null,
... |
{
"abstract": "Epilepsy, commonly encountered by patients with brain tumors, is often refractory to standard therapies. Our aim was to examine the safety and efficacy of pharmaceutical grade cannabidiol (CBD; Epidiolex; Greenwich Biosciences) in those patients with epilepsy with concomitant tumors enrolled in The University of Alabama at Birmingham CBD Program (NCT02700412 and NCT02695537). Of the three patients with refractory seizures and a history of a primary brain tumor, two had improvement in seizure frequency and all three had improvement in seizure severity. These pilot results suggest that CBD should be further studied for the treatment of brain tumor-related epilepsy.",
"affiliations": "a Department of Neurology , University of Alabama at Birmingham , Birmingham , AL , USA.;a Department of Neurology , University of Alabama at Birmingham , Birmingham , AL , USA.;a Department of Neurology , University of Alabama at Birmingham , Birmingham , AL , USA.;a Department of Neurology , University of Alabama at Birmingham , Birmingham , AL , USA.",
"authors": "Warren|Paula Province|PP|;Bebin|E Martina|EM|;Nabors|L Burt|LB|;Szaflarski|Jerzy P|JP|",
"chemical_list": "D063386:Cannabinoid Receptor Agonists; D002185:Cannabidiol",
"country": "England",
"delete": false,
"doi": "10.1080/13554794.2017.1391294",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-4794",
"issue": "23(5-6)",
"journal": "Neurocase",
"keywords": "Brain tumor; CBD; cannabidiol; epilepsy; tumoral epilepsy",
"medline_ta": "Neurocase",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms; D002185:Cannabidiol; D063386:Cannabinoid Receptor Agonists; D002986:Clinical Trials as Topic; D000069279:Drug Resistant Epilepsy; D006801:Humans; D008297:Male; D010865:Pilot Projects; D016896:Treatment Outcome",
"nlm_unique_id": "9511374",
"other_id": null,
"pages": "287-291",
"pmc": null,
"pmid": "29063814",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy.",
"title_normalized": "the use of cannabidiol for seizure management in patients with brain tumor related epilepsy"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US17383",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
"drugadditional": null,
... |
{
"abstract": "A patient with a history of Prinzmetal angina, refractory ventricular fibrillation, cardiac arrest with an implantable cardioverter-defibrillator, and obesity presented to the emergency department at 17 weeks gestational age with a chief complaint of angina and multiple episodes of defibrillation. A T3/4 thoracic epidural was placed to assess the effectiveness of a partial chemical sympathectomy in alleviating symptoms of angina as well as decreasing the amount of defibrillation episodes. Once this proved to be beneficial in accomplishing both of these goals, a more specific approach was designed. A continuous stellate ganglion block was then placed controlling both her angina and preventing further episodes of defibrillation long enough for her pregnancy to progress beyond 24 weeks gestational age.",
"affiliations": "From the Department of Regional Anesthesiology, Ochsner Clinic Foundation, New Orleans, Louisiana.",
"authors": "Scalercio|Lauren|L|;Vitter|Jillian|J|;Elliott|Clint E|CE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000858",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "12(4)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000328:Adult; D000788:Angina Pectoris, Variant; D001340:Autonomic Nerve Block; D005260:Female; D006801:Humans; D011247:Pregnancy; D013233:Stellate Ganglion; D014693:Ventricular Fibrillation; D055815:Young Adult",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "106-108",
"pmc": null,
"pmid": "30102609",
"pubdate": "2019-02-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Placement of a Continuous Stellate Ganglion Block for Treatment of Refractory Ventricular Fibrillation in the Setting of Known Prinzmetal Angina During Pregnancy: A Case Report.",
"title_normalized": "placement of a continuous stellate ganglion block for treatment of refractory ventricular fibrillation in the setting of known prinzmetal angina during pregnancy a case report"
} | [
{
"companynumb": "US-BAYER-2020-047504",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Werner syndrome (WS) confers a high risk of the development of neoplasias, including hematological malignancies, and curative treatment for these malignancies is difficult to achieve. A 44-year-old man with myelodysplastic syndrome was admitted to our hospital. He was diagnosed with mutation-proven WS. He underwent cord blood transplantation (CBT) following fludarabine, busulfan, and melphalan administration. A chimerism analysis of his marrow blood on day 62 showed a donor pattern >95%, which confirmed engraftment. The patient lived for 15 months while maintaining remission of MDS without treatment-related toxicity. Our case shows that CBT can be a treatment modality for WS patients with hematological malignancies.",
"affiliations": "Department of Hematology, Kawasaki Medical School, Japan.;Department of Hematology, Kawasaki Medical School, Japan.;Department of Hematology, Kawasaki Medical School, Japan.;Department of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Japan.;Department of Rheumatology/Orthopedic Surgery, East Medical Center, Tokyo Women's Medical University, Japan.;Department of Hematology, Kawasaki Medical School, Japan.;Department of Pathology, Kawasaki Medical School, Japan.;Department of Hematology, Kawasaki Medical School, Japan.;Department of Hematology, Kawasaki Medical School, Japan.",
"authors": "Hayashi|Kiyohito|K|;Tasaka|Taizo|T|;Kondo|Toshinori|T|;Ishikawa|Yuichi|Y|;Goto|Makoto|M|;Matsuhashi|Yoshiko|Y|;Sadahira|Yoshito|Y|;Sugihara|Takashi|T|;Wada|Hideho|H|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.0317-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3014655810.2169/internalmedicine.0317-17Case ReportSuccessful Cord Blood Transplantation in a Werner Syndrome Patient with High-risk Myelodysplastic Syndrome Hayashi Kiyohito 1Tasaka Taizo 12Kondo Toshinori 1Ishikawa Yuichi 3Goto Makoto 4Matsuhashi Yoshiko 1Sadahira Yoshito 5Sugihara Takashi 1Wada Hideho 1\n1 Department of Hematology, Kawasaki Medical School, Japan\n2 Department of Transfusion Medicine, Saitama Medical Center, Saitama Medical University, Japan\n3 Department of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Japan\n4 Department of Rheumatology/Orthopedic Surgery, East Medical Center, Tokyo Women's Medical University, Japan\n5 Department of Pathology, Kawasaki Medical School, JapanCorrespondence to Dr. Toshinori Kondo, kondot@med.kawasaki-m.ac.jp\n\n24 8 2018 1 1 2019 58 1 109 113 5 10 2017 26 4 2018 Copyright © 2019 by The Japanese Society of Internal Medicine2019The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Werner syndrome (WS) confers a high risk of the development of neoplasias, including hematological malignancies, and curative treatment for these malignancies is difficult to achieve. A 44-year-old man with myelodysplastic syndrome was admitted to our hospital. He was diagnosed with mutation-proven WS. He underwent cord blood transplantation (CBT) following fludarabine, busulfan, and melphalan administration. A chimerism analysis of his marrow blood on day 62 showed a donor pattern ＞95%, which confirmed engraftment. The patient lived for 15 months while maintaining remission of MDS without treatment-related toxicity. Our case shows that CBT can be a treatment modality for WS patients with hematological malignancies. \n\nWerner syndromemyelodysplastic syndromecord blood transplantation\n==== Body\nIntroduction\nWerner syndrome (WS) is a rare progressive disorder characterized by accelerated aging (adult form of progeria). WS is caused by a mutation of the WRN gene, which is located on chromosome 8p (8p12-11.2), and is transmitted as an autosomal-recessive trait. Patients with WS suffer from a high risk of neoplasia, including hematological malignancies (1-3). The hematological malignancies reported in patients with WS include acute leukemia, myelodysplastic syndrome (MDS) (Table), and myelofibrosis (4,5). Patients with WS are sensitive to radiation and DNA-alkylating agents, which may account for the severe adverse effects they experience after chemo-radiotherapy (6). However, at present, knowledge regarding cancer treatment in WS patients remains insufficient. Based on a few case reports that did not support this hypothesis, the practice guideline for WS in Japan recommends that no alteration to cancer treatment be made because of WS, although special caution is required (7). To our knowledge, there has been no study of HSCT in patients with WS with reported complications of hematological malignancies, including MDS.