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"abstract": "OBJECTIVE\nTo evaluate major complications after intravitreal injection of dexamethasone implants (Ozurdex) and their clinical management.\n\n\nMETHODS\nIn a retrospective observational study between 2014 and 2016 at two university hospitals, we reviewed the clinical records of 1241 consecutive macular edema patients treated with the dexamethasone implant, and separated severe adverse events in the injection procedure from those that were post-injection complications. We evaluated the cause and the outcomes in each case.\n\n\nRESULTS\nIn twenty-one procedures (1.69%) we noticed significant complications during and after intravitreal injection of the dexamethasone implant. Complications related to the injection procedure were in one case, that a second implant was injected by mistake in the same eye on the same day. In another case, the implant lodged in the sclera during retraction of the injector needle. Leaking scleral tunnel at the injection site led to hypotony in another case. There were 10 cases of post-injection displacement of the implant into the anterior chamber and one case with a migrated and trapped device between the intraocular lens and an artificial iris. Displacement typically occurred in patients with preexisting risk factors: eyes with complicated intraocular lens implantation, iris reconstruction or iris defects or pseudophakic eyes after vitrectomy were prone to develop this complication. Displacement led to secondary corneal decompensation with pseudohypopyon. One case developed an endophthalmitis, and we observed four cases of retinal detachment. Two eyes presented with long-lasting hypotony due to ciliary insufficiency.\n\n\nCONCLUSIONS\nTreatment with the dexamethasone implant may cause various expected or unexpected complications that may have serious consequences for the patient and require further surgery. To reduce complications, clinicians should evaluate certain risk factors before scheduling patients for dexamethasone implant treatment and use proper injection techniques.",
"affiliations": "Department of Ophthalmology, University Hospital of Heidelberg, Heidelberg 69120, Germany.;Department of Ophthalmology, University Hospital of Heidelberg, Heidelberg 69120, Germany.;Department of Ophthalmology, University Hospital of Heidelberg, Heidelberg 69120, Germany.;Department of Ophthalmology, University Hospital of Heidelberg, Heidelberg 69120, Germany.;Department of Ophthalmology, University Hospital of Heidelberg, Heidelberg 69120, Germany.",
"authors": "Celik|Nil|N|;Khoramnia|Ramin|R|;Auffarth|Gerd U|GU|;Sel|Saadettin|S|;Mayer|Christian S|CS|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.18240/ijo.2020.10.16",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2222-3959",
"issue": "13(10)",
"journal": "International journal of ophthalmology",
"keywords": "Ozurdex; dexamethasone implants; intravitreal implants; intravitreal injection; slow release drug",
"medline_ta": "Int J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101553860",
"other_id": null,
"pages": "1612-1620",
"pmc": null,
"pmid": "33078113",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "28910428;21960148;26442819;21383939;23419308;25411827;26909535;22863290;27800199;26615950;23928945;24246828;15915332;27923521;26540554;24556884;24882964;24648417;24373603;23890421;22537269;22005792;22824616;27530085",
"title": "Complications of dexamethasone implants: risk factors, prevention, and clinical management.",
"title_normalized": "complications of dexamethasone implants risk factors prevention and clinical management"
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"abstract": "Although numerous recent studies have reported the development of sarcoidosis in patients treated with tumor necrosis factor alpha (TNF-α) inhibitors, it is unclear whether the pathogenesis of drug-induced sarcoidosis is identical to that of spontaneous sarcoidosis. We herein present the case of a patient who developed sarcoidosis 6 months after the introduction of etanercept as treatment for rheumatoid arthritis. Typical clinical symptoms with noncaseating epithelioid granulomas detected in a mediastinal lymph node specimen were consistent with the diagnosis of sarcoidosis. Immunohistochemistry revealed Propionibacterium acnes in the noncaseating granulomas. The present findings suggest that Propionibacterium acnes is a cause of sarcoidosis, even when the disease is induced by TNF-α inhibitors.",
"affiliations": "Department of Respiratory Medicine, Toho University Omori Medical Centre, Japan.;Department of Respiratory Medicine, Toho University Omori Medical Centre, Japan.;Department of Respiratory Medicine, Toho University Omori Medical Centre, Japan.;Department of Pathology, Toho University Omori Medical Centre, Japan.;Department of Pathology, Toho University Omori Medical Centre, Japan.;Department of Pathology, Toho University Omori Medical Centre, Japan.;Department of Human Pathology, Tokyo Medical and Dental University, Japan.;Department of Respiratory Medicine, Toho University Omori Medical Centre, Japan.",
"authors": "Isshiki|Takuma|T|;Matsuyama|Hisayo|H|;Sakamoto|Susumu|S|;Honma|Naoko|N|;Mikami|Tetuo|T|;Shibuya|Kazutoshi|K|;Eishi|Yoshinobu|Y|;Homma|Sakae|S|",
"chemical_list": "D018927:Anti-Asthmatic Agents; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.2086-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3062683710.2169/internalmedicine.2086-18Case ReportDevelopment of Propionibacterium acnes-associated Sarcoidosis During Etanercept Therapy Isshiki Takuma 1Matsuyama Hisayo 1Sakamoto Susumu 1Honma Naoko 2Mikami Tetuo 2Shibuya Kazutoshi 2Eishi Yoshinobu 3Homma Sakae 1\n1 Department of Respiratory Medicine, Toho University Omori Medical Centre, Japan\n2 Department of Pathology, Toho University Omori Medical Centre, Japan\n3 Department of Human Pathology, Tokyo Medical and Dental University, JapanCorrespondence to Dr. Takuma Isshiki, Takuma.isshiki@gmail.com\n\n10 1 2019 15 5 2019 58 10 1473 1477 6 9 2018 30 10 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/).Although numerous recent studies have reported the development of sarcoidosis in patients treated with tumor necrosis factor alpha (TNF-α) inhibitors, it is unclear whether the pathogenesis of drug-induced sarcoidosis is identical to that of spontaneous sarcoidosis. We herein present the case of a patient who developed sarcoidosis 6 months after the introduction of etanercept as treatment for rheumatoid arthritis. Typical clinical symptoms with noncaseating epithelioid granulomas detected in a mediastinal lymph node specimen were consistent with the diagnosis of sarcoidosis. Immunohistochemistry revealed Propionibacterium acnes in the noncaseating granulomas. The present findings suggest that Propionibacterium acnes is a cause of sarcoidosis, even when the disease is induced by TNF-α inhibitors. \n\nsarcoidosisetanerceptTNF-αPropionibacterium acnes\n==== Body\nIntroduction\nSarcoidosis is a systemic inflammatory disorder characterized by noncaseating granuloma and commonly manifests in the lungs, eyes, skin, and heart (1). Previous reports indicate that tumor necrosis factor alpha (TNF-α) is critical in the formation of granulomas and is therefore a potential therapeutic target for the treatment of granulomatous diseases. However, some patients with chronic inflammatory disorders such as rheumatoid arthritis (RA) unexpectedly develop sarcoidosis after treatment with TNF-α inhibitors (2, 3). Numerous recent studies have reported cases of sarcoidosis associated with drugs such as TNF-α inhibitors and immune checkpoint inhibitors (4, 5). These cases have been referred to by some researchers as drug-induced sarcoidosis-like reactions (DISRs) (6). Chopra et al. reported that the clinical manifestations of sarcoidosis and DISRs are similar; however, unlike sarcoidosis, DISRs often resolve when the offending drug is discontinued and recur with re-challenge (6). Although the clinical characteristics of these conditions differ to some extent, it is unclear whether the pathogeneses of DISRs and sarcoidosis are distinct.\n\nPropionibacterium acnes (P. acnes) has been extensively studied as a causative microorganism in sarcoidosis (7-11). Interestingly, Negi et al. reported that immunohistochemistry using a specific monoclonal antibody of P. acnes can discriminate sarcoid and non-sarcoid granulomas, including the sarcoid reaction of malignant tumors (11).\n\nWe herein report a case in which sarcoidosis developed during etanercept treatment. Immunohistochemistry revealed P. acnes in the patient's noncaseating granulomas.\n\nCase Report\nA 54-year-old woman was admitted to another hospital in August X for pain in multiple joints. RA was diagnosed and etanercept treatment was started. Congestion of the bulbar conjunctiva developed 6 months after the start of etanercept treatment, and iritis was diagnosed by an ophthalmologist. Bilateral hilar lymphadenopathy was noted in a health exam in December X+1, after which she was referred to our institution for further examination.\n\nA physical examination revealed mild congestion in both eyes but no fever, skin lesions, or abnormal sounds on chest auscultation. A purified protein derivative skin test yielded a negative result. The laboratory findings are summarized in Table 1. The angiotensin-converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R) levels were elevated. Pulmonary function testing revealed a normal respiratory function, and the arterial partial pressure of oxygen (PaO2) was 99.5 mmHg in a blood gas analysis. No abnormal findings were observed on electrocardiography or echocardiography.\n\nTable 1. Laboratory Data on Admission.\n\nBlood chemistry\t\tImmunological variables\t\nTotal protein\t7.2\tg/dL\t\tT-SPOT. TB\tNegative\t\nAlbumin\t3.6\tg/dL\t\tAnti-MAC antibody\tNegative\t\nAspartate aminotransferase\t30\tU/L\t\tAngiotensin-converting enzyme\t28.0\tU/L\t\nLactate dehydrogenase\t217\tU/L\t\tSoluble IL-2 receptor\t1,630\tU/mL\t\nUrea nitrogen\t14\tmg/dL\t\tTumor necrosis factor-α\t3\tpg/mL\t\nCreatinine\t0.6\tmg/dL\t\t\t\t\t\nCalcium\t8.7\tmg/dL\t\tArterial blood gas analysis\t\nPhosphorus\t4.1\tmg/dL\t\tpH\t7.41\t\t\nC-reactive protein\t11.1\tmg/dL\t\tPaCO2\t39.3\tmm Hg\t\nKrebs von den Lungen-6\t269\tU/mL\t\tPaO2\t99.5\tmm Hg\t\nBrain natriuretic peptide\t30.4\tpg/mL\t\t\t\t\t\nProcalcitonin\t0.09\tng/mL\t\t\t\t\t\n\t\t\t\t\t\t\t\nComplete blood count\t\t\t\t\t\t\t\nWhite blood cell count\t5,300\t/μL\t\t\t\t\t\nRed blood cell count\t446×104\t/μL\t\t\t\t\t\nHemoglobin\t13.3\tg/dL\t\t\t\t\t\nPlatelet count\t26.7×104\t/μL\t\t\t\t\t\nPaCO2: partial pressure of arterial carbon dioxide, PaO2: partial pressure of arterial oxygen\n\nA chest radiograph showed bilateral hilar lymphadenopathy, and a contrast-enhanced chest computed tomography (CT) image showed mediastinal and hilar lymphadenopathy (Fig. 1a) without abnormal shadows in the lung fields. Positron emission tomography showed significant increases in the fluoro-2-deoxy-D-glucose uptake in the mediastinal and hilar lymph nodes. Bronchoscopy was performed to confirm the diagnosis. A bronchoalveolar lavage fluid analysis showed an elevated CD4/8 ratio (6.73) and high lymphocyte fraction (macrophages, 63%; lymphocytes, 31%; neutrophils, 5%; and eosinophils, 1%). A tissue specimen was obtained from a mediastinal lymph node (#7) by endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA), and a histopathologic analysis showed formation of a loose noncaseating epithelioid granulomas (Fig. 2a), without evidence of mycobacterium tuberculosis infection, as indicated by Ziehl-Neelsen staining. Immunohistochemistry using a specific monoclonal antibody against P.\nacnes lipoteichoic acid (PAB antibody) (11) revealed P. acnes in several granulomas in the tissue (Fig. 2b). These findings indicated a diagnosis of sarcoidosis, and etanercept treatment was implicated as the cause of the disease.\n\nFigure 1. Chest computed tomography (CT) images. (a) A chest contrast-enhanced CT image obtained on admission. The white arrows indicate mediastinal and hilar lymphadenopathy. (b) At 1 year after the discontinuation of etanercept, the size of the lymph nodes had decreased.\n\nFigure 2. Endobronchial ultrasound-guided transbronchial needle aspiration was used to collect a lymph node specimen. (a) Hematoxylin and Eosin staining shows a noncaseating epithelioid cell granuloma. (b) Immunohistochemical staining with a specific monoclonal antibody against Propionibacterium acnes lipoteichoic acid (PAB antibody) shows positive reaction products (black arrows) in the granuloma.\n\nEtanercept treatment was stopped and a follow-up examination was performed. The serum levels of ACE and sIL-2R gradually decreased without treatment after the discontinuation of etanercept (Fig. 3). A chest CT image showed that the mediastinal and hilar lymph nodes were smaller after 1 year (Fig. 1b), which indicated improvement without therapeutic intervention.\n\nFigure 3. Changes in the serum biomarkers of sarcoidosis after discontinuation of etanercept. The angiotensin-converting enzyme (ACE) and soluble IL-2 receptor (sIL-2R) levels decreased after the cessation of etanercept discontinued.\n\nDiscussion\nSarcoidosis is diagnosed based on compatible clinical features, radiological findings, and histological evidence of noncaseating epithelioid granulomas (1). Our patient developed iritis followed by bilateral hilar lymphadenopathy. In addition, biomarkers, including ACE and sIL-2R, were markedly elevated at the disease onset, which are findings consistent with sarcoidosis. EBUS-TBNA confirmed the presence of noncaseating epithelioid cell granulomas in the mediastinal lymph nodes. The patient developed sarcoidosis during etanercept treatment and improved without therapeutic intervention after the cessation of etanercept. Thus, the final diagnosis was sarcoidosis induced by etanercept.\n\nPrevious studies found that TNF-α was important in granuloma formation in animal models of helminth infection (12-14) and in humans (15, 16). TNF-α is a key cytokine in the pathogenesis of sarcoidosis and a potential target of sarcoidosis treatment. In fact, based on small clinical trials, it has been reported that TNF-α inhibitors other than etanercept might be effective for sarcoidosis treatment (17-19). Interestingly, numerous recent studies have reported the development of sarcoidosis after TNF-α inhibitor treatment for systemic diseases. A literature search identified 63 cases of sarcoidosis due to TNF-α blocker treatment (Table 2). Most cases were caused by etanercept (68%), as occurred in our patient. Infliximab and adalimumab are monoclonal antibodies that recognize monomeric and trimeric soluble TNF and transmembrane TNF. In contrast, etanercept is the extracellular domain of the TNF receptor that is linked to the Fc and which only recognizes soluble trimeric TNF. Although the higher incidence of sarcoidosis due to etanercept treatment may be attributable to these different mechanisms of TNF-α inhibition, the pathogenesis of this condition has not been thoroughly studied.\n\nTable 2. Summary of Reported Cases of Sarcoidosis Development after Treatment with a TNF-α Inhibitor.\n\n\tNo. of patients\tTNF-α inhibitor \nE/I/A\tTime to onset \n(months)\tUnderlying disease\tTreatment\t\nReported cases\t63\t43/12/8\t24±22\tRA 36, AS 11, PsA 10, JIA 4, SAPHO 1, Crohn 1\tDiscontinuation 31 \nCorticosteroids 28 \nNot available 4\t\nPresent case\t1\tEtanercept\t8\tRA\tDiscontinuation\t\nE: etanercept, I: infliximab, A: adalimumab, RA: rheumatoid arthritis, AS: ankylosing spondylitis, PsA: psoriatic arthritis, JIA: juvenile idiopathic arthritis, SAPHO: Sapho syndrome, Crohn: Crohn disease\n\nSarcoidosis is also induced by immune checkpoint inhibitors. Several recent studies reported that sarcoidosis or sarcoid-like granulomatosis developed in patients with malignant tumors treated by monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death 1 (PD-1) (4, 5). Braun et al. reported that the PD-1 pathway in CD4 T cells was upregulated in sarcoidosis (20). PD-1 is a marker of lymphocyte exhaustion; thus, chronic lymphocytic inflammation may be associated with the pathogenesis of sarcoidosis. Enhanced lymphocyte proliferation by blockade of co-inhibitory signalling by immune checkpoint inhibitors is thought to be related to disease development.\n\nSarcoidosis is believed to be caused by an immune response after exposure to environmental factors, including infectious agents, in genetically susceptible individuals. Accumulating evidence suggests that P. acnes is the causative organism of sarcoidosis (7-11), as it is the only microorganism that has been isolated from bacterial cultures of sarcoidosis granulomas (7). In addition, fragments of nucleic acids of P. acnes have been detected in sarcoid lymph nodes by quantitative polymerase chain reactions and in situ hybridization (8-10). In an immunohistochemical study using a PAB antibody, Negi et al. reported a high frequency and specificity of P. acnes in sarcoid granulomas (11). In their analysis, PAB antibodies did not react with non-sarcoid granulomas such as tuberculosis or in sarcoid reactions caused by malignant tumors. Furthermore, findings from case reports and small clinical trials suggest that antibiotics such as tetracyclines and macrolides are effective for treating sarcoidosis (21-23), perhaps because of their anti-inflammatory and anti-microbial effects against infectious microorganisms such as P. acnes.\n\nIn our patient, P. acnes was identified in noncaseating granulomas of sarcoidosis induced by TNF-α inhibitors. It is hypothesized that latent P. acnes infection in the lungs and lymph nodes is activated by environmental factors, which triggers an immune response in patients with P. acnes allergy (24). Thus, we hypothesize that among individuals with systemic immunological disorders and malignant tumors, those with latent P. acnes infection may show aberrant responses to drugs such as TNF-α inhibitors and immune checkpoint inhibitors and consequently develop drug-induced sarcoidosis. This hypothesis suggests that DISRs and sarcoidosis share a pathogenetic mechanism and differ only in the exogenous stimuli that trigger their development. The extrinsic factors that activate the host are distinct in DISRs and are unclear in some patients with sarcoidosis.\n\nConclusions\nTo the best of our knowledge, this is the first case in which P. acnes was detected in the granulomas of a patient with sarcoidosis induced by a TNF-α inhibitor. These findings suggest that P. acnes is a cause of sarcoidosis, even in cases induced by drugs such as TNF-α inhibitors.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nKazutoshi Shibuya: Research funding, Dainippon Sumitomo Pharma. Sakae Homma: Research funding, Nippon Boehringer Ingerheim.\n\nAcknowledgement\nThe authors thank David Kipler for editing the language of the article.\n==== Refs\n1. Hunninghake GW , Costabel U , Ando M , et al \nATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/Wrold Association of Sarcoidosis and other Granulomatous Disorders . Sarcoidosis Vasc Diffuse Lung Dis \n16 : 149 -173 , 1999 .10560120 \n2. Sawahata M , Sugiyama Y , Yamasawa H , et al \nSarcoidosis during etanercept treatment for rheumatoid arthritis in women with a history of bilateral oophorectomy . Sarcoidosis Vasc Diffuse Lung Dis \n33 : 178 -181 , 2016 .27537723 \n3. Daien CL , Monnier A , Claudepierre P , et al \nSarcoid-like granulomatosis in patients with tumor necrosis factor blockers: 10 cases . Rheumatology \n48 : 883 -886 , 2009 .19423648 \n4. Danlos FX , Pages C , Baroudjian B , et al \nNivolumab-induced sarcoid-like granulomatous reaction in a patient with advanced melanoma . Chest \n149 : e133 -e136 , 2016 .27157227 \n5. Reuss JE , Kunk PR , Stowman AM , et al \nSarcoidosis in the settings of combination ipilimumab and nivolumab immunotherapy: a case report & review of the literature . J immunother Cancer \n4 : 94 , 2016 .28031822 \n6. Chopra A , Nautiyal A , Kalkanis A , et al \nDrug-induced sarcoidosis-like reactions . Chest \n154 : 664 -677 , 2018 .29698718 \n7. Homma JY , Abe C , Chosa H , et al \nBacterial investigation on biopsy specimens from patients with sarcoidosis . Jpn J Exp Med \n48 : 251 -255 , 1978 .713130 \n8. Ishige I , Usui Y , Takemura T , et al \nQuantitative PCR of mycobacterial and propionibacterial DNA in lymphoid nodes of Japanese patients with sarcoidosis . Lancet \n354 : 120 -123 , 1999 .10408488 \n9. Eishi Y , Suga M , Ishige I , et al \nQuantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis . J Clin Microbiol \n40 : 198 -204 , 2002 .11773116 \n10. Yamada T , Eishi Y , Ikeda S , et al \nIn situ localization of Propionibacterium acnes DNA in lymph nodes from sarcoidosis patients by signal amplification with catalysed reporter deposition . J Pathol \n198 : 541 -547 , 2002 .12434425 \n11. Negi M , Takemura T , Guzman J , et al \nLocalization of Propionibacterium acnes in granulomas supports a possible etiologic link between sarcoidosis and the bacterium . Mod Pathol \n25 : 1284 -1297 , 2012 .22596102 \n12. Amiri P , Locksley RM , Paraslow TG , et al \nTumor necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice . Nature \n356 : 604 -607 , 1992 .1560843 \n13. Joseph AL , Boros DL \nTumor necrosis fator plays a role in Schistosoma mansoni egg-induced granulomatous inflammation . J Immunol \n151 : 5461 -5471 , 1993 .8228238 \n14. Lukacs NW , Chensue SW , Strieter RM , et al \nInflammatory granuloma formation is mediated by TNF-alpha-inducible intercellular adhesion molecule-1 . J Immunol \n152 : 5883 -5889 , 1994 .7911491 \n15. Prior C , Knight RA , Herold M , et al \nPulmonary sarcoidosis: patterns in cytokines production . Eur Respir J \n9 : 47 -53 , 1996 .8834333 \n16. Ziegenhagen MW , Bender UK , Zissel G , et al \nSarcoidosis: TNF-α release from alveolar macrophages and serum level of sIL-2R are prognostic markers . Am J Respir Crit Care Med \n156 : 1586 -1592 , 1997 .9372680 \n17. Baughman RP , Drent M , Kavuru M , et al \nInfliximab therapy in patients with chronic sarcoidosis and pulmonary involvement . Am J Respir Crit Care Med \n174 : 795 -802 , 2006 .16840744 \n18. Kamphuis LS , Lam-Tse WK , Dik WA , et al \nEfficacy of adalimumab in chronically active and symptomatic patients with sarcoidosis . Am J Respir Crit Care Med \n184 : 1214 -1216 , 2011 .22086995 \n19. Ultz JP , Limper AH , Kalra S , et al \nEtanercept for the treatment of stage 2 and 3 progressive pulmonary sarcoidosis . Chest \n124 : 177 -185 , 2003 .12853521 \n20. Braun NA , Celada LJ , Herazo-Maya JD , et al \nBlockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity . Am J Respir Crit Care Med \n190 : 560 -571 , 2014 .25073001 \n21. Miyazaki E , Ando M , Fukami T , et al \nMinocycline for the treatment of sarcoidosis: is the mechanism of action immunomodulating or antimicrobial effect? \nClin Rheumatol \n27 : 1195 -1197 , 2008 .18458989 \n22. Takemori N , Nakamura M , Kojima M , et al \nSuccessful treatment in a case of Propionibacterium acnes-associated sarcoidosis with clarithromycin administration: a case report . J Med Case Rept \n8 : 15 , 2014 .\n23. Bachelez H , Senet P , Cadranel J , et al \nThe use of tetracyclines for the treatment of sarcoidosis . Arch Dermatol \n137 : 69 -73 , 2001 .11176663 \n24. Eishi Y \nEtiologic aspect of sarcoidosis as an allergic endogenous infection caused by Propionibacterium acnes . Biomed Res Int (Epub ahead of print).\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(10)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Propionibacterium acnes; TNF-α; etanercept; sarcoidosis",
"medline_ta": "Intern Med",
"mesh_terms": "D018927:Anti-Asthmatic Agents; D001172:Arthritis, Rheumatoid; D000068800:Etanercept; D005260:Female; D006099:Granuloma; D006801:Humans; D008198:Lymph Nodes; D008297:Male; D008482:Mediastinum; D008875:Middle Aged; D011425:Propionibacterium acnes; D012507:Sarcoidosis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1473-1477",
"pmc": null,
"pmid": "30626837",
"pubdate": "2019-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10408488;10560120;11176663;11773116;12434425;12853521;1560843;16840744;18458989;19423648;22086995;22596102;23844371;24428939;25073001;27157227;27537723;28031822;29698718;713130;7911491;8228238;8834333;9372680",
"title": "Development of Propionibacterium acnes-associated Sarcoidosis During Etanercept Therapy.",
"title_normalized": "development of propionibacterium acnes associated sarcoidosis during etanercept therapy"
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{
"abstract": "Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking.\n\n\n\nTo provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry.\n\n\n\nSCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record.\n\n\n\nA total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms.\n\n\n\nAllopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months.",
"affiliations": "Drug Safety Monitoring Center, Seoul National University Hospital, Seoul, Korea.;Department of Immunology and Rheumatology, Nepean Hospital, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.;Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.;Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.;Department of Internal Medicine, College of Medicine, Dong-A University, Busan, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Department of Internal Medicine, Ajou University School of Medicine, Suwon, Korea.;Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea.;Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea.;Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea.;Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea.;Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Korea.;Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea.;Department of Internal Medicine, Chosun University Hospital, Gwangju, Korea.;Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea.;Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea.;Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea.;Department of Pharmacology, Catholic University of Korea, College of Medicine, Seoul, Korea.;Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea.;Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea.;Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.;Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea.;Department of Internal Medicine, Medical school of Yeungnam University, Daegu, Korea.;Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea.;Department of Internal Medicine, Jeju National University Hospital, Jeju, Korea.;Department of Internal Medicine, Catholic Kwandong University College of Medicine, Incheon, Korea.;Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea.;Department of Dermatology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea.;Drug Safety Monitoring Center, Seoul National University Hospital, Seoul, Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. Electronic address: helenmed@snu.ac.kr.",
"authors": "Kang|Dong Yoon|DY|;Yun|James|J|;Lee|Suh-Young|SY|;Koh|Young-Il|YI|;Sim|Da Woon|DW|;Kim|Sujeong|S|;Nam|Young Hee|YH|;Park|Jung-Won|JW|;Kim|Sae Hoon|SH|;Ye|Young-Min|YM|;Park|Hye-Kyung|HK|;Kim|Min-Hye|MH|;Jee|Young-Koo|YK|;Jung|Jae-Woo|JW|;Yang|Min-Suk|MS|;Kim|Sang-Heon|SH|;Lee|Jun Kyu|JK|;Kim|Cheol-Woo|CW|;Hur|Gyu Young|GY|;Kim|Mi-Yeong|MY|;Park|Seoung Ju|SJ|;Kwon|Yong Eun|YE|;Choi|Jeong-Hee|JH|;Kim|Joo-Hee|JH|;Kim|Sang Hyon|SH|;La|Hyen O|HO|;Kang|Min-Gyu|MG|;Park|Chan Sun|CS|;Lee|Sang Min|SM|;Jeong|Yi Yeong|YY|;Kim|Hee-Kyoo|HK|;Jin|Hyun Jung|HJ|;Jeong|Jae-Won|JW|;Lee|Jaechun|J|;Lee|Yong Won|YW|;Lee|Seung Eun|SE|;Kim|Myoung Shin|MS|;Kang|Hye-Ryun|HR|;|||",
"chemical_list": "D002220:Carbamazepine; D000493:Allopurinol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2020.09.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "9(2)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Drug hypersensitivity syndrome; Drug-related side effects and adverse reactions; Registries; Republic of Korea; Stevens-Johnson syndrome",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000493:Allopurinol; D002220:Carbamazepine; D006801:Humans; D012042:Registries; D056910:Republic of Korea; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "929-936.e7",
"pmc": null,
"pmid": "32961314",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Nationwide Study of Severe Cutaneous Adverse Reactions Based on the Multicenter Registry in Korea.",
"title_normalized": "a nationwide study of severe cutaneous adverse reactions based on the multicenter registry in korea"
} | [
{
"companynumb": "KR-JNJFOC-20201036562",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": "3",... |
{
"abstract": "Canagliflozin (Invokana) is an innovative treatment for type 2 diabetes mellitus (DM) approved in a new class acknowledged as sodium-glucose co-transporter 2 inhibitors. Acute pancreatitis is a very rare side effect with an incidence <1%. a 50-year-old white male with DM type 2 presented to the emergency department with acute onset of abdominal pain after 4 days treatment with canagliflozin. He was successfully diagnosed with diabetic ketoacidosis induced by acute pancreatitis. Canagliflozin was discontinued. His diabetic ketoacidosis was improved after aggressive intravenous fluid along with intravenous insulin infusion. Our case demonstrates very rare but serious side effect, acute pancreatitis in the use of canagliflozin. As the utility of canagliflozin expands, physicians must be aware of this potentially fatal adverse effect. More specific details on potential candidates for this novel therapy are urgently needed.",
"affiliations": "Department of Pulmonary and Critical Care, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Mayo Clinic, Rochester, MN, USA.",
"authors": "Srivali|Narat|N|;Thongprayoon|Charat|C|;Cheungpasitporn|Wisit|W|;Ungprasert|Patompong|P|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0976-0105.160753",
"fulltext": "\n==== Front\nJ Basic Clin PharmJ Basic Clin PharmJBCPJournal of Basic and Clinical Pharmacy0976-01050976-0113Medknow Publications & Media Pvt Ltd India JBCP-6-10110.4103/0976-0105.160753Case ReportAcute pancreatitis in the use of canagliflozin: A rare side-effect of the novel therapy for type 2 diabetes mellitus Srivali Narat Thongprayoon Charat 1Cheungpasitporn Wisit 1Ungprasert Patompong 1Department of Pulmonary and Critical Care, Mayo Clinic, Rochester, MN, USA1 Department of Medicine, Mayo Clinic, Rochester, MN, USAAddress for correspondence: Dr. Wisit Cheungpasitporn, 200 First Street SW, Mayo Clinic, Rochester, MN 55905, USA. E-mail: cheungpasitporn.wisit@mayo.edu6 2015 June 2015-August 20156 3 101 102 Copyright: © Journal of Basic and Clinical Pharmacy2015This 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.Canagliflozin (Invokana) is an innovative treatment for type 2 diabetes mellitus (DM) approved in a new class acknowledged as sodium-glucose co-transporter 2 inhibitors. Acute pancreatitis is a very rare side effect with an incidence <1%. a 50-year-old white male with DM type 2 presented to the emergency department with acute onset of abdominal pain after 4 days treatment with canagliflozin. He was successfully diagnosed with diabetic ketoacidosis induced by acute pancreatitis. Canagliflozin was discontinued. His diabetic ketoacidosis was improved after aggressive intravenous fluid along with intravenous insulin infusion. Our case demonstrates very rare but serious side effect, acute pancreatitis in the use of canagliflozin. As the utility of canagliflozin expands, physicians must be aware of this potentially fatal adverse effect. More specific details on potential candidates for this novel therapy are urgently needed.\n\nCanagliflozindiabetes ketoacidosisdiabetes mellituspancreatitis\n==== Body\nIntroduction\nCanagliflozin (Invokana) is a novel therapy for type 2 diabetes mellitus (DM) approved in a new class acknowledged as sodium-glucose co-transporter 2 (SGLT2) inhibitors. Canagliflozin inhibits the glucose reabsorption by the kidney, increasing glucose elimination and reducing blood glucose levels in diabetic patients.[12] Acute pancreatitis is a very rare but severe side effect with an incidence <1%.[2] We report a case of a 50-year-old man who received a few doses of canaglifozin and developed pancreatitis-induced diabetic ketoacidosis requiring hospitalization in the intensive care unit.\n\nCase Report\nA 50-year-old white man presented to the emergency department with malaise, weakness, abdominal pain, and loss of vision that progressively worsened over 3 days. He has a history of a long-standing well-controlled type 2 DM treated with insulin, glyburide, and metformin. 4 days before admission his endocrinologist stopped his Lantus (insulin glargine) and prescribed him on canagliflozin 100 mg oral daily along with glyburide and metformin. After 10 days of treatment, he developed malaise, weakness, abdominal pain that progressively worsened. On the day of the presentation, he developed blurry vision.\n\nPhysical examination in the emergency department was remarkable for dry lip and epigastric tenderness. Blood test showed blood glucose of 506 mg/dL; sodium of 125, potassium 6.8, chloride of 94, total carbon dioxide <5 and anion gap of 26 mEq/L; creatinine 2.0 mg/dL, trop I was negative; amylase 643, lipase 982 U/L, aspartate aminotransferase 18 U/L; total bilirubin 0.9 mg/dL; atrial blood gas pH 6.85, partial pressure of carbon dioxide 11 mmHg, partial pressure of oxygen 149 mmHg, bicarbonate 1.9 mmol/L, and electrocardiogram showed normal sinus rhythm but no ST-T change. He was diagnosed diabetic ketoacidosis induced by acute pancreatitis along with acute kidney injury from dehydration. Computed tomography of abdomen demonstrated the evidence of acute inflammation of pancreas. Abdominal ultrasound revealed no gallstones or bile duct dilatation. The patient denied any history of recent alcohol use and his serum triglyceride level was normal at 95 mg/dL (normal range, <150 mg/dL). Therefore, canagliflozin was likely the cause of acute pancreatitis in this case. The patient was treated with aggressive intravenous fluid along with intravenous insulin infusion. His serum creatinine, sodium, potassium, lipase, and amylase level returned to normal after 3 days, and we could stop insulin infusion after the anion gap returned to the normal range. His visions returned to baseline after his blood glucose was well controlled. Canagliflozin was completely discontinued and subcutaneous glargine insulin was restarted. The patient continues to do well at 2-month follow-up visit without any recurrent symptoms.\n\nDiscussion\nCanagliflozin is one of SGLT2 inhibitors and has been approved by the Food and Drug Administration for type 2 DM by inhibiting SGLT2 in the proximal renal tubules. Canagliflozin reduces the reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations. Its safety and effectiveness were assessed in nine clinical trials involving over 10,285 patients with type 2 DM. The trials demonstrated improvement in fasting plasma glucose and glycosylated hemoglobin levels.[1]\n\nThe most common adverse effects described in the clinical trials were genital yeast infections, urinary tract infections, and increased urination.[2] Anaphylaxis[3], acute respiratory distress syndrome[4], or significant electrolyte abnormalities[5] have not been demonstrated in the literature review. An ongoing trial, CANagliflozin cardioVascular Assessment Study,[6] will provide us more information on risks of malignancies, serious cases of pancreatitis, and other adverse events.\n\nIn summary, our case demonstrates very rare but serious side-effect, acute pancreatitis in the use of canagliflozin. As the utility of canagliflozin expands, physicians must be aware of this potentially fatal adverse effect. More specific details on potential candidates for this novel therapy are urgently needed.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Plosker GL Canagliflozin: A review of its use in patients with type 2 diabetes mellitus Drugs 2014 74 807 24 24831734 \n2 Vouyiouklis M Canagliflozin: Improving diabetes by making urine sweet Cleve Clin J Med 2013 80 683 7 24186885 \n3 Techapornroong M Akrawinthawong K Cheungpasitporn W Ruxrungtham K Anaphylaxis: A ten years inpatient retrospective study Asian Pac J Allergy Immunol 2010 28 262 9 21337910 \n4 Srivali N Cheungpasitporn W Chongnarungsin D Edmonds LC White willow bark induced acute respiratory distress syndrome N Am J Med Sci 2013 5 330 23814765 \n5 Ungprasert P Cheungpasitporn W Srivali N Kittanamongkolchai W Bischof EF Life-threatening hypocalcemia associated with denosumab in a patient with moderate renal insufficiency Am J Emerg Med 2013 31 756 e1 2 23399342 \n6 Neal B Perkovic V de Zeeuw D Mahaffey KW Fulcher G Stein P Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS) – A randomized placebo-controlled trial Am Heart J 2013 166 217 23.e11 23895803\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-0113",
"issue": "6(3)",
"journal": "Journal of basic and clinical pharmacy",
"keywords": "Canagliflozin; diabetes ketoacidosis; diabetes mellitus; pancreatitis",
"medline_ta": "J Basic Clin Pharm",
"mesh_terms": null,
"nlm_unique_id": "101599515",
"other_id": null,
"pages": "101-2",
"pmc": null,
"pmid": "26229348",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports",
"references": "23895803;23814765;23399342;24831734;21337910;24186885",
"title": "Acute pancreatitis in the use of canagliflozin: A rare side-effect of the novel therapy for type 2 diabetes mellitus.",
"title_normalized": "acute pancreatitis in the use of canagliflozin a rare side effect of the novel therapy for type 2 diabetes mellitus"
} | [
{
"companynumb": "US-JNJFOC-20150810785",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INSULIN GLARGINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo test the current U.S. Food and Drug Administration (FDA) bioequivalence standard in a comparison of generic and brand-name drug pharmacokinetic (PK) performance in \"generic-brittle\" patients with epilepsy under clinical use conditions.\n\n\nMETHODS\nThis randomized, double-blind, multiple-dose, steady-state, fully replicated bioequivalence study compared generic lamotrigine to brand-name Lamictal in \"generic-brittle\" patients with epilepsy (n = 34) who were already taking lamotrigine. Patients were repeatedly switched between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at the end of each 2-week treatment period yielded two 12-h PK profiles for brand-name and generic forms for each patient. Steady-state area under the curve (AUC), peak plasma concentration (Cmax ), and minimum plasma concentration (Cmin ) data were subjected to conventional average bioequivalence (ABE) analysis, reference-scaled ABE analysis, and within-subject variability (WSV) comparisons. In addition, generic-versus-brand comparisons in individual patients were performed. Secondary clinical outcomes included seizure frequency and adverse events.\n\n\nRESULTS\nGeneric demonstrated bioequivalence to brand. The 90% confidence intervals of the mean for steady-state AUC, Cmax , and Cmin for generic-versus-brand were 97.2-101.6%, 98.8-104.5%, and 93.4-101.0%, respectively. The WSV of generic and brand were also similar. Individual patient PK ratios for generic-versus-brand were similar but not identical, in part because brand-versus-brand profiles were not identical, even though subjects were rechallenged with the same product. Few subjects had seizure exacerbations or tolerability issues with product switching. One subject, however, reported 267 focal motor seizures, primarily on generic, although his brand and generic PK profiles were practically identical.\n\n\nCONCLUSIONS\nSome neurologists question whether bioequivalence in healthy volunteers ensures therapeutic equivalence of brand and generic antiepileptic drugs in patients with epilepsy, who may be at increased risk for problems with brand-to-generic switching. Bioequivalence results in \"generic-brittle\" patients with epilepsy under clinical conditions support the soundness of the FDA bioequivalence standards. Adverse events on generic were not related to the small, allowable PK differences between generic and brand.",
"affiliations": "Department of Neurology, University of Maryland, Baltimore, Maryland, U.S.A.;Food and Drug Administration, White Oak, Maryland, U.S.A.;Food and Drug Administration, White Oak, Maryland, U.S.A.;Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, U.S.A.;Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, U.S.A.;Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, U.S.A.;Department of Neurology, University of Maryland, Baltimore, Maryland, U.S.A.;Food and Drug Administration, White Oak, Maryland, U.S.A.;Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, U.S.A.",
"authors": "Ting|Tricia Y|TY|;Jiang|Wenlei|W|;Lionberger|Robert|R|;Wong|Jessica|J|;Jones|Jace W|JW|;Kane|Maureen A|MA|;Krumholz|Allan|A|;Temple|Robert|R|;Polli|James E|JE|",
"chemical_list": "D000927:Anticonvulsants; D016568:Drugs, Generic; D004364:Pharmaceutical Preparations; D014227:Triazines; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.13095",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "56(9)",
"journal": "Epilepsia",
"keywords": "Bioequivalence; Generic-brittle; Lamotrigine; Narrow therapeutic index; Switchability",
"medline_ta": "Epilepsia",
"mesh_terms": "D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016568:Drugs, Generic; D004827:Epilepsy; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D014227:Triazines; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1415-24",
"pmc": null,
"pmid": "26201987",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard.",
"title_normalized": "generic lamotrigine versus brand name lamictal bioequivalence in patients with epilepsy a field test of the fda bioequivalence standard"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS INC, USA.-2015GMK021696",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"dr... |
{
"abstract": "Mutations in Dedicator of cytokinesis 8 (DOCK8) are a rare cause of combined immunodeficiency associated with atopy, infectious susceptibility, and risk for malignancy. We describe a 22-year-old male with a diagnosis of B cell lymphoblastic leukemia followed by Epstein-Barr virus (EBV)-associated diffuse large B cell lymphoma (DLBCL) with compound heterozygous mutations in DOCK8 and normal intracellular DOCK8 protein expression. Here, B cell lymphoblastic leukemia followed by EBV-associated DLBCL led to the discovery of DOCK8 deficiency. For instances of high clinical suspicion despite normal DOCK8 protein expression, additional functional testing is critical to make a diagnosis. Understanding the spectrum of DOCK8 mutants and their phenotypes will improve our understanding of DOCK8 deficiency.",
"affiliations": "Department of Hematology, Children's Hospital of Orange County, 1201 W. La Veta Avenue, Orange, CA, 92868, USA. dbuchbinder@choc.org.;Department of Pediatrics, University of California at Irvine, Orange, CA, USA.;Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.;Pediatric Oncology Branch, NCI, NIH, Bethesda, MD, USA.;Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.;Department of Pediatrics, University of California at Irvine, Orange, CA, USA.;Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.",
"authors": "Buchbinder|David|D|0000-0002-9470-3473;Kirov|Ivan|I|;Danielson|Jeffrey|J|;Shah|Nirali N|NN|;Freeman|Alexandra F|AF|;Chavan|Rishikesh S|RS|;Su|Helen C|HC|",
"chemical_list": "C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10875-019-00663-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-9142",
"issue": "39(6)",
"journal": "Journal of clinical immunology",
"keywords": "B cell lymphoblastic leukemia; combined immunodeficiency; dedicator of cytokinesis 8; diffuse large B cell lymphoma",
"medline_ta": "J Clin Immunol",
"mesh_terms": "D000483:Alleles; D020031:Epstein-Barr Virus Infections; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors; D004854:Herpesvirus 4, Human; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009154:Mutation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D055815:Young Adult",
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "592-595",
"pmc": null,
"pmid": "31267431",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "19776401;21969276;23380217;24698323;24797421;25422492;25627830;25724123;27207373;28288951;30391550;30565250",
"title": "Compound Heterozygous DOCK8 Mutations in a Patient with B Lymphoblastic Leukemia and EBV-Associated Diffuse Large B Cell Lymphoma.",
"title_normalized": "compound heterozygous dock8 mutations in a patient with b lymphoblastic leukemia and ebv associated diffuse large b cell lymphoma"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US06383",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "Systemic chemotherapy based on 5-fluorouracil (5-FU) is a standard treatment for unresectable or recurrent large intestinal cancer. Although hyperammonemia is a known side effect of 5-FU that can cause serious pathological conditions, only a few cases have been reported. We describe 4 cases of 5-FU-related hyperammonemia with impairment of consciousness in patients who received 5-FU chemotherapy for large intestinal cancer with multiple liver metastases. Hemodialysis was effective in 1 severe case. There have been no detailed reports on the use of hemodialysis for hyperammonemia caused by 5-FU. Renal dysfunction is considered to be a risk factor for hyperammonemia caused by 5-FU and it is necessary to pay particular attention in patients with renal dysfunction who receive chemotherapy with 5-FU. Here we summarize our cases together with 16 previously reported cases of hyperammonemia caused by 5-FU in Japan.",
"affiliations": "Department of Gastroenterology, Muroran City General Hospital.",
"authors": "Iida|Tomoya|T|;Wagatsuma|Kohei|K|;Tani|Motohiro|M|;Sasaki|Hajime|H|;Naganawa|Yumiko|Y|;Isshiki|Hiroyuki|H|;Murakami|Kayo|K|;Satoh|Shuji|S|;Shimizu|Haruo|H|;Kaneto|Hiroyuki|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.112.287",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "112(2)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D006801:Humans; D022124:Hyperammonemia; D007414:Intestinal Neoplasms; D007420:Intestine, Large; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "287-96",
"pmc": null,
"pmid": "25748155",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Four cases of 5-fluorouracil-related hyperammonemia in patients with large intestinal cancer and multiple liver metastases, including a case of hyperammonemia treated using hemodialysis.",
"title_normalized": "four cases of 5 fluorouracil related hyperammonemia in patients with large intestinal cancer and multiple liver metastases including a case of hyperammonemia treated using hemodialysis"
} | [
{
"companynumb": "JP-ACCORD-029607",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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"abstract": "BACKGROUND Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production leading to inflammation in multiple organs; it commonly affects young women in their child-bearing years. Clinical manifestations are diverse and range from mild arthritis to diffuse alveolar hemorrhage (DAH). DAH is a rare and devastating complication of SLE that carries a mortality rate of up to 50%, despite aggressive therapy. CASE REPORT A 21-year-old primigravida at 16 weeks gestation presents with a productive cough, rash, sore throat, and high-grade fever. Chest x-ray suggested multifocal pneumonia. Patient deteriorated despite antibiotics and intravenous (IV) fluids. She developed worsening anemia, leukopenia, and thrombocytopenia. Autoimmune workup was positive for Coombs, antinuclear antibody, anti-smith antibody, and hypocomplementemia. Skin biopsy was consistent with SLE. SLE vasculitis was suspected. She required mechanical intubation for rapid respiratory deterioration, with CT thorax suggesting ARDS. Bronchoscopy was done and confirmed DAH. Her course was further complicated with retinopathy and acute pancreatitis associated with SLE. She was treated with IV steroids, IV cyclophosphamide, and plasmapheresis, with significant clinical improvement and successful extubation. She delivered a healthy baby at 32 weeks gestation. CONCLUSIONS Early recognition and initiation of treatment is critical to survival in DAH and requires a high index of clinical suspicion. Treatment includes high-dose steroids, cyclophosphamide, and plasma exchange. Pregnancy increases the risk of adverse outcome in SLE. Seven cases of DAH in pregnant patients with SLE have been reported. Here, we report a catastrophic presentation of DAH, acute pancreatitis, and retinopathy in a pregnant patient with newly diagnosed SLE.",
"affiliations": "Department of Internal Medicine, Detroit Medical Center Sinai-Grace Hospital/Wayne State University, Detroit, MI, USA.;Department of Rheumatology, Henry Ford Hospital/Wayne State University, Detroit, MI, USA.;Department of Rheumatology, Henry Ford Hospital/Wayne State University, Detroit, MI, USA.;Department of Rheumatology, Henry Ford Hospital/Wayne State University, Detroit, MI, USA.",
"authors": "Yousif|Patrick A|PA|;Moshrefi|Hameadreza|H|;Meysami|Alireza|A|;Alkhatib|Ayad H|AH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.921299",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32284523\n10.12659/AJCR.921299\n921299\nArticles\nLupus-Induced Vasculitis and Multiple Organ Dysfunction Syndrome as the First Presentation of Systemic Lupus Erythematosus (SLE) in Pregnancy\nYousif Patrick A. ABCDEF1 Moshrefi Hameadreza ABCDEF2 Meysami Alireza CDG2 Alkhatib Ayad H. DG2 \n1 Department of Internal Medicine, Detroit Medical Center Sinai-Grace Hospital/Wayne State University, Detroit, MI, U.S.A.\n\n2 Department of Rheumatology, Henry Ford Hospital/Wayne State University, Detroit, MI, U.S.A.\nCorresponding Author: Patrick A. Yousif, e-mail: patrickyousif89@gmail.comAuthors’ 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\nSource of support: Department of Rheumatology at Henry Ford Hospital in Detroit, MI, U.S.A.\n\nConflict of interest: None declared\n\n\n2020 \n14 4 2020 \n21 e921299-1 e921299-7\n10 11 2019 06 2 2020 29 2 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 21-year-old\n\nFinal Diagnosis: Diffuse alveolar hemorrhage\n\nSymptoms: Cough • dyspnea • fever • rash • sore throat Medication: —\n\nClinical Procedure: —\n\nSpecialty: Rheumatology\n\nObjective:\nRare disease Background:\n\nSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production leading to inflammation in multiple organs; it commonly affects young women in their child-bearing years. Clinical manifestations are diverse and range from mild arthritis to diffuse alveolar hemorrhage (DAH). DAH is a rare and devastating complication of SLE that carries a mortality rate of up to 50%, despite aggressive therapy.\n\nCase Report:\nA 21-year-old primigravida at 16 weeks gestation presents with a productive cough, rash, sore throat, and high-grade fever. Chest x-ray suggested multifocal pneumonia. Patient deteriorated despite antibiotics and intravenous (IV) fluids. She developed worsening anemia, leukopenia, and thrombocytopenia. Autoimmune work-up was positive for Coombs, antinuclear antibody, anti-smith antibody, and hypocomplementemia. Skin biopsy was consistent with SLE. SLE vasculitis was suspected. She required mechanical intubation for rapid respiratory deterioration, with CT thorax suggesting ARDS. Bronchoscopy was done and confirmed DAH. Her course was further complicated with retinopathy and acute pancreatitis associated with SLE. She was treated with IV steroids, IV cyclophosphamide, and plasmapheresis, with significant clinical improvement and successful extubation. She delivered a healthy baby at 32 weeks gestation.\n\nConclusions:\nEarly recognition and initiation of treatment is critical to survival in DAH and requires a high index of clinical suspicion. Treatment includes high-dose steroids, cyclophosphamide, and plasma exchange. Pregnancy increases the risk of adverse outcome in SLE. Seven cases of DAH in pregnant patients with SLE have been reported. Here, we report a catastrophic presentation of DAH, acute pancreatitis, and retinopathy in a pregnant patient with newly diagnosed SLE.\n\nMeSH Keywords:\nHemorrhageLupus Erythematosus, SystemicPregnancy\n==== Body\nBackground\nSystemic lupus erythematosus (SLE) is an autoimmune disease that can affect virtually any organ in the body. It is most common in African-American and Hispanic women of child-bearing age. Untreated SLE in pregnancy has been related to more adverse outcomes [1,2]. In addition, uncontrolled SLE in pregnancy can be associated with exacerbations requiring immunosuppressive therapy [3], due to hormonal changes involving estradiol, progesterone, and prolactin, leading to a pro-inflammatory state [2]. There is also a higher morbidity and mortality in SLE patients with lower socioeconomic status. Non-white patients have a higher incidence of SLE, worse outcomes, and lower survival rates [2]. Previous epidemiologic studies have shown that African Americans are especially susceptible. Other ethnicities (e.g., Hispanics) are now being recognized as being at higher risk in the United States [2]. Diffuse alveolar hemorrhage (DAH) is a life-threating complication of SLE and presents with hypoxemia, dyspnea, and a cough with blood-tinged expectoration. Mortality is high at 50%. The most common histopathological diagnosis is pulmonary capillaritis [4]. DAH as a manifestation of lupus is only seen in 1–5% of cases [4]. There have been only 7 cases reported of DAH in pregnancy. We report a case of a young, primigravida female at 16 weeks gestation who presented with cough, rash, sore throat, fever, chills, and dyspnea. CT thorax suggested multifocal pneumonia, and bronchoscopy confirmed DAH. She was also found to have acute pancreatitis and retinopathy associated with SLE during her hospitalization. SLE-associated acute pancreatitis and retinopathy are seen in 0.7–4% and 3–29%, respectively [5,6]. Retinopathy lead to serious visual deficits in up to 29% of patients with active disease [6]. A PubMed search using the key words “DAH,” “SLE,” “acute pancreatitis,” “retinopathy”, and “pregnancy,” dating from 1990–2019 was performed.\n\nCase Report\nA 21-year-old previously healthy primigravida at 16 weeks of gestation with a past medical history of asthma, depression, and anxiety presented to an outside hospital (OSH), and had initially presented at an urgent care clinic for suspected streptococcal pharyngitis. There were no reported sick contacts and she was discharged on oral Amoxicillin 500 mg 2 times daily for 10 days, which she completed, but with no improvement. Two weeks after going to the urgent care clinic, she presented to the emergency department (ED) with fever and sore throat and was discharged home in stable condition. One week later, she broke out in a rash over her hands, feet, and mouth and presented to an OSH ED with worsening symptoms of fever 104°F (40°C), body aches, dry cough and rash. Her only medication was a prenatal vitamin supplement. Her initial vital signs at the OSH ED were temperature 103.8°F (39.8°C), blood pressure 109/57 mmHg, pulse 114 beats per minute, respiratory rate 18 breaths per minute, and 98% oxygen saturation on room air. A physical exam was remarkable for erythematous, slightly indurated plaques with overlying subtle scaling on the glabella, malar cheeks, nasal bridge, and temples, sparing the nasolabial folds and upper chest. Her fingers and palms had scattered vesicles, with some containing hemorrhagic fluid. She was also found to have multiple ulcers in the hard palate. Heart, lung, abdominal, and musculoskeletal exams were unremarkable. Her labs were notable for lactate 2.6, white blood cell count (WBC) 3.3 k/ul, hemoglobin (Hb) 8.3 g/dl, and platelets 157 k/ul. The patient’s peripheral blood smear revealed occasional spherocytes. Her chest x-ray (CXR) on admission was unremarkable and she was given intravenous fluids and IV antibiotics for suspected sepsis.\n\nInitial infectious workup included negative serial blood cultures for 5 days, negative group A streptococci throat culture, and negative nasopharyngeal MRSA culture. The patient met 3/4 Systemic Inflammatory Response Syndrome criteria and remained tachycardic with heart rate of 120s beats per minute, tachypneic with RR of 30 breaths per minute, and T max of 102.8°F (39.3°C) on day 2 of admission, and she was transferred to our facility for escalation of care and bronchoscopy to rule out atypical infection. The patient remained febrile, tachycardic, and borderline hypotensive with systolic blood pressures in the 90–100s mmHg on days 3 and 4. She was started on high-flow nasal cannula for hypoxia. Her antibiotic regimen included intravenous (IV) azithromycin 500 mg daily (7 days total), IV cefepime (2 g every 8 h for 8 days), and IV vancomycin (750 every 8 h for 2 days, increased to 1250 mg every 8 h for 2 days). She was also treated with oral acyclovir 800 mg 5 times daily for 1 day, which was switched to IV acyclovir at 5 mg/kg (230 mg) every 8 h for 1 day. She had persistent fevers with tachycardia and tachypnea on days 2 to 4. She became acutely dyspneic and hypoxic to 88% oxygen saturation on room air on day 4 of admission, with repeat CXR suggesting bilateral pleural effusions with a differential diagnosis of multifocal pneumonia or pulmonary edema (Figure 1). The patient was suspected to have a complicated pneumonia and was treated with antibiotics (see above) and IV fluids. Despite management in the intensive care unit (ICU), her symptoms persisted. CT chest with contrast (Figures 2–4) showed bilateral airspace disease due to multifocal pneumonia versus infectious/inflammatory etiology.\n\nAntibiotics were continued, but an extensive infectious work-up was negative. Further infectious workup included negative Toxoplasmosis gondii PCR and Borrelia burgdorferi IgG/IgM antibody. Acid-fast bacilli cultures were negative. HIV antigen/antibody combo (fourth-generation) was negative. Her respiratory status deteriorated, requiring emergent endotracheal intubation and mechanical ventilation on day 4 of admission.\n\nHer hemoglobin decreased from 7.9 g/dL to 5.7 g/dL on day 4 of admission, with worsening leukopenia 2.6 K/dL, thrombocytopenia 119 000 K/dL, and lymphopenia. Her peripheral smear was negative for signs of hemolysis. The patient had an immunological workup summarized in Table 1. The patient had a positive Coombs test, lactate dehydrogenase (LDH) that ranged from 415 to 789 IU/L (elevated), and haptoglobin at 109 (normal). Antinuclear antibody (ANA) was positive 1: 640 speckled pattern, anti-RNP 113, anti-Smith 103, complement C3 (26), and complement C4 (<8). Negative autoimmune serologies include anti-double-stranded DNA, anti-SSA/Ro, anti-SSB/La, and antiphospholipid antibodies. A skin biopsy was taken from the patient’s lesions and showed interface dermatitis, vacuo-lar with atrophic epidermis, consistent with cutaneous lupus. There were also subtle foci of vascular damage, which raised the possibility of superimposed leukocytoclastic vasculitis. Bronchoalveolar lavage (BAL) confirmed suspicion of alveolar hemorrhage. BAL respiratory culture with gram stain grew 3000 colony-forming unit per mL of Candida albicans, which was also seen on fungal culture. Respiratory viral and bacterial panel were negative and included adenovirus PCR, coronavirus (KKU1, NL63, 2298, OC43) PCR, metapneumovirus PCR, rhino-virus/enterovirus PCR, influenza A (A/H1, A/H3, A/H1-2009) PCR, influenza B PCR, parainfluenza virus 1–4 PCR, RSV PCR, Chlamydophila pneumoniae PCR, and Mycoplasma pneumoniae PCR. Serum herpes simplex types 1 and 2 was not detected.\n\nParvovirus IgM was negative, and IgG was elevated at 0.97 (index). Tuberculosis QuantiFERON gold was negative. Tracheal aspirate acid-fast bacilli were negative times 4. Her estimated proteinuria was 1.83 g/24 h. Her urine sediment did not show dysmorphic cells or red blood cell casts, therefore, due to low suspicion for lupus nephritis, the patient did not have a kidney biopsy. Treatment was initiated with IV methylprednisolone 1 g for 5 days and plasmapheresis for 6 treatments, and she was continued on IV methylprednisolone 1 mg/kg.\n\nDue to patient’s grave clinical status, a multi-specialty collaboration was performed, with shared decision-making with Rheumatology, Maternal Fetal Medicine, Transfusion Medicine, and Critical Care specialists. Due to the patient being intubated, a discussion with the patient’s mother to keep her pregnancy viable and initiation of treatment with cyclophosphamide was consented to after risks and benefits were reviewed.\n\nPrior to treatment with her first dose of cyclophosphamide, the patient developed high fever, hypotension, and tachycardia on high-dose methylprednisolone. Blood cultures showed candidemia, which was treated with intravenous IV fluconazole. Ophthalmology evaluation was negative for viritis, but suggestive of bilateral cotton wool spots favoring retinopathy secondary to SLE. The patient was extubated and received cyclophosphamide IV 500 mg for initial dose, and 1 month later she received 840 mg (500 mg/m2) on the day of discharge. On day 9 of admission, her course was further complicated with acute abdominal pain with lipase 1688, amylase 560, alkaline phosphatase 55 IU/L, total protein 5.2 g/dL, total bilirubin 1.0 md/dL, and albumin 2.6 g/dL. CT chest, abdomen, pelvis without IV contrast was performed to rule out mesenteric ischemia and peritonitis, and confirmed suspicion of acute pancreatitis. The patient was treated with cyclophosphamide prior to developing acute pancreatitis. Rheumatology and General Surgery believed the cause of acute pancreatitis to be due to high disease activity of SLE versus cyclophosphamide. However, drug-induced pancreatitis with cyclophosphamide was considered. The patient was discharged on hydroxychloroquine 200 mg twice daily and a prednisone taper with initial dose of 70 mg daily for 2 weeks, 60 mg daily for 1 month, 50 mg daily for 2 weeks, and 40 mg for 2 weeks prior to delivery. Of note, C-reactive protein level was not assessed during hospitalization due to initial presumed infection. The level was assessed at 1-month follow-up, and was <0.5 mg/dL (negative).\n\nAt 32 weeks gestation, the patient was found to have preterm premature rupture of membranes, which led to spontaneous labor. She was given magnesium sulfate for neuroprotection. She was also continued on outpatient oral prednisone 40 mg daily. The patient successfully delivered a healthy baby at 32 weeks gestation by vaginal delivery.\n\nDiscussion\nSLE is an autoimmune disorder that primarily affects women of child-bearing age. Severe complications of SLE can include lupus nephritis and DAH. Acute pancreatitis is a rare manifestation of SLE, and other causes should be ruled out prior to making the association. SLE during pregnancy is more likely to cause a flare in an untreated primigravida woman. DAH is a rare and rapidly fatal association with SLE. The estimated mortality rate is 50%. However, recent case series have reported an 80% survival rate. DAH consists of 1.3–3.7% of hospital admissions associated with SLE. It usually presents in patients with a previous history of SLE. It can also present as the initial manifestation of lupus, although this is rare. The most common association with DAH is lupus nephritis, seen in about 70% of cases [7–9].\n\nThe differential diagnosis for DAH is broad and can be rheumatologic, infectious, coagulopathic, and pharmacologic. Rheumatologic causes include SLE, Goodpasture’s syndrome, antiphospholipid syndrome, and vasculitis. In pregnant women who present with hemoptysis, other causes need to be excluded prior to making the diagnosis of DAH [10]. This includes trauma, infection (tuberculosis, bacterial, viral, and fungal), malignancy (bronchogenic carcinoma, choriocarcinoma, or carcinoid), vascular (pulmonary hypertension, arteriovenous malformation, pulmonary embolism), connective tissue diseases (SLE, granulomatosis with polyangiitis, Goodpasture’s syndrome), cardiac (cardiomyopathy, mitral valve stenosis, congenital heart disease), pharmacologic (cocaine, anticoagulants, antiplatelets), and pseudohemoptysis (gastrointestinal bleed or epistaxis) [10]. DAH can be a sepsis-mimicker. However, pregnant patient with SLE are susceptible to pneumonia. This is due to both immune dysregulation form SLE and immunosuppressive therapy [3]. In patients with no hemoptysis, diagnosis of DAH can be difficult, as in our case. [10] DAH presents with hypoxemia, dyspnea, and cough that can be blood-tinged. Hemoptysis can be seen in 44% of cases. Patients can also have fever or chest pain. DAH can be confused with pneumonia or pulmonary edema, as seen in our patient, who was initially treated with antibiotics at an OSH, but due to lack of clinical improvement she was transferred to a tertiary care facility. A CXR typically shows bilateral opacification with no peripheral involvement. CT thorax typically shows ground-glass opacifications. BAL shows increase in the number of hemorrhagic aliquots and hemosiderin macrophages that stain Prussian blue [11]. Biopsy shows diffuse alveolar damage, pulmonary capillaritis, and bland pulmonary hemorrhage [7].\n\nThere is a higher risk of complications in untreated and newly diagnosed patients with SLE during pregnancy [1,3]. However, it is not clear if parity has a higher risk of complications, as the data are controversial [3]. These complications can include preterm labor, pre-eclampsia, emergent C-section, deep vein thrombosis (DVT), infection, intrauterine growth restriction, intrauterine fetal death, and spontaneous miscarriage. There is also a 20-fold higher risk of maternal death [1]. Our patient was found to have preterm labor, likely related to SLE. There should be a multidisciplinary approach in the management of women of child-bearing age with SLE, and they should have a preconception risk assessment and pregnancy management with Maternal Fetal Medicine and Rheumatology. It is recommended that SLE should be controlled at least 6–12 months prior to conception. Managing SLE in pregnancy can be difficult, especially with no previous diagnosis, as seen in our patient. Our patient had a strong family history of SLE in her mother and grandmother, both suffering from their initial manifestation of SLE during their first and only pregnancy, stressing the importance of screening these patients prior to pregnancy [1].\n\nThere are no universal guidelines on management of DAH, including pregnant patients. This is due to lack of reported cases and clinical trials. Treatment is based on expert opinion, results of case series, and data from studies involving DAH associated with other types of vasculitis. High clinical consideration, early initial diagnosis, and aggressive treatment with pulse methylprednisolone in combination with cyclophosphamide are the mainstays of treatment for DAH. It is important to have a discussion with the patient about the teratogenic effects of cyclophosphamide, as this drug can cross the placenta and is also associated with premature ovarian failure [1]. The risk of ovarian failure depends on the cumulative effect of the drug dose and the age of the patient, with older women having a higher risk due to less ovarian reserve [3]. The fetal effects of cyclophosphamide from in utero exposure remain unknown. Cyclophosphamide is currently pregnancy category X [3]. A study on the fetal effects of cyclophosphamide in mice was published in 2014 and showed a 6-fold increase of testicular cancer compared to the control group [12]. In addition, decreased spermatogenesis and ovarian follicle numbers were observed in the intervention group [12]. Rituximab has also been used successfully in several case reports, but is not considered the standard of care. Supportive treatment with mechanical ventilation and blood transfusions should be considered if necessary. Plasmapheresis, which helps removes antigen-antibody complexes from the blood, may be used for refractory cases [1,5]. Whether plasmapheresis improves survival is unknown [1].\n\nThere are only 7 case reports of DAH in pregnancy. Table 2 summarizes each case with the year the case was published, age of gestation, treatment modality, and outcome of the pregnancy. In 4 of the 7 reported cases of DAH complicating SLE in pregnancy, the decision was made to terminate the pregnancy and then administer cyclophosphamide. One patient received azathioprine initially, but with recurrence of DAH, IV cyclophosphamide was used. All 7 patients survived. Patients ages ranged from 23 to 38 years old, and gestation age ranged from 17 weeks to 35 weeks. Patients were diagnosed with SLE 13 years, 10 years, 6 years, and 1 month (2 cases) prior to their presentation of DAH. Two cases were diagnosed with SLE in the antepartum period. The first case involved a 38-year-old at 28 weeks gestation requiring emergent C-section due to fetal bradycardia. She was found to have DAH with hemoptysis seen on endotracheal tube during C-section, with radiologic findings and BAL confirming DAH. She was subsequently diagnosed with SLE with positive immunologic findings, lupus nephritis, antiphospholipid syndrome, lymphocytopenia, and thrombocytopenia [10,13–15].\n\nIn the second case, a 35-year-old patient at 30 weeks gestation was diagnosed with DAH. She was initially diagnosed with SLE at 21 weeks gestation. She was suspected to have DAH at 30 weeks gestation when she presented with dyspnea and hemoptysis. Non-contrast CT thorax showed diffuse ground-glass opacities and nodular consolidation. She was treated with pulse methylprednisolone, with some improvement. She delivered a healthy baby at 31 weeks gestation. After C-section, she had a BAL, which confirmed DAH and she was treated with cyclophosphamide and pulse steroids. Her respiratory status had deteriorated, despite these treatments. She was treated with extracorporeal membrane oxygenation and plasmapheresis a total of 3 times, with successful extubation and improvement in respiratory status. Pregnancy was terminated in 4 out of 6 cases [16].\n\nThese cases raise the question of whether immediate delivery in a viable pregnancy should be done when DAH is diagnosed. There are no current guidelines on delivery of the baby in a pregnant patient with DAH. In addition, the prognosis of DAH with delivery is unknown. In cases of high disease activity from SLE refractory to treatment, delivery should be considered [16]. Further studies are needed to determine treatment guidelines and timing of delivery in pregnant patients with SLE and DAH [16]. Current recommendations include a multidisciplinary approach with multiple specialties and expert opinion, in conjunction with having a thorough discussion with the patient, weighing the risks (e.g., fetal growth restriction and SLE aggravation) and benefits of maternal and fetal outcomes [1,16].\n\nFurthermore, our patient was found to have acute pancreatitis likely associated with SLE. Acute pancreatitis is rare in SLE, seen in only 0.7–4% of cases [5]. It is important to rule out pharmacologic, obstructive, and toxic causes of acute pancreatitis before attributing it to SLE. Etiologies of pancreatitis in lupus can be due to medications used to treat lupus, like azathioprine, cyclosporine, and, rarely, cyclophosphamide [5]. Cyclophosphamide was given prior to our patient developing acute pancreatitis and was a considered etiology. However, the patient’s high disease burden of SLE was believed to be the primary cause of acute pancreatitis. There is 1 reported case of DAH and acute pancreatitis in a young non-pregnant female treated successfully with rituximab and cyclophosphamide [5].\n\nWe presented a catastrophic case of lupus-induced vasculitis with multiple organ dysfunction syndrome with manifestations of retinopathy, DAH, and acute pancreatitis, with a prevalence of less than 5% for each. This patient had unusual serologic results, with no detectable plasma anti-dsDNA antibodies and a high titer of anti-Smith antibodies. It has been universally accepted that anti-dsDNA antibodies are correlated with disease activity in SLE patients, especially with lupus nephritis. However, a recent study demonstrated that anti-dsDNA is correlated with clinical and serologic criteria, with no effect on disease activity [17]. In our patient, it is unclear if these manifestations developed as the initial presentation of SLE or if these complications developed as a result of delayed diagnosis and treatment of SLE.\n\nConclusions\nDAH is a life-threatening disease that has a high mortality rate. Early recognition and prompt treatment are important for survival. Undiagnosed and untreated pregnant patients with SLE are more likely to have complications in pregnancy, especially when diagnosis is delayed, and close monitoring is crucial. This case demonstrated a catastrophic presentation of SLE in a pregnant patient with severe multiple organ dysfunction syndrome involving the pulmonary, hematologic, dermatological, ocular, and gastrointestinal systems. In our case, the patient’s lack of response to antibiotics for sepsis, strong family history of SLE, and diagnostic workup prompted our team to pursue the alternative diagnosis of SLE. The patient’s respiratory failure, decrease in hemoglobin, and chest x-ray with worsening opacities heightened our suspicion of DAH. Our case highlights the importance of using a multi-specialty approach for management of this rapidly fatal condition. After using a collaborative approach, treatment with steroids, plasmapheresis, and cyclophosphamide led to survival of both mother and fetus. Further guidelines are needed for management of pregnant patients with SLE and DAH and timing of delivery.\n\nWe would like to thank the Department of Rheumatology at Henry Ford Hospital in Detroit, Michigan for their support for this manuscript.\n\nConflict of interest\n\nNone.\n\nFigure 1. Chest X-ray showing extensive bilateral pleural effusions (arrows), worse on the left, with a differential diagnosis of pulmonary edema versus multifocal pneumonia.\n\nFigure 2. CT Thorax with contrast (transverse view) at the level of the aortic arch showing consolidative opacity (arrows) in the dependent lung bases with patchy consolidative airspace opacity in the upper lungs, concerning for multifocal pneumonia or other infectious/inflammatory etiology. No pleural effusion is seen.\n\nFigure 3. CT thorax with contrast (transverse view) at the level of heart showing bilateral opacifications (arrows).\n\nFigure 4. CT thorax with contrast (sagittal view) showing bilateral opacification (arrows).\n\nTable 1. Autoimmune workup.\n\nAutoimmune workup\tResults\t\nCoombs test\tPositive\t\nAntinuclear antibodies\tPositive\t\nAntinuclear antibody pattern\t1: 640\t\nAntinuclear antibody titers\tSpeckled\t\nAnti-deoxyribonucleic acid antibody (IU/mL)\tNegative\t\nAnti-SSA\tNegative\t\nAnti-SSB\tNegative\t\nSerum C3 complement (mg/dL)\t26\t\nSerum C4 complement (mg/dL)\t<8\t\nAnti-smith antibody\t103\t\nLupus anticoagulant\tNegative\t\nAnti-cardiolipin antibody\tNegative\t\nAnti-beta-2-glycoprotein\tNegative\t\nTable 2. All cases of DAH in SLE during pregnancy.\n\nAuthor\tYear\tAge, yrs\tGA, wks\tDiagnosis, yrs\tSLE manifestations\tMV\tTermination\tTreatment\tOutcome (mother)\t\nBlitz and Fleischer [1]\t2018\t23\t17 (prima)\t17\tHeme, lupus nephritis, skin\tNo\tYes\tMP, CYC, PLEX\tSurvived\nPregnancy terminated, at 17 wks\t\nNg et. al. [10]\t2017\t38\t32\t38\tSkin, nephritis, hematologic, APS\tYes\tNo\tPrednisone\tSurvived\nSuccessful C-section at 32 wks\t\nGaither et al. [13]\t2005\t22\t23\t12\tNephritis\tNo\tNo\tMP, CYC\tSurvived\nSuccessful C-section at 27 wks\t\nKeane et al. [14]\t1997\t23\t21 (prima)\t12\tSkin, arthritis\tYes\tYes\tMP, AZA, CYC, PLEX\tSurvived\t\nChang et al. [15]\t2002\t26\t29\t26\tDAH, nephritis, arthritis\tYes\tNo\tPO CYC, MP, PLEX, CVVH\tSurvived,\nSuccessful Delivery\t\nChang et al. [15]\t2002\t35\t22\t35\tDAH, APS\tYes\tYes\tMP, PLEX, CVVH, CYC\tSurvived\t\nKim et al. [16]\t2019\t35\t30\t35\tNephritis\tYes\tNo\tMP, CYC, PLEX\tSurvived\nSuccessful C-section at 30 wks\t\nPrima – primigravida; MV – mechanical ventilation; APS – antiphospholipid syndrome; CYC – cyclophosphamide; FLEX – plasmapheresis; PO – by mouth; AZA – azathioprine; CVVH – continuous veno-venous hemofiltration; DAH – diffuse alveolar hemorrhage; wks – weeks; yrs – years; MP – methylprednisolone; SLE – systemic lupus erythematosus; GA – gestational age.\n==== Refs\nReferences:\n1. Blitz MJ Fleischer A Severe maternal morbidity associated with systemic lupus erythematosus flare in the second trimester of pregnancy Case Rep Obstet Gynecol 2018 2018 5803479 29862103 \n2. Mendoza-Pinto C Mendez-Martinez S Soto-Santillan P Socioeconomic status and organ damage in Mexican systemic lupus erythematosus women Lupus 2015 24 11 1227 32 26085596 \n3. de Jesus GR Mendoza-Pinto C de Jesus NR Understanding and managing pregnancy in patients with lupus Autoimmune Dis 2015 2015 943490 26246905 \n4. Bajantri B Sapkota B Venkatram S Diffuse alveolar hemorrhage without extrapulmonary manifestations: A rare presentation of lupus Am J Case Rep 2018 19 218 23 29487279 \n5. Gonzalez-Echavarri C Pernas B Severe multiorganic flare of systemic lupus erythematosus successfully treated with rituximab and cyclophosphamide avoiding high doses of prednisone Lupus 2014 23 3 323 26 24531426 \n6. Bhojwani D Rishi E Majumder PD Systemic lupus erythematosus retinopathy in a 32-year-old female: Report of a case Indian J Ophthalmol 2014 62 9 951 52 25370400 \n7. Morales-Nebreda L Alakija O Systemic lupus erythematosus-associated diffuse alveolar hemorrhage: A case report and review of the literature Clin Pulm Med 2018 25 5 166 69 30220838 \n8. Kwok SK Moon SJ Ju JH Diffuse alveolar hemorrhage in systemic lupus erythematosus: risk factors and clinical outcome: Results from affiliated hospitals of Catholic University of Korea Lupus 2011 20 1 102 7 20956464 \n9. Martinez-Martinez MU Abud-Mendoza C Predictors of mortality in diffuse alveolar haemorrhage associated with systemic lupus erythematosus Lupus 2011 20 6 568 74 21558137 \n10. Ng VV Shah MK Oh TT Massive hemoptysis through endotracheal tube during emergency cesarean delivery: a case report and literature review A A Case Rep 2017 9 5 133 35 28542045 \n11. Tolaymat O Berianu F Systemic lupus erythematosus presenting with alveolar hemorrhage Case Rep Rheumatol 2018 2018 8218904 30305976 \n12. Comish PB Drumond AL Kinnell HL Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice PLoS One 2014 9 4 e93311 24691397 \n13. Gaither K Halstead K Mason TC Pulmonary alveolar hemorrhage in a pregnancy complicated by systemic lupus erythematosus J Natl Med Assoc 2005 97 6 831 33 16035585 \n14. Keane MP Van De Ven CJ Lynch JP 3rd McCune WJ Systemic lupus during pregnancy with refractory alveolar haemorrhage: Recovery following termination of pregnancy Lupus 1997 6 9 730 33 9412989 \n15. Chang MY Fang JT Chen YC Huang CC Diffuse alveolar hemorrhage in systemic lupus erythematosus: A single center retrospective study in Taiwan Ren Fail 2002 24 6 791 802 12472201 \n16. Kim HS Jeon HS Han SJ Antepartum diagnosis and treatment of diffuse alveolar hemorrhage in a pregnant woman with systemic lupus erythematosus Perinatology 2019 30 1 32 35 \n17. Gheita TA Abaza NM Hammam N Anti-dsDNA titre in female systemic lupus erythematosus patients: Relation to disease manifestations, damage and antiphospholipid antibodies Lupus 2018 27 7 1081 87 29460701\n\n",
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"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D005260:Female; D006470:Hemorrhage; D006801:Humans; D008171:Lung Diseases; D008180:Lupus Erythematosus, Systemic; D009102:Multiple Organ Failure; D011247:Pregnancy; D011248:Pregnancy Complications; D011650:Pulmonary Alveoli; D014657:Vasculitis; D055815:Young Adult",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e921299",
"pmc": null,
"pmid": "32284523",
"pubdate": "2020-04-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29460701;26246905;29487279;29862103;20956464;12472201;28542045;25370400;9412989;26085596;30220838;24531426;21558137;30305976;24691397;16035585",
"title": "Lupus-Induced Vasculitis and Multiple Organ Dysfunction Syndrome as the First Presentation of Systemic Lupus Erythematosus (SLE) in Pregnancy.",
"title_normalized": "lupus induced vasculitis and multiple organ dysfunction syndrome as the first presentation of systemic lupus erythematosus sle in pregnancy"
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"abstract": "Mediastinal germ cell tumor (MGCT), which accounts for 1% to 3% of extragonadal germ cell tumors, has unique manifestations; it is associated with several types of hematologic malignancy, particularly myeloid neoplasm. The aim of this study was to report the 10-year incidence, clinical characteristics, and outcomes of MGCT at Thailand's national pediatric tertiary referral center. This retrospective study included patients diagnosed with MGCT at the Department of Pediatrics, Siriraj Hospital during 2005 to 2014. Eight patients (all male) were diagnosed with MGCT. Five of 8 patients were found to have hematologic abnormalities. Three patients were diagnosed with acute myeloid leukemia (AML) (one patient with M1, another having M7, and the other with M0). Another patient had mixed MGCT with mediastinal myeloid sarcoma (MMS). The other patient had malignancy-associated hemophagocytic lymphohistiocytosis syndrome (M-HLH). Isochromosome 12p was detected in 3 patients (AML [2], mixed MGCT/MMS [1]). Four of 5 patients with hematologic abnormalities died of hematologic abnormalities or treatment complication (AML [3], M-HLH [1]). One patient with mixed MGCT/MMS survived with chemotherapy. All patients with AML and MMS were nonseminomatous MGCT and the onset of myeloid malignancies were within 1 year after the diagnosis of MGCT. Associated hematologic malignancies should be suspected in MGCT with abnormal blood count or hematologic symptoms. Isochromosome 12p was the most common cytogenetic finding in MGCT-associated myeloid malignancies patients. Those with nonseminomatous MGCT should have their blood count carefully monitored especially during the first year after the diagnosis of MGCT. Better treatment alternatives for MGCT with associated hematologic malignancies are warranted to ameliorate adverse outcomes.",
"affiliations": "Department of Pediatrics, Faculty of Medicine, Srinakharinwirot University.;Department of Pediatrics, Faculty of Medicine, Thammasat University, PathumThani, Thailand.;Departments of Pathology.;Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok.;Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok.;Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok.;Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok.",
"authors": "Sowithayasakul|Panjarat|P|;Sinlapamongkolkul|Phakatip|P|;Treetipsatit|Jitsupa|J|;Vathana|Nassawee|N|;Narkbunnam|Nattee|N|;Sanpakit|Kleebsabai|K|;Buaboonnam|Jassada|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001233",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "40(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D019337:Hematologic Neoplasms; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008479:Mediastinal Neoplasms; D009373:Neoplasms, Germ Cell and Embryonal; D016609:Neoplasms, Second Primary; D012189:Retrospective Studies; D023981:Sarcoma, Myeloid; D062606:Tertiary Care Centers; D013785:Thailand",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "450-455",
"pmc": null,
"pmid": "29864110",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hematologic Malignancies Associated With Mediastinal Germ Cell Tumors: 10 Years' Experience at Thailand's National Pediatric Tertiary Referral Center.",
"title_normalized": "hematologic malignancies associated with mediastinal germ cell tumors 10 years experience at thailand s national pediatric tertiary referral center"
} | [
{
"companynumb": "TH-TEVA-2018-TH-954184",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
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{
"abstract": "BACKGROUND\nIron deficiency is common in non-dialysis chronic kidney disease (ND-CKD) patients and, on occasion, requires parenteral iron therapy. We investigated the effect of intravenous iron repletion on platelet counts in ND-CKD patients with and without concomitant darbepoetin administration.\n\n\nMETHODS\nWe conducted a retrospective analysis of ND-CKD patients with iron deficiency anemia treated with low molecular weight iron dextran (LMWID) between 2005 and 2009 at our CKD clinic. The primary end-point was change in platelet count 60 days post infusion of LMWID in those with and without concomitant darbepoetin administration. Secondary end-points were the correlations between changes in platelet count and iron indices.\n\n\nRESULTS\nA total of 108 patients met inclusion and exclusion criteria. The decrease in platelet counts in response to iron repletion was statistically significant (305.72 ± 108.86 vs 255.58 ± 78.97, P = < .0001). The decrease in platelet count was independent of concomitant darbepoetin use. Bivariate regression analysis between baseline platelet count and transferrin saturation by iron (TSAT) showed a negative association (βTSAT = -5.82, P = .0007) and moderate correlation (R = 0.32). Following iron treatment, the within individual changes in platelet count in 60 days were not related to changes in TSAT (βΔTSAT = -0.41, P = .399) and demonstrated a poor correlation (R = 0.10).\n\n\nCONCLUSIONS\nParenteral iron treatment by LMWID is associated with reduction in platelet counts in iron deficient anemic ND-CKD patients. However, ESA use in the majority of patients prior to intravenous iron administration could have altered platelet production through bone marrow competition.",