\n\nTable. Myelodysplastic Syndrome Reported in Patients with Werner Syndrome.\n\nCase\tSex\tWS diagnostic confidence\tAge at neoplasm diagnosis\tHistopathologic diagnosis\tTreatment\tClinical result\tReference\t\n1\tM\tPossible\t44\tMyelodysplasia/\nmyelofibrosis\tEtoposide\tDied, sepsis\t[16]\t\n2\tM\tPossible\t62\tMyelodysplasia\tTransfusion\tDied, interstitial pneumonitis\t[20]\t\n3\tM\tPossible\t61\tRAEB/\nmyelofibrosis\tTransfusion\tDied, pneumonia\t[21]\t\n4\tM\tProbable\t63\tRAEB\tTransfusion\tDied, pneumonia\t[22]\t\n5\tM\tPossible\t52\tMyelodysplasia\tUnknown\tUnknown\t[23]\t\n6\tM\tDefinite\t29\tRAEB-t\tUnknown\tUnknown\t[24]\t\n7\tF\tProbable\t52\tMyelodysplasia\tWatch & wait\tUnknown\t[25]\t\n8\tM\tDefinite\t43\tRAEB-1\tAzacitidine\tDied, pneumonia\t[26]\t\n9\tM\tDefinite\t44\tRAEB-2\tAllo-HSCT\tComplete remission\tPresent case\t\nWS: Werner syndrome, M: male, F: female, RAEB: refractory anemia with excess of blast, RAEB-t: refractory anemia with excess of blast in transformation, HSCT: hematopoietic stem cell transplantation\n\nWe herein report the case of a patient with WS and MDS who was successfully treated with cord blood transplantation (CBT).\n\nCase Report\nA 44-year-old man with MDS [refractory anemia with excess blasts-2 (RAEB-2)] was referred to our hospital. The patient had atrophic skin with premature wrinkling and a beaked nose that gave his face a bird-like appearance. His medical history indicated that his parents were not consanguineous, and there were no abnormalities noted in his family. He had a history of bilateral cataract surgery. A physical examination revealed that he was 155.0 cm in height (deviation value by age-rank: 22) and 28.7 kg in weight (deviation value by age-rank: 5.5) with a body mass index of 11.9. He had scarce, gray hair, a high-pitched hoarse voice, and calcification of the Achilles' tendons; thus, he had all six of the major signs or symptoms of the WS diagnostic criteria and met four out of the seven minor criteria (8). Laboratory data showed bicytopenia with a platelet count 35×109/L, hemoglobin 5.7 g/dL, and white blood cell count 4.66×109/L.\n\nA bone marrow examination on admission revealed markedly hypercellular marrow with 15.2% myeloblasts. Morphologic dysplasia, such as degranulated neutrophils and separated nuclear megakaryocytes, were observed. Flow cytometry revealed that the blasts were positive for CD13, CD33, CD34, CD56, and HLA-DR and negative for B and T lymphoid lineage markers. A cytogenetic analysis revealed a complex karyotype: 43, XY, add(2)(p11.2), -4, del(5)(q?), add(6)(p21), -7, del(11)(q?), -14, -17, +mar [5/20], 46, XY [15/20]. An immunohistochemical analysis of bone marrow clot sections using a polyclonal antibody against the C-terminus of WRN (Novus Biologicals, Littleton, USA) revealed that all bone marrow cells were negative for WRN; the loss of WRN expression in bone marrow sections has been demonstrated in WS patients only (9). Furthermore, a mutational analysis revealed a WRN gene mutation (data not shown). WRN gene mutation analysis was approved by the ethics committee of Kawasaki Medical School (IRB No. 2004), and the patient provided his written informed consent.\n\nThe patient achieved complete remission with hematologic improvement after his first course of induction chemotherapy, which consisted of idarubicin and cytosine arabinoside. The findings of a karyotype analysis were improved to normal; however, morphological dysplasia remained. The patient was diagnosed with high-risk MDS using the international prognostic scoring system (IPSS, score 3.0, 15.2% myeloblasts, complex karyotype, and cytopenia of 3 lineages), after which he was judged eligible for HSCT.\n\nThe patient had no intellectual disabilities. We obtained informed consent for HSCT from him and his family. Since he did not have a suitable donor with identical human leukocyte antigen (HLA), allogeneic cord blood was selected as the stem cell source for transplantation. Although the patient had WS and a high hematopoietic cell transplantation-comorbidity index (HCT-CI) score of 3 [% of diffusing capacity of the lung Carbon monoxide (DLCO) ＜66%], we selected a myeloablative conditioning regimen for the CBT. After a single course of consolidation therapy, allo-HSCT was performed from 3 of eight HLA-mismatched female cord blood donors (recipient HLA: A1101/2602, B1501, Cw0303/0401, DR0405/1406; donor HLA: A1101/2402, B1501, Cw0303/0401, DR0406/0901). The conditioning regimen consisted of 180 mg/m2 fludarabine (Flu) and 12.8 mg/kg intravenous injection (i.v.) busulfan (Bu) (FluBu4) plus 80 mg/m2 melphalan (Mel). Anti-thymocyte globulin (1.25 mg/kg) was administered on day -2, and only tacrolimus was administered at 0.03 mg/kg/day starting on day -1 for the prophylaxis of graft-versus-host disease (GVHD). After transplantation, he developed pneumonia with alveolar hemorrhage on day 2. He was diagnosed with bacteriemia on day 15. Those treatment-related toxicities were ameliorated by usual treatment and supportive care until day 39. Engraftment of neutrophils (greater than 0.5×109/L), red blood cells (reticulocytes greater than 1%), and platelets (greater than 20×109/L) was observed at day 17, day 30, and day 61, respectively. The immunostaining of bone marrow clot sections on day 30 showed that erythroblasts were positive for WRN, and TP53-positive cells were within 1% of the nucleated cell count (Figure) (9). The onset of acute GVHD was evident in the liver (stage 2) at day 18. Thereafter, the acute GVHD reached grade III with skin stage 3 and gut stage 0 at day 21. We immediately started systemic administration of 2 mg/kg methylprednisolone to gradually decrease the symptoms. A bone marrow examination on day 62 revealed normo-cellular marrow without dysplasia, and a karyotype analysis of the marrow showed a normal female karyotype. A chimerism analysis showed complete chimerism of the donor type above 95%. The patient was discharged from our hospital on day 76 after CBT and maintained complete remission. After that, he lived for 15 months while maintaining remission of MDS, but unfortunately he ultimately died of pneumonia. No post-transplant complications like endocrine dysfunction or second malignancy were observed.\n\nFigure. The immunohistochemical expression of p53 and WRN in a formalin-fixed, paraffin-embedded patient bone marrow clot section is shown. The antibody used for the immunostaining reacted with wild-type WRN but not with the mutated WRN of bone marrow erythroblasts. More than 30% of cells were TP53-positive (black arrows) before CBT, but TP53-positive cells were undetectable after CBT. WRN-positive cells (blue arrows) were completely absent before CBT but present after CBT. CBT: cord blood transplantation\n\nDiscussion\nThe WRN gene encodes a RecQ3-DNA helicase that is necessary for DNA replication and repair. Patients with WS have elevated risks for common, clinically important, age-dependent diseases such as neoplasia and atherosclerotic cardiovascular disease, which are the most common causes of death in patients with WS, at a median of 54 years of age (10,11). At the time of the WS diagnosis, patients have a high prevalence of cataracts (100%), osteoporosis (91%), hypogonadism (80%), diabetes mellitus (71%), neoplasia (43%), and atherosclerosis (40%) (11). Likely causes of the elevated risk of neoplasia in WS are the persistent constitutional genetic instability and DNA-damage sensitivity that are key cellular hallmarks of WS (12).\n\nWS is diagnosed based on distinct clinical signs, but a mutational analysis of the WRN gene can render a definitive diagnosis. This gene analysis is laborious and expensive in a clinical setting. We recently reported the results of an immunohistochemical analysis for the WRN protein using polyclonal serum against its C-terminus (9). The present patient satisfied all six major WS diagnostic criteria and four out of the seven minor criteria. An immunohistochemical analysis revealed that the WRN protein was completely absent in the patient’s bone marrow sections, which confirmed the diagnosis of WS, and the presence of a WRN gene mutation in the patient’s lymphocyte DNA further confirmed the diagnosis. These analyses led to an accurate diagnosis of the patient with WS and RAEB-2.