"affiliations": "Division of Nephrology and Hypertension, Henry Ford Hospital, 2799 W, Grand Blvd, CFP-514, Detroit, MI, USA. lyessay1@hfhs.org.",
"authors": "Yessayan|Lenar|L|;Yee|Jerry|J|;Zasuwa|Gary|G|;Frinak|Stan|S|;Besarab|Anatole|A|",
"chemical_list": "D006397:Hematinics; D007501:Iron",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2369-15-119",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central 1471-2369-15-1192503861410.1186/1471-2369-15-119Research ArticleIron repletion is associated with reduction in platelet counts in non-dialysis chronic kidney disease patients independent of erythropoiesis-stimulating agent use: a retrospective cohort study Yessayan Lenar 1lyessay1@hfhs.orgYee Jerry 1jyee1@hfhs.orgZasuwa Gary 1gzasuwa1@hfhs.orgFrinak Stan 1Sfrinak1@hfhs.orgBesarab Anatole 2abesarab@Fibrogen.com1 Division of Nephrology and Hypertension, Henry Ford Hospital, 2799 W. Grand Blvd, CFP-514, Detroit, MI, USA2 Division of Nephrology and Hypertension, University of California, San Francisco, CA, USA2014 19 7 2014 15 119 119 10 3 2014 16 7 2014 Copyright © 2014 Yessayan et al.; licensee BioMed Central Ltd.2014Yessayan et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIron deficiency is common in non-dialysis chronic kidney disease (ND-CKD) patients and, on occasion, requires parenteral iron therapy. We investigated the effect of intravenous iron repletion on platelet counts in ND-CKD patients with and without concomitant darbepoetin administration.\n\nMethods\nWe conducted a retrospective analysis of ND-CKD patients with iron deficiency anemia treated with low molecular weight iron dextran (LMWID) between 2005 and 2009 at our CKD clinic. The primary end-point was change in platelet count 60 days post infusion of LMWID in those with and without concomitant darbepoetin administration. Secondary end-points were the correlations between changes in platelet count and iron indices.\n\nResults\nA total of 108 patients met inclusion and exclusion criteria. The decrease in platelet counts in response to iron repletion was statistically significant (305.72 ± 108.86 vs 255.58 ± 78.97, P = < .0001). The decrease in platelet count was independent of concomitant darbepoetin use. Bivariate regression analysis between baseline platelet count and transferrin saturation by iron (TSAT) showed a negative association (βTSAT = −5.82, P = .0007) and moderate correlation (R = 0.32). Following iron treatment, the within individual changes in platelet count in 60 days were not related to changes in TSAT (βΔTSAT = −0.41, P = .399) and demonstrated a poor correlation (R = 0.10).\n\nConclusions\nParenteral iron treatment by LMWID is associated with reduction in platelet counts in iron deficient anemic ND-CKD patients. However, ESA use in the majority of patients prior to intravenous iron administration could have altered platelet production through bone marrow competition.\n\nThrombocytosisPlatelet countIron deficiency anemiaErythropoietinIntravenous iron dextran\n==== Body\nBackground\nThrombocytosis may be the result of a clonal disorder or secondary to a reactive process such as acute or chronic inflammation, hyposplenism, malignancy, or iron deficiency. The mechanism of thrombocytosis in iron deficiency related anemia is not completely understood. Thrombocytopoiesis is orchestrated by a complex interplay between growth factors and cytokines. Thrombopoietin is the primary growth factor and regulator of megakaryopoiesis [1]; however, several other cytokines such as interleukin (IL)-1, IL-3, IL-6, IL-11 and tumor necrosis factor are involved in this process [2-7]. Erythropoietin shares some structural features with thrombopoietin and may exhibit synergistic effect on platelet production [8,9]. However, the small degree of functional overlap is not mediated by cross-reactivity at the level of mpl receptor expressed on the surface of megakaryocytes [10]. Treatment with exogenous erythropoietin may increase platelet count [11]. It may be that the mechanism of synergy is mediated through the expression of erythropoietin receptors on megakaryocyte progenitors. It has also been suggested that the mechanism by which erythropoiesis stimulating agents (ESA) increase platelet count may be through the induction of a state of functional iron deficiency [12]. Some have suggested that reactive thrombocytosis, induced by ESA or the resulting iron depletion, may have contributed to the higher-than-expected rates of cerebrovascular accidents and thrombotic events reported in clinical trials of ESA in chronic kidney disease (CKD) patients. At the Henry Ford Hospital Chronic Kidney Disease Clinic, low molecular weight iron dextran (LMWID) in conjunction with ESA is used for non-dialysis chronic kidney disease (ND-CKD) anemia management using a computerized algorithm for dosing. We undertook the present study to evaluate the temporal effect of intravenous iron administration on platelet counts in iron deficient ND-CKD patients and determine if the effect is dependent on concurrent ESA administration.\n\nMethods\nThis single-center retrospective cohort study was approved by our hospital’s institutional review board (IRB project number 6650; Henry Ford Health Systems Institutional Review Board). We performed a chart review of all ND-CKD patients enrolled in our CKD clinic’s computerized anemia management program (CAMP) [13] who received iron dextran (INFeD, Watson Pharmaceuticals, Parsippany, NJ) between August 25, 2005 and March 6, 2009. CAMP is designed to treat anemia of CKD using darbepoetin alpha (DA) and iron treatment algorithms. Data on patients’ hematologic variables are stored in the CAMP database irrespective of whether they received the recommended dose of iron/ESAs. After manual data input, the iron dosing algorithm recommends no iron, oral iron, or 1 g of LMWID over 1.5–2 hours based on hemoglobin, TSAT, and ferritin levels obtained within 30 days of iron infusion. At all times, iron “sufficiency” is to be achieved/maintained with oral or parenteral ID per the algorithm [14]. The dosing of LMWID (500 or 1000 mg) during this study period was at the discretion of the treating physician. DA doses were determined monthly, based on three separate protocols for first, second, and maintenance DA doses with the goal to achieve and maintain Hb in the range of 10.0–12.0 g/dL [13].\n\nEligible patients were adults (≥18 years) with CKD who received a single dose of LMWID during a 2-month period and who were not on maintenance ESA therapy prior to LMWID administration. Exclusion criteria were any of the following: documented surgery, gastrointestinal bleeding, hospitalization during the evaluation period; lack of follow-up on second evaluation (within 37 days from baseline) or on third evaluation (within 37 days from second evaluation); administration of ESAs within 30 days of LMWID infusion. Of the 131 subjects identified, 108 ND-CKD patients met eligibility criteria. All of these study subjects received either a 500 mg or 1000 mg infusion by peripheral vein over 1.5–2.0 hours. No patient received a LMWID test dose and none were premedicated with diphenhydramine. We previously reported that LMWID is safe and effective in the treatment of iron deficiency in ND-CKD [14]. However, because fatal anaphylactic reactions have been reported after administration of LMWID injection, resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available in our CKD clinic.\n\nBaseline platelet counts, hemoglobin and iron indices were obtained within 1 week prior to LMWID administration, at 30 and 60 days post LMWID administration. The primary end-point was the change in platelet count at ~ 60 days from iron administration (baseline) in those with and without concomitant DA administration. Secondary end-points were changes in iron indices at ~ 30 and 60 days from baseline and the correlation between changes in iron indices and platelet count following LMWID administration. To detect a reduction in platelets of 25 000/mm3 with a two-sided 5% significance level and a power of 80%, a sample size of at least 60 patients was necessary to account for an anticipated 20% exclusion, either because of lack of follow-up or presence of intercurrent events. To include at least this number of patients, a 48-month inclusion period was considered.\n\nStatistical analysis was performed using SAS software version 9.3 (SAS Institute, Inc., Cary, NC). We used Student’s paired t-test to measure intra individual changes between time points for platelets, ferritin, and TSAT. Pearson correlation coefficients were used to evaluate the relationship between platelet count and iron indices at baseline as well as between changes in platelet counts and iron indices 60 days post-administration. Categorical variables are presented as frequencies and percentages. Continuous variables are presented using mean ± standard deviation. For all analyses, a P value < .05 was considered significant.\n\nResults\nTable 1 shows demographics and baseline laboratory values of 108 patients receiving LMWID infusions stratified by concomitant DA use. All CKD stages were represented (Table 1). Stages 3 and 4 CKD were the most common and CKD stage 1 was the least common. There were 65 (60%) 1000 mg LMWID infusions and 43 (40%) 500 mg LMWID infusions administered. Of the 108 subjects, 94 received monthly DA injections either on the day of iron infusion or 30 days prior to iron infusion or both; and 14 patients did not receive any DA within 30 days prior to iron infusion or during the evaluation period. Figure 1 shows the mean monthly doses of DA over time in the DA group.\n\nTable 1 Baseline characteristics of patients receiving intravenous iron dextran stratified by darbepoetin exposure\n\n \tDarbepoetin\tNo darbepoetin\tP value\t\nN = 94\tN = 14\t\nDemographics\t \t \t \t\n Age\t69.51 ± 15.90\t67.79 ± 17.26\t0.7088 (T)\t\n Race, n (White, Black, Asian, Hispanic)\t45/47/1/1\t13/1/0/0\t0.0181 (F)\t\n Gender, n (Female/Male)\t58/36\t11/3\t0.2202 (C)\t\nLaboratory\t \t \t \t\n Baseline platelets (1000/mm3)\t304.53 ± 106.97\t313.71 ± 124.87\t0.7699 (T)\t\n Hemoglobin (g/dL)\t9.98 ± 1.22\t11.44 ± 1.43\t<0.0001 (T)\t\n Transferrin saturation (%)\t13.07 ± 6.26\t12.71 ± 4.41\t0.8361 (T)\t\n Ferritin (ng/mL)\t43.07 ± 36.05\t33.50 ± 23.10\t0.3379 (T)\t\nCKD stage\t \t \t \t\n Stage 1\t1 (1%)\t0 (0%)\t0.4453 (C)\t\n Stage 2\t6 (6%)\t0 (0%)\t\n Stage 3\t40 (43%)\t9 (64%)\t\n Stage 4\t38 (40%)\t5 (36%)\t\n Stage 5\t9 (10%)\t0 (0%)\t\nDemographics are reported as frequencies except for age which is reported as mean ± standard deviation. Laboratory parameters are reported as mean ± standard deviation. Chronic kidney disease (CKD) stages are reported as frequencies with percentages in parenthesis. (T) = Two-sided T-Test, (C) = Chi-Square Test, (F) = Fisher Exact Test.\n\nFigure 1 Darbepoetin alfa (mcg) ± SD utilization over duration of study in the group that received Darbepoetin alfa. Pre-baseline indicates within 30 days of iron infusion. Baseline indicates the day of iron infusion.\n\nFollowing administration of LMWID, hemoglobin, ferritin, and iron saturation increased significantly at 30 and 60 days. Concomitantly, at 30 and 60 days, a statistically significant decrease occurred in platelet counts in response to iron repletion (Table 2). When platelet response was stratified according to DA use (Table 3), there was a statistically significant decrease in platelet counts from baseline at 30 days in both groups (DA group 304.53 ± 106.97 vs 274.26 ± 136.27, P = 0.008; No DA group 313.71 ± 124.87 vs 279.00 ± 130.08, P = 0.0021). At 60 days, a statistically significant decrease in platelet counts of approximately 50 000/mm3 was observed in both groups in response to iron repletion. The change in platelet count was similar when stratified according to DA use (−50.12 ± 63.36 for DA group vs −50.29 ± 74.64 for No DA group, P = .9928). Irrespective of iron dose, a decrease in platelet count was observed (Table 4). The change in platelet count 60 days post-LMWID was similar when platelet response was stratified according to dose of LMWID administered (−50.33 ± 61.40 for 500 mg vs −50.02 ± 67.02 for 1000 mg; P = .9806).\n\nTable 2 Parameter comparison at baseline, 30 days and 60 days post-LMWID administration\n\nParameter\tPre-infusion\t30 days\tp-value\t60 days\tp-value\t\nMean ± SD\tMean ± SD\tMean ± SD\t\nPlatelet count (1000/mm3)\t305.72 ± 108.86\t274.71 ± 135.04\t0.0012\t255.58 ± 78.97\t<0.0001\t\nHemoglobin (g/dL)\t10.17 ± 1.34\t11.29 ± 1.66\t<0.0001\t11.38 ± 1.70\t<0.0001\t\nFerritin (ng/mL)\t41.83 ± 34.71\t203.29 ± 168.75\t<0.0001\t154.13 ± 156.39\t<0.0001\t\nTransferrin saturation (%)\t13.03 ± 6.03\t23.62 ± 12.60\t<.00001\t25.06 ± 13.30\t<0.0001\t\nTable 3 Parameter comparison pre-LMWID and post-LMWID infusion stratified by darbepoetin administration\n\nDarbepoetin (N = 94)\t\nParameter\tPre-infusion\t30 days\tp-value\t60 days\tp-value\t\nMean ± SD\tMean ± SD\tMean ± SD\t\nPlatelet count (1000/mm3)\t304.53 ± 106.97\t274.26 ± 136.27\t0.008\t254.41 ± 80.16\t<0.0001\t\nHemoglobin (g/dL)\t9.98 ± 1.22\t11.12 ± 1.61\t<0.0001\t11.22 ± 1.70\t<0.0001\t\nFerritin (ng/mL)\t43.07 ± 36.05\t208.06 ± 171.79\t<0.0001\t150.58 ± 151.79\t<0.0001\t\nTransferrin saturation (%)\t13.07 ± 6.26\t24.32 ± 12.83\t<0.0001\t25.83 ± 13.55\t<0.0001\t\nNo Darbepoetin (N = 14)\t\nParameter\tPre-infusion\t30 days\tp-value\t60 days\tp-value\t\nMean ± SD\tMean ± SD\tMean ± SD\t\nPlatelet count (1000/mm3)\t313.71 ± 124.87\t279.00 ± 130.08\t0.0021\t263.43 ± 72.68\t0.0256\t\nHemoglobin (g/dL)\t11.44 ± 1.43\t12.66 ± 1.51\t0.0049\t12.46 ± 1.30\t0.0053\t\nFerritin (ng/mL)\t33.50 ± 23.10\t135.00 ± 103.01\t0.0276\t192.25 ± 208.21\t0.0620\t\nTransferrin saturation (%)\t12.71 ± 4.41\t16.00 ± 6.07\t0.1047\t16.75 ± 5.92\t0.0683\t\nLMWID = low molecular weight iron dextran.\n\nTable 4 Parameter comparison pre-LMWID and 60 days post-LMWID infusion stratified by iron dextran dose\n\n \tIron dextran 1000 mg\tIron dextran 500 mg\t\nN = 65\tN = 43\t\n \tPre-infusion\tPost-infusion\tP value\tPre-infusion\tPost-infusion\tP value\t\nMean ± SD\tMean ± SD\tMean ± SD\tMean ± SD\t\nPlatelet count (1000/mm3)\t323.54 ± 118.82\t273.52 ± 87.34\t<0.0001\t278.79 ± 86.27\t228.47 ± 54.87\t<0.0001\t\nHemoglobin (g/dL)\t10.24 ± 1.41\t11.60 ± 1.63\t<0.0001\t10.07 ± 1.23\t11.04 ± 1.78\t0.0001\t\nFerritin (ng/mL)\t46.22 ± 38.31\t174.60 ± 158.25\t<0.0001\t35.21 ± 27.54\t122.59 ± 150.15\t0.0005\t\nTransferrin saturation (%)\t13.60 ± 6.43\t24.95 ± 12.12\t<0.0001\t12.16 ± 5.34\t25.24 ± 15.07\t<0.0001\t\nLMWID = low molecular weight iron dextran.\n\nBivariate regression analysis between the baseline platelet count and TSAT revealed a negative association between the 2 variables. The estimated baseline platelet count increased by ≈ 5820 for each 1% decrease in TSAT (βTSAT = −5.82, P = .0007). The correlation coefficient R between baseline platelet and TSAT was 0.32. No association was found between baseline platelet count and ferritin (βferritin = −0.32, P = .2838), and the correlation coefficient R was not significant (R = 0.10, P = .2838).\n\nThe linear correlation between changes in platelet counts and iron indices in response to LMWID at 60 days was also investigated. The change in platelet count in ~ 60 days was neither related to changes in iron saturation (βΔTSAT = −0.41, P = .3991) nor ferritin (βferritin = 0.07, P = .1458), as displayed in Figures 2 and 3, respectively. Both predictor variables exhibited a weak and statistically non-significant correlation with platelet change (R = −0.09, R = −0.15, respectively). To test the robustness of this result, we repeated this analysis after the exclusion of patients who did not have any improvement in their TSAT by 60 days from baseline. The poor correlation persisted even after the exclusion of these patients (R = −0.07934).\n\nFigure 2 Regression fit plot of within individual changes in platelets versus changes in transferrin saturation.\n\nFigure 3 Regression fit plot of within individual changes in platelets versus changes in ferritin.\n\nDiscussion\nSecondary thrombocytosis is associated with many conditions, including acute or chronic inflammation, hyposplenism, and iron deficiency. Although generally regarded as a benign condition, secondary thrombocytosis has been identified as an independent risk factor for thromboembolic events in patients with cancer [15-17]. Similarly, iron deficiency with and without thrombocytosis has been linked to venous thrombosis and stroke [18-20]. Thus, it is biologically plausible that reactive thrombocytosis, induced by ESA or the resulting iron depletion, may have contributed to the higher-than-expected rates of cerebrovascular accidents and thrombotic events reported in clinical trials of ESA in CKD patients (e.g., the cardiovascular risk reduction by early anemia treatment with epoetin beta [CREATE] trial, a trial of end-stage renal disease patients that compared the effects of normal as compared with low hematocrit values in patients with cardiac disease who were receiving hemodialysis and epoetin, and a trial to reduce cardiovascular events with Aranesp therapy [TREAT]) [21-23] as postulated by Streja et al. [24]. In their retrospective analysis of more than 40 000 hemodialysis patients, Streja et al. [24] noted relative thrombocytosis in 15% (defined as platelet count > 300 000 ± 109 000/L), and this was associated with a 30% greater weekly dose of ESA, lower TSAT, and lower serum ferritin concentration. This pattern is reflective of functional iron deficiency at the bone marrow level.\n\nMegakaryopoiesis is regulated by various cytokines [1-7]. The pathophysiologic mechanism behind reactive thrombocytosis in iron deficiency is complex and incompletely understood. Akan et al. [25] demonstrated that the correction of iron deficiency anemia and resolution of thrombocytosis do not alter cytokine levels that are typically elevated in reactive thrombocytosis (IL-6, IL-11, and thrombopoietin). Although the levels of endogenous erythropoietin significantly decreased during correction of iron deficiency, the same response was observed in those with and without thrombocytosis, indicating that erythropoietin is not the principal regulator of thrombocytosis [25].\n\nStudies of intravenous iron undertaken in predialysis chronic renal failure that evaluated hematologic parameters have not reported the effect on platelet counts [26-30]. This observational study evaluated the effect of intravenous LMWID on platelet counts in iron deficient anemic ND-CKD patients with and without concomitant ESA use. We also evaluated the relationship between baseline platelets and iron storage parameters, as well as the relationship between changes in iron storage parameters and platelets. In response to iron administration, a statistically significant decrease occurred in platelet counts of about 50 000/mm3, suggesting a mechanistic link between iron deficiency and platelet counts in patients with ND-CKD. The effect of iron repletion on platelet count was observed in those who did and did not receive ESAs suggesting that the effect of iron repletion on platelet counts is independent of ESA use.\n\nIn our study the correlation between baseline platelet and TSAT was weak to moderate and negative in direction (R = −0.31); this is consistent with previously reported negative associations between baseline iron stores and platelet counts. One recent study showed only a very weak correlation between baseline platelet count and iron stores and no reduction in platelet count after intravenous iron dextran [31]. However, contrary to our study, the after dose values were measured between 10–120 days. Interestingly, when we investigated the relationship of within individual change in platelet count in response to a change in TSAT, we only found a weak and insignificant correlation. This would imply that our current parameters for iron deficiency, TSAT and ferritin, may be insensitive and imprecise measures of iron availability to the bone marrow. To date, the only definitive way in clinical practice to prove the presence of iron deficiency in CKD is to evaluate the erythropoietic response to parenteral iron administration. However, both reticulocyte hemoglobin content (CHr) and the percentage of hypochromic red cells may be better indicators of iron deficiency (CHr area under the curve [AUC] = 0.935 for a cutoff of 29.8 pg, sensitivity 90.7%, specificity 83.1%; percent hypochromic cells AUC = 0.925, cutoff 3.5%, sensitivity 87.3%, and specificity 88.0%) [32] than the traditional measurements of TSAT and ferritin, which have sensitivities and specificities < 80%.\n\nThis study has several limitations. Its retrospective nature makes it subject to selection and information bias. Selection bias was constrained by including all patients within the prespecified dates; however, some patients were excluded because of a lack of follow-up or intercurrent events. Moreover, given the retrospective design, patients with undocumented intercurrent events in our records such as gastrointestinal bleed, infection and surgery may have been included in the study and caused bias in the point estimate of the correlation. However, an uncertainty analysis that was performed with the exclusion of those who did not have any improvement in their TSAT yielded similar results. Additionally, by design, we could not fully control information bias; however, any observer bias was limited by data abstraction from the anemia management database. This study suggests that iron replacement is associated with reduction in platelet counts in iron deficient ND-CKD patients independent of ESA use and extends the observation of Eschbach’s study [33], where it was noted that almost half of their 333 study patients developed iron deficiency with platelet counts increasing following erythropoietin administration to anemic end-stage renal disease patients. Aggressive iron therapy reversed this increase in platelets.\n\nAnother limitation was the absence of data regarding inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, and for this reason, we could not adjust for the effect of inflammatory status, if any, on platelet count change. Furthermore, the majority of our patients did not have thrombocytosis (median = 284 000, interquartile range = 236–359). The decrease in platelet count following LMWID could only be extrapolated to patients within the specified platelet count range in our cohort. Whether iron administration could induce a more pronounced change in platelet count in iron deficient patients with thrombocytosis warrants further investigation.\n\nConclusion\nIn conclusion, our study implies that intravenous iron is associated with reduction in platelet counts independent of ESA use. However, without a control group not receiving IV iron, causation cannot be confirmed. Adequately powered studies are needed to establish an association between thrombocytosis, iron deficiency and thromboembolic events in ND CKD patients.\n\nAbbreviations\nAUC: Area under the curve; CAMP: Computerized anemia management program; CHr: Reticulocyte hemoglobin content; DA: Darbepoetin; ESA: Erythropoietin stimulating agent; IL: Interleukin; LMWID: Low molecular weight iron dextran; ND-CKD: Non-dialysis chronic kidney disease; TSAT: Transferrin saturation.\n\nCompeting interests\nL. Yessayan has nothing to disclose. J. Yee, A. Besarab, S. Frinak and G. Zasuwa are inventors of Computerized Algorithm Management Program (CAMP). A. Besarab has received research funds, grants, or contracts from Affymax, Amgen Inc., Hoffman-La Roche Ltd., Rockwell International, Takeda Pharmaceuticals, VascAlert, Fibrogen Inc., Watson Pharmaceuticals, and Bayer Pharma. J. Yee is a consultant for Amgen, Affymax, Merck, and Alexions and a shareholder in Merck.\n\nAuthors’ contributions\nAB is the principal investigator and conceived the study. LY, JY, GZ and SF contributed to study design. JY, GZ and SF acquired the data. LY, JY and AB analyzed and interpreted the data. LY, JY and AB wrote the manuscript. LY, JY, and AB revised the manuscript for important intellectual content. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-2369/15/119/prepub\n\nAcknowledgements\nThe authors express their gratitude to Sarah Whitehouse, MAW, Department of Internal Medicine, Henry Ford Hospital, for her expert editorial assistance. They also extend their gratitude to Stephanie Stebens, MLIS, Sladen Library, Henry Ford Hospital, for assistance with manuscript preparation.\n==== Refs\nKaushansky K Thrombopoietin: the primary regulator of platelet production Blood 1995 86 2 419 431 7605981 \nHaznedaroglu IC Ertenli I Ozcebe OI Kiraz S Ozdemir O Sayinalp NM Dundar SV Calguneri M Kirazli S Megakaryocyte-related interleukins in reactive thrombocytosis versus autonomous thrombocythemia Acta Haematol 1996 95 2 107 111 8638438 \nWendling F Han ZC Positive and negative regulation of megakaryocytopoiesis Baillieres Clin Haematol 1997 10 1 29 45 9154314 \nHsu HC Tsai WH Jiang ML Ho CH Hsu ML Ho CK Wang SY Circulating levels of thrombopoietic and inflammatory cytokines in patients with clonal and reactive thrombocytosis J Lab Clin Med 1999 134 4 392 397 10521086 \nHamaguchi H Takano N Saito K Enokihara H Furusawa S Shishido H Interaction of monocytes and T cells in the regulation of normal human megakaryocytopoiesis in vitro: role of IL-1 and IL-2 Br J Haematol 1990 76 1 12 20 2223630 \nAlexandrakis MG Passam FH Moschandrea IA Christophoridou AV Pappa CA Coulocheri SA Kyriakou DS Levels of serum cytokines and acute phase proteins in patients with essential and cancer-related thrombocytosis Am J Clin Oncol 2003 26 2 135 140 12714883 \nDan K Gomi S Inokuchi K Ogata K Yamada T Ohki I Hasegawa S Nomura T Effects of interleukin-1 and tumor necrosis factor on megakaryocytopoiesis: mechanism of reactive thrombocytosis Acta Haematol 1995 93 2–4 67 72 7639054 \nBroudy VC Lin NL Kaushansky K Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro Blood 1995 85 7 1719 1726 7535585 \nMetcalf D Di Rago L Mifsud S Synergistic and inhibitory interactions in the in vitro control of murine megakaryocyte colony formation Stem Cells 2002 20 6 552 560 12456963 \nBroudy VC Lin NL Sabath DF Papayannopoulou T Kaushansky K Human platelets display high-affinity receptors for thrombopoietin Blood 1997 89 6 1896 1904 9058709 \nBeguin Y Loo M R'Zik S Sautois B Lejeune F Rorive G Fillet G Effect of recombinant human erythropoietin on platelets in patients with anemia of renal failure: correlation of platelet count with erythropoietic activity and iron parameters Eur J Haematol 1994 53 5 265 270 7813706 \nBeguin Y Erythropoietin and platelet production Haematologica 1999 84 6 541 547 10366799 \nChalhoub E Frinak S Zasuwa G Faber MD Peterson E Besarab A Yee J De novo once-monthly darbepoetin alpha treatment for the anemia of chronic kidney disease using a computerized algorithmic approach Clin Nephrol 2011 76 1 1 8 21722599 \nYessayan L Sandhu A Besarab A Yessayan A Frinak S Zasuwa G Yee J Intravenous iron dextran as a component of anemia management in chronic kidney disease: a report of safety and efficacy Int J Nephrol 2013 2013 703038 23573422 \nKhorana AA Francis CW Culakova E Lyman GH Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study Cancer 2005 104 12 2822 2829 16284987 \nSimanek R Vormittag R Ay C Alguel G Dunkler D Schwarzinger I Steger G Jaeger U Zielinski C Pabinger I High platelet count associated with venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS) J Thromb Haemost 2010 8 1 114 120 19889150 \nZakai NA Wright J Cushman M Risk factors for venous thrombosis in medical inpatients: validation of a thrombosis risk score J Thromb Haemost 2004 2 12 2156 2161 15613021 \nNagai T Komatsu N Sakata Y Miura Y Ozawa K Iron deficiency anemia with marked thrombocytosis complicated by central retinal vein occlusion Intern Med 2005 44 10 1090 1092 16293924 \nKinoshita Y Taniura S Shishido H Nojima T Kamitani H Watanebe T Cerebral venous sinus thrombosis associated with iron deficiency: two case reports Neurol Med Chir (Tokyo) 2006 46 12 589 593 17185884 \nStolz E Valdueza JM Grebe M Schlachetzki F Schmitt E Madlener K Rahimi A Kempkes-Matthes B Blaes F Gerriets T Kaps M Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited. Results of a prospective study J Neurol 2007 254 6 729 734 17450317 \nSingh AK Szczech L Tang KL Barnhart H Sapp S Wolfson M Reddan D Correction of anemia with epoetin alfa in chronic kidney disease N Engl J Med 2006 355 20 2085 2098 17108343 \nBesarab A Bolton WK Browne JK Egrie JC Nissenson AR Okamoto DM Schwab SJ Goodkin DA The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin N Engl J Med 1998 339 9 584 590 9718377 \nPfeffer MA Burdmann EA Chen CY Cooper ME de Zeeuw D Eckardt KU Feyzi JM Ivanovich P Kewalramani R Levey AS Lewis EF McGill JB McMurray JJ Parfrey P Parving HH Remuzzi G Singh AK Solomon SD Toto R A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease N Engl J Med 2009 361 21 2019 2032 19880844 \nStreja E Kovesdy CP Greenland S Kopple JD McAllister CJ Nissenson AR Kalantar-Zadeh K Erythropoietin, iron depletion, and relative thrombocytosis: a possible explanation for hemoglobin-survival paradox in hemodialysis Am J Kidney Dis 2008 52 4 727 736 18760517 \nAkan H Guven N Aydogdu I Arat M Beksac M Dalva K Thrombopoietic cytokines in patients with iron deficiency anemia with or without thrombocytosis Acta Haematol 2000 103 3 152 156 10940653 \nAggarwal HK Nand N Singh S Singh M Hemant Kaushik G Comparison of oral versus intravenous iron therapy in predialysis patients of chronic renal failure receiving recombinant human erythropoietin J Assoc Phys o India 2003 51 170 174 \nCharytan C Qunibi W Bailie GR Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis Nephron Clin Pract 2005 100 3 c55 62 15824508 \nSpinowitz BS Kausz AT Baptista J Noble SD Sothinathan R Bernardo MV Brenner L Pereira BJ Ferumoxytol for treating iron deficiency anemia in CKD J Am Soc Nephrol 2008 19 8 1599 1605 18525001 \nStoves J Inglis H Newstead CG A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin Nephrol Dial Transplant 2001 16 5 967 974 11328902 \nVan Wyck DB Roppolo M Martinez CO Mazey RM McMurray S A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD Kidney Int 2005 68 6 2846 2856 16316362 \nDossabhoy NR Gascoyne R Turley S Intravenous iron repletion does Not significantly decrease platelet counts in CKD patients with iron deficiency anemia Int J Nephrol 2013 2013 878041 23476772 \nUrrechaga E Borque L Escanero JF Erythrocyte and reticulocyte indices in the assessment of erythropoiesis activity and iron availability Int J Lab Hematol 2013 35 2 144 149 23033935 \nEschbach JW Abdulhadi MH Browne JK Delano BG Downing MR Egrie JC Evans RW Friedman EA Graber SE Haley NR Korbet S Krantz SB Lundin AP Nissenson AR Ogden DA Paganini EP Rader B Rutsky EA Stivelman J Stone WJ Teschan P Van Stone JC Van Wyck DB Zuckerman K Adamson JW Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial Ann Intern Med 1989 111 12 992 1000 2688507\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "15()",
"journal": "BMC nephrology",
"keywords": null,
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D018798:Anemia, Iron-Deficiency; D015331:Cohort Studies; D004920:Erythropoiesis; D005260:Female; D005500:Follow-Up Studies; D006397:Hematinics; D006801:Humans; D007262:Infusions, Intravenous; D007501:Iron; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "119",
"pmc": null,
"pmid": "25038614",
"pubdate": "2014-07-19",
"publication_types": "D016428:Journal Article",
"references": "15613021;2688507;10366799;8638438;7605981;23476772;12725261;12456963;11328902;10521086;18760517;23573422;15824508;17185884;17108343;7813706;21722599;10940653;12714883;2223630;18525001;16316362;7535585;9718377;23033935;9154314;19880844;19889150;16284987;16293924;9058709;17450317;7639054",
"title": "Iron repletion is associated with reduction in platelet counts in non-dialysis chronic kidney disease patients independent of erythropoiesis-stimulating agent use: a retrospective cohort study.",
"title_normalized": "iron repletion is associated with reduction in platelet counts in non dialysis chronic kidney disease patients independent of erythropoiesis stimulating agent use a retrospective cohort study"
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"companynumb": "US-AMGEN-USASP2021167710",
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"occurcountry": "US",
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"actiondrug": "5",
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"activesubstancename": "DARBEPOETIN ALFA"
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... |
{
"abstract": "Introduction Mitochondriopathies are pathologies of cell organelles, which are essential for the formation of adenosine triphosphate (ATP), which is responsible for cellular energy stock. When mitochondrial mutations occur, symptoms arise frequently in those organs that rely on a continuous energy supply, such as the nervous system. Although psychiatric illness is increasingly prevalent in patients with mitochondrial disease, less attention has been paid to its psychiatric presentations. Case Report We describe a case of a 21-year-old woman who presented in our outpatient department with panic attacks and depression. The patient experienced major side effects after low-dose sertraline therapy. Conclusion Mitochondriopathies belong to the class of rare illnesses in psychiatry; nevertheless, they require adaptations of psychopharmacological therapy. Psychotropic drugs are potential respiratory chain inhibitors and could lead to distinct side effects.",
"affiliations": null,
"authors": "Mörkl|Sabrina|S|;Tmava|Adelina|A|;Blesl|Claudia|C|;Schmiedhofer|Franziska|F|;Wurm|Walter E|WE|;Holl|Anna|A|;Painold|Annamaria|A|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0043-113824",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0720-4299",
"issue": "85(8)",
"journal": "Fortschritte der Neurologie-Psychiatrie",
"keywords": null,
"medline_ta": "Fortschr Neurol Psychiatr",
"mesh_terms": "D003866:Depressive Disorder; D005260:Female; D006801:Humans; D028361:Mitochondrial Diseases; D009483:Neuropsychological Tests; D016584:Panic Disorder; D010551:Personality; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8103137",
"other_id": null,
"pages": "474-478",
"pmc": null,
"pmid": "28841746",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The power plants of the cell: Treatment of psychiatric symptoms in patients with mitochondriopathy.",
"title_normalized": "the power plants of the cell treatment of psychiatric symptoms in patients with mitochondriopathy"
} | [
{
"companynumb": "AT-ACCORD-058425",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": null,
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{
"abstract": "BACKGROUND\nAlthough Mycobacterium massiliense lung disease is increasing in patients with cystic fibrosis and non-cystic fibrosis bronchiectasis, optimal treatment regimens remain largely unknown. This study aimed to evaluate the efficacy of oral macrolide therapy after an initial 2-week course of combination antibiotics for the treatment of M massiliense lung disease.\n\n\nMETHODS\nSeventy-one patients received oral macrolides, along with an initial 4-week (n = 28) or 2-week (n = 43) IV amikacin and cefoxitin (or imipenem) treatment. These patients were treated for 24 months (4-week IV group) or for at least 12 months after negative sputum culture conversion (2-week IV group).\n\n\nRESULTS\nTotal treatment duration was longer in the 4-week IV group (median, 23.9 months) than in the 2-week IV group (15.2 months; P < .001). The response rates after 12 months of treatment were 89% for symptoms, 79% for CT scanning, and 100% for negative sputum culture results in the 4-week IV group. In the 2-week IV group, these values were 100% (P = .057), 91% (P = .177), and 91% (P = .147), respectively. Acquired macrolide resistance developed in two patients in the 2-week IV group. Genotyping analyses of isolates from patients who did not achieve negative sputum culture conversion during treatment and from those with positive culture results after successful treatment completion revealed that most episodes were due to reinfection with different genotypes of M massiliense.\n\n\nCONCLUSIONS\nOral macrolide therapy after an initial 2-week course of combination antibiotics might be effective in most patients with M massiliense lung disease.\n\n\nBACKGROUND\nClinicalTrials.gov; No.: NCT00970801; URL: www.clinicaltrials.gov.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: wjkoh@skku.edu.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, and Seoul National University College of Medicine, Seoul, South Korea.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Korean Institute of Tuberculosis, Cheongju, South Korea.;Korean Institute of Tuberculosis, Cheongju, South Korea.;Division of Mycobacterial and Respiratory Infections, Department of Medicine, National Jewish Health, Denver, Colorado.;Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.",
"authors": "Koh|Won-Jung|WJ|;Jeong|Byeong-Ho|BH|;Jeon|Kyeongman|K|;Kim|Su-Young|SY|;Park|Kyoung Un|KU|;Park|Hye Yun|HY|;Huh|Hee Jae|HJ|;Ki|Chang-Seok|CS|;Lee|Nam Yong|NY|;Lee|Seung-Heon|SH|;Kim|Chang Ki|CK|;Daley|Charles L|CL|;Shin|Sung Jae|SJ|;Kim|Hojoong|H|;Kwon|O Jung|OJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018942:Macrolides; D002440:Cefoxitin; D015378:Imipenem; D000583:Amikacin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2016.05.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "150(6)",
"journal": "Chest",
"keywords": "Mycobacterium abscessus; Mycobacterium massiliense; macrolides; nontuberculous mycobacteria; treatment",
"medline_ta": "Chest",
"mesh_terms": "D000284:Administration, Oral; D000583:Amikacin; D000900:Anti-Bacterial Agents; D002440:Cefoxitin; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015378:Imipenem; D018942:Macrolides; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D011446:Prospective Studies; D013183:Sputum; D016896:Treatment Outcome",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "1211-1221",
"pmc": null,
"pmid": "27167209",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Oral Macrolide Therapy Following Short-term Combination Antibiotic Treatment of Mycobacterium massiliense Lung Disease.",
"title_normalized": "oral macrolide therapy following short term combination antibiotic treatment of mycobacterium massiliense lung disease"
} | [
{
"companynumb": "KR-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-132690",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFOXITIN SODIUM"
},
... |
{
"abstract": "Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.",
"affiliations": "Università di Milano, Luigi Sacco University Hospital, Department of Biomedical and Clinical Sciences L. Sacco, Milan, Italy.;Università di Milano, Luigi Sacco University Hospital, Department of Biomedical and Clinical Sciences L. Sacco, Milan, Italy.;Università di Milano, Luigi Sacco University Hospital, Department of Biomedical and Clinical Sciences L. Sacco, Milan, Italy.;Università di Milano, Luigi Sacco University Hospital, Department of Infectious Diseases, Milan, Italy.;Università di Milano, Luigi Sacco University Hospital, Department of Infectious Diseases, Milan, Italy. Electronic address: cristina.gervasoni@unimi.it.",
"authors": "Pezzani|Maria Diletta|MD|;Resnati|Chiara|C|;Di Cristo|Valentina|V|;Riva|Agostino|A|;Gervasoni|Cristina|C|",
"chemical_list": "D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D015235:HLA-B Antigens; C484830:HLA-B*57:01 antigen; C106538:abacavir",
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nBraz J Infect Dis\nBraz J Infect Dis\nThe Brazilian Journal of Infectious Diseases\n1413-8670\n1678-4391\nElsevier\n\nS1413-8670(16)30043-5\n10.1016/j.bjid.2016.03.002\nCase Report\nAbacavir-induced liver toxicity\nPezzani Maria Diletta a\nResnati Chiara a\nDi Cristo Valentina a\nRiva Agostino b\nGervasoni Cristina cristina.gervasoni@unimi.it\nb⁎\na Università di Milano, Luigi Sacco University Hospital, Department of Biomedical and Clinical Sciences L. Sacco, Milan, Italy\nb Università di Milano, Luigi Sacco University Hospital, Department of Infectious Diseases, Milan, Italy\n⁎ Corresponding author. cristina.gervasoni@unimi.it\n04 4 2016\nSep-Oct 2016\n04 4 2016\n20 5 502504\n10 1 2016\n13 3 2016\n© 2016 Elsevier Editora Ltda.\n2016\nElsevier Editora Ltda.\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/).\nAbacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.\n\nKeywords\n\nHIV\nAbacavir\nLiver toxicity\n==== Body\npmcIntroduction\n\nDrug-induced hepatotoxicity represents an important side effect of highly active antiretroviral therapy (HAART), complicates the management of HIV-infected patients and, although infrequently, may have serious consequences.1 Possible pathogenic mechanisms involved in hepatotoxicity are multiple, including direct drug toxicity, immune reconstitution in the presence of hepatitis C (HCV) and/or hepatitis B (HBV) co-infections, hypersensitivity reactions with liver involvement, and mitochondrial toxicity.1\n\nAbacavir (ABC)-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients,2 with a handful of cases reported in non carriers of the HLA allele risk.3, 4 All cases happened in patients on a stable nevirapine (NVP)-based regimen after switching to ABC from another nucleoside analog. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable NVP-based regimen with no history of liver problems or alcohol abuse after switching to ABC. In order to assess the incidence of ABC liver toxicity in the HIV population treated with ABC, lamivudine, and NVP, which is a poorly investigated but currently used combination in clinical practice, mainly in countries with economic constraints, we investigated the reasons for ABC discontinuation in patients on NVP-based regimens from our clinical database.\n\nCase report\n\nA 33-year-old woman was switched from tenofovir/emtricitabine/NVP to ABC/lamivudine/NVP after seven years on initial treatment to avoid tenofovir related long-term toxicity. Our choice was based on the low body weight of the patient – which is risk factor for the development of long-term tenofovir complications5 – and the observed mild increase in serum creatinine concentrations. She tested negative for HLA B*5701 and hepatitis viruses. Her transaminases levels had always been normal along her antiretroviral treatment but eight weeks after switching to ABC aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels progressively increased to 222 and 518 UI/mL, respectively. The patient has always been asymptomatic. Serology for hepatitis A (HAV IgM), hepatitis B (HBsAg, HBcAbIgM), and hepatitis C (HCVAb) were negative, as were hepatitis C viral load (HCV RNA undetectable). Autoantibody screening tests were negative. The patient did not take concomitant medications after switching to ABC and was not given acetaminophen, a drug known to induce liver toxicity eventually exacerbated by ABC.6 Given the previous long term tolerability to NVP, ABC was discontinued and the patient was switched back to tenofovir with subsequent normalization of AST and ALT within six weeks.\n\nIn order to properly address the incidence of ABC liver toxicity in patients on stable treatment with NVP, we retrospectively searched our clinical database and identified 1004 male and female HIV-infected patients referring to our Department between 2000 and 2013 who began receiving ABC as part of their first or subsequent antiretroviral treatment regimen. Eighty-three HIV-infected patients (51 males, 32 females), with a median age of 46 years (range 30–72), received a stable NVP-containing regimen before starting ABC. The main reasons for switching to ABC were (a) lipodystrophy and lipid abnormalities in patients treated with zidovudine (27 patients); (b) to avoid tenofovir related toxicity (38 patients); stavudine and didanosine replacement (10 patients). Overall, 26 out of the 83 (24%) patients subsequently discontinued ABC treatment due to the following reasons: virologic failure (n = 11), rash (n = 5), in three cases before the availability of genetic testing for HLA B*5701, gastrointestinal side effects (n = 2), pregnancy (n = 2), patient request (n = 2), one patient discontinued due to change in treatment strategy, one patient due to high cardiovascular risk, and hepatotoxicity (n = 2, both cases tested negative for HLA B*5701). Of the two suspensions due to hepatotoxicity, one patient had no viral hepatitis co-infection and presented clinical and demographic characteristics similar to those described in previous reports,3, 4 while the other was coinfected with HCV and had not had previous raise in liver enzymes. Interestingly, 82% (9 out of the 11 pts) of the virologic failures were observed in patients with a long history of HIV treatment including antiretroviral regimens that are no longer recommended.\n\nDiscussion\n\nABC-induced liver injury in the context of a negative HLA B*5701 test is an uncommon event. As a matter of fact, extensive evidence is now available showing that HLA-B*5701 screening is an effective way to prevent hypersensitivity to ABC in susceptible subjects.7, 8 To the best of our knowledge only three cases of hepatotoxicity occurring in HLA B*5701-negative patients with no viral hepatitis co-infection or history of alcohol abuse have been reported; all cases were on a stable NVP-based regimen after switching to ABC from another nucleoside analog.3, 4 Here, we confirm these findings by documenting that in our cohort ABC-related hepatotoxicity was an uncommon, but clinically relevant event. A pharmacokinetic drug-to-drug interaction between ABC and NVP is unlikely because ABC is not metabolized by cytochromial enzymes.9 We have also excluded a potential contribution of acetaminophen on the observed ABC/NVP-related liver toxicity6 because this drug was used, if any, in very few patients from our cohorts and for short time periods. Accordingly, potential pharmacodynamic mechanisms explaining ABC/NVP liver toxicity can be eventually advocated. Indeed, evidence is available showing that both drugs separately can favor the bioactivation of reactive molecules capable of forming protein products ultimately leading to liver toxicity.10, 11, 12 On the other hand, it should be considered that very limited and scanty data are available not only on the safety but also on the efficacy ABC/lamivudine/NVP combination,13, 14 despite the fact that this regimen has now become a very attractive option for the very low cost, limited metabolic impact, and low pill burden. We, therefore, extended previous findings by assessing the frequency of ABC-related hepatotoxicity in HIV-infected patients on NVP based-regimens and by describing the efficacy of this regimen in a real life scenario. Indeed, a higher incidence of virologic failure was found in our cohort of patients compared with the only available study to date which has formally investigated ABC/lamivudine/NVP as a simplification strategy for HIV patients with undetectable viral load.13 The possibility that the increased pill burden (as in the case of switching from zidovudine + lamivudine coformulation to ABC/lamivudine as single components) might have contributed, at least in part, to the virologic failures observed in patients cannot be definitively ruled out. It should be considered, however, that large part of our failures were driven by events occurring in patients with long term history of antiretroviral therapy which included mono or dual regimens no longer recommended. As a result, it can be reasonably speculated that some of the virologic failures apparently observed with ABC may have been significantly influenced by previous antiretroviral regimens.\n\nIn conclusion, clinicians should remain alert for signs of hepatitis in patients treated with ABC, while, at the same time, consider the efficacy of ABC/lamivudine/NVP combination as a simplification option only in patients not previously treated with suboptimal antiretroviral regimens.\n\nConflicts of interest\n\nCG has received educational grants from Merck Sharp & Dome, Janssen-Cilag, Bristol Myers Squibb, Gilead and Abbvie. AR has received educational grants from Merck Sharp & Dome, Janssen-Cilag, Bristol Myers Squibb, Gilead, ViiV and Novartis.\n==== Refs\nReferences\n\n1 Núñez M. Clinical syndromes and consequences of antiretroviral-related hepatotoxicity Hepatology 52 2010 1143 1155 20812358\n2 Hughes C.A. Foisy M.M. Dewhurst N. Abacavir hypersensitivity reaction: an update Ann Pharmacother 42 2008 387 396 18303141\n3 Di Filippo E. Ripamonti D. Rizzi M. Abacavir-induced liver toxicity in an HIV-infected patient AIDS 28 2014 613 24469001\n4 Soni S. Churchill D.R. Gilleece Y. Abacavir-induced hepatotoxicity: a report of two cases AIDS 22 2008 2557 2558 19005287\n5 Gervasoni C. Meraviglia P. Landonio S. Low body weight in females is a risk factor for increased tenofovir exposure and drug-related adverse events PLoS One 8 2013 e80242 24312465\n6 Blas-García A. Martí-Rodrigo A. Víctor V.M. The purine analogues abacavir and didanosine increase acetaminophen-induced hepatotoxicity by enhancing mitochondrial dysfunction J Antimicrob Chemother 2016 (epub head of print)\n7 Ma J.D. Lee K.C. Kuo G.M. HLA-B*5701 testing to predict abacavir hypersensitivity PLoS Curr 2 2010 RRN1203 21151380\n8 Phillips E. Mallal S. Successful translation of pharmacogenetics into the clinic: the abacavir example Mol Diagn Ther 13 2009 1 9 19351209\n9 Yuen G.J. Weller S. Pakes G.E. A review of the pharmacokinetics of abacavir Clin Pharmacokinet 47 2008 351 371 18479171\n10 Grilo N.M. Antunes A.M. Caixas U. Monitoring abacavir bioactivation in humans: screening for an aldehyde metabolite Toxicol Lett 219 2013 59 64 23467017\n11 Caixas U. Antunes A.M. Marinho A.T. Evidence for nevirapine bioactivation in man: searching for the first step in the mechanism of nevirapine toxicity Toxicology 301 2012 33 39 22750752\n12 Jesson J. Dahourou D.L. Renaud F. Adverse events associated with abacavir use in HIV-infected children and adolescents: a systematic review and meta-analysis Lancet HIV 3 2016 e64 e75 26847228\n13 Cabello Úbeda A. Sanz Moreno J. Williams F. Górgolas M. Efficacy and safety of nevirapine + Kivexa (abacavir/lamivudine) as a simplification strategy for HIV patients with undetectable viral load J Acquir Immune Defic Syndr 58 2011 e95 e96 22005001\n14 Podzamczer D. Rojas J.F. Neves I. Effectiveness and tolerability of abacavir-lamivudine-nevirapine (ABC/3TC/NVP) in a multicentre cohort of HIV-infected, ARV-naïve patients J Int AIDS Soc 17 2014 19773 25397517\n\n",
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"journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases",
"keywords": "Abacavir; HIV; Liver toxicity",
"medline_ta": "Braz J Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D056486:Chemical and Drug Induced Liver Injury; D015224:Dideoxynucleosides; D005260:Female; D015658:HIV Infections; D015235:HLA-B Antigens; D006801:Humans; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome",
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"title": "Abacavir-induced liver toxicity.",
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"abstract": "Lung adenocarcinoma is the most common pathological pattern of lung cancer. During the past decades, a number of targeted agents have been explored to treat advanced lung adenocarcinoma. In the present clinical practice, antagonists of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF)-directed therapies are widely used. In the former category, the agent erlotinib (tyrosine kinase inhibitor) has shown obvious advantages over cytotoxic therapy. Anti-VEGF therapy bevacizumab used for lung adenocarcinoma was recommended in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) as first-line therapy. Similarly, apatinib is speculated to response by selectively inhibiting the vascular endothelial growth factor receptor-2. The patient with unknown EGFR status benefited 5-month progressive free survival (PFS) from erlotinib, and then another 5.1-month PFS with combined treatment of apatinib, which suggested a new option for lung adenocarcinoma. However, when dabigatran was used to cancer-related venous thromboembolism during apatinib therapy, extensive subcutaneous bleeding occurred, warning us against the risks of bleeding. Besides, hypertension and anorexia were observed, causing dosage adjustment.",
"affiliations": "Department of China-Japan Friendship Hospital, Beijing University of Chinese Medicine.;Department of Oncology, China-Japan Friendship Hospital, Chaoyang.;Department of Oncology, Beijing Chest Hospital, Tongzhou, Beijing, People's Republic of China.;Department of China-Japan Friendship Hospital, Beijing University of Chinese Medicine.;Department of China-Japan Friendship Hospital, Beijing University of Chinese Medicine.;Department of China-Japan Friendship Hospital, Beijing University of Chinese Medicine.;Department of China-Japan Friendship Hospital, Beijing University of Chinese Medicine.;Department of China-Japan Friendship Hospital, Beijing University of Chinese Medicine.;Department of China-Japan Friendship Hospital, Beijing University of Chinese Medicine.",
"authors": "Peng|Yanmei|Y|;Cui|Huijuan|H|;Liu|Zhe|Z|;Liu|Daiwei|D|;Liu|Fan|F|;Song|Yazhong|Y|;Duan|Hua|H|;Qiu|Yuqin|Y|;Li|Qiang|Q|",
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"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S130990ott-10-2289Case ReportApatinib to combat EGFR-TKI resistance in an advanced non-small cell lung cancer patient with unknown EGFR status: a case report Peng Yanmei 1Cui Huijuan 2Liu Zhe 3Liu Daiwei 1Liu Fan 1Song Yazhong 1Duan Hua 1Qiu Yuqin 1Li Qiang 11 Department of China-Japan Friendship Hospital, Beijing University of Chinese Medicine2 Department of Oncology, China-Japan Friendship Hospital, Chaoyang3 Department of Oncology, Beijing Chest Hospital, Tongzhou, Beijing, People’s Republic of ChinaCorrespondence: Huijuan Cui, Department of Oncology, China-Japan Friendship Hospital, No 2, Yinghua Dong Jie, Chaoyang District, Beijing 100029, People’s Republic of China, Tel +86 139 1183 5018, Email cuihj1963@sina.com2017 26 4 2017 10 2289 2295 © 2017 Peng et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Lung adenocarcinoma is the most common pathological pattern of lung cancer. During the past decades, a number of targeted agents have been explored to treat advanced lung adenocarcinoma. In the present clinical practice, antagonists of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF)-directed therapies are widely used. In the former category, the agent erlotinib (tyrosine kinase inhibitor) has shown obvious advantages over cytotoxic therapy. Anti-VEGF therapy bevacizumab used for lung adenocarcinoma was recommended in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) as first-line therapy. Similarly, apatinib is speculated to response by selectively inhibiting the vascular endothelial growth factor receptor-2. The patient with unknown EGFR status benefited 5-month progressive free survival (PFS) from erlotinib, and then another 5.1-month PFS with combined treatment of apatinib, which suggested a new option for lung adenocarcinoma. However, when dabigatran was used to cancer-related venous thromboembolism during apatinib therapy, extensive subcutaneous bleeding occurred, warning us against the risks of bleeding. Besides, hypertension and anorexia were observed, causing dosage adjustment.\n\nKeywords\nNSCLCepidermal growth factor receptorvascular endothelial growth factorvenous thromboembolismdabigatran\n==== Body\nIntroduction\nLung cancer is one of the leading causes of morbidity and mortality among cancer patients, posing a major threat to public health.1 In China, lung adenocarcinoma makes the maximum proportion. In Asian non-small cell lung cancer (NSCLC) patients, about 40%–60% epidermal growth factor receptor (EGFR) mutations are detected, for which anti-EGFR agents, erlotinib (F Hoffmann-La Roche Ltd, Basel, Switzerland), are proposed to use. Nowadays, EGFR-tyrosine kinase inhibitor (TKI) resistance is a popular research hotspot.\n\nApatinib (Hengrui Pharmaceutical Co. Ltd, Jiangsu, People’s Republic of China) is a novel tyrosine kinase inhibitor that selectively inhibits the VEGF-2 and inhibits VEGF-mediated endothelial cell migration and proliferation, thus blocking new blood vessel formation in tumor tissue.2,3 Currently, phase II/III clinical trials in China have approved the indication of chemotherapy-refractory advanced metastatic gastric cancer.4,5 The phase I clinical trial showed a potential targeted treatment for advanced lung cancer, metastatic breast cancer, and advanced hepatocellular carcinoma.6\n\nWe here report a case of apatinib’s response in an advanced NSCLC patient with EGFR-TKI resistance, who died of severe pneumonia with disease progression. As far as we know, this is the first report of the combination treatment with apatinib and erlotinib combating acquired EGFR-TKI resistance.\n\nCase report\nIn August 2014, the male patient had a sudden chest distress and cough but without phlegm. Computed tomography (CT) of chest in Beijing Chest Hospital showed a mass in the left upper lung sized ~41×27 mm, with segmented edge, metastasis in mediastinal 4R,7 regions and ipsilateral hilar lymph nodes, and right pulmonary pleura with micronodulaire. Cranial magnetic resonance imaging (MRI), abdominal CT, and bone scans were found normal. On September 28, 2014, adenocarcinoma was diagnosed by fine-needle aspiration biopsy under ultrasonic bronchoscope (Figure 1). EGFR test was unable to perform because of the small size of specimens. The patient was diagnosed with lung adenocarcinoma on the left upper lobe with poorly differentiated stage IIIb.\n\nFrom October 3, 2014, to March 3, 2015, the patient was treated with the first-line chemotherapy (gemcitabine 2.2 g days 1 and 8, 8 plus cisplatin 50 mg days 1–3, every 21 days) at Beijing Chest Hospital. The overall efficacy evaluation by thoracic CT was partial response (PR) after six therapy circles. The partial radiotherapy of mediastinum and mass in the left lobe was from April 20 to June 1, 2015, in Cancer Hospital, Chinese Academic of Medical Sciences, and the efficacy evaluation was PR. Left headache with blurred vision occurred on August 26, 2015. Cranial MRI showed metastasis in the left occipital lobe. Whole-brain radiotherapy and dehydration treatment eliminated the syndrome, and MRI showed edema, which was obviously alleviated, but the tumor in the left lobe was increased. Because of unbearable adverse events (AEs), especially gastrointestinal side effects, the patient asked for targeted therapy despite the unknown EGFR status. On September 30, 2015, the patient refused to receive re-biopsy and started taking erlotinib (150 mg/day) as the second-line therapy. Imageological examination demonstrated stable disease, verifying erlotinib was effective to the patient. However, cranial MRI on December 27, 2015, revealed edema aggravated. The patients received gamma knife radiation for brain metastasis in Beijing Tian Tan Hospital on December 30, 2015. Chest CT showed that the solid mass in the left upper lobe was slightly enlarged on February 26, 2016 (Figure 2A). A bone scan suggested bone metastases and the encephaledem slightly deteriorated (Figure 3A), a possible indication of progressive disease (PD) and erlotinib resistance. Combined use of erlotinib and apatinib (250 mg/day) was chosen as the third-line therapy from March 17, 2016 (Table 1) in China-Japan Friendship Hospital. After approximately a month’s treatment, the chest CT on April 25, 2016, showed cavitation formed in the solid mass of the left lobe, and the solid mass was significantly reduced with stable mediastinal lymph node (Figure 2B). Cranial MRI on April 27, 2016, showed edema in the left occipital lobe alleviated (Figure 3B). Monthly imageological examination revealed the effectiveness of the combination treatment (Figures 2C–F and 3C–E). Circulation tumor cell from the patient’s plasma reported 3.87 FU/3 mL within normal limits on July 7, 2016, whereas 30.1 FU/3 mL on August 29, 2016, beyond normal limits. The contrast might imply disease progression. Ultimately, another 5.1-month PFS was achieved and severe pneumonia took away the patient’s life with disease progression on August 31, 2016.\n\nThe left upper limb was found swelling on July 5, 2016, and ultrasonography showed venous thromboembolism (VTE). Fraxiparine, low molecular weight heparin (LMWH) calcium, was applied to anticoagulant therapy for the monitoring coagulation function from July 8, 2016. On July 26, 2016, ultrasonography showed the sign of vascular recanalization and reduction of swelling. Considering the difficulty complying with INR monitoring, the patient requested medication on discharge, so dabigatran (Boehringer Ingelheim Pharmaceutical Co., Ingelheim, Germany), a new oral anticoagulants, was chosen. On August 21, 2016, the patient suddenly felt dizzy with spraying vomit, and extensive subcutaneous hemorrhage occurred. On August 25, the patient was hospitalized and treated with hemostasis and plasma supplement as the blood routine (Figure 4), and activated partial thromboplastin time (Figure 5) was monitored, stopping taking dabigatran. Ultrasonography presented no thrombus despite recurred swelling in the left upper limb (Figure 6) until his death. Written informed consent was obtained from the patient’s wife for publication of the details and accompanying images for this study.\n\nDiscussion\nThe patient was initially diagnosed with left lung adenocarcinoma via pathology tests. Platinum-based doublets chemotherapy was recommended as the first-line therapy. Systemic chemotherapy and local radiotherapy were given to the patient, and disease recurrence was observed after 2 months. Due to the small size of specimens, gene test cannot be performed. However, considering the high rate of EGFR mutation in Asians, erlotinib was chosen as the second-line therapy without EGFR test when the patient refused to receive chemotherapy. Evaluation after application of erlotinib for 1 month was effective, suggesting the patient might be harboring EGFR mutation. After 5 months, drug resistance occurred, which in most patients after 9–13 months of treatment.7–9 The following therapeutic strategy is to develop third-generation drugs against T790M resistance mutation or to investigate new combination strategies to overcome this resistance. However, plasma test (cfDNA) was not introduced by China-Japan Friendship Hospital then. Neither was osimertinib against T790M-positive NSCLC in Mainland China.10 Herein, the patient would like to accept combination targeted treatment.\n\nAngiogenesis plays a significant role in carcinoma growth and metastasis, while the VEGF signaling is the key pathway in vascular endothelial cells.11 In vitro study has verified that the co-treatment with anti-VEGF therapy could enhance antitumor activity of anti-EGFR therapy.12 Targeting angiogenesis by inhibition of VEGFs was shown to be effective for lung cancer,13 including bevacizumab and apatinib.\n\nBevacizumab, a humanized monoclonal antibody against VEGF, has been recommended as the first-line therapy for lung adenocarcinoma until disease progression in NCCN Guidelines.14 In the randomized open-label phase III BEVERLY study, the combined treatment of erlotinib and bevacizumab was significantly better than erlotinib alone in terms of PFS in patients with nonsquamous NSCLC with activating EGFR mutations, suggesting the possible combination strategy to combat EGFR-TKI resistance.15 Furthermore, a systematic review and meta-analysis validated the benefits of PFS and overall response rate from the second-line co-treatment of NSCLC with bevacizumab and erlotinib.16 Case reports also indicated that the combination of bevacizumab and erlotinib enhanced the efficacy against central nervous system metastasis, especially leptomeningeal carcinomatosis after failure of erlotinib.17,18 Like bevacizumab, apatinib is a kind of vascular endothelial growth inhibitor, while the oral agent ensures the ease in use and is affordable to the patient, considering the patient’s choice of having targeted treatment at home. Apatinib, is also a novel oral anti-angiogenesis agent, potently suppressing the c-kit and c-src, and inhibiting the cellular phosphorylation of VEGFR-2, c-kit, and PDGFR beta,2 achieved certain antitumor drug effect and clinical benefits. Median overall survival and PFS were also significantly improved in the apatinib group compared with the placebo group in phase III trial.5 In light of the above, it should be considered to use apatinib to combat TKI resistance. The patient benefited another 5.1-month PFS after confronting erlotinib resistance.\n\nDuring the treatment of apatinib, the patient suffered from AEs, causing dosage adjustment. In phase II trial, the dosing regimen of 850 mg once daily was recommended for the treatment of gastric cancer.4 Hypertension, hand-food syndrome, and proteinuria were known to be the most common AEs of antiangiogenic agents in the phase I/II/III trials, and the incidence of hematologic toxicities was low.4–6 After this patient taking the minimum dosage of 250 mg once daily for ~1 month, thoracic CT and cranial MRI showed marked benefits, although facing the challenge of hypertension as well as bleeding when dabigatran was used. The dosage was constantly adjusted in accordance with the disease changes, reaching a maximum of 250 mg once daily. Dosing of apatinib requires adjustments in different cancers and populations to optimize efficacy and benefits to patients.\n\nCancer patients are more vulnerable to VTE. A recent study showed that a cumulative VTE incidence was as low as 3.2% over a follow-up of 2.5 years, a much lower risk compared with new diagnosis.19 The patient had cancer-related VTE after 23 months of cancer diagnosis. According to the current guidelines, patients are usually treated with anticoagulation for at least 3 months,20 especially those with cancer-related thrombosis who would benefit a lot from anticoagulation therapy, while the therapeutic regimen should adjust with cancer status.21 The current standard of care in patients with cancer and VTE is LMWH.22 Fraxiparine was given for 18 days and dabigatran was given for 27 days as outpatient treatment for the patient before wide-spread subcutaneous hemorrhage occurred.\n\nDabigatran, a new oral anticoagulant, is the direct thrombin inhibitor. In the sister trials RE-COVER and RE-COVER II,23,24 treatment with dabigatran for VTE in patients with cancer offers a similarly effective, safe, and more convenient alternative to VKA in terms of fixed drug dosing. Renal and hepatic functions of this patient were found normal after dabigatran was taken; however, subcutaneous hemorrhage could not be well controlled. The patient had lower blood platelet and higher APTT. No medication can effectively neutralize the anticoagulant effect in China at present. Probably, apatinib might worsen the bleeding by blocking new blood vessel formation or having interactions with dabigatran. Current studies showed that apatinib was metabolized primarily by CYP3A4/5;25 however, dabigatran was metabolized by esterases in the plasma and liver without significant involvement of CYP3A4.26,27 They might have a low potential for drug–drug interactions though other more specific profile is unknown.\n\nConclusion\nApatinib may be a recommendation for lung cancer patients and such studies are ongoing. To date, no evidence has been published on the use of apatinib against EGFR-TKI resistance in patients. Our study indicates that apatinib could be a potential option to combat EGFR-TKI resistance. However, further studies are required to verify these findings as well as more exploration on pharmacological dosage and AEs is needed.\n\nAcknowledgments\nThis case report was supported by China-Japan Friendship Hospital and Beijing Chest Hospital. We would like to thank Professor Qing Wu (English Department, School of Humanities, Beijing University of Chinese Medicine, Beijing, China) for English language editing. The authors thank the patient and his wife.\n\nAuthor contributions\n\nYP, HC, ZL, and DL was responsible for collection and assembly of the patient’s data. YP, FL, YS, HD, YQ, and QL performed data analysis and literature search. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Tumor section staining with hematoxylin and eosin (400×).\n\nFigure 2 Thoracic computed tomography (CT) showing a mass in the left upper lobe before taking apatinib (A), an obvious cavitation in the mass (B), mass increasing after apatinib suspension for 6 days (C), cavitation extending gradually with added dose of apatinib via monthly CT examination (D and E), and an overall increase of mass despite the larger cavitation (F). The red arrows indicate specific region of tumor.\n\nFigure 3 Cranial MRI showing the encephaledem in the occipital lobe of the head (A), encephaledem obviously alleviating (B), slightly worsening after suspension of apatinib for 6 days (C), the encephaledem basically under control as shown by CT every 2 months (D and E).\n\nAbbreviations: MRI, magnetic resonance imaging; CT, computed tomography.\n\nFigure 4 The venous blood routine from anticoagulant therapy.\n\nFigure 5 The activated partial thromboplastin time from anticoagulant therapy.\n\nFigure 6 The subcutaneous hemorrhage in limbs on August 31, 2016.\n\nTable 1 Medication of apatinib combined with erlotinib\n\nTime periods (in 2016)\tTime duration (days)\tApatinib dose (mg)\tErlotinib dose (mg)\tReasons for dosage adjustment\t\nFrom March 17 to April 6\t20\t250 qd\t150 qd\tStart from the minimum dosage\t\nFrom April 7 to May 6\t30\t250 qod from April 7\n500 qod from April 8\t150 qd\tGradually add the dosage to guarantee the curative effect\t\nFrom May 7 to 12\t6\tSuspension\t150 qd\tFear of bleeding caused by quickly emerging cavitation; hypertension\t\nFrom May 13 to 28\t16\t250 per 72 h\t150 qd\tResume taking the medicine because of the increasing mass\t\nFrom May 29 to June 23\t10\t250 per 48 h\t150 qd\tReturn to original dosage\t\nFrom June 14 to June 23\t10\t250\n2 days consecutively and 1 day cessation\t150 qd\tGradually return to original dosage\t\nFrom June 24 to July 8\t16\t250 qd\t150 qd\tGradually return to original dosage\t\nFrom July 9 to August 24\t46\t250 qd\t150 qod\tMaintenance treatment; anorexia, feebleness; VTE\t\nFrom August 25 to 31\t7\tSuspension\tSuspension\tExtensive subcutaneous hemorrhage; disease progression to death\t\nAbbreviations: qd, every day; qod, every other day; VTE, venous thromboembolism.\n==== Refs\nReferences\n1 Torre LA Bray F Siegel RL Ferlay J Lieuleut J Jemal A Global Cancer Statistics, 2012 CA Cancer J Clin 2015 65 2 87 108 25651787 \n2 Tian S Quan H Xie C YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo Cancer Sci 2011 102 7 1374 1380 21443688 \n3 Ding J Chen X Gao Z Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans Drug Metab Dispos 2013 41 6 1195 1210 23509226 \n4 Li J Qin S Xu J Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial J Clin Oncol 2013 31 26 3219 3225 23918952 \n5 Li J Qin S Xu J Trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction J Clin Oncol 2016 34 13 1448 26884585 \n6 Li J Zhao X Chen L Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies BMC Cancer 2010 10 529 20923544 \n7 Zhou C Wu YL Chen G Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, pen-label, randomised, phase 3 study Lancet Oncol 2011 12 8 735 742 21783417 \n8 Rosell R Carcereny E Gervais R Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial Lancet Oncol 2012 13 239 246 22285168 \n9 Wu YL Zhou C Liam CK Firstline erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study Ann Oncol 2015 26 1883 1889 26105600 \n10 Mok TS Wu YL Ahn MJ Planchard D. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer N Engl J Med 2017 376 629 640 27959700 \n11 Chatterjee S Heukamp LC Siobal M Tumor VEGF: VEGFR2 autocrine feed forward loop triggers angiogenesis in lung cancer J Clin Invest 2013 123 4 1732 1740 23454747 \n12 Li H Takayama K Wang S Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression Cancer Chemother Pharmacol 2014 74 6 1297 1305 25344762 \n13 Folkman J Angiogenesis in cancer, vascular, rheumatoid and other disease Nat Med 1995 1 1 27 31 7584949 \n14 Ettinger DS Wood DE Akerley W NCCN Guidelines Insight: non-small cell lung cancer, version 4. 2016 J Natl Compr Canc Netw 2016 14 3 255 264 26957612 \n15 Gridelli C Rossi A Ciardiello F BEVERLY: rationale and design of a randomized open-label phase III trial comparing bevacizumab plus erlotinib versus erlotinib alone as first-line treatment of patients with EGFR-mutated advanced nonsquamous non-small-cell lung cancer Clin Lung Cancer 2016 17 5 461 465 27209164 \n16 Zhang S Mao XD Wang HT Cai F Xu J Efficacy and safety of bevacizumab plus erlotinib versus bevacizumab or erlotinib alone in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis BMJ Open 2016 6 6 e011714 \n17 Ariyasu R Horiike A Koyama J Efficacy of bevacizumab and erlotinib combination for leptomeningeal carcinomatosis after failure of erlotinib Anticancer Drugs 2017 \n18 Sakata Y Kawamura K Shinqu N Ichikado K Erlotinib plus bevacizumab as an effective treatment for leptomeningeal metastases from EGFR mutation-positive non-small cell lung cancer Lung Cancer 2016 99 120 122 27565925 \n19 Prandoni P Casiglia E Piccioli A The risk of cancer in patients with venous thromboembolism does not exceed that expected in the general population after the first 6 months J Thromb Haemost 2010 8 5 1126 1127 20149076 \n20 O’Connell C How I treat incidental pulmonary embolism Blood 2015 125 12 1877 1882 25533036 \n21 Kearon C Akl EA Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism Blood 2014 123 12 1794 1801 24497538 \n22 Lee AY Levine MN Baker RI Low-molecular weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer N Engl J Med 2003 349 2 146 153 12853587 \n23 Schulman S Kearon C Kakkar AK Dabigatran versus warfarin in the treatment of acute venous thromboembolism N Engl J Med 2009 361 24 2342 2352 19966341 \n24 Schulman S Kakkar AK Goldhaber SZ Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis Circulation 2014 129 7 764 772 24344086 \n25 Ding JF Chen XY Gao ZW Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans Drug Metab Dispos 2013 41 6 1195 1210 23509226 \n26 Scaglione F New oral anticoagulants: comparative pharmacology with vitamin K antagonists Clin Pharmacokinet 2013 52 2 69 82 23292752 \n27 Short NJ Connors JM New oral anticoagulants and the cancer patient Oncologist 2014 19 1 82 93 24319019\n\n",
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"keywords": "NSCLC; dabigatran; epidermal growth factor receptor; vascular endothelial growth factor; venous thromboembolism",
"medline_ta": "Onco Targets Ther",
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"references": "21443688;25533036;24319019;7584949;26105600;23292752;23509226;19966341;22285168;26884585;27565925;24344086;20149076;25651787;28225456;23454747;26957612;21783417;27363819;27209164;23918952;12853587;20923544;24497538;27959700;25344762",
"title": "Apatinib to combat EGFR-TKI resistance in an advanced non-small cell lung cancer patient with unknown EGFR status: a case report.",
"title_normalized": "apatinib to combat egfr tki resistance in an advanced non small cell lung cancer patient with unknown egfr status a case report"
} | [
{
"companynumb": "CN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-025153",
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"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Depression-, anxiety-, OCD- and autism-related behaviors were assessed in 118 high-functioning individuals with autism spectrum disorders (ASD) and in 2016 controls. The ASD group had a higher rate of clinical depression and markedly higher \"insomnia\" and \"restlessness\" scores. Network analysis and hierarchical cluster analysis in the ASD group revealed that depression and anxiety items clustered together, but separately from autism-related items. Compared to controls, \"insomnia\" and \"restlessness\" items in the ASD network of depression items were much more central (higher closeness, and betweenness centrality). Combined networks of depression-, anxiety-, and OCD-related items revealed that the control group depression item module was not preserved in ASD. The results indicate that depression is atypical in autism and suggest specific intervention targets.",
"affiliations": "Child Study Center, Yale University School of Medicine, 230 S. Frontage Rd, New Haven, CT, 06519, USA. farhad.montazeri-lemraski@yale.edu.;Department of Child and Adolescent Psychiatry, Department of Psychiatry, University of Groningen, University of Groningen Medical Center, Groningen, The Netherlands.;Department of Child and Adolescent Psychiatry, Department of Psychiatry, University of Groningen, University of Groningen Medical Center, Groningen, The Netherlands.;Child Study Center, Yale University School of Medicine, 230 S. Frontage Rd, New Haven, CT, 06519, USA.",
"authors": "Montazeri|Farhad|F|http://orcid.org/0000-0001-8061-5184;de Bildt|Annelies|A|;Dekker|Vera|V|;Anderson|George M|GM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10803-019-03914-4",
"fulltext": null,
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"issn_linking": "0162-3257",
"issue": "50(5)",
"journal": "Journal of autism and developmental disorders",
"keywords": "Anxiety; Autism spectrum disorder; Clustering analysis; Depression; Gaussian graphical modeling; Module preservation analysis; Network analysis",
"medline_ta": "J Autism Dev Disord",
"mesh_terms": "D000293:Adolescent; D001007:Anxiety; D000067877:Autism Spectrum Disorder; D002648:Child; D000078332:Data Analysis; D003863:Depression; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D011595:Psychomotor Agitation; D007319:Sleep Initiation and Maintenance Disorders",
"nlm_unique_id": "7904301",
"other_id": null,
"pages": "1580-1595",
"pmc": null,
"pmid": "30778821",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Network Analysis of Behaviors in the Depression and Autism Realms: Inter-Relationships and Clinical Implications.",
"title_normalized": "network analysis of behaviors in the depression and autism realms inter relationships and clinical implications"
} | [
{
"companynumb": "US-OTSUKA-2020_017369",
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"activesubstancename": "ARIPIPRAZOLE"
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... |
{
"abstract": "Pancreatic pseudocyst formation with extension into the mediastinum is an uncommon complication of pancreatitis that can result in numerous pulmonary and cardiac complications. We present a case of a 56-year-old man with a history of recurrent pancreatitis who presented with haemoptysis. His initial workup was consistent with diffuse alveolar haemorrhage for which he was treated with glucocorticoids. After failure to improve, further imaging demonstrated a complex fluid collection in the mediastinum consistent with extension of his pre-existing pancreatic pseudocyst, leading to erosion into the right lower lobe of the lung. This case highlights a rare pulmonary complication of pancreatitis and underscores the importance of proper identification of this condition to guide successful management.",
"affiliations": "Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.;Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA lijo_illipparambil@urmc.rochester.edu.;Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.",
"authors": "Clark|Heather Lynn|HL|;Illipparambil|Lijo C|LC|;Khurana|Sandhya|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240677",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "pancreas and biliary tract; pancreatitis; respiratory medicine",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D006469:Hemoptysis; D006801:Humans; D008297:Male; D008482:Mediastinum; D008875:Middle Aged; D010192:Pancreatic Pseudocyst; D050500:Pancreatitis, Chronic",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
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"pmid": "34210696",
"pubdate": "2021-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mediastinal pancreatic pseudocyst masquerading as diffuse alveolar haemorrhage.",
"title_normalized": "mediastinal pancreatic pseudocyst masquerading as diffuse alveolar haemorrhage"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-144296",
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"abstract": "A primary aortoduodenal fistula (PADF) has rarely been reported as a complication of testicular cancer. A 48-year-old Japanese male with relapsed retroperitoneal lymph node metastases received four courses of paclitaxel, ifosfamide, and cisplatin (TIP). On day 19 of the fourth cycle of TIP, he developed hematochezia and hypovolemic shock. Angiography confirmed the presence of a PADF, and we then deployed an endovascular stent graft in the aorta. Although the bleeding improved, the patient died of re-bleeding that developed 18 days later. It is important to recognize this severe complication in order to achieve its early diagnosis and optimal surgical intervention.",
"affiliations": "Department of Urology, International University of Health and Welfare Narita Hospital, Narita, Japan.;Department of Urology, International University of Health and Welfare Narita Hospital, Narita, Japan.;Department of Urology, International University of Health and Welfare Narita Hospital, Narita, Japan.;Department of Radiology, International University of Health and Welfare Narita Hospital, Narita, Japan.;Department of Vascular Surgery, International University of Health and Welfare Narita Hospital, Narita, Japan.;Department of Urology, International University of Health and Welfare Narita Hospital, Narita, Japan.",
"authors": "Sakurai|Hiromichi|H|;Kawai|Koji|K|;Onozawa|Mizuki|M|;Akahane|Masaaki|M|;Takizawa|Reo|R|;Miyazaki|Jun|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2021.101746",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420\nElsevier\n\nS2214-4420(21)00186-8\n10.1016/j.eucr.2021.101746\n101746\nOncology\nPrimary aortoduodenal fistula in testicular cancer: A fatal complication associated with retroperitoneal lymph node metastasis\nSakurai Hiromichi a\nKawai Koji a\nOnozawa Mizuki a\nAkahane Masaaki b\nTakizawa Reo c\nMiyazaki Jun jmiyazaki@iuhw.ac.jp\na∗\na Department of Urology, International University of Health and Welfare Narita Hospital, Narita, Japan\nb Department of Radiology, International University of Health and Welfare Narita Hospital, Narita, Japan\nc Department of Vascular Surgery, International University of Health and Welfare Narita Hospital, Narita, Japan\n∗ Corresponding author. Department of Urology, International University of Health and Welfare Narita Hospital, 852 Hatakeda Narita, Chiba, 286-0124, Japan. jmiyazaki@iuhw.ac.jp\n08 6 2021\n11 2021\n08 6 2021\n39 10174623 5 2021\n5 6 2021\n6 6 2021\n© 2021 The Authors. 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/).\nA primary aortoduodenal fistula (PADF) has rarely been reported as a complication of testicular cancer. A 48-year-old Japanese male with relapsed retroperitoneal lymph node metastases received four courses of paclitaxel, ifosfamide, and cisplatin (TIP). On day 19 of the fourth cycle of TIP, he developed hematochezia and hypovolemic shock. Angiography confirmed the presence of a PADF, and we then deployed an endovascular stent graft in the aorta. Although the bleeding improved, the patient died of re-bleeding that developed 18 days later. It is important to recognize this severe complication in order to achieve its early diagnosis and optimal surgical intervention.\n\nKeywords\n\nTesticular cancer\nAortoduodenal fistula\nRetroperitoneal lymph node metastasis\n==== Body\nIntroduction\n\nA primary aortoenteric fistula is a rare and potentially fatal clinical disorder caused by the spontaneous erosion of the aorta into the gastrointestinal tract. Over half of the fistulas occurred between the aorta and the duodenum (usually its third portion), followed by cases between the aorta and the esophagus.1 Although duodenal involvement by retroperitoneal lymph node (RPLN) metastasis is frequently seen in testicular cancer, primary aortoduodenal fistula (PADF) is extremely rare. We describe PADF affecting a patient after chemotherapy for relapsed RPLN metastasis.\n\nCase presentation\n\nA 48-year-old Japanese male with testicular cancer was referred to our hospital. At the previous hospital, he received the diagnosis of right testicular seminoma with pT4. Computed tomography (CT) revealed multiple liver metastases and showed that bulky RPLN metastasis invaded the third portion of the duodenum (Fig. 1A). Laboratory tests showed a human chorionic gonadotropin (hCG) level of 24 IU/L, LDH at 1060 IU/L, and normal alfa-fetoprotein. Four cycles of bleomycin, etoposide, and cisplatin (BEP) had been administered at the previous hospital. In the BEP regimen, the cisplatin dose was reduced to 90%, and the start of the fourth cycle of BEP was delayed by 1 week.Fig. 1 CT/PET-CT images at different time points over the patient's course. A: Pretreatment CT showing bulky retroperitoneal lymph node (RPLN) metastasis invading the third portion of the duodenum (arrow). B: CT at 1 month after the completion of the BEP revealed the residual RPLN mass. C: PET-CT before the start of the salvage chemotherapy, showing strong 18F-FDG uptake (arrow) in the RPLN metastases. D: CT showing a dilated bowel loop fulfilled with a massive clot and direct extravasation of contrast from the aorta into the third portion of the duodenum (arrow).\n\nFig. 1\n\nAfter the completion of the BEP regimen, the patient's hCG and LDH values were normalized, and contrast-enhanced CT (Fig. 1B) and positron emission tomography (PET)-CT at 1 month after the completion of the BEP revealed the disappearance of liver metastases; however, a 4-cm RPLN mass remained with positive 18-fluorodeoxyglucose (18F-FDG) uptake. Six weeks later, the patient was referred to our hospital for further management.\n\nBecause the tumor markers were in the normal range at the time of referral, we considered that retroperitoneal lymph node dissection (RPLND) was reasonable treatment option. But, repeat PET-CT performed at our hospital showed increasing 18F-FDG uptake in RPLN metastases (Fig. 1C), and new uptake was observed in the right iliac lymph node metastases. Since those findings indicated disease progression, we decided to perform salvage chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP) rather than RPLND. No severe adverse effects were observed during the TIP treatment, but CT after two courses of TIP demonstrated that the RPLN metastasis did not respond to chemotherapy.\n\nThe adverse effect of two additional courses of TIP was also acceptable, but the patient developed sudden-onset hematochezia and hypovolemic shock on day 19 of the fourth cycle of TIP. Blood tests showed hemoglobin 4.7 g/dL, neutrophil count 4.8 × 109/L, and platelet count 4.9 × 109/L. CT depicted a dilated bowel loop fulfilled with a massive clot and a direct extravasation of contrast from the aorta into the third portion of the duodenum (Fig. 1D). The RPLN mass remained without a decrease in size. Endoscopic therapy was considered to be impossible because of the massive bowel clot. Since a patient was hemodynamically unstable, a decision was made to attempt angioembolization rather than surgical repair. Emergent angiography confirmed the presence of a PADF (Fig. 2A), and we then deployed an endovascular stent graft in the aorta. Control angiography showed minimal residual hemorrhage (Fig. 2B). Extensive fluid infusion and blood transfusion were needed to maintain the patient's blood pressure.Fig. 2 Abdominal angiogram. A: Emergent angiography confirming the presence of a PADF (arrow). B: Control angiography showing minimal residual hemorrhage after the placement of an endovascular stent graft.\n\nFig. 2\n\nDespite intensive care, the patient developed sepsis, disseminated intravascular coagulation (DIC), and multiple organ failure (MOF). Definitive surgical repair awaited the patient's recovery from MOF and DIC, but massive bleeding recurred 18 days after the first hemorrhage, and the patient died. Both septic shock due to graft infection and uncontrolled bleeding were considered to be cause of death. Permission for autopsy was refused.\n\nDiscussion\n\nOver 80% of primary aortoenteric fistulas are associated with an aneurysmal aorta which is followed by a foreign body, tuberculosis infection, and tumor. Saers and Scheltinga identified eight cases (10%) of cancer-associated primary aortoenteric fistulas among 81 reported cases.1 RPLN is the most common metastatic site of testicular cancer, and even though RPLN metastases with duodenum involvement are frequently seen, PADF is extremely rare as a complication of testicular cancer. To our knowledge, only four such cases of PADF are reported in the literature.2, 3, 4, 5 Two of those four patients had undergone RPLN dissection and radiation 13 years and 20 years before the development of the PADF.2,3 One of the patients suffered from a PADF 4 weeks after receiving BEP for RPLN metastases, and an autopsy confirmed a PADF secondary to extensive metastatic choriocarcinoma.5 A PADF is thus not necessary directly caused by chemotherapy. In our patient's case, although an autopsy was not performed, the lack of a response to chemotherapy suggested residual cancer cells in his RPLN metastases. The reduced intensity of the initial BEP might have been responsible for the patient's refractory disease.\n\nThe classic triad of PADF is upper gastrointestinal hemorrhage, abdominal pain, and a pulsating abdominal mass, but this triad was present in only 11% of the reported cases.1 The most frequently used diagnostic modalities were endoscopy and CT followed by angiography. However, the endoscopic diagnosis of the lower third of the duodenum is complicated, especially when the presence of a massive clot is involved as in the present case. In contrast, CT is less invasive and easier to perform. The confirmation of a PADF is based on the extravasation of contrast agent into the bowel, but this is observed in only approx. 25% of the cases. The presence of air within the aortic wall, focal bowel wall thickening, and the disruption of the aortic fat cover are CT findings suggesting a PADF.1\n\nPADF has been recognized as a highly fatal entity, but the proportion of patients who undergo surgery has increased over time, and the overall mortality rate has diminished. Investigations of cases reported between 1994 and 2003 showed that 84% of 81 patients with a PADF underwent surgery, and the mortality rate was 34%.1 It is important to recognize this severe disease in order to achieve an early diagnosis and provide the optimal surgical intervention.\n\nConclusions\n\nPADF is a rare but severe complication that can occur in testicular cancer with RPLN metastases. Bleeding can be fatal, an early diagnosis and prompt treatment are mandatory.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\n\nThe authors have no conflict of interest to disclose.\n\nAcknowledgements\n\nWe thank our colleagues for their support. This work was supported by 10.13039/501100001691 JSPS KAKENHI Grant Number JP19K09705 and JP21K09410.\n==== Refs\nReferences\n\n1 Saers S.J. Scheltinga M.R. Primary aortoenteric fistula Br J Surg 92 2005 143 152 15685700\n2 Kalman D.R. Barnard G.F. Massimi G.J. Swanson R.S. Primary aortoduodenal fistula after radiotherapy Am J Gastroenterol 90 1995 1148 1150 7611215\n3 Jayarajan S. Napolitano L.M. Rectenwald J.E. Upchurch G.R. Jr. Primary aortoenteric fistula and endovascular repair Vasc Endovasc Surg 43 2009 592 596\n4 Nord C. Fosså S.D. Giercksky K.E. Gastrointestinal presentation of germ cell malignancy Eur Urol 38 2000 721 724 11111190\n5 Hansen K.S. Sheley R.C. Aortoenteric fistula in advanced germ cell tumor: a rare lethal complication J Urol 167 2002 2131 11956460\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "39()",
"journal": "Urology case reports",
"keywords": "Aortoduodenal fistula; Retroperitoneal lymph node metastasis; Testicular cancer",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101746",
"pmc": null,
"pmid": "34189050",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": "19640906;11956460;11111190;7611215;15685700",
"title": "Primary aortoduodenal fistula in testicular cancer: A fatal complication associated with retroperitoneal lymph node metastasis.",
"title_normalized": "primary aortoduodenal fistula in testicular cancer a fatal complication associated with retroperitoneal lymph node metastasis"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2021INT000153",
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"patient": {
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"activesubstancename": "CISPLATIN"
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{
"abstract": "Drug-induced liver injury is hardly diagnosed, considering not only the wide range of hepatotoxic substances but also the diversity of associated phenotypes and the absence of specific biomarkers. Symptom chronology, drug or toxic exposure, and temporal association help to establish the diagnosis. Exposure to isopropanol has known but rare toxic effects. We report the clinical case of a 33-year-old female hairdresser admitted to the hospital with fatigue, epigastric pain, and jaundice. She presented the following values: aspartate aminotransferase, 485 U/L; alanine transaminase, 908 U/L; ALP, 240 U/L; GGT, 370 U/L; total bilirubin, 3.5 mg/dL; and direct bilirubin, 2.1 mg/dL. Albumin, platelet, and INR values were normal. Structural, infectious, immune, and vascular causes were excluded. Liver biopsy was suggestive of toxic hepatitis. A possible association with ibuprofen intake was considered. The patient resumed professional activity, with fatigue and jaundice relapse, as well as a new liver enzyme increase, despite ibuprofen withdrawal. It was concluded that a new hair product containing isopropanol had recently been introduced. As soon as its professional use was discontinued, there was no recurrence of the symptoms. Given the temporal association between the development of acute hepatitis and the use of an isopropanol-containing product, liver toxicity by exposure to isopropanol was assumed. This substance is metabolized in the liver and toxicity may occur by ingestion, skin exposure, or inhalation, and it is described in cases of occupational or accidental exposure. The treatment is symptomatic and comprises toxic suspension.",
"affiliations": "Internal Medicine Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal.;Internal Medicine Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal.;Internal Medicine Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal.;Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal.;Internal Medicine Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal.;Internal Medicine Department, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal.",
"authors": "Soares Santos|Daniela|D|;Nunes|Ana Luísa Luísa|ALL|;Matos|Ana Luísa|AL|;Lai|Ana|A|;Santos|Arsénio|A|;Carvalho|Armando|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000510035",
"fulltext": null,
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"issn_linking": "2387-1954",
"issue": "28(3)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Drug-induced liver injury; Hairdresser; Hepatotoxicity; Isopropanol; Occupational liver disease",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "198-201",
"pmc": null,
"pmid": "34056043",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "14748412;30926241;18409681;31540728;11568359;9713251;2870460",
"title": "A Case of Liver Injury after Exposure to Isopropanol: A Challenging Diagnosis.",
"title_normalized": "a case of liver injury after exposure to isopropanol a challenging diagnosis"
} | [
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"companynumb": "PT-PERRIGO-20PT014132",
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{
"actiondrug": "1",
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"activesubstancename": "IBUPROFEN"
},
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{
"abstract": "A patient with coronary artery fistula should be considered as high risk for intraoperative hemodynamic decompensation. In this article, we report the case of a 70-year-old man affected by a complex congenital coronary artery fistula defect. The patient underwent general anesthesia for spine surgery with permissive hypotension. The development of sudden intraoperative tachyarrhythmia with hemodynamic instability required immediate resuscitation and interruption of surgery. The claim advanced is that in patients with a coronary artery fistula permissive hypotension might be considered an option only if strictly necessary and real-time cardiac monitoring including transesophageal echocardiography is available to immediately detect and treat acute cardiac impairment.",
"affiliations": "Anesthesia and Intensive Care 1, Department of Anesthesia and Intensive Care, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.;Department of Medicine, University of Udine, Udine, Italy.;Anesthesia and Intensive Care 1, Department of Anesthesia and Intensive Care, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.;Humanitas University, Rozzano, Italy.;Anesthesia and Intensive Care 1, Department of Anesthesia and Intensive Care, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.;Anesthesia and Intensive Care Clinic, Department of Anesthesia and Intensive Care, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.;Anesthesia and Intensive Care Clinic, Department of Anesthesia and Intensive Care, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.;Anesthesia and Intensive Care 1, Department of Anesthesia and Intensive Care, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.",
"authors": "Deana|Cristian|C|https://orcid.org/0000-0002-1626-3177;Baron|Daniele|D|;Barbariol|Federico|F|;Negri|Katerina|K|https://orcid.org/0000-0002-9469-4781;Vecil|Marco|M|;Vetrugno|Luigi|L|;Bove|Tiziana|T|;Monte|Amato De|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1089253220922329",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1089-2532",
"issue": "24(4)",
"journal": "Seminars in cardiothoracic and vascular anesthesia",
"keywords": "acute heart failure; coronary fistula; permissive hypotension; prone position; transesophageal echocardiography",
"medline_ta": "Semin Cardiothorac Vasc Anesth",
"mesh_terms": "D000368:Aged; D001281:Atrial Fibrillation; D003331:Coronary Vessels; D017548:Echocardiography, Transesophageal; D004554:Electric Countershock; D006439:Hemodynamics; D006801:Humans; D007022:Hypotension; D007431:Intraoperative Complications; D008297:Male; D013616:Tachycardia, Sinus; D016157:Vascular Fistula",
"nlm_unique_id": "9807630",
"other_id": null,
"pages": "369-373",
"pmc": null,
"pmid": "32456533",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Complex Coronary Artery Fistula as a Potential Cause of Sudden Intraoperative Hemodynamic Compromise: A Case Report.",
"title_normalized": "a complex coronary artery fistula as a potential cause of sudden intraoperative hemodynamic compromise a case report"
} | [
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"companynumb": "IT-MYLANLABS-2021M1041695",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPOFOL"
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{
"abstract": "Among infant malignancies, congenital tumors, especially those of the central nervous system (CNS), constitute a rather unique subgroup. Poor survival rates (28% in CNS tumors) may be attributed to the aggressive biology as well as specific therapeutic limitations innate to the young age of affected patients. Our patient developed synchronous congenital tumors: an atypical teratoid/rhabdoid tumor (AT/RT) localized in the right lateral ventricle of the brain and a malignant rhabdoid tumor (MRT) in the soft tissue of the right orbit. A de novo germline chromosomal deletion in 22q encompassing the SMARCB1 gene was detected, prompting the diagnosis of a de novo rhabdoid tumor predisposition syndrome 1 (RTPS1). The patient was reported to the European Rhabdoid Registry (EU-RHAB) and treated according to the Rhabdoid 2007 recommendation. Despite the very young age of the patient, the initially desperate situation of RTPS1, and the synchronous localization of congenital rhabdoid tumors, intensive chemotherapy was well tolerated; the child is still in complete remission 5 years following diagnosis. In conclusion, RTPS1 with congenital synchronous MRTs is not necessarily associated with a detrimental outcome. Intensive multidrug chemotherapy, including high dose chemotherapy, may be feasible and justified.",
"affiliations": "Swabian Children's Cancer Center, Children's Hospital Augsburg, Augsburg, Germany.;Department of Pediatric Oncology, Children's Hospital St. Augustin, Sankt Augustin, Germany.;Institute of Neuropathology, University Hospital Münster, Münster, Germany.;Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.;Swabian Children's Cancer Center, Children's Hospital Augsburg, Augsburg, Germany.;Institute of Pathology, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.;Swabian Children's Cancer Center, Children's Hospital Augsburg, Augsburg, Germany; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany. Electronic address: michael.fruehwald@klinikum-augsburg.de.",
"authors": "Seeringer|Angela|A|;Reinhard|Harald|H|;Hasselblatt|Martin|M|;Schneppenheim|Reinhard|R|;Siebert|Reiner|R|;Bartelheim|Kerstin|K|;Leuschner|Ivo|I|;Frühwald|Michael C|MC|",
"chemical_list": "D000970:Antineoplastic Agents; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors",
"country": "United States",
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"issue": "207(9)",
"journal": "Cancer genetics",
"keywords": "Atypical teratoid/rhabdoid tumor; multimodal therapy; rhabdoid tumor predisposition syndrome 1; synchronous congenital tumors",
"medline_ta": "Cancer Genet",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D009378:Neoplasms, Multiple Primary; D009918:Orbital Neoplasms; D018335:Rhabdoid Tumor; D000071796:SMARCB1 Protein; D017741:Survivors; D013724:Teratoma; D014157:Transcription Factors",
"nlm_unique_id": "101539150",
"other_id": null,
"pages": "429-33",
"pmc": null,
"pmid": "25262118",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Synchronous congenital malignant rhabdoid tumor of the orbit and atypical teratoid/rhabdoid tumor--feasibility and efficacy of multimodal therapy in a long-term survivor.",
"title_normalized": "synchronous congenital malignant rhabdoid tumor of the orbit and atypical teratoid rhabdoid tumor feasibility and efficacy of multimodal therapy in a long term survivor"
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"abstract": "Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline PALB2 variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of RB1. We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.",
"affiliations": "Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.;Biotech Research & Innovation Centre (BRIC) and Finsen Laboratory, University of Copenhagen and Rigshospitalet, 2200 Copenhagen, Denmark.;Hubertus Wald Tumorzentrum, University Cancer Center Hamburg (UCCH), 20251 Hamburg, Germany.;Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.;Department of Urology, St. Antonius-Hospital, 48599 Gronau, Germany.;German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.;Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.;Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.;German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.;Division of Theoretical Bioinformatics, DKFZ, 69120 Heidelberg, Germany.;Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.;NCT Dresden, 01307 Dresden, Germany.;Progether Prostate Cancer Network, 0349 Oslo, Norway.;German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.;German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.;Bioinformatics and Omics Data Analytics, DKFZ, 69120 Heidelberg, Germany.;Health Data Science Unit, Bioquant, Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany.;Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.;German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.;German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.;Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.;NCT Dresden, 01307 Dresden, Germany.;Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.;Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.",
"authors": "Horak|Peter|P|0000-0003-4536-9306;Weischenfeldt|Joachim|J|;von Amsberg|Gunhild|G|;Beyer|Burkhard|B|;Schütte|Andreas|A|;Uhrig|Sebastian|S|;Gieldon|Laura|L|;Klink|Barbara|B|;Feuerbach|Lars|L|;Hübschmann|Daniel|D|0000-0002-6041-7049;Kreutzfeldt|Simon|S|;Heining|Christoph|C|;Maier|Sebastian|S|;Hutter|Barbara|B|;Penzel|Roland|R|;Schlesner|Matthias|M|0000-0002-5896-4086;Eils|Roland|R|;Sauter|Guido|G|;Stenzinger|Albrecht|A|;Brors|Benedikt|B|;Schröck|Evelin|E|;Glimm|Hanno|H|;Fröhling|Stefan|S|;Schlomm|Thorsten|T|",
"chemical_list": "D000076164:Fanconi Anemia Complementation Group N Protein; C512790:PALB2 protein, human; D010793:Phthalazines; D010879:Piperazines; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases; C531550:olaparib",
"country": "United States",
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"doi": "10.1101/mcs.a003657",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 3083341610.1101/mcs.a003657MCS003657HorResearch ReportResponse to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance Olaparib in PALB2 mutated prostate cancerOlaparib in PALB2 mutated prostate cancerhttp://orcid.org/0000-0003-4536-9306Horak Peter 123Weischenfeldt Joachim 424von Amsberg Gunhild 5Beyer Burkhard 6Schütte Andreas 7Uhrig Sebastian 389Gieldon Laura 101112Klink Barbara 101112Feuerbach Lars 38http://orcid.org/0000-0002-6041-7049Hübschmann Daniel 131415Kreutzfeldt Simon 13Heining Christoph 11121617Maier Sebastian 18Hutter Barbara 38Penzel Roland 319http://orcid.org/0000-0002-5896-4086Schlesner Matthias 20Eils Roland 2122Sauter Guido 23Stenzinger Albrecht 319Brors Benedikt 38Schröck Evelin 101112Glimm Hanno 1112161725Fröhling Stefan 12325Schlomm Thorsten 24251 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;2 DKFZ-Heidelberg Center for Personalized Oncology (HIPO), 69120 Heidelberg, Germany;3 German Cancer Consortium (DKTK), 69120 Heidelberg, Germany;4 Biotech Research & Innovation Centre (BRIC) and Finsen Laboratory, University of Copenhagen and Rigshospitalet, 2200 Copenhagen, Denmark;5 Hubertus Wald Tumorzentrum, University Cancer Center Hamburg (UCCH), 20251 Hamburg, Germany;6 Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;7 Department of Urology, St. Antonius-Hospital, 48599 Gronau, Germany;8 Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, 69120 Heidelberg, Germany;9 Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany;10 Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany;11 NCT Dresden, 01307 Dresden, Germany;12 German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;13 Division of Theoretical Bioinformatics, DKFZ, 69120 Heidelberg, Germany;14 Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany;15 Division of Stem Cells and Cancer, DKFZ, Heidelberg, Germany and Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany;16 Department of Translational Medical Oncology, NCT Dresden, 01307 Dresden, Germany;17 University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany;18 Progether Prostate Cancer Network, 0349 Oslo, Norway;19 Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany;20 Bioinformatics and Omics Data Analytics, DKFZ, 69120 Heidelberg, Germany;21 Health Data Science Unit, Bioquant, Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany;22 Center for Digital Health, Berlin Institute of Health and Charité Universitätsmedizin Berlin, 10178 Berlin, Germany;23 Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;24 Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany25 Shared last authorship\n\nCorresponding authors: peter.horak@nct-heidelberg.de; thorsten.schlomm@charite.de4 2019 5 2 a0036577 11 2018 8 2 2019 © 2019 Horak et al.; Published by Cold Spring Harbor Laboratory Press2019This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline PALB2 variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of RB1. We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.\n\nprostate cancerDKFZ-Heidelberg Center for Personalized OncologyH021\n==== Body\nINTRODUCTION\nWith growing evidence for the clinical activity of PARP inhibitors in several cancer entities, mutations in genes involved in HR are increasingly recognized as possible biomarkers, although the molecular events responsible for the development of resistance are incompletely understood (Lord and Ashworth 2017). Advanced prostate cancer is often characterized by germline and somatic alterations of genes involved in DNA repair via homologous recombination (HR) (Pritchard et al. 2016), which have also been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition in advanced disease. These data also suggest that a substantial proportion of advanced prostate cancer patients may display “BRCAness” and can benefit from PARP inhibition and/or platinum-based chemotherapy (Lord and Ashworth 2016). Data from a phase 2 study of olaparib in metastatic castration-resistant prostate cancer (CRPC) revealed that 88% of patients that had a response to olaparib harbored one or more deleterious alterations in DNA repair genes (Mateo et al. 2015). Here we report the first case of a pathogenic germline PALB2 (partner and localizer of BRCA2) variant that confers sensitivity to PARP inhibition in a patient with prostate cancer.\n\nClinical Presentation\nThe patient was diagnosed with locally advanced prostate adenocarcinoma at the age of 43. His family history was not suggestive of a hereditary cancer predisposition syndrome. The prostate-specific antigen (PSA) level at diagnosis was 76 ng/mL. Because of massive bladder neck infiltration, the patient underwent initial transurethral resection, followed by 6 mo of neoadjuvant combined hormonal therapy with leuprorelin and bicalutamide (PSA nadir 0.6 ng/mL) and radical retropubic prostatectomy. Even though the patient had a PSA response, postoperative staging and grading exposed a large tumor with nodal metastasis and positive surgical margins (pT4, pN1, cM0, R1) and a Gleason score of 5 + 4 = 9. Within a month after radical surgery, and despite ongoing hormonal therapy, the patient became castration-refractory and was treated with six cycles of docetaxel chemotherapy. Unfortunately, prostate-specific membrane antigen positron emission tomography after completion of chemotherapy demonstrated disseminated bone and lymph node metastases. Because of a PSA response during chemotherapy, four additional cycles of docetaxel were administered. Zoledronic acid was added to the treatment regimen. The patient developed fatigue and his general condition worsened because of progressive disease and accumulating side effects of chemotherapy (fatigue and muscular weakness leading to Eastern Cooperative Oncology Group [ECOG] and World Health Organization [WHO] Score 3). Following PSA and radiographic progression with hepatic metastases, therapy with abiraterone acetate and prednisolone was initiated, which could not bring about any treatment benefit.\n\nThe primary tumor from the radical prostatectomy was analyzed using whole-genome sequencing and made available for clinical interpretation within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program (Horak et al. 2017). We identified a pathogenic, heterozygous germline PALB2 mutation (Table 1) with somatic loss of heterozygosity in the tumor as well as a mutational signature suggestive of defective DNA repair via homologous recombination when analyzing the entirety of somatic SNVs (Alexandrov et al. 2013). This prompted a molecularly informed tumor board recommendation by the NCT MASTER molecular tumor board of PARP inhibitor treatment with or without platinum-based chemotherapy as well as genetic counseling. Single-agent treatment with the PARP inhibitor olaparib resulted in substantial improvement of clinical symptoms, and only moderate side effects (e.g., anemia CTCAE Grade 2) were observed. Remarkably, the patient restarted physical activities and his general condition improved (ECOG/WHO Score 1). However, staging after 6 wk revealed disease progression with 24.1% increase of target lesions. In addition, the PSA value increased during treatment with olaparib monotherapy from 15.2 µg/L to 110 µg/L, whereas LDH decreased from 471 U/L to 297 U/L. Because of the considerable clinical improvement, olaparib treatment was continued and cisplatin (30 mg/m2 i.v. weekly) was added. Magnetic resonance imaging after 2 mo of olaparib/cisplatin therapy showed disease stabilization by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria (Fig. 1). Addition of cisplatin resulted in a mild decrease of PSA to 96.4 µg/L as well as of LDH to 278 U/L. However, worsening anemia (CTCAE Grade 3) required transfusion of red blood cells and we observed decreasing neutrophil counts (CTCAE Grade 2).\n\nFigure 1. Magnetic resonance imaging of liver metastases (A) before and (B) after 2 mo of olaparib/cisplatin treatment. Two hepatic lesions were selected and their largest diameters measured in comparison according to RECIST 1.1 criteria as defined by PCGW3. Sum of longest diameters of the two target lesions was 6.22 cm before and 5.40 cm after olaparib/cisplatin treatment (13% decrease).\n\nTable 1. Variant table\n\nGene\tChromosome\tHGVS cDNA\tHGVS protein\tVariant type\tPredicted effect\tdbSNP\tGenotype\tClinVar\t\nPALB2\t16\tNM_024675.3:c.509_510delGA\tp.Arg170Ilefs\tFrameshift deletion\tLoss of function\trs515726123\tGermline heterozygous\t132267\t\nThree months thereafter, the lymphatic and hepatic metastases progressed and clinical symptoms worsened. At time of radiological progression PSA had further decreased to 50.9 µg/L, whereas LDH dramatically increased to 1501 U/L. Given the patient's young age and his desire to continue treatment, several experimental salvage regimens were administered. However, no durable stabilization of disease could be achieved and the patient died 5 mo later.\n\nGermline and Somatic Genomic Alterations\nTo identify molecular alterations that could inform experimental therapy in this patient, we used whole-genome and transcriptome sequencing data from the prostatectomy specimen that were obtained at diagnosis within the ICGC early-onset prostate cancer project (Weischenfeldt et al. 2013) as well as whole-exome and transcriptome sequencing data from a liver metastasis that was obtained upon progression on PARP Inhibitor therapy two and a half years later. Single nucleotide variants (SNVs), small insertions and deletions (indels), copy-number variations (CNVs), genomic structural variations, and gene fusions were interpreted with regard to their clinical significance and ranked according to therapeutic relevance.\n\nAnalysis of the primary tumor revealed 14 somatic nonsynonymous SNVs and two somatic indels including a known TP53 missense variant, NM_000546.5:c.451C>T, p.(Pro151Ser) (rs28934874) in the DNA-binding domain, which has been previously described as a pathogenic mutation in prostate cancer (Supplemental Table S1; Shi et al. 2002).\n\nWe detected a germline frameshift deletion in PALB2, NM_024675.3:c.509_510del, p.Arg170Ilefs*14 (rs515726123) (Table 1), which has already been described as a pathogenic Polish founder mutation associated with a predisposition for breast and ovarian cancer (Dansonka-Mieszkowska et al. 2010). This variant demonstrated somatic loss of heterozygosity with a mutational frequency of 70% in the primary tumor tissue. PALB2 is responsible for BRCA2 nuclear localization and DNA damage response (Xia et al. 2006) and serves as a molecular adaptor between BRCA1 and BRCA2 (Sy et al. 2009). Therefore, absence of PALB2 leads to impaired recruitment of BRCA2 and RAD51 to sites of DNA damage, making it a bona fide tumor suppressor. Germline loss-of-function mutations of PALB2 have been primarily associated with hereditary susceptibility to breast, ovarian, and pancreatic cancer (Jones et al. 2009; Antoniou et al. 2014; Southey et al. 2016), whereas homozygous loss of function leads to Fanconi anemia (Reid et al. 2007; Xia et al. 2007).\n\nInterestingly, we detected no other genetic hallmarks of prostate cancer, such as a TMPRSS2-ETS fusion or PTEN inactivation. We also observed prominent amplification (total copy number of 6) of the MYC proto-oncogene on Chromosome 8q24 (Fig. 2A), a common alteration in prostate cancer associated with increased aggressiveness (Van Den Berg et al. 1995; Jenkins et al. 1997; Fromont et al. 2013), which was accompanied by increased MYC mRNA expression. Another amplicon on Chromosome 2p24 encompassed the MYC family member MYCN. However, MYCN mRNA expression was not elevated in the primary tumor, in agreement with the observation that MYC and MYCN activation are mutually exclusive events in advanced prostate cancer (Boutros et al. 2015) and MYCN expression is often associated with a neuroendocrine phenotype (Beltran et al. 2016). Of note, MYCN expression was increased 4.8-fold in the therapy-resistant metastasis as compared to the primary tumor. Comparison of the primary and metastatic samples demonstrated no apparent evolution of CNVs contributing to additional oncogenic events, whereas extensive genomic rearrangements were evident at both time points (Fig. 2A). We also performed a supervised analysis of known mutational signatures (Alexandrov et al. 2013) and observed a strong contribution of signature Alexandrov-COSMIC 3, which is associated with defective HR DNA repair, to the mutational catalog in both the primary tumor and the metastasis (Fig. 2B).\n\nThe liver metastasis harbored 69 somatic nonsynonymous SNVs and two somatic indels (Supplemental Table S1). The TP53 mutation as well as five other SNVs and both indels identified in the primary tumor could not be detected in the metastasis, suggesting subclonal selection and evolution of the primary tumor during therapy. However, the distribution of allele frequencies of synonymous and nonsynonymous SNVs in both samples was influenced mainly by the tumor cell content and similar between the two samples (Fig. 2C). Interestingly, the metastasis carried a novel translocation, resulting in an in-frame fusion of RB1 exon 3 and exon 2 of COL28A1, encoding a collagen subtype, and was predicted to cause loss of retinoblastoma protein function (Fig. 3). We also observed discrete changes in the transcriptional profile, in particular up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype such as MYCN, AURKA, EZH2, and DNMT1 (Beltran et al. 2016).\n\nFigure 2. (A) DNA copy-number profiles of the primary tumor (upper panel) and metastasis (lower panel). (B) Relative contributions of mutational signatures (Alexandrov-COSMIC, AC) in the primary tumor (upper panel) and metastasis (lower panel) depicting the prevalence of the AC3 signature. (C) Distribution of measured allele frequencies of all somatic synonymous and nonsynonymous SNVs in both samples.\n\nFigure 3. Fusion between exon 3 of RB1 and exon 2 of COL28A1. Upper panels show the sequencing coverage and exon structure of the RB1 and COL28A1 as well as the structure of the putative fusion transcript. Chromatogram of the Sanger sequencing showing the nucleotide sequence of the fusion region is shown below.\n\nDISCUSSION\nOur observations suggest that deleterious germline PALB2 variants represent an actionable target in metastatic CRPC and support extended genomic testing in this patient population. CRPC has been reported to be a very heterogeneous entity and several molecular subtypes have recently been defined (Aggarwal et al. 2017). Among these, tumors with DNA repair alterations might be particularly amenable to precision oncology approaches as a plethora of DNA repair genes may be linked to PARP inhibitor sensitivity. Recent studies have established the occurrence of germline PALB2 mutations in prostate cancer as well as the sensitivity of other PALB2 deficient tumor entities to PARP inhibition (Erkko et al. 2007; Mateo et al. 2015). However, not every patient with DNA repair defects may experience clinical benefit, and the identification and detailed characterization of predictive biomarkers is an ongoing effort. A germline missense variant in the FANCA gene has been associated with exceptional response to platinum in neuroendocrine prostate cancer (Beltran et al. 2015). In our case, we observed an initial response to PARP inhibition combined with platinum-based therapy, which was followed by progression of an aggressive tumor resistant to further treatment and displaying newly acquired somatic genetic alterations typically associated with neuroendocrine prostate cancer, such as an inactivating RB1 fusion and elevated MYCN expression (Tan et al. 2014; Beltran et al. 2016). We did not find evidence for restoration of HR proficiency leading to secondary resistance to olaparib. We also hypothesize that resistance to PARP inhibition in prostate adenocarcinoma with “BRCAness” might co-occur with the emergence of neuroendocrine transdifferentiation (Akamatsu et al. 2018).\n\nIn summary, this comprehensive genomic and transcriptomic analysis indicates that pathogenic germline mutations in PALB2 are associated with hallmarks of defective HR, including extensive structural genomic rearrangements and enrichment of specific mutational signatures, and might predict response to PARP inhibition as well as platinum-based chemotherapy. We propose that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to define the entire spectrum of predictive biomarkers.\n\nMETHODS\nNext-Generation Sequencing, Bioinformatic Analysis, and Target Validation\nWhole-genome, whole-exome, and RNA sequencing were performed as described previously (Weischenfeldt et al. 2013; Kordes et al. 2016). The fusion transcript was validated by Sanger sequencing. SNVs and indels were identified using previously reported bioinformatics pipelines (Weischenfeldt et al. 2013). Structural variants were called with CREST (Wang et al. 2011). CNVs were extracted from whole-exome sequencing data with CNVkit (version 0.8.3.dev0). For the extraction of CNVs from whole-genome sequencing data we used our in-house CNV calling pipeline ACEseq (version 1.0.189) (Kleinheinz et al. 2017). A supervised analysis of mutational signatures to determine the contributions of known mutational signatures to the mutational catalog of individual samples was performed as described previously (Dieter et al. 2017). RNA-sequencing reads were mapped to the GRCh37.p13 assembly of the human reference genome using STAR 2.4.1c with the following alignment parameters:–outFilterMultimapNmax 10 –outFilterScoreMinOverLread 0.66 –outFilterMatchNmin 0 –outFilterMatchNminOverLread 0.66 –outFilterMismatchNmax 10 –outFilterMismatchNoverLmax 0.3 –clip5pNbases 0 –clip3pNbases 0 –clip3pAfterAdapterNbases 0 –clip3pAdapterSeq AGATCGGAAGAG –clip3pAdapterMMp 0.1 –seedSearchLmax 0 –seedSearchStartLmax 50 –alignIntronMin 21 –alignIntronMax 0 –alignMatesGapMax 0 –alignEndsType Local –alignSoftClipAtReferenceEnds No –chimSegmentMin 15 –chimScoreMin 1 –chimJunctionOverhangMin 15. The expression of genes annotated in the GencodeV19 gene model was quantified with featureCounts (version 1.4.6-p2) (Liao et al. 2014). High-confidence gene fusion predictions were extracted from chimeric alignments produced by STAR using our in-house pipeline Arriba (version 0.8), which removes recurrent alignment artifacts, transcript variants also observed in normal tissue, and reads with low sequence complexity as well as events with short anchors or breakpoints in close proximity or a low number of supporting reads relative to the overall number of predicted events in a gene. Sequencing coverage metrics are provided in Supplemental Table S2.\n\nADDITIONAL INFORMATION\nData Deposition and Access\nThe raw analytical data have been deposited in the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/datasets) under accession numbers EGAS00001000383 (primary tumor, patient ID EOPC-125) and EGAS00001003133 (metastasis). Oncological outcome data were collected via the Progether PROM's (patient reported outcome measurement) interface (www.progether.com).\n\nEthics Statement\nProstate tumor samples and a matched normal blood sample were obtained following written informed consent under an institutional review board–approved protocol covering all aspects relevant to clinical cancer genome sequencing. This study was approved and conducted in accordance with the Declaration of Helsinki.\n\nAuthor Contributions\nP.H., S.U., L.F., B.H., H.G., S.F., and T.S. were involved in the conception and design of the study. P.H., J.W., G.v.A., Bu.B., A.S., S.U., L.F., B.K., L.G., D.H., S.K., C.H., B.H., and R.P. collected and assembled the data. All authors performed data analysis and interpretation. P.H., J.W., S.U., B.K., L.G., S.F., and T.S. wrote the manuscript, and all authors approved the final version and are accountable for all aspects of the work.\n\nFunding\nThis work was supported by grant H021 from the DKFZ-Heidelberg Center for Personalized Oncology.\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n\nSupplementary Material\nSupplemental Material\n [Supplemental material is available for this article.]\n==== Refs\nREFERENCES\nAggarwal \nRR , Feng \nFY , Small \nEJ . 2017 \nEmerging categories of disease in advanced prostate cancer and their therapeutic implications . Oncology \n31 : 467 –474 .28620903 \nAkamatsu \nS , Inoue \nT , Ogawa \nO , Gleave \nME . 2018 \nClinical and molecular features of treatment-related neuroendocrine prostate cancer . 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JAMA Oncol \n1 : 466 –474 . 10.1001/jamaoncol.2015.1313 26181256 \nBeltran \nH , Prandi \nD , Mosquera \nJM , Benelli \nM , Puca \nL , Cyrta \nJ , Marotz \nC , Giannopoulou \nE , Chakravarthi \nBV , Varambally \nS , \n2016 \nDivergent clonal evolution of castration-resistant neuroendocrine prostate cancer . Nat Med \n22 : 298 –305 . 10.1038/nm.4045 26855148 \nBoutros \nPC , Fraser \nM , Harding \nNJ , de Borja \nR , Trudel \nD , Lalonde \nE , Meng \nA , Hennings-Yeomans \nPH , McPherson \nA , Sabelnykova \nVY , \n2015 \nSpatial genomic heterogeneity within localized, multifocal prostate cancer . Nat Genet \n47 : 736 –745 . 10.1038/ng.3315 26005866 \nDansonka-Mieszkowska \nA , Kluska \nA , Moes \nJ , Dabrowska \nM , Nowakowska \nD , Niwinska \nA , Derlatka \nP , Cendrowski \nK , Kupryjanczyk \nJ . 2010 \nA novel germline PALB2 deletion in Polish breast and ovarian cancer patients . BMC Med Genet \n11 : 20 \n10.1186/1471-2350-11-20 20122277 \nDieter \nSM , Heining \nC , Agaimy \nA , Huebschmann \nD , Bonekamp \nD , Hutter \nB , Ehrenberg \nKR , Fröhlich \nM , Schlesner \nM , Scholl \nC , \n2017 \nMutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma . Ann Oncol \n28 : 142 –148 . 10.1093/annonc/mdw446 27687311 \nErkko \nH , Xia \nB , Nikkilä \nJ , Schleutker \nJ , Syrjäkoski \nK , Mannermaa \nA , Kallioniemi \nA , Pylkäs \nK , Karppinen \nSM , Rapakko \nK , \n2007 \nA recurrent mutation in PALB2 in Finnish cancer families . Nature \n446 : 316 –319 . 10.1038/nature05609 17287723 \nFromont \nG , Godet \nJ , Peyret \nA , Irani \nJ , Celhay \nO , Rozet \nF , Cathelineau \nX , Cussenot \nO . 2013 \n8q24 amplification is associated with Myc expression and prostate cancer progression and is an independent predictor of recurrence after radical prostatectomy . Hum Pathol \n44 : 1617 –1623 . 10.1016/j.humpath.2013.01.012 23574779 \nHorak \nP , Klink \nB , Heining \nC , Gröschel \nS , Hutter \nB , Fröhlich \nM , Uhrig \nS , Hübschmann \nD , Schlesner \nM , Eils \nR , \n2017 \nPrecision oncology based on omics data: the NCT Heidelberg experience . Int J Cancer \n141 : 877 –886 . 10.1002/ijc.30828 28597939 \nJenkins \nRB , Qian \nJ , Lieber \nMM , Bostwick \nDG . 1997 \nDetection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization . Cancer Res \n57 : 524 –531 .9012485 \nJones \nS , Hruban \nRH , Kamiyama \nM , Borges \nM , Zhang \nX , Parsons \nDW , Lin \nJC , Palmisano \nE , Brune \nK , Jaffee \nEM , \n2009 \nExomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene . Science \n324 : 217 \n10.1126/science.1171202 19264984 \nKleinheinz \nK , Bludau \nI , Huebschmann \nD , Heinold \nM , Kensche \nP , Gu \nZ , Lopez \nC , Hummel \nM , Klapper \nW , Moeller \nP , \n2017 \nACEseq—allele specific copy number estimation from whole genome sequencing . bioRxiv \n10.1101/210807 \nKordes \nM , Röring \nM , Heining \nC , Braun \nS , Hutter \nB , Richter \nD , Geörg \nC , Scholl \nC , Gröschel \nS , Roth \nW , \n2016 \nCooperation of BRAFF595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling . Leukemia \n30 : 937 –946 . 10.1038/leu.2015.319 26582644 \nLiao \nY , Smyth \nGK , Shi \nW . 2014 \nfeatureCounts: an efficient general purpose program for assigning sequence reads to genomic features . Bioinformatics \n30 : 923 –930 . 10.1093/bioinformatics/btt656 24227677 \nLord \nCJ , Ashworth \nA . 2016 \nBRCAness revisited . Nat Rev Cancer \n16 : 110 –120 . 10.1038/nrc.2015.21 26775620 \nLord \nCJ , Ashworth \nA . 2017 \nPARP inhibitors: synthetic lethality in the clinic . Science \n355 : 1152 –1158 . 10.1126/science.aam7344 28302823 \nMateo \nJ , Carreira \nS , Sandhu \nS , Miranda \nS , Mossop \nH , Perez-Lopez \nR , Nava Rodrigues \nD , Robinson \nD , Omlin \nA , Tunariu \nN , \n2015 \nDNA-repair defects and olaparib in metastatic prostate cancer . N Engl J Med \n373 : 1697 –1708 . 10.1056/NEJMoa1506859 26510020 \nPritchard \nCC , Mateo \nJ , Walsh \nMF , De Sarkar \nN , Abida \nW , Beltran \nH , Garofalo \nA , Gulati \nR , Carreira \nS , Eeles \nR , \n2016 \nInherited DNA-repair gene mutations in men with metastatic prostate cancer . N Engl J Med \n375 : 443 –453 . 10.1056/NEJMoa1603144 27433846 \nReid \nS , Schindler \nD , Hanenberg \nH , Barker \nK , Hanks \nS , Kalb \nR , Neveling \nK , Kelly \nP , Seal \nS , Freund \nM , \n2007 \nBiallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer . Nat Genet \n39 : 162 –164 . 10.1038/ng1947 17200671 \nShi \nXB , Nesslinger \nNJ , Deitch \nAD , Gumerlock \nPH , deVere White \nRW . 2002 \nComplex functions of mutant p53 alleles from human prostate cancer . Prostate \n51 : 59 –72 . 10.1002/pros.10072 11920959 \nSouthey \nMC , Goldgar \nDE , Winqvist \nR , Pylkäs \nK , Couch \nF , Tischkowitz \nM , Foulkes \nWD , Dennis \nJ , Michailidou \nK , van Rensburg \nEJ , \n2016 \nPALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS . J Med Genet \n53 : 800 –811 . 10.1136/jmedgenet-2016-103839 27595995 \nSy \nSM , Huen \nMS , Chen \nJ . 2009 \nPALB2 is an integral component of the BRCA complex required for homologous recombination repair . Proc Natl Acad Sci \n106 : 7155 –7160 . 10.1073/pnas.0811159106 19369211 \nTan \nHL , Sood \nA , Rahimi \nHA , Wang \nW , Gupta \nN , Hicks \nJ , Mosier \nS , Gocke \nCD , Epstein \nJI , Netto \nGJ , \n2014 \nRb loss is characteristic of prostatic small cell neuroendocrine carcinoma . Clin Cancer Res \n20 : 890 –903 . 10.1158/1078-0432.CCR-13-1982 24323898 \nVan Den Berg \nC , Guan \nXY , Von Hoff \nD , Jenkins \nR , Bittner , Griffin \nC , Kallioniemi \nO , Visakorpi , McGill , Herath \nJ , \n1995 \nDNA sequence amplification in human prostate cancer identified by chromosome microdissection: potential prognostic implications . Clin Cancer Res \n1 : 11 –18 .9815882 \nWang \nJ , Mullighan \nCG , Easton \nJ , Roberts \nS , Heatley \nSL , Ma \nJ , Rusch \nMC , Chen \nK , Harris \nCC , Ding \nL , \n2011 \nCREST maps somatic structural variation in cancer genomes with base-pair resolution . Nat Methods \n8 : 652 –654 . 10.1038/nmeth.1628 21666668 \nWeischenfeldt \nJ , Simon \nR , Feuerbach \nL , Schlangen \nK , Weichenhan \nD , Minner \nS , Wuttig \nD , Warnatz \nHJ , Stehr \nH , Rausch \nT , \n2013 \nIntegrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer . Cancer Cell \n23 : 159 –170 . 10.1016/j.ccr.2013.01.002 23410972 \nXia \nB , Sheng \nQ , Nakanishi \nK , Ohashi \nA , Wu \nJ , Christ \nN , Liu \nX , Jasin \nM , Couch \nFJ , Livingston \nDM . 2006 \nControl of BRCA2 cellular and clinical functions by a nuclear partner, PALB2 . Mol Cell \n22 : 719 –729 . 10.1016/j.molcel.2006.05.022 16793542 \nXia \nB , Dorsman \nJC , Ameziane \nN , de Vries \nY , Rooimans \nMA , Sheng \nQ , Pals \nG , Errami \nA , Gluckman \nE , Llera \nJ , \n2007 \nFanconi anemia is associated with a defect in the BRCA2 partner PALB2 . Nat Genet \n39 : 159 –161 . 10.1038/ng1942 17200672\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "5(2)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "prostate cancer",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000328:Adult; D019008:Drug Resistance, Neoplasm; D000076164:Fanconi Anemia Complementation Group N Protein; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms; D000073658:Loss of Function Mutation; D008297:Male; D010793:Phthalazines; D010879:Piperazines; D057285:Precision Medicine; D011471:Prostatic Neoplasms; D056286:Retinoblastoma Binding Proteins; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30833416",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17200672;17287723;19264984;20122277;25099575;24323898;19369211;23574779;17200671;9815882;9012485;16793542;28620903;24227677;11920959;23410972;27595995;21666668;27687311;26005866;28302823;26181256;26855148;23945592;26775620;26510020;26582644;28597939;27433846;29396873",
"title": "Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance.",
"title_normalized": "response to olaparib in a palb2 germline mutated prostate cancer and genetic events associated with resistance"
} | [
{
"companynumb": "DE-MYLANLABS-2020M1002109",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
},
"drugadditional": nul... |
{
"abstract": "A 45-year-old woman with pulmonary sarcoidosis diagnosed 5 years previously, who was on treatment with prednisone and methotrexate for 1year, developed partial seizure with secondary generalization. MRI showed three non-cavitary enhancing lesions in the cerebello-occipital region. These lesions were presumed to be neurosarcoidosis. Methotrexate was discontinued, prednisone dose was increased and azathiopurine and levetiracetam were added. While on treatment, follow up imaging showed enlarging brain lesions. Biopsy of the lesions showed Epstein Barr virus (EBV) positive diffuse B cell lymphoma. Immunosuppressants were tapered off and she was begun on Rituximab. Because of lack of improvement after 4 cycles of Rituximab, she was then treated with high dose Methotrexate and Temozolamide. We present this case as a diagnostic challenge. New enhancing brain lesions occurring in a patient with long standing sarcoidosis, while likely to be neurosarcoidosis, may be due to a complication of immunosuppressant therapy. The need for early biopsy, if the lesions do not improve, should be considered.",
"affiliations": "SUNY Upstate Medical University. PandeyS@upstate.edu.",
"authors": "Pandey|Subodh|S|;Mukhopadhyay|Sanjay|S|;Iannuzzi|Michael C|MC|;Sah|Birendra P|BP|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-0490",
"issue": "31(1)",
"journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG",
"keywords": null,
"medline_ta": "Sarcoidosis Vasc Diffuse Lung Dis",
"mesh_terms": "D001927:Brain Diseases; D001932:Brain Neoplasms; D002493:Central Nervous System Diseases; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016393:Lymphoma, B-Cell; D008875:Middle Aged; D012507:Sarcoidosis",
"nlm_unique_id": "9610928",
"other_id": null,
"pages": "62-6",
"pmc": null,
"pmid": "24751455",
"pubdate": "2014-04-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "New brain lesions in a patient with sarcoidosis: is it neurosarcoidosis?",
"title_normalized": "new brain lesions in a patient with sarcoidosis is it neurosarcoidosis"
} | [
{
"companynumb": "US-ZYDUS-011827",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "Methotrexate therapy has been associated with occurrence and/or accelerated progression of malignancies. We describe a patient who developed widespread bone metastases of a previously confined to the prostate gland prostate cancer shortly after starting methotrexate therapy for rheumatoid arthritis and large granular lymphocyte leukemia. We believe an immunosuppressive milieu brought on by the methotrexate use in this case is responsible for the rapid progression of prostate cancer leading to the patient's demise. To the best of our knowledge, no association has been made to date between the therapy with methotrexate and a fulminant course of a previously indolent prostate cancer. Given its utilization in a variety of benign and malignant conditions and the ageing population, caution is advised with the use of this agent, especially in the presence of an underlying malignancy.",
"affiliations": "Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA.",
"authors": "Joseph|Ranjit|R|;Bockorny|Bruno|B|;Dasanu|Constantin A|CA|",
"chemical_list": "D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1177/1078155213484787",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "20(2)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Methotrexate; large granular lymphocyte leukemia; prostate cancer; rheumatoid arthritis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008727:Methotrexate; D011471:Prostatic Neoplasms",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "149-53",
"pmc": null,
"pmid": "23676505",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methotrexate therapy leading to a rapid progression of a previously indolent prostate cancer: is immunosuppression to blame?",
"title_normalized": "methotrexate therapy leading to a rapid progression of a previously indolent prostate cancer is immunosuppression to blame"
} | [
{
"companynumb": "PHHY2013US090425",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"d... |
{
"abstract": "Brain tumors harbor various BRAF alterations, the vast majority of which are the BRAF kinase-activating V600E mutation. BRAF mutations are most frequently detected in certain subtypes of low-grade glioma, such as pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT). However, it is unclear whether gliomas harboring BRAF mutations can be invariably regarded as these glioma subtypes or their derivatives. To address this question, we analyzed 274 gliomas in our institutional case series. We performed high-resolution melting analyses and subsequent direct Sanger sequencing on DNA isolated from snap-frozen tumor tissues. As expected, BRAF mutations were detected in the aforementioned low-grade gliomas: in 4/27 PAs, 2/3 PXAs, 4/8 GGs, and 1/6 DNTs. In addition to these gliomas, 1/2 astroblastomas (ABs) and 2/122 glioblastomas (GBs) harbored BRAF mutations. Pathological investigation of the two GBs revealed that one was a GB displaying epithelial features that presumably arose from a precedent GG, whereas the other GB, which harbored a rare G596 A mutation, showed marked epithelial features, including astroblastic rosettes. Our results indicate that in addition to being present in established BRAF-associated gliomas, BRAF mutations might be associated with epithelial features in high-grade gliomas, including sheet-like arrangement of polygonal tumor cells with a plump cytoplasm and astroblastic rosettes, and thus could potentially serve as a genetic marker for these features.",
"affiliations": "Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurosurgery, Kitakyushu Municipal Medical Center, Kitakyushu, Japan.;Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Hatae|Ryusuke|R|;Hata|Nobuhiro|N|;Suzuki|Satoshi O|SO|;Yoshimoto|Koji|K|;Kuga|Daisuke|D|;Murata|Hideki|H|;Akagi|Yojiro|Y|;Sangatsuda|Yuhei|Y|;Iwaki|Toru|T|http://orcid.org/0000-0001-7826-870X;Mizoguchi|Masahiro|M|;Iihara|Koji|K|",
"chemical_list": "C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf",
"country": "Australia",
"delete": false,
"doi": "10.1111/neup.12347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-6544",
"issue": "37(3)",
"journal": "Neuropathology : official journal of the Japanese Society of Neuropathology",
"keywords": "BRAF; G596 A; astroblastic rosette; glioblastoma; glioma",
"medline_ta": "Neuropathology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms; D002648:Child; D002675:Child, Preschool; D004847:Epithelial Cells; D005260:Female; D005910:Glioma; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf; D055815:Young Adult",
"nlm_unique_id": "9606526",
"other_id": null,
"pages": "191-199",
"pmc": null,
"pmid": "27792249",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A comprehensive analysis identifies BRAF hotspot mutations associated with gliomas with peculiar epithelial morphology.",
"title_normalized": "a comprehensive analysis identifies braf hotspot mutations associated with gliomas with peculiar epithelial morphology"
} | [
{
"companynumb": "JP-009507513-1706JPN006946",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Acute liver failure (ALF) is associated with significant morbidity and mortality. Studies have implicated the immune response, especially monocyte/macrophages as being important in dictating outcome.\n\n\n\nTo investigate changes in the circulating monocytes and other immune cells serially in patients with ALF, relate these with cytokine concentrations, monocyte gene expression and patient outcome.\n\n\n\nIn a prospective case-control study in the Scottish Liver Transplant Unit, Royal Infirmary Edinburgh, 35 consecutive patients admitted with paracetamol-induced liver failure (POD-ALF), 10 patients with non-paracetamol causes of ALF and 16 controls were recruited. The peripheral blood monocyte phenotype was analysed by flow cytometry, circulating cytokines quantified by protein array and monocyte gene expression array performed and related to outcome.\n\n\n\nOn admission, patients with worst outcomes after POD-ALF had a significant monocytopenia, characterised by reduced classical and expanded intermediate monocyte population. This was associated with reduced circulating lymphocytes and natural killer cells, peripheral cytokine patterns suggestive of a 'cytokine storm' and increased concentrations of cytokines associated with monocyte egress from the bone marrow. Gene expression array did not differentiate patient outcome. At day 4, there was no significant difference in monocyte, lymphocyte or natural killer cells between survivors and the patients with adverse outcomes.\n\n\n\nSevere paracetamol liver failure is associated with profound changes in the peripheral blood compartment, particularly in monocytes, related with worse outcomes. This is not seen in patients with non-paracetamol-induced liver failure. Significant monocytopenia on admission may allow earlier clarification of prognosis, and it highlights a potential target for therapeutic intervention.",
"affiliations": "MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.;MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.;MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.;MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.;MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.;Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.",
"authors": "Moore|J K|JK|;MacKinnon|A C|AC|;Man|T Y|TY|;Manning|J R|JR|;Forbes|S J|SJ|;Simpson|K J|KJ|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D016207:Cytokines; D000082:Acetaminophen",
"country": "England",
"delete": false,
"doi": "10.1111/apt.13878",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "45(3)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury; D016207:Cytokines; D005260:Female; D006801:Humans; D007970:Leukopenia; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D009000:Monocytes; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "443-454",
"pmc": null,
"pmid": "27896824",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patients with the worst outcomes after paracetamol (acetaminophen)-induced liver failure have an early monocytopenia.",
"title_normalized": "patients with the worst outcomes after paracetamol acetaminophen induced liver failure have an early monocytopenia"
} | [
{
"companynumb": "GB-JNJFOC-20170110557",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Giant cell tumor (GCT) of bone is a locally aggressive tumor with low metastatic potential, usually originating in long bones. Numerous spinal examples have been reported and thus GCTs can be encountered by neuropathologists. We describe a 69-year-old man with more than a 10-year history of GCT primary to the femur that had recently metastasized to the occipital skull bone. The patient had been receiving denosumab, an adjuvant therapy for GCT, prior to the metastasis. Review of the histological features of the original primary tumor in the femur showed archetypal features of GCT, but the posttreatment occipital skull metastasis showed a predominantly low-to-medium cell density spindle cell tumor with complete depletion of osteoclastic giant cells. Although this effect of the drug is increasingly being recognized by soft tissue pathologists, the current case illustrates the potentially confusing histology of postdenosumab-treated GCT for neuropathologists. The absence of giant cells leads the posttherapy primary or metastatic lesion to show histologic similarity to a multitude of benign and malignant fibro-osseous lesions or spindle cell sarcoma and highlights the importance of eliciting appropriate clinical history.",
"affiliations": "Department of Pathology.;Departments of Pathology, Neurology and Neurosurgery, University of Colorado, Aurora, Colorado.",
"authors": "Gilani|Ahmed|A|;Kleinschmidt-DeMasters|Bette K|BK|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "England",
"delete": false,
"doi": "10.1093/jnen/nlz100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3069",
"issue": "78(12)",
"journal": "Journal of neuropathology and experimental neurology",
"keywords": "Anti-RANKL monoclonal antibody; Bone tumors; Denosumab; Giant cell tumor; Metastasis; Occipital bone; Sarcoma",
"medline_ta": "J Neuropathol Exp Neurol",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D000069448:Denosumab; D005269:Femur; D018212:Giant Cell Tumor of Bone; D006801:Humans; D008297:Male; D009777:Occipital Bone; D012888:Skull Neoplasms",
"nlm_unique_id": "2985192R",
"other_id": null,
"pages": "1171-1173",
"pmc": null,
"pmid": "31665371",
"pubdate": "2019-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Denosumab Therapy Obscures Histological Features of Giant Cell Tumor of Bone.",
"title_normalized": "denosumab therapy obscures histological features of giant cell tumor of bone"
} | [
{
"companynumb": "US-AMGEN-USASP2019115038",
"fulfillexpeditecriteria": "2",
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"abstract": "A 39-year-old man with anemia presented at our hospital in November 2011. Peripheral blood analysis revealed lymphocytosis with a large granular lymphocyte (LGL) count of 2,272/µl, with CD3+, CD4-, CD8+, CD56-, TCR-αβ+; Southern blotting analysis revealed clonal TCR Cβ 1 gene rearrangement, leading to the diagnosis of T-LGL leukemia. In June 2012, the patient was administered with cyclophosphamide as an initial treatment because he developed transfusion-dependent anemia. His anemia improved, and the treatment was discontinued in March 2013. However, anemia recurred in March 2014. The administration of cyclophosphamide was resumed; however, it was subsequently replaced with cyclosporine because of the risk of secondary cancer due to the long-term use of cyclophosphamide. However, his anemia did not improve. Further, the patient was administered with prednisone, methotrexate, and pentostatin; however, the transfusion-dependent state persisted with the cumulative transfusion of 186 RBC units until March 2016. After CD52 expression on the surface of LGL cells was confirmed, treatment with alemtuzumab, which is a monoclonal antibody against CD52, was initiated in April 2016 and the dose was gradually increased from 3 mg to 30 mg thrice per week. The patient's anemia began to improve 1 week after initiating alemtuzumab treatment, and he became transfusion-independent in the second week. Although alemtuzumab treatment was discontinued at the fifth week on the basis of a positive test result for CMV antigenemia, the result consequently became negative after ganciclovir treatment. To date, the patient's hemoglobin level has been maintained at approximately 12 g/dl without any treatment. Herein we reported the case of a patient having LGL leukemia with refractory anemia that was successfully treated using alemtuzumab.",
"affiliations": "Department of Hematology, NTT Medical Center Tokyo.;Department of Hematology, NTT Medical Center Tokyo.;Department of Hematology, NTT Medical Center Tokyo.;Department of Hematology, NTT Medical Center Tokyo.;Department of Hematology, NTT Medical Center Tokyo.;Department of Hematology, NTT Medical Center Tokyo.;Department of Hematology, NTT Medical Center Tokyo.;Department of Hematology, NTT Medical Center Tokyo.",
"authors": "Iijima|Kimiko|K|;Hirao|Masako|M|;Hino|Toshiya|T|;Kamoda|Yoshimasa|Y|;Iizuka|Hiromitsu|H|;Kida|Michiko|M|;Hangaishi|Akira|A|;Usuki|Kensuke|K|",
"chemical_list": "D000074323:Alemtuzumab",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.2392",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Alemtuzumab; Anemia; Large granular lymphocyte leukemia",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D000740:Anemia; D005434:Flow Cytometry; D006801:Humans; D054066:Leukemia, Large Granular Lymphocytic; D008297:Male",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "2392-2396",
"pmc": null,
"pmid": "29332872",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of large granular lymphocytic leukemia accompanied by refractory anemia with alemtuzumab.",
"title_normalized": "successful treatment of large granular lymphocytic leukemia accompanied by refractory anemia with alemtuzumab"
} | [
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"abstract": "We present a case of an 82-year-old man with new-onset neuromyelitis optica (NMO) spectrum disorder, the treatment of which was complicated by a severe pre-existing prednisone allergy. His age caused much initial doubt about his diagnosis, and his corticosteroid allergy altered our management as we attempted to minimize risk to the patient. Our patient was a healthy 82-year-old, right-handed man who presented with sensory loss of the bilateral lower extremities and progressive, painless vision loss. MRI showed bilateral pre-chiasmatic optic nerve and optic chiasm enhancement, along with enhancement within the thoracic spinal cord from T3 to T7. Serum NMO-IgG was positive with a titer >1: 100,000. Due to concern of allergic reaction, our patient initially refused high-dose Solu-Medrol and opted to try plasma exchange alone, but due to worsening of his symptoms we attempted to use dexamethasone as it had a theoretically lower risk of adverse reaction with a known prednisone allergy. There are several cases of elderly-onset NMO in the literature but this is the only case we could find of NMO accompanied by a rare severe allergy to prednisone. This case demonstrates the relative safety of dexamethasone as an alternative to methylprednisolone for acute management of NMO spectrum disorder, though efficacy has not been established in major trials. Cross-reactivity between various systemic corticosteroids is not as well established as topical corticosteroids, so it is difficult to assess the probability of a reaction between prednisone and methylprednisolone.",
"affiliations": "Department of Neurology, University of Oklahoma, Oklahoma City, Oklahoma, USA.;Department of Neurology, University of Oklahoma, Oklahoma City, Oklahoma, USA.;Department of Neurology, University of Oklahoma, Oklahoma City, Oklahoma, USA.;Department of Neurology, University of Oklahoma, Oklahoma City, Oklahoma, USA.",
"authors": "Hollen|Christopher|C|;Suhaib|Omer|O|;Farrow|Aaron|A|;Sidorov|Evgeny|E|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000485120",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. 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 10.1159/000485120crn-0010-0025Case ReportElderly-Onset Neuromyelitis Optica Spectrum Disorder with Pre-Existing Prednisone Allergy Hollen Christopher *Suhaib Omer Farrow Aaron Sidorov Evgeny Department of Neurology, University of Oklahoma, Oklahoma City, Oklahoma, USA*Chris Hollen, Department of Neurology, University of Oklahoma, 920 Stanton L. Young Boulevard, Suite 2040, Oklahoma City, OK 73104-5036 (USA), E-Mail Christopher-hollen@ouhsc.eduJan-Apr 2018 23 1 2018 23 1 2018 10 1 25 28 1 9 2017 8 11 2017 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We present a case of an 82-year-old man with new-onset neuromyelitis optica (NMO) spectrum disorder, the treatment of which was complicated by a severe pre-existing prednisone allergy. His age caused much initial doubt about his diagnosis, and his corticosteroid allergy altered our management as we attempted to minimize risk to the patient. Our patient was a healthy 82-year-old, right-handed man who presented with sensory loss of the bilateral lower extremities and progressive, painless vision loss. MRI showed bilateral pre-chiasmatic optic nerve and optic chiasm enhancement, along with enhancement within the thoracic spinal cord from T3 to T7. Serum NMO-IgG was positive with a titer >1: 100,000. Due to concern of allergic reaction, our patient initially refused high-dose Solu-Medrol and opted to try plasma exchange alone, but due to worsening of his symptoms we attempted to use dexamethasone as it had a theoretically lower risk of adverse reaction with a known prednisone allergy. There are several cases of elderly-onset NMO in the literature but this is the only case we could find of NMO accompanied by a rare severe allergy to prednisone. This case demonstrates the relative safety of dexamethasone as an alternative to methylprednisolone for acute management of NMO spectrum disorder, though efficacy has not been established in major trials. Cross-reactivity between various systemic corticosteroids is not as well established as topical corticosteroids, so it is difficult to assess the probability of a reaction between prednisone and methylprednisolone.\n\nKeywords\nNeuromyelitis opticaSystemic corticosteroid allergyElderly-onset neuromyelitis opticaOptic neuritis\n==== Body\nBackground\nNeuromyelitis optica (NMO) spectrum disorder is an autoimmune disease of the central nervous system, characterized by inflammation of the optic nerves and longitudinal lesions of the spinal cord. Aquaporin-4-immunoglobulin is highly specific for NMO. The median onset is typically around 40 years of age, though there are several cases in the literature remarkable for onset in patients up to their late 80s [1]. High-dose corticosteroids (methylprednisolone 1,000 mg daily for 3–5 days) are the mainstay of management of initial and acute attacks. Plasma exchange (PLEX) is typically utilized for patients with severe symptoms or those who are not responsive to the initial regimen of corticosteroids. Allergies to systemic corticosteroids are very uncommon, though severe reactions including angioedema and anaphylaxis following oral or intravenous corticosteroids have been described [2].\n\nCase Presentation\nAn 82-year-old, right-handed Caucasian man was admitted to our neurology service due to rapidly progressive, painless vision loss and sensory loss of the bilateral lower extremities. Prior to the onset of symptoms he was healthy and independent in his activities of daily living. Initially, his vision began to deteriorate in the left eye 2 weeks prior to presentation, and 1 week later he began to have painless vision loss in the right eye. Subsequently, he began to experience abdominal pain in a band around his umbilicus along with numbness that began in the mid-trunk and gradually extended to include his lower extremities, which ultimately led to his presentation to our emergency department.\n\nHis initial examination showed preserved light perception in the left eye with impaired perception of motion and no light perception in the right eye. He had patchy sensory loss to all modalities below T10. He was hyperreflexic in the left lower extremity with crossed adductors, crossed patellar reflex, and an extensor plantar response on the left. He had no discernable weakness or cranial nerve abnormalities. MRI brain/orbits, C-spine, and T-spine with/without contrast revealed bilateral pre-chiasmatic optic nerve and optic chiasm enhancement, along with patchy but longitudinally extensive hyperintense STIR signal and post-contrast enhancement within the thoracic spinal cord from T3 to T7.\n\nInitial laboratory testing was unremarkable, including CBC, comprehensive metabolic panel, B12, copper, rapid plasma regain, antinuclear antibodies, erythrocyte sedimentation rate, and C-reactive peptide. His CSF revealed 10 WBCs, 9 RBCs, glucose 52 (roughly 2/3 serum glucose), and protein 59. CSF oligoclonal bands were negative. Serum angiotensin-converting enzyme was low at 3.\n\nBased on his imaging and CSF findings his working diagnosis was NMO, but neurosarcoidosis was also on our differential given his abnormal age for presentation of NMO. He initially refused steroids, opting for PLEX alone due to the severe reaction he had to oral prednisone 2 months prior (angioedema with airway compromise). He completed 5 rounds of PLEX (every 48 h for 10 days). However, by hospital day 4 his symptoms worsened. His sensory level now extended from T4 and he began to have weakness of the bilateral lower extremities. Ultimately, his serum NMO-IgG returned positive with a titer >1: 100,000, confirming our diagnosis. He reconsidered his position on attempting intravenous steroids given the worsening strength of his upper extremities. Based on the suspicion of lowest probability of cross-reactivity, we initiated dexamethasone, opting for 25 mg every 6 h followed by a taper for 2 days. We moved the patient to an intensive care bed for close monitoring in the event of a severe reaction requiring intubation. His symptoms persisted but did not worsen. However, he suffered from psychosis and hallucinations likely as a consequence of steroid administration on his final 2 days of high-dose dexamethasone. He was ultimately discharged to a rehab facility prior to returning home and arrangements were made to prepare for outpatient rituximab infusions for NMO maintenance therapy.\n\nDiscussion\nWe present a case of an elderly man with new onset of NMO spectrum disorder. There have been at least 4 cases of elderly-onset NMO with onset after the age of 80 described in the literature, with the oldest at age 90, but this is the only case we could find of NMO accompanied by a rare severe allergy to prednisone. NMO is characterized by longitudinal lesions of the spinal cord and optic nerves. It follows a relapsing course in the vast majority of patients and is associated with NMO-IgG antibodies, which are highly specific. The 2015 diagnostic criteria for NMO spectrum disorder includes at least 1 core clinical characteristic, a positive test for aquaporin-4-IgG, and exclusion of alternative diagnoses [3]. As has been reported in other cases of NMO in the elderly, the diagnosis was initially placed into some doubt by the patient's age. However, our patient's classic longitudinally extensive thoracic spine lesion, involvement of the bilateral optic nerves/optic chiasm, and lack of history of malignancy provided a high degree of clinical suspicion. Transverse myelitis appears to be the most common initial presenting feature of NMO in the elderly, which is also consistent with late-onset multiple sclerosis where spinal lesions are much more common as compared to early-onset multiple sclerosis [4].\n\nManagement of acute attacks of NMO is centered on intravenous corticosteroids. The Neuromyelitis Optica Study Group suggests 5 consecutive days of methylprednisolone followed by an oral steroid taper depending on the severity of the attack and confirmation of NMO diagnosis. If symptoms do not improve, 5–7 cycles of therapeutic PLEX may be beneficial. A study of 21 patients carried out by Menon et al. [5] suggests that intravenous dexamethasone is a fairly comparable, effective, and safe treatment option for patients with demyelinating optic neuritis. However, evidence for the best choice of treatment for acute attacks of NMO is limited.\n\nCorticosteroid allergies are rare, particularly to systemic corticosteroids. Urticarial and dermatologic reactions are most frequent, but anaphylaxis and angioedema can occur in response to corticosteroids [6]. There are four classes of corticosteroids outlined in the Coopman classification of corticosteroids, based on structural composition and dermatologic testing. The Coopman classification system separates methylprednisolone and prednisone in a separate class from dexamethasone, and some small series have suggested hydrocortisone/methylprednisolone may exhibit more cross-reactivity than halogenated steroids like betamethasone or dexamethasone. However, this classification system was designed to address dermatologic reactions to topical steroids and may not adequately reflect potential cross-reactivity between various systemic corticosteroids. Cross-reactivity between systemic corticosteroids has not been well established, in part because the process of creating water-soluble steroids for intravenous use requires coupling to an ester which may modify the allergenicity of corticosteroids [7]. Since we cannot base our clinical counseling on chemical structure or classification to reliably predict potential cross-reactivity, careful challenge testing in a controlled environment must be employed when intradermal testing is not available or impractical. Intradermal testing is available to confirm hypersensitivity reactions if suspected, though a graded challenge is not standardized.\n\nIn summary, we present a case of an elderly man with NMO with a conundrum of acute management with a previous severe reaction to prednisone. After a review of the available literature, it appeared optimal to initiate intravenous dexamethasone rather than methylprednisolone. Though cross-reactivity between different systemic corticosteroids is not entirely clear, it was felt to be less likely between these two agents. Importantly, in the elderly it is critical to keep NMO in mind in cases of painless vision loss or evidence of typical spinal lesions, even though it is uncommon in this population. Our patient appeared to have no worsening of his symptoms, but steroids were not administered until 14 days after the onset of his vision loss, so it is likely that he did not receive the maximal benefit of acute therapy.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare. No funding was received for this study.\n==== Refs\nReferences\n1 Loh KP Brennan MJ Elderly-onset neuromyelitis optica spectrum disorders J Am Geriatr Soc 2015 63 411 412 25688626 \n2 Rachid R Hypersensitivity to systemic corticosteroids: an infrequent but potentially life- threatening condition J Allergy Clin Immunol 2011 127 524 528 21093900 \n3 Wingerchuk DM International consensus diagnostic criteria for neuromyelitis optica spectrum disorders Neurology 2015 85 177 189 26092914 \n4 Krumbholz M Very late-onset neuromyelitis optica spectrum disorder beyond the age of 75 J Neurol 2015 262 1379 1384 25957640 \n5 Menon V Comparative evaluation of megadose methylprednisolone with dexamethasone for treatment of primary typical optic neuritis Indian J Ophthalmol 2007 55 355 359 17699944 \n6 Erdmann SM Anaphylaxis induced by glucocorticoids J Am Board Fam Pract 2005 18 143 146 15798144 \n7 Torres MJ Canto G Hypersensitivity reactions to corticosteroids Curr Opin Allergy Clin Immunol 2010 10 273 279 20502322\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "10(1)",
"journal": "Case reports in neurology",
"keywords": "Elderly-onset neuromyelitis optica; Neuromyelitis optica; Optic neuritis; Systemic corticosteroid allergy",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "25-28",
"pmc": null,
"pmid": "29515420",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "26092914;25957640;15798144;20502322;21093900;17699944;25688626",
"title": "Elderly-Onset Neuromyelitis Optica Spectrum Disorder with Pre-Existing Prednisone Allergy.",
"title_normalized": "elderly onset neuromyelitis optica spectrum disorder with pre existing prednisone allergy"
} | [
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"companynumb": "US-TEVA-2018-US-926511",
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"activesubstancename": "DEXAMETHASONE"
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"abstract": "Minocycline hydrochloride, a synthetic tetracycline, is a systemic antibiotic that has received much attention over the past several years. Currently, minocycline is considered the most widely prescribed oral antibiotic in the management of acne. Minocycline has been associated with autoimmune events, hepatitis, lupus-like syndromes, serum sickness, vasculitis, Sweet's syndrome, and hyperpigmentation. We report a case of a patient who developed drug-induced immune thrombocytopenic purpura (DITP) after taking minocycline. The initial clinical presentation of nonpalpable, discrete nonblanching petechiae and cayenne pepper-like macules on his lower legs was diagnosed as pigmented purpuric dermatosis (Schamberg's disease). We report the first case of DITP with the clinical picture of Schamberg's disease associated with minocycline therapy.",
"affiliations": "Department of Dermatology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA.",
"authors": "D'Addario|Stephen F|SF|;Bryan|Matthew E|ME|;Stringer|Warren A|WA|;Johnson|Sandra Marchese|SM|",
"chemical_list": "D008911:Minocycline",
"country": "United States",
"delete": false,
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"issn_linking": "1545-9616",
"issue": "2(3)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D010859:Pigmentation Disorders; D016553:Purpura, Thrombocytopenic, Idiopathic",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "320-3",
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"pubdate": "2003-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced immune thrombocytopenia presenting as Schamberg's disease.",
"title_normalized": "minocycline induced immune thrombocytopenia presenting as schamberg s disease"
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"abstract": "Epstein-Barr virus (EBV) is a member of the herpesvirus family that is associated with various disease manifestations, including EBV-associated colitis. There are few case reports describing hemorrhage associated with EBV colitis. We report a 61-year-old woman with acute gastrointestinal bleeding due to EBV colitis after initiation of methylprednisolone and enoxaparin for spinal cord infarction. To our knowledge, there are only a few case reports of hemorrhagic EBV colitis. Perhaps we need to have a higher suspicion for EBV in cases of colitis associated with hemorrhage even in relatively immunocompetent patients.",
"affiliations": "Department of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA.;Department of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA.;Department of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA.;Department of Pathology, Thomas Jefferson University Hospital, Philadelphia, PA.",
"authors": "Denicola|Richard P|RP|;Coben|Robert|R|;Katz|Leo|L|;McCue|Peter A|PA|",