\n\nMDS is a hematologic disorder that typically presents with one or more lineage cytopenias. The therapeutic options for MDS include supportive care, various intensities of chemotherapy, or participation in a clinical trial. The patient’s IPSS risk category is used in planning the therapeutic options. HSCT is a high-intensity therapy and the only method of curing MDS. Due to the fact that allogeneic HSCT was deemed necessary in our patient, we chose standard doses of induction chemotherapy to obtain early remission. The outcome of patients who receive allogeneic HSCT depends upon several factors, including their age, performance status, major comorbid conditions, and the availability of a suitable donor.\n\nAbnormal carbohydrate metabolism, endocrine dysfunction, and arteriosclerosis in patients with WS may correspond to a higher HCT-CI score. Patients with an HCT-CI score higher than 3 have a higher non-relapse mortality (NRM) rate, which exceeds 40% even in a young population with less-advanced disease (13). Therefore, there are more difficulties associated with performing HSCT in patients with WS than in those without WS. Recently, FluBu4 (Flu plus a myeloablative dose of 12.8 mg/m2 intravenous Bu) has become widely accepted as a myeloablative regimen for allogeneic HSCT from related or unrelated donors, with acceptable regimen-related toxicities and NRM compared with other myeloablative regimens. The safety profile of Bu was strengthened by the development of an intravenous form; however, the FluBu4 regimen is associated with a relatively high relapse rate (14). In contrast, according to a recent report, the addition of Mel to the FluBu4 regimen improved the engraftment rate and decreased the relapse rate (15). Furthermore, they demonstrated that an intravenous BU/Flu+Mel or TBI regimen is feasible in CBT, and a myeloablative dose of intravenous BU does not increase NRM, even in patients with high-risk disease with old age and/or comorbidities, and may be associated with a decreased relapse rate (16). As a result, the FluBu4 regimen can accommodate a further cytotoxic agent or total-body irradiation without increasing the likelihood of NRM (17-19).\n\nHigh-intensity chemotherapy is associated with a reduced risk of relapse; however, it is also associated with increased treatment-related toxicity. Therefore, there are few reports of MDS patients with WS who have received chemotherapy (Table, 20-27). In the present case, the FluBu4 plus Mel regimen was suitable as a reduced-toxicity myeloablative regimen for allogeneic HSCT. The addition of Mel might enhance antileukemic activities and improve engraftment. Thus, the FluBu4 regimen plus Mel was safely used for HSCT in a patient with WS with a high-risk HCT-CI score.\n\nA number of cases of WRN patients with hematological malignancy have been reported, but there have been no reports of WRN patients treated with allogeneic HSCT. The findings in the present case highlight a new choice of treatment for hematological malignancies in WRN patients. Future studies should gather and compare data on various treatments according to the state of WRN patients with hematological malignancies.\n\nIn conclusion, CBT conditioned with the FluBu4 plus Mel regimen using intravenous Bu was an effective and safe conditioning regimen for an MDS patient with WS. However, knowledge concerning HSCT for patients with WS is limited, so careful observation will be needed until the long-term safety of allo-HSCT to a WRN patient can be confirmed.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nGoto M , Miller RW , Ishikawa Y , et al \nExess of rare cancers in Werner syndrome (adult progeria) . Cancer Epidemiol Biomarkers Prev \n5 : 239 -246 , 1996 .8722214 \n2. \nIshikawa Y , Sugano H , Matsumoto T , et al \nUnusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race . Cancer \n85 : 1345 -1352 , 1999 .10189141 \n3. \nSugimoto M , Fruichi Y , Ide T , Goto M \nInvolvement of WRN helicase in immortalization and tumorigenesis by the telomeric crisis pathway (review) . Oncol Lett \n2 : 609 -611 , 2011 .22848235 \n4. \nBjörnberg A \nWerner’s syndrome and malignancy . Acta Derm Venereol \n56 : 149 -150 , 1976 .58524 \n5. \nSato K , Goto M , Nishioka K , et al \nWerner’s syndrome associated with malignancies: five case reports with a survey of case histories in Japan . Grontology \n34 : 212 -218 , 1988 .\n6. \nSeiter K , Qureshi A , Liu D , et al \nSevere toxicity following induction chemotherapy for acute myelogenous leukemia in a patient with Werner’s syndrome . Leuk Lymphoma \n46 : 1091 -1095 , 2005 .16019564 \n7. [The practice guideline for Werner syndrome] Yokote K, Ed. [Internet]. [cited 2018 Apr. 10]. Available from: http://www.m.chiba-u.jp/dept/clin-cellbiol/files/5215/0752/8288/guideline.pdf (in Japanese).\n8. \nTakemoto M , Mori S , Kuzuya M , et al \nDiagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey . Geriatr Gerontol Int \n13 : 475 -481 , 2013 .22817610 \n9. \nSadahira Y , Sugihara T , Goto M , et al \nWRN protein as a novel erythroblast immunohistochemical marker with applications for the diagnosis of Werner syndrome . Virchows Arch \n466 : 343 -350 , 2015 .25503078 \n10. \nYokote K , Chanprasert S , Lee L , et al \nWRN mutation update: mutation spectrum, patient registries, and translational prospects . Hum Mutat \n38 : 7 -15 , 2017 .27667302 \n11. \nHuang S , Lee L , Hanson NB , et al \nThe spectrum of WRN mutations in Werner syndrome patients . Hum Mutat \n27 : 558 -567 , 2006 .16673358 \n12. \nMonnat RJ Jr \nHuman RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology . Semin Cancer Biol \n20 : 329 -339 , 2010 .20934517 \n13. \nSorror ML , Maris MB , Storb R , et al \nHematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT . Blood \n106 : 2912 -2919 , 2005 .15994282 \n14. \nShimoni A , Hardan I , Shem-Tov N , et al \nAllogeneic hematopoietic stem cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity . Leukemia \n20 : 322 -328 , 2006 .16307018 \n15. \nYamamoto H , Uchida N , Yuasa M , et al \nA novel reduced-toxicity myeloablative conditioning regimen using full-dose busulfan, fludarabine, and melphalan for single cord blood transplantation provides durable engraftment and remission in nonremission myeloid malignancies . Biol Blood Marrow Transplant \n22 : 1844 -1850 , 2016 .27345142 \n16. \nYamamoto H , Uchida N , Matsuno N , et al \nI.v. BU/fludarabine plus melphalan or TBI in unrelated cord blood transplantation for high risk hematological disease . Bone Marrow Transplant \n50 : 607 -609 , 2015 .25621796 \n17. \nCiurea SO , Andersson BS \nBusulfan in hematopoietic stem cell transplantation . Biol Blood Marrow Transplant \n15 : 523 -536 , 2009 .19361744 \n18. \nAbedin S , Peres E , Levine JE , et al \nDouble umbilical cord blood transplantation after novel myeloablative conditioning using a regimen of fludarabine, busulfan, and total lymphoid irradiation . Biol Blood Marrow Transplant \n20 : 2062 -2066 , 2014 .25046834 \n19. \nSanz J , Boluda JC , Martin C , et al \nSingle-unit umbilical cord blood transplantation from unrelated donors in patients with hematological malignancy using busulfan, thiotepa, fludarabine, and ATG as myeloablative conditioning regimen . Bone Marrow Transplant \n47 : 1287 -1293 , 2012 .22327127 \n20. \nKatayama T , Saito A , Watanabe R , Kobayashi M , et al \nA case of Werner's syndrome associated with myelodysplastic syndrome and myelofibrosis . Rinsho Ketsueki \n33 : 858 , 1992 (in Japanese).\n21. \nTaketomi K , Goto Y , Arai I , Ichinose M , Kinoshita K \nAn autopsy case of Werner's syndrome associated with meningioma and myelodysplastic syndrome . To-Nyo-Byo \n33 : 180 , 1990 (in Japanese).\n22. \nSakagami Y , Kato Y , Hatta K , Kusumi F , et al \nA case of Werner's syndrome associated with RAEB and myelofibrosis . Naika Hokan \n37 : 295 , 1990 (in Japanese).\n23. \nMita M , Ishibashi T , Shichishima T , Maruyama Y \nMyelodysplastic syndrome with multiple chromosome aberrations in a patient with Werner's syndrome . Rinsho Ketsueki \n37 : 725 -730 , 1996 (in Japanese, Abstract in English).8827885 \n24. \nArai H , Saito Y , Uzuka Y , et al \nA case of Werner's syndrome in association with leukemia . Tohoku Igaku Zasshi \n96 : 34 -39 , 1983 (in Japanese, Abstract in English).\n25. \nUndar L , Karadogan I , Artvinli M , Karpuzoglu G \nMyelodysplastic syndrome in a patient with Werner's syndrome . Acta Haematol \n92 : 150 -153 , 1994 .7871956 \n26. \nOchi M , Igase M , Nagai A , et al \nA case of Werner syndrome with chromosomal abnormality . Nihon Ronen Igakkai Zasshi (Jpn J Geriatr) \n43 : 639 -642 , 2006 (in Japanese, Abstract in English).\n27. \nTamura Y , Hasegawa N , Takeda Y , et al \nAzacitidine treatment for myelodysplastic syndrome in a patient with Werner syndrome . Rinsho Ketsueki \n57 : 160 , 2016 (in Japanese).\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(1)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Werner syndrome; cord blood transplantation; myelodysplastic syndrome",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D036101:Cord Blood Stem Cell Transplantation; D006801:Humans; D008297:Male; D009190:Myelodysplastic Syndromes; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014898:Werner Syndrome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "109-113",