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"doi": "10.14309/crj.0000000000000238",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JACGCRJACGCRJAC9ACG Case Reports Journal2326-3253Wolters Kluwer Maryland, MD ACGCR-19-044410.14309/crj.000000000000023800011Case ReportColonAcute Gastrointestinal Hemorrhage due to Epstein-Barr Virus Colitis Denicola Richard P. MD1Coben Robert MD1Katz Leo MD1McCue Peter A. MD21 Department of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA2 Department of Pathology, Thomas Jefferson University Hospital, Philadelphia, PACorrespondence: Richard P. Denicola, MD. 132 South 10th St, Suite 480, Philadelphia, PA 19107 (Richard.Denicola@jefferson.edu).10 2019 15 10 2019 6 10 e0023813 6 2019 28 8 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.ABSTRACT\nEpstein-Barr virus (EBV) is a member of the herpesvirus family that is associated with various disease manifestations, including EBV-associated colitis. There are few case reports describing hemorrhage associated with EBV colitis. We report a 61-year-old woman with acute gastrointestinal bleeding due to EBV colitis after initiation of methylprednisolone and enoxaparin for spinal cord infarction. To our knowledge, there are only a few case reports of hemorrhagic EBV colitis. Perhaps we need to have a higher suspicion for EBV in cases of colitis associated with hemorrhage even in relatively immunocompetent patients.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nEpstein-Barr virus (EBV) is a member of the herpesvirus family that is associated with various disease manifestations such as infectious mononucleosis, chronic active EBV infection, x-linked lymphoproliferative disease, nasopharyngeal carcinoma, Burkitt's lymphoma, Hodgkin's disease, and acquired immunodeficiency syndrome or posttransplantation-associated lymphoproliferative disease.1,2 The virus spreads through oral secretions where it replicates and sheds, leading to a primary infection that is controlled by the host's natural killer cells and CD4+ and CD8+ cytotoxic T-cells.1 The initial infection is largely asymptomatic or nonspecific with sore throat and malaise. However, patients may have typical infectious mononucleosis symptoms, including pharyngitis, fever, and lymphadenopathy.3 HLA-restricted cytotoxic T-cells and CD8+ T-cells are important in controlling EBV in the latency phase in which case the virus infects the host's B cells.1 Disruption to these host immune responses can lead to reactivation. The physiologic stimuli that trigger this reactivation are not well described in humans although humanized mice models have been developed to better model EBV disease in vivo.2,4 This reactivation can manifest as infectious mononucleosis or as other rarer complications including, but not limited to, hematologic derangements (hemolytic anemia, thrombocytopenia, aplastic anemia, etc.), neurologic complications (Guillain-Barré syndrome, facial nerve palsy, aseptic meningitis, transverse myelitis, etc.), splenic rupture, and upper airway obstruction.3,5 However, only a few case reports have described hemorrhagic EBV colitis.\n\nCASE REPORT\nA 61-year-old woman with a history of tobacco abuse, cervical cancer, diabetes mellitus, obstructive sleep apnea, hyperlipidemia, and a new diagnosis of spinal cord infarction complicated by paraparesis and dysesthesias presented to a university medical center with painless, bright red blood per rectum. The patient had recently been treated for spinal cord infarction with 5 days of methylprednisolone at a dose of 1,000 mg intravenous daily, followed by a 5-day prednisone taper starting at 40 mg daily and therapeutic enoxaparin. Her symptoms rapidly improved from paraparesis to ambulating in a matter of days. She was discharged to a short-term rehabilitation center. While at the rehabilitation center, the patient developed a significant gastrointestinal hemorrhage with hemodynamic instability and a decrease in serum hemoglobin levels from 12 to 7 g/dL upon admission to a community hospital. She was noted to have maroon-colored stools and required 2 units of packed red blood cells. She underwent upper endoscopy revealing a normal esophagus, stomach, and duodenum. Colonoscopy revealed nonbleeding diverticula and normal mucosa. The patient experienced no further bleeding and was transferred back to the university medical center for workup of worsening lower extremity weakness that developed after the gastrointestinal hemorrhage.\n\nOne week into her hospitalization, she began to have maroon-colored stools with a hemoglobin trend from 9.0 to 7.0 g/dL, but not requiring red blood cell transfusion. She had no abdominal pain at this time. As part of her neurologic workup, she underwent a computed tomography angiogram study of the chest, abdomen, and pelvis, which demonstrated air-fluid levels on the left side of the colon, but normal abdominopelvic vasculature. She underwent repeat colonoscopy revealing multiple areas of patchy discontinuous ulceration with friability and bleeding on contact throughout the whole colon (Figure 1). These findings were compatible with colitis and appeared to be ischemic. Cold forceps biopsies were performed for histology. In situ hybridization stain demonstrated the presence of intracellular EBV consistent with EBV-associated colitis (Figure 2). This diagnosis was confirmed by a second pathologist. Infectious disease was consulted, and therapeutic intravenous ganciclovir was started. Neurology and infectious disease consults recommended outpatient repeat MRI of the spine to evaluate for EBV myelitis as a cause of spinal cord findings. The patient was transitioned to oral valganciclovir and discharged to a short-term rehabilitation center.\n\nFigure 1. Colonoscopy showing (A) a linear streak of erythema and friable mucosa in the distal transverse colon and (B) an area of erythema and friability with contact oozing of blood in the proximal descending colon.\n\nFigure 2. Hematoxylin and eosin stain showing (A) acute colitis (20×) and (B) the presence of intracellular Epstein-Barr virus (40×).\n\nDISCUSSION\nWe describe a case of hemorrhagic EBV colitis in a presumed immunocompetent patient that strongly mimicked ischemic colitis by history and colonoscopy. It is conceivable that this presentation was multifactorial, including elements of both EBV and ischemic colitis. The patient's diabetes and recent presumed spinal cord infarction suggestive of the hypercoagulable state are risk factors for intestinal ischemia. Her previous colonoscopy could have been a risk factor for intestinal ischemia. However, her symptoms preceded the initial colonoscopy at the community hospital. It was our clinical impression that ischemic colitis was not the driving factor, given the prolonged course with the absence of abdominal symptoms, lack of documented hypotension with normal abdominopelvic vasculature on imaging, and absence of clear ischemic colitis on histology. Because of the undetectable serum EBV DNA polymerase chain reaction at the time of diagnosis, the infectious disease consultant felt that it was likely reactivation rather than primary infection. Other than the short course of methylprednisolone, the patient had not received any other immunocompromising medications.\n\nTo our knowledge, there are only a few case reports of hemorrhagic EBV colitis; however, these cases are associated with much higher levels of immunosuppression. Matsumoto et al reported a case of a 56-year-old man who experienced hemorrhage colitis from reactivation of EBV and cytomegalovirus (CMV) while undergoing antithymocyte globulin and cyclosporine therapy for severe aplastic anemia.6 The initial colonoscopy demonstrated severe colitis, but on biopsy, only nonspecific inflammation was seen on histology. A second colonoscopy on the same patient demonstrated the positive immunohistochemical presence of both EBV and CMV as well as positive serum CMV antigen and EBV DNA. After completion of the immunosuppressive therapy and treatment of CMV/EBV, there was resolution of the bloody diarrhea. Interestingly, after an increase in cyclosporine dose 6 months later, the same patient had recurrence of severe bloody diarrhea and positive EBV on biopsy and in the serum.6\n\nRarely, we may see superimposed EBV infection in our inflammatory bowel disease-afflicted patients such as was seen in Afzal's 21-year-old patient with ulcerative colitis who presented with mixed bloody diarrhea and colonoscopy images and histology consistent with ulcerative colitis that failed to improve with standard medical therapy. The diagnosis of EBV was made only after revisiting the pathology slides and testing for EBV DNA after inflammatory bowel disease treatment failure. The patient was then treated with ganciclovir with a significant improvement in symptoms.7 These 2 case reports describe immunocompromised patients in whom a high suspicion of EBV was required to make the diagnosis. Despite the short course of steroids in our patient, there were no other obvious immunosuppressive factors involved. Moreover, the pattern of injury in our patient closely mimicked ischemic colitis which seemed unlikely to be the driving factor in her clinical course. Perhaps, we need to have a higher suspicion for EBV in cases of colitis even in immunocompetent patients.\n\nDISCLOSURES\nAuthor contributions: RP Denicola wrote the manuscript. R. Cohen revised the manuscript, approved the final version, and is the article guarantor. L. Katz and PA McCue analyzed and interpreted the data.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Cohen JI \nEpstein–Barr virus infection . N Engl J Med. \n2000 ;343 (7 ):481 –92 .10944566 \n2. Murata T \nRegulation of Epstein–Barr virus reactivation from latency . Microbiol Immunol. \n2014 ;58 (6):307 –17 .24786491 \n3. Luzuriaga K Sullivan JL \nInfectious mononucleosis . N Engl J Med. \n2010 ;362 :1993 –2000 .20505178 \n4. Stanfield BA Luftig MA \nRecent advances in understanding Epstein-Barr virus . F1000Res . 2017 ;6 :386 .28408983 \n5. Eligio P Delia R Valeria G \nEBV chronic infections . Mediterr J Hematol Infect Dis . 2010 ;2 (1 ):e2010022 .21415952 \n6. Matsumoto H Kimura Y Murao T \nSevere colitis associated with both Epstein-Barr virus and cytomegalovirus reactivation in a patient with severe aplastic anemia . Case Rep Gastroenterol. \n2014 ;8 :240 –4 .25120415 \n7. Afzal M Nigam GB \nEBV colitis with ulcerative colitis: A double whammy . BMJ Case Rep. \n2018 ;2018 :bcr-2018 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "6(10)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00238",
"pmc": null,
"pmid": "31832465",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "25120415;28408983;24786491;20505178;21415952;10944566;29960963",
"title": "Acute Gastrointestinal Hemorrhage due to Epstein-Barr Virus Colitis.",
"title_normalized": "acute gastrointestinal hemorrhage due to epstein barr virus colitis"
} | [
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"companynumb": "US-ZYDUS-048415",
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"abstract": "OBJECTIVE\nThe initiation of a pharmacist-managed clinic to ensure appropriate use of erythropoietin-stimulating agents (ESAs) at a Veterans Affairs medical center is described.\n\n\nCONCLUSIONS\nA drug-use evaluation (DUE) in 2005 showed that ESA therapy met all of the institution's usage criteria in only 2 of 49 patients receiving ESAs. A protocol was developed and approved for pharmacist management of ESA therapy; physicians refer all patients beginning or currently receiving ESAs to a clinic established for pharmacist management of this therapy. The clinic initiated iron therapy when a patient's transferrin saturation (TSAT) was <20% and serum ferritin concentration was <100 ng/ mL, indicating low iron stores. Hemoglobin, TSAT, and ferritin levels at baseline and after four months of clinic management were compared for 35 patients, as were the costs of ESA therapy before and after clinic enrollment. Hemoglobin levels improved significantly within one month, and cost savings were substantial. Six months after clinic implementation, ESA therapy for 27 of 29 patients was in compliance with DUE criteria.\n\n\nCONCLUSIONS\nPharmacist management of patients receiving ESA therapy was effective in improving hemoglobin levels and compliance with criteria for ESA use, and it achieved substantial cost savings.",
"affiliations": "Erie Veterans Affairs Medical Center, Erie, PA 16504, USA. stephanie.clapp@va.gov",
"authors": "Clapp|Stephanie E|SE|;Bardo|Jamie A|JA|;Chrymko|Margaret M|MM|",
"chemical_list": "D011994:Recombinant Proteins; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D000068817:Epoetin Alfa",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp070228",
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"issn_linking": "1079-2082",
"issue": "65(15)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000554:Ambulatory Care Facilities; D000068256:Darbepoetin alfa; D017723:Drug Utilization Review; D017850:Economics, Pharmaceutical; D000068817:Epoetin Alfa; D004921:Erythropoietin; D019983:Guideline Adherence; D006801:Humans; D010595:Pharmacists; D011994:Recombinant Proteins; D014481:United States",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1458-63",
"pmc": null,
"pmid": "18653817",
"pubdate": "2008-08-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Implementation of a pharmacist-managed clinic for patients receiving erythropoietin-stimulating agents.",
"title_normalized": "implementation of a pharmacist managed clinic for patients receiving erythropoietin stimulating agents"
} | [
{
"companynumb": "US-AMGEN-USASP2020008768",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"actiondrug": "6",
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"activesubstancename": "ERYTHROPOIETIN"
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... |
{
"abstract": "BACKGROUND\nAntiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.\n\n\nRESULTS\n1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).\n\n\nCONCLUSIONS\nEFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.\n\n\nBACKGROUND\nwww.ClinicalTrials.gov NCT00084136. Please see later in the article for the Editors' Summary.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine, Aurora, United States of America. thomas.campbell@ucdenver.edu",
"authors": "Campbell|Thomas B|TB|;Smeaton|Laura M|LM|;Kumarasamy|N|N|;Flanigan|Timothy|T|;Klingman|Karin L|KL|;Firnhaber|Cynthia|C|;Grinsztejn|Beatriz|B|;Hosseinipour|Mina C|MC|;Kumwenda|Johnstone|J|;Lalloo|Umesh|U|;Riviere|Cynthia|C|;Sanchez|Jorge|J|;Melo|Marineide|M|;Supparatpinyo|Khuanchai|K|;Tripathy|Srikanth|S|;Martinez|Ana I|AI|;Nair|Apsara|A|;Walawander|Ann|A|;Moran|Laura|L|;Chen|Yun|Y|;Snowden|Wendy|W|;Rooney|James F|JF|;Uy|Jonathan|J|;Schooley|Robert T|RT|;De Gruttola|Victor|V|;Hakim|James Gita|JG|;|||",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pmed.1001290",
"fulltext": "\n==== Front\nPLoS MedPLoS MedPLoSplosmedPLoS Medicine1549-12771549-1676Public Library of Science San Francisco, USA 22936892PMEDICINE-D-11-0297710.1371/journal.pmed.1001290Research ArticleMedicineEfficacy and Safety of Three Antiretroviral Regimens for Initial\nTreatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational\nSettings Evaluation of Antiretrovirals in Diverse\nSettingsCampbell Thomas B. \n1\n\n*\nSmeaton Laura M. \n2\nKumarasamy N. \n3\nFlanigan Timothy \n4\nKlingman Karin L. \n5\nFirnhaber Cynthia \n6\nGrinsztejn Beatriz \n7\nHosseinipour Mina C. \n8\nKumwenda Johnstone \n9\nLalloo Umesh \n10\nRiviere Cynthia \n11\nSanchez Jorge \n12\nMelo Marineide \n13\nSupparatpinyo Khuanchai \n14\nTripathy Srikanth \n15\nMartinez Ana I. \n5\nNair Apsara \n16\nWalawander Ann \n16\nMoran Laura \n17\nChen Yun \n2\nSnowden Wendy \n18\nRooney James F. \n19\nUy Jonathan \n20\nSchooley Robert T. \n21\nDe Gruttola Victor \n2\nHakim James Gita \n22\nfor the PEARLS study team of the ACTGPEARLS study team of the ACTGSwann Edith Ph.D.HIV Research Branch, TRP, DAIDS, NIAD, NIH, Bethesda,\nMarylandBarnett Ronald L. Ph.D.ACTG Operations Centre, Social & Scientific Systems, Inc.\nSilver Spring, MarylandBrizz Barbara B.S.N., M.H.S.Ed.ACTG Operations Center, Social & Scientific Systems, Inc.\nSilver Spring, MarylandDelph Yvette M.D.ACTG Operations Center, Social & Scientific Systems, Inc.\nSilver Spring, MarylandGettinger Nikki M.P.H.ACTG Operations Center, Social & Scientific Systems Inc.\nSilver Spring, MarylandMitsuyasu Ronald T. M.D.UCLA CARE Center, Los Angeles, CaliforniaEshleman Susan M.D.Johns Hopkins University, Baltimore, MarylandSafren Steven Ph.D.Harvard Medical School, Boston, MassachusettsFiscus Susan A. Ph.D.Department of Microbiology & Immunology, University of\nNorth Carolina, School of Medicine, Chapel Hill, North\nCarolinaAndrade Adriana M.D., M.P.H.Division of Infectious Diseases, John Hopkins University,\nBaltimoreHaas David W. M.D.Infectious Diseases, Vanderbilt University, Nashville,\nTennesseeAmod Farida MB CHBFCPath, FCP, Department of Medicine, Nelson R Mandela School of\nMedicine, Durban, South AfricaBerthaud Vladimir M.D.Infectious Disease, Vanderbilt University Medical Centre,\nNashville, TennesseeBollinger Robert C. M.D.Division of Infectious Diseases, John Hopkins University,\nBaltimore, MarylandBryson Yvonne M.D.Pediatric Infectious Disease Dept., UCLA School of Medicine,\nLos Angeles, CaliforniaCelentano David Sc.D., M.H.S.Department of Epidemiology, Johns Hopkins School of Hygiene and\nPublic Health, Baltimore, MarylandChilongozi David C.O., M.P.H.UNC HIVNET, UNC Project, Lilongwe, MalawiCohen Myron M.D.University of North Carolina, Chapel Hill, North CarolinaCollier Ann C. M.D.University of Washington, ACTU, Harborview Medical Centre,\nSeattle, WashingtonCurrier Judith Silverstein M.D., M.ScUniversity of California, Los Angeles, CaliforniaCu-Uvin Susan M.D.The Miriam Hospital, Brown University, Immunology Centre,\nProvidence, Rhode IslandEron Joseph M.D.Division of Infectious Diseases, Dept. of Medicine, University\nof North Carolina, Chapel Hill, North CarolinaFlexner Charles M.D.Johns Hopkins University Hospital, Baltimore, MarylandGallant Joel E. M.D., M.P.H.Division of Infectious Diseases, Johns Hopkins University\nSchool of Medicine, Baltimore, MarylandGulick Roy M. M.D., M.P.H.The Cornell Clinical Trials Unit, New York, New YorkHammer Scott M. M.D.Division of Infectious Diseases, Columbia Presbyterian Medical\nCentre, New York, New YorkHoffman Irving P.A., M.P.H.University of North Carolina, Chapel Hill, North CarolinaKazembe Peter MBCHB FRCP(C)Baylor College of Medicine-Abbott Fund Children's Clinical\nCentre of Excellence, Lilongwe, MalawiKumwenda Newton M.P.H., Ph.D.Johns Hopkins Project, MalawiLama Javier R. M.D., M.P.H.Investigaciones Medicas en Salud (INMENSA), Lima, PeruLawrence Jody M.D.University of California, San Francisco, Adult AIDS Clinical\nTrials Unit, San Francisco, CaliforniaMaponga Chiedza Pharm.D., DaTISMedical University of Zimbabwe, ZimbabweMartinson Francis M.D.UNC Project, LilongweMayer Kenneth M.D.Division of Infectious Diseases, Brown University School of\nMedicine, Memorial Hospital of Rhode Island, Pawtucket, Rhode\nIslandNielsen Karin M.D.UCLA School of Medicine, Los Angeles, CaliforniaPendame Richard B. M.D., M.P.H.MalawiRamratnam Bharat M.D.Laboratory of Retrovirology, Division of Infectious Diseases,\nBrown University Medical School, Providence, Rhode IslandSanne Ian Ph.D.University of Witwatersrand, Johannesburg, South AfricaSevere Patrice M.D.Internal Medical, Infectious Diseases, Institute de\nLaboratories et de Recherches, Port-au-Prince, HaitiSirisanthana Thira M.D.Research Institute for Health Sciences, Chiang Mai University,\nChiang Mai, ThailandSolomon Suniti M.D.YRG Centre for AIDS Research and Education, Chennai,\nIndiaTabet Steve M.D.University of Washington, Harborview Medical Centre, Seattle,\nWashingtonTaha Taha M.D.Johns Hopkins University, School of Hygiene & Public\nHealth, Baltimore, Marylandvan der Horst Charles M.D.Department of Medicine, University of North Carolina, Chapel\nHill, North CarolinaWanke Christine M.D.Tufts University School of Medicine, Boston,\nMassachusettsGormley Joan B.S.N.The Miriam Hospital, Immunology Centre, Providence, Rhode\nIslandMarcus Cheryl J. R.N., B.S.N.University of North Carolina, Chapel Hill, North CarolinaPutnam Beverly R.N., M.S.N.University of Colorado Health Sciences, Denver, Colorado;\nSmanga Ntshele, Community Advisory Board Member, Durban, South\nAfricaLoeliger Edde M.D.Clinical Development & Medical Affairs, Greenford,\nMiddlesexPappa Keith A. Pharm, D.GlaxoSmithKline, Infectious Diseases Medicine, Triangle Park,\nNorth CarolinaWebb Nancy M.S.Frontier Science & Technology Research Foundation, Inc.,\nAmherst, MassachusettsShugarts David L. M.A.University of Colorado Health Sciences, Denver, ColoradoWinters Mark A. M.S.Stanford University Medical Center, Division of Infectious\nDisease, Stanford, CaliforniaDescallar Renard S. Steele Joseph Wulfsohn Michael Said Farideh Chen Yue Martin John C Bischofberger Norbert Cheng Andrew Jaffe Howard M.D.Gilead Sciences, Foster City, CaliforniaSharma Jabin M.H.S.YRG Centre for AIDS Research and Education, IndiaPoongulali S. M.B.B.S..,D.G.O..,M.Sc.YRG Centre for AIDS Research and Education, Chennai,\nIndiaCardoso Sandra Wagner Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz,\nBrazilFaria Deise Lucia Instituto de Pesquisa Clinica Evandro Chagas-Fiocruz,\nBrazilBerendes Sima M.D.College of Medicine, Blantyre, MalawiBurke Kelly M.P.HBlantyre, MalawiMngqibisa Rosie M.B.Ch.B.Nelson Mandela School of Medicine, Durban, South AfricaKanyama Cecelia M.B.B.S.Kamuzu Central Hospital, Lilongwe, MalawiKayoyo Virginia Kamuzu Central Hospital, Lilongwe, MalawiSamaneka Wadzanai P. M.D.University of Zimbabwe College of Health Sciences, Harare,\nZimbabweChisada Anthony M.D.University of Zimbabwe College of Health Sciences, Harare,\nZimbabweFaesen Sharla University of the Witwatersrand, Johannesburg, South\nAfricaChariyalertsak Suwat M.D., Ph.D.Chiang Mai University, Chiang Mai, ThailandSantos Breno M.D.Hospital Conceicao, Porto Alegre, BrazilLira Rita Alves M.D.Hospital Conceicao, Porto Alegre, BrazilJoglekar Anjali A. M.B.B.S.National AIDS Research Institute, Pune, IndiaRosa Alberto La M.D.Asociacion Civil Impacta Salud y Educacion - Miraflores, Lima,\nPeruInfante Rosa M.D.Investigaciones Medicas en Salud – INMENSA, Lima, PeruJain Mamta M.D.UT Southwestern Medical Center at Dallas, Dallas, TexasPetersen Tianna M.S.UT Southwestern Medical Center at Dallas, Dallas, TexasGodbole Sheela M.D., M.B.B.S.NARI Clinic at NIV, Pune, IndiaDhayarkar Sampada M.B.B.S.NARI Clinic at NIV, Pune, IndiaFeinberg Judith M.D.University of Cincinnati, Cincinnati, OhioBaer Jenifer R.N., B.S.N.University of Cincinnati, Cincinnati, OhioPollard Richard B. M.D.UC Davis School of Medicine, Davis, CaliforniaAsmuth David M.D.UC Davis School of Medicine, Davis, CaliforniaGangakhedkar Raman R M.P.H., Dc.H., M.B.B.S.NARI Clinic at Gadikhana Dr. Kotnis Municipal Dispensary, Pune,\nIndiaGaikwad Asmita M.B.B.S.NARI Clinic at Gadikhana Dr. Kotnis Municipal Dispensary, Pune,\nIndiaRay M. Graham R.N., M.S.N.University of Colorado Hospital, Aurora, ColoradoBasler Cathi R.N., A.N.P-BC, A.C.R.N.University of Colorado Hospital, Aurora, ColoradoPara Michael F. M.D.The Ohio State University, OhioWatson Kathy J. R.N.The Ohio State University, OhioTaiwo Babafemi M.B.B.S.Northwestern University, Chicago, IllinoisMcGregor Donna M.S.N.Northwestern University, Chicago, IllinoisBalfour Henry H. M.D.University of Minnesota, Minneapolis, MinnesotaMullan Beth University of Minnesota, Minneapolis, MinnesotaKim Ge-Youl B.S.N.Washington University, Saint Louis, MissouriKlebert Michael K. Ph.D. R.N. A.N.P-B.C.Washington University, Saint Louis, MissouriCox Gary Matthew M.D.Duke University Medical Center, Durham, North CarolinaSilberman Martha R.N.Duke University Medical Center, Durham, North CarolinaMildvan Donna M.D.Beth Israel Medical Center, New York, New YorkRevuelta Manuel M.D.Beth Israel Medical Center, New York, New YorkTashima Karen T. M,D.The Miriam Hospital, Providence, Rhode IslandPatterson Helen The Miriam Hospital, Providence, Rhode IslandGeiseler P. Jan M.D.University of Southern California; Los Angeles,\nCaliforniaSantos Bartolo R.N.University of Southern California, Los Angeles,\nCaliforniaDaar Eric S M.D.Harbor-UCLA, Los Angeles, CaliforniaLopez Ruben M.D.Harbor-UCLA, Los Angeles, CaliforniaFrarey Laurie A.N.P.-C.University of North Carolina, Chapel Hill, North CarolinaCurrin David R.N. C.C.R.C.University of NorthCarolina, Chapel Hill, North CarolinaHaas David H. M.D.Vanderbilt University, Nashville, TennesseeBailey Vicki L. R.N.Vanderbilt University, Nashville, TennesseeTebas Pablo M.D.Hospital of the University of Pennsylvania, Philadelphia,\nPennsylvaniaZifchak Larisa R.N.Hospital of the University of Pennsylvania, Philadelphia,\nPennsylvaniaNoel-Connor Jolene R.N.Columbia University, New York, New YorkTorres Madeline R.N.Columbia University, New York, New YorkSha Beverly E. M.D.Rush University Medical Center, Chicago, IllinoisFritsche Janice M. M.S., A.P.R.N., B.C.Rush University Medical Center, Chicago, IllinoisCespedes Michelle M.D.New York University/NYC HHC at Bellevue Hospital Center, New\nYork, New YorkForcht Janet R.N.New York University/NYC HHC at Bellevue Hospital Center, New\nYork, New YorkO'Brien William A. M.D.The University of Texas Medical Branch, Galveston, TexasMogridge Cheryl R.N.The University of Texas Medical Branch, Galveston, TexasHurley Christine R.N.AIDS Care, Georgetown University, Washington (D.C.)Corales Roberto D.O.AIDS Care, Georgetown University, Washington (D.C.)Palmer Maria P.A.UCLA CARE Center, Los Angeles, CaliforniaAdams Mary R.N. M.Ph.University of Rochester, Rochester, New YorkLuque Amneris M.D.University of Rochester, Rochester, New YorkLopez-Detres Luis B.A.Cornell University, New York, New YorkStroberg Todd R.N.Cornell University, New York, New York \n¶\n1 Division of Infectious Diseases, Department of\nMedicine, University of Colorado School of Medicine, Aurora, United States of\nAmerica2 Center for Biostatistics in AIDS Research,\nHarvard School of Public Health, Boston, Massachusetts, United States of\nAmerica3 YRG Centre for AIDS Research & Education,\nChennai, India4 Brown Medical School, Providence, Rhode\nIsland, United States of America5 National Institutes of Health, Bethesda,\nMaryland, United States of America6 Clinical HIV Research Unit, Department of\nMedicine, Faculty of Health Sciences, University of the Witwatersrand,\nJohannesburg, South Africa7 Evandro Chagas Clinical Research Institute,\nFiocruz, Rio de Janeiro, Brazil8 Kamuzu Central Hospital, Lilongwe,\nMalawi9 Department of Medicine, College of Medicine,\nBlantyre, Malawi10 Nelson R. Mandela School of Medicine,\nDurban, South Africa11 Institut Nacional de laboratoire et de\nRecherches, Port-au-Prince, Haiti12 Asociación Civil Impacta Salud y Educación,\nLima, Peru13 Servico de Infectology, Hospital Nossa\nSenhora da Conceicao-GHC, Porto Alegre, Brazil14 Department of Medicine and Research\nInstitute for Health Sciences, Chiang Mai University, Chiang Mai,\nThailand15 National AIDS Research Institute, Pune,\nIndia16 Frontier Science & Technology Research\nFoundation, Amherst, Massachusetts, United States of America17 Social & Scientific Systems, Inc, Silver\nSpring, Maryland, United States of America18 GlaxoSmithKline, Research Triangle Park,\nNorth Carolina, United States of America19 Gilead Sciences, Inc., Foster City,\nCalifornia, United States of America20 Bristol-Myers Squibb Company, Plainsboro,\nNew Jersey, United States of America21 University of California San Diego, San\nDiego, United States of America22 University of Zimbabwe College of Health\nSciences, Harare, ZimbabweDeeks Steven G. Academic EditorSan Francisco General Hospital, United States of\nAmerica¶ Membership of the AIDS Clinical Trials Group PEARLS Team is provided in the\nAcknowledgments.\n\n* E-mail: thomas.campbell@ucdenver.eduTBC has received payments for lectures from, and served as a consultant for\nGlaxoSmithKline. TF has stock ownership in Abbot, Bristol-Myers Squibb,\nGilead Sciences, GlaxoSmithKline and has served as a consultant for Gilead\nSciences. WS is an employee of GlaxoSmithKline. JFR is an employee and\nstockholder of Gilead Sciences. JU is an employee of Bristol-Myers Squibb.\nRTS has served as a consultant to GlaxoSmithKline, Gilead Sciences, Merck\nand Bristol-Myers Squibb. RTS has served as a member of Data and Safety\nMonitoring Boards for Gilead Sciences and had research contracts with Merck\nand Bristol-Myers Squibb. LMS, KLK, CF, BG, MCH, JK, UL, CR, JS, MM, KS, ST,\nAIM, AN, AW, LM, YC, VDG and JGH declare no conflicts of interest.\n\nConceived and designed the experiments: TBC LMS NK TF KLK BG MCH JK UL KS ST\nAIM AN AW RTS VDG JGH. Performed the experiments: TBC NK TF KLK CF BG MCH JK\nUL CR JS MM KS ST AIM AN AW LM RTS JGH. Analyzed the data: LMS VDG YC.\nContributed reagents/materials/analysis tools: WS JFR JU. Wrote the first\ndraft of the manuscript: TBC. Contributed to the writing of the manuscript:\nTBC LMS NK TF KLK CF BG MCH JK UL CR JS MM KS ST AIM LM YC WS JFR JU RTS VDG\nJGH. ICMJE criteria for authorship read and met: TBC LMS NK TF\nKLK CF BG MCH JK UL CR JS MM KS ST AIM AN AW LM YC WS JFR JU RTS VDG JGH.\nAgree with manuscript results and conclusions: TBC LMS NK TF KLK CF BG MCH\nJK UL CR JS MM KS ST AIM AN AW LM YC WS JFR JU RTS VDG JGH. Enrolled\npatients: TBC NK TF CF BG MCH JK UL CR JS MM KS ST RTS JGH.\n\n8 2012 14 8 2012 22 8 2012 9 8 e10012902 12 2011 5 7 2012 2012This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.\nWhat Is the Optimal First Line Antiretroviral Therapy in\nResource-Limited Settings? \nThomas Campbell and colleagues report findings of a randomized trial conducted in\nmultiple countries regarding the efficacy of antiretroviral regimens with\nsimplified dosing.\n\nBackground\nAntiretroviral regimens with simplified dosing and better safety are needed\nto maximize the efficiency of antiretroviral delivery in resource-limited\nsettings. We investigated the efficacy and safety of antiretroviral regimens\nwith once-daily compared to twice-daily dosing in diverse areas of the\nworld.\n\nMethods and Findings\n1,571 HIV-1-infected persons (47% women) from nine countries in four\ncontinents were assigned with equal probability to open-label antiretroviral\ntherapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir\nplus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus\nemtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC\nand EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the\nupper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35\nwhen 30% of participants had treatment failure.\n\nAn independent monitoring board recommended stopping study follow-up prior to\naccumulation of 472 treatment failures. Comparing EFV+FTC-TDF to\nEFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment\nfailures (18%) among 526 participants versus 98 failures among 519\nparticipants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74).\nSafety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF\nversus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76;\np<0.001) and there was a significant interaction\nbetween sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI\n0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to\nEFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures\n(21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519\nparticipants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04;\np = 0.007).\n\nConclusion\nEFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial\npopulation, recruited in diverse multinational settings. Superior safety,\nespecially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are\nadvantageous for use of this regimen for initial treatment of HIV-1\ninfection in resource-limited countries. ATV+DDI+FTC had inferior efficacy\nand is not recommended as an initial antiretroviral regimen.\n\nTrial Registration\n\nwww.ClinicalTrials.gov\nNCT00084136\n\n\n\nPlease see later in the article for the Editors' Summary.\n\n\nEditors' Summary\nBackground\nDespite the enormous gains in reducing HIV-related illness and death over the\npast decade, there are still considerable challenges to meeting the global\ngoal of universal access to highly active antiretroviral treatment—a\ncombination of effective drugs that attack the HIV virus in various ways—to\neveryone living with HIV/AIDS who could benefit from treatment. In\nrecognition of the related financial, technical, and system obstacles to\nproviding universal access to HIV treatment, in 2010 the UN agency\nresponsible for HIV/AIDS—UNAIDS—launched an ambitious plan called Treatment\n2.0, which aims to simplify the way HIV treatment is currently provided. One\nof the main focuses of Treatment 2.0 is to simplify drug regimes for the\ntreatment of HIV and to make treatment regimes less toxic. In line with\nTreatment 2.0, the World Health Organization currently recommends that\nantiretroviral regimens for the initial treatment of HIV should include two\nnucleoside reverse transcriptase inhibitors (zidovudine or tenofovir\ndisoproxil fumarate [DF] with lamivudine or emtricitabine) and a\nnon-nucleoside reverse transcriptase inhibitor (efavirenz or\nnevirapine.)\n\nWhy Was This Study Done?\nMost of the evidence about the safety and effectiveness of clinical trials\ncome from clinical trials in high-income countries and thus is not generally\nrepresentative of the majority of people with HIV. So in this study, the\nresearchers conducted a randomized controlled trial in diverse populations\nin many different settings to investigate whether antiretroviral regimens\nadministered once daily were as effective as twice-daily regimens and also\nwhether a regimen containing the drug atazanavir administered once daily was\nas safe and effective as a regimen containing efavirenz—data from previous\nstudies have suggested that atazanavir has characteristics, such as its side\neffect profile, which may make it more suitable for low income settings.\n\nWhat Did the Researchers Do and Find?\nThe researchers recruited eligible patients from centers in Brazil, Haiti,\nIndia, Malawi, Peru, South Africa, Thailand, the United States, and\nZimbabwe—almost half (47%) were women. Then the researchers randomly\nassigned participants to one of three regimens: efavirenz 600 mg daily plus\nco-formulated lamivudine-zidovudine 150 mg/300 mg twice daily (EFV+3TC-ZDV);\nor atazanavir 400 mg once daily, plus didanosine-EC 400 mg once daily, plus\nemtricitabine 200 mg once daily (ATV+DDI+FTC); or efavirenz 600 mg once\ndaily plus coformulated emtricitabine-tenofovir-DF 200 mg/300 mg once daily\n(EFV+FTC-TDF). During the study period ATV+DDI+FTC was found to be inferior\nto EFV+3TC-ZDV, so the Multinational Data Safety Monitoring Board ordered\nthis arm of the trial to stop. Then a year later, due to the low number of\ntreatment failures (deaths, severe HIV disease, or serious opportunistic\ninfections) in the remaining two arms, the board advised the trial to stop\nearly. So the researchers analyzed the data obtained up to this point and\npooled the results from all of the centers.\n\nThe researchers found that during an average of 184 weeks of follow-up, there\nwere 95 treatment failures (18%) among 526 participants taking EFV+FTC-TDF\ncompared to 98 failures among 519 participants taking EFV+3TC-ZDV. During an\naverage 81 weeks follow-up, there were 108 failures (21%) among 526\nparticipants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants\nassigned to EFV+3TC-ZDV. As for safety, 243 (46%) participants assigned to\nEFV+FTC-TDF reached a safety endpoint (grade 3 disease, abnormal lab\nmeasurement, or the need to change drug) compared to 313 (60%) in the\nEFV+3TC-ZDV group. Importantly, the researchers found that there was greater\nrisk of safety events for women assigned to EFV+3TC-ZDV and also that the\natazanavir-based regimen had a higher relative efficacy in women compared to\nmen.\n\nWhat Do These Findings Mean?\nThese findings suggest that in diverse populations, EFV+FTC-TDF is as\neffective as EFV+3TC-ZDV but importantly, the once-daily dosing of\nEFV+FTC-TDF makes this regimen useful for the initial treatment of HIV,\nespecially in low-income countries. Therefore, as per the guidance in\nTreatment 2.0, EFV+FTC-TDF in a single combination tablet that can be taken\nonce a day is an attractive option. These findings also indicate that as\nATV+DDI+FTC was found to be inferior to the other regimens, this combination\nshould not be used in the initial treatment of HIV. These findings also add\nto the evidence that antiretroviral efficacy and safety can differ between\nwomen and men and support further development of sex-specific\nrecommendations for antiretroviral regimen options.\n\nAdditional Information\nPlease access these Web sites via the online version of this summary at\nhttp://dx.doi.org/10.1371/journal.pmed.1001290.\n\nThe UNAIDS website has more information about Treatment 2.0; and the WHO website provides\ntechnical information\n\n\nFor an introduction to the treatment of HIV/AIDS see http://www.avert.org/treatment.htm; the AVERT site\nalso has personal\nstories from women living with HIV/AIDS\n\n\nAIDSmap provides information for individuals and communities\naffected by HIV/AIDS\n\n\nThe ACTG website provides information about research to improve treatment of HIV and related\ncomplications\n\n\nThe study was funded by the National Institute of Allergy and\nInfectious Diseases and the following National Institutes of Health: grants\nAI68636, AI68634, A1069432, AI069476, AI069518, AI069426, AI069518, AI069436,\nAIO69463, AI069399, AI069401, AI069421, AI069417, AI069438, AI069438, AI046376,\nAI069417, AI069513, AI38858, AI069417, AI69450, AI069474, AI069471, AI27661,\nAI069495, AI069484, AI47370, A1069472, AI069428, A1069424, AI069423, AI050410,\nAI-069439; AI54999, RR024975, A1069467, AI045008, AI069470, AI069471, AI069532,\nAI032782, AI069511, AI069424, AI069471, AI69419, RR024996, RR00865, RR024160,\nRR024156, RR025747, RR00424 and RR025780. Employees of the NIAID participated as\nstudy team members and authors of this manuscript. The NIAID provided\nrecommendations on the study design and approved the final study design, but had\nno role in data collection and analysis, decision to publish, or preparation of\nthe manuscript. The pharmaceutical sponsors (Boehringer Ingelheim, Bristol-Myers\nSquibb, Gilead Sciences, and GlaxoSmithKline) provided study drug and Gilead\nSciences provided funding to purchase study drug that was not otherwise\navailable. Bristol Myers Squibb provided atazanavir, didanosine-EC and efavirenz\n(with consent of Merck); Gilead Sciences, Inc. provided emtricitabine,\ntenofovir-DF, emtricitabine/tenofovir-DF; GlaxoSmithKline provided lamivudine,\nzidovudine and lamivudine/zidovudine; and Boehringer Ingelheim Pharmaceuticals,\nInc. provided nevirapine. Representatives of the pharmaceutical company sponsors\nparticipated as study team members and authors of this manuscript, but did not\nparticipate in data collection, data analyses or interpretation. Bristol Myers\nSquibb, Gilead Sciences Inc., GlaxoSmithKline and Boehringer Ingelheim\nPharmaceuticals, Inc. had no role in study design, data collection and analysis,\ndecision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\nIncreased effectiveness of HIV-1 treatment through optimizing antiretroviral regimens\nfor simplification and reduced toxicity is a priority in the recent UNAIDS Treatment\n2.0 initiative [1],[2]. Treatment 2.0\nemphasizes that effective antiretroviral regimens with simplified dosing, fewer side\neffects, and lower long-term toxicity are needed to minimize requirements for\nlaboratory monitoring and maximize the efficiency of antiretroviral delivery.\nHowever, most existing knowledge of antiretroviral safety and efficacy comes from\nclinical trials in high-income countries with study populations not representative\nof the global diversity of people infected with HIV-1. Prospective comparisons of\nantiretroviral efficacy and safety in diverse multinational settings with\nrepresentative proportions of women are needed to better inform the choice of\nantiretroviral drugs for initial HIV-1 treatment.\n\nWorld Health Organization (WHO, 2010 revision) guidelines recommend initiation of\nantiretroviral therapy with two nucleoside reverse transcriptase inhibitors (NRTI)\n(zidovudine [ZDV] or tenofovir disoproxil fumarate [DF] with lamivudine [3TC] or\nemtricitabine [FTC) and a non-nucleoside reverse transcriptase inhibitor (NNRTI)\n(efavirenz [EFV] or nevirapine) [3]. Randomized clinical trials conducted in developed countries provide\nevidence that these regimens are safe and effective [4]–[6]. Although a regimen of FTC, tenofovir-DF\n(TDF), and EFV meets criteria outlined in Treatment 2.0 including low toxicity and\nsimplified once-daily dosing, the comparative safety and efficacy of this regimen in\nlow-resource settings is unknown.\n\nCompared to EFV, the HIV-1 protease inhibitor atazanavir (ATV) lacks known\nteratogenicity and is active against NNRTI-resistant virus. These features are\npotentially advantageous for use of ATV in resource-limited settings where use of\nsingle dose nevirapine for prevention of mother-to-child transmission of HIV-1 could\nincrease the risk of NNRTI-resistant virus in women and their sexual partners.\nPrevious studies of antiretroviral naïve persons provide evidence that ATV without\nritonavir boosting is safe and efficacious: Unboosted ATV had similar efficacy\ncompared to EFV when given with co-formulated 3TC-ZDV [7], similar efficacy compared to\nritonavir-boosted ATV when given with extended release stavudine and 3TC [8], and comparable activity to\nnelfinavir when given with didanosine and stavudine [9]. Previous studies also provide evidence\nthat, when given with EFV, the NRTI combination of didanosine and FTC (or 3TC) is\nsafe and efficacious and has comparable activity to 3TC-ZDV and stavudine plus 3TC\n[10]–[14]. Thus, taken together\navailable data predict that a regimen of ATV, didanosine, and FTC would have\nantiviral efficacy comparable to 3TC-ZDV and EFV; however, direct comparisons of\nthese two regimens have not been performed previously.\n\nMethods\nStudy Design and Participants\nThe Prospective Evaluation of Antiretrovirals in Resource Limited Settings\n(PEARLS) study of the AIDS Clinical Trials Group (ACTG) evaluated two\nhypotheses: (1) Antiretroviral regimens administered once daily are non-inferior\nto twice-daily regimens; (2) A regimen containing ATV administered once daily\nwithout ritonavir boosting is non-inferior to an EFV-based regimen. Study design\ndetails are available at ClinicalTrials.gov NCT00084136 and in the study\nprotocol provided in Text S1. The CONSORT checklist used for\npreparation of this manuscript is provided in Text\nS2.\n\nEnrollment was limited to the following ACTG international sites: Instituto de\nPesquisa Clinica Evandro Chagas, Rio de Janeiro, Brazil; Hospital Nossa Senhora\nda Conceicao-GHC, Porto Alegre, Brazil; Les Centres GHESKIO, Port-au-Prince,\nHaiti; YRG Centre for AIDS Research & Education, Chennai, India; National\nAIDS Research Institute, Pune, India; College of Medicine Clinical Research\nSite, Blantyre, Malawi; Kamuzu Central Hospital, Lilongwe, Malawi; Asociacion\nCivil Impacta Salud y Educacion - Miraflores and San Miguel Clinical Research\nSite, Lima, Peru; Durban Adult HIV Clinical Research Site, Durban, South Africa;\nUniversity of Witwatersrand Clinical HIV Research Unit, Johannesburg, South\nAfrica; Research Institute for Health Sciences, Chiang Mai, Thailand; and\nParirenyatwa Hospital Clinical Research Center, Harare, Zimbabwe. All ACTG sites\nin the United States were also eligible to enroll participants. Enrollment in\nthe US was limited to no more than 18% of total; the remaining enrollment was\ndistributed equally across the international sites with an option for\ninternational sites to request additional enrollment once their initial quota of\n100 participants was filled.\n\nEligible participants were ≥18 y, had documented HIV-1 infection, CD4+\nlymphocytes <300 cells/µl, and ≤7 d of cumulative antiretroviral therapy\nprior to study entry. Persons with absolute neutrophils <750/µl, hemoglobin\n<7.5 g/dl, calculated creatinine clearance <60 ml/min, or aspartate\ntransaminase or alanine transaminase greater than 5-fold above the upper limit\nof normal were excluded. Women of reproductive potential were non-pregnant and,\nif participating in sexual activity that could lead to pregnancy, agreed to use\ncontraception (two forms if taking EFV). Persons with serious chronic, acute, or\nrecurrent infections had completed ≥14 d of therapy and were clinically\nstable.\n\nRandomization\nSites enrolled participants through a centralized web-based system. The ACTG Data\nManagement Center (Frontier Science & Technology Research Foundation)\nrandomly assigned participants 1∶1∶1 to an open-label regimen of EFV 600 mg\ndaily plus co-formulated 3TC-ZDV 150 mg/300 mg twice daily (EFV+3TC-ZDV); or ATV\n400 mg once daily with food, plus didanosine-EC (DDI) 400 mg once daily taken on\nan empty stomach 1 h before or 2 h after the ATV dose, plus FTC 200 mg once\ndaily (ATV+DDI+FTC); or EFV 600 mg once daily plus co-formulated FTC-TDF 200\nmg/300 mg once daily (EFV+FTC-TDF). Permuted block randomization was stratified\nby country (nine levels) and screening plasma HIV-1 RNA (<100,000 versus\n≥100,000 copies/ml). Treatment assignment was revealed after successful\nenrolment at the local site on the web-based system.\n\nProcedures\nA targeted physical exam, medication review, adherence interview and pill counts,\nserum chemistries, liver function tests, pregnancy test, CD4+ lymphocyte count,\nand plasma HIV-1 RNA were scheduled at least every 8 wk. All study drug\nmodifications including initial doses, participant-initiated and/or\nprotocol-mandated interruptions, substitutions, and permanent discontinuation\nand reasons for modification were assessed at each visit. Adverse events (signs,\nsymptoms, and laboratory results) used US Division of AIDS (DAIDS) scale for\nseverity grading [15].\nDiagnosis criteria were standardized across sites using ACTG Appendix 60 (see\nText\nS3). Plasma HIV-1 RNA was measured in real time by the Roche Amplicor\nMonitor assay (v1.5) at laboratories participating in the DAIDS Virology Quality\nAssurance program.\n\nOutcomes\nThe primary efficacy endpoint (treatment failure) was time from randomization to\nfirst occurrence of any of the following: (1) death; (2) HIV-1 disease\nprogression defined as new or recurrent WHO stage 4 diagnosis (excluding\nHIV-1-associated nephropathy or cardiomyopathy) [3], Chagas' diseases, or chronic\nmicrosporidiosis or cyclosporidiosis occurring at least 12 wk following\nrandomization and not part of immune reconstitution inflammatory syndrome\n(IRIS); or (3) virologic failure defined as two successive measurements of\nplasma HIV-1 RNA≥1,000 copies/ml, with the first measurement at the week 16\nvisit or later (≥14 wk after randomization), regardless of study treatment\nhistory or status (intention-to-treat). Participants who did not meet primary\nendpoint criteria at any time were censored at the last study visit at which\nplasma HIV-1 RNA was measured. Disease progression and IRIS events were reviewed\nand adjudicated by a panel of five physician team members who were blinded to\nparticipant identity, clinic site, demographic characteristics, and study\ntreatment. Study treatment information was also ignored for the mortality and\nHIV-1 disease progression components, so the analysis for the primary efficacy\nendpoint was fully intent-to-treat. A post hoc sensitivity analysis that\nexplored whether crossover could explain observed results was also\nperformed.\n\nThe primary safety endpoint was the earliest of the following times: date of\nonset of grade ≥3 (at least one grade higher than entry) sign/symptom, date of\nspecimen collection of a grade ≥3 (at least one grade higher than entry)\nlaboratory abnormality, or date of last dose of randomized study treatment\nbefore any modification to that treatment (change in drug dosage, addition of\nanother antiretroviral drug, or discontinuation of any component of the\nrandomized antiretroviral regimen). Elevated serum bilirubin concentration was\nexcluded from the laboratory abnormality component of this endpoint only,\nbecause it is usually asymptomatic and not associated with known adverse\noutcomes. Any signs, symptoms, or changes in antiretroviral therapy that\nresulted from elevated bilirubin were captured in the other components of the\ncomposite safety endpoint. Participants who did not meet the safety endpoint\ndefinition were censored at the earlier of the last study visit or final\nmedication dose. Because study treatment modification was part of the composite\nprimary safety endpoint, this analysis was necessary as-treated.\n\nFirst antiretroviral regimen discontinuation was time to premature\ndiscontinuation of study participation, failure to take antiretrovirals for ≥8\nconsecutive wk, or switch to another antiretroviral regimen. Prespecified\nantiretroviral substitutions not included in the definition of regimen\ndiscontinuation were as follows: Substitutions of stavudine for ZDV were not\ncounted as endpoints in this analysis because WHO guidelines (2003 revision)\nwhen PEARLS was implemented listed 3TC-ZDV as the initial recommendation for the\nnucleoside analog component of an antiretroviral regimen with substitution of\nother nucleosides, including stavudine, if needed. In 2006 the protocol was\nmodified to include TDF for ZDV as a prespecified non-endpoint in response to\nthe 2006 revision of the WHO guidelines that listed ZDV and TDF as the preferred\ninitial nucleoside analog reverse transcriptase inhibitors to be combined with\n3TC or FTC. Substitutions of DDI for TDF and TDF for DDI were not counted as\nendpoints because both drugs are once daily nucleoside analogs. Likewise,\nsubstitutions of nevirapine for EFV were prespecified as non-endpoints because\nboth drugs are in the NNRTI class and can be dosed once daily.\n\nPlasma HIV-1 RNA below lower quantitation limit (<400 copies/ml) was a\nsecondary endpoint that used the closest value to the scheduled visit. Another\nsecondary endpoint, time to loss of virologic response (TLOVR) included an\nanalysis as specified in US Food and Drug Administration (FDA) guidelines where\nall antiretroviral substitutions were counted as endpoints [16], and an analysis where the prespecified\nantiretroviral substitutions did not count as endpoints. Immunologic failure was\ndefined as CD4+ lymphocytes <100 cells/µl at 48 wk or later. Those not\nmeeting the immunologic failure secondary endpoint were censored at the study\nvisit week of last CD4+ lymphocyte count.\n\nSample Size\nAssumptions included a non-inferiority threshold hazard (relative risk ratio) of\n1.35, overall 30% treatment failure rate within the two arms compared under the\nalternative of equivalence (hazard ratio [HR] = 1.0), and one-sided significance\n≤0.05. The estimated statistical power for the primary efficacy comparison by a\none-sided log-rank test comparison of ATV and EFV+FTC-TDF arms to EFV+3TC-ZDV\nwas 80% for a sample size of 456 per arm with inflation by 10% to account for\nlosses to follow-up. The study did not have a fixed follow-up duration, but was\nplanned to continue until 30% of participants experienced a primary efficacy\nendpoint.\n\nStudy Oversight and Monitoring\nThe study was approved by the institutional review boards and ethics committees\nat each participating institution. Written, informed consent was obtained from\nstudy participants, and human experimentation guidelines of the US Department of\nHealth and Human Services were followed.\n\nThe US National Institute of Allergy and Infectious Diseases (NIAID)\nMultinational Data Safety Monitoring Board (DSMB) reviewed safety and efficacy\nat least yearly. The prespecified stopping guidelines were only for early\nevidence of inferiority of an experimental arm, based upon Haybittle-Peto\nbounds. On 6 May 2008, ATV+DDI+FTC was found to be inferior to EFV+3TC-ZDV for\nthe primary efficacy endpoint at median follow-up of 72 wk. The HR for time to\nregimen failure was 1.67 (99.98% CI 1.0–2.75; p = 0.001),\nreflecting 104 failures in the ATV+DDI+FTC arm compared to 67 failures in the\nEFV+3TC-ZDV arm. These CIs reflect those data available at interim review by the\nDSMB, which prespecified 99.98% intervals to correspond to\np = 0.001 Haybittle-Peto bounds for superiority (and likewise,\ninferiority). Study participants, investigators, institutional review boards,\nand ethics committees were informed of the DSMB findings on 23 May 2008, and\nparticipants still taking ATV+DDI+FTC were switched to alternative\nantiretroviral regimens. The DSMB did not report any findings related to the\ncomparison of the EFV+FTC-TDF and EFV+3TC-ZDV arms so these arms were not\nmodified and the investigators remained blinded to outcomes in those arms until\ncompletion of all study follow-up.\n\nOn 3 November 2009, the DSMB concluded that the remarkably low rate of new\nendpoints in the EFV+FTC-TDF and EFV+3TC-ZDV arms made it unlikely that the\nstudy would reach the planned 30% rate of primary endpoint within 2 y (or even\nconsiderably longer) and continuation of study follow-up for two more years\nwould likely improve precision of the comparison by only a small amount. The\nDSMB recommended that “it was simply not practical to continue until 274 events\n(30%) and that no statistical penalty needed to be paid for stopping before\nthen.” The ACTG followed the DSMB recommendations and closeout visits were\nconducted between 1 April and 31 May 2010.\n\nStatistical Methods\nAnalyses for the comparison of ATV+DDI+FTC to EFV+3TC-ZDV used data collected\nfrom 1 May 2005 through 22 May 2008. Analyses for comparison of EFV+FTC-TDF to\nEFV+3TC-ZDV used data collected through 31 May 2010. The study was designed to\ntest the primary efficacy hypothesis of non-inferiority using an upper bound of\na one-sided, 0.05 level interval. Early study closure prompted a revised\nanalysis plan for pairwise comparison. Since comparison of the ATV+DDI+FTC and\nEFV+3TC-ZDV arms used additional data collected between 4 March to 22 May 2008,\ntwo-sided 95% CIs and associated p-values are presented here.\nAs the closure of the EFV+FTC-TDF and EFV+3TC-ZDV arms was not due to the\nprespecified stopping guidelines, we followed the DSMB recommendations on\nsignificance level and focused inferential procedure for the primary efficacy\noutcome on estimating treatment difference effect size and its related range of\nplausible values, rather than hypothesis testing. Specifically, two-sided 95%\nCIs for treatment difference (parameterized as the relative difference by HR)\nwere provided. Parallel methods were used for secondary efficacy outcomes (for\nconsistency) and safety outcomes (by original plan). p-Values\nbased upon stratified log-rank test with a null hypothesis of no difference\nbetween randomized arms were provided only for secondary efficacy and safety\noutcomes. Time-to-event outcome distributions were summarized by the method of\nKaplan and Meier, and compared between randomized groups by log-rank test\nstratified by randomized allocation. HRs were estimated from Cox proportional\nhazards regression; HR variation over time was based on a test for interaction\nbetween treatment group and time. Cumulative probabilities of time-to-event\nendpoints used Greenwood estimates of variation for CI formulation. For each of\nthe primary efficacy and safety time-to-event outcomes, the proportional hazards\nassumption was tested through introducing an interaction term between treatment\ngroup and time, and was not rejected in any case (all\np>0.18). Interactions between study treatment and\npretreatment covariates were tested individually by Cox regression. Estimated\nbinomial proportions were compared between arms using Fisher exact test and 95%\nexact CIs. Comparisons of CD4+ cells over time used a one-sided, 0.025-level\nWei-Johnson test [17].\n\nResults\nStudy Participants\nBetween May 2005 and July 2007, 1,571 participants were randomized to one of the\nthree treatment arms (Figure\n1): Brazil (n = 31), Haiti\n(n = 100), India (n = 255), Malawi\n(n = 221), Peru (n = 134), South Africa\n(n = 210), Thailand (n = 100), US\n(n = 210), and Zimbabwe (n = 110). There\nwere 739 women (47%) and 787 (50%) participants were Black or African American.\nThere were 434 ongoing infections at study entry (Table S1)\nthat were treated according to local standard of care. The five most common\nongoing infections were oropharyngeal candidiasis (77 cases), pulmonary\ntuberculosis (73 cases), mucocutaneous herpes simplex virus (65 cases),\nanogenital warts (56 cases), and other or vulvovaginal candidiasis (44 and 32\ncases, respectively). Together, these six diagnoses accounted for 80% of the\nongoing infections at study entry.\n\n10.1371/journal.pmed.1001290.g001Figure 1 Flow diagram for participant outcomes.\nThe outcomes of all participants randomized to the three arms are\nprovided. The most common prior antiretroviral exposure was for\nprevention of mother-to-child transmission of HIV-1 with either ZDV\nmonotherapy (19 women; median duration 32 d; intraquartile range 30–60\nd) or a single dose of nevirapine in the peripartum period (16 women).\nContinuous variable values are the median for the treatment arm.\nCreatinine clearance was calculated by Crockoft-Gault equation.\nFollow-up visits were conducted for 1,571 participants. ATV plus FTC and\nDDI follow-up was terminated on 22 May 2008 in response to the DSMB\nrecommendation and comparison of ATV plus FTC and DDI to EFV plus\n3TC-ZDV used data available up to the time of the ATV arm closure (red\nbox); median follow-up 81 wk. Comparison of EFV plus FTC-TDF to EFV plus\n3TC-ZDV used all follow-up data for participants in these arms through\n31 May 2010 (green box); median follow-up 184 wk.\n\nFollow-up\nOutcomes are summarized in Figure\n1; 99% of expected study visits were completed. Median follow-up was\n81 wk for comparison of ATV+DDI+FTC to EFV+3TC-ZDV and 184 wk for the comparison\nof EFV+FTC-TDF to EFV+3TC-ZDV. There were 47 deaths (3%) and 183 (12%)\nparticipants did not complete study follow-up; 126 (8%) left prior to regimen\nfailure. The risk ratio of any premature study discontinuation for participants\nallocated to ATV+DDI+FTC versus EFV+3TC-ZDV was 0.80 (CI 0.54–1.18;\np = 0.26) and for EFV+FTC-TDF versus EFV+3TC-ZDV was 0.79\n(CI 0.59–1.06; p = 0.12). The primary endpoint analyses\nincluded all 1,571 participants according to randomized treatment\nassignment.\n\nEfficacy of ATV Plus DDI and FTC\nRisk of treatment failure primary endpoint was greater for participants assigned\nto ATV+DDI+FTC compared to EFV+3TC-ZDV with 108 (20.5%) versus 76 (14.6%)\nfailures, respectively (Table\n1). The between-arm difference in primary endpoint failure rates\npersisted over time (Figure\n2A). The most common cause of treatment failure was confirmed plasma\nHIV-1 RNA ≥1,000 copies/ml (82% of primary endpoints). The lower bounds of the\n95% CIs for the relative hazard of both treatment and virologic failure, but not\ndisease progression and death, for comparison of the ATV and EFV+3TC-ZDV arms\nexcluded 1.0 (Table 1). 30\ndisease progression events (15 in the ATV+DDI+FTC arm and 15 in the EFV+3TC/ZDV\narm) did not meet the definition of treatment failure because of either being\ndiagnosed within the first 12 wk of study follow-up (15 events) and/or being\npart of an IRIS event (15 events). Men randomized to ATV+DDI+FTC had higher risk\nof treatment failure compared to men randomized to EFV+3TC-ZDV (HR 2.14, CI\n1.42–3.42) but a difference in regimen efficacy was not detected in women (Figure 3A, left side). No\nsignificant statistical interactions between treatment effect and race and\nethnicity, country, or viral load stratum were observed.\n\n10.1371/journal.pmed.1001290.g002Figure 2 Efficacy and safety of randomized study treatment over time.\n(A–H) black circles, EFV plus 3TC-ZDV; red triangles, ATV plus DDI-EC and\nFTC; green squares, EFV plus FTC-TDF. (A–B) Estimated cumulative\nprobability of antiretroviral regimen failure defined by the\nprotocol-specified primary efficacy endpoint: comparison of EFV plus\n3TC-ZDV to ATV plus FTC and DDI (A) and EFV plus FTC-TDF (B). (C–D)\nProportion of participants with plasma HIV-1 RNA less than 400 copies/ml\nfor comparison of EFV plus 3TC-ZDV to ATV plus FTC and DDI (C) and EFV\nplus FTC-TDF (D). These comparisons included all randomized study\nparticipants according to assigned study treatment. The analysis that\ncounted missing values as greater than 400 copies/ml (open symbols) is\ntruncated at the maximum potential duration of study follow-up for\nparticipants who entered the study at the end of the enrollment period\n(144 wk). (E–F) Median change in CD4+ lymphocyte count from screening\nvalue over time for comparison of EFV plus 3TC-ZDV to ATV plus FTC and\nDDI (E) and EFV plus FTC-TDF (F). (G–H) Estimated cumulative probability\na safety endpoint over time for comparison of EFV plus 3TC-ZDV to ATV\nplus FTC and DDI (G) and EFV plus FTC-TDF (H). For (A–D, G and H), bars\nrepresent the 95% CI for the estimate. For (E–F), bars represent the\ninterquartile range. (A–H) The number of evaluable participants at each\ntime point is provided for each randomized treatment assignment.\n\n10.1371/journal.pmed.1001290.g003Figure 3 Subgroup analysis for primary efficacy and safety endpoints by\nrandomly assigned antiretroviral treatment.\nSubgroup analyses were conducted for the baseline covariates\nself-reported sex and race/ethnicity and the countries in which the\nparticipating research sites were located. The relative risk and 95% CIs\nare provided for all participants (overall) and for each subgroup.\np-Value represents interaction test between\nbaseline covariate and randomized treatment group. Comparisons between\nATV plus DDI and FTC and EFV plus 3TC-ZDV are in red. Comparisons\nbetween EFV plus FTC-TDF and EFV plus 3TC-ZDV are in green. (A)\nTreatment failure (efficacy) composite endpoint. (B) Safety events\ncomposite endpoint.\n\n10.1371/journal.pmed.1001290.t001Table 1 Primary and secondary time-to-event outcomes for the comparison of\natazanavir plus didanosine-EC and emtricitabine to efavirenz plus\nlamivudine-zidovudine using data collected through 22 May 2008.\nStudy Endpoint\t\nn Events\tHR (95% CI)a\n\t\np-Valueb\n\tEvents per 100 Person-Years (95%\nCI)\t\n\tATV+DDI+FTC\tEFV+3TC-ZDV\t\t\tATV+DDI+FTC\tEFV+3TC-ZDV\t\nTreatment failure (composite endpoint)\t108\t76\t1.51 (1.12–2.04)\t0.007\t13.3 (11.0–16.1)\t8.9 (7.1–11.2)\t\nAll deathc\n\t9\t10\t0.88 (0.36–2.17)\t0.78\t1.0 (0.5–1.9)\t1.1 (0.6–2.0)\t\nAll initial HIV-1 disease progressiond\n,\ne\n\t18\t10\t1.80 (0.83–3.90)\t0.14\t2.0 (1.3–3.2)\t1.1 (0.6–2.1)\t\nAll initial confirmed virologic failuree\n,\nf\n\t92\t63\t1.56 (1.12–2.16)\t0.008\t11.2 (9.1–13.7)\t7.3 (5.7–9.4)\t\nSafety events (composite endpoint)e\n,\ng\n\t210\t252\t0.73 (0.60–0.88)\t0.001\t30.8 (26.9–35.2)\t43.0 (38.0–48.6)\t\nAll initial antiretroviral dose\nmodificationse\n,\nh\n\t149\t172\t0.80 (0.65–1.00)\t0.05\t9.9 (8.4–11.6)\t12.2 (10.5–14.2)\t\nAll initial grade 3 or 4 signs or symptomsd\n,\ne\n\t69\t98\t0.66 (0.48–0.90)\t0.008\t8.2 (6.5–10.4)\t12.6 (10.3–15.3)\t\nAll initial grade 3 or 4 laboratory\nabnormalitiesd\n,\ne\n,\ng\n\t76\t119\t0.58 (0.43–0.78)\t0.0003\t9.2 (7.3–11.5)\t16.1 (13.4–19.3)\t\nFirst antiretroviral regimen\ndiscontinuationi\n\t149\t103\t1.57 (1.22–2.01)\t0.0005\t9.9 (8.4–11.6)\t6.2–(5.1–7.5)\t\nImmunologic failurej\n\t19\t23\t0.82 (0.44–1.52)\t0.53\t2.1 (1.3–3.3)\t2.5 (1.7–3.8)\t\na Also known as relative risk. Estimated from Cox regression model\nstratified by both country and RNA stratum and including randomized\ntreatment group as sole covariate.\n\nb \np-Value calculated from stratified log-rank test\nbetween arms.\n\nc The five most common causes of death were infection (six deaths),\nliver disease (three deaths), malignancy (two deaths), suicide (two\ndeaths), and unknown cause (two deaths).\n\nd Disease progression diagnoses are in Table\nS2; grade 3 and 4 laboratory events in Table\nS3; and signs and symptoms in Table\nS4.\n\ne All events meeting these criteria are reported; some participants met\ncriteria for multiple endpoints.\n\nf Confirmed plasma HIV RNA≥1,000 copies/ml at study week 16 or\nlater.\n\ng Elevated bilirubin concentration not included.\n\nh Change in any component of initial randomized antiretroviral\nregimen.\n\ni The following antiretroviral substitutions were prespecified and were\nnot included in this endpoint: TDF for DDI, stavudine or TDF for\nZDV, or nevirapine for EFV.\n\nj CD4+ lymphocytes <100/µl at week 48 or later.\n\nPlasma HIV-1 RNA was below 400 copies/ml in 82% of participants randomized to\nATV+DDI+FTC versus 88% randomized to EFV+3TC-ZDV at 24 wk\n(p = 0.004) (Figure 2C). In the FDA TLOVR analysis disallowing any antiretroviral\nsubstitution, there was no difference between treatment arms at 48 wk (135\nversus 149; p = 0.3). In the TLOVR analysis that did not\npenalize for prespecified antiretroviral drug substitutions, the number of\nendpoints was greater for ATV+DDI+FTC compared to EFV+3TC-ZDV at 48 wk (135\nversus 85; p<0.001).\n\nRisk of immunologic failure was low and did not differ between arms (Table 1). CD4+ lymphocyte\nincreases from baseline were 187/µl and 152/µl in the ATV+DDI+FTC and\nEFV+3TC-ZDV arms, respectively, at 48 wk and were significantly greater in\nATV+DDI+FTC at all time points evaluated (all individual\np-values<0.05; one-sided test over 96 wk,\np<0.001) (Figure 2E).\n\nRegimen Discontinuation for ATV Plus DDI and FTC\nInitial antiretroviral regimen discontinuation was due to non-prespecified drug\nsubstitutions (61% of all observed discontinuations), premature discontinuation\nof study follow-up (30%), permanent discontinuation of all antiretroviral\ntherapy (8%), and temporary discontinuation of all antiretroviral therapy for\nmore than 8 wk (1%). Risk of this endpoint, when protocol-specified drug\nsubstitutions were not counted, was significantly greater among participants\nrandomized to ATV+DDI+FTC (Table\n1). The most common reasons for non-prespecified drug substitutions\namong persons randomized to ATV+DDI+FTC were virologic failure (40 cases),\ntuberculosis treatment (28 cases), clinical adverse events (23 cases), and\nlaboratory abnormalities (10 cases).\n\nSafety of ATV Plus DDI and FTC\nExcluding hyperbilirubinemia, which is an expected effect of ATV treatment, there\nwere fewer safety endpoints among participants randomized to ATV+DDI+FTC\ncompared to EFV+3TC-ZDV (Figure\n2G; Table 1).\nEstimated probability of a safety endpoint by week 48 was 32.6% (CI 28.8%–36.8%)\nversus 42.3% (CI 38.2–46.7%). There was a significant interaction between study\ntreatment and both sex and plasma HIV-1 RNA strata for the primary safety\nendpoint (p = 0.01 for both) (Figure 3B, left side). Women randomized to\nATV+DDI+FTC had lower risk of a safety endpoint compared to women randomized to\nEFV+3TC-ZDV (HR 0.56, CI 0.42–0.74). Among men, risk difference for the primary\nsafety endpoint between arms was attenuated (HR 0.92, CI 0.71–1.19). The risk of\na safety endpoint for the lower versus the upper plasma HIV-1 RNA strata were\n0.55 (CI 0.41–0.73) and 0.89 (CI 0.70–1.15), respectively. There were no\nsignificant interactions between race or country and assigned treatment for the\nprimary safety endpoint.\n\nThere were fewer initial dose modifications among participants randomized to\nATV+DDI+FTC compared to EFV+3TC-ZDV (Table 1). The estimated cumulative\nprobability of any dose modification of the assigned antiretroviral regimen at\n48 wk was 20.7% (CI 17.5%–24.4%) compared to 25.7% (CI 22.1%–29.7%),\nrespectively. Excluding hyperbilirubinemia, there were fewer severe or\npotentially life-threatening laboratory abnormalities in ATV+DDI+FTC (Tables 1 and S3); the\nestimated cumulative probability at 48 wk was 12.4% (CI 9.9%–15.6%) compared to\n21.0% (CI 17.7%–24.8%). There was a lower risk of a severe or life-threatening\nsign or symptom in the ATV+DDI+FTC arm (Tables 1 and S4). At 48\nwk the cumulative probabilities of a new severe or life-threatening sign or\nsymptom were 10.5% (CI 8.1%–13.4%) and 16.5% (CI 13.5%–20.0%) for the\nATV+DDI+FTC and EFV+3TC-ZDV arms, respectively.\n\nNeurological symptoms, cachexia/weight loss, and dermatologic symptoms occurred\nin 13 (2%), 5 (1%), and 8 (2%) participants assigned to ATV+DDI+FTC,\nrespectively, compared to 22 (4%), 17 (3%), and 15 (3%) participants assigned to\nEFV+3TC-ZDV (Table S3). Participants assigned to ATV+DDI+FTC were more likely to\nhave a new diagnosis of serious renal disease (19 [4%] versus 5 [1%]\nparticipants; nominal p = 0.006) (Tables S5\nand S6).\n\nEfficacy of EFV+FTC-TDF\nThere were 95 (18.0%) and 98 (18.8%) treatment failures in the EFV+FTC-TDF and\nEFV+3TC-ZDV arms, respectively, and the range of the relative risk difference\nwas 0.72 to 1.27 (Table\n2). Treatment failure relative risk did not change significantly over\ntime (p = 0.9) (Figure 2B). There were no significant statistical interactions\nbetween antiretroviral regimen treatment effect and sex, race and ethnicity,\ncountry, or viral load stratum (Figure 3A, right side). The most common cause of regimen failure was\nconfirmed plasma HIV-1 RNA≥1,000 copies/ml (81% of all primary endpoints). The\nrange of the relative risk difference for virologic failure was 0.72 to 1.36\n(Table 2). Of 156\ninitial virologic failures, 64 (41%) and 125 (80%) occurred within the first 24\nwk and 96 wk of follow-up, respectively. There were no significant differences\nin the risk of HIV-1 disease progression or death between arms. 25 disease\nprogression events (15 in the EFV+FTC/TDF arm and ten in the EFV+3TC/ZDV arm)\ndid not meet the definition of the treatment failure endpoint due to either\nbeing diagnosed within the first 12 wk of study follow-up (12 events) and/or\nbeing part of an IRIS event (13 events).\n\n10.1371/journal.pmed.1001290.t002Table 2 Primary and secondary time-to-event outcomes for comparison of\nefavirenz plus emtricitabine-tenofovir-DF to efavirenz plus\nlamivudine-zidovudine using data collected through 31-May-2010.\nStudy Endpoint\tNumber of Events\tHazard Ratio (95% CI)a\n\t\np-Valueb\n\tEvents per 100 Person-Years (95%\nCI)\t\n\tEFV+FTC-TDF\tEFV+3TC-ZDV\t\t\tEFV+FTC-TDF\tEFV+3TC-ZDV\t\nTreatment failure (composite endpoint)\t95\t98\t0.95 (0.72–1.27)\tNA\t5.4 (4.4–6.7)\t5.8 (4.7–7.0)\t\nAll deathc\n\t18\t20\t0.90 (0.48–1.70)\t0.74\t0.9 (0.6–1.5)\t1.1 (0.7–1.7)\t\nAll initial HIV-1 disease progressiond\n,\ne\n\t11\t12\t0.89 (0.39–2.01)\t0.77\t0.6 (0.3–1.0)\t0.7 (0.4–1.1)\t\nAll initial confirmed virologic failuree\n,\nf\n\t78\t78\t0.99 (0.72–1.36)\t0.95\t4.4 (3.6–5.5)\t4.5 (3.6–5.7)\t\nSafety events (composite endpoint)\t243\t313\t0.64 (0.54–0.76)\t<0.0001\t17.6 (15.5–19.9)\t28.7 (25.7–32.0)\t\nAll initial antiretroviral dose\nmodificationse\n,\ng\n\t140\t222\t0.54 (0.44–0.67)\t<0.0001\t8.1 (6.9–9.6)\t15.6 (13.7–17.8)\t\nAll initial grade 3 or 4 signs or symptomsd\n,\ne\n\t115\t116\t0.96 (0.74–1.24)\t0.73\t6.9 (5.8–8.3)\t7.4 (6.1–8.8)\t\nAll initial grade 3 or 4 laboratory\nabnormalitiesd\n,\ne\n\t98\t154\t0.55 (0.43–0.71)\t<0.0001\t5.8 (4.8–7.1)\t10.8 (9.2–12.6)\t\nFirst antiretroviral regimen\ndiscontinuationh\n\t125\t147\t0.83 (0.65–1.05)\t0.12\t7.1 (5.9–8.4)\t8.6 (7.4–10.2)\t\nImmunologic failurei\n\t33\t30\t1.08 (0.66–1.79)\t0.75\t1.8 (1.3–2.5)\t1.6 (1.1–2.3)\t\na Also known as relative risk. Estimated from Cox regression model\nstratified by both country and RNA stratum and including randomized\ntreatment group as sole covariate.\n\nb \np-Value calculated from stratified log-rank test\nbetween arms. Not applicable (NA) because no formal hypothesis\ntesting was performed based on DSMB recommendations.\n\nc The five most common causes of death were infection (17 deaths) and\nunknown cause (five deaths) followed by suicide, trauma, and stroke\n(three deaths each).\n\nd Disease progression diagnoses are in Table\nS7; grade 3 and 4 laboratory adverse events in Table\nS8; and signs and symptoms in Table\nS9.\n\ne All events meeting these criteria are reported; some participants met\ncriteria for multiple endpoints.\n\nf Confirmed plasma HIV RNA≥1,000 copies/ml at study week 16 or\nlater.\n\ng Change in any component of initial randomized antiretroviral\nregimen.\n\nh The following antiretroviral substitutions were prespecified and were\nnot included in this endpoint: stavudine or TDF for ZDV, nevirapine\nfor EFV, or didansoine for TDF.\n\ni CD4+ lymphocytes <100/µl at week 48 or later.\n\nThere were no differences between EFV+FTC-TDF and EFV+3TC-ZDV for plasma HIV-1\nRNA<400 copies/ml at 24 and 48 wk (p = 0.12 and 0.60,\nrespectively; missing imputed as ≥400 copies/ml) and the kinetics of attaining\nand maintaining plasma HIV-1 RNA suppression were similar in both arms over time\n(Figure 2D). In the FDA\nTLOVR analysis disallowing any antiretroviral substitution there were fewer\nevents in EFV+FTC-TDF arm at 48 wk (99 versus 153; p<0.001)\nand 96 wk (124 versus 186; p<0.001). In the TLOVR analysis\nthat did not penalize for prespecified antiretroviral drug substitutions, there\nwas no difference between treatment arms at 48 or 96 wk (86 events in each arm,\np = 0.99 and 111 versus 116 events;\np = 0.74, respectively).\n\nRisk of immunologic failure was low (Table 2). Median absolute CD4+ lymphocytes\nincreased from 167 cells/µl at screening to 452 cells/µl at 192 wk and there was\nno significant difference between the EFV+FTC-TDF and EFV+3TC-ZDV arms over time\n(one-sided p = 0.06) (Figure 2F).\n\nRegimen Discontinuation for EFV+FTC-TDF\nAntiretroviral regimen discontinuation was due to non-prespecified drug\nsubstitutions (44% of all observed discontinuations), premature discontinuation\nof study follow-up (44%), temporary discontinuation of all antiretroviral\ntherapy for more than 8 wk (8%), and permanent discontinuation of all\nantiretroviral therapy (4%). Risk of this endpoint, when protocol-specified drug\nsubstitutions were not counted, did not differ significantly between EFV+FTC-TDF\nand EFV+3TC-ZDV (Table 2).\nThe most common reasons for non-prespecified drug substitutions among persons\nrandomized to EFV+FTC-TDF and EFV+3TC-ZDV were virologic failure (44 versus 40\ncases), clinician/participant decision (seven cases each), and pregnancy (seven\ncases each).\n\nSafety of EFV+FTC-TDF\nThere were fewer safety endpoints among participants assigned to EFV+FTC-TDF\ncompared to EFV+3TC-ZDV (Table\n2). Estimated probability of a safety endpoint by week 192 was 45.5%\n(CI 41.3%–50.0%) versus 61.5% (CI 57.1%–65.9%). Relative risk of a safety\nendpoint between arms did not vary over time (p = 0.8) (Figure 2H). There was a\nsignificant interaction between sex and study treatment for the primary safety\nendpoint (Figure 3B, right\nside). Women randomized to EFV+FTC-TDF had lower risk of a safety endpoint\ncompared to women randomized to EFV+3TC-ZDV (HR 0.50, CI 0.39–0.64). Among men,\nrisk difference for the primary safety endpoint between arms was attenuated (HR\n0.79, CI 0.62–1.00). There were no significant interactions between race,\ncountry, or entry plasma HIV-1 RNA stratum and assigned treatment arm for the\nprimary safety endpoint (Figure\n3B, right side).\n\nAmong the individual safety endpoint components, there were significantly fewer\ninitial dose modifications among participants randomized to EFV+FTC-TDF compared\nto EFV+3TC-ZDV (Table 2).\nThe estimated cumulative probability of any dose modification of the assigned\ntreatment arms at 192 wk was 25.9% (CI 22.3%–30.0%) compared to 43.9% (CI\n39.6%–48.5%), respectively. At any time prior to meeting the primary efficacy\nendpoint, six (1%) participants assigned to EFV+FTC-TDF switched to ZDV (not\nprespecified) and 46 (8.9%) participants assigned to EFV+3TC-ZDV switched to TDF\n(prespecified). Adjustment for effects of crossover from FTC-TDF to 3TC-ZDV and\n3TC-ZDV to FTC-TDF, including risk time and events during crossover, did not\nsignificantly affect the risk ratio estimate for the primary efficacy comparison\n(adjusted HR = 0.94).\n\nThere were fewer severe or potentially life-threatening laboratory abnormalities\nin the EFV+FTC-TDF arm compared to the EFV+3TC-ZDV arm (Tables 2 and S8). The\nestimated cumulative probability of a severe or potentially life-threatening\nlaboratory abnormality at 192 wk was 19.7% (CI 16.4%–23.7%) compared to 30.9%\n(CI 27.0%–35.2%). Neutropenia was the most common adverse laboratory abnormality\namong persons assigned to EFV+3TC-ZDV, but the risk of laboratory abnormalities\nbetween arms remained significant when neutropenia events were excluded (HR\n0.71, CI 0.52–0.96; p = 0.03). There were five severe or\npotentially life-threatening elevations of serum creatinine among participants\nassigned to EFV+FTC-TDF and two among participants assigned to EFV+3TC-ZDV. The\nrisk of a severe or life-threatening sign or symptom was not significantly\ndifferent between arms (Tables\n2 and S9). Participants assigned to EFV+FTC-TDF had fewer serious\nmetabolic diagnoses compared to participants assigned to EFV+3TC-ZDV (three\nversus 19 cases; p<0.001) (Tables S10\nand S11)\nwith seven diagnoses of lipoatrophy and two diagnoses of lipoaccumulation in the\nEFV+3TC-ZDV arm compared to none in the EFV+FTC-TDF arm.\n\nCo-infection with Mycobacterium tuberculosis\n\nA total of 172 (10.9%) participants were diagnosed with tuberculosis: 91\nparticipants had active tuberculosis at the time of study entry and continued\ntuberculosis treatment during study follow-up. 81 participants had a new\ndiagnosis of active tuberculosis after study entry. During study follow-up 28\nparticipants randomized to ATV+DDI+FTC had an initial antiretroviral drug\nsubstitution because of need for anti-tuberculosis therapy triggering the\nantiretroviral regimen switch outcome. No participants randomized to EFV plus\n3TC-ZDV or EFV plus FTC-TDF had an antiretroviral drug substitution because of\nanti-tuberculosis treatment.\n\nPregnancy\nThere were 62 pregnancies among 58 women in the trial population. For the\ncomparison of ATV+DDI+FTC to EFV+3TC-ZDV there were 20 and eight pregnancies,\nrespectively, and the incidence of pregnancy among women of childbearing\npotential was 4.8 per 100 person-years (95% CI 3.1–7.4) versus 1.9 per 100\nperson-years (95% CI 1.0–3.9). Of these 28 pregnancies, there were 12 live\nbirths, nine spontaneous abortions, five induced abortions, one intrauterine\nfetal demise, and one ectopic pregnancy. For the comparison of EFV+FTC/TDF to\nEFV+3TC-ZDV there were 20 and 22 pregnancies, respectively, and the incidence of\npregnancy among women of childbearing potential was 2.3 per 100 person-years\n(95% CI 1.5–3.6) versus 2.6 per 100 person-years (95% CI 1.7–3.9). Of these 42\npregnancies, there were 14 live births, 11 spontaneous abortions, seven induced\nabortions, two intrauterine fetal demise, and eight women remained pregnant at\nthe time of study closure.\n\nDiscussion\nA unique feature of PEARLS is the prospective enrollment of a study population from\nlow-, intermediate-, and high-income countries on four continents with near equal\nproportions of men and women. The distribution of enrollment by country, uniform\nentry criteria, and quality assurance measures across study sites allowed direct and\nhighly powered comparisons of antiretroviral regimen efficacy in HIV-1-infected\npersons with diverse racial, cultural, and demographic characteristics. In this\ncontext, ATV+DDI+FTC had inferior efficacy compared to EFV+3TC-ZDV and is not\nrecommend as an initial antiretroviral regimen. The regimen of EFV+FTC-TDF had\nsimilar high and durable efficacy with a significant safety advantage compared to\nEFV+3TC-ZDV.\n\nPEARLS was the first clinical trial to prospectively evaluate ATV+DDI+FTC. This\nregimen had significantly inferior virological efficacy as demonstrated by highly\nsignificant greater rates of protocol defined virologic failure (plasma HIV-1\nRNA≥1,000 copies/ml at week 16 or later) and significantly less viral suppression\n(plasma HIV-1 RNA <400 copies/ml) at 24 wk, which was a prespecified secondary\nendpoint. PEARLS was not designed to directly compare individual antiretroviral\nagents within regimens, so the reason for inferiority of this antiretroviral\ncombination is uncertain. Participants were instructed to take DDI on an empty\nstomach at a separate time from when ATV was taken with food. The possibility that\nthis inconvenient dosing schedule could have affected adherence to the ATV+DDI+FTC\nregimen is being investigated. There was no significant interaction between\ntreatment effect and baseline viral load stratum for the comparison of ATV+DDI+FTC\nto EFV+3TC/ZDV. However, there was a significant difference in treatment effect\nbetween women and men for the efficacy of ATV+DDI+FTC and the inferior efficacy of\nthis regimen compared to EFV+3TC-ZDV was most pronounced among men. Several previous\nstudies demonstrated higher serum protease inhibitor concentrations among women\n[18]–[20], so we are currently\ninvestigating whether inadequate ATV exposure in men in the ATV+DDI+FTC arm explains\nthe interaction between sex and treatment efficacy in PEARLS. Given that women had\nsignificantly better relative efficacy with this regimen than men, whether or not\nthis regimen should be used for initial treatment of HIV-1-infected women remains an\nunanswered question.\n\nOverall, the ATV+DDI+FTC arm had superior safety compared to EFV+3TC/ZDV. Although\nabsolute number of events was small, participants assigned to ATV+DDI+FTC had\ngreater frequency of serious renal disease. Previous large studies in which ATV,\ndidanosine, and FTC were components of other multidrug antiretroviral regimens did\nnot report this toxicity [7]–[14].\nParticipants assigned to ATV+DDI+FTC had greater CD4+ lymphocyte increases than\nparticipants in the EFV+3TC/ZDV arm. Since there was a trend toward more new AIDS\nendpoints in the ATV arm compared to the EFV arm (18 versus 10;\np = 0.14) (see Table\n1), there was no evidence that the statistically significant difference\nin CD4+ cell count increase was associated with a clinical benefit.\n\nPEARLS is the second randomized clinical trial to compare EFV+FTC-TDF and EFV+3TC-ZDV\nin an initial antiretroviral regimen. The study populations of the previous study\n(GS-01-934) [6] and PEARLS\nare different. Compared to GS-01-934, PEARLS had a larger sample size for the\ncomparison of EFV+FTC-TDF to EFV+3TC-ZDV (1,045 versus 515) and a larger proportion\nof women (46% versus 14%), African race (50% versus 23%), Asian race (23% versus\n≤4%), Hispanic ethnicity (20% versus 16%), and greater geographic diversity (North\nAmerica, Caribbean, South America, Africa and Asia versus North America and Europe).\nThese differences in study populations, and their potential effects on study\noutcomes, should be considered when comparing the results of GS-01-934 and\nPEARLS.\n\nA second key finding of PEARLS is that EFV+FTC-TDF and EFV+3TC-ZDV had very similar\ntreatment failure rates and both regimens suppressed plasma HIV-1 RNA below 400\ncopies/ml for greater than 80% of participants for up to 144 wk. Given the precision\nof the confidence bounds on the efficacy comparisons, we conclude that these\nregimens had similar efficacy for initial treatment of HIV-1. GS-01-934 reached\ndifferent conclusions about the relative efficacy of these two antiretroviral\nregimens [6]. It is\npossible that differences in the study populations between PEARLS and GS-01-934\ncontributed to the different efficacy conclusions, but the finding that sex, race,\nethnicity, or geography did not affect relative regimen efficacy in PEARLS (Figure 2A, right panel) does not\nsupport this explanation. The conclusion of the GS-01-934 study that EFV+FTC-TDF had\nsuperior efficacy to EFV+3TC-ZDV was based on an FDA TLOVR primary endpoint that\nassigned equal consequence to changes in the randomized drug assignments regardless\nof the reason for change. When the FDA TLOVR algorithm was evaluated as secondary\nendpoint in PEARLS we also found significant superiority of EFV+FTC-TDF, but a TLOVR\nalgorithm that did not count protocol-prespecified drug substitutions as endpoints\ndid not detect a difference between arms. The discordant findings of the two TLOVR\nanalyses in PEARLS suggest that the different conclusions of GS-934 and PEARLS about\nrelative regimen efficacy could be due to whether or not drug substitutions for\ntoxicity management were included in the primary efficacy endpoint. Inclusion of\ndrug discontinuation for toxicity management in an efficacy endpoint has the\npotential to lead to inaccurate conclusions about regimen efficacy. This point is\nillustrated in the efficacy comparison of ATV+DDI+FTC to EFV+3TC-ZDV in PEARLS. In\nthe FDA TLOVR the inferior efficacy of ATV+DDI+FTC was masked by the higher rate of\ndrug substitutions in the EFV+3TC-ZDV arm, whereas in PEARLS the primary endpoint\ncomparison and the TLOVR that did not count protocol-specified drug substitutions\nATV+DDI+FTC had clearly inferior efficacy.\n\nAnother important finding of PEARLS is that EFV+FTC-TDF had superior safety with\nsignificantly less laboratory adverse events compared to EFV+3TC-ZDV. This finding\nalso differs from GS-01-934, which had overall higher rates of primary safety events\nthan PEARLS [6], but did\nnot detect a significant difference in clinical or laboratory adverse events between\narms. Since the better safety of EFV+FTC-TDF in PEARLS was most pronounced in women,\nwe speculate that the larger number of women in PEARLS allowed us to detect this\nsafety difference.\n\nThe between-arm differences in the PEARLS primary safety analyses were driven largely\nby higher rates of neutropenia and anemia resulting in protocol-recommended drug\nsubstitutions in the EFV+3TC-ZDV arm. Neutropenia and anemia are well-described\ntoxicities of ZDV [21], and\nneutropenia has been associated with increased risk of serious bacterial infections\nin HIV-infected people [22]–[25].\nThus the risk, potential consequences and the laboratory monitoring required to\ndetect and manage neutropenia and anemia are important considerations when deciding\nwhether to initiate antiretroviral treatment with EFV+3TC-ZDV. Although no apparent\ndifferences in the occurrence of clinical events as a complication of neutropenia or\nanemia were observed in PEARLS, potential consequences could have been attenuated by\nfrequent laboratory monitoring and standard procedures for clinical management of\nadverse events specified in the protocol. The finding that the EFV+FTC-TDF arm had\nsignificantly fewer serious metabolic diagnoses (which included lipoatrophy and\nlipodystrophy) is an important safety advantage of this regimen that was also\nobserved in GS-01-934 [26].\nAlthough renal impairment has been associated with TDF, renal adverse events were\nuncommon in the EFV+FTC-TDF arm of PEARLS.\n\nAll HIV-1 protease inhibitors, even with ritonavir boosting, have a significant\npharmacokinetic interaction with rifampin that decreases protease inhibitor\nconcentrations and potentially reduces anti-HIV-1 efficacy [3]. Thus use of HIV-1 protease inhibitors in\npersons with active tuberculosis is not recommended if other options are available.\nAlthough active tuberculosis was relatively uncommon in PEARLS participants overall,\ntreatment of tuberculosis was the third most common cause of the antiretroviral\nregimen discontinuation endpoint in the ATV plus DDI and FTC arm largely because of\nthe requirement to substitute for ATV if there was concomitant use of rifampin.\nThere was no prescribed substitution for EFV if rifampin was used and\ndiscontinuation due to tuberculosis treatment did not occur in either EFV containing\narm.\n\nHalf of HIV-1 infections worldwide occur in women [27], but historically women are\nunderrepresented in clinical trials of antiretroviral therapy [28]. Almost half of PEARLS participants\nwere women so we were able to evaluate potential interactions between sex and\ntreatment effect and safety. Our findings of greater risk of safety events for women\nassigned to EFV+3TC-ZDV and higher relative efficacy of an ATV-based regimen in\nwomen compared to men add to a growing body of evidence that antiretroviral efficacy\nand safety can differ in women and men [29]–[31], and support further development of\nsex-specific recommendations for both antiretroviral regimen choice and toxicity\nmonitoring. When treating HIV-1-infected women with EFV it is important to recognize\nthe teratogenic risk during the first trimester of pregnancy. In PEARLS, women of\nreproductive potential were treated with EFV only if they agreed to use effective\nbirth control methods and close monitoring was performed to detect pregnancies early\nto ensure that EFV was used safely. Despite these requirements, there were 62\npregnancies during study follow-up, including 42 in the two EFV-containing arms. It\nis also notable that the incidence of pregnancy of women of child-bearing potential\nwas higher in the ATV+DDI+FTC arm, which had less stringent contraception\nrequirements, compared to the EFV-containing arms. The outcomes of the live births\nto women in the PEARLS study are reported elsewhere [32].\n\nThere are limitations to consider in the application of the study findings to\nresource-limited settings. PEARLS was conducted at clinical research sites\naffiliated with academic medical centers in large cities and these environments are\nundoubtedly different from community clinics or rural health care facilities. The\nentry criteria resulted in recruitment of a relatively health study population with\na low prevalence of co-morbidities. Although most participants had a pretreatment\nCD4+ lymphocyte count that put them at risk for AIDS-related complications,\nrelatively few reported prior or current AIDS-related infection or malignancy at\nbaseline. Data concerning potential participants who were screened and found not to\nmeet entry criteria were not collected so it is unclear how representative our study\npopulation was of other HIV-1-infected persons in care at the study sites. Intense\nclinical and laboratory monitoring required by the study design could also have\naffected safety and efficacy outcomes through improved adherence and retention in\ncare. To date, we have only investigated the influence of factors such as\nrace/ethnicity, sex, and geography on treatment effect (e.g., the performance of one\nregimen relative to another regimen). Although we did not detect interactions\nbetween race/ethnicity and geography and treatment effect, this finding does not\nmean that these factors do not affect antiretroviral efficacy or safety and further\nanalyses to explore these possibilities are ongoing.\n\nTo our knowledge, PEARLS is the first study to recruit a study population with this\nracial, geographic, and sex diversity for a prospective randomized clinic trial of\nantiretroviral therapy. This unique feature of PEARLS likely contributed to the\nidentification of previously unrecognized sex-related differences in antiretroviral\nefficacy and safety, and provides an evidence base to better guide the choice of an\ninitial antiretroviral regimen in multinational settings. The efficacy and safety of\nEFV+FTC-TDF in this diverse study population, especially in HIV-1-infected women,\ncombined with the availability of these three drugs in a single co-formulated tablet\nwith once-daily dosing make this an attractive regimen for initiation of\nantiretroviral therapy in resource-constrained settings by the criteria outlined in\nUNAIDS Treatment 2.0 [1].\n\nSupporting Information\nAlternative Language Abstract S1 \nSpanish translation of the abstract by Jorge Sanchez.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Alternative Language Abstract S2 \nPortuguese translation of the abstract by Beatriz\nGrinszteyn.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Alternative Language Abstract S3 \nThai translation of the abstract by Khuanchai Supparatpinyo.\n\n\n(DOCX)\n\nClick here for additional data file.\n\n Alternative Language Abstract S4 \nCreole translation of the abstract by Cynthia Reverie.\n\n\n(DOCX)\n\nClick here for additional data file.\n\n Alternative Language Abstract S5 \nFrench translation of the abstract by Cynthia Reverie.\n\n\n(DOCX)\n\nClick here for additional data file.\n\n Table S1 \nType of infectious diagnoses at study entry.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S2 \nType of opportunistic infections observed for comparison of\nATV+DDI-EC+FTC to EFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S3 \nAll new laboratory events of grade 3 or higher for comparison of\nATV+DDI-EC+FTC to EFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S4 \nAll new signs and symptoms of grade 3 or higher for comparison of\nATV+DDI-EC+FTC to EFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S5 \nAll new serious non-AIDS diagnoses for comparison of ATV+DDI-EC+FTC to\nEFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S6 \nNew serious non-AIDS diagnosis categories compared for ATV+DDI-EC+FTC\nversus EFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S7 \nType of opportunistic infections observed for comparison of EFV+FTC-TDF\nto EFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S8 \nAll new laboratory events of grade 3 or higher for comparison of\nEFV+FTC-TDF to EFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S9 \nAll new signs and symptoms of grade 3 or higher for comparison of\nEFV+FTC-TDF to EFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S10 \nAll new serious non-AIDS diagnoses for comparison of EFV+FTC-TDF to\nEFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Table S11 \nNew serious non-AIDS diagnosis categories compared for EFV+FTC-TDF\nversus EFV+3TC-ZDV.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Text S1 \nStudy protocol.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Text S2 \nCONSORT checklist.\n\n\n(DOC)\n\nClick here for additional data file.\n\n Text S3 \nAppendix 60. Diagnoses appendix.\n\n(PDF)\n\nClick here for additional data file.\n\n Contributors\nThe authors thank the PEARLS study participants who volunteered their time and\nefforts. The authors acknowledge the contributions of the following PEARLS\ninvestigators: Edith Swann, Ph.D., HIV Research Branch, TRP, DAIDS, NIAD, NIH,\nBethesda, Maryland; Ronald L. Barnett, Ph.D., ACTG Operations Centre, Social\n& Scientific Systems, Inc. Silver Spring, Maryland; Barbara Brizz, B.S.N.,\nM.H.S.Ed., ACTG Operations Center, Social & Scientific Systems, Inc. Silver\nSpring, Maryland; Yvette Delph, M.D., ACTG Operations Center, Social &\nScientific Systems, Inc. Silver Spring, Maryland; Nikki Gettinger, M.P.H., ACTG\nOperations Center, Social & Scientific Systems Inc. Silver Spring, Maryland;\nRonald T. Mitsuyasu, M.D., UCLA CARE Center, Los Angeles, California; Susan\nEshleman, M.D., Johns Hopkins University, Baltimore, Maryland; Steven Safren,\nPh.D., Harvard Medical School, Boston, Massachusetts; Susan A. Fiscus, Ph.D.,\nDepartment of Microbiology & Immunology, University of North Carolina,\nSchool of Medicine, Chapel Hill, North Carolina; Adriana Andrade, M.D., M.P.H.,\nDivision of Infectious Diseases, John Hopkins University, Baltimore; David W.\nHaas, M.D., Infectious Diseases, Vanderbilt University, Nashville, Tennessee;\nFarida Amod, MB CHB, FCPath, FCP, Department of Medicine, Nelson R Mandela\nSchool of Medicine, Durban, South Africa; Vladimir Berthaud, M.D., Infectious\nDisease, Vanderbilt University Medical Centre, Nashville, Tennessee; Robert C.\nBollinger, M.D., Division of Infectious Diseases, John Hopkins University,\nBaltimore, Maryland; Yvonne Bryson, M.D., Pediatric Infectious Disease Dept.,\nUCLA School of Medicine, Los Angeles, California; David Celentano, Sc.D.,\nM.H.S., Department of Epidemiology, Johns Hopkins School of Hygiene and Public\nHealth, Baltimore, Maryland; David Chilongozi, C.O., M.P.H., UNC HIVNET, UNC\nProject, Lilongwe, Malawi; Myron Cohen, M.D., University of North Carolina,\nChapel Hill, North Carolina; Ann C. Collier, M.D., University of Washington,\nACTU, Harborview Medical Centre, Seattle, Washington; Judith Silverstein\nCurrier, M.D., M.Sc, University of California, Los Angeles, California; Susan\nCu-Uvin, M.D., The Miriam Hospital, Brown University, Immunology Centre,\nProvidence, Rhode Island; Joseph Eron, M.D., Division of Infectious Diseases,\nDept. of Medicine, University of North Carolina, Chapel Hill, North Carolina;\nCharles Flexner, M.D., Johns Hopkins University Hospital, Baltimore, Maryland;\nJoel E. Gallant, M.D., M.P.H., Division of Infectious Diseases, Johns Hopkins\nUniversity School of Medicine, Baltimore, Maryland; Roy M. Gulick, M.D., M.P.H.,\nThe Cornell Clinical Trials Unit, New York, New York; Scott M. Hammer, M.D.,\nDivision of Infectious Diseases, Columbia Presbyterian Medical Centre, New York,\nNew York; Irving Hoffman, P.A., M.P.H., University of North Carolina, Chapel\nHill, North Carolina; Peter Kazembe, MBCHB FRCP(C), Baylor College of\nMedicine-Abbott Fund Children's Clinical Centre of Excellence, Lilongwe, Malawi;\nNewton Kumwenda, M.P.H., Ph.D., Johns Hopkins Project, Malawi; Javier R. Lama,\nM.D., M.P.H., Investigaciones Medicas en Salud (INMENSA), Lima, Peru; Jody\nLawrence, M.D., University of California, San Francisco, Adult AIDS Clinical\nTrials Unit, San Francisco, California; Chiedza Maponga, Pharm.D., DaTIS,\nMedical University of Zimbabwe, Zimbabwe; Francis Martinson, M.D., UNC Project,\nLilongwe; Kenneth Mayer, M.D., Division of Infectious Diseases, Brown University\nSchool of Medicine, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island;\nKarin Nielsen, M.D., UCLA School of Medicine, Los Angeles, California; Richard\nB. Pendame M.D., M.P.H., Malawi; Bharat Ramratnam, M.D. Laboratory of\nRetrovirology, Division of Infectious Diseases, Brown University Medical School,\nProvidence, Rhode Island; Ian Sanne, University of Witwatersrand, Johannesburg,\nSouth Africa; Patrice Severe, M.D. Internal Medical, Infectious Diseases,\nInstitute de Laboratories et de Recherches, Port-au-Prince, Haiti; Thira\nSirisanthana, M.D., Research Institute for Health Sciences, Chiang Mai\nUniversity, Chiang Mai, Thailand; Suniti Solomon, M.D., YRG Centre for AIDS\nResearch and Education, Chennai, India; Steve Tabet, M.D., University of\nWashington, Harborview Medical Centre, Seattle, Washington; Taha Taha, M.D.,\nJohns Hopkins University, School of Hygiene & Public Health, Baltimore,\nMaryland; Charles van der Horst, M.D., Department of Medicine, University of\nNorth Carolina, Chapel Hill, North Carolina; Christine Wanke, M.D., Tufts\nUniversity School of Medicine, Boston, Massachusetts; Joan Gormley, B.S.N., The\nMiriam Hospital, Immunology Centre, Providence, Rhode Island; Cheryl J. Marcus,\nR.N., B.S.N., University of North Carolina, Chapel Hill, North Carolina; Beverly\nPutnam, R.N., M.S.N., University of Colorado Health Sciences, Denver, Colorado;\nSmanga Ntshele, Community Advisory Board Member, Durban, South Africa; Edde\nLoeliger, M.D., Clinical Development & Medical Affairs, Greenford,\nMiddlesex; Keith A. Pappa, Pharm, D., GlaxoSmithKline, Infectious Diseases\nMedicine, Triangle Park, North Carolina; Nancy Webb, M.S., Frontier Science\n& Technology Research Foundation, Inc., Amherst, Massachusetts; David L.\nShugarts, M.A., University of Colorado Health Sciences, Denver, Colorado; Mark\nA. Winters, M.S., Stanford University Medical Center, Division of Infectious\nDisease, Stanford, California; Renard S. Descallar, Joseph Steele, Michael\nWulfsohn, Farideh Said, Yue Chen, John C Martin, Norbert Bischofberger, Andrew\nCheng, and Howard Jaffe, M.D., Gilead Sciences, Foster City, California; Jabin\nSharma, M.H.S., YRG Centre for AIDS Research and Education, India; S.Poongulali,\nM.B.B.S..,D.G.O..,M.Sc., YRG Centre for AIDS Research and Education, Chennai,\nIndia; Sandra Wagner Cardoso, Instituto de Pesquisa Clinica Evandro\nChagas-Fiocruz, Brazil; Deise Lucia Faria, Instituto de Pesquisa Clinica Evandro\nChagas-Fiocruz, Brazil; Sima Berendes, M.D., College of Medicine, Blantyre,\nMalawi; Kelly Burke, M.P.H, Blantyre, Malawi; Rosie Mngqibisa, M.B.Ch.B., Nelson\nMandela School of Medicine, Durban, South Africa; Cecelia Kanyama, M.B.B.S.,\nKamuzu Central Hospital, Lilongwe, Malawi; Virginia Kayoyo, Kamuzu Central\nHospital, Lilongwe, Malawi; Wadzanai P. Samaneka, M.D., University of Zimbabwe\nCollege of Health Sciences, Harare, Zimbabwe; Anthony Chisada, M.D., University\nof Zimbabwe College of Health Sciences, Harare, Zimbabwe; Sharla Faesen,\nUniversity of the Witwatersrand, Johannesburg, South Africa; Suwat\nChariyalertsak, M.D., Ph.D., Chiang Mai University, Chiang Mai, Thailand; Breno\nSantos, M.D., Hospital Conceicao, Porto Alegre, Brazil; Rita Alves Lira, M.D.,\nHospital Conceicao, Porto Alegre, Brazil; Anjali A. Joglekar, M.B.B.S., National\nAIDS Research Institute, Pune, India; Alberto La Rosa, M.D., Asociacion Civil\nImpacta Salud y Educacion - Miraflores, Lima, Peru; Rosa Infante, M.D.,\nInvestigaciones Medicas en Salud – INMENSA, Lima, Peru; Mamta Jain, M.D., UT\nSouthwestern Medical Center at Dallas, Dallas, Texas; Tianna Petersen, M.S., UT\nSouthwestern Medical Center at Dallas, Dallas, Texas; Sheela Godbole, M.D.,\nM.B.B.S., NARI Clinic at NIV, Pune, India; Sampada Dhayarkar, M.B.B.S., NARI\nClinic at NIV, Pune, India; Judith Feinberg, M.D., University of Cincinnati,\nCincinnati, Ohio; Jenifer Baer, R.N., B.S.N., University of Cincinnati,\nCincinnati, Ohio; Richard B. Pollard, M.D., UC Davis School of Medicine, Davis,\nCalifornia; David Asmuth, M.D., UC Davis School of Medicine, Davis, California;\nRaman R Gangakhedkar, M.P.H., Dc.H., M.B.B.S., NARI Clinic at Gadikhana Dr.\nKotnis Municipal Dispensary, Pune, India; Asmita Gaikwad, M.B.B.S., NARI Clinic\nat Gadikhana Dr. Kotnis Municipal Dispensary, Pune, India; M. Graham Ray, R.N.,\nM.S.N.; University of Colorado Hospital, Aurora, Colorado; Cathi Basler, R.N.,\nA.N.P-BC, A.C.R.N., University of Colorado Hospital, Aurora, Colorado; Michael\nF. Para, M.D., The Ohio State University, Ohio; Kathy J. Watson, R.N., The Ohio\nState University, Ohio; Babafemi Taiwo, M.B.B.S., Northwestern University,\nChicago, Illinois; Donna McGregor, M.S.N., Northwestern University, Chicago,\nIllinois; Henry H. Balfour, M.D., University of Minnesota, Minneapolis,\nMinnesota; Beth Mullan, University of Minnesota, Minneapolis, Minnesota; Ge-Youl\nKim, B.S.N.. Washington University, Saint Louis, Missouri; Michael K. Klebert,\nPh.D. R.N. A.N.P-B.C., Washington University, Saint Louis, Missouri; Gary\nMatthew Cox, M.D., Duke University Medical Center, Durham, North Carolina;\nMartha Silberman, R.N., Duke University Medical Center, Durham, North Carolina;\nDonna Mildvan, M.D., Beth Israel Medical Center, New York, New York; Manuel\nRevuelta, M.D., Beth Israel Medical Center, New York, New York; Karen T.\nTashima, M,D., The Miriam Hospital, Providence, Rhode Island; Helen Patterson,\nThe Miriam Hospital, Providence, Rhode Island; P. Jan Geiseler, M.D., University\nof Southern California; Los Angeles, California; Bartolo Santos, R.N.,\nUniversity of Southern California, Los Angeles, California; Eric S Daar, M.D.,\nHarbor-UCLA, Los Angeles, California; Ruben Lopez, M.D., Harbor-UCLA, Los\nAngeles, California; Laurie Frarey, A.N.P.-C., University of North Carolina,\nChapel Hill, North Carolina; David Currin, R.N. C.C.R.C., University of\nNorthCarolina, Chapel Hill, North Carolina; David H. Haas, M.D., Vanderbilt\nUniversity, Nashville, Tennessee; Vicki L. Bailey, R.N., Vanderbilt University,\nNashville, Tennessee; Pablo Tebas, M.D., Hospital of the University of\nPennsylvania, Philadelphia, Pennsylvania; Larisa Zifchak, R.N., Hospital of the\nUniversity of Pennsylvania, Philadelphia, Pennsylvania; Jolene Noel-Connor,\nR.N., Columbia University, New York, New York; Madeline Torres, R.N., Columbia\nUniversity, New York, New York; Beverly E. Sha, M.D., Rush University Medical\nCenter, Chicago, Illinois; Janice M. Fritsche, M.S., A.P.R.N., B.C., Rush\nUniversity Medical Center, Chicago, Illinois; Michelle Cespedes, M.D., New York\nUniversity/NYC HHC at Bellevue Hospital Center, New York, New York; Janet\nForcht, R.N., New York University/NYC HHC at Bellevue Hospital Center, New York,\nNew York; William A. O'Brien, M.D., The University of Texas Medical Branch,\nGalveston, Texas; Cheryl Mogridge, R.N., The University of Texas Medical Branch,\nGalveston, Texas; Christine Hurley, R.N., AIDS Care, Georgetown University,\nWashington (D.C.); Roberto Corales, D.O., AIDS Care, Georgetown University,\nWashington (D.C.); Maria Palmer, P.A., UCLA CARE Center, Los Angeles,\nCalifornia; Mary Adams, R.N. M.Ph., University of Rochester, Rochester, New\nYork; Amneris Luque, M.D., University of Rochester, Rochester, New York; Luis\nLopez-Detres, B.A., Cornell University, New York, New York; Todd Stroberg, R.N.,\nCornell University, New York, New York; and the HIV Prevention Trials Network\n(HPTN) for assistance with protocol design. We thank the members of the NIAID\nMultinational DSMB for their careful oversight and thoughtful recommendations\nduring the design and conduct of this study.\n\nAbbreviations\n3TClamivudine\n\nACTGAIDS Clinical Trials Group\n\nATVatazanavir\n\nDDIdidanosine-EC\n\nDFdisoproxil fumarate\n\nDSMBData Safety Monitoring Board\n\nEFVefavirenz\n\nFDAUS Food and Drug Administration\n\nFTCemtricitabine\n\nHRhazard ratio\n\nIRISimmune reconstitution inflammatory syndrome\n\nNNRTInon-nucleoside reverse transcriptase inhibitor\n\nPEARLSProspective Evaluation of Antiretrovirals in Resource Limited\nSettings\n\nTDFtenofovir-DF\n\nTLOVRtime to loss of virologic response\n\nZDVzidovudine\n==== Refs\nReferences\n1 World Health Organization (2010) Treatment\n2.0: Is this the future of treatment? World Health Organization. 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J Acquir\nImmune Defic Syndr \n32 : 18 –29 .12514410 \n10 \nBerenguer J , Gonzalez J , Ribera E , Domingo P , Santos J , et al (2008 ) Didanosine,\nlamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for\nthe initial treatment of HIV type 1 infection: final analysis (48 weeks) of\na prospective, randomized, noninferiority clinical trial, GESIDA\n3903 . Clin Infect Dis \n47 : 1083 –1092 .18781872 \n11 \nMolina JM , Journot V , Morand-Joubert L , Yeni P , Rozenbaum W , et al (2005 ) Simplification\ntherapy with once-daily emtricitabine, didanosine, and efavirenz in\nHIV-1-infected adults with viral suppression receiving a protease\ninhibitor-based regimen: a randomized trial . J\nInfect Dis \n191 : 830 –839 .15717256 \n12 \nMolina JM , Journot V , Furco A , Palmer P , De CN , et al (2007 ) Five-year follow\nup of once-daily therapy with emtricitabine, didanosine and efavirenz\n(Montana ANRS 091 trial) . Antivir Ther \n12 : 417 –422 .17591032 \n13 \nSanchez-Conde M , Palacios R , Sanz J , Rodriguez-Novoa S , Rivas P , et al (2007 ) Efficacy and\nsafety of a once daily regimen with efavirenz, lamivudine, and didanosine,\nwith and without food, as initial therapy for HIV Infection: the ELADI\nstudy . AIDS Res Hum Retroviruses \n23 : 1237 –1241 .17961110 \n14 \nSaag MS , Cahn P , Raffi F , Wolff M , Pearce D , et al (2004 ) Efficacy and\nsafety of emtricitabine vs stavudine in combination therapy in\nantiretroviral-naive patients: a randomized trial .\nJAMA \n292 : 180 –189 .15249567 \n15 Division of AIDS (2004; 2010) Table for\ngrading the severity of adult and pediatric adverse events Available: http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf.\nAccessed 12 January 2011.\n16 US Department of Health and Human Services\nFood and Drug Administration Center for Drug Evaluation and Research (2002)\nGuidance for industry: antiretroviral drugs using plasma HIV RNA measurements -\nclinical considerations for accelerated and traditional approval. Available:\nhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070968.pdf.\nAccessed 13 October 2010.\n17 \nXu X , Tian L , Wei LJ (2003 ) Combining dependent tests for linkage\nor association across multiple phenotypic traits .\nBiostatistics \n4 : 223 –229 .12925518 \n18 \nFletcher CV , Jiang H , Brundage RC , Acosta EP , Haubrich R , et al (2004 ) Sex-based\ndifferences in saquinavir pharmacology and virologic response in AIDS\nClinical Trials Group Study 359 . J Infect\nDis \n189 : 1176 –1184 .15031785 \n19 \nKing JR , Kakuda TN , Paul S , Tse MM , Acosta EP , et al (2007 ) Pharmacokinetics\nof saquinavir with atazanavir or low-dose ritonavir administered once daily\n(ASPIRE I) or twice daily (ASPIRE II) in seronegative\nvolunteers . J Clin Pharmacol \n47 : 201 –208 .17244771 \n20 \nPai MP , Schriever CA , az-Linares M , Novak RM , Rodvold KA (2004 ) Sex-related differences in the\npharmacokinetics of once-daily saquinavir soft-gelatin capsules boosted with\nlow-dose ritonavir in patients infected with human immunodeficiency virus\ntype 1 . Pharmacotherapy \n24 : 592 –599 .15162893 \n21 \nRichman DD , Fischl MA , Grieco MH , Gottlieb MS , Volberding PA , et al (1987 ) The toxicity of\nazidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related\ncomplex. A double-blind, placebo-controlled trial . N\nEngl J Med \n317 : 192 –197 .3299090 \n22 \nJacobson MA , Liu RC , Davies D , Cohen PT (1997 ) Human immunodeficiency virus\ndisease-related neutropenia and the risk of hospitalization for bacterial\ninfection . Arch Intern Med \n157 : 1825 –1831 .9290541 \n23 \nMoore RD , Keruly JC , Chaisson RE (1995 ) Neutropenia and bacterial infection\nin acquired immunodeficiency syndrome . Arch Intern\nMed \n155 : 1965 –1970 .7575050 \n24 \nHermans P , Sommereijns B , Van CN , Clumeck N (1999 ) Neutropenia in patients with HIV\ninfection: a case control study in a cohort of 1403 patients between 1982\nand 1993 . J Hematother Stem Cell Res \n8 \nSuppl 1 :\nS23 –S32 .10596033 \n25 \nKuritzkes DR , Parenti D , Ward DJ , Rachlis A , Wong RJ , et al (1998 ) Filgrastim\nprevents severe neutropenia and reduces infective morbidity in patients with\nadvanced HIV infection: results of a randomized, multicenter, controlled\ntrial . AIDS \n12 : 65 –73 .9456256 \n26 \nPozniak AL , Gallant JE , DeJesus E , Arribas JR , Gazzard B , et al (2006 ) Tenofovir\ndisoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose\nzidovudine/lamivudine and efavirenz in antiretroviral-naive patients:\nvirologic, immunologic, and morphologic changes–a 96-week\nanalysis . J Acquir Immune Defic Syndr \n43 : 535 –540 .17057609 \n27 Joint United Nations Programme on HIV/AIDS\n(UNAIDS) (2010) Global report: UNAIDS report on the global AIDS epidemic 2010.\nAvailable: http://www.unaids.org/globalreport/Global_report.htm. Accessed\n14 September 2011.\n28 \nd'Arminio MA , Gonzalez L , Haberl A , Sherr L , Ssanyu-Sseruma W , et al (2010 ) Better mind the\ngap: addressing the shortage of HIV-positive women in clinical\ntrials . AIDS \n24 : 1091 –1094 .20386426 \n29 \nMoore RD , Fortgang I , Keruly J , Chaisson RE (1996 ) Adverse events from drug therapy for\nhuman immunodeficiency virus disease . Am J\nMed \n101 : 34 –40 .8686712 \n30 \nCurrier JS , Spino C , Grimes J , Wofsy CB , Katzenstein DA , et al (2000 ) Differences\nbetween women and men in adverse events and CD4+ responses to nucleoside\nanalogue therapy for HIV infection. The AIDS Clinical Trials Group 175\nTeam . J Acquir Immune Defic Syndr \n24 : 316 –324 .11015147 \n31 \nClark R (2005 ) Sex differences in antiretroviral\ntherapy-associated intolerance and adverse events .\nDrug Saf \n28 : 1075 –1083 .16329711 \n32 \nNielsen-Saines K , Komarow L , Cu-Uvin S , Jourdain G , Klingman K , et al (2012 ) Assessment of\nsafety and toxicity following maternal antiretroviral exposure in infants\nborn To HIV-infected women enrolled in antiretroviral treatment protocols in\ndiverse areas of the world. Eighteen month results of AIDS Clinical Trials\nGroup (ACTG) Study 5190/Pediatric AIDS Clinical Trials Group (PACTG)\n1054 . Pediatrics \n129 :\ne1525 –e1532 .22585772\n\n",
"fulltext_license": "CC0",
"issn_linking": "1549-1277",
"issue": "9(8)",
"journal": "PLoS medicine",
"keywords": null,
"medline_ta": "PLoS Med",
"mesh_terms": "D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D038622:Internationality; D008297:Male; D009169:Mycobacterium tuberculosis; D011247:Pregnancy; D013997:Time Factors; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "101231360",
"other_id": null,
"pages": "e1001290",
"pmc": null,
"pmid": "22936892",
"pubdate": "2012",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "9456256;12925518;3299090;12514410;16421366;17961110;17971713;15249567;8686712;22585772;21353697;15115831;15247553;10601505;17244771;15717256;7575050;15162893;15031785;16329711;10596033;20386426;17057609;18781872;17591032;11015147;9290541",
"title": "Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.",
"title_normalized": "efficacy and safety of three antiretroviral regimens for initial treatment of hiv 1 a randomized clinical trial in diverse multinational settings"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP020417",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EFAVIRENZ"
},
"drugadditional"... |
{
"abstract": "Paclitaxel and carboplatin upregulate thymidine phosphorylase and thus may provide synergistic antitumor activity in combination with capecitabine (CTX). We, therefore, performed a phase I/II study of CTX. In the phase I study, patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8-21, every 4 weeks. Phase II patients with advanced adenocarcinoma of unknown primary (ACUP) were treated at the maximal tolerable dose. The phase I study enrolled 29 patients evaluable for dose limiting toxicity. The recommended phase II dose was capecitabine 750 mg/m(2) bid, paclitaxel 60 mg/m(2)/week and carboplatin AUC of 6. There were 9 confirmed responses, 5 partial responses and disease stabilization >3 months in 14 patients. The phase II study was prematurely terminated at 25 patients due to cessation of funding. The objective response rate was 32 % (95 % CI 0.15-0.54), the median progression-free survival 5.5 months (95 % CI 2.8-10.8 months) and the median overall survival 10.8 months (95 % CI 6.0-32.0 months). CTX demonstrated acceptable tolerability and antitumor activity. At the recommended dose level in patients with ACUP, this regimen showed encouraging preliminary activity.",
"affiliations": "Richard Solove Research Institute, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, 320 W 10th Avenue, Columbus, OH, 43221, USA. sameh.mikhail@osumc.edu.;Richard Solove Research Institute, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, 320 W 10th Avenue, Columbus, OH, 43221, USA.;Richard Solove Research Institute, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, 320 W 10th Avenue, Columbus, OH, 43221, USA.;Richard Solove Research Institute, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, 320 W 10th Avenue, Columbus, OH, 43221, USA.;Richard Solove Research Institute, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, 320 W 10th Avenue, Columbus, OH, 43221, USA.;Richard Solove Research Institute, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, 320 W 10th Avenue, Columbus, OH, 43221, USA.;Richard Solove Research Institute, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, 320 W 10th Avenue, Columbus, OH, 43221, USA.;Richard Solove Research Institute, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital, 320 W 10th Avenue, Columbus, OH, 43221, USA.",
"authors": "Mikhail|Sameh|S|;Lustberg|Maryam B|MB|;Ruppert|Amy S|AS|;Mortazavi|Amir|A|;Monk|Paul|P|;Kleiber|Barbara|B|;Villalona-Calero|Miguel|M|;Bekaii-Saab|Tanios|T|",
"chemical_list": "D011355:Prodrugs; D000069287:Capecitabine; D016190:Carboplatin; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; D017239:Paclitaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-015-2877-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "76(5)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Capecitabine; Carboplatin; Carcinoma of unknown primary; Esophageal; Paclitaxel; Thymidine phosphorylase",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D065767:Activation, Metabolic; D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D016190:Carboplatin; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D004938:Esophageal Neoplasms; D005221:Fatigue; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006402:Hematologic Diseases; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms; D009382:Neoplasms, Unknown Primary; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D011355:Prodrugs; D013939:Thymidine Phosphorylase; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1005-12",
"pmc": null,
"pmid": "26416564",
"pubdate": "2015-11",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Biomodulation of capecitabine by paclitaxel and carboplatin in advanced solid tumors and adenocarcinoma of unknown primary.",
"title_normalized": "biomodulation of capecitabine by paclitaxel and carboplatin in advanced solid tumors and adenocarcinoma of unknown primary"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US08508",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nExperiences of buprenorphine-naloxone (BNX) sublingual film injection are not well documented or understood. We examined how people who inject BNX film seek and share information about this practice, document the methods used to prepare BNX film for injection, and report participants' experiences of this practice.\n\n\nMETHODS\nInterviews were (n = 16) conducted with people who indicated that they had injected BNX film since its introduction onto the Australian market. Semistructured interviews were recorded and transcribed. NVivo10 program (QSR International) was used to analyse the data using qualitative description methodology.\n\n\nRESULTS\nParticipants largely reported similar BNX film preparation techniques, although the texture of BNX film during preparation to inject was reported to be unusual (gluggy), and there were many varied accounts associated with the amount of water used. Physical harms reported as associated with injecting BNX film were described (including local and systemic issues); participants reported injecting the film to enhance its immediate effects, yet generally reported that sublingual administration provided longer-lasting effects.\n\n\nCONCLUSIONS\nUnderstanding knowledge acquisition about injecting new formulations of opioid substitution therapy is crucial in developing more effective harm-reduction strategies. Dissemination by peer networks to those who are currently or planning to inject BNX film regarding the 'gelatine like' texture when mixing, using only cold water and double filtering is important to ensure safer injecting practices. Findings from this study highlight the importance of peer networks for the dissemination of harm-reduction information. Introduction of new formulations internationally requires more qualitative studies to inform safer practices.",
"affiliations": "Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia.;Department of Sociology and Social Policy, Sydney University, Sydney, Australia.;National Drug Research Institute, Faculty of Health Sciences, Curtin University, Melbourne, Australia.;National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia.;National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia.;National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia.;Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia.;The Langton Centre, South Eastern Sydney Local Health District Drug and Alcohol Services, NSW Health, Sydney, Australia.",
"authors": "White|Nancy|N|http://orcid.org/0000-0002-2301-8778;Flaherty|Ian|I|;Higgs|Peter|P|;Larance|Briony|B|;Nielsen|Suzanne|S|;Degenhardt|Louisa|L|;Ali|Robert|R|;Lintzeris|Nicholas|N|",
"chemical_list": "D000069479:Buprenorphine, Naloxone Drug Combination",
"country": "Australia",
"delete": false,
"doi": "10.1111/dar.12308",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-5236",
"issue": "34(6)",
"journal": "Drug and alcohol review",
"keywords": "buprenorphine-naloxone; harm reduction; intravenous drug abuse; patient non-adherence; qualitative research",
"medline_ta": "Drug Alcohol Rev",
"mesh_terms": "D000286:Administration, Sublingual; D000328:Adult; D001315:Australia; D000069479:Buprenorphine, Naloxone Drug Combination; D005260:Female; D006801:Humans; D007407:Interviews as Topic; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D063487:Prescription Drug Misuse; D036301:Qualitative Research; D015819:Substance Abuse, Intravenous; D055815:Young Adult",
"nlm_unique_id": "9015440",
"other_id": null,
"pages": "623-9",
"pmc": null,
"pmid": "26179339",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Injecting buprenorphine-naloxone film: Findings from an explorative qualitative study.",
"title_normalized": "injecting buprenorphine naloxone film findings from an explorative qualitative study"
} | [
{
"companynumb": "AU-RB PHARMACEUTICALS LIMITED-RB-082016-2015",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE\\NALOXONE"
},
... |
{
"abstract": "Our unique case of Richter's Transformation presenting as leptomeningial infiltration in a CLL patient receiving venetoclax raises questions on whether the drug penetrates the blood-brain barrier and at what extend, especially in reduced doses given for drug-drug interactions.",
"affiliations": "1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.;1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece.",
"authors": "Dimou|Maria|M|https://orcid.org/0000-0001-8197-9895;Bitsani|Aikaterini|A|;Roumelioti|Maria|M|;Dimitrakopoulou|Aglaia|A|;Iliakis|Theodore|T|;Pardalis|Vasileios|V|;Grafakos|Ioannis|I|;Kalyva|Sotiria|S|;Markopoulos|Athanasios|A|;Kyrtsonis|Marie-Christine|MC|;Panayiotidis|Panayiotis|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4002",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4002\nCCR34002\nCase Report\nCase Reports\nRichter's transformation as leptomeningeal infiltration in a chronic lymphocytic leukemia patient receiving venetoclax. Could blood‐brain barrier be a disease “sanctuary” during venetoclax treatment?\nDIMOU et al.\nDimou Maria https://orcid.org/0000-0001-8197-9895\n1 msdimou@gmail.com\n\nBitsani Aikaterini 1\nRoumelioti Maria 1\nDimitrakopoulou Aglaia 1\nIliakis Theodore 1\nPardalis Vasileios 1\nGrafakos Ioannis 1\nKalyva Sotiria 1\nMarkopoulos Athanasios 1\nKyrtsonis Marie‐Christine 1\nPanayiotidis Panayiotis 1\n1 1st Propedeutic Internal Medicine Clinic Hematology Department and Molecular Laboratory in Hematology National and Kapodistrian University of Athens Athens Greece\n* Correspondence\nMaria Dimou, 1st Propedeutic Internal Medicine Clinic, Hematology Department and Molecular Laboratory in Hematology, National and Kapodistrian University of Athens, Athens, Greece.\nEmail: msdimou@gmail.com\n\n04 3 2021\n4 2021\n9 4 10.1002/ccr3.v9.4 22492253\n09 1 2021\n16 2 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nOur unique case of Richter's Transformation presenting as leptomeningial infiltration in a CLL patient receiving venetoclax raises questions on whether the drug penetrates the blood‐brain barrier and at what extend, especially in reduced doses given for drug‐drug interactions.\n\nOur unique case of Richter's Transformation presenting as leptomeningial infiltration in a CLL patient receiving venetoclax raises questions on whether the drug penetrates the blood‐brain barrier and at what extend, especially in reduced doses given for drug‐drug interactions.\n\nblood‐brain barrier\nchronic lymphocytic leukemia\nleptomeningeal infiltration\nRichter's transformation\nvenetoclax\nsource-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:27.04.2021\nDimou M , Bitsani A , Roumelioti M , et al. Richter's transformation as leptomeningeal infiltration in a chronic lymphocytic leukemia patient receiving venetoclax. Could blood‐brain barrier be a disease “sanctuary” during venetoclax treatment?. Clin Case Rep. 2021;9 :2249–2253. 10.1002/ccr3.4002\n==== Body\n1 INTRODUCTION\n\nWe present a unique Richter's transformation case in CNS with identical to CLL clonal origin, in a patient treated with venetoclax. With our case, we make implications on whether venetoclax penetrates the blood‐brain barrier and we address the debating issue of the appropriate venetoclax dose in case of drug‐drug interactions.\n\nRichter's transformation (RT) is the development of high‐grade non‐Hodgkin lymphoma or Hodgkin disease in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma(SLL). 1\n\nClinical features associated with RT include systemic symptoms (59%), progressive lymphadenopathy (64%), extranodal involvement (41%), elevation of lactate dehydrogenase (LDH) (82%), and monoclonal gammopathy(44%). Systemic symptoms include fever, weight loss, and/or drenching night sweats. 2\n\nMost (80%) RT cases presenting as high‐grade B‐cell non‐Hodgkin lymphoma have the same clonal origin with the underling CLL/SLL and only 20% arise from a different clone. 3 , 4 The knowledge of clonal relationship between the non‐Hodgkin lymphoma and CLL is important because the prognosis varies; when the clonal origin is identical, survival is reported to be very short (8‐14 months), but when it is different, survival is reported to be comparable to that of patients with de novo diffuse large B‐cell lymphoma(DLBCL). 3\n\nRichter's transformation occurs in approximately 2%‐10% of CLL patients during their disease course, with a transformation rate of 0.5%‐1% per year. 5 Risk factors associated with RT include clinical characteristics (eg, Rai stage), genetic CLL characteristics (eg, BCL‐2 germ line polymorphisms, NOTCH‐1 mutations, TP53 disruption), biological CLL characteristics (eg, IgVH mutational status), and type of therapy. 3 , 4 , 5\n\nThere are no data to support that novel agents (B‐cell receptor‐BCR‐inhibitors or BCL‐2 inhibitor) are associated with increased RT incidence in comparison with chemotherapy/chemoimmunotherapy. 6 , 7 , 8 However, in all published clinical‐trial and real‐world data with these new agents, RT typically appears early, within 1 year of the treatment initiation. 6 , 7 , 8\n\nCentral nervous system (CNS) involvement is rare in RT 2 with unknown definite incidence, since the only existing data are case reports. Half of these cases present as leptomeningeal infiltration. 9 , 10 , 11\n\nWe present a very unusual RT case with leptomeningeal infiltration by high‐grade B‐cell non‐Hodgkin lymphoma in a CLL patient treated with venetoclax.\n\n2 CASE PRESENTATION\n\nA 56‐year‐old female patient was diagnosed with CLL (CD5+, CD23+, FMC7weak, CD79bweak, CD20weak, sIgκweak), Binet stage B, asymptomatic in January 2008. She remained under close monitoring until January 2011, when she developed Coomb's positive autoimmune hemolytic anemia (AIHA), which was successfully managed with corticosteroids and cyclosporine. In April 2011, progressive splenomegaly and lymphadenopathy occurred. The IgVH sequencing analysis 12 showed an unmutated VH1‐69*10 clone. FISH analysis for del17p was negative, and no TP53 mutations were identified by Sanger sequencing. The patient received rituximab‐chlorambucil (10 mg/m2 for 7 days), but progressive disease (PD) was noted after 3 months of therapy (June 2011). She subsequently received 6 cycles of FCR (fludarabine‐cyclophosphamide‐rituximab) between June 2011 and November 2011, achieving partial remission (PR), and then, she remained under close follow‐up. In June 2012, the patient presented serous lesions (bullae) in lower extremities. A biopsy revealed paraneoplastic pemphigus. There was no CLL progression at this time. Corticosteroids and rituximab were given without improvement and finally treatment with azathioprine (100 mg QD) resulted in resolution of the lesions.\n\nIn June 2015 (48 months after FCR), PD with progressive splenomegaly (7 cm below left costal margin‐blcm), lymphadenopathy, and thrombocytopenia (PLTs = 78 109/L) was noticed. No del17p/TP53 mutations were detected and bone marrow karyotype was normal. The patient received ibrutinib (starting dose 420 mg QD) but severe bruising of upper and lower extremities occurred. Until December 2015, the patient was receiving ibrutinib at the lower dose of 140 mg QD due to recurrence of bruising at higher doses. CLL remained stable during ibrutinib treatment, and the patient was switched to idelalisib/rituximab in February 2016. No del17p/TP53 mutations were detected at that time and bone marrow karyotype was normal. With idelalisib/rituximab, an initial improvement of splenomegaly (best response 3 cm blcm) and lymphadenopathy was noted, but 6 months later (September 2016), PD was noticed, with fever, bulky, and progressive splenomegaly (20 cm blcm), lymphadenopathy, and thrombocytopenia. A new bone marrow karyotype at that time was complex (more than 5 chromosomal abnormalities, including del17p):\n\n46,XX,del(6)(q21q24),‐17,+mar[3]/46,XX,‐6,+der(?)t(1;?)(q21;?)[4]/46,XX[16].\n\nWe decided to treat the patient with venetoclax (available through an early‐access program). The ramp‐up period of venetoclax started on October 24, 2016. Her complete blood counts (CBC) were as follows: WBC = 21.5 109/L, lymph = 95%, Hb = 8.6 g/dL, and PLTs = 52 109/L. The patient received the final dose of 400 mg QD on November 29, 2016. At this time, there was considerable improvement of the disease burden: no fever, good performance status (PS), spleen size reduction to 7 cm blcm, no peripheral lymphadenopathy. CBC: WBC = 2.2 109/L, PMN = 1.3 109/L (with GCSF support), Hb = 8.9 g/dL, PLTs = 75 109/L.\n\nOn March 20, 2017, reactivation of AIHA was noticed. venetoclax was discontinued and the patient received corticosteroids and cyclosporine, which managed to control AIHA.\n\nOn April 27, 2017, venetoclax was reinitiated through a new ramp‐up period with cyclosporine, to a final dose of 200 mg QD, due to CYP3A interactions. Despite venetoclax dose reduction, neutropenia grade 4 occurred mandating continuous GCSF administration and further dose reduction of venetoclax to 100 mg QD. There was adequate control (PR) of CLL for almost 20 months, with further reduction of splenomegaly to 2 cm blcm, no B symptoms, improved PS:0, no need for transfusions, adequate PLTs: 70‐90.000/μL, Hb between 11‐12 g/dL, and PMN: 1000‐1500/μL, with frequent GCSF support.\n\nIn June 2018 (20 months after venetoclax initiation), the patient developed walking and speech difficulties. She was admitted to the hospital with confusion and impaired mental status on June 23, 2018. On physical examination, there was reappearance of splenomegaly (8 cm blcm), with no palpable lymphadenopathy. She was afebrile without significant deterioration of CBC: WBC = 2,7 109/L, PMN = 2.2 109/L, Lymph = 0.3 109/L, Hb = 9.6 g/dL, and PLTs = 51 109/L. Serum LDH was normal and no serum monoclonal protein was detected. Serum biochemistry analysis was within normal limits. No lesions were found in brain MRI. The cerebrospinal fluid (CSF) aspiration analysis showed 2.4 109 cells/L and increased protein level = 1510 mg/L (range; 150‐450). The cytospin of the aspirate stained with May‐Grunwald‐Giemsa (Figure 1A) revealed monomorphous large, cerebriform lymphoid cells with nucleoli. The CSF cells' immunophenotype showed a large clonal B lymphoid population(98% of cells): sIg κweak, CD20dim, CD79b neg, CD5neg, CD23+, CD200+ (Figure 1B). Lymphocytes with the same morphology and immunophenotype were present in peripheral blood (1%) and in bone marrow (50%).\n\nFIGURE 1 Cerebrospinal fluid (CSF): A, cytospin, stained with May‐Gruenwald‐Giemsa: monomorphous large cerebriform lymphoid cells with nucleoli. B, CSF Immunophenotype: large B lymphocytes, CD5 neg, CD79b neg, kweak, CD20dim, CD200+\n\nWe performed mutational analysis of the IgVH genes according to BIOMED‐2 recommendations 12 in the CSF sample and we found the identical unmutated VH sequence (VH1‐69*10) as in the diagnosis sample (Jan‐2008, 99.18% identity to germ line sequence).\n\nThe patient received high‐dose dexamethasone (40 mg QD) for 4 days and intrathecal infusion of dexamethasone (8 mg) and methotrexate (15 mg), but she died in coma 7 days later, on July 4, 2018.\n\n3 DISCUSSION\n\nTo the best of our knowledge, this is the first case of RT presenting as leptomeningeal infiltration by high‐grade B‐cell non‐Hodgkin lymphoma in a CLL patient, treated with venetoclax. It is also the first reported case that IgVH mutational analysis has been performed and revealed identical clonal origin of CLL and RT during venetoclax treatment. 7 Morphologically, the lymphoma cells were large with nucleoli and had lost CD5 antigen positivity. This unusual type of RT has been anecdotally described previously in CLL patients treated with chemotherapy (mainly purine analogs). 9 , 10 , 11\n\nRichter's transformation has been described in CLL patients treated with novel agents (ibrutinib, idelalisib, venetoclax). 5 , 6 , 7 The incidence of RT for these patients ranges between 4.5% and 16% and has been found to be higher during the 1st year of treatment and among patients with del17p. 5 , 6 , 7 , 8 This observation implies that some patients enter treatment with pre‐existing occult features of RT. 7 , 8 Most of the cases involve transformation to high‐grade B‐cell lymphomas(mainly DLBCL). 5 , 6 , 7 , 8 Our patient had high‐risk characteristics when venetoclax was initiated: complex karyotype, del17p, heavily pretreated(4 previous lines of therapy), excessive splenomegaly, failure to both ibrutinib and idelalisib. With these high‐risk characteristics, one could suggest that RT “foci” might be already present. However, sustained PR was obtained with venetoclax for almost 2 years, with improved patient's quality of life.\n\nAnother question arising from this unusual RT case is whether venetoclax penetrates the CNS blood‐brain barrier, since RT occurrence mainly affected CNS and the patient finally died due to neurological complications. Very few published data exist: in animal studies with mice receiving radiolabeled intravenous venetoclax, CSF levels of the drug were absent (below measurable limits). 13 However, in a recent case report of a patient receiving venetoclax and intrathecal therapy (cytarabine and methotrexate) for CLL relapse in CNS, clearance of CNS disease was observed. In this patient, venetoclax CNS levels were measured at 0.1% of the plasma venetoclax concentrations. 14 Our RT case with CNS localization during venetoclax treatment implies that CSF concentrations of the drug may be suboptimal, allowing a “sanctuary” for CLL evolution. However, no formal measurement of CSF venetoclax levels was performed. One, of course, might argue that low venetoclax dose (100 mg/d) could be a reason for low/absent CSF concentrations. As mentioned, the venetoclax dose was reduced to our patient due to the concomitant use of the moderate CYP3A inhibitor cyclosporine and severe neutropenia. Our case suggests that venetoclax dose reductions in CLL treatment, in the setting of toxicity and/or CYP3A interactions, should be very carefully done, in multiresistant CLL patients with adverse cytogenetic and molecular features.\n\nFinally, our case confirms that RT remains an unmet therapeutic need in CLL patients, even in the era of new “targeted” therapies.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nMD has written the manuscript and was the treating physician of the patient. All other authors have corrected and approved the manuscript and were actively involved in the treatment of the patient.\n\nETHICAL APPROVAL\n\nThe patient had given her consent for the writing of her clinical case.\n\nACKNOWLEDGMENTS\n\nNone. Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 Tsimberidou AM , Keating KJ . Richter syndrome: biology, incidence, and therapeutic strategies. Cancer. 2005;103 (2 ):216‐228.15578683\n2 Omoti CE , Omoti AE . Richter syndrome: a review of clinical, ocular, neurological and other manifestations. Br J Haematol. 2008;142 :709‐716.18492119\n3 Rossi D , Spina V , Deambrogi C , et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117 (12 ):3391‐3401.21266718\n4 Mao Z , Quintanilla‐Martinez L , Raffeld M , et al. IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B‐cell lymphoma and Hodgkin lymphoma in association with B‐cell chronic lymphocytic leukemia (B‐CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol. 2007;31 (10 ):1605‐1614.17895764\n5 Parikh SA , Rabe KG , Call TG , et al. Diffuse large B‐cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013;162 (6 ):774‐782.23841899\n6 Mato AR , Nabhan C , Barr PM , et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016;128 (18 ):2199‐2205.27601462\n7 Anderson MA , Tam C , Lew T , et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood. 2017;129 :3362‐3370.28473407\n8 Maddocks KJ , Ruppert AS , Lozanski G , et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1 (1 ):80‐87.26182309\n9 Lane PK , Townsend RM , Beckstead JH , et al. Central nervous system involvement in a patient with chronic lymphocytic leukemia and non‐HodgkinΆs lymphoma (Richters syndrome), with concordant cell surface immunoglobulin isotypic and immunophenotypic markers. Am J Clin Pathol. 1988;89 :254‐259.3341285\n10 Robertson LE , Pugh W , O’Brien S , et al. Richter’s syndrome: a report on 39 patients. J Clin Oncol. 1993;11 :1985‐1989.8410123\n11 Agard G , Hamidou M , Leautez S , et al. Localisation neurome´ninge´e dΆum syndrome de Richter. La Revue de Me´decine Intern. 1999;20 :64‐67.\n12 van Dongen JJ , Langerak AW , Brüggemann M , et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T‐cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED‐2 Concerted Action BMH4‐CT98‐3936. Leukemia. 2003;17 (12 ):2257‐2317.14671650\n13 European Medicine Agency . Venclyxto. Assessment Report. EMA/725631/2016 Committee for Medicinal Products for Human Use (CHMP). 13 October 201\n14 Reda G , Cassin R , Dovrtelova G , et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica. 2019;104 (5 ):e222‐e223.30765472\n\n",
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"journal": "Clinical case reports",
"keywords": "Richter's transformation; blood‐brain barrier; chronic lymphocytic leukemia; leptomeningeal infiltration; venetoclax",
"medline_ta": "Clin Case Rep",
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"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "30765472;15578683;17895764;27601462;14671650;10220822;3341285;8410123;26182309;23841899;21266718;28473407;18492119",
"title": "Richter's transformation as leptomeningeal infiltration in a chronic lymphocytic leukemia patient receiving venetoclax. Could blood-brain barrier be a disease \"sanctuary\" during venetoclax treatment?",
"title_normalized": "richter s transformation as leptomeningeal infiltration in a chronic lymphocytic leukemia patient receiving venetoclax could blood brain barrier be a disease sanctuary during venetoclax treatment"
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"abstract": "Combined antiretroviral treatment (cART) traditionally consists of three antiretroviral medications, while two-drug regimens (2DR), historically used infrequently, recently been suggested to be non-inferior to three-drug regimens, is emerging as a potential treatment option and is currently a recommended option for treatment initiation in many guidelines.\n\n\n\nCharacterize the indications and clinical efficacy of 2DR use at a real-life setting in a nation-wide survey.\n\n\n\nA cross-sectional survey of Israeli patients treated by 2DR until July 2019, included demographic, immunologic, virologic, genotypic and biochemical/metabolic parameters at diagnosis, ART initiation, 2DR initiation and following 24, 48, 96 and 144 weeks of 2DR treatment.\n\n\n\n176 patients were included in the study. In contrast to historical data implicating ART resistance and adverse effects as the major reasons leading to 2DR switching, treatment simplification was the main reason leading to 2DR treatment in 2019. 2DR that included INSTI and PI were more commonly used in cases of drug resistance, while a combination of INSTI and NNRTI was used in all other 2DR indications. A switch to 2DR induced a mean CD4 T cell increase from 599 cells/μl at treatment initiation to 680 cells/μl at 96 weeks of treatment p<0.001 and viral suppression improvement from 73.9% at initiation to 87.0% at 48 weeks of treatment (p = 0.004). PI and INSTI 2DR was inferior in suppressing viral levels compared to other 2DRs but used for subset of more complex patients.\n\n\n\n2DR in a large-scale real-life nation-wide survey proved to be safe and effective. Most 2DRs, other than PI and INSTI, were similarly effective in suppressing HIV viremia and in elevating CD4 T cell counts.",
"affiliations": "The Hebrew University Hadassah Medical School, Jerusalem, Israel.;Institute of Allergy, Immunology and AIDS Rambam Medical Center, Haifa, Israel.;Crusaid Kobler AIDS Center, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Allergy, Clinical Immunology and AIDS Unit, Kaplan Medical Center, Rehovot, Israel.;Institute of Allergy, Immunology and AIDS Rambam Medical Center, Haifa, Israel.;HIV Service, Internal Medicine C Department, Hillel Yaffe Medical Center, Hadera, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Department of Clinical Microbiology and Infectious Diseases, Hadassah AIDS Center, Hadassah Hebrew University Medical Center, Jerusalem, Israel.",
"authors": "David|Daniel|D|;Kedem|Eynat|E|;Turner|Dan|D|;Levy|Itzchak|I|;Elbirt|Daniel G|DG|;Shahar|Eduardo|E|;Istumin|Valery|V|;Mor|Orna|O|0000-0003-3207-4226;Chowers|Michal|M|;Elinav|Hila|H|0000-0001-9046-8130",
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"fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nPLoS ONE\n1932-6203\nPublic Library of Science San Francisco, CA USA\n\n10.1371/journal.pone.0259271\nPONE-D-21-15985\nResearch Article\nBiology and Life Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nProtease Inhibitor Therapy\nMedicine and Health Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nProtease Inhibitor Therapy\nMedicine and Health Sciences\nPublic and Occupational Health\nPreventive Medicine\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nProtease Inhibitor Therapy\nBiology and Life Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nMedicine and Health Sciences\nImmunology\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nMedicine and Health Sciences\nPublic and Occupational Health\nPreventive Medicine\nVaccination and Immunization\nAntiviral Therapy\nAntiretroviral Therapy\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nImmunodeficiency Viruses\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nImmunodeficiency Viruses\nHIV\nBiology and life sciences\nOrganisms\nViruses\nRNA viruses\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nMicrobiology\nMedical Microbiology\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nPathogens\nMicrobial Pathogens\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nBiology and Life Sciences\nOrganisms\nViruses\nViral Pathogens\nRetroviruses\nLentivirus\nHIV\nMedicine and Health Sciences\nPharmaceutics\nDrug Therapy\nBiology and Life Sciences\nMicrobiology\nVirology\nViral Transmission and Infection\nViral Load\nMedicine and Health Sciences\nPharmacology\nDrugs\nAntimicrobials\nAntivirals\nReverse Transcriptase Inhibitors\nBiology and Life Sciences\nMicrobiology\nMicrobial Control\nAntimicrobials\nAntivirals\nReverse Transcriptase Inhibitors\nBiology and Life Sciences\nMicrobiology\nVirology\nAntivirals\nReverse Transcriptase Inhibitors\nBiology and Life Sciences\nBiochemistry\nGlycobiology\nGlycosylamines\nNucleosides\nMedicine and Health Sciences\nPharmaceutics\nDrug Therapy\nCardiovascular Therapy\nLong term dual antiretroviral therapy: A real life retrospective countrywide Israeli study\nReal life experience of dual ART regimens.\nDavid Daniel Data curation Formal analysis Investigation Writing – original draft Writing – review & editing 1\nKedem Eynat Data curation Investigation Writing – review & editing 2\nTurner Dan Data curation Investigation Writing – review & editing 3 4\nLevy Itzchak Data curation Investigation Writing – review & editing 4 5\nElbirt Daniel G. Data curation Writing – review & editing 6\nShahar Eduardo Data curation Writing – review & editing 2\nIstumin Valery Writing – review & editing 7\nhttps://orcid.org/0000-0003-3207-4226\nMor Orna Data curation 4 8\nChowers Michal Data curation Investigation Writing – review & editing 4 9\nhttps://orcid.org/0000-0001-9046-8130\nElinav Hila Conceptualization Data curation Formal analysis Investigation Methodology Writing – original draft Writing – review & editing 10 *\n1 The Hebrew University Hadassah Medical School, Jerusalem, Israel\n2 Institute of Allergy, Immunology and AIDS Rambam Medical Center, Haifa, Israel\n3 Crusaid Kobler AIDS Center, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel\n4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel\n5 Infectious Disease Unit, Chaim Sheba Medical Center, Ramat Gan, Israel\n6 The Allergy, Clinical Immunology and AIDS Unit, Kaplan Medical Center, Rehovot, Israel\n7 HIV Service, Internal Medicine C Department, Hillel Yaffe Medical Center, Hadera, Israel\n8 Central Virology Laboratory, Ministry of Health, Public Health Services, The Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel\n9 Infectious Diseases Unit, Meir Medical Center, Kfar Saba, Israel\n10 Department of Clinical Microbiology and Infectious Diseases, Hadassah AIDS Center, Hadassah Hebrew University Medical Center, Jerusalem, Israel\nMenéndez-Arias Luis Editor\nConsejo Superior de Investigaciones Cientificas, SPAIN\nCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: hilaelinav@gmail.com\n29 10 2021\n2021\n16 10 e025927114 5 2021\n17 10 2021\n© 2021 David et al\n2021\nDavid et al\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nAim\n\nCombined antiretroviral treatment (cART) traditionally consists of three antiretroviral medications, while two-drug regimens (2DR), historically used infrequently, recently been suggested to be non-inferior to three-drug regimens, is emerging as a potential treatment option and is currently a recommended option for treatment initiation in many guidelines.\n\nPurpose\n\nCharacterize the indications and clinical efficacy of 2DR use at a real-life setting in a nation-wide survey.\n\nMethods\n\nA cross-sectional survey of Israeli patients treated by 2DR until July 2019, included demographic, immunologic, virologic, genotypic and biochemical/metabolic parameters at diagnosis, ART initiation, 2DR initiation and following 24, 48, 96 and 144 weeks of 2DR treatment.\n\nResults\n\n176 patients were included in the study. In contrast to historical data implicating ART resistance and adverse effects as the major reasons leading to 2DR switching, treatment simplification was the main reason leading to 2DR treatment in 2019. 2DR that included INSTI and PI were more commonly used in cases of drug resistance, while a combination of INSTI and NNRTI was used in all other 2DR indications. A switch to 2DR induced a mean CD4 T cell increase from 599 cells/μl at treatment initiation to 680 cells/μl at 96 weeks of treatment p<0.001 and viral suppression improvement from 73.9% at initiation to 87.0% at 48 weeks of treatment (p = 0.004). PI and INSTI 2DR was inferior in suppressing viral levels compared to other 2DRs but used for subset of more complex patients.\n\nConclusions\n\n2DR in a large-scale real-life nation-wide survey proved to be safe and effective. Most 2DRs, other than PI and INSTI, were similarly effective in suppressing HIV viremia and in elevating CD4 T cell counts.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.\nData Availability\n\nAll relevant data are within the manuscript and its Supporting Information files.\n==== Body\npmcIntroduction\n\nCombined antiretroviral treatment (cART) evolved from a single drug therapy [1] to a triple drugs combination that inhibit HIV replication by distinct mechanisms of activity and enabled to achieve long durable viral suppression [2, 3]. Consequently, ART comprised of 2 NRTIs plus non nucleotide analog reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI) or integrase inhibitor (INSTI), became the common practice in the management of HIV patients [4]. cART has been proven to suppress viral replication, improve clinical outcomes and decrease mortality among HIV infected patients, thereby converting HIV from a terminal disease to a chronic and manageable disorder [5, 6]. With the increase in life expectancy and long term medication exposure, multiple adverse effects, including cardiovascular, renal, neurological, and bone manifestations developed in chronically treated people living with HIV [7]. In some cases of patients suffering of severe adverse effects and multiple drugs viral resistance, unavailability of better options dictated the use of dual effective antiretroviral therapy. The encouraging results obtained with dual therapy in these selected patients and the desire to minimize drug toxicities were the rational for multiple clinical trials studying the effect of dual and monotherapy in HIV [8], with controversial results noted [9–12]. The improved efficacy of INSTIs recently enabled to reassess the dual ART option, with an aim to maintain adequate virologic suppression with reduced incidence of adverse effects in selected cases [13–15]. Moreover, the encouraging results of the SWORD-1 and SWORD-2 trials [16, 17], motivated some clinicians to switch patients to dual therapy even in cases of clinically stable disease, in order to simplify ART and avoid future adverse effects.\n\nA total of 7970 people living with HIV in Israel, are currently followed and treated in eight HIV centers. The aim of this study was to evaluate the real-life usage of two drug regimens (2DR) in Israel, to characterize the different regimens used in different HIV centers, the rationale leading to switching to 2DR, and the clinical outcomes of this practice.\n\nMethods\n\nPatient information was retrieved from the local databases of seven Israeli HIV centers between July 2019 to August 2019. Included were all the HIV patients who were treated by two drug regimens (2DR) at the time point of data collection in these centers (up to 31.7.2019, n = 176). No exclusion criteria were implemented to reflect the real-life implications of dual therapy. The data collected included demographic, immunologic, virologic, resistance profile and biochemical/metabolic parameters at diagnosis, ART initiation, 2DR initiation and after 24, 48, 96 and 144 weeks of 2DR treatment±8 weeks. Immunologic and virologic data included CD4 count (cells/μl), CD8 count (cells/μl), HIV viral load (VL, copies/ml), Hepatitis B virus (HBV) and Hepatitis C virus (HCV) serology. The biochemical/metabolic parameters included renal function (creatinine levels, mg/dl), liver aminotransferase activity (AST & ALT levels, IU/ml), lipid profile, including triglycerides (TG, mg/dl), total cholesterol (mg/dl), low density lipoprotein (LDL, mg/dl), high density lipoprotein levels (HDL, mg/dl), and glucose levels (mg/dl). We documented the indication/s for 2DR initiation, the type of ART used before and after the switch to 2DR, the number of regimens that the patient has been treated with until 2DR. Resistance mutations documented at diagnosis, during follow up to 2DR switching and after 2DR initiation. Drug-resistance mutations were identified using the Stanford University HIV Drug-Resistance Database [18]. Changing treatment from two pills to a similar single tablet regimen (STR) was not considered as a switch to a new regimen. Undetectable viral load was defined as below detection limit according to the kit used by the HIV virology lab. Patients that featured a documented follow-up period of less than 24 weeks from initiation of dual therapy to data collection, and have therefore undergone only a descriptive analysis, while not being included in the 2DR efficacy analysis. For the analysis of annual switching to 2DR, we included patients who were switched from 1.8.2019 to 31.12.2019. These patients were not included in any other analysis.\n\nStatistical analysis\n\nTo evaluate the clinical efficacy of 2DR therapy over time, repeated measures ANOVA model was applied for assessment of quantitative variables. Assessing trend over time for quantitative variables which were not normally distributed, was performed using the non-parametric Friedman test. Testing the change between two time points for quantitative variables, was performed using a paired t-test. Testing the change between two time points for categorical variables, was performed by applying the McNemar or the McNemar-Bowker test. Pearson’s Chi-square test and Fisher’s exact test were used for testing the association between two categorical variables. All statistical tests were two-tailed and a p-value of less than 0.05 was considered statistically significant. Statistical analysis was carried out using IBM SPSS Statistics version 24.0.\n\nEthics\n\nThe study was approved by IRB committees of all participating HIV Centers.\n\nApproval number of Hadassah Medical center IRB 0574-18-HMO, approval number of Rambam Medical Center IRB 0428-19-RMC, approval number of Kaplan Medical Center IRB 0036-10-KMC, approval number of Meir Medical Center 001-19-MMC, approval number of Sourasky Medical Center IRB 0741-18-TLV, approval number of Sheba Medical Center IRB 5838-19-SMC. No approval was required from Hillel Yaffe Medical Center as no patients were treated with 2DR at the study data collection. All committees granted a formal waiver of informed consents as data was retrospective and analyzed anonymously.\n\nResults\n\nIn reviewing all the medical records of patients living with HIV and followed by the participating 7 HIV centers, we identified 173 patients who were switched to dual therapy, and 3 patients who initiated 2 antiretroviral drug regimens as their primary ART regimen until 31.7.2019. In total, we were able to survey the data of 94% of 7970 people living with HIV in Israel, as one HIV center did not participate in the study. The rate of patients treated with dual therapy was comparable between the centers and ranged from 1.6% to 4%. Seventy-one precents of the patients were males and 40% were born in Israel, while Ethiopia was the main country of origin for immigrants. Patients were previously heavily treated for a mean of 8.57 years and a mean number of treatment switches totaled 2.08 as indicated in Table 1. Although the first switch to dual therapy was performed in 2003, further switching to 2DR was incidental until 2014 and a real escalation of the usage of 2DR was noted only in 2015 (Fig 1A). More than half of the patients (55.1%) were switched to dolutegravir (DTG) plus rilpivirine (RPV), with the second most common combination being dolutegravir (DTG) plus boosted darunavir (DRV) (18.2%). The rest of the regimens varied (Fig 1B).\n\n10.1371/journal.pone.0259271.g001 Fig 1 2DR initiation.\n\nA: Yearly number of patients that started/ switched to treatment with dual therapy. B: Dual regimens used by class. INSTI- integrase inhibitor, NNRTI- non nucleoside analog reverse transcriptase inhibitor, PI- protease inhibitor, NRTI- nucleoside analog reverse transcriptase inhibitor.\n\n10.1371/journal.pone.0259271.t001 Table 1 Basic characteristics of study participants.\n\nCategory\tFrequency (N)\tPrevalence (%)\t\t\t\t\t\nGender M/F\t\t125/51\t71.0%/29%\t\t\t\t\t\nCountry of birth\tIsrael\t70\t39.8\t\t\t\t\t\n\tAfrica\t53\t30.1\t\t\t\t\t\n\tEurope\t37\t21\t\t\t\t\t\n\tAmerica\t9\t5.1\t\t\t\t\t\n\tAsia\t7\t4.0\t\t\t\t\t\nHBV +/-/unk\t\t2/167/8\t1.1/94.4/4.5\t\t\t\t\t\nHCV +/-/unk\t\t14/155/8\t7.9/87.6/4.5\t\t\t\t\t\nCategory\tN\tMean\tMedian\tStd. Dev.\tRange\t\t\t\t\t\nAge at Diagnosis\t171\t37.02\t35\t12\t1–69\t\t\t\t\t\nAge at beginning of ART\t143\t39.76\t38\t11.5\t1–69\t\t\t\t\t\nCD4 at diagnosis cell/μ\t104\t360.46\t331.5\t280.6\t3–1181\t\t\t\t\t\nNadir CD4 cell/μ\t120\t219.5\t179\t186.2\t3–775\t\t\t\t\t\nCD4 at treatment initiation cell/μ\t119\t287.5\t259\t230\t3–1181\t\t\t\t\t\nYears of treatment before 2DR initiation\t143\t8.57\t7.0\t6.3\t0–24\t\t\t\t\t\nNumber of ART switches before 2DR\t152\t2.08\t2\t2.04\t0–13\t\t\t\t\t\nAge at 2DR initiation\t176\t49.1\t49.5\t12.1\t18–80\t\t\t\t\t\nCD4 at 2DR initiation\t170\t569.18\t525.0\t305.1\t3–1536\t\t\t\t\t\nVL at 2DR treatment initiation copies/ml\t169\t23093\t0\t154201\t0–1.5*107\t\t\t\t\t\nmajor mutation N (%)\t\t\t\t\t\t\t\t\t\t\nART\t48 (27.3)\t\t\t\t\t\t\t\t\t\nNRTI\t43 (24.4)\t\t\t\t\t\t\t\t\t\nNNRTI\t26 (14.8)\t\t\t\t\t\t\t\t\t\nPI\t18 (10.2)\t\t\t\t\t\t\t\t\t\nINSTI\t4 (2.3)\t\t\t\t\t\t\t\t\t\nTreatment before 2DR\tN\tAge at 2DR initiation mean (SD)\tYears of ART before 2DR mean (SD)\t# of previous switches mean (SD)\tCD4 at 2DR initiation mean (SD)\tVL at 2DR initiation mean (SD)\t% VL detec\tReason for 2DR switch (1 st +2 nd ) (%)\t% Of patients with ART mutation\t\n2 NRTI + INSTI\t84\t49.18 (12.8)\t6.7 (5.6)\t1.64 (1.64)\t607.0 (312)\t17341 (123367)\t21.0\trenal (27.4) simp (27.4)\t19\t\n2 NRTI + PI\t27\t46.81 (9.845)\t9.2 (5.7)\t1.75 (1.15)\t423.9 (269.9\t23754 (71110)\t40.7\tresis (51.9) renal (44.4)\t48.1\t\n2 NRTI +NNRTI\t26\t49.27 (12.7)\t10.9 (5.9)\t2.13 (2.6)\t561.6 (250.6)\t63736 (325100)\t21.7\trenal (23.1 osteo (19.2)\t15\t\n1/2 NRTI + INSTI + PI\t11\t48.2 (11.3)\t8.6 (5.78)\t3.33 (2.4)\t543.2 (208.7)\t9743 (32256)\t27.3\tresis (27.3) renal (27.3) simp (27.3)\t54.6\t\nNNRTI + INSTI + PI\t9\t51.5 (7.4)\t15.2 (5.06)\t4.13 (2.6)\t684.3 (438.5)\t0 (0)\t0\tresis (44.4) simp (22)\t66.7\t\n1/2 NRTI+ NNRTI + INSTI\t4\t56.5 (11.7)\t17.25 (3.18)\t4.0 (2.8)\t702.3 (413.5)\t0 (0)\t0\tsimp (75) cardi (25) lipid (25)\t0\t\n1/2 NRTI +NNRTI +PI\t3\t65.3 (9.2)\t19.0 (1.4)\t4.5 (3.5)\t690.7 (190.3)\t0 (0)\t0\tsimp (33) neuro (33.5) osteo (33.3)\t33\t\nNNRTI + INSTI + CCR5-in\t1\t59\t22.5\t5\t525\t0\t0\tsimp\t0\t\nNNRTI + PI + CCR5-in\t1\t51\t5.5\t3\t1159\t0\t0\tsimp\t0\t\nUnknown\t7\t45.1 (13.6)\t5.2 (4.1)\t1.8 (2.0)\t523.7 (260.9)\t573.3 (1096)\t66.6\t-\t28.6\t\nNaive\t3\t39.6\t0\t0\t328\t55125\t\t\t\t\nBasic characteristics of patients including in the study, including all the patients, and stratified according to treatment regimen before 2DR.\n\nINSTI- integrase inhibitor, NNRTI- non nucleoside analog reverse transcriptase inhibitor, PI- protease inhibitor, NRTI- nucleoside analog reverse transcriptase inhibitor. CCR5 in- CCR5 inhibitor, unk- unknown. #- number, % VL Detec- % of patients with detectable VL at switch, resis- resistance, osteo- osteoporosis, simp- simplification, cardi- cardiovascular risk or disease, lipid- hyperlipidemia, neuro- neurological.\n\nThe most common reasons for switching to 2DR were renal toxicity (26.1%), therapy simplification (25.0%) and resistance to prior ART (22.7%). Other, less common reasons were cardiovascular toxicity, osteoporosis, and gastrointestinal adverse effects. Forty patients featured more than one reason for 2DR initiation, all of which were documented (Table 2). The indication for changing patients to dual therapy changed over time. While resistance constituted a major indication in 2013–2015, treatment simplification became a major indication from 2018 (Fig 2). The combination of DTG+DRV was the most common regimen used in the ART resistant indication, while DTG+RPV treatment was the most common 2DR combination used in most other indications (Table 2).\n\n10.1371/journal.pone.0259271.g002 Fig 2 Reasons for 2DR initiation by indication.\n\nEach indication is represented as the percent of patients that were switched due to this indication in each year from 2010–2019. Some patients had more than one indication for 2DR switch.\n\n10.1371/journal.pone.0259271.t002 Table 2 2DR switches-reasons, regimens and patient characteristics.\n\nReason for 2DR initiation N (%)\tMost common ART before switching to 2DR N (%)\tMost common 2DR regimen N (%)\tMean Age Y (SD)\tGender M/F\tTreatment before 2DR Y (SD)\tSwitches N (SD)\t% Detec VL\tDocumented resistance %\t\nRenal 46 (26.1)\t2 NRTI + INSTI 23 (50.0)\tDTG+RPV 26 (56.5)\t51.5 (10.6)\t37/9\t6.6 (5.2)\t1.6 (1.3)\t15.6\t15.2\t\nSimplification 44 (25.0)\t2 NRTI + INSTI 24 (55.8)\tDTG+RPV 33 (76.7)\t49.3 (14.1)\t28/16\t9.8 (6.3)\t2.5 (2.2)\t18.6\t18.2\t\nResistance 40 (22.7)\t2NRTI + INSTI 14 (35.0)\tDTG+DRV 20 (50.0)\t46.8 (11.4)\t27/13\t9.9 (6.1)\t2.6 (2.4)\t52.6\t67.5\t\nGastrointestinal 15 (8.5)\t2NRTI + INSTI 10 (66.7)\tDTG+RPV 11 (73.7)\t48\t9/6\t5.5\t2.3 (3.2)\t6.7\t13.3\t\nCardiovascular 13 (7.4)\t2NRTI + INSTI 7 (53.8)\tDTG+RPV 10 (71.4)\t57 (9.5)\t11/2\t9.8 (7.9)\t2.27 (2.3)\t25\t15.4\t\nOsteoporosis 13 (7.4)\t2NRTI + NNRTI/INSTI 10 (66.7)\tDTG+RPV 8 (61.5)\t54.9 (10.9)\t8/5\t10.9 (5.37)\t2.8 (2.3)\t15.4\t15.4\t\nHyperlipidemia 8 (4.5)\t2NRTI + INSTI 3 (37.5)\tDTG+RPV 4 (50)\t48.8 (6.9)\t7/1\t8.8 (6.37)\t1.6 (1.3)\t0\t12.5\t\nNeurological 6 (3.4)\t2NRTI + NNRTI 3 (42.8)\tDTG+RPV 4 (57.1)\t51.1\t6/1\t6.2\t2.0(1.7)\t50\t0\t\nHypersensitivity 5 (2.8)\t2NRTI + INSTI 2 (40)\tRAL+DRV 2 (40)\t48.6 (14.3)\t4/1\t6.7 (7.5)\t2.2 (1.3)\t80\t20\t\nDrug interactions 4 (2.2)\t2NRTI + INSTI 2 (50)\tDTG+RPV 3 (75)\t48.75 (6.8)\t2/2\t13 (6.2)\t3.67 (1.5)\t0\t0\t\nUnknown 24 (13.5)\t2NRTI + INSTI 10 (41.7)\tDTG+RPV 12 (50)\t50\t21/3\t8.6\t\t\t\t\nINSTI- integrase inhibitor, NNRTI- non nucleoside analog reverse transcriptase inhibitor, PI- protease inhibitor, NRTI- nucleoside analog reverse transcriptase inhibitor, N- number, SD- standard deviation, % detect VL- % of patients with detectable VL at 2DR switch.\n\nTwenty-four patients (13.6%) experienced a second switch to a different 2DR, performed primarily for treatment simplification, hyperlipidemia, drug interactions, and renal toxicity. The majority of patients that underwent a second switch to 2DR (75%) were treated with a PI combined with INSTI as the initial 2DR and most of them were switched DTG+RPV as second 2DR. Nine patients (5.1%) were switched back to triple drug therapy, due to DDI, simplification, cardiotoxicity and other non-specified adverse events or unknown reasons (Table 3).\n\n10.1371/journal.pone.0259271.t003 Table 3 Switch to second 2DR or 3DR.\n\nN (%)\t2nd 2DR\t3DR\t\n24\t9\t\n1st 2DR N (%)\tPI+INSTI\t18 (75)\t2 (22.2)\t\nNNRTI+INSTI\t(16.7)\n\n\t4 (44.4)\t\nNRTI+PI\t1 (4.2)\t3 (33.3)\t\n2 PI\t1 (4.2)\t0\t\nNNRTI+PI\t0\t\t\n2nd regimen N (%)\tPI+INSTI\t11 (45.8)\t0\t\nNNRTI+INSTI-\t9 (37.5)\t0\t\nINSTI+NRTI-\t3 (12.5)\t8 (88.8)\t\nNNRTI+PI\t1 (4.1)\t0\t\nPI monotherapy\t\t1 (11.1)\t\nReason for switch N (%)\tSimplification\t9 (37.5)\t3 (33.3)\t\nHyperlipidemia\t3 (12.5)\t0\t\nDrug interaction\t2 (8.3)\t1 (11.1)\t\nRenal, GI, resistance, OP\t1 each (4.2)\t1 (11.1)\t\nCVD\t\t1 (11.1)\t\nneurotoxicity\t\t1 (11.1)\t\nAE- other\t\t3 (33.3)\t\nSwitch to second 2DR or 3DR-regimens by class 1st 2DR, regimens by class 2nd 2DR, regimens of 3DR and reasons for switch. INSTI- integrase inhibitor, NNRTI- non nucleoside analog reverse transcriptase inhibitor, PI- protease inhibitor, NRTI- nucleoside analog reverse transcriptase inhibitor. N- number. GI- gastrointestinal, CVD- cardiovascular disease, OP- osteoporosis. Some patients had more than one reason for switch.\n\nRepeated CD4 count (cells/μl) measurements conducted in 92 patients with a complete follow up at 24, 48 and 96 weeks after 2DR initiation demonstrated a significant gradual increase in CD4 counts upon 2DR treatment from an average of 599 cells/μl at treatment initiation, to 614 cells/μl, 645 cells/μl and 680 cells/μl at 24, 48 and 96 weeks, respectively (p<0. 001, Fig 3). Seventy-two of these patients started 2DR with an undetectable VL, 17 were detectable and in 3 patients VL was not documented. Three naïve patients who started 2DR as their primary ART were excluded from this analysis. As corroboration of the above results, we performed a paired t-test in 140 patients that had follow ups of at least 96W but had some missing CD4 T cell values along this follow-up period, which indicated an increase in CD4 T cell counts from a mean of 583 cells/μl at initiation of 2DR to 654 cells/μl at 96 weeks (p<0.001).\n\n10.1371/journal.pone.0259271.g003 Fig 3 CD4 progression after switch to 2DR.\n\n92 patients with consecutive CD4 measurements were included. Results are expressed ± SE. *** p<0.0001 ** p = 0.02 *p = 0.038.\n\nTo further assess the efficacy of dual therapy on viral suppression we binned VL values into three groups–“undetectable VL(UD)”, “low VL” (UD<VL<200), and “high VL” (VL = >200). Comparing the undetectable VL rate at 2DR initiation and 48 weeks demonstrated a significant increase in undetectability rate from 74.6% to 87.3% and a decrease in the low and high VL groups (P = 0.004). Significant results were also observed when comparing VL at 2DR initiation, 24 and 144 weeks of follow-up (86.1% & 87.0% P = 0.003 and p = 0.041, respectively).\n\nTo differentiate the efficacy of different 2DR regimens, we compared the changes in viral suppression between patients who were switched to the newer and approved 2DR regimens dolutegravir+rilpivirine (DTG+RPV) or dolutegravir+lamivudine (DTG+3TC) and those treated by other 2DR regimens. As treatment simplification was the main indication to change to DTG+RPV or DTG+3TC, this patient subset featured a higher rate of undetectable VL at 2DR initiation (82.3% vs 62.6%, p = 0.006). We further compared the rate of patients who were undetectable at the 2DR initiation but became detectable at week 24, 48, 96 or 144 in each of the 2DR subsets. In the DTG+RPV and DTG+3TC group, the rate was significantly lower than in the other regimens (14.2% vs 28.5%, p = 0.007). Additionally, 72.2% of the DTG+RPV or DTG+3TC patients who initiated the 2DR with detectable viral load featured a completely suppressed viral load at all subsequent follow up time points, while the conversion rate to undetectability was only 52.2% in a group that included patients treated with other 2DR regimens. This difference did not reach statistically significance (p = 0.091), but the total effect indicated favorably to DTG+RPV and DTG+3TC treatment (p = 0.004). Application of the same analysis to other 2DR regimens indicated that 45% of patients treated with INSTI & PI, became completely suppressed, compared with an 73.9% in patients treated by other regimens (p = 0.038), (Fig 4). This analysis suggests that the of INSTI+PI combination is inferior in efficacy compared to other 2DR combinations, although the higher rate of failure could be attributed to the baseline higher prevalence of resistance (57% vs 13.8%) in this group of patients, and lower compliance (Table 4).\n\n10.1371/journal.pone.0259271.g004 Fig 4 Viral suppression by different 2DR by class.\n\nUD at 2DR initiation- percent of total patients that started each 2DR combination. UD at 2DR initiation and at any follow up- percent of patients that started 2DR with undetectable viral load and were suppressed in every test- week 24, 48 96 and 144. Detectable at 2DR initiation and UD at any follow up- percent of patients that started with detectable viral load but later were suppressed in every test at week 24, 48 96 and 144. Patients that were changed to 2DR that was composed of PI and INSTI had lower rates of suppressed viral load and higher rates of failure in comparison to patients in other 2DR. p <0.05 McNemar test.\n\n10.1371/journal.pone.0259271.t004 Table 4 2DR regimens- patients characteristics and resistance profile.\n\n\tN\tAge at 2DR Y (SD)\tYears of HIV Y (SD)\tYears of ART Y (SD)\tN of switches (SD)\tReasons for 2DR\t% Detect VL\t% Resistance associated mutations\t\nAny\tNRTI\tNNRTI\tPI\tINSTI\t\nAll patients\t176\t49.0 (12.1)\t12.2 (7.7)\t8.57 (6.2)\t2.12 (2.1)\tRenal 26% Simp 24.3%\t24.2\t27.2%\t24.3%\t14.7%\t10.2%\t1.7%\t\nNNRTI+INSTI\t102\t49 (11.8)\t11.8 (7.5)\t8.86 (6.3)\t2.12 (2)\tSimp 34% Renal 27%\t14.6%\t13.6%\t10.7%\t5.8%\t5.8%\t1%\t\nPI+ INSTI\t54\t47.4 (12)\t12.5 (7.9)\t8.6 (6)\t2.2 (2.1)\tResis 50% Renal 24%\t35.2%\t57.4%\t53.7%\t35.2%\t20.4%\t3.7%\t\nNRTI+ INSTI\t11\t60 (12.5)\t12.7 (9.0)\t6.5 (7.5)\t1.67 (2.1)\tCardio 18% Renal 18%\t30%\t0%\t0%\t0%\t0%\t0%\t\n2DR regimens- patients characteristics and resistance profile. INSTI- integrase inhibitor, NNRTI- non nucleoside analog reverse transcriptase inhibitor, PI- protease inhibitor, NRTI- nucleoside analog reverse transcriptase inhibitor. N- number SD- standard deviation, Reasons for 2DR- two most frequent reasons for switch in related group of patients, simp- simplification, resis- resistance, cardio- cardiovascular risk or disease, % detect VL- % of patients with detectable VL at 2DR switch.\n\nDrug resistance associated mutations that were documented as naïve patients or due to virological failure, were documented in 48 (27.2%) of the patients and 24.3%, 14.7%, 10.2% and 2.3% of the patients had a least 1 mutation for NRTI, NNRTI, PI and INSTI respectively. The Mutation M184V in RT was documented in 18.6% of the patients and K103N in 4.5%. The rate of resistance was 40% in patients that were detectable at 2DR initiation with 32.5%, 22.2%, 7.5% and 5% of the patients harboring at least one mutation to NRTI, NNRTI, PI and INSTI respectively. As described above, resistance prevalence was 40% in patients that were detectable at 2DR initiation and 32% of the patients that were not completely virologically suppressed after 2DR switch had previously documented resistance- 27% for NRTI, 13.5% for NNRTI and 16.2% PI. No resistance mutations were documented to evolve in any of the patients that had detectable VL after 2DR.\n\nOne hundred and thirty eight patients had virological data at week 48, 18 of whom (13%) had a detectable viral load. Nine of these non-virologically suppressed patients, had a viral load of 0–200 copies/ml, while 9 featured a viral load of above 200 copies/ml. Eleven (61.1%) who featured a detectable viral load at week 48 of 2DR treatment also had a detectable viral load at treatment initiation. In comparison, only 25% of virally undetected patients at 48W featured a detectible viral load at treatment initiation (p<0.01). Surprisingly, the rate of documented resistance was lower (but non significantly) in the 48W detectable patients in comparison to the undetectable patients (16.6% vs 30.5% p = 0.414). Analysis of the patients who were detectable vs. undetectable in 96W yielded similar results. These results possibly stemming from adherence issues or resistance that was not documented due to low viremia.\n\nA non-significant increase in triglycerides (p = 0.591), glucose (p = 0.562) creatinine (p = 0.426) and HDL levels (p = 0.355), and a decrease in AST (p = 0.41), ALT (p = 0.157) and total cholesterol levels (p = 0.834) were documented following the switch. Analyzing LDL levels in 46 patients with available results at 2DR initiation, 24W, 48W and 96W, of whom 23.9% were pretreated with PI, and in 26.1% PI was one of the 2DR components, indicated a significantly decreased from 112.98±30 mg/dl to 103.4± 29.8 mg/dl (p = 0.021). This effect also trended by comparing by paired T test of LDL at dual initiation and 96W of 79 patients (113.6±32 mg/dl vs 106.99±31.2 p = 0.067) but was not reproduced in 24W and 48W (p = 0.29 and P = 0.665 respectively).\n\nDiscussion\n\nDual therapy for HIV-infected patients has been proven to be non-inferior to standard triple anti-retroviral therapy in randomized, double-blind controlled trials both in experienced [16] and naive HIV patients [9, 17, 19] while was unsuccessful in others [11, 20]. Currently, dual therapy (DTG+3TC) is recommended by many international guidelines for treatment initiation and other 2DR regimens are recommended as secondary treatment [21–23]. In Israel, 2DR was sporadically used in rare cases featuring significant drug resistance, even before 2DR was firmly established by large-scale trials [9], or made available in a convenient single tablet formulation (DTG+RPV or DTG+3TC) [17, 24]. The ensuing real-life adaptation of 2DR in several indications, as summarized in this country-wide survey, highlights some interesting and potentially important findings. First, efficacy of dual therapy in real life is supported both by significant CD4 increment after switching to 2DR, and by improved viral suppression in most regimens, but apparently lower efficacy in those combining INSTI with PI. Of note, in our study, INSTI combined with PI was provided to patients with higher rates of resistance mutations and detectable VL, which may reflect prior (and maybe current) low compliance, and potentially contribute to the different outcomes. Our results corroborate with other real life observational studies as the recent EuroSIDA report that indicated similar viral suppression rate and immunological response in 423 patients switching or starting 2DR, compared to 4327 naïve or experience patients who started 3DR regimens [25]. In our survey, the rate of 2DR usage was low in all HIV centers (1.6–4%), reflecting a more conservative approach and the lack of financial restrictions in choosing ART combinations in Israel.\n\nSecond, our study demonstrates that in many cases, the rationale for 2DR switch is motivated by a need to reduce previous treatment toxicity (58% of switches). In our cohort, we noted a trend towards 2DR improving hyperlipidemia, which reached statistical significance by 96W. This trend merits further larger-scale follow-up studies.\n\nAn observational study evaluating 121 patients treated with RAL combined with PI, reported that approximately 70% of them remained on this regimen with a median treatment duration of 60 months, with treatment simplification being the main reason for 2DR discontinuation in half the 2DR-failing patients [26]. Moreover, only three patients out of 81 (3.7%) who were switched to RAL/DRV/r experienced a virological failure [27]. Indeed, in our cohort, of 54 patients switching to a 2DR combining PI and INSTI, three (5.5%) featured a virological failure, and were switched back to 3DR, while 18 patients were switched to a second line 2DR, mainly due to a need for treatment simplification and 62.9% patients were maintained on PI+INSTI. Cappeti et al. reported similar results [13]. Likewise, Diaco et al. [28], reported only three patients returning to their previous 3DR and one patient experiencing viral failure (5.7%) in a single center 2DR de-escalation study. Although a major indication for 2DR was drug resistance in our cohort, analyzing undetectability at 2DR switch and during long term follow up, combined with similar rate of resistance, our results suggest that low adherence seems to be a major factor for virological failure that is observed in long term follow up 2DR,\n\nOur study features several limitations stemming mainly from its retrospective design, including a lack of a control group treated with 3DR, and heterogenous ART regimens used before and after the switch to 2DR. Additionally, since 2DR was not prevalent before 2017, patients were excluded from our long-term metabolic and efficacy analysis due to a short follow up. Furthermore, due to the cross-sectional design of the study, we may have not identified patients that were switched to 2DR and switched back to 3DR before July 2019 and might have missed an excessive discontinuation rate of certain combinations.\n\nIn summary, our study indicates that two drug regimens are safe and effective in a real-life context, taking into account the impact of such treatment on virological suppression, immunological response and metabolic effects. The combination of PI and INSTI provided to a complex subset of patients was documented to be inferior to other 2DR combinations in this setting. Other long-term effects, such as enhanced cognitive impairment, the effect of viral transmission by sexual contact or from mother to child should be further explored by prospective, long term follow-up studies.\n\nSupporting information\n\nS1 Dataset (XLSX)\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Fischl MA , Richman DD , Grieco MH , Gottlieb MS , Volberding PA , Laskin OL , et al . The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987;317 (4 ):185–91. doi: 10.1056/NEJM198707233170401 3299089\n2 Gulick RM , Mellors JW , Havlir D , Eron JJ , Gonzalez C , McMahon D , et al . Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997;337 (11 ):734–9. doi: 10.1056/NEJM199709113371102 9287228\n3 Hammer SM , Squires KE , Hughes MD , Grimes JM , Demeter LM , Currier JS , et al . A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997;337 (11 ):725–33. doi: 10.1056/NEJM199709113371101 9287227\n4 Stanley SK KJaMotpocpfto H . Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. MMWR. 1998;47 (RR-%):42–8.\n5 May MT , Gompels M , Delpech V , Porter K , Orkin C , Kegg S , et al . Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy. AIDS. 2014;28 (8 ):1193–202. doi: 10.1097/QAD.0000000000000243 24556869\n6 Antiretroviral Therapy Cohort C . Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet. 2008;372 (9635 ):293–9. doi: 10.1016/S0140-6736(08)61113-7 18657708\n7 Schouten J , Wit FW , Stolte IG , Kootstra NA , van der Valk M , Geerlings SE , et al . Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. Clin Infect Dis. 2014;59 (12 ):1787–97. doi: 10.1093/cid/ciu701 25182245\n8 Arribas JR , Horban A , Gerstoft J , Fatkenheuer G , Nelson M , Clumeck N , et al . The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010;24 (2 ):223–30. doi: 10.1097/QAD.0b013e3283348944 20010070\n9 Cahn P , Andrade-Villanueva J , Arribas JR , Gatell JM , Lama JR , Norton M , et al . Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis. 2014;14 (7 ):572–80. doi: 10.1016/S1473-3099(14)70736-4 24783988\n10 Stellbrink HJ , Le Fevre E , Carr A , Saag MS , Mukwaya G , Nozza S , et al . Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment. AIDS. 2016;30 (8 ):1229–38. doi: 10.1097/QAD.0000000000001058 26854810\n11 Pett SL , Amin J , Horban A , Andrade-Villanueva J , Losso M , Porteiro N , et al . Maraviroc, as a Switch Option, in HIV-1-infected Individuals With Stable, Well-controlled HIV Replication and R5-tropic Virus on Their First Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Plus Ritonavir-boosted Protease Inhibitor Regimen: Week 48 Results of the Randomized, Multicenter MARCH Study. Clin Infect Dis. 2016;63 (1 ):122–32. doi: 10.1093/cid/ciw207 27048747\n12 Perez-Molina JA , Rubio R , Rivero A , Pasquau J , Suarez-Lozano I , Riera M , et al . Dual treatment with atazanavir-ritonavir plus lamivudine versus triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week results from a randomised, open-label, non-inferiority trial. Lancet Infect Dis. 2015;15 (7 ):775–84. doi: 10.1016/S1473-3099(15)00097-3 26062881\n13 Capetti AF , Sterrantino G , Cossu MV , Cenderello G , Cattelan AM , De Socio GV , et al . Salvage therapy or simplification of salvage regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects: an Italian cohort. Antivir Ther. 2017;22 (3 ):257–62. doi: 10.3851/IMP3095 27661787\n14 Maggiolo F , Gulminetti R , Pagnucco L , Digaetano M , Benatti S , Valenti D , et al . Lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients. BMC Infect Dis. 2017;17 (1 ):215. doi: 10.1186/s12879-017-2311-2 28302065\n15 Borghetti A , Baldin G , Ciccullo A , Gagliardini R , D’Avino A , Mondi A , et al . Virological control and metabolic improvement in HIV-infected, virologically suppressed patients switching to lamivudine/dolutegravir dual therapy. J Antimicrob Chemother. 2016;71 (8 ):2359–61. doi: 10.1093/jac/dkw147 27147306\n16 Llibre JM , Hung CC , Brinson C , Castelli F , Girard PM , Kahl LP , et al . Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391 (10123 ):839–49. doi: 10.1016/S0140-6736(17)33095-7 29310899\n17 Aboud M , Orkin C , Podzamczer D , Bogner JR , Baker D , Khuong-Josses MA , et al . Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies. Lancet HIV. 2019;6 (9 ):e576–e87. doi: 10.1016/S2352-3018(19)30149-3 31307948\n18 HIV drug resistance database [Internet]. [cited 16.9.2021]. Available from: https://hivdb.stanford.edu/.\n19 Cahn P , Madero JS , Arribas JR , Antinori A , Ortiz R , Clarke AE , et al . Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Treatment-Naive Adults With HIV-1 Infection: 96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical Trials. J Acquir Immune Defic Syndr. 2020;83 (3 ):310–8. doi: 10.1097/QAI.0000000000002275 31834000\n20 Staszewski S , Morales-Ramirez J , Tashima KT , Rachlis A , Skiest D , Stanford J , et al . Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med. 1999;341 (25 ):1865–73. doi: 10.1056/NEJM199912163412501 10601505\n21 Arribas J MJ , Buckley RDM ,Bracchi M , Dedes N , Horban A ,Katlama C , et al . European AIDS clinical Society guidelines 2020 [Available from: https://www.eacsociety.org/guidelines/eacs-guidelines/.\n22 Updated recommendations on HIV prevention, infant diagnosis, antiretroviral initiation and monitoring 2021 [Available from: https://www.who.int/publications/i/item/9789240022232.\n23 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV 2021 [Available from: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-new-guidelines.\n24 Cahn P , Madero JS , Arribas JR , Antinori A , Ortiz R , Clarke AE , et al . Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393 (10167 ):143–55. doi: 10.1016/S0140-6736(18)32462-0 30420123\n25 Neesgaard B , Pelchen-Matthews A , Ryom L , Florence E , Peters L , Roen A , et al . Uptake and effectiveness of two-drug compared with three-drug antiretroviral regimens among HIV-positive individuals in Europe. AIDS. 2019;33 (13 ):2013–24. doi: 10.1097/QAD.0000000000002320 31335807\n26 Jablonowska E , Pulik P , Kalinowska A , Gasiorowski J , Parczewski M , Bociaga-Jasik M , et al . Dual therapy based on raltegravir and boosted protease inhibitors—the experience of Polish centers. Arch Med Sci. 2018;14 (4 ):860–4. doi: 10.5114/aoms.2016.62445 30002705\n27 Jablonowska E , Pulik P , Kalinowska A , Gasiorowski J , Parczewski M , Bociaga-Jasik M , et al . Efficacy and safety of nucleoside-sparing regimen based on raltegravir and ritonavir-boosted darunavir in HIV-1-infected treatment-experienced patients. J Med Virol. 2017;89 (12 ):2122–9. doi: 10.1002/jmv.24826 28390164\n28 Diaco ND , Strickler C , Giezendanner S , Wirz SA , Tarr PE . Systematic De-escalation of Successful Triple Antiretroviral Therapy to Dual Therapy with Dolutegravir plus Emtricitabine or Lamivudine in Swiss HIV-positive Persons. EClinicalMedicine. 2018;6 :21–5. doi: 10.1016/j.eclinm.2018.11.005 31193647\n\n",