"pmc": null,
"pmid": "30146558",
"pubdate": "2019-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10189141;15994282;16019564;16307018;16673358;17073296;19361744;20934517;22327127;22817610;22848235;25046834;25503078;25621796;27345142;27667302;3053337;58524;7871956;8722214;8827885",
"title": "Successful Cord Blood Transplantation in a Werner Syndrome Patient with High-risk Myelodysplastic Syndrome.",
"title_normalized": "successful cord blood transplantation in a werner syndrome patient with high risk myelodysplastic syndrome"
} | [
{
"companynumb": "JP-ACCORD-071475",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nTo report the case of a prolonged intravenous ketorolac continuous infusion given via a central line in a cancer patient with intractable bone pain.\n\n\nMETHODS\nA 56-year-old Hispanic man with stage IV non-small-cell lung cancer and multiple bone metastases was admitted to the hospital for intractable pain inadequately controlled at home by conventional therapy. He was treated with an intravenous continuous infusion of ketorolac 120 mg in 250 mL of NaCl 0.9% infused over 24 hours. The ketorolac was given via a central line for 14 days in addition to fentanyl patient-controlled analgesia. Over this time period the patient reported his pain to be well controlled. His requests for bolus doses of fentanyl decreased dramatically and the dose of the continuous intravenous fentanyl was reduced by 22%. In addition, the total daily dose of ketorolac was reduced following a change from intermittent bolus dosing to a continuous infusion.\n\n\nCONCLUSIONS\nThe management of cancer pain secondary to bone metastasis is a difficult and challenging problem frequently encountered by the healthcare team. The use of nonsteroidal antiinflammatory drugs (NSAIDs) as adjuvant therapy is a common practice. However, many terminally ill patients are unable to take oral medications, thus limiting NSAID treatment options. Ketorolac tromethamine is approved by the Food and Drug Administration (FDA) as a parenteral NSAID. As with other NSAIDs, the risk of adverse drug reactions must be considered when using this class of medication. The FDA has approved ketorolac for the short-term (< or = 5 d) management of moderately severe acute pain that requires analgesia at the opioid level, usually in the postoperative setting. However, certain patients may benefit from long-term use exceeding the FDA-recommended guidelines of 5 days of maximum therapy.\n\n\nCONCLUSIONS\nA prolonged central intravenous ketorolac continuous infusion was successful in treating a cancer patient with intractable bone pain secondary to widely metastatic non-small-cell lung cancer.",
"affiliations": "School of Pharmacy, University of the Pacific, San Diego, CA, USA.",
"authors": "Gordon|R L|RL|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D014325:Tromethamine; D020911:Ketorolac Tromethamine; D014046:Tolmetin; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.17205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "32(2)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D001859:Bone Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D002405:Catheterization, Central Venous; D004359:Drug Therapy, Combination; D005283:Fentanyl; D006801:Humans; D007262:Infusions, Intravenous; D020911:Ketorolac Tromethamine; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010148:Pain, Intractable; D014046:Tolmetin; D014325:Tromethamine",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "193-6",
"pmc": null,
"pmid": "9496404",
"pubdate": "1998-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolonged central intravenous ketorolac continuous infusion in a cancer patient with intractable bone pain.",
"title_normalized": "prolonged central intravenous ketorolac continuous infusion in a cancer patient with intractable bone pain"
} | [
{
"companynumb": "US-PFIZER INC-202101069000",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL CITRATE"
},
"drugadditional": "3",
... |
{
"abstract": "Bleomycin, etoposide, and cisplatin (BEP) is the most common and successful chemotherapy regimen for germ-cell tumor (GCT) patients, accompanied by a bleomycin-induced dose-dependent lung toxicity in certain patients. In an attempt to reduce bleomycin-toxicity, we developed a modified-BEP (mBEP) regimen.\n\n\n\nBetween August 2008 and February 2018, 182 unselected mainly testicular GCT patients (39 with adjuvant purpose and 143 with curative purpose) received a tri-weekly 5-day hospitalization schedule with bleomycin 15 U intravenous (IV) push on day 1 and 10 U IV continuous infusion over 12 hours on days 1 to 3, cisplatin 20 mg/m IV, and etoposide 100 mg/m IV on days 1 to 5. Pulmonary toxicity was assessed through chest computed tomography scan and clinical monitoring.\n\n\n\nMedian number of mBEP cycles was 3 (range: 1 to 4). In the curative setting, according to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic system, 112, 21, and 9 patients had good-risk, intermediate-risk, and poor-risk class, respectively; 66 (46%) patients had complete response (CR), 67 (47%) had partial response (52 of whom became CR afterwards), 6 (4%) had stable disease (that in 3 became CR afterwards), 3 (2%) progressed, and 1 (1%) died of brain stroke. At a median follow-up of 2.67 years (interquartile range: 1.23-5.00 y), 1 and 5-year overall survival and progression-free survival were 99% and 95%, and 90% and 88%, respectively. In the entire patient population, there was grade 3/4 neutropenia in 92 patients (51%), febrile neutropenia in 11 patients (6%), grade 1/2 nausea in 74 patients (41%), and no death due to pulmonary toxicity.\n\n\n\nIn GCT patients, our mBEP-schedule would suggest an effective treatment modality without suffering meaningful pulmonary toxicity.",
"affiliations": "Medical Division of Urogenital and Head and Neck Cancer.;Medical Division of Urogenital and Head and Neck Cancer.;Department of Statistics and Quantitative Methods, University of Milano-Bicocca.;Department of Statistics and Quantitative Methods, University of Milano-Bicocca.;Medical Division of Urogenital and Head and Neck Cancer.;Medical Division of Urogenital and Head and Neck Cancer.;Pharmacy Service.;Medical Division of Urogenital and Head and Neck Cancer.;New Drugs and Early Drug Development for Innovative Therapies Division, Department of Oncology and Haemato-Oncology, IEO European Institute of Oncology, IRCCS, University of Milan.;Interventional Radiology Division.;Department of Oncology and Hemato-Oncology, Division of Radiotherapy, IEO European Institute of Oncology, IRCCS, University of Milan.;Department of Urology, IEO European Institute of Oncology, IRCCS.;Pharmacy Service.;Department of Urology, IEO European Institute of Oncology, IRCCS.;Medical Division of Urogenital and Head and Neck Cancer.",
"authors": "Aurilio|Gaetano|G|;Verri|Elena|E|;Frassoni|Samuele|S|;Bagnardi|Vincenzo|V|;Cossu Rocca|Maria|M|;Cullurà|Daniela|D|;Milani|Martina|M|;Mascia|Roberta|R|;Curigliano|Giuseppe|G|;Orsi|Franco|F|;Jereczek-Fossa|Barbara A|BA|;Musi|Gennaro|G|;Omodeo Salè|Emanuela|E|;De Cobelli|Ottavio|O|;Nolè|Franco|F|",
"chemical_list": "D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0000000000000679",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "43(6)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D002173:Cancer Care Facilities; D002945:Cisplatin; D004334:Drug Administration Schedule; D005047:Etoposide; D006801:Humans; D008171:Lung Diseases; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "381-387",
"pmc": null,
"pmid": "32079853",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Modified-BEP Chemotherapy in Patients With Germ-Cell Tumors Treated at a Comprehensive Cancer Center.",