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"abstract": "We describe a case of Purtscher-like retinopathy associated with adult-onset Still's disease, complicated by the development of central serous chorioretinopathy secondary to high dose corticosteroids.\nA 53 year old female diagnosed with adult-onset Still's disease (AOSD) presented to us with findings consistent with Purtscher-like retinopathy in both eyes, with 20/70 visual acuity in the right eye and 20/20 visual acuity in the left eye. She was initiated on high dose corticosteroids by her rheumatologists for her AOSD. A month later, her vision worsened significantly to counting fingers at 3 feet in the right eye and 20/60 visual acuity in the left. Her examination revealed serous macular detachments involving her fovea consistent with central serous chorioretinopathy secondary to exogenous steroids. After discussion with her rheumatologists, she was tapered off her steroids quickly and bridged to steroid sparing agents, with subsequent resolution of her serous macular detachments and improvement of vision back to baseline.\nThe association of Purtscher-like retinopathy and AOSD is important from a multidisciplinary standpoint due to the possibility of life-threatening systemic thrombotic microangiopathy. In addition, patients undergoing treatment for AOSD with exogenous corticosteroids may develop central serous retinopathy with vision loss, and may require quick transitioning to steroid-sparing agents if focal laser is not feasible.",
"affiliations": "Department of Ophthalmology, University of Mississippi Medical Center, Jackson, MS, USA.;Department of Ophthalmology, University of Mississippi Medical Center, Jackson, MS, USA.",
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"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30027-X\n10.1016/j.ajoc.2020.100631\n100631\nCase Report\nPurtscher-like retinopathy in adult-onset Still's disease, complicated by treatment-related central serous chorioretinopathy\nTang Anthony A. Lin Albert L. alin@umc.edu∗∗ Department of Ophthalmology, University of Mississippi Medical Center, Jackson, MS, USA\n∗ Corresponding author. Department of Ophthalmology, 2500 N. State Street, Jackson, MS, 39216, USA. alin@umc.edu\n25 2 2020 \n6 2020 \n25 2 2020 \n18 10063119 7 2019 18 11 2019 21 2 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/).Purpose\nWe describe a case of Purtscher-like retinopathy associated with adult-onset Still's disease, complicated by the development of central serous chorioretinopathy secondary to high dose corticosteroids.\n\nObservations\nA 53 year old female diagnosed with adult-onset Still's disease (AOSD) presented to us with findings consistent with Purtscher-like retinopathy in both eyes, with 20/70 visual acuity in the right eye and 20/20 visual acuity in the left eye. She was initiated on high dose corticosteroids by her rheumatologists for her AOSD. A month later, her vision worsened significantly to counting fingers at 3 feet in the right eye and 20/60 visual acuity in the left. Her examination revealed serous macular detachments involving her fovea consistent with central serous chorioretinopathy secondary to exogenous steroids. After discussion with her rheumatologists, she was tapered off her steroids quickly and bridged to steroid sparing agents, with subsequent resolution of her serous macular detachments and improvement of vision back to baseline.\n\nConclusion and Importance\nThe association of Purtscher-like retinopathy and AOSD is important from a multidisciplinary standpoint due to the possibility of life-threatening systemic thrombotic microangiopathy. In addition, patients undergoing treatment for AOSD with exogenous corticosteroids may develop central serous retinopathy with vision loss, and may require quick transitioning to steroid-sparing agents if focal laser is not feasible.\n\nKeywords\nAdult-onset Still's diseasePurtscher-like retinopathyCentral serous chorioretinopathy\n==== Body\n1 Introduction\nAdult-onset Still's disease (AOSD) is a rare multi-organ inflammatory disease that can present with a daily spiking fever, arthralgia/arthritis, neutrophil-dominant leukocytosis, hepatosplenomegaly, and evanescent salmon-colored maculopapular rashes.1 A retrospective study estimated the annual incidence of AOSD to be 0.16/100000, affecting both genders equally.2 Because of the breadth of organ systems AOSD can affect, AOSD is typically a diagnosis of exclusion. In the absence of other diseases, the Yamaguchi criteria can be implemented to help identify AOSD since there are no definitive tests. AOSD has a bimodal age distribution between the ages of 15–25 and 36–46.3 Previous studies have elaborated on the impact of AOSD on multiple organ systems, but other than uveitis, ophthalmologic manifestations are rare. However, a Purtscher-like retinopathy (PLR) has been described several reports in the literature.4, 5, 6, 7, 8, 9 In this report, we describe a case of PLR associated with AOSD, complicated by central serous chorioretinopathy caused by high dose corticosteroids.\n\n1.1 Case\nA 53-year-old African American female originally presented to an outside health facility with a rash on her arms that later spread to her trunk and legs. She denied any recent history of travel or tick exposure. After a negative rapid strep throat test, she was sent home on a short low dose steroid taper and amoxicillin. One week after her initial presentation of the rash, she developed myalgia, weakness, fatigue, dyspnea on exertion, and a 102.5 °F fever and went to a different health facility for care. Work-up revealed an elevated white blood cell count of 12.0 × 109/L, erythrocyte sedimentation rate (ESR) of 55 mm/hr and C-reactive protein (CRP) 14.9 mg/mL. She received vancomycin and piperacillin/tazobactam empirically with a diagnosis of fever of unknown origin and was discharged. Three days later, she presented to our facility with the symptoms mentioned above with minimal improvement other than reduction of her fever to 100.1 °F.\n\nAfter admission to the medical team with rheumatological consultation, her work-up, including thyroid stimulating hormone, lipids, hepatitis panel, liver enzymes, antistreptolysin O, procalcitonin, viral flu titers, fibrinogen, HIV, SPEP, inguinal lymph node biopsy, and blood cultures were unremarkable. As a diagnosis of exclusion, AOSD was suspected due to her physical exam findings along with an elevated ESR, CRP, ferritin, and lactate dehydrogenase (LDH). She was started on high dose corticosteroids and methotrexate, and then subsequently discharged as her fever improved on corticosteroids. She was readmitted a month later after finishing her course on corticosteroids due to worsening labs, with ferritin trending up to 20,000 ng/mL and LDH of 1,367 units/liter. She was restarted on high dose intravenous corticosteroids, with which her labs trended down, and she was discharged again with a longer corticosteroid taper. During her admission, she developed blurry vision and photopsias, and was quickly referred to the ophthalmology service upon discharge.\n\nOn initial presentation, best corrected visual acuity (BCVA) in the right eye (OD) was 20/70 and 20/20 in the left eye (OS). Intraocular pressure, pupils, extraocular motility, confrontational visual fields, and anterior segment were normal. Fundus examination revealed peripapillary cotton wool spots with hemorrhages present that were consistent with Purtscher-like retinopathy. Early blockage in the peripapillary retina secondary to cotton wool spots was noted on fluorescein angiography (FA), along with mild proximal venous staining and late leakage in the affected vessels (Fig. 1). Optical coherence tomography (OCT) showed focal lesions of ganglion cell thickening consistent with cotton wool spots, but no other abnormalities. PLR was made as a tentative diagnosis secondary to her AOSD, and observation other than treatment of her AOSD was recommended. A few days after her initial visit, she developed severe odynophagia and hypotension for which she was admitted back into the hospital. She was initially started on fluconazole and acyclovir, but later switched to ganciclovir when her cytomegalovirus (CMV) titers were found to be elevated. An esophagogastroduodenoscopy revealed chronic gastritis. In addition, during her hospital stay she developed acute thrombocytopenia with schistocytes on peripheral smear and low fibrinogen (<200 mg/dl). She was treated for disseminated intravascular coagulation with fresh frozen plasma and cryoprecipitate. Hematology work-up was unremarkable for an exact underlying cause other than her disseminated CMV causing macrophage activation syndrome. After improvement in her presenting symptoms, she was discharged on high dose oral steroids, and her methotrexate was held due to her CMV viremia.Fig. 1 Top - Fundus photos of both eyes on initial visit. Middle - Early phase FA. Bottom - late phase FA.\n\nFig. 1\n\nShe followed up one month after her initial ophthalmology presentation due to worsening vision. On exam, BCVA worsened to counting fingers at 3 feet OD and 20/60 OS. Fundus examination revealed her cotton wool spots resolving, but she now had new serous macular detachments affecting the fovea. FA demonstrated minimal new changes from the original FA other than slight leakage at the optic nerve in both eyes. Indocyanine green angiography (ICG) revealed inferior venous beading of the arcade vessels with multiple inferior, mildly dilated hyperfluorescent choroidal vessels, but no focal areas of leakage or pooling (Fig. 2). No angiographic evidence of classic central serous chorioretinopathy was noted on FA or ICG. OCT demonstrated serous subfoveal macular detachments in both eyes (Fig. 3). Her findings were consistent with corticosteroid-induced central serous chorioretinopathy, and her chronic course of high dose steroids was thought to be the culprit. Neither focal laser nor photodynamic therapy were considered viable treatment options due to the lack of focal areas of leakage on angiography. After discussion with her rheumatology team, her corticosteroids were tapered again after her CMV viremia cleared, and was then restarted on methotrexate and bridged to anakinra. Subsequent visits demonstrated both an improvement in subretinal fluid and vision with a corresponding lower dose of corticosteroids. Three months after the initials steroid taper, her vision returned to baseline (BCVA of 20/50 OD and 20/20 OS).Fig. 2 Top - Fundus photos one month after initial visit. Top middle - Early phase FA. Middle bottom - late phase FA. Bottom - ICG angiography of both eyes.\n\nFig. 2Fig. 3 Top - Baseline visit OCT of both eyes. Middle top - OCT of both eyes 1 month after presentation with new serous detachments. Middle bottom - OCT of both eyes 6 weeks after development of CSR while tapering steroids. Bottom - OCT almost 3 months after development of CSR while off steroids and on methotrexate and anakinra. BCVA of 20/50 in the right eye and 20/20 in the left eye.\n\nFig. 3\n\n2 Discussion\nAOSD was first described in 1896 in adults with similar findings as children with systemic juvenile idiopathic arthritis that did not meet the full criteria for rheumatoid arthritis. The etiology of AOSD is still unknown. The typical symptoms seen in AOSD are intermittent daily fevers, salmon-pink maculopapular rashes, and arthritis. Elevated ESR, CRP, and ferritin levels are common lab findings in this disease. Though not a diagnostic finding of AOSD, there have been several instances of PLR associated with AOSD in the literature. Since PLR is often asymptomatic because it is fovea sparing, PLR may be possibly more common in AOSD than previously thought. In this case, PLR developed secondary to AOSD that was later complicated by central serous chorioretinopathy from exogenous corticosteroids.\n\nThe exact pathophysiology of PLR is still debated, but the most accepted mechanism currently involves microembolization of retinal vasculature.12 The resulting microvascular occlusions of the nerve fiber layer result in the characteristic cotton wool spots noted on fundoscopic exam. AOSD causes activation of the complement system and leukocyte aggregation, which can cause leukoembolization in the retina. As the inflammatory disease is treated, the leukoembolization is thought to resolve along with treatment, resulting in resolution of exam findings. Some reports described an association of a life-threatening systemic thrombotic microangiography (TMA) with PLR in AOSD, as demonstrated in this report. However, it is not clear whether the PLR precedes TMA as a prognostic indicator, if PLR is secondary to TMA, or occurs in conjunction with TMA.5,8,9 In our case, our patient developed disseminated intravascular coagulation, a form of TMA, after being diagnosed with PLR, but was managed successfully.\n\nThe general treatment algorithm of AOSD starts with anti-inflammatories, typically high dose corticosteroids, with a prolonged taper of corticosteroids if the disease is controlled.10 Steroid-sparing agents such as methotrexate and azathioprine are then used if AOSD is not adequately managed by high dose corticosteroids or recurs during corticosteroid taper. For recalcitrant AOSD after the previous treatments, biologics such as interleukin-1 and interleukin-6 inhibitors can be used for immunomodulation. Though the literature suggests some cases of PLR improving with high dose corticosteroids, currently there is no evidence high dose corticosteroids specifically for PLR associated with AOSD improves long-term vision.7,11,12 In this case, exogenous corticosteroids, known to be a risk factor for central serous chorioretinopathy, induced a secondary central serous chorioretinopathy with subsequent vision loss.13,14 One report has described the development of central serous chorioretinopathy in AOSD after exogenous steroids, but unlike our case, PLR did not develop and angiography revealed expansile dots amenable to focal photodynamic therapy.15 In our patient, vision improvement and reduction in subretinal fluid directly correlated with a decreasing dose of steroids as well as resuming methotrexate, with eventual bridging to anakinra.\n\n3 Conclusion\nThe association of PLR with AOSD is a finding both ophthalmologists and rheumatologists should both be aware of, especially since no visual symptoms may be initially present. With the increasing number of reports describing PLR with AOSD, this association may possibly be more prevalent than once thought. Multidiscplinary management of AOSD along with complete ophthalmological examination may be warranted due to the association of PLR with possible life-threatening TMA. Last, any patient with deteriorating vision while on treatment for AOSD needs a prompt fundoscopic exam with ancillary testing to assess for treatment complications. In this case, the development of central serous chorioretinopathy on exogenous corticosteroids, not amenable focal laser or photodynamic therapy, warranted changing treatment to steroid-sparing agents quickly with corticosteroid taper to both improve vision and to treat the patient's AOSD. Recognition of these potential issues of PLR associated with AOSD is critical between disciplines in order to optimize both systemic and ophthalmologic management.\n\nPatient consent\nConsent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nDeclaration of competing interests\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n1 Yamaguchi M. Ohta A. Tsunematsu T. Preliminary criteria for classification of adult Still's disease J Rheumatol 19 1992 424 430 1578458 \n2 Akkara Veetil B.M. Yee A.H. Warrington K.J. Aksamit A.J. Jr. Mason T.G. Aseptic meningitis in adult onset Still's disease Rheumatol Int 32 12 2012 4031 4034 20495923 \n3 Owlia M.B. Mehrpoor G. Adult-onset Still's disease : a review Indian J Med Sci 63 5 2009 207 221 19584494 \n4 Yachoui R. Purtscher-like retinopathy associated with adult-onset still disease Retin Cases Brief Rep 12 4 2018 Fall 379 381 28060136 \n5 El Karoui K. Karras A. Lebrun G. Thrombotic microangiopathy and purtscher-like retinopathy associated with adult-onset still's disease: a role for glomerular vascular endothelial growth factor? Arthritis Rheum 61 2009 1609 1613 19877102 \n6 Buyukavsar C. Karagoz E. Sonmez M. A rare ocular manifestation of adult onset still's disease: purtscher’s-like retinopathy Ocul Immunol Inflamm 26 2 2018 286 291 27599266 \n7 Liu F.C. Chiang S.Y. Chang D.M. Purtscher’s-like retinopathy as an initial presentation of adult-onset Still's disease: a case report and review of the literature Clin Rheumatol 26 2007 1204 1206 16900301 \n8 Okwuosa T.M. Lee E.W. Starosta M. Purtscher’s-like retinopathy in a patient with adult-onset still's disease and concurrent thrombotic thrombocytopenic purpura Arthritis Rheum 57 2007 182 185 17266110 \n9 Masuyama A. Kobayashi H. Kobayashi Y. A case of adult-onset Still's disease complicated by thrombotic thrombocytopenic purpura with retinal microangiopathy and rapidly fatal cerebral edema Mod Rheumatol 23 2 2013 Mar 379 385 22623015 \n10 Mitrovic S. Fautrel B. Complications of adult-onset Still's disease and their management Expet Rev Clin Immunol 14 5 2018 May 351 365 \n11 Miguel A.I. Henriques F. Azevedo L.F. Systematic review of Purtscher's and Purtscher-like retinopathies Eye 27 1 2013 Jan 1 13 23174749 \n12 Agrawal A. McKibbin M. Purtscher's retinopathy: epidemiology, clinical features and outcome Br J Ophthalmol 91 11 2007 Nov 1456 1459 17556428 \n13 Carvalho-Recchia C.A.1 Yannuzzi L.A. Negrão S. Corticosteroids and central serous chorioretinopathy Ophthalmology 109 10 2002 Oct 1834 1837 12359603 \n14 Gupta S.R. Suhler E.B. Rosenbaum J.T. The dilemma of central serous retinopathy, a corticosteroid-induced complication, in patients with ocular inflammatory disease J Rheumatol 37 9 2010 Sep 1973 1974 20810529 \n15 Liu T. Dong Y. Zong D.F. A case of adult-onset Still's disease presenting with multifocal central serous chorioretinopathy Eur Rev Med Pharmacol Sci 18 3 2014 421 425 24563445\n\n",
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"abstract": "Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.",
"affiliations": "Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.;Department of Pharmacy, Kyushu University Hospital, Fukuoka, 812-8582, Japan.;Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.;Department of Pharmacy, Kyushu University Hospital, Fukuoka, 812-8582, Japan.;Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.;Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. satomsdb@pharm.med.kyushu-u.ac.jp.",
"authors": "Fu|Rao|R|;Tajima|Soichiro|S|;Suetsugu|Kimitaka|K|;Watanabe|Hiroyuki|H|;Egashira|Nobuaki|N|;Masuda|Satohiro|S|",
"chemical_list": "D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D054316:Biomarkers, Pharmacological; D065095:Calcineurin Inhibitors; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D007166:Immunosuppressive Agents; D000071068:Lipocalin-2; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A",
"country": "United States",
"delete": false,
"doi": "10.1038/s41401-018-0070-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1671-4083",
"issue": "40(2)",
"journal": "Acta pharmacologica Sinica",
"keywords": "CYP2C19; CYP3A5; MDR1; NGAL; cyclosporine A; tacrolimus",
"medline_ta": "Acta Pharmacol Sin",
"mesh_terms": "D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D054316:Biomarkers, Pharmacological; D065095:Calcineurin Inhibitors; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D016903:Drug Monitoring; D006084:Graft Rejection; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007166:Immunosuppressive Agents; D000071068:Lipocalin-2; D016377:Organ Transplantation; D020641:Polymorphism, Single Nucleotide",
"nlm_unique_id": "100956087",
"other_id": null,
"pages": "151-159",
"pmc": null,
"pmid": "29950613",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "10491726;10945321;11371998;11823861;11876576;11956505;12085010;12172213;12183280;12239231;12563178;12817518;12975316;13680536;1373650;1374612;14501869;14510951;14514731;14747421;15048793;15116055;15149320;15226679;15285851;15711640;15811456;15919502;15928679;16012079;16042669;16084851;16212633;16272749;16413244;16424824;16528543;16612333;1699911;17035613;17042920;1715244;17429034;17495880;17519790;17678545;18165774;18252812;18475181;18519927;19067682;19139162;19212447;19218475;19249502;19321980;19349640;19376366;19545678;19665407;19881258;19906031;20038391;20072790;20187665;20458311;20725108;20970601;21094057;21158923;21168598;21383650;21839244;22106961;23175667;23435265;23617933;23720091;23796509;23903271;24059111;24266830;24438378;2445722;24475383;24521021;24691060;24739669;24861504;24911663;24931259;25032096;25072153;25170223;25240575;25242754;25246772;25329716;25420835;25565672;25884518;25894154;25903959;25989460;26097572;26125566;26199736;26239045;26407820;26622455;26705892;26856709;26888217;27314545;3198493;3292818;6382005;7535213;7685934;8787947;8827397;8969;9461608;9617556;9649648;9696431",
"title": "Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation.",
"title_normalized": "biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-05637",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drug... |
{
"abstract": "Vigabatrin therapy is commonly used in infants diagnosed with tuberous sclerosis complex, particularly in the setting of epilepsy. Utilization of vigabatrin can result in bilateral and symmetric abnormal sequence changes within the deep brain matter and brainstem on magnetic resonance imaging. These abnormalities occur predominantly in infancy, are reversible, and can be asymptomatic or result in symptomatic clinical manifestations. We present a case with classic neuroimaging findings. Familiarity with these findings can prevent unnecessary follow up tests or studies and the cost of continuing or discontinuing vigabatrin therapy should be weighed heavily against the potential manifestation of extrapyramidal symptoms.",
"affiliations": "Department of Radiology, Brookwood Baptist Health Network, Princeton Baptist Medical Center, Birmingham, Alabama, USA.;Department of Radiology, Children's of Alabama, Birmingham, Alabama, USA.",
"authors": "Craft|Joseph Franklin|JF|;Cardenas|Agustin M|AM|",
"chemical_list": "D020888:Vigabatrin",
"country": "United States",
"delete": false,
"doi": "10.3941/jrcr.v15i2.3918",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1943-0922",
"issue": "15(2)",
"journal": "Journal of radiology case reports",
"keywords": "MRI; Pediatric Neuroimaging; Tuberous Sclerosis Complex; VABAM; Vigabatrin; Vigabatrin Toxicity; Vigabatrin-associated brain abnormalities",
"medline_ta": "J Radiol Case Rep",
"mesh_terms": "D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D014402:Tuberous Sclerosis; D020888:Vigabatrin",
"nlm_unique_id": "101494925",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "33717406",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "23199677;23789722;18783433;20384718;22979977;26306928;28230253",
"title": "Vigabatrin-associated Reversible MRI Abnormalities in an Infant with Tuberous Sclerosis.",
"title_normalized": "vigabatrin associated reversible mri abnormalities in an infant with tuberous sclerosis"
} | [
{
"companynumb": "US-TEVA-2021-US-1966676",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VIGABATRIN"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nVisual field deterioration caused by secondary empty sella after cabergoline therapy for prolactinoma is a rare event. Chiasmapexy is performed to treat empty sella syndrome. Although various materials have been used for the elevation of the optic chasm, the most appropriate material remains to be established. Here, we describe the efficiency of chiasmapexy for empty sella syndrome following dopamine agonist treatment and the utility of septal cartilage and sphenoidal sinus bone as materials for chiasmapexy.\n\n\nMETHODS\nA 35-year-old male with a history of cabergoline therapy for prolactinoma presented with visual deterioration. His magnetic resonance imaging revealed optic chiasm herniation into the empty sella. Endoscopic endonasal transsphenoidal chiasmapexy was performed using septal cartilage and sphenoidal sinus bone as materials for elevating the chiasm. Visual function improved immediately after operation.\n\n\nCONCLUSIONS\nChiasmapexy is an effective surgical method for treating visual deterioration caused by empty sella after cabergoline treatment. Endoscopic endonasal chiasmapexy with septal cartilage and sphenoidal sinus bone is a considerable option because it is minimally invasive and involves decreased risk of infection.",
"affiliations": "Department of Neurosurgery, Keio University School of Medicine, Sinjuku-ku, Tokyo, Japan. Electronic address: searoad@mail.goo.ne.jp.;Department of Neurosurgery, Keio University School of Medicine, Sinjuku-ku, Tokyo, Japan.;Department of Neurosurgery, Keio University School of Medicine, Sinjuku-ku, Tokyo, Japan.;Department of Otolaryngology, Keio University School of Medicine, Sinjuku-ku, Tokyo, Japan.;Department of Otolaryngology, Keio University School of Medicine, Sinjuku-ku, Tokyo, Japan.;Department of Otolaryngology, Keio University School of Medicine, Sinjuku-ku, Tokyo, Japan.;Department of Neurosurgery, Keio University School of Medicine, Sinjuku-ku, Tokyo, Japan.",
"authors": "Ishihara|Eriko|E|;Toda|Masahiro|M|;Sasao|Ryota|R|;Ozawa|Hiroyuki|H|;Saito|Shin|S|;Ogawa|Kaoru|K|;Yoshida|Kazunari|K|",
"chemical_list": "D018491:Dopamine Agonists; D000077465:Cabergoline",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.10.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "121()",
"journal": "World neurosurgery",
"keywords": "Autologous cartilage/bone; Cabergoline therapy; Empty sella syndrome; Endonasal chiasmapexy; Prolactinoma",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D016025:Bone Transplantation; D000077465:Cabergoline; D002356:Cartilage; D018491:Dopamine Agonists; D004652:Empty Sella Syndrome; D006801:Humans; D008297:Male; D057605:Natural Orifice Endoscopic Surgery; D015175:Prolactinoma; D014182:Transplantation, Autologous; D014786:Vision Disorders",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "145-148",
"pmc": null,
"pmid": "30315973",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Endonasal Chiasmapexy Using Autologous Cartilage/Bone for Empty Sella Syndrome After Cabergoline Therapy for Prolactinoma.",
"title_normalized": "endonasal chiasmapexy using autologous cartilage bone for empty sella syndrome after cabergoline therapy for prolactinoma"
} | [
{
"companynumb": "JP-IMPAX LABORATORIES, LLC-2018-IPXL-04056",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CABERGOLINE"
},
"drugadditio... |
{
"abstract": "Hydroxychloroquine (HCQ) and chloroquine are used worldwide for malaria as well as connective and rheumatological disorders. They have been reported to be linked to myopathy in patients. We report four patients who were receiving HCQ as part of treatment for connective tissue disorder and who presented with myopathy. The muscle biopsy in these patients was consistent with findings of HCQ toxicity. HCQ muscle toxicity is usually self-limiting after discontinuation of the drug. It also usually tends to be under-reported due to presence of various confounding factors. This warrants close monitoring and consideration of muscle biopsy as part of initial work up of patients who present with myopathy while receiving HCQ.",
"affiliations": "Department of Neurology, Olive-View UCLA Medical Center, Los Angeles, California, USA.;Department of Pathology and Laboratory Medicine - Neuropathology and Electron Microscopy, UCLA David Geffen School of Medicine, Los Angeles, California, USA.;Indira Gandhi Medical College, Shimla, India.;Department of Neurology, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.",
"authors": "Khosa|Shaweta|S|https://orcid.org/0000-0003-0677-7550;Khanlou|Negar|N|https://orcid.org/0000-0002-7308-9363;Khosa|Gurveer S|GS|;Mishra|Shri K|SK|https://orcid.org/0000-0002-4391-9522",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
"country": "Australia",
"delete": false,
"doi": "10.1111/neup.12520",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-6544",
"issue": "38(6)",
"journal": "Neuropathology : official journal of the Japanese Society of Neuropathology",
"keywords": "chloroquine; hydroxychloroquine; myopathies; toxicity; vacuolar myopathy",
"medline_ta": "Neuropathology",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001327:Autoimmune Diseases; D001343:Autophagy; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged; D008928:Mitochondria; D009135:Muscular Diseases",
"nlm_unique_id": "9606526",
"other_id": null,
"pages": "646-652",
"pmc": null,
"pmid": "30411412",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Hydroxychloroquine-induced autophagic vacuolar myopathy with mitochondrial abnormalities.",
"title_normalized": "hydroxychloroquine induced autophagic vacuolar myopathy with mitochondrial abnormalities"
} | [
{
"companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201812-004050",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "OBJECTIVE\nThere are limited data on the efficacy and tolerability of VCD chemotherapy in transplant-non-eligible (TNE) newly diagnosed myeloma (NDMM) patients. In this retrospective study, we set out to evaluate this triplet combination in this setting across Thames Valley Cancer Network (UK).\n\n\nMETHODS\nThe primary end point was overall response rate (ORR). Secondary outcomes included event-free survival (EFS), overall survival (OS) and adverse events (AEs).\n\n\nRESULTS\nIn a total cohort of 158 patients, ORR for total cohort was 72.1%. Median EFS was 10.5 months, and for subgroups by age (<75:11.7 vs ≥75:10.3 months, P = .124), by Charlson Co-morbidity Index (CCI) (<5:11.1 vs ≥5:8.2 months, P = .345). The 4-month landmark analysis showed the following median EFS results: by cumulative bortezomib dose (≥26 mg/m2 : 9.0 months vs <26 mg/m2 : 6.4, P = .13), by cumulative cyclophosphamide dose (≥7000 mg: 9.2 vs <7000 mg: 7.0 months, P = .02) and by cumulative dexamethasone dose (>600 mg: 7.8 vs ≤600 mg: 8.3 months, P = .665). Median OS was 46.9 months. The incidence rate of AE was as follows: any grade (76.8%), ≥G3 (27.1%), ≥G3 haematological AEs (7.9%), any grade infections (31.1%) and ≥G3 infections (11.9%).\n\n\nCONCLUSIONS\nThis study demonstrated a good ORR achieved from fixed duration VCD, which was reasonably well tolerated. This was followed by modest median EFS. We envisage that the latter may be improved in this patient group with the use of a higher cumulative bortezomib dose (≥26 mg/m2 ) which showed a trend for improved EFS although without statistical significance (P = .13), and with the use of a higher cumulative cyclophosphamide doses (≥7000 mg, P = .02), subject to tolerability and close monitoring.",
"affiliations": "Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Haematology, Laiko General Hospital, Athens, Greece.;Royal Berkshire NHS Foundation Trust, Reading, UK.;Buckinghamshire Healthcare NHS Trust, Aylesbury, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Great Western Hospitals NHS Foundation Trust, Swindon, UK.;Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Wexham Park Hospital, Slough, UK.;Frimley Health NHS Foundation Trust, Frimley, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.",
"authors": "Rampotas|Alexandros|A|https://orcid.org/0000-0002-2681-5860;Djebbari|Faouzi|F|https://orcid.org/0000-0001-9578-7632;Panitsas|Fotios|F|;Lees|Charlotte|C|;Tsagkaraki|Ismini|I|;Gomes|Ana Rita|AR|;Prideaux|Steve|S|;Chen|Lucia|L|;Prodger|Catherine|C|;Khera|Akhil|A|;Gray|Nicola|N|;Ellis|Lauren|L|;Sangha|Gavinda|G|;Lim|Wen Yuen|WY|;Eyre|Toby A|TA|;Moore|Sally|S|;Ramasamy|Karthik|K|;Kothari|Jaimal|J|",
"chemical_list": "D003907:Dexamethasone; D003520:Cyclophosphamide; D013713:Teniposide",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13588",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "106(4)",
"journal": "European journal of haematology",
"keywords": "bortezomib; co-morbidities; cumulative dose; elderly; myeloma",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000066491:Clinical Decision-Making; D003520:Cyclophosphamide; D003907:Dexamethasone; D019468:Disease Management; D005260:Female; D019538:Health Care Surveys; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011379:Prognosis; D013713:Teniposide; D016896:Treatment Outcome; D006113:United Kingdom",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "563-573",
"pmc": null,
"pmid": "33496996",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and tolerability of VCD chemotherapy in a UK real-world dataset of elderly transplant-ineligible newly diagnosed myeloma patients.",
"title_normalized": "efficacy and tolerability of vcd chemotherapy in a uk real world dataset of elderly transplant ineligible newly diagnosed myeloma patients"
} | [
{
"companynumb": "GB-TAKEDA-2021TUS050597",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAfter tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 were introduced for the treatment of chronic myeloid leukemia, clinical outcomes have improved dramatically. However, together with the increase in the survival rate, a more frequent occurrence of secondary malignancies has been observed as well. TKIs have been demonstrated to be a risk factor of malignancies such as non-Hodgkin lymphoma, prostate cancer, and skin cancer. However, lymphoplasmacytic lymphoma (LPL) has never been reported as a secondary malignancy after TKI treatment in chronic myeloid leukemia (CML).\nAn 81-year-old male patient diagnosed with CML and treated with TKIs for a long period (15 years) was admitted due to a chief complaint of abdominal pain. A large abdominal mass was detected by imaging that included computed tomography.\n\n\nMETHODS\nLPL was confirmed from biopsies after ultrasonography and sigmoidoscopy. Serum IgM level was increased and M protein and monoclonal gammopathy, IgM_kappa light chain type were detected.\n\n\nMETHODS\nThe patient received six cycles of R-CHOP chemotherapy.\n\n\nRESULTS\nAfter chemotherapy, he showed response. The sizes of the abdominal mass and lymph nodes decreased; moreover, serum M protein and IgM levels decreased, as well.\n\n\nCONCLUSIONS\nHerein, for the first time, we describe a patient who developed LPL as a secondary malignancy after administration of TKIs for the treatment of CML. Our observations indicate the importance of awareness of this secondary malignancy that can develop in CML patients treated with TKIs.",
"affiliations": "Department of Internal Medicine.;Department of Internal Medicine.;Department of Internal Medicine.;Department of Pathology, Chonbuk National University Medical School, Jeonju, Republic of Korea.;Department of Internal Medicine.",
"authors": "Lee|Chang-Hoon|CH|;Jeon|So Yeon|SY|;Yhim|Ho-Young|HY|;Jang|Kyu Yun|KY|;Kwak|Jae-Yong|JY|",
"chemical_list": "D000970:Antineoplastic Agents; D007075:Immunoglobulin M; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D016044:Fusion Proteins, bcr-abl; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000019962",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32384445\nMD-D-19-04070\n10.1097/MD.0000000000019962\n19962\n4800\nResearch Article\nClinical Case Report\nOccurrence of lymphoplasmacytic lymphoma in a chronic myeloid leukemia patient following long-term treatment with tyrosine kinase inhibitors\nA case reporthttp://orcid.org/0000-0002-1317-4646Lee Chang-Hoon MD, PhDa Jeon So Yeon MD, PhDa Yhim Ho-Young MD, PhDa Jang Kyu Yun MD, PhDb Kwak Jae-Yong MD, PhDa∗ Saranathan. Maya a Department of Internal Medicine\nb Department of Pathology, Chonbuk National University Medical School, Jeonju, Republic of Korea.\n∗ Correspondence: Jae-Yong Kwak, Department of Internal Medicine, Chonbuk National University Medical School, 20 Geonji-ro, Deokjin-gu, Jeonju, 54907, Republic of Korea (e-mail: jykwak@jbnu.ac.kr).\n08 5 2020 \n5 2020 \n99 19 e1996225 5 2019 31 1 2020 17 3 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nIntroduction:\nAfter tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 were introduced for the treatment of chronic myeloid leukemia, clinical outcomes have improved dramatically. However, together with the increase in the survival rate, a more frequent occurrence of secondary malignancies has been observed as well. TKIs have been demonstrated to be a risk factor of malignancies such as non-Hodgkin lymphoma, prostate cancer, and skin cancer. However, lymphoplasmacytic lymphoma (LPL) has never been reported as a secondary malignancy after TKI treatment in chronic myeloid leukemia (CML).\n\nPatient concerns:\nAn 81-year-old male patient diagnosed with CML and treated with TKIs for a long period (15 years) was admitted due to a chief complaint of abdominal pain. A large abdominal mass was detected by imaging that included computed tomography.\n\nDiagnosis:\nLPL was confirmed from biopsies after ultrasonography and sigmoidoscopy. Serum IgM level was increased and M protein and monoclonal gammopathy, IgM_kappa light chain type were detected.\n\nInterventions:\nThe patient received six cycles of R-CHOP chemotherapy.\n\nOutcomes:\nAfter chemotherapy, he showed response. The sizes of the abdominal mass and lymph nodes decreased; moreover, serum M protein and IgM levels decreased, as well.\n\nConclusion:\nHerein, for the first time, we describe a patient who developed LPL as a secondary malignancy after administration of TKIs for the treatment of CML. Our observations indicate the importance of awareness of this secondary malignancy that can develop in CML patients treated with TKIs.\n\nKeywords\nchronic myeloid leukemialymphoplasmacytic lymphomatyrosine kinase inhibitorOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nChronic myeloid leukemia (CML) is one of myeloproliferative neoplasms characterized by proliferation of myeloid cells in both bone marrow and peripheral blood. It is associated with BCR-ABL1 fusion gene that is formed as a result of translocation of chromosomes 9 and 22. Tyrosine kinase inhibitors (TKIs) bind to the kinase domain of BCR-ABL1 fusion protein and suppress its abnormal activity and downstream signaling pathways. After imatinib, a first-generation TKI, had been introduced as first-line treatment of chronic phase (CP) of CML, the 10-year overall survival (OS) increased to 83%.[1] Furthermore, the five-year OS of 94% and 91% was achieved after the second-generation TKIs nilotinib and dasatinib were approved as the first-line treatment of CML-CP.[2] Despite TKIs improved the survival rate, an increased rate of secondary malignancies in TKI-treated CML patients has been reported. In particular, TKIs have been discussed as a risk factor of secondary malignancies, such as prostate, colorectal cancer, and non-Hodgkin's lymphoma (NHL).[2,3]\n\nLymphoplasmacytic lymphoma (LPL) is a low-grade B-cell lymphoma characterized by immunoglobulin M (IgM) monoclonal gammopathy. These malignant cells derive from B-cell arrest after somatic hypermutation in germinal center.[4] Increased serum level of IgM pentamer induces hyperviscosity of blood, which in turn causes vision disturbances and neurological symptoms that are observed in this disease. Rituximab-based chemotherapy regimens such as bendamustine + rituximab, bortezomib + dexamethasone + rituximab, and rituximab + cyclophosphamide + dexamethasone are preferred as initial therapy for LPL.\n\nThere have been described cases of CML that occurred in patients with Waldenström's macroglobulinemia (WM), a chlinicopathological LPL entity,[5,6] however, to the best of our knowledge, there have been no case reports yet of LPL occurrence in TKI-treated CML patients. Here, we present the first such case of a CML patient who developed LPL after administration of TKIs.\n\n2 Case presentation\nAn 81-year-old man was admitted to the Department of Hematology/Oncology, because of persistent abdominal pain in September 2018. He received a diagnosis of CML-CP and started to take hydroxyurea in March 2002. From February 2003, imatinib at a daily dose of 400 mg was prescribed, because disease progression to the accelerated phase was detected by bone marrow examination. He started to take dasatinib from August 2010, because the loss of molecular response to imatinib was detected. The BCR-ABL/ABL ratio examined by real-time PCR had increased from 0.035688 to 0.166125. The major molecular response (MMR; IS ≤ 0.1%) was not obtained over 2 years, however, no additional mutations were detected. Therefore, radotinib (800 mg daily) was prescribed in November 2012. MMR (IS: 0.066%) was achieved in September 2015, and the patient developed a complete molecular response in August 2016.\n\nWhen he was admitted because of a chief complaint of abdominal pain, physical examination showed a blood pressure of 125/68 mmHg, pulse rate of 75/min, respiratory rate of 18/min, and body temperature of 36.9°C. Complete blood count showed a white blood cell count of 9430/μL, hemoglobin level of 11.6 g/dL, and platelet count of 174,000/μL. To evaluate the cause of abdominal pain, a computed tomography (CT) scan was performed. A large peritoneal mass (151 × 115 mm) was found in the central part of abdomen that was adjacent to the small intestine and sigmoid colon (Fig. 1). A large infiltrative mass with central ulceration at 20 cm from the anal verge was detected by sigmoidoscopy and a tissue sample was taken (Fig. 2). Ultrasonography-guided percutaneous biopsy of abdominal mass was also performed. As a result, a diagnosis of lymphoplasmacytic lymphoma was confirmed (CD20, CD10, BCL2; positive) in both tissue samples (Fig. 3). Furthermore, 18fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET-CT) was performed to determine lymphoma stage. FDG-avid mass involving small intestine and sigmoid colon was detected and multiple lymph nodes from the chest to pelvic cavity were involved (Fig. 4). There was no evidence of lymphoma infiltration in the bone marrow. Serum IgM level was increased up to 1631.0 mg/dL. M protein level of 0.99 g/dL and monoclonal gammopathy, IgM_kappa light chain type were detected by serum protein electrophoresis and immunofixation EP, respectively. As somatic mutations of MYD88 are associated with approximately 90% of LPL/WM cases,[7] we performed next-generation sequencing of the sample from this patient. MYD88 mutations were not detected, however, we found TP53 p.Y236C and p.A283P mutations. The patient received chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and methylprednisolone).[8] Separate CT and 18F-FDG PET/CT scans followed after six cycles of the chemotherapy. The sizes of the abdominal mass and lymph nodes decreased on both CT and 18F-FDG PET-CT scan images (Figs. 1 and 4). Serum M protein and IgM levels decreased to 0.13 g/dL and 280.2 mg/dL, respectively. The duration of follow-up is 17 years after he was diagnosed with CML and 6 months after diagnosed with LPL.\n\nFigure 1 Abdominopelvic CT scan shows that large peritoneal mass (151 × 115 mm) decreased (79 × 74 mm) after 6 cycles of R-CHOP chemotherapy.\n\nFigure 2 A large infiltrative mass with central ulceration at 20 cm from anal verge was detected by sigmoidoscopy.\n\nFigure 3 Histologic findings of lymphoplasmacytic lymphoma. The tumor composes of monotonous small lymphocytes and plasma cells. The small B lymphocytes are positive for CD20 and BCL2, but negative for CD5, CD10, BCL6, CD23, and CD3. The plasma cells are positive for CD138 and MUM-1, and shows kappa immunoglobulin light-chain restriction: positive for kappa light chain but negative for lambda light chain. Original magnification: ×400.\n\nFigure 4 18F-FDG PET-CT shows that both size and FDG-uptake of the peritoneal mass decreased after 6 cycles of R-CHOP chemotherapy. At the time of diagnosis of LPL (A & B) and after 6 cycles of R-CHOP (C & D).\n\n3 Discussion\nConstitutional activation of BCR/ABL1 tyrosine kinase is induced by the translocation of chromosomes 9 and 22, yielding t(9;22)(q34;q11). The unusually short chromosome 22 containing BCR/ABL1 fusion gene is called Philadelphia chromosome. TKIs are competitive inhibitors of ABL protein tyrosine kinase that block ATP binding site.[9–11] After TKIs were prescribed for CML-CP patients as first-line treatment, the survival rate dramatically improved. The percentage of patients with 10-year OS after imatinib administration was 83%, whereas 91% and 94% had five-year OS after the treatment with nilotinib and dasatinib, respectively.[1]\n\nDespite the outstanding therapeutic efficacy of TKIs, there are some adverse effects associated with the use of these drugs, such as edema, congestive heart failure, pleural effusion, liver enzyme elevation, myelosuppression, and QT prolongation. Secondary malignancy has been reported as a long-term adverse effect in the patients receiving TKIs. Gunnarsson et al reported that 7.5% (65 out of 868 patients) of Swedish patients diagnosed with CML between 2002 and 2011 developed secondary malignancies with median follow-up of 3.7 (0 to 9.9) years.[12] According to Yin et al, 3.14% (7 out of 223 patients) of Chinese patients developed secondary malignancy after 51 (12–76) months of median duration of treatment of TKIs. Dose of imatinib was 400 and 600 mg for chronic phase and accelerated phase patient, respectively.[13] Duman et al, also reported that patients who had received 400 mg of imatinib developed secondary malignancy and interval between starting TKI therapy and development of malignancy was between 14 months to 7 years.[14] Our patient was exposed to TKIs for 15 years and it is longer than the exposure period reported in the literature. Considering the increasing survival rate of CML patients after TKIs use, it is important to note that secondary malignancy can occur even 10 years or longer after start of TKIs. Roy et al, reported that the incidence of secondary malignancy, especially, prostate cancer increased in a cohort of patients who received IFN-α following treatment with imatinib as therapy for CML.[15] However, it has been revealed that the rates of solid cancers, such as prostate cancer, colorectal cancer, breast cancer, malignant melanoma, pancreas, and kidney cancer, in CML patients were not statistically different from those in general population.[16] But on the other hand, the number of NHL cases was significantly higher in CML patients taking TKIs than in general population.[2]\n\nSeveral possible mechanisms whereby secondary malignancy may develop in TKI-treated CML patients have been suggested. First, differentiation and function of T lymphocytes is likely affected by TKIs. It has been shown that imatinib disturbs proliferation of memory cytotoxic T lymphocytes (CTLs) in a murine model, whereas dasatinib exerts even stronger inhibitory effects on human effector T cell functions and proliferation than imatinib.[17,18] Second, differentiation and antigen-presenting function of dendritic cells (DCs) could be disturbed by TKIs. Imatinib inhibits the development of human CD34+ progenitors to DCs, and DCs exposed to imatinib are less potent at inducing primary CTL responses.[19] Rix et al reported that dasatinib also inhibits Bruton's tyrosine kinase, which plays a key role in DC maturation and function.[20]\n\nNot only TKIs targeting BCR/ABL1 but also the inhibitors that block JAK 1/2 for the treatment of myeloproliferative neoplasms have been reported to increase the risk of NHL. Porpaczy et al reported that risk of B-cell lymphomas in MPN patients treated with JAK 1/2 inhibitors (5.8%) was 16-fold higher than that of control group that received conventional treatment (0.36%).[21] Suppression of the JAK/STAT pathway causes dysfunction of CTL and NK cells, and this results in abnormal B-cell clonal expansion. MPN patients developing B-cell lymphoma exhibited mutations in TP53, MYC, BCL2, and BCL6.\n\nOur CML patient received imatinib, dasatinib, and radotinib consecutively and was exposed to TKIs for a total of 15 years. We believe that such long-term exposure to TKIs promoted not only dysregulation of immune system but also development of LPL as another malignancy. After the patient was diagnosed with LPL, he was treated with six cycles of R-CHOP chemotherapy. He showed partial response, and we continue monitoring him. TP53 gene encodes tumor suppressor protein, p53, which activates DNA repair protein and suppresses cell proliferation on DNA damage recognition. It has been reported that TP53 mutation is associated with poor outcome in the majority of B-cell lymphomas, including LPL. Poulain et al reported that WM patients with the mutated TP53 locus showed shorter median OS (6 years) comparing with that of patients with wild type TP53 (18 years).[22]TP53 mutation was detected by NGS in this patient, and he is therefore thought to have a poor prognosis.\n\n4 Conclusion\nDespite NHL is one of the most frequent secondary malignancies, LPL has not been reported previously as a secondary malignancy in TKI-treated CML patients. We suggest that sequencing, such as NGS, will help to evaluate the risk of development of secondary malignancy by detection of additional mutations in TKI-treated CML patients. Furthermore, we believe that early diagnosis of secondary malignancies could improve survival of CML patients.\n\nAuthor contributions\nConceptualization: Jae-Yong Kwak.\n\nData curation: So Yeon Jeon.\n\nResources: Kyu Yun Jang.\n\nSupervision: Jae-Yong Kwak.\n\nValidation: Ho-Young Yhim.\n\nWriting – original draft: Chang-Hoon Lee.\n\nWriting – review & editing: Ho-Young Yhim.\n\nAbbreviations: CML = chronic myeloid leukemia, LPL = lymphoplasmacytic lymphoma, NHL = non-Hodgkin's lymphoma, R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and methylprednisolone; TKI = tyrosine kinase inhibitor, WM = Waldenström's macroglobulinemia.\n\nHow to cite this article: Lee CH, Jeon SY, Yhim HY, Jang KY, Kwak JY. Occurrence of lymphoplasmacytic lymphoma in a chronic myeloid leukemia patient following long-term treatment with tyrosine kinase inhibitors: A case report. Medicine. 2020;99:19(e19962).\n\nInformed written consent was obtained from the patient for publication of this case report and accompanying images.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Saglio G Jabbour E \nFirst-line therapy for chronic phase CML: selecting the optimal BCR-ABL1-targeted TKI\n. Leuk Lymphoma \n2018 ;59 :1523 –38\n.28972424 \n[2] Miranda MB Lauseker M Kraus MP \nSecondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV\n. Leukemia \n2016 ;30 :1255 –62\n.26859076 \n[3] Kumar V Garg M Chaudhary N \nAn observational study on risk of secondary cancers in chronic myeloid leukemia patients in the TKI era in the United States\n. PeerJ \n2018 ;6 :e4342 .29456888 \n[4] Kaseb H Gonzalez-Mosquera LF Mewawalla P \nCancer, Lymphoplasmacytic Lymphoma (Waldenstrom Macroglobulinemia)\n. Treasure Island (FL): StatPearls; 2019 .\n[5] Majado MJ Gonzalez Garcia C Marin-Blazquez MD \nAppearance of a chronic myeloid leukemia in Waldenstrom's macroglobulinemia\n. Sangre (Barc) \n1992 ;37 :465 –6\n.1293799 \n[6] Vitali C Bombardieri S Spremolla G \nChronic myeloid leukemia in Waldenstrom's macroglobulinemia\n. Arch Intern Med \n1981 ;141 :1349 –51\n.6791603 \n[7] Rossi D \nRole of MYD88 in lymphoplasmacytic lymphoma diagnosis and pathogenesis\n. Hematology Am Soc Hematol Educ Program \n2014 ;2014 :113 –8\n.25696843 \n[8] Buske C Hoster E Dreyling M \nThe addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG)\n. Leukemia \n2009 ;23 :153 –61\n.18818699 \n[9] An X Tiwari AK Sun Y \nBCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review\n. Leuk Res \n2010 ;34 :1255 –68\n.20537386 \n[10] Manley PW Cowan-Jacob SW Mestan J \nAdvances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia\n. Biochim Biophys Acta \n2005 ;1754 :3 –13\n.16172030 \n[11] Olivieri A Manzione L \nDasatinib: a new step in molecular target therapy\n. Ann Oncol \n2007 ;18 : Suppl 6 : vi42 –46\n.17591830 \n[12] Gunnarsson N Stenke L Hoglund M \nSecond malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era\n. Br J Haematol \n2015 ;169 :683 –8\n.25817799 \n[13] Yin XF Wang JH Li X \nIncidence of second malignancies of chronic myeloid leukemia during treatment with tyrosine kinase inhibitors\n. Clin Lymphoma Myeloma Leuk \n2016 ;16 :577 –81\n.27397576 \n[14] Duman BB Paydas S Disel U \nSecondary malignancy after imatinib therapy: eight cases and review of the literature\n. Leuk Lymphoma \n2012 ;53 :1706 –8\n.22329351 \n[15] Roy L Guilhot J Martineau G \nUnexpected occurrence of second malignancies in patients treated with interferon followed by imatinib mesylate for chronic myelogenous leukemia\n. Leukemia \n2005 ;19 :1689 –92\n.16015386 \n[16] Pilot PR Sablinska K Owen S \nEpidemiological analysis of second primary malignancies in more than 9500 patients treated with imatinib\n. Leukemia \n2006 ;20 :148 [author reply 149] .16292349 \n[17] Mumprecht S Matter M Pavelic V \nImatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections\n. Blood \n2006 ;108 :3406 –13\n.16873671 \n[18] Weichsel R Dix C Wooldridge L \nProfound inhibition of antigen-specific T-cell effector functions by dasatinib\n. Clin Cancer Res \n2008 ;14 :2484 –91\n.18413841 \n[19] Appel S Boehmler AM Grunebach F \nImatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells\n. Blood \n2004 ;103 :538 –44\n.14504105 \n[20] Rix U Hantschel O Durnberger G \nChemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets\n. Blood \n2007 ;110 :4055 –63\n.17720881 \n[21] Porpaczy E Tripolt S Hoelbl-Kovacic A \nAggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy\n. Blood \n2018 ;132 :694 –706\n.29907599 \n[22] Poulain S Roumier C Bertrand E \nTP53 mutation and its prognostic significance in Waldenstrom's macroglobulinemia\n. Clin Cancer Res \n2017 ;23 :6325 –35\n.28754818\n\n",
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"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D003520:Cyclophosphamide; D004317:Doxorubicin; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D007075:Immunoglobulin M; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D016609:Neoplasms, Second Primary; D011241:Prednisone; D011860:Radiography, Abdominal; D000069283:Rituximab; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014750:Vincristine; D008258:Waldenstrom Macroglobulinemia",
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"title": "Occurrence of lymphoplasmacytic lymphoma in a chronic myeloid leukemia patient following long-term treatment with tyrosine kinase inhibitors: A case report.",
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"abstract": "Neonatal diabetes (NDM) is defined as diabetes that occurs in the first 6 months of life, the majority of cases are due to sporadic mutations. ATP-sensitive potassium channels located in the beta cells of the pancreas play a major role in insulin secretion and blood glucose homeostasis. Mutations that alter the function of these channels may lead to NDM. We report a case of a 26-year-old Irish woman who was diagnosed with NDM at the age of 4 weeks and treated as type 1 diabetes mellitus, with multiple daily injections of insulin with suboptimal glycaemic control and frequent episodes of hypoglycaemic. She underwent genetic testing for NDM and was diagnosed with a KCNJ11 gene mutation. She was transitioned to high dose glibenclamide at the age of 16 years, but the trial failed due to poor glycaemic control and patient preference, and she was restarted on insulin. At 24 years of age, she was successfully transitioned from insulin (total daily dose 50 units) to high dose sulfonylurea (SU) (glibenclamide 15 mg twice daily). This resulted in optimal control of blood glucose (HbA1C fell from 63 to 44 mmol/mol), lower rates of hypoglycaemic and better quality of life. This case demonstrates that a second trial of SU in later life may be successful.",
"affiliations": "Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland dr.sulaiman.hajji@gmail.com.;Endocrine and Diabetes, Saint James's Hospital, Dublin, Ireland.;Endocrinology and Diabetes, South Infirmary Victoria University Hospital, Cork, Ireland.;Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland.",
"authors": "Hajji|Sulaiman|S|;Aljenaee|Khaled|K|;Garrahy|Aoife|A|;Byrne|Maria|M|",
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"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n33837025\nbcr-2020-239973\n10.1136/bcr-2020-239973\nCase Report\n1506\n1325\n77\n159\nSuccessful transition from insulin to sulfonylurea, on second attempt, in a 24-year-old female with neonatal diabetes secondary to KCNJ11 gene mutation\nHajji Sulaiman 1\nAljenaee Khaled 2\nGarrahy Aoife 3\nByrne Maria 1\n1 Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland\n2 Endocrine and Diabetes, Saint James's Hospital, Dublin, Ireland\n3 Endocrinology and Diabetes, South Infirmary Victoria University Hospital, Cork, Ireland\nCorrespondence to Sulaiman Hajji; dr.sulaiman.hajji@gmail.com\n2021\n9 4 2021\n9 4 2021\n14 4 e23997319 3 2021\n© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nNeonatal diabetes (NDM) is defined as diabetes that occurs in the first 6 months of life, the majority of cases are due to sporadic mutations. ATP-sensitive potassium channels located in the beta cells of the pancreas play a major role in insulin secretion and blood glucose homeostasis. Mutations that alter the function of these channels may lead to NDM. We report a case of a 26-year-old Irish woman who was diagnosed with NDM at the age of 4 weeks and treated as type 1 diabetes mellitus, with multiple daily injections of insulin with suboptimal glycaemic control and frequent episodes of hypoglycaemic. She underwent genetic testing for NDM and was diagnosed with a KCNJ11 gene mutation. She was transitioned to high dose glibenclamide at the age of 16 years, but the trial failed due to poor glycaemic control and patient preference, and she was restarted on insulin. At 24 years of age, she was successfully transitioned from insulin (total daily dose 50 units) to high dose sulfonylurea (SU) (glibenclamide 15 mg twice daily). This resulted in optimal control of blood glucose (HbA1C fell from 63 to 44 mmol/mol), lower rates of hypoglycaemic and better quality of life. This case demonstrates that a second trial of SU in later life may be successful.\n\ndiabetes\ngenetics\nspecial-featureunlocked\n==== Body\nBackground\n\nNeonatal diabetes (NDM) occurs in approximately one in 100 000–300 000 live births and is mostly monogenic in nature. Mutations in KCNJ11 and ABCC8, encoding the two subunits kir6.2 and sulfonylurea receptors (SUR) of the ATP‐sensitive potassium channel located on the beta cells of the pancreas respectively, can cause NDM. Identifying this type of monogenic diabetes carries many important implications for patient care; including the long-term management plan (sulfonylureas (SUs) rather than insulin therapy), expected disease course and complications. Appropriate therapy will result in better outcome, and quality of life.1 2\n\nCase presentation\n\nWe report a case of a 28-year-old Irish woman diagnosed initially with diabetes mellitus at the age of 4 weeks (1991). She was born at term and was small for gestational age, 2.6 kg. She was admitted to hospital at 4 weeks of age with weight loss to 2.3 kg, dehydration, fever, napkin and oral thrush. Her HbA1C was 83.0 mmol/mol, she was ketotic and her pH was 7.0. She was diagnosed and treated as type 1 diabetes mellitus. After adequate control of her blood glucose, she was discharged home on subcutaneous multiple daily injections (MDI) of insulin. Her anti-GAD and anti-islet cell antibodies were both negative. During her follow-up with the paediatric team, no developmental delay, seizure disorder or muscle weakness was identified. She has three healthy older brothers with no history of diabetes mellitus, but two members of her extended family had diabetes as shown in figure 1 family pedigree.\n\nFigure 1 Family pedigree.\n\nInvestigations\n\nThe patient was admitted to hospital at 4 weeks of age and was diagnosed as type 1 diabetes mellitus and her anti-GAD and anti-islet cell antibodies were both negative.\n\nAt the age of 16 years (2007), she underwent genetic testing for NDM\n\nand was diagnosed with a KCNJ11 gene mutation (R201H genotype).\n\nDifferential diagnosis\n\nShe was diagnosed and treated as type 1 diabetes mellitus with MDI of insulin. Due to her onset of diabetes, a suspicion of NDM was raised and proven by genetic testing.\n\nTreatment\n\nAt age of 16, She was admitted to the hospital to facilitate transfer from insulin therapy to SU (glibenclamide) as per guidelines.2 She was taking Insulatard 24 units daily, Novorapid 2–3 units for breakfast and 9–10 units before dinner. She initially experienced nausea when she started glibenclamide and was treated with motilium. She persisted with SU therapy and was discharged home on a dose of 0.5 mg/kg/day. This was further increased as outpatient to 1 mg/kg/day, she weighed 68 kg. Insulin therapy was never fully discontinued as she continued to take small doses of Novorapid premeals. And due to persistent elevation of her basal glucose levels, she was started on insulin detemir four units BD. She was tolerating the glibenclamide well, but in view of the fact that she had to inject insulin, she decided that she would prefer to just inject insulin and stopped the glibenclamide.\n\nFour years later, she was referred to our adult service in 2011. Her diabetes was poorly controlled with an average HbA1C of 65–75 mmol/mol throughout the preceding years. She had a history of two hospital admissions due to symptomatic hypoglycaemic. Her only diabetic complication was background diabetic retinopathy, first diagnosed at age 19 years.\n\nHowever, at the age of 24 years (2015), after attending a NDM meeting in Exeter, she wanted to retry SUs. Her HbA1C was 63 mmol/mol and her total daily dose of insulin was 50 units at that time. She was successfully transitioned to glibenclamide 0.44 mg/kg/day resulting in optimal diabetes control with a fall in HbA1C to 44 mmol/mol over 2 years (figure 2). Her C-peptide level was 28 pmol/L postprandially—pre glibenclamide and 1680 pmol/L postprandially after starting glibenclamide.\n\nFigure 2 HbA1C trend over years (2011–2020) demonstrating marked improvement with glibenclamide.\n\nOutcome and follow-up\n\nShe was maintained on glibenclamide 15 mg po bd, the control of her blood sugar readings remained excellent with infrequent episodes of hypoglycaemic as shown in figure 3 demonstrating her daily patterns of glucose readings using libre freestyle over 2 weeks in 2017 on glibenclamide 15 mg po bd, with HBAIC of 44 mmol/mol in 2017. The hypoglycemic episodes shown on the sensor data were not associated with symptoms and only detected by the sensor. Glibenclamide was increased to 0.57 mg/kg/day (20 mg po bd) in September 2019 as her HbA1C rose to 57 mmol/mol when she was stressed at work with an inconsistent routine and eating more carbohydrate. Her HbA1C rose to 61 mmol/mol in January 2020. She has subsequently reduced glibenclamide to 15 mg po bd in February 2020 because she was experiencing symptomatic hypoglycaemic at night 8–10 hours after exercise on the higher dose. Her HbA1C dropped to 51 mmol/mol in March 2020. Apart from background diabetic retinopathy, she has no microvascular complications of diabetes. Her weight reduced from 69.7 kg in 2015 to 64 kg in 2020. After 24 years on insulin therapy, the patient’s quality of life is much improved with SU. She was following up every 3–6 months at diabetes centre—The Mater Misericordiae University Hospital, with marked improvement and control in her blood sugar readings and HbA1c levels.\n\nFigure 3 Daily patterns of glucose readings using libre freestyle over 2 weeks in 2017 on glibenclamide 15 mg po bd.\n\nDiscussion\n\nThe beta cells of the pancreas have a large number of glucose transporters (GLUT 2) that allow glucose influx into the beta cells at a rate that is proportional to blood glucose concentration. The glucose goes through physiological processes which ends in the formation of ATP. An increase in ATP leads to closure of ATP-sensitive potassium channels of the cell, with resultant depolarisation of the cell membrane thereby producing an influx of calcium that stimulate insulin secretion.3 ATP-sensitive potassium channels are composed of eight protein subunits including the family of Kir6.x (eg, Kir6.2) and the SUR. Heterozygous activating mutations in KCNJ11, which is the gene responsible for (Kir6.2) transcription, impairs the ability of ATP to close the channel; thereby inhibiting insulin secretion and leading to NDM.\n\nDiabetes mellitus is an etiologically heterogeneous disorder, often classified into polygenic or monogenic disorders. Only 1%–2% of cases are secondary to a single gene mutation (monogenic). NDM is defined as diabetes that occurs within the first 6 months of life. Most cases of NDM are sporadic resulting from de novo mutations. The most common genetic cause of permanent NDM is an activating mutation in KCNJ11.4 Unless genetic testing is considered, this type of diabetes can be misdiagnosed as type 1 diabetes. The distinction between NDM and type 1 diabetes is crucial, as it informs treatment decisions (insulin vs SUs), understanding of associated conditions and surveillance of complications.1 2 NDM due to a mutation in KCNJ11 can be subdivided into two subgroups, those who had only diabetes and those who had diabetes and shared neurologic abnormalities. Low birth weight is a characteristic of most patients, as noticed in our patient. Developmental delay, muscle weakness, epilepsy and dysmorphic features (prominent metopic suture, a downturned mouth and bilateral ptosis) can also be features.5\n\nThe majority of cases of KCNJ11 mutations (approximately 90%) can be transferred from insulin to oral SUs, leading to better glycaemic control, as is demonstrated in our case. The response to SUs is explained by the ability of the drug to close the mutant ATP-sensitive potassium channels, thereby increasing insulin secretion in response to glucose metabolism.2 While the majority of reported successfully transferred patients are children, the excellent response to SUs at the age of 24 years in our case supports the principle that the beta cells can survive and respond to SUs treatment even after decades of exogenous insulin treatment.4 6 In a retrospective cohort study of 58 individuals with NDM due to KCNJ11 mutations identified through the University of Chicago,6 the authors conclude that patients require higher doses of SUs if it was initiated at an older age, with 10/17 patients who initiated SU therapy after the age of 13 years requiring additional therapy to achieve glycaemic control. This can be explained by the age-related loss of beta cells. It was suggested that the beta cell population is established at a very young age, with decreasing proliferation occurring with increasing age during childhood.7 Despite this, previous studies,8 and our case, demonstrate that age should not be a contraindication to transition. The mutation subtype can also influence the success of transition to SUs and required dose (low vs high dose); variable response to SUs was observed from different genetic subtypes of KCNJ11 mutation including the R201H genotype of our case.9\n\nIn our case, the failure of the initial attempt to transition to SU therapy at age 16 highlights the complexities of diabetes management in this age group, while the successful transition at age 24 using an identical protocol emphasises the importance of reassessing treatment regimes in young adulthood. Puberty is very challenging in a child with diabetes. In puberty, several factors may contribute to poor glycaemic control; first, lean body mass doubles in a small period of time, so insulin requirement is increased. Second, insulin resistance is increased during the pre- and pubertal period. Third, certain behavioural changes occurring during adolescence may worsen glycaemic control.10 This may explain why transition to glibenclamide in our patient failed at age of 16. In patients with NDM, the dose of glibenclamide should be increased as the teenager grows. So, during puberty, high dose of glibenclamide (0.5–1 mg/kg/day) is usually used. Increasing the dose in NDM is safe and is unlikely to cause any increase in hypoglycaemic risk, unlike in type 2 diabetes mellitus.11 However, postprandial hypoglycaemic is reported by patients with KCNJ11 on SU treatment due an inability to modulate insulin secretion in response to low carbohydrate meals. For that reason, it is recommended that affected patients avoid missed meals or meals lacking carbohydrate while on SU treatment.12\n\nEvidence is lacking regarding the most appropriate treatment of affected women with NDM during pregnancy. Usually, the choice to transfer to insulin is considered preconception but, if done too close to pregnancy, unstable glycaemic control can have potential consequences regarding fetal outcome. If the foetus inherits a KATP NDM mutation from their mother they have greatly reduced insulin secretion in utero that reduces fetal growth by ~900 g. Treating the mother with glibenclamide in the third trimester treats the affected foetus in utero, normalising fetal growth, but is not desirable, especially in the high doses used in this condition, if the foetus is unaffected. Our patient has been advised to attend our pre pregnancy clinic when she is planning pregnancy.\n\nIn summary, NDM secondary to KCNJ11 mutation should be considered in patients with diabetes mellitus diagnosed within the first 6 months of life. Often patients exhibit better glycaemic responses to SUs compared with MDI of insulin thereby improving quality of life and lowering the incidence of diabetes complications. In our case, the successful transition to SU at age 24 years highlights the importance of attempting transfer to SU in adult diabetic clinics, even if this failed during puberty.\n\nLearning points\n\nNeonatal diabetes mellitus (NDM) secondary to KCNJ11 mutation should be considered in patients with diabetes mellitus diagnosed within the first 6 months of life.\n\nPatients with NDM exhibit better glycaemic responses to sulfonylureas (SU) compared with multiple daily injections of insulin.\n\nThe importance of attempting transfer patient with NDM to SU in adult diabetic clinics, even if this failed during puberty.\n\nTwitter: @dr_sulaiman_h\n\nContributors: SH was directly involved in patient care, conception and design by SH and KA; data interpretation by SH, KA and AG; report was written by SH, KA, AG and MB. All authors have contributed to the manuscript editing.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Naylor RN, Greeley SAW, Bell GI, et al . Genetics and pathophysiology of neonatal diabetes mellitus. J Diabetes Investig 2011;2 :158–69. 10.1111/j.2040-1124.2011.00106.x\n2 Pearson ER, Flechtner I, Njølstad PR, et al . Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006;355 :467–77. 10.1056/NEJMoa061759 16885550\n3 Akrouh A, Halcomb SE, Nichols CG, et al . Molecular biology of K(ATP) channels and implications for health and disease. IUBMB Life 2009;61 :971–8. 10.1002/iub.246 19787700\n4 Greeley SAW, Zielinski MC, Poudel A. Case Report: Preservation of Reduced Numbers of Insulin-Positive Cells in Sulfonylurea-Unresponsive KCNJ11 -related Diabetes. J Clin Endocrinol Metab 2016;102 :2821–6.\n5 Gloyn AL, Pearson ER, Antcliff JF, et al . Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004;350 :1838–49. 10.1056/NEJMoa032922 15115830\n6 Thurber BW, Carmody D, Tadie EC, et al . Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes. Diabetologia 2015;58 :1430–5. 10.1007/s00125-015-3593-9 25877689\n7 Gregg BE, Moore PC, Demozay D, et al . Formation of a human β-cell population within pancreatic islets is set early in life. J Clin Endocrinol Metab 2012;97 :3197–206. 10.1210/jc.2012-1206 22745242\n8 Malecki MT, Skupien J, Klupa T, et al . Transfer to sulphonylurea therapy in adult subjects with permanent neonatal diabetes due to KCNJ11-activating [corrected] mutations: evidence for improvement in insulin sensitivity. Diabetes Care 2007;30 :147–9. 10.2337/dc06-1628 17192350\n9 Babiker T, Vedovato N, Patel K, et al . Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes. Diabetologia 2016;59 :1162–6. 10.1007/s00125-016-3921-8 27033559\n10 Chowdhury S. Puberty and type 1 diabetes. Indian J Endocrinol Metab 2015;19 :51–4. 10.4103/2230-8210.155402\n11 Bowman P, Sulen Åsta, Barbetti F, et al . Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study. Lancet Diabetes Endocrinol 2018;6 :637–46. 10.1016/S2213-8587(18)30106-2 29880308\n12 Bowman P, McDonald TJ, Knight BA, et al . Patterns of postmeal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-KATP-channel pathways. BMJ Open Diabetes Res Care 2019;7 :e000721. 10.1136/bmjdrc-2019-000721\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "14(4)",
"journal": "BMJ case reports",
"keywords": "diabetes; genetics",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D003920:Diabetes Mellitus; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying; D011788:Quality of Life; D013453:Sulfonylurea Compounds; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33837025",
"pubdate": "2021-04-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15115830;17192350;27802092;24843477;19787700;29880308;22745242;31908791;25877689;16885550;27033559;25941652",
"title": "Successful transition from insulin to sulfonylurea, on second attempt, in a 24-year-old female with neonatal diabetes secondary to KCNJ11 gene mutation.",
"title_normalized": "successful transition from insulin to sulfonylurea on second attempt in a 24 year old female with neonatal diabetes secondary to kcnj11 gene mutation"
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"companynumb": "IE-MYLANLABS-2021M1040420",
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"abstract": "Blockade of programmed cell death-1 (PD-1) has become one of the most promising immunotherapies for many human cancers. However, immune-related adverse events can be produced by anti-PD-1 therapy. Uveitis is a rare but potentially devastating side effect of anti-PD-1 therapy. Delay in diagnosis or improper treatment may eventually lead to irreversible blindness. Therefore, it is important for the oncologist and the ophthalmologist to recognize and manage this adverse event properly in patients receiving anti-PD-1 therapy in a timely manner. Here we present a grade 4 panuveitis with bilateral serous retinal detachment following treatment with nivolumab for metastatic renal cell carcinoma. Oral prednisone, topical steroid eye drops, periorbital injection of steroid and finally intravitreal injection of steroid implant were administered in our patient. We observed that intravitreal injection of dexamethasone implant, but not the periorbital injection of steroid or the steroid eye drops, was effective to control the posterior uveitis and serous retinal detachment. Oral prednisone was also effective, but it might affect the efficacy of anti-PD-1 therapy and promote tumor growth. We also summarize 15 cases of uveitis reported to date related to nivolumab or pembrolizumab therapy in the present study. The symptoms, signs, potential underlying mechanisms and treatment options regarding this adverse event are discussed.",
"affiliations": "Department of Ophthalmology and Vision Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai, 200031, China.;Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Ophthalmology and Vision Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai, 200031, China. linglingchen98@hotmail.com.",
"authors": "Wang|Wei|W|;Lam|Wai-Ching|WC|;Chen|Ling|L|http://orcid.org/0000-0003-2430-8432",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00262-018-2260-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-7004",
"issue": "68(1)",
"journal": "Cancer immunology, immunotherapy : CII",
"keywords": "Anti-PD-1; Dexamethasone implant; Retinal detachment; Uveitis",
"medline_ta": "Cancer Immunol Immunother",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D008875:Middle Aged; D000077594:Nivolumab; D015864:Panuveitis; D012163:Retinal Detachment",
"nlm_unique_id": "8605732",
"other_id": null,
"pages": "85-95",
"pmc": null,
"pmid": "30311026",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent grade 4 panuveitis with serous retinal detachment related to nivolumab treatment in a patient with metastatic renal cell carcinoma.",
"title_normalized": "recurrent grade 4 panuveitis with serous retinal detachment related to nivolumab treatment in a patient with metastatic renal cell carcinoma"
} | [
{
"companynumb": "CN-MYLANLABS-2019M1010713",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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"drugadditional": "3",... |
{