"title_normalized": "modified bep chemotherapy in patients with germ cell tumors treated at a comprehensive cancer center"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1074129",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "A 68-year-old man was diagnosed with rectal cancer on colonoscopy and liver metastasis of rectal cancer on abdominal computed tomography(CT). He underwent resection of the primary lesion, and the final diagnosis was A, N1, H1, P0, M0, fStage IV. After resection of the primary lesion, he received chemotherapy with mFOLFOX6 plus cetuximab. After 6 courses of the treatment, CT revealed partial response of the liver metastasis. Then, he underwent resection of the liver metastasis. The pathological finding revealed that the resected specimen had no cancer cells. After resection of the liver metastasis, he received 6 courses of chemotherapy with the same regimen, and relapse-free survival continues until the time of this writing.",
"affiliations": "Dept. of Gastroenterological Surgery, Higashiosaka City General Hospital.",
"authors": "Konishi|Ken|K|;Ikenaga|Masakazu|M|;Ohta|Katsuya|K|;Nakashima|Shinsuke|S|;Nakagawa|Tomo|T|;Endo|Syunji|S|;Yamada|Terumasa|T|;Chihara|Takeshi|T|;Nishijima|Junichi|J|",
"chemical_list": "D009944:Organoplatinum Compounds; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(8)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068818:Cetuximab; D003131:Combined Modality Therapy; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D009944:Organoplatinum Compounds; D012004:Rectal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1003-7",
"pmc": null,
"pmid": "27539045",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Liver Metastasis from Colorectal Cancer That Showed a Pathological Complete Response to mFOLFOX6 plus Cetuximab.",
"title_normalized": "a case of liver metastasis from colorectal cancer that showed a pathological complete response to mfolfox6 plus cetuximab"
} | [
{
"companynumb": "JP-ACCORD-049755",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Several cases of psoriasis associated with bullous disorders have been reported, and it is clearly recognized that bullous pemphigoid (BP) is the most common bullous disorder observed in association with psoriasis, especially after ultraviolet (UV)B and psoralen UVA therapy. Moreover, other medications have been repeatedly reported to induce bullous diseases, especially pemphigus vulgaris. We report for the first time a case of BP possibly induced by losartan, an angiotensin II antagonist, in a patient with a severe psoriatic background. Angiotensin II type 1 receptor antagonists belong to a new class of drug for hypertension or congestive heart failure with established efficacy and few side-effects. Coexistence of psoriasis vulgaris with bullous diseases represents also a difficult therapeutic challenge. This rare case of psoriasis and generalized BP triggered by a sartan drug was treated with rituximab and etanercept.",
"affiliations": "Department of Dermatology, University of Rome Tor Vergata, Rome, Italy. rositasaraceno@yahoo.it",
"authors": "Saraceno|R|R|;Citarella|L|L|;Spallone|G|G|;Chimenti|S|S|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab; D019808:Losartan",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2230.2007.02603.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "33(2)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D047228:Angiotensin II Type 1 Receptor Blockers; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D003875:Drug Eruptions; D006801:Humans; D007155:Immunologic Factors; D019808:Losartan; D008297:Male; D008875:Middle Aged; D010391:Pemphigoid, Bullous; D011565:Psoriasis; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "154-5",
"pmc": null,
"pmid": "18021271",
"pubdate": "2008-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A biological approach in a patient with psoriasis and bullous pemphigoid associated with losartan therapy.",
"title_normalized": "a biological approach in a patient with psoriasis and bullous pemphigoid associated with losartan therapy"
} | [
{
"companynumb": "IT-009507513-0711ITA00022",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LOSARTAN POTASSIUM"
},
"drugadditional": "1",... |
{
"abstract": "Adrenal suppression (AS) is an under-recognised side effect of glucocorticoid (GC) use. AS may go undetected until a physiological stress precipitates an adrenal crisis. The incidence of AS has not been established. We sought to estimate the minimum national incidence and presenting features of paediatric symptomatic AS.\n\n\n\nThrough the established methodology of the Canadian Paediatric Surveillance Program, over 2500 paediatricians were surveyed monthly for 2 years (April 2010-March 2012) to report new cases of symptomatic AS.\n\n\n\nForty-six cases of symptomatic AS were confirmed. The estimated annual incidence is 0.35/100 000 children aged 0-18 years (95% CI 0.26 to 0.47). The most common presentations were growth failure (35%), non-specific symptoms (28%) or both (13%). Adrenal crisis occurred in six cases (13%). Thirty-seven children (80%) had received inhaled corticosteroid (ICS) alone or in combination with other GC forms. Many children received high but commonly prescribed doses of ICS.\n\n\n\nAS is responsible for significant morbidity in children, including susceptibility to adrenal crisis. The minimal estimated incidence reported is for the entire paediatric population and would be much higher in the at-risk group (ie, children treated with GCs). Close monitoring of growth and possible symptoms of AS, which may be non-specific, are important in children on all forms of GC therapy including ICS. To reduce the risk of AS, physicians must be aware of the risk of AS, revisit GC doses frequently and use the lowest effective dose.",
"affiliations": "Department of Pediatrics (Endocrinology), Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.;Department of Pediatrics (Endocrinology), IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.;Department of Pediatrics (Endocrinology), IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.;Department of Pediatrics (Hematology Oncology), Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.;Department of Pediatrics (Rheumatology), Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.;Department of Pediatrics (Gastroenterology), Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada.;Department of Pediatrics (Allergy), IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.;Department of Pediatrics (Endocrinology), Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.",
"authors": "Goldbloom|Ellen B|EB|;Mokashi|Arati|A|;Cummings|Elizabeth A|EA|;Abish|Sharon|S|;Benseler|Susanne M|SM|;Huynh|Hien Q|HQ|;Watson|Wade|W|;Ahmet|Alexandra|A|",
"chemical_list": "D005938:Glucocorticoids; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1136/archdischild-2016-311223",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9888",
"issue": "102(4)",
"journal": "Archives of disease in childhood",
"keywords": "adrenal crisis; adrenal insufficiency; adrenal suppression; asthma; glucocorticoids",
"medline_ta": "Arch Dis Child",
"mesh_terms": "D000280:Administration, Inhalation; D000293:Adolescent; D000309:Adrenal Insufficiency; D002170:Canada; D002648:Child; D002675:Child, Preschool; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006854:Hydrocortisone; D007223:Infant; D008297:Male; D011446:Prospective Studies",
"nlm_unique_id": "0372434",
"other_id": null,
"pages": "338-339",
"pmc": null,
"pmid": "28320817",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Symptomatic adrenal suppression among children in Canada.",
"title_normalized": "symptomatic adrenal suppression among children in canada"
} | [
{
"companynumb": "CA-MYLANLABS-2017M1033956",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
"drugadditional": null,
... |
{
"abstract": "Donepezil toxicity can present similarly to beta-blocker overdose and colitis. Symptoms include confusion, diaphoresis, and bradycardia. In patients with suspected medication-related toxicities, it is important to consider all possible causative agents in the active medication list.",
"affiliations": "Department of Pharmacy Services Indiana University Health, Methodist Hospital Indianapolis Indiana.;Department of Pharmacy Services Hartford Hospital Hartford Connecticut.;Department of Pharmacy Services Brigham and Women's Hospital Boston Massachusetts.",
"authors": "Gust|Carmen|C|https://orcid.org/0000-0002-6788-3130;Pugliese|Nicholas|N|https://orcid.org/0000-0002-1195-5676;Stern|Gretchen|G|https://orcid.org/0000-0002-5168-5236",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3245",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3245\nCCR33245\nCase Report\nCase Reports\nSuspected donepezil toxicity: A case report\nGUST et al.Gust Carmen https://orcid.org/0000-0002-6788-3130\n1\ncarmengust@creighton.edu Pugliese Nicholas https://orcid.org/0000-0002-1195-5676\n2\n Stern Gretchen https://orcid.org/0000-0002-5168-5236\n3\n \n1 \nDepartment of Pharmacy Services\nIndiana University Health, Methodist Hospital\nIndianapolis\nIndiana\n\n\n2 \nDepartment of Pharmacy Services\nHartford Hospital\nHartford\nConnecticut\n\n\n3 \nDepartment of Pharmacy Services\nBrigham and Women’s Hospital\nBoston\nMassachusetts\n\n* Correspondence\n\nCarmen Gust, Indiana University Health, Methodist Hospital, Department of Pharmacy Services, Indianapolis, IN.\n\nEmail: carmengust@creighton.edu\n\n03 9 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.122818 2823\n20 1 2020 08 5 2020 22 7 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nDonepezil toxicity can present similarly to beta‐blocker overdose and colitis. Symptoms include confusion, diaphoresis, and bradycardia. In patients with suspected medication‐related toxicities, it is important to consider all possible causative agents in the active medication list.\n\nDonepezil toxicity can present similarly to beta‐blocker overdose and colitis. Symptoms include confusion, diaphoresis, and bradycardia. In patients with suspected medication‐related toxicities, it is important to consider all possible causative agents in the active medication list.\n\n\n\nbeta‐blockerDonepeziltoxicity source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nGust \nC \n, \nPugliese \nN \n, \nStern \nG \n. Suspected donepezil toxicity: A case report\n. Clin Case Rep . 2020 ;8 :2818 –2823\n. 10.1002/ccr3.3245\n==== Body\n1 INTRODUCTION\nDonepezil is an acetylcholinesterase inhibitor (AChEI) that prevents the breakdown of acetylcholine, a neurotransmitter, which is depleted in patients with Alzheimer's disease and dementia.\n1\n There are few reports showcasing donepezil toxicity in the literature and even less that display a coinciding beta‐blocker toxicity.\n2\n, \n3\n, \n4\n, \n5\n, \n6\n, \n7\n, \n8\n This case highlights symptoms representative of a donepezil toxicity and risks that may occur even at the manufacturer's recommended doses.\n\nThe American Geriatrics Society's Beer's list recognizes donepezil as a high‐risk medication in older adults due to increased rates of orthostatic hypotension and bradycardia within this population.\n9\n Some common (>10%) adverse reactions of donepezil include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia. Other less common (1%‐10%) adverse effects are insomnia, emesis, gastritis, hypertension, syncope, bradycardia, chills, generalized coldness, pain, dizziness, abnormal gait, confusion, fatigue, diaphoresis, abdominal pain, bloating, and constipation and were reported to occur more often in females of advancing age.\n10\n Toxicity symptoms reported in other case reports included: nausea, vomiting, confusion, somnolence, diaphoresis and bradycardia with greater prominence at higher donepezil doses.\n2\n, \n3\n, \n4\n, \n5\n, \n6\n, \n7\n, \n8\n In addition, postmarketing data have revealed hyperglycemia and hypothermia reported in less than 1% of patients.\n10\n One of the dose‐related signs of toxicity in animals was lower body surface temperature.\n\nLike donepezil toxicity, altered mental status and bradycardia commonly occur with beta‐blocker toxicity. Hypothermia can occur with both agents; however, it is less prevalent in beta‐blocker toxicity. Other effects seen with beta‐blocker toxicity include hypotension, respiratory depression, seizure, hypoglycemia, and bronchospasm.\n11\n, \n12\n When AChEIs are co‐administered with heart rate‐lowering agents like beta‐blockers, a theoretical risk of enhanced bradycardia exists.\n12\n Beta‐blockers lower the heart rate by blocking beta‐1 receptors and impeding the action of epinephrine and norepinephrine.\n13\n AChEIs increase acetylcholine at the synapses and affect the parasympathetic innervation of the heart, resulting in decreased sinoatrial‐ and atrioventricular node conduction and decreased heart rate.\n14\n\n\n\n2 CASE HISTORY\nA 96‐year‐old female patient presented to the emergency department when her son reported she was difficult to awaken, diaphoretic and had an altered mental status compared to baseline. On the day of admission, the patient awoke in her usual state of health, able to converse, and ambulate, but prior to dinner, her son noted the patient was lethargic and unable to ambulate to the bathroom. The family also reported that the patient had been suffering from intermittent diarrhea and abdominal pain the past several months but was otherwise in her normal state of health. During a geriatric appointment three months prior, diarrhea and postprandial discomfort were noted with a possible relation to her donepezil dose, but the medical team chose to continue her donepezil as prescribed and monitor her symptoms. The patient's heart rate at this visit was 64 beats per minute (BPM) and weight was 99 pounds (45 kg).\n\nThe patient's history was notable for arteriosclerotic heart disease, chronic renal impairment, dementia, gastroesophageal reflux disease, hyperlipidemia, hypertension, and sensorineural hearing loss. Home medications included aspirin 81 mg daily, atorvastatin 40 mg nightly, donepezil 10 mg daily, esomeprazole 40 mg daily, and metoprolol succinate 50 mg nightly. Donepezil was prescribed two years ago, with the last dose change being one year ago from 5 mg to 10 mg daily and no metoprolol dose changes were made within the past two years. Her last metoprolol and donepezil doses were presumed to be given the evening and morning prior to admission, respectively.\n\n2.1 Differential diagnosis, investigations, and treatment\nUpon initial observation, the patient was nonconversant and diaphoretic with abdominal tenderness and minimal response to stimulation. Vitals were notable for a 2 kg weight loss and a heart rate of 36 BPM; an electrocardiogram (ECG) revealed sinus bradycardia with nonspecific T wave abnormalities (see vitals in Table 1 and ECG in Figure 1). Baseline laboratories were pertinent for leukocytosis (10.3x103/L) with neutrophilic predominance, hyperglycemia (123 mg/dL) hypocarbia (20 mmol/L), and euthyroid (TSH = 0.72 μIU/mL). The patient was admitted to a general medicine floor for further workup of bradycardia and possible colitis.\n\nTable 1 Initial ED Vitals\n\nBP (mm Hg)\tHR (bpm)\tRR\tTemp (˚F)\tWt (kg)\tHeight (cm)\t\n140/52\t36\t11\t96.8\t43.1\t145\t\nAbbreviations: BP, blood pressure; HR, heart rate; RR, respiratory rate, Wt, weight.\n\nJohn Wiley & Sons, LtdFigure 1 Electrocardiogram (ECG)\n\nOn day one of the hospital admission, continuous telemetry was initiated, and metoprolol was held. Then, 500 mL of 5% dextrose with 0.9% saline was administered along with 2 g of magnesium and 10 mEq of potassium. A computed tomography scan was performed, and results were suggestive of colitis. Stool cultures were ordered, and the presumed colitis was empirically treated with intravenous (IV) ciprofloxacin and metronidazole. At approximately 0100 on day two, the patient's resting heart rate dropped from 40 BPM into the 30 s. In the event of a beta‐blocker toxicity, a 3 mg IV injection of glucagon was administered, and the patient's heart rate temporarily increased to 82 BPM after 30 minutes. A glucagon infusion was then initiated at 2 mg/h for 2 hours. During this time, the heart rate ranged between 39 and 89 BPM (see Figure 2 for heart rate, temperature, and glucagon trends). Following this, a two‐hour interruption in the glucagon infusion occurred due to the bag running out. Consequently, the heart rate decreased to 48 BPM and the patient also became hypothermic with an oral temperature of 90°F. The glucagon infusion was resumed at 3 mg/h, and the heart rate remained between 53 and 63 BPM over the course of the next 6.5 hours. The patient was still hypothermic at approximately 0800, so a warming blanket was applied with good effect. Throughout the afternoon, the patient became more alert and oriented, and the heart rate stabilized around 53 BPM. The glucagon infusion was stopped at 1500. After stopping the infusion on day two, the heart rate ranged between 58 BPM and 69 BPM throughout the day.