"abstract": "To describe retinal arterial occlusion and vasculitis following intravitreal brolucizumab administration in a patient with neovascular age-related macular degeneration (nAMD).\nAn 88-year-old Caucasian woman with neovascular age-related macular degeneration (nAMD) complained of painless loss of vision with light sensitivity in both eyes (OU) four weeks after bilateral intravitreal brolucizumab. Upon examination, her visual acuity decreased to 20/40 in the right eye (OD) and 20/50 in the left eye (OS). Examination revealed 0.5+ and 1+ anterior chamber cells in OD and OS, respectively. The patient was treated with 1% prednisolone acetate eyedrops in both eyes, and after several weeks, the anterior chamber cells resolved. However, the patient still reported a decline in visual acuity (VA). Fluorescein angiography (FA) revealed retinal arterial occlusion, vasculitis, and optic nerve inflammation in the left eye. Retinal intra-arterial grayish materials were also detected. Laboratory evaluations were performed for common infectious and inflammatory causes and were normal or negative. A delayed inflammatory reaction to brolucizumab was suspected as the cause of the ocular inflammation and retinal vasculitis. An intravitreal dexamethasone implant was inserted into the left eye to treat the inflammation. One week after the dexamethasone implant, VA improved to 20/40 in OU; FA showed improvement, but residual peri-vascular leakage remained.\nMedication-associated uveitis is a rare adverse effect that can lead to vision loss. The index report illustrates a case of intraocular inflammation, retinal arterial vaso-occlusion and vasculitis associated with intravitreal brolucizumab. The delay in developing uveitis suggests that the inflammation is due to a delayed hypersensitivity reaction which can occur several days or weeks after administration of the inciting agent. Recently, several cases of uveitis and vasculitis associated with brolucizumab have been presented and those cases have similar features compared to the index case (1). Therapy with steroids (either intraocular or systemic), after infectious etiologies have been excluded, may be beneficial in halting inflammation and preventing further vision loss.",
"affiliations": "Southwest Eye Consultants, Durango, CO, USA.;Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Sierra Eye Associates, Reno, NV, USA.",
"authors": "Haug|Sara J|SJ|;Hien|Doan Luong|DL|;Uludag|Gunay|G|;Ngoc|Than Trong Tuong|TTT|;Lajevardi|Sherin|S|;Halim|M Sohail|MS|;Sepah|Yasir J|YJ|;Do|Diana V|DV|;Khanani|Arshad M|AM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100680",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30051-7\n10.1016/j.ajoc.2020.100680\n100680\nCase Report\nRetinal arterial occlusive vasculitis following intravitreal brolucizumab administration\nHaug Sara J. shaug@sweyeconsultants.coma∗ Hien Doan Luong b Uludag Gunay b Ngoc Than Trong Tuong b Lajevardi Sherin bc Halim M. Sohail bd Sepah Yasir J. bd Do Diana V. b Khanani Arshad M. ef a Southwest Eye Consultants, Durango, CO, USA\nb Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USA\nc University of California, Davis, CA, USA\nd Ocular Imaging Research and Reading Center (OIRRC), Sunnyvale, USA\ne Sierra Eye Associates, Reno, NV, USA\nf University of Nevada, Reno, NV, USA\n∗ Corresponding author.Southwest Eye Consultants, 270 East 8th Avenue, N-101, Durango, Colorado, USA. shaug@sweyeconsultants.com\n31 3 2020 \n6 2020 \n31 3 2020 \n18 10068022 3 2020 27 3 2020 28 3 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/).Purpose\nTo describe retinal arterial occlusion and vasculitis following intravitreal brolucizumab administration in a patient with neovascular age-related macular degeneration (nAMD).\n\nObservation\nAn 88-year-old Caucasian woman with neovascular age-related macular degeneration (nAMD) complained of painless loss of vision with light sensitivity in both eyes (OU) four weeks after bilateral intravitreal brolucizumab. Upon examination, her visual acuity decreased to 20/40 in the right eye (OD) and 20/50 in the left eye (OS). Examination revealed 0.5+ and 1+ anterior chamber cells in OD and OS, respectively. The patient was treated with 1% prednisolone acetate eyedrops in both eyes, and after several weeks, the anterior chamber cells resolved. However, the patient still reported a decline in visual acuity (VA). Fluorescein angiography (FA) revealed retinal arterial occlusion, vasculitis, and optic nerve inflammation in the left eye. Retinal intra-arterial grayish materials were also detected. Laboratory evaluations were performed for common infectious and inflammatory causes and were normal or negative. A delayed inflammatory reaction to brolucizumab was suspected as the cause of the ocular inflammation and retinal vasculitis. An intravitreal dexamethasone implant was inserted into the left eye to treat the inflammation. One week after the dexamethasone implant, VA improved to 20/40 in OU; FA showed improvement, but residual peri-vascular leakage remained.\n\nConclusion\nMedication-associated uveitis is a rare adverse effect that can lead to vision loss. The index report illustrates a case of intraocular inflammation, retinal arterial vaso-occlusion and vasculitis associated with intravitreal brolucizumab. The delay in developing uveitis suggests that the inflammation is due to a delayed hypersensitivity reaction which can occur several days or weeks after administration of the inciting agent. Recently, several cases of uveitis and vasculitis associated with brolucizumab have been presented and those cases have similar features compared to the index case (1). Therapy with steroids (either intraocular or systemic), after infectious etiologies have been excluded, may be beneficial in halting inflammation and preventing further vision loss.\n\nKeywords\nOcclusive vasculitisRetinal vasculitisIntraocular inflammationBrolucizumabAge-related macular degeneration\n==== Body\n1 Introduction\nIntravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the gold standard for the treatment of various retinal vascular diseases including neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO). Brolucizumab is the latest FDA-approved anti-VEGF agent that was shown to be non-inferior to aflibercept in visual acuity outcomes in the pivotal HAWK and HARRIER clinical trials.2 In the phase 3 clinical trials of brolucizumab for nAMD, ocular inflammation was reported to be higher in the brolucizumab group compared to aflibercept (1.4–2.2% vs 0–0.3%, respectively), but no cases of retinal vasculitis were reported.1 More recently, there have been reports of inflammation, vasculitis, and arterial occlusions associated with brolucizumab in post-marketing surveillance.1,3\n\nWe herein report a case of a patient with neovascular AMD who developed ocular inflammation and occlusive retinal vasculitis in both eyes (OU) one month after intravitreal brolucizumab administration.\n\n2 Case report\nAn 88-year-old Caucasian woman with active neovascular AMD complained of painless decreased vision and light sensitivity in OU, four weeks after receiving her first intravitreal brolucizumab therapy (6 mg/0.05 ml) in OU. Her medical history was significant for Type 2 diabetes without retinopathy, nephropathy, or neuropathy. She had no medical history of hyperlipidemia or myocardial infarction. Surgical history was significant only for pacemaker placement and cataract extraction with posterior chamber intraocular lenses in OU. Current medications include atenolol, levothyroxine and warfarin. Family history and detailed review of systems were noncontributory. Prior to receiving brolucizumab, the patient had received bevacizumab in right eye (OD) in 2014 and was switched to ranibizumab in 2016. The left eye (OS) progressed to nAMD in 2017 and also received ranibizumab. In total, 26 intravitreal injections of ranibizumab were given in OD and 21 intravitreal injections of ranibizumab in OS. The decision to switch to brolucizumab was made given the persistent subretinal fluid, particularly in OD.\n\nOn examination four weeks after brolucizumab injection, visual acuity (VA) had decreased from 20/30 to 20/40 in OD and from 20/25 to 20/50 in OS. Intraocular pressure (IOP) was within normal limits in OU. Anterior chamber evaluation revealed 0.5+ and 1+ cells in OD and OS, respectively. Posterior examination revealed drusen and retina pigment epithelial (RPE) changes in OU, with patchy atrophy in OD but no evidence of posterior inflammation or vitritis. Comparing OCT images from before brolucizumab injection to images at current presentation, there was a reduction in subretinal fluid, OD > OS (Fig. 1A and B). The patient was started on prednisolone acetate 1% drops four times daily for the anterior inflammation in OU. Over the next two weekly follow-up visits, the anterior chamber cells resolved and the subretinal fluid continued to improve in OD (Fig. 1C). However, the patient reported persistent decline in VA and started to experience flashing lights in OS. Examination revealed supratemporal retinal vessel sheathing in OD (Fig. 2A) and temporal retinal vessel sheathing and superior optic nerve edema in OS (Fig. 3A); there were discrete intra-arterial grayish materials in OS. Fluorescein angiography was performed and revealed arteriovenous occlusion and vasculitis with vascular and superior optic nerve leakage in OS (Fig. 3C). A delayed inflammatory reaction to brolucizumab was suspected. An extensive work up including complete blood counts, C-reactive protein, erythrocyte sedimentation rate, c-ANCA, p-ANCA, angiotensin converting enzyme, lysozyme, Quantiferon Gold, syphilis screen, herpes simplex and varicella zoster IgG and IgM were conducted and all were negative or within normal limits. Hemoglobin A1C was 6.0%. Chest X-ray and urinalysis were also within normal limits. Intravitreal dexamethasone implant was inserted in OS to decrease the intraocular inflammation. One week after dexamethasone implant placement, VA improved to 20/40 in OU and repeated FA showed improved but persistent peri-vascular and optic disc leakage (Fig. 3F). At two weeks, repeated FA showed resolved peri-vascular and optic disc leakage; however, the temporal retinal artery occlusion remained (Fig. 3H).Fig. 1 Optical coherence tomography (Spectralis; Heidelberg Engineering, Heidelberg, Germany) of the right (OD) and left (OS) eyes. Before intravitreal brolucizumab injection in both eyes (row A), after 4 weeks (row B), after 6 weeks (row C), after 8 weeks and before intravitreal dexamethasone implant in OS (row D), two weeks post-intravitreal dexamethasone implant (row E).\n\nFig. 1Fig. 2 Fundus photos and fluorescein angiography of the right eye (RE) 8 weeks after intravitreal brolucizumab (top row), one weeks later (middle row) and two weeks later (bottom row) showing area of pigmentary changes (A and C), supratemporal retinal vessel sheathing (black arrow-A). Staining of a segment of the superior arcade retinal arterial (white arrow) is noted in the late phase, (C and F) which resolved spontaneously after 2 weeks (I).\n\nFig. 2Fig. 3 Fundus photos and fluorescein angiography of the left eye 8 weeks after intravitreal brolucizumab and before intravitreal dexamethasone implant (top row), showing discrete intraarterial grayish materials (gold arrows-A), retinal vessel sheathing and superior optic nerve edema (blue arrow-A) and vasculitis with vascular and superior optic nerve leakage (white arrow-C). One week after dexamethasone implant (middle row), sheathing of temporal retinal arcade and superior optic nerve edema (blue arrow-D) were still present. Much improved but persistent peri-vascular and optic disc leakage, and temporal retinal vaso-obliteration in the late phase (white arrow-F) with visible intraarterial grayish materials (black arrow-F). At two weeks (bottom row) the inferior temporal retinal artery showed delayed filling (red arrow-H) compared to the superior temporal retinal artery (green arrow-H) and intraarterial blockages in late phase (black arrow-I). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\n3 Discussion\n3.1 Generating a diagnosis\nWe have presented a case of an 88-year-old female with nAMD who developed bilateral intraocular inflammation after intravitreal brolucizumab. Initially, both eyes presented with mild anterior uveitis without posterior involvement. Subsequently, within two weeks, the left eye displayed posterior involvement with retinal intra-arterial deposition of grayish materials and vasculitis which progressed to vascular occlusion. The differential diagnosis for occlusive retinal vasculitis includes systemic vasculitis and connective tissue diseases such as Adamantiades-Behçet's disease, multiple sclerosis, granulomatosis with polyangiitis, and systemic lupus erythematosus, among others. There are also common infectious etiologies which can lead to occlusive vasculitis including tuberculosis, herpes, and syphilis.\n\nIn this index case, there were neither retinochoroidal lesions, systemic manifestation, nor abnormalities in blood evaluation to suggest a systemic or infectious etiology. The excellent response to steroidal implant further excluded infectious causes. Another possibility is Eales disease which is a bilateral idiopathic obliterative vasculopathy that usually involves the peripheral retina of young male adults. Middle-age female patients diagnosed with unilateral Eales disease have been reported to have occlusive disease4; however, in our patient there was no evidence of retinal vein involvement and peripheral neovascularization. Given the timely manner of the occurrence and exclusion of other possibilities, this index patient was diagnosed with possible delayed or type IV hypersensitivity to brolucizumab. The patient had received multiple intravitreal ranibizumab treatments previously in both eyes without any sequelae.\n\n3.2 Delayed-type hypersensitivity\nHypersensitivity reactions after anti-VEGF therapy have been reported, mostly type I hypersensitivity reactions due to substances used during intravitreal injection5,6 and type IV or delayed-type hypersensitivity reactions to the anti-VEGF agent itself.7,8 It is important to recognize type IV reaction as it usually happens later than other types of reactions and can become more severe during re-challenge.\n\nIn the CATT trial, the percentage of ocular adverse events including uveitis, scleritis, and anterior chamber inflammation were 0.3%–0.7% in ranibizumab and bevacizumab groups, respectively.9 In the HAWK and HARRIER studies, uveitis was noted in 5 (1.4%), 8 (2.2%) and 1 (0.3%) cases in brolucizumab 3 mg, brolucizumab 6 mg and aflibercept 2 mg group, respectively.2 In addition to commonly seen adverse events (AEs), the frequency of intraocular inflammation noted was relatively high in those clinical trials compared to what has been reported for ranibizumab and aflibercept.2,9,10 As described in the studies, intraocular inflammation included anterior chamber flare, anterior chamber inflammation, iritis, iridocyclitis, vitreous haze, vitritis, and choroiditis.2,10, 11, 12 Most of these intraocular inflammations were categorized as mild to moderate and were treated with a course of topical corticosteroid/anti-infective agents.2 Based on the reports of phase 2 and 3 clinical trials, brolucizumab was well tolerated and the safety profile of ocular and non-ocular AEs were comparable to ranibizumab and aflibercept(2, 10–12). To date, the most frequently reported ocular AEs related to brolucizumab treatment are conjunctival hemorrhage, vitreous floaters, reduced visual acuity and eye pain.2,10,11\n\n3.3 Why does ocular inflammation happen with intravitreal brolucizumab?\nThe present case is the first published report of arteriovenous occlusion with vasculitis, possible type IV hypersensitivity reaction, after intravitreal brolucizumab for the treatment of nAMD. Brolucizumab is a humanized, single-chain variable fragment that is no longer dependent on a heavy molecular support structure but still retains full binding capacity to its target. These molecules are composed of the monoclonal antibody's variable light and heavy chain domains tethered by a flexible linker, resulting in a small protein fragment of ~26 kDa,11,13,14 which is the smallest of the anti-VEGF antibodies evaluated in humans. The brolucizumab molecule is substantially smaller than aflibercept and ranibizumab, which have molecular masses of 97–115 kDa and 48 kDa, respectively. Such a size difference gives brolucizumab theoretically better target-tissue penetration and therefore higher concentration which allows up to 6 mg of brolucizumab in a single 50-μL intravitreal injection, which is considered 11 to 22 times greater than what can be clinically administered for aflibercept and ranibizumab, respectively.11\n\nTo protect visual function, the eye has special mechanisms to prevent invasion of infectious agents and inflammation through anatomical mechanisms and cytokines responses.15 Anatomical mechanisms, such as lack of efferent lymphatics and the presence of the blood–retinal barrier, protect the eye from toxic substances. In addition, oral and intravenous drugs achieve therapeutic levels in intraocular tissues16 whereas mechanisms involving cytokines, such as upregulation of tumor growth factor-beta (TGF-β) and alpha-neuropeptide [alpha-melanocyte stimulating hormone (α-MSH)], prevent inflammation by various mechanisms. It suppresses IFN-γ production,17 activates regulatory T cells and suppresses delayed-type hypersensitivity-mediating T cells.18 Furthermore, it suppresses the innate immunity and the interface between innate and adaptive immunity19 and also promotes immune privilege in the posterior segment.20 The ocular immune privilege has been known for more than 100 years and was first noted by Van Dooremal. In 1873, he observed the growth of tumor cells implanted into the anterior chamber of rabbit's eyes. However, when such tumor cells were placed elsewhere in a rabbit's body, they showed significantly less or even no signs of growth. The finding suggested a different immune response in the eye compared to other regions of the body.21 Seventy five years later, ocular immune privilege was first defined experimentally by Medawar and his colleagues by placing skin and/or other types of grafts in the anterior chamber of the eye and the brain22,23. They defined immune privilege as a tissue site that supports prolong survival of histo-incompatible tissue grafts. Subsequently, this phenomenon was termed Anterior Chamber–Associated Immune Deviation (ACAID). High doses of intravitreal foreign protein may not be a concern if these defense mechanisms are intact. The index patient had diabetes (concurrent with AMD) which is one of known causes of inner blood–retinal barrier breakdown and increase in inflammatory cytokines.24 It can be hypothesized that the combination of intravitreal high concentration of protein with diseases resulting in an increase of inflammatory markers such as diabetes, in particular, and even in systemic vasculitic diseases, connective tissue diseases, or any preceding intraocular inflammation may outweigh the protective mechanisms, which ultimately leads to an inflammatory response inside the vessels (such as accumulation of immune complexes) along the vessel wall where the plasma is in contact with the foreign protein. In addition, pericytes and endothelial cells are likely the earliest cells to die in diabetic retinopathy with vascular occlusion.25 Therefore, vasculitis in such condition may lead to severe vascular occlusion.\n\nOn February 23, 2020, the American Society of Retina Specialists (ASRS) provided a statement to its members on reported cases of ocular inflammation since the FDA approval of brolucizumab on October 7, 2019. Up to that date, the ASRS has received reports of inflammation following brolucizumab administration. In addition to cases of mild-moderate intraocular inflammation, these reports have included 14 cases of vasculitis, of which 11 were designated as occlusive retinal vasculitis by the reporting providers. The ASRS indicated that “some cases of occlusive vasculitis may initially be subtle or present in a delayed fashion.” Novartis, the manufacturer of brolucizumab, is compiling reported cases of inflammation post brolucizumab administration in the real world and is providing safety updates on www.brolucizumab.info.\n\n3.4 Treatment\nIt is important to detect early type IV hypersensitivity reactions. They are distinguished from other hypersensitivity reactions by the lag time from exposure to the antigen until the response is evident (1–3 days) or in some cases it can be up to 6 weeks before symptoms and clinical findings present.7 In this case, visual disturbances and anterior reactions were noted and persisted four weeks after injections in OU. Vaso-occlusion and vasculitis OS mainly involved retinal arteries and foci of vasculitis detected on FA after eight weeks. Given the potential for severe vision loss in the left eye, immediate treatment while waiting for evaluation was warranted. Local steroid seemed appropriate in this situation. There are several options including periocular and intravitreal corticosteroids with triamcinolone acetate, corticosteroid implants with or dexamethasone or fluocinolone acetonide. In cases of bilateral involvements or persistence after dexamethasone intravitreal implants, systemic steroid (if diabetic control is not a concern) may be administered and pars plana vitrectomy may be considered to reduce the anti-VEGF load and increase clearance.\n\nHowever, there remains a clinically important question: if the patient has recurrent choroidal neovascularization (CNV) activity, should the patient be treated again with brolucizumab or with another anti-VEFG or PDT? Currently, Novartis recommends withholding additional brolucizumab if intraocular inflammation has occurred after its use. If CNV activity has responded to therapy with another anti-VEGF agent without any observed intraocular inflammation, then one can consider resuming that agent. In addition, the patient can elect to undergo formal allergy evaluation with intradermal or other testing.\n\n4 Conclusion\nIn conclusion, medication-associated uveitis is a rare adverse effect of drug administration that can typically induce mild to severe intraocular inflammation that can lead to different severity of visual loss. Being vigilant to the potential ocular inflammation that can occur with anti-VEGF therapy, evaluating patients urgently if they develop new symptoms post injection, early evaluation of other underlying causes of inflammation, immediate cessation of the offending agent, and prompt employment of topical, local and/or systemic corticosteroids to control the inflammation may lead to stabilization and prevention of further visual loss.\n\nPatient consent\nVerbal and written consents have been obtained from the patient.\n\nFunding\nResearch to Prevent Blindness Departmental Challenge Award and National Eye Institute of the National Institutes of Health P30 Grant (EY026877) have been awarded to the Byers Eye Institute at Stanford University.\n\nAuthorship\nAll authors attest that they met the current ICMJE criteria.\n\nDeclaration of competing of interest\nThe authors declare that there are no conflicts of interest related to this article.\n==== Refs\nReferences\n1 Dugel P.U. Expanded week 96 safety outcomes: analysis of pooled data from HAWK & HARRIER studies Presented at the 2020 Meeting of the Macula Society, March 19 to 22, San Diego, California 2017 \n2 Dugel P.U. Koh A. Ogura Y. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration Ophthalmology 127 1 2020 72 84 30986442 \n3 Nguyen Q.D. Das A. Do D.V. Brolucizumab: evolution through preclinical and clinical studies and the implications for the management of neovascular age-related macular degeneration [published online ahead of print, 2020 Jan 17] Ophthalmology 2020 S0161-6420(20)30041-5 \n4 Nicolcescu A. Mocanu C. Dinu L. Olaru A. Ionete M. Stefanescu D.A. Unilateral Eales' disease a case report Rom J Ophthalmol 61 2 2017 144 149 29450389 \n5 Veramme J. de Zaeytijd J. Lambert J. Lapeere H. Contact dermatitis in patients undergoing serial intravitreal injections Contact Dermatitis 74 1 2016 18 21 26489693 \n6 Kleris R.S. Keswani A. Lugar P. The eyes have it: eyelid swelling and rash in a 79-year-old woman with macular degeneration Allergy & rhinology (Providence, RI) 9 2018 2152656718763385 \n7 Nagai N. Ibuki M. Shinoda H. Kameyama K. Tsubota K. Ozawa Y. Maculopapular rash after intravitreal injection of an antivascular endothelial growth factor, aflibercept, for treating age-related macular degeneration: a case report Medicine (Baltim) 96 21 2017 e6965-e \n8 Meredith G.G. Schkade P.A. Joondeph B.C. Allergic reaction UPON intravitreal administration OF anti-vascular endothelial growth factor Agents Retin Cases Brief Rep 13 3 2019 287 289 28301410 \n9 Ranibizumab and bevacizumab for neovascular age-related macular degeneration N Engl J Med 364 20 2011 1897 1908 21526923 \n10 Dugel P.U. Jaffe G.J. Sallstig P. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: a randomized trial Ophthalmology 124 9 2017 1296 1304 28551167 \n11 Holz F.G. Dugel P.U. Weissgerber G. Single-chain antibody fragment vegf inhibitor RTH258 for neovascular age-related macular degeneration: a randomized controlled study Ophthalmology 123 5 2016 1080 1089 26906165 \n12 Semeraro F. Morescalchi F. Duse S. Parmeggiani F. Gambicorti E. Costagliola C. Aflibercept in wet AMD: specific role and optimal use Drug Des Dev Ther 7 2013 711 722 \n13 Auf der Maur A. Escher D. Barberis A. Antigen-independent selection of stable intracellular single-chain antibodies FEBS Lett 508 3 2001 407 412 11728462 \n14 Thiel M.A. Coster D.J. Standfield S.D. Penetration of engineered antibody fragments into the eye Clin Exp Immunol 128 1 2002 67 74 11982592 \n15 de Andrade F.A.F.S. Benchimol E.I. Fiorot S.H. Provenzano J. Martins V.J. Levy R.A. The autoimmune diseases of the eyes Autoimmun Rev 15 2016 258 271 26655327 \n16 Smith R.S. Rudt L.A. Ocular vascular and epithelial barriers to microperoxidase Invest Ophthalmol Vis Sci 14 7 1975 556 560 \n17 Taylor A.W. Streilein J.W. Cousins S.W. Alpha-melanocyte-stimulating hormone suppresses antigen-stimulated T cell production of gamma-interferon Neuroimmunomodulation 1 3 1994 188 194 7489333 \n18 Taylor A.W. Modulation of regulatory T cell immunity by the neuropeptide alpha-melanocyte stimulating hormone Cell Mol Biol 49 2 2003 143 149 12887097 \n19 Nishida T. Miyata S. Itoh Y. Anti-inflammatory effects of alpha-melanocyte-stimulating hormone against rat endotoxin-induced uveitis and the time course of inflammatory agents in aqueous humor Int Immunopharm 4 8 2004 1059 1066 \n20 Taylor A.W. Alpha-melanocyte stimulating hormone (alpha-MSH) is a post-caspase suppressor of apoptosis in RAW 264.7 macrophages PloS One 8 8 2013 e74488 \n21 Van Dooremall J.C. Die entwicklung der in fremden grund versetzten lebenden gewebe Albrecht Von Graefes Arch Ophthalmol 19 1873 358 373 \n22 Medawar P.B. A second study of the behaviour and fate of skin homografts in rabbits: a Report to the War Wounds Committee of the Medical Research Council J Anat 79 Pt 4 1945 157 1576.4 \n23 Medawar P.B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye Br J Exp Pathol 29 1 1948 58 69 18865105 \n24 Kwon J.-W. Jee D. Aqueous humor cytokine levels in patients with diabetic macular edema refractory to anti-VEGF treatment PloS One 13 9 2018 e0203408-e \n25 Shin E.S. Sorenson C.M. Sheibani N. Diabetes and retinal vascular dysfunction J Ophthalmic Vis Res 9 3 2014 362 373 25667739\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "18()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Age-related macular degeneration; Brolucizumab; Intraocular inflammation; Occlusive vasculitis; Retinal vasculitis",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "100680",
"pmc": null,
"pmid": "32258827",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "18865105;28538392;29977647;29450389;26906165;23990705;30986442;30204781;28551167;28301410;12887097;25667739;32107066;806549;15222980;17104981;7489333;11982592;11728462;21526923;26655327;24009773;26489693",
"title": "Retinal arterial occlusive vasculitis following intravitreal brolucizumab administration.",
"title_normalized": "retinal arterial occlusive vasculitis following intravitreal brolucizumab administration"
} | [
{
"companynumb": "NVSC2020US102241",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BROLUCIZUMAB-DBLL"
},
"drugadditional": "4",
... |
{
"abstract": "Epoprostenol, a synthetic prostaglandin I2 (PGI2) analog, has been the mainstay of treatment for severe pulmonary arterial hypertension (PAH) for the last two decades. Treprostinil, another synthetic prostaglandin analog, and selexipag, an oral selective Inositol Phosphate (IP) prostacyclin receptor agonist, have also been approved for treatment of PAH. Prostacyclin and its analogs cause a variety of side effects in patients with PAH; however, thyroid dysfunction is rarely reported.\n\n\n\nAfter treating an index case of thyroid dysfunction occurring after initiation of epoprostenol, we reviewed our databases of PAH patients treated with epoprostenol, treprostinil or selexipag to identify the occurrence of this association.\n\n\n\nWe identified six cases of thyroid dysfunction in our cohort: five after initiation of an intravenous prostacyclin (epoprostenol) and one after initiation of an oral prostacyclin receptor agonist (selexipag). Four of the patients presented with hyperthyroidism and two with a large autoimmune goiter. Graves' disease was seen in three patients, Hashimoto's disease in two patients and thyrotoxicosis in one patient.\n\n\n\nTherapy with medications targeting the prostacyclin pathway is a potential risk factor for the development of symptomatic thyroid disease.",
"affiliations": "Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. aamenon@bwh.harvard.edu.;Houston Methodist Hospital Lung Center, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX, USA.;Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, MA, USA.;Pulmonary, Critical Care and Sleep Medicine, Tufts University Medical Center, Boston, MA, USA.",
"authors": "Menon|Aravind A|AA|0000-0002-0211-4509;Sahay|Sandeep|S|;Braverman|Lewis E|LE|;Farber|Harrison W|HW|",
"chemical_list": "D000081:Acetamides; D000959:Antihypertensive Agents; D011719:Pyrazines; C523468:selexipag; D011464:Epoprostenol",
"country": "United States",
"delete": false,
"doi": "10.1007/s00408-019-00283-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0341-2040",
"issue": "197(6)",
"journal": "Lung",
"keywords": "Epoprostenol; Hyperthyroidism; Prostanoids; Pulmonary hypertension; Selexipag",
"medline_ta": "Lung",
"mesh_terms": "D000081:Acetamides; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents; D011464:Epoprostenol; D005260:Female; D006042:Goiter; D006111:Graves Disease; D050031:Hashimoto Disease; D006801:Humans; D006980:Hyperthyroidism; D008297:Male; D000081029:Pulmonary Arterial Hypertension; D011719:Pyrazines; D013967:Thyroiditis, Autoimmune; D013971:Thyrotoxicosis",
"nlm_unique_id": "7701875",
"other_id": null,
"pages": "761-768",
"pmc": null,
"pmid": "31696306",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": "21546436;26699168;19837821;4310087;11399743;8053614;20152223;12234951;18572079;23474667;2675123;12426269;8532025;23041000;26320113;26219978;11035704;20631450;22136263;28890480;18506008;11401596;12446266;19289321;19386333;24371842;3543972;2444991;22112709;2107780;10555089;10559121;12578873;17646607;10733441;11999999;3023225",
"title": "Thyroid Dysfunction in Patients with Pulmonary Artery Hypertension (PAH): The Effect of Therapies Affecting the Prostanoid Pathway.",
"title_normalized": "thyroid dysfunction in patients with pulmonary artery hypertension pah the effect of therapies affecting the prostanoid pathway"
} | [
{
"companynumb": "US-TEVA-2019-US-1160119",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPOPROSTENOL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy and safety of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma (MM), who previously responded to bortezomib.\n\n\nMETHODS\nRetrospective analysis of 76 MM patients, who had achieved at least a partial response (PR) on initial bortezomib therapy in our hospital from May 2006 to August 2011, received bortezomib retreatment when they relapsed or progressed.\n\n\nRESULTS\nThe overall response rate (ORR) was 60.5%, among them 6.5% patients achieved CR, 5.8% patients achieved very good partial response (VGPR), 38.2% patients achieved PR. Then we further stratified all patients into 3 groups according to the response of initial bortezomib therapy, including CR group, VGPR group and PR group. After bortezomib retreatment, the ORR of the 3 groups was 84.6%, 73.1% and 43.2%, respectively. According to the response of bortezomib retreatment, the patients were divided into 2 groups: group 1 who at least achieved PR, group 2 who showed no response. The median progression-free survival (PFS) after bortezomib retreatment for group 1 and 2 was 7(1-39) and 5(1-14) months, respectively (P>0.05), while the median overall survival (OS) after bortezomib retreatment was 16(2-64) and 8(1-28) months, respectively (P<0.05). Adverse events (AE) were identified in 88% patients during bortezomib retreatment, including neutropenia, diarrhea and thrombocytopenia, only 9.2%(7 patients) reached Ⅲ-Ⅳ grade of AE. Severe peripheral neuropathy occurred in only one patient.\n\n\nCONCLUSIONS\nBortezomib retreatment regimen is demonstrated a higher response rate in patients who achieved deeper response in initial treatment, with no more adverse events.",
"affiliations": "Department of Hematology, The Second Military Medical University, Shanghai, China.",
"authors": "Lu|Jing|J|;Hou|Jian|J|;Zhang|Chun-yang|CY|;Yuan|Zhen-gang|ZG|;Lan|Hai-feng|HF|;Zhou|Fan|F|;Fan|Jian-ling|JL|;Zhou|Li-li|LL|;Du|Juan|J|;Jiang|Hua|H|;Jin|Li-na|LN|;Zeng|Tian-mei|TM|;Fu|Wei-jun|WJ|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0253-2727.2013.04.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-2727",
"issue": "34(4)",
"journal": "Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi",
"keywords": null,
"medline_ta": "Zhonghua Xue Ye Xue Za Zhi",
"mesh_terms": "D000328:Adult; D000368:Aged; D001897:Boronic Acids; D000069286:Bortezomib; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8212398",
"other_id": null,
"pages": "309-12",
"pmc": null,
"pmid": "23668202",
"pubdate": "2013-04",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "The efficacy and safety analysis of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma.",
"title_normalized": "the efficacy and safety analysis of bortezomib retreatment in 76 patients with relapsed refractory multiple myeloma"
} | [
{
"companynumb": "CN-TAKEDA-2016MPI007713",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": "3",
... |
{
"abstract": "Osteoradionecrosis is one of many potentially severe complications of radiotherapy for nasopharyngeal carcinoma. Osteoradionecrosis of the skull base is life-threatening due to the critical proximity of the pathological process to vital structures, for example, the intracranial cavity, the upper spine, and major blood vessels. Reconstructive options following surgical debridement of the anterior skull base and upper spine osteonecrosis have been scarcely described in the literature.\nWe present a rare case of osteoradionecrosis of the clivus and cervical vertebrae C1-C2 in a patient previously treated with chemoradiotherapy for nasopharyngeal carcinoma, presenting as severe soft tissue infection of the neck. Aggressive surgical debridement and reconstruction with a two-paddle free anterolateral thigh flap was performed using a combination of transcervical and transnasal endoscopic approaches. A novel endoscopic procedure in the sphenoid sinus enabled flap anchoring in this complex area.\nSurgical modalities for osteoradionecrosis of the skull base and upper spine are discussed and review of the literature is presented.\nReconstruction of the anterior skull base with a well-vascularized free flap following ablative surgery should be considered in management of life-threatening osteoradionecrosis of the area. Endoscopic opening of the sphenoid sinus and creating a funnel-shaped stem is a newly described technique that guarantees precise placement of the flap and is a valuable adjunct to the reconstructive armamentarium.",
"affiliations": "Department of Plastic, Reconstructive and Hand Surgery, Hebrew University School of Medicine, Hadassah Medical Center, Jerusalem, Israel.;Department of Otolaryngology / Head and Neck Surgery, Hebrew University School of Medicine, Hadassah Medical Center, Jerusalem, Israel.;Department of Otolaryngology / Head and Neck Surgery, Hebrew University School of Medicine, Hadassah Medical Center, Jerusalem, Israel.;Department of Plastic, Reconstructive and Hand Surgery, Hebrew University School of Medicine, Hadassah Medical Center, Jerusalem, Israel.",
"authors": "Chapchay|Katya|K|https://orcid.org/0000-0001-9193-9280;Weinberger|Jeffrey|J|;Eliashar|Ron|R|;Adler|Neta|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0003489419865558",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4894",
"issue": "128(12)",
"journal": "The Annals of otology, rhinology, and laryngology",
"keywords": "anterolateral thigh flap; endoscopic sinus surgery; nasopharyngeal carcinoma; osteoradionecrosis; skull base reconstruction",
"medline_ta": "Ann Otol Rhinol Laryngol",
"mesh_terms": "D002574:Cervical Vertebrae; D059248:Chemoradiotherapy; D003388:Cranial Fossa, Posterior; D003646:Debridement; D004724:Endoscopy; D058752:Free Tissue Flaps; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D010025:Osteoradionecrosis; D019651:Reconstructive Surgical Procedures",
"nlm_unique_id": "0407300",
"other_id": null,
"pages": "1134-1140",
"pmc": null,
"pmid": "31353927",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Anterior Skull Base Reconstruction following Ablative Surgery for Osteoradionecrosis: Case Report and Review of Literature.",
"title_normalized": "anterior skull base reconstruction following ablative surgery for osteoradionecrosis case report and review of literature"
} | [
{
"companynumb": "IL-MYLANLABS-2019M1123741",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Necrotising autoimmune myopathy (NAM) is an immune-mediated myopathy that may be associated with statin use, malignancy or an autoimmune connective tissue disease, but it can also be idiopathic. Anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy is an extremely rare side effect of statin use, occurring in approximately 2-3 out of every 100 000 patients who use statins. Patients typically present with subacute proximal muscle weakness and creatine kinase levels >10 times the upper limit of normal. The diagnosis is suggested by muscle biopsy showing necrotic fibres with minimal inflammation along with positive anti-HMGCR antibodies. Treatment nearly always requires multiple immunosuppressive agents, the earlier use of which is associated with improved outcomes. Reports of statin-induced NAM leading to heart failure are limited. We present the case of a 69-year-old woman with statin-induced NAM who presented with acute systolic heart failure. Early initiation of high-dose corticosteroids and IVIG resulted in significant improvement in her symptoms.",
"affiliations": "Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Rheumatology, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Pitlick|Mitchell|M|;Ernste|Floranne|F|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D000069059:Atorvastatin; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D003402:Creatine Kinase; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(5)",
"journal": "BMJ case reports",
"keywords": "drugs: musculoskeletal and joint diseases; heart failure; musculoskeletal syndromes; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D000069059:Atorvastatin; D003402:Creatine Kinase; D005260:Female; D054143:Heart Failure, Systolic; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases; D008775:Methylprednisolone; D018908:Muscle Weakness; D009135:Muscular Diseases; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31068355",
"pubdate": "2019-05-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25855481;16980718;26192196;30026996;29480216;19813188;27752355;30364043;30221193;29691272;23519993;29651118;25765229;30464165;24268006;26886523",
"title": "Anti-HMGCR myopathy presenting with acute systolic heart failure.",
"title_normalized": "anti hmgcr myopathy presenting with acute systolic heart failure"
} | [
{
"companynumb": "PHHY2019US125437",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Infectious scleritis by Pseudomonas aeruginosa is a well-known vision-threatening disease. In particular, scleral trauma following pterygium surgery may increase the risk of sclera inflammation. Surgical debridement and repair is necessary in patients who do not respond to medical treatments, such as topical and intravenous antibiotics. We reports herein the effectiveness of an autologous perichondrium conchal cartilage graft for infectious scleritis caused by Pseudomonas aeruginosa. This procedure was performed on four eyes of four patients with infectious scleritis who had previously undergone pterygium surgery at Gyeongsang National University Hospital (GNUH), Jinju, Korea from December 2011 to May 2012. Pseudomonas aeruginosa was identified in cultures of necrotic scleral lesion before surgery. The conchal cartilage perichondrium graft was transplanted, and a conjunctival flap was created on the scleral lesion. The autologous perichondrium conchal cartilage graft was successful and visual outcome was stable in all patients, with no reports of graft failure or infection recurrence. In conclusion, autologous perichondrium conchal cartilage graft may be effective in surgical management of Pseudomonal infectious scleritis when non-surgical medical treatment is ineffective. Further studies in larger, diverse populations are warranted to establish the effectiveness of the procedure.",
"affiliations": "Department of Ophthalmology, Gyeongsang National University College of Medicine, Jinju, Korea.;Department of Ophthalmology, Gyeongsang National University College of Medicine, Jinju, Korea.;Department of Ophthalmology, Gyeongsang National University College of Medicine, Jinju, Korea.;Department of Otolaryngology, Gyeongsang National University College of Medicine, Jinju, Korea.;Department of Ophthalmology, Gyeongsang National University College of Medicine, Jinju, Korea.;Department of Ophthalmology, Gyeongsang National University College of Medicine, Jinju, Korea.;Gyeongsang Institute of Health Science, Gyeongsang National University, Jinju, Korea.",
"authors": "Yoo|Woong Sun|WS|;Kim|Che Ron|CR|;Kim|Byung Jae|BJ|;Ahn|Seong Ki|SK|;Seo|Seong Wook|SW|;Yoo|Ji Myong|JM|;Kim|Seong Jae|SJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2015.56.6.1738",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 2644666210.3349/ymj.2015.56.6.1738Case ReportOphthalmologySuccessful Treatment of Infectious Scleritis by Pseudomonas aeruginosa with Autologous Perichondrium Graft of Conchal Cartilage Yoo Woong Sun 1Kim Che Ron 1Kim Byung Jae 1Ahn Seong Ki 2Seo Seong Wook 13Yoo Ji Myong 13Kim Seong Jae 131 Department of Ophthalmology, Gyeongsang National University College of Medicine, Jinju, Korea.2 Department of Otolaryngology, Gyeongsang National University College of Medicine, Jinju, Korea.3 Gyeongsang Institute of Health Science, Gyeongsang National University, Jinju, Korea.\nCorresponding author: Dr. Seong Jae Kim, Department of Ophthalmology, College of Medicine; and Gyeongsang Institute of Health Science, Gyeongsang National University, 79 Gangnam-ro, Jinju 52727, Korea. Tel: 82-55-750-8171, Fax: 82-55-758-4158, maya12kim@naver.com01 11 2015 25 9 2015 56 6 1738 1741 26 6 2014 02 9 2014 16 10 2014 © Copyright: Yonsei University College of Medicine 20152015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Infectious scleritis by Pseudomonas aeruginosa is a well-known vision-threatening disease. In particular, scleral trauma following pterygium surgery may increase the risk of sclera inflammation. Surgical debridement and repair is necessary in patients who do not respond to medical treatments, such as topical and intravenous antibiotics. We reports herein the effectiveness of an autologous perichondrium conchal cartilage graft for infectious scleritis caused by Pseudomonas aeruginosa. This procedure was performed on four eyes of four patients with infectious scleritis who had previously undergone pterygium surgery at Gyeongsang National University Hospital (GNUH), Jinju, Korea from December 2011 to May 2012. Pseudomonas aeruginosa was identified in cultures of necrotic scleral lesion before surgery. The conchal cartilage perichondrium graft was transplanted, and a conjunctival flap was created on the scleral lesion. The autologous perichondrium conchal cartilage graft was successful and visual outcome was stable in all patients, with no reports of graft failure or infection recurrence. In conclusion, autologous perichondrium conchal cartilage graft may be effective in surgical management of Pseudomonal infectious scleritis when non-surgical medical treatment is ineffective. Further studies in larger, diverse populations are warranted to establish the effectiveness of the procedure.\n\nScleritisPseudomonas aeruginosaear cartilageautograftGyeongsang National University HospitalGNUHBRIF-2014-0003\n==== Body\nINTRODUCTION\nScleritis is an ocular inflammatory disease with variety of clinical presentations and etiologic factors. Etiologic factors of scleritis vary from idiopathic to autoimmune to infectious.12 However, infectious scleritis is rare, occurring in about 5-10% of all cases, and typically occurs following trauma or surgery, most commonly pterygium surgery.23 As reported previously in India,2 Taiwan3 and western country,4 infectious scleritis had various etiologies, and the most common causative organism of infectious scleritis is Pseudomonas aeruginosa, which has a particularly poor prognosis. Inappropriate treatment of Pseudomonal infectious scleritis may cause severe thinning and melting of the sclera, leading to even eye perforation, and resulting in endophthalmitis and blindness.234\n\nA variety of non-surgical strategies are used for infectious scleritis caused by bacteria, including systemic, topical, and subconjunctival antibiotics, as well as antibiotic-containing wound irrigation solutions.5 However, medical therapy alone is effective only in 18% of cases, as most cases require surgical debridement.4 In the last decade, many tissues and synthetic materials have been used as reconstructive materials, e.g., sclera, cornea, dermis, autologous fascia lata, and Gore-Tex. However, no universally acceptable material has yet been identified. Conchal cartilage has been used in the field of otolaryngology such as septoplasty and ophthalmological procedures such as tarsal reconstruction, and it provided good functional and mechanical integrity in the reconstructed lesion.6 This case report describes the use of autologous perichondrium conchal cartilage graft in four patients with Pseudomonal infectious scleritis.\n\nCASE REPORT\nWe described herein four eyes of four patients who underwent autologous perichondrium conchal cartilage grafts from December 2011 to May 2012 at Gyeongsang National University Hospital (GNUH), Jinju, Korea. This study was approved by the GNUH Institutional Review Board and conducted in accordance with the tenets of the Declaration of Helsinki.\n\nThree women (aged 77, 61, and 78 years, respectively) and one man (aged 69 years) were enrolled in our study. None of the patients had systemic disease, and all eyes had a history of pterygium excision surgery approximately 10 years ago in 3 patients and 20 years ago in 61-year-old patient, but no specific previous ocular history otherwise. Before referred to our center, all eyes were treated with topical moxifloxacin 0.5% and tobramycin and without any systemic or topical steroid therapy at local clinics. According to Snellen visual acuity, initial best corrected visual acuity (BCVA) were 20/25, 20/20, 20/25, and 20/63, respectively. Intraocular pressure was in the normal range for all patients. Slit lamp examination showed scleral melting with calcified plaque and subconjunctival abscesses (Table 1).\n\nBefore the procedure, patients' scleras were scraped from the base of the active lesion for culture and smears, and then stained with Gram and potassium hydroxide (KOH). In all cases, Gram stain revealed Gram negative rod organisms and negative KOH stains. Initially, moxifloxacin 0.5% (Vigamox®, Alcon, TX, USA) and topical fortified ceftazidime (Tazime®, Hanmi, Seoul, Korea) were applied in every hour, and intravenous ceftazidime (50 mg/mL) were administered twice a day, because of strong suspicion of Pseudomonas infection. However, surgery was ultimately recommended because these non-surgical treatments did not improve the scleral lesions, as shown by scleral thinning and melting along with subconjunctival abscesses. The scleral lesions were cultured before surgery, and Pseudomonas aeruginosa was found in all cultures.\n\nFor graft surgery, perichondrium was obtained by otolaryngologists under local anesthesia. The planned area of dissection was marked, and the posterior surface of the auricular cartilage was incised. The dissection was performed down to the perichondrium level and preceded medially above the auricular perichondrium. Auricular cartilage was obtained, leaving the perichondrium attached to the posterior cartilage surface. The incision of subcutaneous tissue and skin was approximated with sutures. The perichondrium was peeled from the cartilage and designed. Ophthalmologic surgery was performed under retrobulbar anesthesia. Necrotized sclera tissues were removed to expose the normal sclera. After defining the borders of the surgical bed to be reinforced, the perichondrium of ear cartilage was fashioned to the appropriate size and thickness. The graft was secured to the edges of the resection site using interrupted 10-0 nylon sutures and covered with a conjunctival flap obtained from the surrounding site by using 10-0 nylon sutures (Fig. 1). On the day after surgery, moxifloxacin 0.5%, topical fortified ceftazidime, and intravenous ceftazidime (50 mg/mL) were administered and then gradually tapered off according to the treatment effect.\n\nNo recurrence was noted after surgery in all cases until last follow up (Fig. 2). The final BCVA were 20/20, 20/20, 20/20, and 20/25, respectively.\n\nDISCUSSION\nAlthough the scleral inflammatory pathways have been investigated in several studies,78 the exact pathogenic mechanisms are not completely clear. However, a disordered immune response leads to both tissue and blood vessel damage, and scleral trauma after surgery may further increase the risk of sclera inflammation and necrosis.49\n\nThe epidemiology of infectious scleritis is complex and varies greatly, depending on geographic region.234 In developing countries, fungal etiologies are more common, related to difference in climate.2 However, two large retrospective studies in United States4 and Taiwan3 showed that infectious scleritis caused by bacteria such as Pseudomonas aeruginosa is the most common form in developed countries, accounting for about 85% of all bacterial scleritis cases. Medical management of infectious scleritis includes systemic, topical, and subconjunctival antibiotics, as well as wound irrigation with an antibiotic solution.5 However, most cases require surgical debridement, as only 18% of cases are sufficiently treated with medical therapy alone.4\n\nMany tissues and synthetic materials have been used as reconstructive materials in the last decade,10 including sclera, cornea, dermis, autologous fascia lata, and Gore-Tex, although no universally acceptable materials have been identified. Togo, et al.11 suggested that cells harvested from ear cartilage differentiate into cartilage cells, fat cells, and osteocytes. Thus, the mesodermal stem cells in the ear cartilage perichondrium may be a valuable candidate for surgical management of infectious scleritis due to fast vessel formation and graft re-epithelialization, which promotes successful graft stabilization.\n\nAutologous perichondrium of conchal cartilage grafting had favorable surgical outcomes in our four cases of infectious scleritis caused by Pseudomonas aeruginosa. The structural integrity of the globe was ultimately preserved, the grafts showed good vascularization and epithelialization, visual acuity remained stable, and no graft failures were reported following this management.\n\nIn conclusion, autologous conchal cartilage perichondrium grafts maintained functional and structural integrity of the globe and resulted in successful cosmetic and visual outcomes in four cases of infectious scleritis caused by Pseudomonas aeruginosa. Further studies, such as cohort studies, comparative observational studies, and clinical trials, involving a larger number of patients, are warranted to further assess the success of this novel surgical technique for surgical management of Pseudomonal infectious scleritis.\n\nACKNOWLEDGEMENTS\nThis work was supported by Biochemical Research Institute funds (grant no. GNUHBRIF-2014-0003) from the Gyeongsang National University Hospital (Jinju, Korea).\n\nThe authors have no financial conflicts of interest.\n\nFig. 1 Intraoperative photographs of the transplantation of perichondrium of conchal cartilage graft. (A) After debridement, necrotic and melted sclera tissue is shown. (B) Perichondrium is harvested from patient's conchal cartilage. (C) The perichondrium graft (asterisk) was transplanted over the sclera defect and sutured with 10-0 nylon sutures. (D) Conjunctival flap over the perichondrium graft is shown.\nFig. 2 Photographs of the Pseudomonal infectious scleritis cases. (A, B, and C) Patient 1. (D, E, and F) Patient 2. (G, H, and I) Patient 3. (J, K, and L) Patient 4. (A, D, G, and J) In cases before surgery, severe conjunctival injection and scleral melting with calcified plaque deposits are shown. (B, E, H, and K) Intraoperative photograph of cases shows transplantated perichondrium of conchal cartilage (asterisk) over melting scleral lesion. (C, F, I, and L) After transplantation of perichondrium and conjunctival flap, lesions revealed a structurally and cosmetically stable appearance.\nTable 1 Demographics and Clinical Findings of 4 Patients with Pseudomonal Infectious Scleritis Treated with Autologous Perichodrium Graft of Conchal Cartilage\nCase\tGender/age\tType of scleritis\tPrior surgery\tTime between prior surgery and onset (yrs)\tSymptoms\tSigns\tInitial BCVA\tFinal BCVA\tInitial IOP (mm Hg)\tFinal IOP (mm Hg)\t\n1\tF/77\tNecrotizing\tPterygium excision\t10\tOcular pain\tScleral melting\t20/25\t20/20\t15\t16\t\nCalcified plaque\t\n2\tF/61\tNecrotizing\tPterygium excision\t20\tOcular pain\tScleral melting\t20/20\t20/20\t14\t17\t\nCalcified plaque\t\n3\tF/78\tNecrotizing\tPterygium excision\t10\tOcular pain\tScleral melting\t20/25\t20/20\t11\t13\t\nCalcified plaque\t\n4\tM/69\tNecrotizing\tPterygium excision\t10\tOcular pain\tScleral melting\t20/63\t20/25\t12\t16\t\nCalcified plaque\t\nM, male; F, female; BCVA, best corrected visual acuity; IOP, intraocular pressure.\n==== Refs\n1 Shang Y Han S Li J Ren Q Song F Chen H The clinical feature of Behçet's disease in Northeastern China Yonsei Med J 2009 50 630 636 19881965 \n2 Jain V Garg P Sharma S Microbial scleritis-experience from a developing country Eye (Lond) 2009 23 255 261 18219336 \n3 Ho YF Yeh LK Tan HY Chen HC Chen YF Lin HC Infectious scleritis in Taiwan-a 10-year review in a tertiary-care hospital Cornea 2014 33 838 843 24977990 \n4 Hodson KL Galor A Karp CL Davis JL Albini TA Perez VL Epidemiology and visual outcomes in patients with infectious scleritis Cornea 2013 32 466 472 22902495 \n5 Lin CP Shih MH Tsai MC Clinical experiences of infectious scleral ulceration: a complication of pterygium operation Br J Ophthalmol 1997 81 980 983 9505823 \n6 Parodi PC Calligaris F De Biasio F De Maglio G Miani F Zeppieri M Lower lid reconstruction utilizing auricular conchal chondralperichondral tissue in patients with neoplastic lesions Biomed Res Int 2013 2013 837536 23865069 \n7 Watson P Romano A The impact of new methods of investigation and treatment on the understanding of the pathology of scleral inflammation Eye (Lond) 2014 28 915 930 24875228 \n8 Watson P Hazleman BL McCluskey P Favesio CE The sclera and systemic disorders 3rd ed London JP Medical Ltd. 2012 \n9 Paula JS Simão ML Rocha EM Romão E Velasco Cruz AA Atypical pneumococcal scleritis after pterygium excision: case report and literature review Cornea 2006 25 115 117 16331053 \n10 Nguyen QD Foster CS Scleral patch graft in the management of necrotizing scleritis Int Ophthalmol Clin 1999 39 109 131 10083910 \n11 Togo T Utani A Naitoh M Ohta M Tsuji Y Morikawa N Identification of cartilage progenitor cells in the adult ear perichondrium: utilization for cartilage reconstruction Lab Invest 2006 86 445 457 16625212\n\n",
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"affiliations": "Department of Internal Medicine, Mayo Clinic, Rochester, USA.",
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"abstract": "OBJECTIVE\nBoth paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent cancer of the cervix, and the combination of these two agents has shown activity and possible synergism in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent cervical cancer to evaluate its activity.\n\n\nMETHODS\nThirty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m2 administered intravenously over a 3-hour period followed by cisplatin 75 mg/m2 administered intravenously with granulocyte colony-stimulating factor support. The chemotherapy was administered every 3 weeks for a maximum of six courses.\n\n\nRESULTS\nSixteen patients (47%; 95% confidence interval, 30% to 65%) achieved an objective response, including five complete responses and 11 partial responses. Responses occurred in 28% of patients with disease within the radiation field only and in 57% of patients with disease involving other sites. The median duration of response was 5.5 months, and the median times to progression and survival for all patients were 5 and 9 months, respectively. Grade 3 or 4 toxicities included anemia in 18% of patients and granulocytopenia in 15% of patients. Fifty-three percent of patients developed some degree of neurotoxicity; 21% of cases were grade 2 or worse.\n\n\nCONCLUSIONS\nThe combination of paclitaxel with cisplatin seems relatively well tolerated and moderately active in patients with metastatic or recurrent cervical cancer. The significant incidence of neurotoxicity is of concern, and alternative methods of administration of the two agents could be evaluated. Then, further study of this combination, alone or with the addition of other active agents, is warranted.",
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"abstract": "Tetrahydrobiopterin (BH4) is a cofactor that participates in the biogenesis reactions of a variety of biomolecules, including l-tyrosine, l-3,4-dihydroxyphenylalanine, 5-hydroxytryptophan, nitric oxide, and glycerol. Dihydropteridine reductase (DHPR, EC 1.5.1.34) is an enzyme involved in the BH4 regeneration. DHPR deficiency (DHPRD) is an autosomal recessive disorder, leading to severe and progressive neurological manifestations, which cannot be exclusively controlled by l-phenylalanine (l-Phe) restricted diet. In fact, the supplementation of neurotransmitter precursors is more decisive in the disease management, and the administration of sapropterin dihydrochloride may also provide positive effects. From the best of our knowledge, there is limited information regarding DHPRD in the past 5 years in the literature. Here, we describe the medical journey of the first patient to have DHPRD confirmed by molecular diagnostic methods in Brazil. The patient presented with two pathogenic variants of the quinoid dihydropteridine reductase (QDPR) gene-which codes for the DHPR protein, one containing the in trans missense mutation c.515C>T (pPro172Leu) in exon 5 and the other containing the same type of mutation in the exon 7 (c.635T>C [p.Phe212Ser]). The authors discuss their experience with sapropterin dihydrochloride for the treatment of DHPRD in this case report.",
"affiliations": "Centro Universitário Estácio de Ribeirão Preto São Paulo Brazil.;Centro Universitário Estácio de Ribeirão Preto São Paulo Brazil.;Centro Universitário Estácio de Ribeirão Preto São Paulo Brazil.;Centro Universitário Estácio de Ribeirão Preto São Paulo Brazil.;Centro Universitário Estácio de Ribeirão Preto São Paulo Brazil.;Centro Paulista de Diagnóstico e Pesquisa em Genética Clínica São Paulo Brazil.;Laboratório DLE Bioquímica Genética Rio de Janeiro Brazil.;Centro Universitário Estácio de Ribeirão Preto São Paulo Brazil.;Division of Metabolism University Children's Hospital Zürich Switzerland.",
"authors": "Lourenço|Charles Marques|CM|https://orcid.org/0000-0002-2296-6098;Dovidio|Janaina|J|;Lopes|Isabela F|IF|;Silva|Laís C|LC|;Almeida|Marcela|M|;Vagnini|Laura|L|;Fonseca|Jacqueline|J|;Carneiro|Zumira A|ZA|;Thöny|Beat|B|",
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"fulltext": "\n==== Front\nJIMD Rep\nJIMD Rep\n10.1002/(ISSN)2192-8312\nJMD2\nJIMD Reports\n2192-8304\n2192-8312\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n10.1002/jmd2.12224\nJMD212224\nCase Report\nCase Reports\nSapropterin dihydrochloride therapy in dihydropteridine reductase deficiency: Insight from the first case with molecular diagnosis in Brazil\nLourenço et al.\nLourenço Charles Marques https://orcid.org/0000-0002-2296-6098\n1 charlesgenetica@gmail.com\n\nDovidio Janaina 1\nLopes Isabela F. 1\nSilva Laís C. 1\nAlmeida Marcela 1\nVagnini Laura 2\nFonseca Jacqueline 3\nCarneiro Zumira A. 1\nThöny Beat 4\n1 Centro Universitário Estácio de Ribeirão Preto São Paulo Brazil\n2 Centro Paulista de Diagnóstico e Pesquisa em Genética Clínica São Paulo Brazil\n3 Laboratório DLE Bioquímica Genética Rio de Janeiro Brazil\n4 Division of Metabolism University Children's Hospital Zürich Switzerland\n* Correspondence\nCharles Marques Lourenço, MD, PhD, Centro Universitário Estácio de Ribeirão Preto, Rua Abrahão Issa Halach, 980, Ribeirânia, 14096‐160, Ribeirão Preto, São Paulo, Brazil.\nEmail: charlesgenetica@gmail.com\n\n05 5 2021\n9 2021\n61 1 10.1002/jmd2.v61.1 1924\n03 4 2021\n03 12 2020\n19 4 2021\n© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nTetrahydrobiopterin (BH4) is a cofactor that participates in the biogenesis reactions of a variety of biomolecules, including l‐tyrosine, l‐3,4‐dihydroxyphenylalanine, 5‐hydroxytryptophan, nitric oxide, and glycerol. Dihydropteridine reductase (DHPR, EC 1.5.1.34) is an enzyme involved in the BH4 regeneration. DHPR deficiency (DHPRD) is an autosomal recessive disorder, leading to severe and progressive neurological manifestations, which cannot be exclusively controlled by l‐phenylalanine (l‐Phe) restricted diet. In fact, the supplementation of neurotransmitter precursors is more decisive in the disease management, and the administration of sapropterin dihydrochloride may also provide positive effects. From the best of our knowledge, there is limited information regarding DHPRD in the past 5 years in the literature. Here, we describe the medical journey of the first patient to have DHPRD confirmed by molecular diagnostic methods in Brazil. The patient presented with two pathogenic variants of the quinoid dihydropteridine reductase (QDPR) gene—which codes for the DHPR protein, one containing the in trans missense mutation c.515C>T (pPro172Leu) in exon 5 and the other containing the same type of mutation in the exon 7 (c.635T>C [p.Phe212Ser]). The authors discuss their experience with sapropterin dihydrochloride for the treatment of DHPRD in this case report.\n\nBH4 deficiency\ndihydropteridine reductase (DHPR) gene\nhyperphenylalaninemia\nl‐DOPA\ntetrahydrobiopterin\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:02.09.2021\nLourençoCM, DovidioJ, LopesIF, et al. Sapropterin dihydrochloride therapy in dihydropteridine reductase deficiency: Insight from the first case with molecular diagnosis in Brazil. JIMD Reports. 2021;61 :19–24. 10.1002/jmd2.12224\n\nCommunicating Editor: Peter Burgard\n==== Body\npmc Synopsis\n\nDHPR deficiency leads to severe and progressive neurological manifestations, which can be controlled by l‐Phe‐restricted diets in association with the administration of dopaminergic agonists. Sapropterin dihydrochloride alone was able to prevent the neurodevelopmental delay progression in the absence of a l‐Phe‐restricted diet.\n\n1 INTRODUCTION\n\nTetrahydrobiopterin (BH4) is a critical cofactor for several enzymes involved in the hydroxylation of aromatic amino acids, producing l‐tyrosine, l‐3,4‐dihydroxyphenylalanine (l‐DOPA), and 5‐hydroxytryptophan (5‐HTP). BH4 is also required for the production of nitric oxide and glycerol by different enzyme pathways. The synthesis and regeneration of BH4 is a multistage enzymatic process.1 The presence of pathogenic variants in the genes encoding these enzymes cause BH4 deficiencies, leading to a severe depletion of monoamine neurotransmitters (norepinephrine, epinephrine, dopamine, and indolamine serotonin), as well as hyperphenylalaninemia (HPA).2, 3, 4\n\nDihydropteridine reductase (DHPR, EC 1.6.99.7) is an enzyme involved in the regeneration of BH4. DHPR deficiency (DHPRD, OMIM 612676) is an autosomal recessive genetic disorder caused by mutations in the quinoid dihydropteridine reductase (QDPR) gene. This is a 7‐exon gene (NCBI numbers NG_008763.1 for genomic DNA and NM_000320.3 for cDNA), located in chromosome 4p.15.32, and it encodes the DHPR enzyme. Biallelic pathogenic variants in the QDPR gene lead to BH4‐deficient HPA and insufficient synthesis of monoamine neurotransmitters in the central nervous system (CNS).1\n\nPatients with DHPRD commonly have an early symptoms onset. The symptoms include hypotonia or trunk hypotonia, movement disorders (mainly dystonia) with distal hypertonia, parkinsonism/hypokinetic rigid syndrome (consisting of bradykinesia or hypokinesia), extrapyramidal rigidity (“cogwheel rigidity”), rest tremor, impaired motor development and cognitive impairment, irritability and mood swings, neonatal dysphagia, lethargy, delayed language acquisition, temperature‐control disorders, and myoclonic seizures.1, 5, 6\n\nThe first documented case of DHPRD was in a 14‐year‐old male patient who had seizures and neurological deterioration even while being treated for a reputed phenylketonuria, which was diagnosed at the age of 3 weeks in 1975.7 Since then, researchers have cloned the human QDPR gene and reported a phenotypic diversity, thus allowing a greater understanding of the disease and treatment options. Overall, 303 cases had been listed in the BIODEF, an international database of BH4 deficiencies, as of October 2020. Besides this, the database contains 83 variants (unfortunately not giving details on the genotype). These mutations include missense and nonsense mutations, deletions, splice site alterations, and duplications or deletion‐insertions, and are spread over the 7 exons of the QDPR gene.\n\nIn accordance with the recent consensus guidelines for the diagnosis and treatment of BH4 deficiencies,1 all patients who presented with HPA in the newborn screening test should be referred to a specialised metabolic center for further diagnosis, prompt initiation of treatment, and appropriate follow‐up. The diagnosis of BH4 deficiencies includes (a) evaluation of blood l‐Phe concentration; (b) measurement of pterins in urine or blood samples; (c) lumbar puncture for the quantification of neurotransmitters and their metabolites in the cerebrospinal fluid (CSF); (d) evaluation of the enzymatic activity involved in the synthesis and regeneration of BH4. Genetic testing of the QDPR is also recommended to confirm the diagnosis.4, 7\n\nThe first‐line treatment of DHPR includes the administration of neurotransmitter precursors l‐DOPA/DOPA‐decarboxylase inhibitors and 5‐HTP in order to normalise the levels of monoamine neurotransmitters.8, 9 Treatment should be initiated as soon as possible and most likely continued throughout the patient's lifetime.10, 11 As cerebral folate deficiency is a major finding in DHPRD, folinic acid supplementation may also be required as soon as its levels are low. The administration of folinic acid (in combination with other medications) improves motor and cognitive functioning in patients with movement disorders or epileptic seizures.1 Dopamine agonists and monoamine oxidase inhibitors can also be considered as second‐line treatment in all BH4 deficiencies in combination with first‐line therapy if residual symptoms persist. Finally, in case of proven seizures, the administration of antiseizure drugs may be needed.\n\nIt has been shown that the HPA may be controlled with l‐Phe‐restricted diets and/or supplementation with sapropterin dihydrochloride (Kuvan, BioMarin Pharmaceuticals, Novato, California), a synthetic BH4 analogue. There is evidence that the restoration of BH4 bioavailability may prevent the neurodevelopmental delay in patients with BH4 deficiency.12, 13\n\nIn the present study, we report on the first case of a patient with DHPRD confirmed by molecular diagnosis in Brazil. Interestingly, the patient presented with a milder clinical phenotype of the disease, making the diagnosis more difficult. The therapeutic management, including the effects of sapropterin dihydrochloride, is documented here.\n\n2 CASE REPORT\n\nAn 11‐year‐old male patient with young, non‐consanguineous parents was referred to a clinical geneticist to investigate hypotonia and persistent non‐phenylketonuria HPA.\n\nExcept for mild, premature placental displacement in the second month of pregnancy, no other complications occurred. There was no exposure to teratogenic agents during pregnancy. The patient was born at term by caesarean delivery in 2009. At birth, the patient's weight was 3115 g and his height was 52 cm. The APGAR evaluation was 10/10. Both the patient and mother were discharged 48 hours after the birth.\n\nThe neonatal screening test showed HPA (8.4 mg/dL, 509 μmol/L), which was confirmed in different samples. On the basis of this finding, the patient was diagnosed with phenylketonuria and was referred to an outpatient medical service for follow‐up treatment and a protein‐restricted diet was instituted.\n\nThe patient started walking at 1.3 years of age. Despite high adherence to a l‐Phe‐restricted diet, the patient's language acquisition was delayed (the first words were spoken at 2 years of age), resulting in referral to a speech therapist.\n\nAt 3 years of age, the patient had two seizure episodes accompanied by fever and cyanosis. Phenobarbital (2 mg/kg/day) was prescribed, and neuroimaging tests (computed tomography of the skull and magnetic resonance imaging of the brain) showed no evidence of abnormal activity. Electroencephalogram study showed diffuse disorganisation of the basal activity. The results were compatible with focal epilepsy.\n\nThe patient's caregivers denied that the patient had experienced any previous surgeries, other health issue, or prolonged hospitalization. No similar cases were found in the family. The caregivers stopped the l‐Phe‐restrictive diet when the patient was 3 years old because of the lack of cognitive improvement. Table 1 details the annual median of blood l‐Phe levels from 2009 to 2013. l‐Phe levels were consistently above the normal range (0.2‐4.0 mg/dL, 12‐240 μmol/L) during the evaluated period, revealing HPA.\n\nTABLE 1 Five‐year evaluations of blood l‐Phe\n\nYear of evaluation\tAnnual median ± SD (min; max)\tNumber of evaluations performed/year\t\n2009\t5.06 ± 6.5 (0.12; 16.32)\t9\t\n2010\t1.36 ± 0.75 (0.6; 2.65)\t6\t\n2011a\t1.61 ± 0.48 (0.94; 2.12)\t7\t\n2012\t3.84 ± 4.27 (0.61; 13.25)\t11\t\n2013\t4.23 ± 1.61 (2.8; 5.98)\t3\t\nNote: Tests were performed using a dried blood spot. Normal range was 0.2 to 4.0 mg/dL. SD: standard deviation; min and max: minimal and maximal obtained values, respectively.\n\na Indicates the implementation of the dihydrochloride sapropterin treatment.\n\nDue to the electroencephalographic alterations, the patient was referred to the Neurogenetics Service, where the hypothesis of a BH4 deficiency was formulated. Subsequently, the patient was subjected to an evaluation of neurotransmitters in the CSF and a DHPR activity assay, as detailed in Table 2. The diagnosis of DHPRD was confirmed by the low DHPR enzymatic activity together with the identification of two variants in the QDPR gene. More specifically, the genetic analysis was performed by PCR, followed by exon amplification of the QDPR gene, revealing that the patient is a compound heterozygote presenting two in trans missense‐mutated variants: c.515C>T (pPro172Leu) in exon 5 and c.635T>C (p.Phe212Ser) in exon 7. The first variant was inherited from the father and the second was inherited from the mother.\n\nTABLE 2 Biochemical and genetic tests by the time of diagnosis\n\nAssessment performed\tResults\t\nDHPR enzymatic activity\t0.0 (NR: 1.8 to 3.8 mU/mg Hb)\t\nPterins in CSF\tNeopterin: 20.1 (NR: 15‐35 nmol/L)\n\nBiopterin: 26 (NR: 20‐70 nmol/L)\n\n5‐MTHF: 35.2 (NR: 64‐182 nmol/L)\n\n\t\nMolecular study of QDPR gene\tc.515C>T (p.Prol172Leu) in exon 5\n\nc.635T>C (p.Phe212Ser) in exon 7\n\n\t\nAbbreviations: CSF, cerebrospinal fluid; DHPR, dihydropteridine reductase; NR, normal range; QDPR, quinoid dihydropteridine reductase; and 5MTHF, 5‐methyltetrahydrofolic acid.\n\nPhysical assessment revealed symmetrical facies with mild facial diparesis, absence of ophthalmoplegia, unaltered eye movements, presence of mild tremors during rest, preserved muscle strength, mild dysmetria, dysdiadokinesia, generalized hypotonia, hypoactivity, cutaneous‐plantar osteotendinous reflexes in flexion, and atypical gait.\n\nThe initial treatment consisted of the association of l‐DOPA and carbidopa at the respective doses of 2 and 0.5 mg/kg and supplementation with 20 mg 5‐HT and 15 mg folinic acid. When l‐DOPA was administered three times per day, the patient failed to tolerate it and the drug was withdrawn. The l‐Phe‐restricted diet was reimplemented.\n\nIn order to avoid neurodevelopmental delay, the administration of 20 mg/kg/day of sapropterin dihydrochloride started when the patient was 8 years old. Of note, sapropterin dihydrochloride remarkably reduced the blood l‐Phe levels of the patient, as shown in Figure 1. As the patient evolved with l‐DOPA‐induced dyskinetic movements, l‐DOPA was withdrawn and the dose of sapropterin dihydrochloride was increased to 30 mg/kg/day. Currently, this dose of sapropterin dihydrochloride has maintained the patient's l‐Phe blood levels within the normal range even with the absence of dietotherapy. The patient's blood level was 1.9 mg% in June 2020 (recommended range: 2‐6 mg%, dried blood spot evaluated by colorimetric enzyme assay).\n\nFIGURE 1 Three‐year blood l‐Phe evaluation. Blood l‐Phe tested from dried blood spot using tandem mass spectrometry (normal range: 25‐90.7 mcmol/L). The arrow represents the start of the 20 mg/kg/day sapropterin dihydrochloride treatment. The administration of 30 mg/kg/day was initiated in March 2019\n\n3 DISCUSSION\n\nIn the case reported here, two distinct missense mutations inherited from each progenitor were found: c.635T>C (p.Phe212Ser) in exon 7 and c.515C>T (p.Prol172Leu) in exon 5. Notably, both mutations have previously been described as pathogenic.14 Considering heritability and genetic counseling, the chances of this couple having another child affected by this disease would be 25% in each pregnancy. In this particular patient, this genotype is associated with a milder phenotype, contributing to a delayed diagnosis.\n\nThe clinical presentation can be severe, specifically in contrast to other BH4Ds; however, the phenotypic spectrum is broad and mild cases are also described in DHPRD. In this case study, the patient did not present with severe manifestations in the first year of life. After that, the patient developed dysdiadochokinesia, generalized hypotonia, hypoactive osteotendinous reflexes, and difficulty in walking.\n\nWhen HPA is detected in the newborn screening test, the evaluation of phenylalanine hydroxylase activity should be investigated in order to rule out phenylketonuria.1 In the event of HPA with unaltered activity of phenylalanine hydroxylase, dried blood spot, or urinary pterins dosage, DHPR enzyme activity must be performed, as well as lumbar puncture for the quantification of neurotransmitters and their metabolites in CSF. Genetic testing of the proband and the progenitors should also be performed; however, the testing is not already globally available. The CSF analysis can reveal reduced concentrations of the metabolites homovanillic acid and 5‐hydroxyindoleacetic acid, derived from the metabolism of dopamine and serotonin, respectively. Low levels of 5‐methyltetrahydrofolate (5‐MTHF) can also be detected.15 The investigation of pterins in CSF of the patient showed a reduced level of BH4, neopterin, and folates, which is compatible with DHPRD and this was confirmed by the molecular diagnosis. Moreover, as the clinical phenotype of BH4 deficiencies may overlap with numerous other disorders, such as cerebral palsy,16 early onset parkinsonism, oculogyric crises, and diurnal fluctuation of symptoms may be useful clinical features for differential diagnosis.1\n\nThe patient was treated with a combination of low doses of l‐DOPA and carbidopa, as well as 5‐HTP and folinic acid. It is worth noting that cases have been reported in which neonate patients with milder phenotypes were exclusively treated with restrictive diets.17 Although our patient adhered well to the diet, it was not sufficient to lower the blood l‐Phe concentration. Thus, to avoid neurological damage, the administration of monoamine neurotransmitter precursors was initiated. In spite of the treatment, the blood l‐Phe levels remained persistently increased and the patient continued to suffer seizures and neurodevelopmental delay. In fact, it has been reported that patients with DHPR may develop neurological symptoms even with blood l‐Phe levels within the normal range.6\n\nSapropterin dihydrochloride at the dose of 20 mg/kg/day was initiated to avoid neurodevelopmental delay. In parallel, the patient evolved with remarkable dyskinetic movements. However, as the patient could not tolerate the progressive staggering of the l‐DOPA doses, a combination of l‐DOPA and carbidopa was instituted. Since the administration of l‐DOPA per se can exacerbate the neurological symptoms,4 the dose of sapropterin dihydrochloride was increased to 30 mg/kg/day and the combination of l‐DOPA and carbidopa was withdrawn. Of note, this pharmacological treatment significantly reduced the dyskinetic movements and allowed the intake of natural protein in the diet. Finally, multidisciplinary monitoring with rehabilitation therapies, such as physical and occupational therapies, and psychopedagogy constituted a valuable strategy for the early detection and resolution of concerns related to the patient's disease.\n\n4 CONCLUSIONS\n\nWe have described here the first Brazilian case of DPHRD confirmed by molecular diagnosis. In spite of a high adherence to a l‐Phe‐restricted diet, the patient progressed with neurodevelopmental delay (such as delayed language acquisition) and movement disorders, which were exacerbated by the staggering of the dopaminergic agonists. Sapropterin dihydrochloride, which was initially supplemented to prevent neurodevelopmental delay, was able to control HPA and the movement disorders, allowing the intake of natural proteins in the diet. This case report reinforces the need for investigation of BH4 deficiencies in all patients with increased blood l‐Phe concentrations who evolve with neurological symptoms.\n\nCONFLICT OF INTEREST\n\nCharles M. Lourenço, Janaina Dovidio, Isabela F Lopes, Laís C Silva, Marcela Almeida, Laura Vagnini, Jacqueline Fonseca, Zumira A. Carneiro, and Beat Thöny declare no conflict of interest.\n\nACKNOWLEDGMENTS\n\nThe authors would like to thank the patient and his caregivers for sharing his medical journal. The authors also acknowledge the laboratory support by technicians Corinne Gemperle‐Britschgi (Division of Metabolism) and Anahita Rassi (Division of Clinical Chemistry and Biochemistry) at the University Children's Hospital Zürich. Financial support has been provided to support medical writing of the manuscript by BioMarin Brasil Farmacêutica Ltda., but the publication was developed independently by the authors who are entirely responsible for the scientific content of the manuscript. Camilla Patti Hissamura and Stream Medical Affairs provided medical writer services for the elaboration of this manuscript.\n\nInformed Consent\n\nAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 2013, as revised in 2000. The Ethical Committee from the Centro Universitário Estácio De Ribeirão Preto approved the study under the #170623317700005581 protocol. Written informed consent for publication of this case report and any accompanying images was obtained from the parents of the patient. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal.\n==== Refs\nREFERENCES\n\n1 OpladenT, López‐LasoE, Cortès‐SaladelafontE, et al. Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis. 2020;15 (1 ):126. 10.1186/s13023-020-01379-8.32456656\n2 LongoN. Disorders of biopterin metabolism. J Inherit Metab Dis. 2009;32 (3 ):333‐342. 10.1007/s10545-009-1067-2.19234759\n3 WernerER, BlauN, ThönyB. Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J. 2011;438 (3 ):397‐414. 10.1042/bj20110293.21867484\n4 BrennenstuhlH, Jung‐KlawitterS, AssmannB, OpladenT. Inherited disorders of neurotransmitters: classification and practical approaches for diagnosis and treatment. Neuropediatrics. 2019;50 (1 ):2‐14. 10.1055/s-0038-1673630.30372766\n5 BlauN, ThönyB, RennebergA, ArnoldLA, HylandK. Dihydropteridine reductase deficiency localized to the central nervous system. J Inherit Metab Dis. 1998;21 (4 ):433‐434. 10.1023/a:1005327313348.9700606\n6 KhatamiS, DehnabehSR, ZeinaliS, et al. Four years of diagnostic challenges with tetrahydrobiopterin deficiencies in Iranian patients. JIMD Rep. 2017;32 :7‐14. 10.1007/8904_2016_572.27246466\n7 OpladenT, Abu SedaB, RassiA, ThönyB, HoffmannGF, BlauN. Diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots: further development of the method and 5 years experience. J Inherit Metab Dis. 2011;34 (3 ):819‐826. 10.1007/s10545-011-9300-1.21416196\n8 PonzoneA, SpadaM, FerrarisS, DianzaniI, de SanctisL. Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev. 2004;24 (2 ):127‐150. 10.1002/med.10055.14705166\n9 LuDY, YeJ, HanLS, et al. QDPR gene mutation and clinical follow‐up in Chinese patients with dihydropteridine reductase deficiency. World J Pediatr. 2014;10 (3 ):219‐226. 10.1007/s12519-014-0496-7.25124972\n10 NiuDM. Disorders of BH4 metabolism and the treatment of patients with 6‐pyruvoyl‐tetrahydropterin synthase deficiency in Taiwan. Brain Dev. 2011;33 (10 ):847‐855. 10.1016/j.braindev.2011.07.009.21880449\n11 ShintakuH. Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab. 2002;3 (2 ):123‐131. 10.2174/1389200024605145.12003346\n12 BlauN, MartinezA, HoffmannGF, ThönyB. DNAJC12 deficiency: a new strategy in the diagnosis of hyperphenylalaninemias. Mol Genet Metab. 2018;123 (1 ):1‐5. 10.1016/j.ymgme.2017.11.005.29174366\n13 AniksterY, HaackTB, VilbouxT, et al. Biallelic mutations in DNAJC12 cause hyperphenylalaninemia, dystonia, and intellectual disability. Am J Hum Genet. 2017;100 (2 ):257‐266. 10.1016/j.ajhg.2017.01.002.28132689\n14 BlauN, BaluyotMM, CarducciC, SalvaticiE. BIODEFdb International Database of BH4 Deficiencies. http://www.biopku.org/biodef/BIODEF_Results.asp. Accessed August 2020\n15 BonaféL, ThönyB, LeimbacherW, KieratL, BlauN. Diagnosis of dopa‐responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts. Clin Chem. 2001;47 (3 ):477‐485.11238300\n16 FriedmanJ, RozeE, AbdenurJE, et al. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol. 2012;71 (4 ):520‐530. 10.1002/ana.22685.22522443\n17 BlauN, HeizmannCW, SperlW, et al. Atypical (mild) forms of dihydropteridine reductase deficiency: neurochemical evaluation and mutation detection. Pediatr Res. 1992;32 (6 ):726‐730. 10.1203/00006450-199212000-00021.1283784\n\n",
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"title": "Sapropterin dihydrochloride therapy in dihydropteridine reductase deficiency: Insight from the first case with molecular diagnosis in Brazil.",
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"abstract": "Imatinib mesylate is the standard treatment of chronic myeloid leukemia (CML). Despite imatinib is being used in the treatment of other malignancies as well, its potential role on de novo tumor growth is not known. Secondary malignancies are rarely seen in patients with CML and particularly in those receiving imatinib. Here, we present a CML patient taking imatinib therapy that was diagnosed to have breast cancer and received adjuvant chemo-and radiotherapy with imatinib. We tried to explain co-occurrence of these rare events by probable pathogenetic mechanisms.",
"affiliations": "Department of Internal Medicine, Divisions of Hematology, Marmara University Hospital, Istanbul, Turkey.",