\n\nFigure 2 Displays a timeline of the patient's heart rate and temperature, along with the corresponding glucagon administration\n\nOn the third day, the care team re‐evaluated the patient's current medications and discontinued the home medication of donepezil, out of concern that it may have contributed to the patient's symptoms. Up to this point no doses of donepezil were given during the patient's stay. The heart rate on day three ranged from 58 to 70 BPM. The patient's white count also improved, shifting from 11.58 K/µL on day two to 7.05 K/µL on day three.\n\n2.2 Outcome and follow‐up\nOn day four the heart rate ranged from 57 BPM while sleeping to 78 BPM while wake. The patient's mental status and overall health improved. On day five, the patient was re‐started on her metoprolol succinate and donepezil at half dose, 25 mg nightly and 5 mg daily, respectively. The patient's median heart rate was 64 BPM (similar to her baseline heart rate) and the temperature stabilized at 97.3°F. On day six, the patient was discharged with plans to complete a seven‐day course of antibiotics, continue reduced dose of metoprolol 25 mg nightly and further decrease donepezil to 2.5 mg daily. The patient was discharged on day six with two more days of antibiotic therapy (ciprofloxacin and metronidazole) and complete resolution of her symptoms. Heart rate 10 days after discharge was 78 BPM and patient was back to her usual state of health. Six months later, the donepezil dose was increased back to 10 mg daily. One week after dose change, the patient had worsening abdominal pain and diarrhea and heart rate at office visit was 64 BPM.\n\n2.3 Other case reports\nAfter review of the literature, the following cases reported donepezil toxicities. A 79‐year‐old female patient presented with lethargy and vomiting after erroneously receiving a 50 mg dose of donepezil, rather than her prescribed 5 mg dose. Her vital signs included a blood pressure of 167/83 mm Hg, a heart rate of 56 BPM, and a respiratory rate of 16 breaths per minute. Her skin was pale and diaphoretic. The patient was treated with a total of 3 mg of atropine and returned to baseline by day two in the hospital.\n2\n Another case of an 84‐year‐old man that ingested a 35 mg dose of donepezil reported symptoms of nausea, vomiting, diarrhea, fatigue, excessive sweating, and disorientation. His vital signs included a blood pressure of 131/58 mm Hg, a heart rate of 50 BPM, and a respiratory rate of 16 breaths per minute. The patient's heart rate fluctuated between 50 and 60 BPM, and QTc prolongation was also reported. The patient received a dose of atropine 0.5 mg IV when his heart rate fell below 50 BPM. The patient's bradycardia and QTc prolongation resolved, and the patient returned home after six days in the hospital.\n3\n The third donepezil case occurred in a 74‐year‐old female that took nine times her regular dose of donepezil (45 mg) and reported symptoms of nausea, vomiting, drowsiness, flushing, and diarrhea, but returned to baseline after stopping her donepezil dose and a day of home observation.\n4\n\n\n\nTwo cases of donepezil toxicity have also been reported at therapeutic doses. A 90‐year‐old man's dose of donepezil increased from 5 mg to 10 mg. The patient's body temperature was 96.8°F, blood pressure was 158/49 mm Hg, and heart rate was 36 BPM. An ECG revealed an advanced 2:1 atrioventricular block and QT prolongation. The patient's donepezil was discontinued and 30 mg of orciprenaline was administered. By the fifth day, the patient's ECG and other symptoms had normalized.\n5\n The second case involved an 87‐year‐old woman with a history of bradycardia, atrial fibrillation, and QT prolongation. Patient's home medications included cilostazol, amlodipine, spironolactone, warfarin, and donepezil. She was admitted to the hospital after a fall caused by syncope. Her temperature was 97.5°F, blood pressure was 115/63 mm Hg, heart rate was 40 BPM, and QT prolongation was reported. She also complained of nausea and vomiting. Orciprenaline 30 mg daily was administered to prevent progression of bradycardia. On the fifth day, the donepezil was discontinued, and her heart rate increased to 55 BPM. On day 18, the QT prolongation resolved.\n6\n\n\n\n3 DISCUSSION\nSuitable management of donepezil overdose should include donepezil discontinuation and supportive care. IV atropine therapy at 1mg to 2 mg may be considered to reverse cholinergic effects, including bradycardia seen with donepezil toxicity.\n7\n, \n10\n Similarly, fluids and atropine may also be used to treat bradycardia due to beta‐blocker overdose. If this is not effective, other treatment options for beta‐blocker toxicity include IV glucagon, IV calcium salts, vasopressor therapy, high‐dose insulin with glucose infusions, and lipid emulsion therapy.\n11\n, \n15\n, \n16\n As beta‐blocker toxicity could have been on the differential for this case, glucagon was used. Glucagon exhibits positive inotropic and chronotropic effects on the heart through stimulation of glucagon receptors which increase cyclic‐AMP in the sinoatrial node to increase heart rate.\n17\n Animal studies have shown that mice without glucagon receptors have naturally decreased heart rates and altered parasympathetic control compared to mice with glucagon receptors. When cats and dogs were exposed to glucagon, heart rates significantly increased from baseline by approximately 22 to 30%. These results suggest glucagon plays a key role in heart rate control independent of medication exposure. Thus, glucagon's transient increased effect on the patient's heart rate was likely due to its mechanism of action and not an antidotal effect for beta‐blocker toxicity.\n18\n\n\n\nThe altered pharmacodynamics of aging can cause up to a 17% decrease in clearance of donepezil in older adults and result in higher serum levels of donepezil.\n9\n While the bradycardic effects may have been compounded by metoprolol, the hypotension, hypoglycemia, and respiratory depression commonly seen in beta‐blocker toxicity were not observed in this case. This patient had multiple cholinergic symptoms including abdominal pain, diaphoresis, diarrhea, emesis, nausea, and salivation, along with hyperglycemia, which are unique to donepezil toxicity (Figure 3). Additionally, the patient's bradycardia and other symptoms started to resolve approximately 70 hours after the last donepezil dose, which coincides with donepezil's half‐life.\n10\n Alternatively, metoprolol's half‐life ranges from 3 to 7 hours.\n19\n\n\n\nFigure 3 Displays symptoms unique to donepezil and metoprolol toxicities along with colitis and those that overlap. Bold symptoms represent those that the patient experienced.\n10\n, \n11\n, \n21\n\n\n\nDonepezil should be used with caution in older adult patients, especially those with multiple medications and comorbidities. Donepezil is recorded on the Beer's Criteria list due to the increased risk of orthostatic hypotension, syncope, and bradycardia that can occur when used in older adults.\n9\n In addition, the medication is metabolized in the liver and hepatic impairment increases with age due to decrease in liver volume and hepatic blood flow.\n6\n Finally, low‐weight patients (<55 kg; similar to this patient) may experience more nausea, vomiting, and weight loss than other patients taking donepezil.\n10\n For this reason, the Canadian labeling of donepezil recommends a maximum dose of 5 mg once daily instead of the United States labeling of up to 10 mg twice daily in older adult women (≥ 85 years old) with low body weight (<55 kg).\n20\n The patient experienced a four‐pound weight loss and had complained of stomach discomfort in the two months prior to admission. The weight loss and potential decrease in nutrition may have resulted in an increase in serum concentrations of donepezil as this medication has a large volume of distribution and is 96% protein bound.\n10\n Though the patient's donepezil dose had not changed in the last year, the bradycardia and other side effects may have not manifested until these pharmacokinetic changes occurred.\n\nOther than a purely medication driven event, the patient's presentation and improvement may also be somewhat explained by presumed colitis and antibiotic treatment. The patient had mild leukocytosis, abdominal pain, bloating, diarrhea, fatigue, hyperglycemia, and altered mental status. However, other common symptoms of colitis including fever, chills, and dehydration were absent in our patient, making it difficult to fully explain the symptoms with one diagnosis (Figure 3).\n21\n\n\n\nThe only way to be certain the signs and symptoms were part of a donepezil toxicity would be to complete a thorough toxicology screen of metoprolol and donepezil serum concentrations in the patient's blood. Unfortunately, these toxicity screens can be expensive and are not the standard of care for a suspected overdose with either of these medications. A reasonable alternative to toxicology information is the use of the Naranjo Adverse Drug Reaction Probability Scale (Table 2). After the adverse event occurred, an evaluation was conducted using the Naranjo Scale and resulted in a +6, indicating donepezil was a probable cause of the patient's symptoms. While the score is compelling, it is important to note the Naranjo scale has not been validated to detect complex interactions involving more than one medication or disease state.\n22\n\n\n\nTable 2 Naranjo Adverse Drug Reaction Probability Scale. The total score is categorized into one of four categories: ≥ 9 indicates definite adverse drug reaction (ADR), 5‐8 indicates probable ADR, 1‐4 indicates possible ADR, and 0 indicates doubtful ADR\n\nQuestion\tYes\tNo\tDo Not Know\t\nAre there previous conclusive reports on this reaction?\t+1\t0\t0\t\nDid the adverse event appear after the suspected medicine was administered?\t+2\t‐1\t0\t\nDid the adverse reaction improve when the medicine was discontinued or a specific antagonist was administered?\t+1\t0\t0\t\nDid the adverse reaction reappear when the medicine was re‐administered?\t+2\t‐1\t0\t\nAre there alternate causes (other than the medicine) that could solely have caused the reaction?\t‐1\t+2\t0\t\nWas the medicine detected in the blood (or other fluids) in a concentration known to be toxic?\t+1\t0\t0\t\nWas the reaction more severe when the dose was increased or less severe when the dose was decreased?\t+1\t0\t0\t\nDid the patient have a similar reaction to the same or similar medicines in any previous exposure?\t+1\t0\t0\t\nWas the adverse event confirmed by objective evidence?\t+1\t0\t0\t\nJohn Wiley & Sons, Ltd4 CONCLUSION\nAll recent and active medications should be assessed as contributing factors when a patient presents with abnormal symptoms and possible medication toxicities. In this specific case, it is even more important to complete a differential diagnosis when drugs and diseases have overlapping symptoms, as donepezil's cholinergic symptoms present similarly to a beta‐blocker overdose and colitis. The symptoms of emesis, nausea, salivation, and hyperglycemia were likely linked to donepezil toxicity and not due to other factors. In addition, the patient's bradycardia, hypothermia, mental status change, fatigue, abdominal pain, and diarrhea may also be linked to donepezil toxicity but overlap with metoprolol toxicity and infective colitis symptoms. Understanding the unique symptoms of each possible offending agent can help providers optimize therapy, withdraw potentially offending agents, and discontinue unnecessary treatment.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nCG: Performed chart review of patient case and wrote the manuscript with support from authors 2 and 3. Nicholas Pugliese, PharmD: Supported author 1 in writing of manuscript, figure development, and curating background and discussion of the manuscript. Gretchen Stern, PharmD, BCPS: Conceived idea of manuscript and reviewed manuscript. All authors discussed the conclusions and contributed to the final manuscript.\n\nRESEARCH AND ETHICS AND PATIENT CONSENT\nConsent was not required per institution protocol and waived per the Institutional Review Board at Brigham and Women's Hospital in Boston, Massachusetts.\n==== Refs\nREFERENCES\n1 \n\nRelkin \nNR \n, \nReichman \nWE \n, \nOrazem \nJ \n, et al. A large community based, open‐label trial of donepezil in the treatment of Alzheimer's disease\n. Dement Geriatr Cogn Disord . 2003 ;16 (1 ):15 ‐24\n.12714795 \n2 \n\nShepherd \nG \n, \nKlein‐Schwartz \nW \n, \nEdwards \nR \n. Donepezil overdose: a tenfold dosing error\n. Ann Pharmacother . 1999 ;33 (7–8 ):812 ‐815\n.10466911 \n3 \n\nStellpflug \nSJ \n, \nFritzlar \nSJ \n, \nCole \nJB \n, et al. Cardiotoxic overdose treated with intravenous fat emulsion and high‐dose insulin in the setting of hypertrophic cardiomyopathy\n. J Med Toxicol . 2011 ;7 (2 ):151 ‐153\n.21174185 \n4 \n\nGreene \nYM \n, \nNoviasky \nJ \n, \nTariot \nPN \n. Donepezil overdose\n. J Clin Psychiatry . 1999 ;60 (1 ):56 ‐57\n.10074883 \n5 \n\nTanaka \nA \n, \nKoga \nS \n, \nHiramatsu \nY \n. Donepezil‐induced adverse side effects of cardiac rhythm: 2 cases report of atrioventricular block and Torsade de Pointes\n. Intern Med . 2009 ;48 :1219 ‐1223\n.19602789 \n6 \n\nThornton \nSL \n, \nClark \nRF \n. Encephalopathy from unintentional donepezil and memantine ingestion\n. Pediatr Emerg Care . 2014 ;30 (9 ):649 ‐650\n.25186510 \n7 \n\nMottram \nAR \n, \nTer Haar \nE \n. Donepezil overdose‐trending levels and symptoms\n. Case Rep Intern Med . 2014 ;1 (2 ):80 ‐82\n.\n8 \n\nSavage \nR \n. Donepezil: Syncope, Heart Block and Beta‐adrenergic Blockade\n. Medsafe . 2013 ;34 (3 ):30 .\n9 \nAmerican Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults\n. J Am Geriatr Soc . 2019 ;67 (4 ):674 ‐694\n.30693946 \n10 \nProduct information\n. Aricept (Donepezil hydrochloride) tablet. Woodcliff Lake, NJ : Eisai Co., Ltd; February 2012 .\n11 \n\nTucker \nWD \n, \nSankar \nP \n, \nTheetha Kariyanna \nP \n. Selective Beta-1-Blockers. [Updated 2020 May 3] . In: StatPearls [Internet]. Treasure Island, FL : StatPearls Publishing \n2020 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499982/ (accessed on 2020 Aug 11).\n12 \n\nLifshitzz \nM \n, \nZucker \nN \n, \nZalzstein \nE \n. Acute dilated cardiomyopathy and central nervous system toxicity following propranolol intoxication\n. Pediatr Emerg Care . 1999 ;15 (4 ):262 .10460081 \n13 \n\nPark‐Wyllie \nLY \n, \nMamdani \nMM \n, \nLi \nP \n, \nGill \nSS \n, \nLaupacis \nAndreas \n, \nJuurlink \nDN \n. Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population‐Based Study\n. PLoS Medicine . 2009 ;6 (9 ):e1000157 \n10.1371/journal.pmed.1000157 .19787032 \n14 \n\nGordan \nR \n, \nGwathmey \nJK \n, \nXie \nLH \n. Autonomic and endocrine control of cardiovascular function\n. World J Cardiol . 2015 ;7 (4 ):204 ‐214\n.25914789 \n15 \n\nBarton \nCA \n, \nJohnson \nNB \n, \nMah \nND \n, et al. Successful treatment of a massive metoprolol overdose using intravenous lipid emulsion and hyperinsulinemia/euglycemia therapy\n. Pharmacotherapy . 2015 ;35 (5 ):e56 ‐e60\n.25908023 \n16 \n\nDoepker \nB \n, \nHealy \nW \n, \nCortez \nE \n, et al. High‐dose insulin and intravenous lipid emulsion therapy for cardiogenic shock induced by intentional calcium‐channel blocker and beta‐blocker overdose: a case series\n. J Emerg Med . 2014 ;46 (4 ):486 ‐490\n.24530120 \n17 \n\nHernández‐Cascales \nJ \n. Does glucagon have a positive inotropic effect in the human heart?\n\nCardiovasc Diabetol . 2018 ;17 (1 ):148 .30482191 \n18 \n\nPetersen \nKM \n, \nBøgevig \nS \n, \nHolst \nJJ \n, et al. Hemodynamic effects of glucagon: a literature review\n. J Clin Endocrinol Metab . 2018 ;103 (5 ):1804 ‐1812\n.29546411 \n19 \nProduct information\n. Toprol‐XL (Metoprolol Succinate) tablet. Södertälj, Sweden: AstraZeneca AB, March 2006 .\n20 \nProduct information\n. Aricept (Donepezil hydrochloride) tablet, Aricept RDT (donepezil hydrochloride) rapidly disintegrating tablet. Kirkland, Quebec: Pfizer Canada Inc., Eisai Co., Ltd; December 2014 .\n21 \n\nPark \nT \n, \nCave \nD \n, \nMarshall \nC \n. Microscopic colitis: A review of etiology, treatment and refractory disease\n. World J Gastroenterol . 2015 ;21 (29 ):8804 ‐8810\n.26269669 \n22 \n\nComfort \nS \n, \nDorrell \nD \n, \nMeireis \nS \n, et al. MOdified NARanjo Causality Scale for ICSRs (MONARCSi): A Decision Support Tool for Safety Scientists\n. Drug Saf . 2018 ;41 (11 ):1073 ‐1085\n.29876835\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "8(12)",
"journal": "Clinical case reports",
"keywords": "Donepezil; beta‐blocker; toxicity",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2818-2823",
"pmc": null,
"pmid": "33363829",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "19787032;30482191;21174185;30693946;24530120;25186510;29876835;12714795;10466911;29546411;25914789;25908023;10074883;10460081;19602789;26269669",
"title": "Suspected donepezil toxicity: A case report.",
"title_normalized": "suspected donepezil toxicity a case report"
} | [
{
"companynumb": "US-PFIZER INC-2020353918",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.