"authors": "Kaygusuz-Atagunduz|Isik|I|;Toptas|Tayfur|T|;Yumuk|Fulden|F|;Firatli-Tuglular|Tulin|T|;Bayik|Mahmut|M|",
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"abstract": "Allogeneic hematopoietic stem-cell transplantation (HSCT) is, at present, the only potentially curative therapy for myelofibrosis (MF). Despite many improvements, outcomes of HSCT are still burdened by substantial morbidity and high transplant-related mortality. Allogeneic transplant is generally considered in intermediate-2 and high-risk patients aged <70 years, but the optimal selection of patients and timing of the procedure remains under debate, as does as the role of JAK inhibitors in candidates for HSCT. Starting from a real-life clinical case scenario, herein we examine some of the crucial issues of HSCT for MF in light of recent refinements on MF risk stratification, data on the use of ruxolitinib before and after transplant and findings on the impact of different conditioning regimens and donor selection.",
"affiliations": "Division of Hematology and Bone Marrow Transplantation, Department of Medical Area, University of Udine, Udine, Italy. mario.tiribelli@uniud.it.;Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.;Department of Oncology, Division of Hematology, Azienda USL Toscana Nord Ovest, Lucca, Italy.;Division of Cellular Biotechnologies and Hematology, University Sapienza, Roma, Italy.;Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.",
"authors": "Tiribelli|Mario|M|http://orcid.org/0000-0001-9449-2621;Palandri|Francesca|F|;Sant'Antonio|Emanuela|E|;Breccia|Massimo|M|;Bonifacio|Massimiliano|M|",
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"fulltext": "\n==== Front\nBone Marrow Transplant\nBone Marrow Transplant\nBone Marrow Transplantation\n0268-3369 1476-5365 Nature Publishing Group UK London \n\n683\n10.1038/s41409-019-0683-1\nReview Article\nThe role of allogeneic stem-cell transplant in myelofibrosis in the era of JAK inhibitors: a case-based review\nhttp://orcid.org/0000-0001-9449-2621Tiribelli Mario mario.tiribelli@uniud.it 1 Palandri Francesca 2 Sant’Antonio Emanuela 3 Breccia Massimo 4 Bonifacio Massimiliano 5 1 0000 0001 2113 062Xgrid.5390.fDivision of Hematology and Bone Marrow Transplantation, Department of Medical Area, University of Udine, Udine, Italy \n2 grid.412311.4Institute of Hematology “L. and A. Seràgnoli”, Sant’Orsola-Malpighi University Hospital, Bologna, Italy \n3 Department of Oncology, Division of Hematology, Azienda USL Toscana Nord Ovest, Lucca, Italy \n4 grid.7841.aDivision of Cellular Biotechnologies and Hematology, University Sapienza, Roma, Italy \n5 0000 0004 1763 1124grid.5611.3Section of Hematology, Department of Medicine, University of Verona, Verona, Italy \n18 9 2019 \n18 9 2019 \n2020 \n55 4 708 716\n30 5 2019 29 7 2019 2 8 2019 © The Author(s), under exclusive licence to Springer Nature Limited 2019Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Allogeneic hematopoietic stem-cell transplantation (HSCT) is, at present, the only potentially curative therapy for myelofibrosis (MF). Despite many improvements, outcomes of HSCT are still burdened by substantial morbidity and high transplant-related mortality. Allogeneic transplant is generally considered in intermediate-2 and high-risk patients aged <70 years, but the optimal selection of patients and timing of the procedure remains under debate, as does as the role of JAK inhibitors in candidates for HSCT. Starting from a real-life clinical case scenario, herein we examine some of the crucial issues of HSCT for MF in light of recent refinements on MF risk stratification, data on the use of ruxolitinib before and after transplant and findings on the impact of different conditioning regimens and donor selection.\n\nSubject terms\nMyeloproliferative diseaseMedical researchissue-copyright-statement© Springer Nature Limited 2020\n==== Body\nIntroduction\nMyelofibrosis (MF) is a myeloproliferative neoplasm that may present as primary (PMF) or as the evolution of a previous polycythemia vera (PV) or essential thrombocythemia (ET), in which case it is referred to as secondary myelofibrosis (SMF) [1]. MF is a clonal stem-cell process that gives rise to bone marrow fibrosis, extramedullary hematopoiesis, frequent splenomegaly and anemia, constitutional symptoms, and cachexia; its clinical course is defined by a tendency toward leukemic progression and shortened survival [2].\n\nPatients with intermediate- or high-risk disease are candidates for therapy that may include conventional drugs (e.g., hydroxyurea), transfusions, splenectomy or, more recently, JAK inhibitors such as ruxolitinib. These treatments have the major aim of improving both symptoms and overall survival, as well as quality of life [2]. However, allogeneic hematopoietic stem-cell transplantation (HSCT) currently remains the only therapy that may modify the natural history of MF [3]. As a consequence, the number of allogeneic HSCTs performed for MF has been increasing over the past years, despite the approval of JAK inhibitors [2, 4]. Notwithstanding, HSCT is associated with high treatment-related morbidity and mortality, particularly in older adults, where the risk of the procedure may outweigh the risk of disease. Moreover, HSCT requires both good performance status and a suitable stem-cell donor [4]: in recent years, the number of patients undergoing transplants using matched unrelated donors (MUD) and employing reduced-intensity conditioning (RIC) regimens has increased significantly, representing more than two-thirds of all HSCTs [5]. Nevertheless, rates of mortality and relapse related to transplant remain high, thus posing a major challenge to hematologists. Herein, a case-based review is used as the basis to briefly review the role of HSCT in MF in the current era of JAK inhibitors.\n\nCase presentation\nA 51-year-old woman was admitted to the emergency department in December 2003 for balance disorder and was found to have extreme thrombocytosis (platelets 2667 × 103/µL) and mild leukocytosis (WBC 19.0 × 103/µL with 89% neutrophils). Bone marrow biopsy and aspirate were consistent with ET, karyotype was 46XX, and molecular analysis was negative for BCR/ABL. The patient was treated with hydroxyurea with partial hematologic remission; in 2004 anagrelide therapy was started, with complete normalization of platelet counts and without significant toxicity.\n\nStarting August 2011 progressive thrombocytopenia and splenomegaly developed, and in November 2013 a bone marrow biopsy documented progression to SMF. The patient was negative for the JAK2 V617F mutation, and the IPSS score was 1 (circulating blasts 4%), corresponding to an intermediate-1 risk group. A few months later, the decision was made to enroll the patient in a protocol testing ruxolitinib in MF (JUMP trial, NCT01493414). Complete blood count (CBC) was: Hb 10.9 g/dL, platelets 92 × 103/µL, WBC 19.0 × 103/µL (neutrophils 72%, blasts 3%); spleen was palpable at 7 cm below the left costal margin (LCM). Electrocardiogram revealed a previous anteroseptal myocardial infarction and first-degree atrioventricular block. Ruxolitinib was started at 5 mg BID on April 2014; at the time of initiation, the patient had no relevant symptoms (DIPSS score of 1 due to circulating blasts). After 6 months of therapy, spleen size was unchanged, and the dose of ruxolitinib was increased to 10 mg BID, without any significant reduction in spleen size at any of the subsequent evaluations. However, the ruxolitinib dose was not further escalated due to platelet counts <100 × 103/µL.\n\nIn October 2016, 2.5 years after starting ruxolitinib, at which time the patient was 65 years old, the spleen was palpable at 9 cm below LCM and CBC was as follows: Hb 9.8 g/dL, platelets 89 × 103/µL, WBC 34.9 × 103/µL (neutrophils 48%, blasts 8%). Bone marrow biopsy revealed grade 3 fibrosis. The DIPSS score was 4 and the risk group was intermediate-2. The patient exited the formal protocol, but continued ruxolitinib therapy at 10 mg BID with the addition of hydroxyurea 1 g/day due to leukocytosis and increasing splenomegaly.\n\nIn August 2017, at the age of 66, CBC was substantially unchanged and spleen size had further increased; DIPSS score was 5 (high risk). Calreticulin (CALR) gene analysis revealed a type 2 mutation. An echocardiogram and pulmonary function tests were performed, and the patient was evaluated by the allogeneic HSCT team in October 2017.\n\nDue to the lack of a sibling donor, a search for a MUD started in November 2017, while the patient continued treatment with ruxolitinib and hydroxyurea. The patient began transfusions with red cells in November 2017, and in February 2018 she experienced repeated episodes of congestive heart failure requiring cardiovascular therapy. In March 2018, bone marrow biopsy showed grade 3 fibrosis and osteosclerosis. The patient now required continuous transfusion with 4 units of red cells per month; spleen size was stable, but abdominal ultrasound revealed portal and splenic vein thrombosis that prompted introduction of heparin therapy.\n\nIn April 2018, an 8/8 HLA-MUD was identified. Pretransplant comorbidity index (HTC-CI) score according to Sorror [6] was 5 (congestive heart failure, reduced DLCO, depression). In June 2018, the patient underwent allogeneic HSCT with PB-derived stem cells; harvest consisted of 5.8 × 106/kg CD34+ cells and 52.2 × 107/kg CD3+ cells. The dose of ruxolitinib was quickly tapered starting from 7 days before and stopped the day before the start of the conditioning regimen. The non-myeloablative conditioning (MAC) regimen consisted of fludarabine 30 mg/m2 on day −8 to day −3 and thiotepa 6 mg/kg for 2 doses on days −4 and −3, while prophylaxis for graft-versus-host disease (GvHD) included cyclosporine A, short-course methotrexate, and ATG thymoglobulin (3.5 mg/kg for two doses). Prophylaxis for Epstein Barr virus consisted of rituximab 200 mg/m2 on day −2.\n\nThe posttransplant period was characterized by suspected veno-occlusive disease, with jaundice, weight gain, and abdominal discomfort, which was treated with defibrotide for 18 days. The patient did not develop acute GvHD. Neutrophil recovery (ANC > 1000) was documented on day +17, while platelet recovery (PLT > 30,000/mmc) was attained only on day +90; due to poor graft function, GCSF and transfusions were needed in the months following SCT. Posttransplant chimerism analysis performed on peripheral blood CD3+ cells at 1, 3, and 4 months after SCT showed ≥95% of donor cells.\n\nAt last follow up, 5 months after HSCT, the patient was in stable conditions, with no signs or symptoms of GvHD. The spleen was palpable at 5 cm from LCM and CBC was as follows: Hb 8.5 g/dL, platelets 53 × 103/µL, WBC 3.6 × 103/µL (neutrophils 60%, lymphocytes 20%, no precursor nor blasts); transfusion of red cells is needed about once weekly.\n\nDiscussion\nThe present case report allows for several observations on management of MF in the era of JAK inhibitors, as summarized in Fig. 1.Fig. 1 Key points in optimization of stem-cell transplantation in myelofibrosis patients. MF myelofibrosis, TRM transplant-related mortality, MRD marrow-related donor, MUD marrow-unrelated donor, GvHD graft-vs-host disease, MRD minimal residual disease, DLI donor lymphocyte infusion\n\n\n\nPretransplant evaluation: prognostic scores and considerations about use of JAK inhibitors\nThe mean age of patients diagnosed with MF is more than 65 years [7], and the age of the patient described herein is in line with this affirmation. At about 8 years after initial diagnosis of ET, progressive thrombocytopenia and splenomegaly were observed, and bone marrow biopsy documented progression to SMF. The management of SMF is almost identical to that of de novo PMF [8], despite the biological differences between primary and secondary MF. Initially, the patient’s DIPSS score was 1 with risk group intermediate-1 and, accordingly, HSCT was not considered to be a frontline therapeutic option, since it was largely performed in younger, fit patients with higher risk disease [9]. Moreover, while some studies have identified that subclonal nondriver mutations (i.e., ASXL1, EZH2, IDH1/2, and SRSF2) have an adverse effect on overall and leukemia-free survival [10, 11], and therefore may be used as a decisional tool for transplant (MIPPS70 [12]), this kind of analysis was not available in clinical practice in 2013, and the only information about the mutational status of our patient was the negativity for JAK2 V617F. It should also be pointed out that the prognostic impact of subclonal mutations has been mostly studied in cases of PMF, while its relevance in SMF has not yet been demonstrated [13]. Indeed, given the older age and likely coexistence of medical conditions, most patients are not considered for HSCT because of concerns regarding treatment-related toxicity [2], and some studies have reported decreased survival in patients older than 55 years of age [14, 15]. Based on these considerations, the patient was proposed enrollment in a protocol for ruxolitinib treatment, due to the presence of splenomegaly [16]. A similar approach has also been recently recommended by a panel of experts from the European LeukemiaNet and the Italian Society of Hematology [17].\n\nAfter almost 3 years on ruxolitinib at what was considered to be the maximal tolerable dose, splenomegaly and thrombocytopenia were still evident and even considering that the patient was 66 years old, she was referred to evaluation by an allogeneic HSCT team, since her DIPSS score had increased to 4, corresponding to an intermediate-2 risk group. There is some discrepancy on the utility of DIPSS score in predicting outcomes [2]. While some studies have shown better outcomes for patients transplanted with a lower DIPSS score [18], patients with low-risk disease are generally not considered for transplant because survival rates appear to be higher with pharmacologic and supportive therapy, at least in the pre-ruxolitinib era [2, 19]. In addition, a clear distinction has to be made between the prognostic score related to MF itself, and the prognostic score about transplant risk. Prognostication about disease evolution can be made using simple clinical variables (IPSS or DIPSS score, [20, 21]) or considering biological characteristics such as cytogenetic (DIPSS-plus, [22]), driver mutations (MYSEC-PM, [23]) or the combination of driver and subclonal mutations (MIPSS-70, [12]). It is presently unclear which score is more accurate in defining the indication for transplant, particularly when a patient falls in categories with markedly different survival expectations. Retrospective classification of our patient revealed that at the time of SMF diagnosis she was at intermediate-2 risk according to MYSEC-PM, and at intermediate-1 risk according to DIPSS, with a projected survival of 4.5 and 14.1 years, respectively. This kind of discrepancy between risk models may occur in up to 50% of patients with SMF [24] and poses a significant challenge in transplant indication, since EBMT/ELN recommendations suggest that HSCT should be offered only to eligible patients whose survival is expected to be <5 years [13]. In such cases, we believe that information from MYSEC-PM, the only scoring system specifically developed for SMF, should outweigh the risk assessment obtained from IPSS, DIPPS, DIPSS-plus or MIPSS70, which were developed in patients with PMF and are less accurate in discriminating different prognostic groups in SMF patients [25, 26]. Moreover, we have to bear in mind that all the presently available prognostic scores have been built on cohorts of patients who were not exposed to novel drugs such as ruxolitinib, and the weight of treatment-related clinical changes on single prognostic variables compared to MF-related changes is unclear. For example, many patients on ruxolitinib develop anemia (+2 points according to the DIPSS prognostic model) but ameliorate systemic symptoms (−1 point), therefore potentially changing several times over months their prognostic group. Altogether, these considerations reflect the uncertainty about prognostic scores alone in defining transplant indication. In this regard, it should be underlined that the predictive efficacy of MYSEC-PM score in ruxolitinib-treated patients has been validated in a retrospective study [24] and that two recent reports from the EBMT and the Spanish registry confirmed the efficacy of MYSEC-PM, as well as its superiority over DIPSS or IPSS scores, in predicting posttransplant survival [27, 28]. Of note, about 60% of patients in both these series belonged to the low or intermediate-1 MYSEC-PM risk group, and downgrading from higher IPSS categories was mainly related to the large effect of age in the MYSEC-PM model: in fact, only a minority of patients in a transplant age (i.e., <70 years) are categorized in intermediate-2 or high MYSEC-PM risk. This large contribution of age to the scoring system may thus decrease its sensitivity to the other disease-related adverse risk factors (e.g., circulating blasts), which could be important for transplant decisions [28].\n\nRisk factors for survival after transplant comprise high transfusion requirement, massive splenomegaly, non-sibling donor type [29], advanced age, JAK2 V617F-mutated status, constitutional symptoms [10], and HLA-mismatched donor [11]. Of note, patients in these studies were quite heterogeneous and no unifying prognostic variables can be identified, except for age (>55–57 years). Recently, a new Myelofibrosis Transplant Scoring System (MTSS) was proposed to predict survival after HSCT on the basis of the following clinical and molecular variables: leukocytes >25 × 109/L, platelets <150 × 109/L, Karnofsky scale <90%, age >57 years, ASXL1 mutation (1 point each), JAK2-mutated or triple negative status (2 points), and mismatched unrelated donor (2 points) [27]. According to these variables, patients were stratified in low (score 0–2), intermediate (score 3–4), high (score 5), and very high (score >5) risk groups with a 5-year survival estimation of 83%, 64%, 37%, and 22%, respectively.Prognostic scores: key points\t\n• New scoring systems have been recently developed for PMF (MIPSS70) and SMF (MYSEC-PM) prognostication, and for transplant outcome (MTTS).\t\n• Still, IPSS and DIPSS are widely used in clinical practice and for the transplant-decision process, although the MYSEC-PM score has been proved to be more accurate in SMF patients.\t\n• Impact of subclonal mutations in SMF deserves confirmation.\t\n• The weight of prognostic variables in patients treated with JAK inhibitors has not been still assessed prospectively.\t\n\n\nBesides these prognostic scores, a further element of uncertainty is how to consider the response to ruxolitinib or other JAK inhibitors. It is possible that patients who do not respond to ruxolitinib, even after dose optimization, should be referred early for HSCT. In fact, non-responsiveness to ruxolitinib could eventually be considered as a major selection criterion for referral to HSCT, although more studies are needed to determine the timing at which HSCT should be considered in a non-responsive patient. In a small cohort of patients (n = 22) briefly exposed to ruxolitinib before planned HSCT (median treatment duration 97 days, range 20–316), 1-year OS was superior for patients with spleen response to ruxolitinib than for patients who failed or lost their response [30]. In addition, a larger study on 100 patients treated with JAK inhibitors (ruxolitinib 90%, others 10%) showed that 2-year OS ranged from 91% for patients experiencing clinical improvement to 32% for those developing leukemic transformation on treatment with JAK inhibitors; patients with stable disease or transient response had an intermediate prognosis [21]. If a favorable response to JAK inhibitors leads to a better transplant outcome because patients who respond to JAK inhibitors have an intrinsic more favorable biology or because JAK inhibitors ameliorate the clinical status of patients remains an unanswered question.\n\nFinally, we recently reported on a large multicenter cohort of patients treated with ruxolitinib in real life (40% aged <65 years), showing that 18 and 22% of cases were treated for >12 months even with unstable or no spleen response, respectively [31], reflecting a common tendency to use ruxolitinib in clinical practice as a strategy to delay HSCT rather than a bridge to it.Pretransplant ruxolitinib: key points\t\n• Response to ruxolitinib is associated with favorable outcomes after HSCT.\t\n• Patients failing ruxolitinib therapy should be considered as candidates for HSCT within 6–12 months, if suitable.\t\n\n\nTransplant and posttransplant evaluation: realization, management and outcome\nAccording to the revised 2018 ELN recommendations [32], patients with intermediate-1 risk disease should be considered as eligible for HSCT in the presence of detrimental prognostic factors, such as adverse cytogenetics or mutations [33–36], high need for transfusions [37], or >2% of circulating blasts [38]. All these conditions were met in the present case, except for the lack of information about molecular status when we decided to candidate the patient to HSCT. Prior to HSCT we documented grade 3 fibrosis and osteosclerosis at bone marrow reevaluation, and mutational analysis of the CALR gene revealed a type 2 mutation. This is of interest as patients with mutations in the CALR gene appear to have better overall survival [4] and better posttransplant outcomes [39, 40], even though the prognostic significance of type 2/type 2-like CALR mutations seems to be less favorable than type 1/type 1-like mutations [35, 41]. Furthermore, during the pretransplantation waiting period, the patient’s DIPSS score had raised to 5, and she was thus considered as high risk.\n\nIron overload is common in MF due to the high requirement for transfusions and the disease-associated inflammatory state; moreover, MF patients have been shown to have higher levels of hepcidin than normal controls, and increased levels of hepcidin and ferritin appear to be a DIPSS-plus-independent adverse prognostic factor for survival [42]. Iron chelation with deferasirox was associated to erythroid improvement and reduction or abolition of transfusion dependence in 15–40% of MF patients [43, 44]. Due to the adverse effects of iron overload on HSCT outcomes [45], evaluation of pretransplant iron status is recommended and treatment with deferasirox may be beneficial in terms of posttransplant engraftment and long-term outcomes [46, 47].\n\nSplenomegaly negatively affects HSCT outcomes as it may be associated with poor graft function and increased mortality [48]. Despite these observations, it remains uncertain if splenectomy prior to transplantation is associated with improved outcomes. At present, there is some evidence to support pretransplant splenectomy [49–51], but postoperative complications, present in around one-half of all patients [52], could lead to delays in HSCT. Therefore, it is accepted that clinical decisions on surgical reduction of spleen size should be made on an individualized basis [19]. In the present case, pre-HSCT splenectomy was not taken into consideration given the presence of clinically significant portal and splenic vein thrombosis, necessitating administration of heparin, and transfusion-dependent anemia.\n\nThere is general agreement that, as for other diseases, an HLA-matched donor, either sibling or unrelated, is associated with superior overall survival [27, 53], although some experiences found a worse outcome in MF patients transplanted from an unrelated donor, regardless of HLA-matching status [54]. However, there is increasing evidence about the use of alternative donors. Raj et al. reported on 56 MF patients transplanted between 2009 and 2015 from a family mismatched donor (i.e., relatives with ≥2 Ag HLA different from recipient), with a 2-year overall survival rate of 56% but a rather high non-relapse mortality (NRM) of 38% at 2 years [55]. In a recent retrospective review, NRM and 4-year OS rates were similar in patients receiving their first transplant from HLA-matched related donor peripheral blood stem cells or from HLA-MUD bone marrow, while long-term survival was inferior in patients transplanted from umbilical cord blood, partly due to higher NRM [56]. Information about haploidentical related donor in MF is still scarce; in a comparison between HLA-identical sibling and “alternative” donors, including 20 haploidentical, transplanted in the years 2011–2014, Bregante et al. found similar survival rates in the two cohorts (72% and 69%, respectively) [57].\n\nWith regards to the conditioning regimen, there are limited data on the choice of the optimal regimen give the lack of prospective clinical trials comparing MAC to RIC in MF [58]. However, retrospective studies in the pre-ruxolitinib era have reported that ideal candidates for MAC are younger patients (<40 years old), without comorbidities and with HLA-identical sibling donor [59], while RIC may be preferred in patients older than 50 years [4, 58, 60]. Accordingly, RIC with fludarabine + thiotepa was adopted in the present case. A recent prospective randomized study compared fludarabine in combination with busulfan or thiotepa as conditioning regimen in 60 patients undergoing HSCT for MF, showing comparable clinical outcome in the two arms [51]. However, other available data are somewhat discrepant on the outcomes of patients undergoing fludarabine-melphalan based RIC regimens [54, 61]. Recently, Gupta et al. reported a prospective trial of ruxolitinib treatment followed by a RIC regimen: the cumulative incidences of graft failure, NRM, acute GvHD, and chronic GvHD at 24 months were 16%, 28%, 64%, and 76%, respectively; 2-year overall survival was 61 and 70% for patients receiving transplant from related or unrelated donor, respectively. The role of pretransplant ruxolitinib is also supported by a retrospective study of 159 MF patients receiving (29%) or not receiving ruxolitinib (71%) at any time before HSCT: graft failure, time to engraftment, and NRM were similar, while a trend for lower risk of relapse was seen in the ruxolitinib group [62]. Moreover, there was no difference in any outcome variable between those who responded to ruxolitinib and those who failed or lost response to the drug [62]. Another aspect that remains unclear is the rate and schedule for pretransplantation discontinuation of ruxolitinib. In our case, ruxolitinib was quickly tapered downward at 1 week prior to HCT and stopped the day before starting the conditioning regimen. This decision was largely made upon empirical considerations and on the observation that following interruption or discontinuation of ruxolitinib symptoms of MF may return over a period of ~1week [63]. Some studies have suggested that ruxolitinib should be continued near to the start of conditioning therapy [30, 53, 60], while a recent experience reported the safety of continuing low-dose ruxolitinib (5 mg BID) until stable engraftment in 12 MF patients undergoing allogeneic transplant [64]. Drug discontinuation symptoms were reported to be more common in patients who had a longer interval between last dose of a JAK1/2 inhibitor and beginning of the conditioning regimen, with 29% of patients developing symptoms with an interval ≥6 days compared with only 7% among those with an interval <6 days [53]. Moreover, the possible appearance of significant clinical events related to discontinuation of ruxolitinib may occur, which may even lead to delay in HSCT [53].Transplant procedure: key points\t\n• HLA-matched sibling or unrelated donor is the preferable choice, but there is increasing evidence of feasibility of HSCT form alternative donors.\t\n• Patients older than 50 years should receive a RIC transplant.\t\n• The conditioning regimen is based on fludarabine combined with either busulfan, thiotepa or melphalan.\t\nPatients receiving pretransplant ruxolitinib should be tapered and discontinued just before starting the conditioning regimen to avoid a cytokine rebound.\t\n\n\nLastly, the role of ruxolitinib post HSCT remains unclear and there is very limited information to guide clinicians. The presence of minimal residual disease (MRD) or overt relapse after HSCT pose a significant clinical challenge, and MF recurrence remains the main cause of death in the long term, as has been recently demonstrated in a large retrospective analysis on over 1000 patients with MF transplanted between 1995 and 2014 in Europe [65]. Detection of posttransplant relapse may be challenging, as bone marrow fibrosis may persist for months after HSCT [66] and molecular monitoring is not yet standardized. While detection of JAK2 mutations after transplant has been found to predict MF relapse [67], no data are available on the role of CALR, MPL or monitoring other molecular markers and their role in guiding therapy. In view of the lack of uniform criteria, we propose serial monitoring (e.g., at 3, 6, and 12 months after HSCT) of bone marrow biopsy and driver mutations present in individual MF patients.\n\nIn patients relapsing after transplant, discontinuation of immunosuppressive drugs, administration of donor lymphocyte infusion (DLI), chemotherapy, and second allogeneic transplant has been proposed [68]. Response to DLI seems to be more effective in patients with recurrence of MRD and monitored by JAK2 mutation levels in peripheral blood than in patients with full clinical relapse [69]. A role of JAK inhibitors in this setting appears reasonable, but still scarcely defined [70]. More recently, ruxolitinib has also emerged as an option for treating steroid-resistant acute and chronic GVHD [71], and promising results have been reported in a small group of MF patients who were treated with low-dose ruxolitinib until stable engraftment [64].Posttransplant management: key points\t\n• Albeit the limited experience, there seems to be a role for ruxolitinib in the peri- and posttransplant period.\t\n• Optimal histological and molecular monitoring of MF after HSCT is still to be defined.\t\n\n\nConclusion\nHSCT remains the main curative option for MF patients even in the era of JAK inhibitors. Eligibility for transplant should rely on the integrated evaluation of disease- and transplant-related risk factors, particularly in older adults. A thorough mutational analysis covering driver and subclonal mutations may help to define indication for HSCT in lower-risk fit patients. RIC nowadays represents the most common type of HSCT in MF, and busulfan or thiotepa plus fludarabine are both appropriate conditioning regimens. Response to ruxolitinib as a “bridge to transplant” can be obtained in about 30–50% of patients and predicts a favorable outcome after HSCT.\n\nSome of the most pressing issues to be studied in future prospective clinical trials involve the place and duration of JAK inhibitors in the pretransplant period (together with an optimized timing sequence for discontinuation), early versus late transplantation, and the role of ruxolitinib or other drugs in managing patients in the posttransplant period.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nEditorial assistance for the manuscript was provided by Health Publishing & Services srl and supported by an unrestricted grant from Novartis Farma Italy.\n\nCompliance with ethical standards\nConflict of interest\nMT has received honoraria from and has served on speakers’ bureaus for Novartis, BMS, Pfizer, and Incyte. MB received honoraria from and has served on speakers’ bureaus for Amgen, Incyte, Pfizer, and Novartis. FP has received honoraria from and has served on speakers’ bureaus for Novartis. Massimo Breccia received honoraria from Novartis, Pfizer, Incyte, Celgene. ESA has no conflict of interest to report.\n==== Refs\nReferences\n1. Arber DA Orazi A Hasserjian R Thiele J Borowitz MJ Le Beau MM The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Blood 2016 127 20 2391 405 10.1182/blood-2016-03-643544 27069254 \n2. Jain T Mesa RA Palmer JM Allogeneic stem cell transplantation in myelofibrosis Biol Blood Marrow Transpl 2017 23 1429 36 10.1016/j.bbmt.2017.05.007 \n3. Deeg HJ Gooley TA Flowers ME Sale GE Slattery JT Anasetti C Allogeneic hematopoietic stem cell transplantation for myelofibrosis Blood 2003 102 3912 8 10.1182/blood-2003-06-1856 12920019 \n4. 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Passamonti F Cervantes F Vannucchi AM Morra E Rumi E Pereira A A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment) Blood 2010 115 1703 8 10.1182/blood-2009-09-245837. 20008785 \n22. Gangat N Caramazza D Vaidya R George G Begna K Schwager S DIPSS plus: a refined dynamic international prognostic scoring system for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status J Clin Oncol 2011 29 392 7 10.1200/JCO.2010.32.2446. 21149668 \n23. Passamonti F Giorgino T Mora B Guglielmelli P Rumi E Maffioli M A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis Leukemia 2017 31 2726 31 10.1038/leu.2017.169. 28561069 \n24. Palandri F Palumbo GA Iurlo A Polverelli N Benevolo G Breccia M Differences in presenting features, outcome and prognostic models in patients with primary myelofibrosis and post-polycythemia vera and/or post-essential thrombocythemia myelofibrosis treated with ruxolitinib. New perspective of the MYSEC-PM in a large multicenter study() Semin Hematol 2018 55 248 55 10.1053/j.seminhematol.2018.05.013. 30502854 \n25. Hernandez-Boluda JC Pereira A Gomez M Boque C Ferrer-Marin F Raya JM The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis Haematologica 2014 99 e55 57 10.3324/haematol.2013.101733 24488561 \n26. Masarova L Bose P Daver N Pemmaraju N Newberry KJ Manshouri T Patients with post-essential thrombocythemia and post-polycythemia vera differ from patients with primary myelofibrosis Leuk Res 2017 59 110 6 10.1016/j.leukres.2017.06.001 28601551 \n27. Gagelmann N Ditschkowski M Bogdanov R Bredin S Robin M Cassinat B Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation Blood 2019 10.1182/blood-2018-12-890889. 30760453 \n28. Hernandez-Boluda JC Pereira A Correa JG Alvarez-Larran A Ferrer-Marin F Raya JM Performance of the myelofibrosis secondary to PV and ET-prognostic model (MYSEC-PM) in a series of 262 patients from the Spanish registry of myelofibrosis Leukemia 2018 32 553 5 10.1038/leu.2017.297 28935991 \n29. Bacigalupo A Soraru M Dominietto A Pozzi S Geroldi S Van Lint MT Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type Bone Marrow Transpl 2010 45 458 63 10.1038/bmt.2009.188. \n30. Stubig T Alchalby H Ditschkowski M Wolf D Wulf G Zabelina T JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis Leukemia 2014 28 1736 8 10.1038/leu.2014.86. 24569777 \n31. Palandri F Palumbo GA Bonifacio M Breccia M Latagliata R Martino B Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: results from a multicentre study on 284 patients Leuk Res 2018 74 86 8 10.1016/j.leukres.2018.10.001. 30321784 \n32. Barbui T Tefferi A Vannucchi AM Passamonti F Silver RT Hoffman R Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet Leukemia 2018 32 1057 69 10.1038/s41375-018-0077-1. 29515238 \n33. Caramazza D Begna KH Gangat N Vaidya R Siragusa S Van Dyke DL Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients Leukemia 2011 25 82 88 10.1038/leu.2010.234. 20944670 \n34. Guglielmelli P Lasho TL Rotunno G Score J Mannarelli C Pancrazzi A The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients Leukemia 2014 28 1804 10 10.1038/leu.2014.76. 24549259 \n35. Tefferi A Lasho TL Finke C Belachew AA Wassie EA Ketterling RP Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact Leukemia 2014 28 1568 70 10.1038/leu.2014.83. 24569778 \n36. Tefferi A Nicolosi M Mudireddy M Lasho TL Gangat N Begna KH Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients Leukemia 2018 32 1189 99 10.1038/s41375-018-0018-z. 29472717 \n37. Elena C Passamonti F Rumi E Malcovati L Arcaini L Boveri E Red blood cell transfusion-dependency implies a poor survival in primary myelofibrosis irrespective of IPSS and DIPSS Haematologica 2011 96 167 70 10.3324/haematol.2010.031831. 20884708 \n38. Rago A Latagliata R Montanaro M Montefusco E Andriani A Crescenzi SL Hemoglobin levels and circulating blasts are two easily evaluable diagnostic parameters highly predictive of leukemic transformation in primary myelofibrosis Leuk Res 2015 39 314 7 10.1016/j.leukres.2015.01.001. 25636356 \n39. Kroger N Panagiota V Badbaran A Zabelina T Triviai I Araujo Cruz MM Impact of molecular genetics on outcome in myelofibrosis patients after allogeneic stem cell transplantation Biol Blood Marrow Transpl 2017 23 1095 101 10.1016/j.bbmt.2017.03.034. \n40. Panagiota V Thol F Markus B Fehse B Alchalby H Badbaran A Prognostic effect of calreticulin mutations in patients with myelofibrosis after allogeneic hematopoietic stem cell transplantation Leukemia 2014 28 1552 5 10.1038/leu.2014.66. 24504025 \n41. Guglielmelli P Rotunno G Fanelli T Pacilli A Brogi G Calabresi L Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis Blood Cancer J 2015 5 e360 10.1038/bcj.2015.90. 26473532 \n42. Pardanani A Finke C Abdelrahman RA Lasho TL Tefferi A Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis Am J Hematol 2013 88 312 6 10.1002/ajh.23406 23450619 \n43. Elli EM Belotti A Aroldi A Parma M Pioltelli P Pogliani EM Iron chelation therapy with deferasirox in the management of iron overload in primary myelofibrosis Mediterr J Hematol Infect Dis 2014 6 e2014042. 10.4084/MJHID.2014.042. 24959339 \n44. Latagliata R Montagna C Porrini R Di Veroli A Leonetti SC Niscola P Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase Eur J Haematol 2016 96 643 9 10.1111/ejh.12674. 26277477 \n45. Meyer SC O'Meara A Buser AS Tichelli A Passweg JR Stern M Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation Biol Blood Marrow Transpl 2013 19 440 4 10.1016/j.bbmt.2012.10.012. \n46. Jaekel N Lieder K Albrecht S Leismann O Hubert K Bug G Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation Bone Marrow Transpl 2016 51 89 95 10.1038/bmt.2015.204. \n47. Vallejo C Batlle M Vazquez L Solano C Sampol A Duarte R Phase IV open-label study of the efficacy and safety of deferasirox after allogeneic stem cell transplantation Haematologica 2014 99 1632 7 10.3324/haematol.2014.105908. 24997153 \n48. Ciurea SO Sadegi B Wilbur A Alagiozian-Angelova V Gaitonde S Dobogai LC Effects of extensive splenomegaly in patients with myelofibrosis undergoing a reduced intensity allogeneic stem cell transplantation Br J Haematol 2008 141 80 3 10.1111/j.1365-2141.2008.07010.x. 18324970 \n49. Stewart WA Pearce R Kirkland KE Bloor A Thomson K Apperley J The role of allogeneic SCT in primary myelofibrosis: a British Society for blood and marrow transplantation study Bone Marrow Transpl 2010 45 1587 93 10.1038/bmt.2010.14. \n50. Tefferi A Mesa RA Nagorney DM Schroeder G Silverstein MN Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients Blood 2000 95 2226 33 10.1182/blood.V95.7.2226 10733489 \n51. Patriarca F, Masciulli A, Bacigalupo A, Bregante F, Pavoni C, Finazzi MC. et al. Busulfan or thiotepa based conditioning in myelofibrosis: a phase II multicenter randomized study from the GITMO group. Biol Blood Marrow Transpl. 2019. 10.1016/j.bbmt.2018.12.064.\n52. Robin M Zine M Chevret S Meignin V Munoz-Bongrand N Moatti H The impact of splenectomy in myelofibrosis patients before allogeneic hematopoietic stem cell transplantation Biol Blood Marrow Transpl 2017 23 958 64 10.1016/j.bbmt.2017.03.002. \n53. Shanavas M Popat U Michaelis LC Fauble V McLornan D Klisovic R Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to janus kinase 1/2 inhibitors Biol Blood Marrow Transpl 2016 22 432 40 10.1016/j.bbmt.2015.10.005 \n54. Rondelli D Goldberg JD Isola L Price LS Shore TB Boyer M MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis Blood 2014 124 1183 91 10.1182/blood-2014-04-572545 24963042 \n55. Raj K, Eikema DJ, McLornan DP, Olavarria E, Blok HJ, Bregante S, et al. Family mismatched allogeneic stem cell transplantation for myelofibrosis: report from the chronic malignancies Working Party of European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transpl. 2018. 10.1016/j.bbmt.2018.10.017.\n56. Murata M, Takenaka K, Uchida N, Ozawa Y, Ohashi K, Kim SW et al. Comparison of outcomes of allogeneic transplantation for primary myelofibrosis among hematopoietic stem cell source groups. Biol Blood Marrow Transplant. 2019. 10.1016/j.bbmt.2019.02.019.\n57. Bregante S Dominietto A Ghiso A Raiola AM Gualandi F Varaldo R Improved outcome of alternative donor transplantations in patients with myelofibrosis: from unrelated to haploidentical family donors Biol Blood Marrow Transpl 2016 22 324 9 10.1016/j.bbmt.2015.09.028. \n58. Atilla E Ataca Atilla P Demirer T A review of myeloablative vs reduced intensity/non-myeloablative regimens in allogeneic hematopoietic stem cell transplantations Balk Med J 2017 34 1 9 10.4274/balkanmedj.2017.0055 \n59. Ballen KK Shrestha S Sobocinski KA Zhang MJ Bashey A Bolwell BJ Outcome of transplantation for myelofibrosis Biol Blood Marrow Transpl 2010 16 358 67 10.1016/j.bbmt.2009.10.025. \n60. Jaekel N Behre G Behning A Wickenhauser C Lange T Niederwieser D Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib Bone Marrow Transpl 2014 49 179 84 10.1038/bmt.2013.173. \n61. Robin M Porcher R Wolschke C Sicre de Fontbrune F Alchalby H Christopeit M Outcome after transplantation according to reduced-intensity conditioning regimen in patients undergoing transplantation for myelofibrosis Biol Blood Marrow Transpl 2016 22 1206 11 10.1016/j.bbmt.2016.02.019 \n62. Shahnaz Syed Abd Kadir S Christopeit M Wulf G Wagner E Bornhauser M Schroeder T Impact of ruxolitinib pretreatment on outcomes after allogeneic stem cell transplantation in patients with myelofibrosis Eur J Haematol 2018 101 305 17 10.1111/ejh.13099 29791053 \n63. Ruxolitinib, Summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/jakavi-epar-product-information_en.pdf.\n64. Kroger N Shahnaz Syed Abd Kadir S Zabelina T Badbaran A Christopeit M Ayuk F Peritransplantation ruxolitinib prevents acute graft-versus-host disease in patients with myelofibrosis undergoing allogenic stem cell transplantation Biol Blood Marrow Transpl 2018 24 2152 6 10.1016/j.bbmt.2018.05.023 \n65. Robin M de Wreede LC Wolschke C Schetelig J Eikema DJ Van Lint MT Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis Haematologica 2019 10.3324/haematol.2018.205211. 31467131 \n66. Kroger N Kvasnicka M Thiele J Replacement of hematopoietic system by allogeneic stem cell transplantation in myelofibrosis patients induces rapid regression of bone marrow fibrosis Fibrogenes Tissue Repair 2012 5 Suppl 1 S25 10.1186/1755-1536-5-S1-S25 \n67. Alchalby H Badbaran A Zabelina T Kobbe G Hahn J Wolff D Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis Blood 2010 116 3572 81 10.1182/blood-2009-12-260588 20489052 \n68. McLornan DP Szydlo R Robin M van Biezen A Koster L Blok HJP Outcome of patients with Myelofibrosis relapsing after allogeneic stem cell transplant: a retrospective study by the Chronic Malignancies Working Party of EBMT Br J Haematol 2018 182 418 22 10.1111/bjh.15407 29808926 \n69. Kroger N Alchalby H Klyuchnikov E Badbaran A Hildebrandt Y Ayuk F JAK2-V617F-triggered preemptive and salvage adoptive immunotherapy with donor-lymphocyte infusion in patients with myelofibrosis after allogeneic stem cell transplantation Blood 2009 113 1866 8 10.1182/blood-2008-11-190975. 19228938 \n70. Janson D Ayuk FA Wolschke C Christopeit M Badbaran A von Pein U-M Ruxolitinib for myelofibrosis patients relapsing after allogeneic hematopoietic transplantation; abstract presented at ASH 2016 Blood 2016 128 1948 10.1182/blood.V128.22.1948.1948 \n71. Betts BC Abdel-Wahab O Curran SA,St Angelo ET Koppikar P Heller G Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen Blood 2011 118 5330 9 10.1182/blood-2011-06-363408. 21917753\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0268-3369",
"issue": "55(4)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000075242:Janus Kinase Inhibitors; D055728:Primary Myelofibrosis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "708-716",
"pmc": null,
"pmid": "31534197",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "12920019;28832353;15994282;22212965;27037840;20428194;23619563;29226763;29713873;22280409;19812383;27740634;22234678;26293647;18988864;20008785;21149668;28561069;30502854;24488561;28601551;30760453;28935991;24569777;30321784;29515238;20944670;24549259;24569778;29472717;20884708;25636356;24504025;26473532;23450619;24959339;26277477;24997153;18324970;24963042;29791053;31467131;20489052;29808926;19228938;21917753",
"title": "The role of allogeneic stem-cell transplant in myelofibrosis in the era of JAK inhibitors: a case-based review.",
"title_normalized": "the role of allogeneic stem cell transplant in myelofibrosis in the era of jak inhibitors a case based review"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1048952",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
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{
"abstract": "Children of women treated with antiepileptic drugs (AEDs) are at increased risk of adverse outcomes detectable in the neonatal period, which may be associated with the amount of AEDs in the fetal circulation. Placental passage of AEDs can be measured by calculating the ratio of umbilical cord to maternal AED concentrations collected at delivery. The aims of this study were to determine the umbilical cord concentrations and umbilical-to-maternal ratios for AEDs, and whether higher cord concentrations are associated with increased risk of neonatal complications. AED cord and maternal blood concentrations from 70 mother-newborn dyads and neonatal complications were recorded. Logistic regressions were performed to determine the association between AED concentrations and complications. Mean umbilical-to-maternal ratios for total concentrations ranged from 0.79 for carbamazepine to 1.20 for valproic acid, and mean umbilical-to-maternal ratios for free concentrations ranged from 0.86 for valproic acid to 1.42 for carbamazepine, indicating complete placental passage. Neither umbilical cord concentrations nor umbilical-to-maternal ratios were associated with adverse neonatal outcomes. Additional investigations are warranted to delineate the relationship between quantified fetal AED exposure and neonatal complications.",
"affiliations": "Brigham and Women's Hospital, Boston, Massachusetts, U.S.A.;University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.;University of Miami Miller School of Medicine, Miami, Florida, U.S.A.;Emory University School of Medicine, Atlanta, Georgia, U.S.A.;Brigham and Women's Hospital, Boston, Massachusetts, U.S.A.",
"authors": "Bank|Anna M|AM|;Stowe|Zachary N|ZN|;Newport|D Jeffrey|DJ|;Ritchie|James C|JC|;Pennell|Page B|PB|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.13733",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "58(5)",
"journal": "Epilepsia",
"keywords": "Antiepileptic drugs; Epilepsy; Placental passage; Pregnancy; Umbilical cord concentrations",
"medline_ta": "Epilepsia",
"mesh_terms": "D000927:Anticonvulsants; D001714:Bipolar Disorder; D036861:Delivery, Obstetric; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy; D005260:Female; D005312:Fetal Blood; D006801:Humans; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D010920:Placenta; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012307:Risk Factors",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "e82-e86",
"pmc": null,
"pmid": "28387929",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "21652013;26147878;11879354;23352199;27502786;20692811;15857447;18058331;7758253;12366729;1464299",
"title": "Placental passage of antiepileptic drugs at delivery and neonatal outcomes.",
"title_normalized": "placental passage of antiepileptic drugs at delivery and neonatal outcomes"
} | [
{
"companynumb": "US-JNJFOC-20170606771",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
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... |
{
"abstract": "Evidence on the evolution of graft function in kidney transplant recipients recovering from coronavirus disease-2019 (COVID-19) is lacking. This multicenter observational study evaluated the short-term clinical outcomes in recipients with acute kidney injury (AKI) secondary to COVID-19. Out of 452 recipients following up at five centers, 50 had AKI secondary to COVID-19. 42 recipients with at least 3-month follow-up were included. Median follow-up was 5.23 months [IQR 4.09-6.99]. Severe COVID-19 was seen in 21 (50%), and 12 (28.6%) had KDIGO stage 3 AKI. Complete recovery of graft function at 3 months was seen in 17 (40.5%) patients. Worsening of proteinuria was seen in 15 (37.5%) patients, and 4 (9.5%) patients had new onset proteinuria. Graft failure was seen in 6 (14.3%) patients. Kidney biopsy revealed acute tubular injury (9/11 patients), thrombotic microangiopathy (2/11), acute cellular rejection (2/11), and chronic active antibody-mediated rejection (3/11). Patients with incomplete recovery were likely to have lower eGFR and proteinuria at baseline, historical allograft rejection, higher admission SOFA score, orthostatic hypotension, and KDIGO stage 3 AKI. Baseline proteinuria and the presence of orthostatic hypotension independently predicted incomplete graft recovery. This shows that graft recovery may remain incomplete after AKI secondary to COVID-19.",
"affiliations": "Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.;Department of Nephrology, Apollo Hospital, Navi Mumbai, India.;Kimaya Kidney Care, Thane, India.;Yashwant Kidney Care, Pune, India.;Amardeep Kidney Care, Akola, India.;Department of Nephrology, Seth G.S.M.C. and K.E.M. Hospital, Mumbai, India.",
"authors": "Bajpai|Divya|D|0000-0003-2294-0506;Deb|Satarupa|S|;Bose|Sreyashi|S|;Gandhi|Chintan|C|;Modi|Tulsi|T|;Katyal|Abhinav|A|;Saxena|Nikhil|N|;Patil|Ankita|A|;Thakare|Sayali|S|;Pajai|Atim E|AE|;Haridas|Ashwathy|A|;Keskar|Vaibhav S|VS|;Jawale|Sunil Y|SY|;Sultan|Amar G|AG|;Jamale|Tukaram E|TE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/tri.13886",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "34(6)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "COVID-19; acute kidney injury; graft function; kidney transplantation; outcomes; recovery",
"medline_ta": "Transpl Int",
"mesh_terms": "D058186:Acute Kidney Injury; D000086382:COVID-19; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D000086402:SARS-CoV-2; D066027:Transplant Recipients",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "1074-1082",
"pmc": null,
"pmid": "33884672",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "32525010;4360465;30619688;32844546;32847984;9824069;32327202;32691342;32624283;12206970;33199414;21436288;32529737;33073066;33246166;33067383",
"title": "Recovery of kidney function after AKI because of COVID-19 in kidney transplant recipients.",
"title_normalized": "recovery of kidney function after aki because of covid 19 in kidney transplant recipients"
} | [
{
"companynumb": "IN-ASTELLAS-2021US049443",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe risks of ovarian hyperstimulation syndrome (OHSS) involve high estrogen (E2) levels. We report two breast cancer patients with polycystic ovarian syndrome who underwent fertility preservation and had severe OHSS; their E2 levels were lowered using aromatase inhibitors (AI).\n\n\nMETHODS\nA 36-year-old woman underwent controlled ovarian stimulation (COS) with AI and cryopreserved 10 blastocysts. She was hospitalized with OHSS (E2 = 139.1 pg/mL). She improved with infusion alone. A 31-year-old woman underwent COS with AI and cryopreserved 8 blastocysts. She was hospitalized for OHSS (E2: 429 pg/mL). Her vascular endothelial growth factor (VEGF) levels were high (62 pg/mL) at 8 days after the procedure. She needed hospitalization for 9 days. The planned adjuvant therapy was delayed for a week in both cases.\n\n\nCONCLUSIONS\nElevated VEGF levels should be considered as a risk factor of OHSS even if E2 levels are low with AI treatment.",
"affiliations": "Department of Obstetrics and Gynecology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan. Electronic address: h107621@med.u-ryukyu.ac.jp.;Department of Obstetrics and Gynecology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan.;Department of Obstetrics and Gynecology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan.",
"authors": "Oishi|Sugiko|S|;Mekaru|Keiko|K|;Nakamura|Rie|R|;Miyagi|Maho|M|;Akamine|Kozue|K|;Heshiki|Chiaki|C|;Aoki|Yoichi|Y|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.tjog.2021.07.028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-4559",
"issue": "60(5)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "Aromatase inhibitors; Estrogens; Fertility preservation; Ovarian hyperstimulation syndrome; Polycystic ovary syndrome",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": null,
"nlm_unique_id": "101213819",
"other_id": null,
"pages": "931-934",
"pmc": null,
"pmid": "34507678",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Two cases of polycystic ovary syndrome with onset of severe ovarian hyperstimulation syndrome following controlled ovarian stimulation with aromatase inhibitors for fertility preservation before breast cancer treatment.",
"title_normalized": "two cases of polycystic ovary syndrome with onset of severe ovarian hyperstimulation syndrome following controlled ovarian stimulation with aromatase inhibitors for fertility preservation before breast cancer treatment"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-316990",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
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"abstract": "A 70-year-old African American man suffered anoxic encephalopathy following a choking episode. He had a history of hypertension, which was being treated with lisinopril, an angiotensin-converting enzyme inhibitor (ACEI). Soon after the patient's admission to an intensive care unit, his tongue began to swell until it reached more than twice its normal size and extended almost 2 inches outside his mouth. When the swelling did not diminish after 2 weeks, a diagnosis of ACEI-induced angioedema was determined. ACEIs have the potential to cause angioedema through an uncommon effect on the angiotensin-renin vascular control system. Lingual angioedema can be life-threatening due to the possibility of severe compromise of the airway and thus may require immediate intubation. After the ACEI is discontinued, swelling may remain if there is continued pressure from the maxillary and mandibular incisors on the dorsal and lingual surfaces of the tongue. In this case, the patient was comatose and unable to voluntarily move the tongue; therefore, relief from pressure was easily accomplished, and the edema was eventually diminished through a team effort in which a dentist instructed the nursing personnel on proper placement of Molt mouth props.",
"affiliations": null,
"authors": "Saunders|Ralph H|RH|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D017706:Lisinopril",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-6771",
"issue": "65(4)",
"journal": "General dentistry",
"keywords": "geriatric dentistry; lingual angioedema; oral medicine",
"medline_ta": "Gen Dent",
"mesh_terms": "D000368:Aged; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D003937:Diagnosis, Differential; D006801:Humans; D017706:Lisinopril; D008260:Macroglossia; D008297:Male; D010348:Patient Care Team",
"nlm_unique_id": "7610466",
"other_id": null,
"pages": "60-62",
"pmc": null,
"pmid": "28682284",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of persistent lingual angioedema: a team approach.",
"title_normalized": "management of persistent lingual angioedema a team approach"
} | [
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"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2018-04188",
"fulfillexpeditecriteria": "2",
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"activesubstancename": "LISINOPRIL"
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"abstract": "A 28-year-old woman presented with abdominal pain. Prior to admission she had injected human chorionic gonadotropin (hCG) intramuscularly as part of a weight loss programme. A computed tomography detected a thrombosis of the superior mesenteric vein and with a gynaecologic scan she was found to be six weeks pregnant despite using oral contraception. Treatment with anticoagulant therapy was started, and a surgical abortion was performed. hCG bought illegal is used as a part of a weight loss program. Whether HCG injected in small amounts is a risk factor of venous thrombosis and whether it is able to reduce the effect of oral contraception is unknown.",
"affiliations": "Gynækologisk Afdeling, Hillerød Hospital, Dyrehavevej 29, 3400 Hillerød. line.thellesen@regionh.dk.",
"authors": "Thellesen|Line|L|;Jørgensen|Louise|L|;Regeur|Jakob von Halling|Jv|;Løkkegaard|Ellen|E|",
"chemical_list": "D019440:Anti-Obesity Agents; D006063:Chorionic Gonadotropin",
"country": "Denmark",
"delete": false,
"doi": null,
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"issn_linking": "0041-5782",
"issue": "176(30)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000028:Abortion, Induced; D000328:Adult; D019440:Anti-Obesity Agents; D006063:Chorionic Gonadotropin; D005260:Female; D006801:Humans; D008641:Mesenteric Vascular Occlusion; D008642:Mesenteric Veins; D011247:Pregnancy; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": "1410-1",
"pmc": null,
"pmid": "25292236",
"pubdate": "2014-07-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serious complications to a weight loss programme with HCG.",
"title_normalized": "serious complications to a weight loss programme with hcg"
} | [
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"companynumb": "DK-FRESENIUS KABI-FK201606747",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
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"activesubstance": {
"activesubstancename": "CHORIOGONADOTROPIN ALFA"
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"abstract": "Nocardiosis is a rare, life-threatening, opportunistic, and suppurative infection. Its clinical manifestation lacks specificity, which makes early diagnosis difficult. A retrospective analysis of the clinical records of 11 patients with nocardiosis admitted to our hospital from January 2013 to November 2018 was conducted. All patients had at least one underlying disorder, such as an autoimmune disease (6/11), a blood malignancy (2/11), avascular necrosis of the femoral head (1/11), bronchiectasis (1/11), or pneumonia (1/11). The first-line treatment was trimethoprim-sulfamethoxazole (TMP-SMX); one or two additional antibiotics were given according to the drug-sensitive test. The median time from onset to treatment was 3 weeks (ranging from 1 to 9 weeks). The median duration of treatment after diagnosis was 20.5 weeks (ranging from 7 to 47 weeks). Eight patients were discharged and survived, and three patients died. This indicates that early use of TMP-SMX combined with sensitive antibiotics could improve the condition of patients and improve the cure rate (8/11). Clinically, it is necessary to consider the possibility of nocardiosis in patients with long-term use of immunosuppressants and poor response to treatment of common bacterial infections. Early diagnosis, timely treatment, and combination drug therapy are keys to improving the outcomes of patients with nocardiosis.",
"affiliations": "Department of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People's Republic of China.;Department of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People's Republic of China.;Department of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People's Republic of China.;Department of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People's Republic of China.;Department of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People's Republic of China.;Department of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People's Republic of China.;Department of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People's Republic of China.;Department of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People's Republic of China.",
"authors": "Li|Yiqing|Y|;Tang|Ting|T|;Xiao|Jie|J|;Wang|Jieyu|J|;Li|Boqi|B|;Ma|Liping|L|;Xie|Shuangfeng|S|;Nie|Danian|D|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.1515/med-2020-0196",
"fulltext": "\n==== Front\nOpen Med (Wars)\nOpen Med (Wars)\nmed\nOpen Medicine\n2391-5463\nDe Gruyter\n\nmed-2020-0196\n10.1515/med-2020-0196\nResearch Article\nClinical analysis of 11 cases of nocardiosis\nLi Yiqing 1\nTang Ting 1tangt27@mail2.sysu.edu.cn\n\nXiao Jie\nWang Jieyu\nLi Boqi\nMa Liping\nXie Shuangfeng\nNie Danian niedn@mail.sysu.edu.cn\n\nDepartment of Hematology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, People’s Republic of China\n1 Yiqing Li and Ting Tang Contributed equally.\n\n08 4 2021\n2021\n16 1 610617\n17 5 2020\n05 2 2021\n24 2 2021\n© 2021 Yiqing Li et al., published by De Gruyter\n2021\nYiqing Li et al., published by De Gruyter\nhttps://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License.\n\nAbstract\n\nNocardiosis is a rare, life-threatening, opportunistic, and suppurative infection. Its clinical manifestation lacks specificity, which makes early diagnosis difficult. A retrospective analysis of the clinical records of 11 patients with nocardiosis admitted to our hospital from January 2013 to November 2018 was conducted. All patients had at least one underlying disorder, such as an autoimmune disease (6/11), a blood malignancy (2/11), avascular necrosis of the femoral head (1/11), bronchiectasis (1/11), or pneumonia (1/11). The first-line treatment was trimethoprim–sulfamethoxazole (TMP–SMX); one or two additional antibiotics were given according to the drug-sensitive test. The median time from onset to treatment was 3 weeks (ranging from 1 to 9 weeks). The median duration of treatment after diagnosis was 20.5 weeks (ranging from 7 to 47 weeks). Eight patients were discharged and survived, and three patients died. This indicates that early use of TMP–SMX combined with sensitive antibiotics could improve the condition of patients and improve the cure rate (8/11). Clinically, it is necessary to consider the possibility of nocardiosis in patients with long-term use of immunosuppressants and poor response to treatment of common bacterial infections. Early diagnosis, timely treatment, and combination drug therapy are keys to improving the outcomes of patients with nocardiosis.\n\nKeywords\n\nNocardia infections\nimmunosuppressive agents\ndiagnosis\ntherapeutics\n==== Body\n1 Introduction\n\nThe pathogen of nocardiosis is Nocardia, which is a slow-growing gram-positive aerobic bacterium with acid-fast staining properties [1]. Nocardia is an opportunistic pathogen that can cause local or systemic suppurative infections in humans and animals, some of which are life-threatening [2]. The clinical features of nocardiosis always lack specificity, making early diagnosis difficult. The gold standard for diagnosis of Nocardia infection is based on the isolation and identification of Nocardia via 16S ribosomal ribonucleic acid (rRNA) sequencing from humoral secretions or tissues, such as blood, sputum, pus, pleural effusion, cerebrospinal fluid, and pulmonary puncture samples [3,4,5]. A full 2–3 weeks may lapse between specimen collection and detection of Nocardia [1,6]. Nocardia spp. can be classified into different species with the comprehensive application of biochemical techniques, including 16S rRNA PCR-based assays and multi-site sequencing analysis [3,7,8]. Because of the relatively long duration and strict requirements for Nocardia detection, gene sequencing is not always available. In our report, the strains of Nocardia in six patients could not be identified because of the limitations of the experimental conditions.\n\nPositive results for nocardiosis are frequently followed by immediate appropriate treatment and prolonged maintenance therapy. In terms of treatment for Nocardia infection, the optimal therapeutic agent, route of administration, and duration of treatment have not been well established. Most treatments are based on the results of basic research, animal models, and recommendations from experts [7,9]. Trimethoprim–sulfamethoxazole (TMP–SMX) and linezolid have strong inhibitory effects on Nocardia in vitro [3]. TMP–SMX can be used as an initial empirical treatment [10,11]. Different strains of Nocardia have different levels of antimicrobial resistance, and some of them may be resistant to sulfonamides [12,13]. It is particularly important to identify Nocardia and perform drug-sensitive tests. In 2011, the Clinical and Laboratory Standards Institute M24-A2 guidelines published an approved broth-microdilution method for susceptibility testing of aerobic actinomycetes [14]. The first-line medications include TMP–SMX, oxazolidinones (linezolid), aminoglycosides (amikacin and tobramycin), carbapenems (imipenem), ß-lactams (ceftriaxone and amoxicillin-clavulanic acid), macrolides (clarithromycin), quinolones (moxifloxacin, ciprofloxacin, and levofloxacin), and tetracyclines (minocycline). The second-line medications include cephalosporins (cefepime and cefotaxime) and tetracyclines (doxycycline). For patients with disseminated diseases, central nervous system (CNS) involvement, and/or severe Nocardia infection, a three-drug regimen including TMP–SMX, amikacin, and imipenem or ceftriaxone is recommended [8,15]. Although the duration of treatment for nocardial infections is unclear, 6 weeks of treatment for topical nocardiosis and 6 months to 1 year of treatment for systemic nocardiosis are recommended. The duration of treatment depends on the response to the therapy and the immune function of the patient [8,15].\n\nIn this study, we retrospectively analyzed the clinical records of patients with nocardiosis who were admitted to our hospital in the last 5 years (January 2013 to November 2018). We also reviewed the relevant literature to provide references for early diagnosis and treatment of nocardiosis.\n\n2 Methods\n\nIn this retrospective study, 11 patients with nocardiosis from our hospital who were diagnosed with conventional phenotypic and biochemical species identification were included. Over the 5-year period from January 2013 to November 2018, demographic data (such as age, sex, underlying diseases, and risk factors), clinical manifestations, radiological investigation, pathology features, treatment, and patient outcomes were reviewed. Mixed infection was considered if evidence of infection of microorganisms other than Nocardia was found 7 days before or 7 days after the date of the nocardiosis diagnosis. The research related to human use has been approved by the Medical Ethics Committee of Sun Yat-sen Memorial Hospital.\n\n2.1 Statistical analysis\n\nStatistical analyses were performed using Statistical Product and Service Solutions (SPSS) Software, version 25, to calculate the median.\n\n3 Results\n\n3.1 Demographic data and underlying diseases\n\nEleven patients (seven males and four females) were diagnosed with nocardiosis (Table 1). The median age was 42 years (12–78 years). All patients had at least one underlying disease, such as an autoimmune disease (6/11), blood malignancy (2/11), avascular necrosis of the femoral head (1/11), bronchiectasis (1/11), and pneumonia (1/11). Immunosuppressive or cytotoxic agents were used in eight patients. The median hospitalization time was 23 days (6–58 days). Six patients received invasive procedures. Mixed infection was present in three patients: Acinetobacter baumannii, Candida albicans, and Proteusbacillus vulgaris infection.\n\nTable 1 Demographic and underlying disease for the patients with nocardiosis\n\nNo.\tAge (years)\tGender\tDiagnosis\tUnderlying diseases\tImmunosuppressant or chemotherapy\tHospitalization time (days)\tInvasive procedures\t\n1\t26\tMale\tDisseminated nocardiosis (Nocardia farcinica) (lung, head, blood)\tUndifferentiated connective tissue disease, cerebral vasculitis\tMethylprednisolone, azathioprine\t28\tNone\t\n2\t53\tFemale\tPulmonary nocardiosis (Nocardia otitidiscaviarum)\tBronchiectasis\tNone\t7\tNone\t\n3\t42\tMale\tPulmonary nocardiosis\tNephrotic syndrome, diabetes mellitus\tMethylprednisolone, cyclosporine\t58\tTrachea cannula, pleural drainage, CVC, bronchofiberscope\t\n4\t57\tMale\tLeft hip joint nocardiosis (Nocardia brasiliensis)\tAvascular necrosis of the femoral head\tNone\t52\tArthroscopy, articular cavity cleaning\t\n5\t23\tMale\tDisseminated nocardiosis (skin, blood)\tSystemic lupus erythematosus, lupus nephritis, generalized psoriasis\tMethylprednisolone, hydroxychloroquine\t15\tNone\t\n6\t78\tMale\tDisseminated nocardiosis (Nocardia asteroids) (lung, blood)\tAdult onset Still’s disease\tMethylprednisolone, cyclosporine\t6\tNone\t\n7\t22\tFemale\tSkin nocardiosis\tSystemic lupus erythematosus, lupus nephritis, lupus gastrointestinal damage\tPrednisone, hydroxychloroquine, methotrexate\t36\tIncision and drainage for abscesses\t\n8\t58\tFemale\tDisseminated nocardiosis (lung, skin, abdominal cavity)\tSystemic lupus erythematosus, lupus nephritis, lupus blood system damage, lupus cardiac system damage; secondary Sjogren’s syndrome\tMethylprednisolone, cyclosporine, hydroxychloroquine\t15\tNone\t\n9\t56\tMale\tPulmonary nocardiosis\tPneumonia\tNone\t22\tBronchoscope submucosal biopsy, lung puncture biopsy\t\n10\t12\tFemale\tDisseminated nocardiosis (skin, lung)\tAcute myelogenous leukemia (M1)\tIA, MA\t34\tSkin biopsy, nodule biopsy, PICC\t\n11\t34\tMale\tDisseminated nocardiosis (Nocardia reynolds) (skin, soft tissue, lung)\tT lymphocytic lymphoma, post-allogeneic HSCT, chronic graft versus host disease\tMethylprednisolone, cyclosporine\t23\tAbscess incision, abscess debridement exploration\t\nAbbreviations: IA: idarubicin, cytarabine. MA: mitoxantrone, cytarabine. HSCT: hematopoietic stem cell transplantation. CVC: central venous catheter. PICC: peripherally inserted central catheter.\n\n3.2 Clinical features and auxiliary examination\n\nThe clinical manifestations of nocardiosis were variable, nonspecific, and heterogeneous (Table 2). The most common symptoms were fever (10/11), cough (7/11), expectoration (7/11), and pain (7/11) including joint pain (2/11), chest pain (2/11), headache (1/11), back pain (1/11), and abdominal pain (1/11). Chest tightness, shortness of breath, weight loss, and fatigue were also frequently noted. In patients with pulmonary nocardiosis, mass shadows (4/11), pleural effusion (3/11), multiple nodules (2/11), cavities (2/11), and bronchiectasis (1/11) were shown by chest radiography. Routine blood examinations revealed seven cases of leucocytosis. The pathological features were neutrophil infiltration, suppurative or granulomatous inflammation, and a suspiciously positive reaction to acid-fast staining (Figure 1).\n\nTable 2 Clinical, laboratory, and radiological features of the patients\n\nNo.\tDiagnosis\tClinical manifestations\tBlood routine\tRadiographic findings\t\nWBC (×109/L)\tNeu (×109/L)\tPCT (ng/mL)\t\n1\tDisseminated nocardiosis (Nocardia farcinica) (lung, head, blood)\tFever (39.6°C), cough, expectoration, headache\t10.9\t10.46\t0.18\tChest CT showed multiple patchy, mass dense shadows and cavities\t\n2\tPulmonary nocardiosis (Nocardia otitidiscaviarum)\tFever (39.0°C), cough, expectoration, blood-stained sputum, chest tightness\t4.36\t2.66\tNone\tChest CT showed multiple bronchiectasis with infection\t\n3\tPulmonary nocardiosis\tFever (39.5°C), cough, expectoration, chest tightness, chest pain, shortness of breath\t10.25\t8.8\t5.8\tChest CT showed multiple nodules, cavities, and pleural effusion\t\n4\tLeft hip joint nocardiosis (Nocardia brasiliensis)\tLeft hip pain, weight loss\t7.37\t5.51\t0.42\tX-ray of hip joint showed ischemic necrosis combined with osteoarthritis on bilateral femoral head\t\n5\tDisseminated nocardiosis (skin, blood)\tFever (39.6°C), skin erythema, desquamation and pruritus, back pain\t11.46\t9.9\t0.14\tLumbar X-ray and chest X-ray showed no abnormalities\t\n6\tDisseminated nocardiosis (Nocardia asteroids) (lung, blood)\tFever (39.4°C), chills, cough, expectoration, limbs weakness\t10.38\t10.06\tNone\tChest X-ray showed multiple cloud-like mass shadows\t\n7\tSkin nocardiosis\tFever (38.2°C), abdominal pain, vomiting, fatigue, purulent, and ulcerated on right foot\t10.69\t10.18\tNone\tChest X-ray and abdominal ultrasound showed no abnormalities\t\n8\tDisseminated nocardiosis (lung, skin, abdominal cavity)\tFever (40.0°C), cough, expectoration, skin abscess, abdominal distension\t7.1\t6.63\t0.25\tChest CT showed double pneumonia and pleural effusion\t\n9\tPulmonary nocardiosis\tFever (39.0°C), cough, expectoration, chest tightness, chest pain, shortness of breath, weight loss\t27.75\t24.21\t1.07\tPET–CT showed massive hypermetabolic lesions, multiple strips, and mass shadows around the lesion, pleural effusion\t\n10\tDisseminated nocardiosis (skin, lung)\tFever (40.0°C), skin abscess in both lower extremities\t4.45\t3.08\t0.1\tChest CT showed high-density shadow and exudation\t\n11\tDisseminated nocardiosis (Nocardia reynolds) (skin, soft tissue, lung)\tFever (38.6°C), cough, expectoration, pain on left elbow\t13.4\t8.13\t0.17\tChest CT showed multiple nodules\t\nAbbreviations: WBC: white blood cell. N: neutrophilia cell. PCT: procalcitonin. CT: computed tomography. PET–CT: positron emission tomography-computed tomography.\n\nFigure 1 Pathological features of nocardiosis patients. (a) The histopathology of the right lung mass of patient No. 9 showed chronic granulomatous inflammation and hyperplasia of fibrous tissue and lymphoid tissue with necrosis (HE staining, ×200 magnification). (b) Acid-fast staining of the left calf gastrocnemius muscle of the patient No. 10. The result was suspected to be positive (×400 magnification). (c) The histopathology of the gastrocnemius muscle in the left leg of patient No. 10 suggested some neutrophil infiltration and a small number of mild atypical cells, consistent with suppurative inflammation (HE staining, ×100 magnification). (d) The histopathology of the abscess in the left upper limb of patient No. 11 showed chronic purulent inflammation, hyperplasia of fibrous and granulation tissue, and more purulent exudate (HE staining, ×100 magnification).\n\n3.3 Diagnosis, treatment, and outcomes\n\nThe diagnoses of all patients were confirmed by microbiologic studies. Patient specimens were obtained from blood (4/11), sputum (2/11), pus (2/11), joint fluid (1/11), and biopsy (1/11). Using 16S rRNA gene polymerase chain reaction (PCR) for species identification, 5 of 11 cases were classified into specific genotypes: N. asteroids, N. otitidiscaviarum, N. brasiliensis, N. farcinica, and N. Reynolds. Two cases were initially misdiagnosed as pulmonary tuberculosis (Table 3).\n\nTable 3 Antibiotic regimens and outcomes of the patients\n\nNo.\tDiagnosis\tDiagnostic approach\tMisdiagnosis\tTime from onset to treatment (weeks)\tTreatment time after diagnosis (weeks)\tTherapeutic response time (weeks)\tAntimicrobials before diagnosis\tAntimicrobials after diagnosis\tOutcomes\t\n1\tDisseminated nocardiosis (Nocardia farcinica) (lung, head, blood)\tBlood culture\tNone\t2\t47\t8\tMeropenem, Linezolid\tTMP–SMX, Meropenem\tImproved and survival\t\n2\tPulmonary nocardiosis (Nocardia otitidiscaviarum)\tSputum culture\tNone\t1\t17\t3\tPiperacillin Sodium and Sulbactum sodium\tTMP–SMX, Piperacillin tazobactam\tImproved and survival\t\n3\tPulmonary nocardiosis\tSputum culture\tNone\t3\t7\t2\tLinezolid\tTMP–SMX, Meropenem\tImproved and survival\t\n4\tLeft hip joint nocardiosis (Nocardia brasiliensis)\tJoint fluid culture\tNone\t9\t20\t1\tCefuroxime sodium, Doxycycline, Vancomycin\tTMP–SMX, Rifampicin, Streptomycin\tImproved and survival\t\n5\tDisseminated nocardiosis (skin, blood)\tBlood culture\tNone\t2\t23\t1\tCefoperazone Sodium and Sulbactam Sodium\tTMP–SMX, Levofloxacin\tImproved and survival\t\n6\tDisseminated nocardiosis (Nocardia asteroids) (lung, blood)\tBlood culture\tPulmonary tuberculosis\t3\tUnknown\tUnknown\tMeropenem, Linezolid\tTMP–SMX, Imipenem, Minocycline\tDischarged to another hospital and died\t\n7\tSkin nocardiosis\tPus culture\tNone\t8\t40\t4\tCefoperazone Sodium and Sulbactam Sodium, Ornidazale\tTMP–SMX, Streptomycin, Moxifloxacin\tImproved and survival\t\n8\tDisseminated nocardiosis (lung, skin, abdominal cavity)\tBlood culture\tNone\t2\tUnknown\tUnknown\tMeropenem\tTMP–SMX, Levofloxacin\tDischarged to home and died\t\n9\tPulmonary nocardiosis\tTissue biopsy\tPulmonary tuberculosis\t9\tUnknown\tUnknown\tAmikacin, Levofloxacin\tTMP–SMX Linezolid, Imipenem\tDischarged to home and died\t\n10\tDisseminated nocardiosis (skin, lung)\tDiagnostic therapy\tNone\t2\t21\t4\tCefoperazone Sodium and Sulbactam Sodium, Vancomycin\tTMP–SMX, Linezolid\tImproved and survival\t\n11\tDisseminated nocardiosis (Nocardia reynolds) (skin, soft tissue, lung)\tPus culture\tNone\t3\t12\t1\tPiperacillin Sodium and Sulbactum sodium\tTMP–SMX, Linezolid, Levofloxacin\tImproved and survival\t\n\nIn all cases, treatment was initiated after diagnosis based on TMP–SMX combined with one or two antibiotics according to the results of drug-sensitive tests. These additional antibiotics were carbapenems (4/11), quinolones (4/11), oxazolidinones (3/11), streptomycin (2/11), tetracycline (1/11), piperacillin ß-lactams (1/11), and rifampicin (1/11). Six patients (6/11) were treated with two antibiotics, and five patients (5/11) were treated with three antibiotics. Most of the patients received antibiotic therapy for a prolonged period.\n\nThe median time from onset to treatment was 3 weeks (1–9 weeks), and the median duration of treatment after diagnosis was 20.5 weeks (7–47 weeks). The defined response time to Nocardia treatment mainly referred to the time when the clinical symptoms began to abate, including improvement confirmed by chest imaging, a return to normal body temperature, and a reduction in other clinical symptoms. In patients who responded to anti-Nocardia treatment, the median response time was 2.5 weeks (1–8 weeks). Regarding outcomes, eight patients were discharged after improvement and survived, and three patients died (Table 3).\n\n4 Discussion\n\nNocardia is a genus of prokaryotes, firmicutes, actinomycetes, and gram-positive aerobic bacteria. This genus is widely distributed in the environment (e.g., soil, water, air, grass, and rotting plants), and most of the species are saprophytic non-pathogenic bacteria [4]. Since the French veterinarian Edmund Nocard first discovered them in 1888 [15], more than 100 species of Nocardia have been reported [1]. The important pathogens involved in human nocardiosis are Nocardia asteroids, Nocardia brasiliensis, Nocardia farcinica, Nocardia cyriacigeorgica, and Nocardia otitidiscaviarum. N. asteroids is the most common isolated species [7,16].\n\nNocardia is a genus of opportunistic pathogens that mainly affects patients with deficient cellular immunity, such as those with a history of long-term steroid or immunosuppressant use, organ or stem cell transplantation, diabetes, acquired immune deficiency syndrome (AIDS), or chronic lung disease [6,9]. As widely described in the literature, the administration of corticosteroids and/or immunosuppressants is the most common predisposing factor [17,18]. Eight patients in our report received immunosuppressive or cytotoxic agents, which was consistent with previous reports and indicated that nocardiosis is an opportunistic infection usually occurring in patients with immune deficiencies.\n\nNocardia can spread to almost all parts of the body through the blood from the lungs (especially the upper lobes of the lungs) or infected areas of the skin. As inhalation is the main route of transmission for Nocardia, the respiratory tract is the most affected organ, followed by the CNS, skin and soft tissue, kidneys, and peritoneum [19,20,21]. The symptoms of CNS infection include headache, meningeal irritations, seizures, and focal neurological dysfunction. The main manifestations of skin and soft tissue infection are local abscesses [3,5,8]. In this study, 8 of 11 patients (72.73%) had pulmonary infections and presented with cough, expectoration, chest pain, and hemoptysis. Six patients showed disseminated nocardiosis involving lung, blood, joint, head, skin, and soft tissue. All six patients had received corticosteroid or immunosuppressant treatment. The radiological abnormalities in pulmonary nocardiosis are diverse, not pathognomonic, and may mimic a multitude of pulmonary diseases. As the clinical symptoms are similar to tuberculosis, pulmonary nocardiosis is easy to misdiagnose as pulmonary tuberculosis when cultures are not available or confirmative. Two patients in our study (No. 6 and 9) were initially misdiagnosed with pulmonary tuberculosis and received anti-tuberculosis treatment before nocardiosis was confirmed. Both patients died as a result of the progression of nocardiosis, suggesting that misdiagnosis and delayed treatment could cause patient deaths.\n\nIn our study, all patients received combination therapy with antibiotics. Eight patients were discharged from the hospital after timely diagnosis and treatment. Patient No. 11 was a recipient of allogeneic hematopoietic stem cell transplant (HSCT) with chronic graft-versus-host-disease (cGVHD) and was receiving corticosteroids and cyclosporins. He was admitted to the hospital with fever, swelling, and pain in the left upper limb and trunk. An incision to drain an abscess on the left upper limb was performed (Figure 2). A bacterial culture of pus suggested nocardiosis (identified and classified as Nocardia reynolds several days later). Then, TMP–SMX and levofloxacin were given. After 3 days, linezolid was added according to the results of a drug-sensitive test. The symptoms of the patient significantly regressed with no new lesions occurring 1 week after treatment. The duration of therapy was 12 weeks. No relapse was noted after 12 months. Patient No. 10 was a 12-year-old female with acute myeloid leukemia. She complained of fever and painful swelling erythematous lesions on both lower extremities. Bacterial cultures of pus were repeatedly performed, but the results were negative. A biopsy of the left gastrocnemius muscle was performed, displaying neutrophil infiltration, which was consistent with suppurative inflammation. Acid-fast staining was also suspiciously positive. TMP–SMX plus linezolid was used as a diagnostic treatment. The lesions on the lower extremities healed significantly. The duration of therapy was 21 weeks. She had no evidence of recurrence after an 18-month follow-up. Three patients died. One patient (No. 8), who had systemic lupus erythematosus (SLE), was admitted to the hospital with fever, cough, and expectoration. A blood culture was performed immediately, and a positive result of Nocardia was reported 6 days later. She was diagnosed with disseminated Nocardia. TMP–SMX and levofloxacin were given initially, but her condition worsened. After 3 days, the drug-sensitive test indicated that the bacterium was sensitive to linezolid and aminoglycoside, but the patient gave up and was discharged from the hospital for economic reasons. Active stage SLE, bloodstream infection, and no use of sensitive antibiotics contributed to the death of the patient. The other two patients did not receive anti-Nocardia treatment because they were initially misdiagnosed with pulmonary tuberculosis. Both of these patients died because of delayed treatment of Nocardia. Therefore, our study suggests that nocardiosis should be considered in patients with impairment of immunity, particularly in those who do not respond to routine antibiotic therapy. Misdiagnosis and inappropriate management may cause poor outcomes.\n\nFigure 2 Abscess on the left upper limb of patient No. 11. (a and b) Surgical debridement of the abscess on the left upper limb was performed. (c) The photograph of the left upper limb 12 months after surgery showed that the wound was entirely healed.\n\nIn summary, nocardiosis is a relatively rare, opportunistic infection with variable clinical manifestations. Nocardiosis should be considered in patients with infections that rapidly progress or who respond poorly to treatment for common bacterial infections, especially those with a history of long-term steroid and/or immunosuppressant use. In this study, symptoms improved quickly after initiation of therapy based on TMP–SMX combined with carbapenems or other antibiotics according to drug sensitivity in 8 of 11 Nocardia infections. Our work suggests that early diagnosis, timely treatment, and combination drug therapy are keys to improving patient outcomes.\n\nFunding information: This study was supported by the Guangdong Science and Technology Department (grant no. 2016A020215062 and A2019207), and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313612, 2016A030313270, and 2016A030313360).\n\nConflict of interest: The authors have no conflicts of interest.\n\nData availability statement: All data generated or analyzed during this study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Coussement J, Lebeaux D, Rouzaud C, Lortholary O. Nocardia infections in solid organ and hematopoietic stem cell transplant recipients. Curr Opin Infect Dis. 2017;30(6):545–51.\nCoussement J Lebeaux D Rouzaud C Lortholary O Nocardia infections in solid organ and hematopoietic stem cell transplant recipients Curr Opin Infect Dis 2017 30 6 545 51 28922286\n[2] Abreu C, Rocha-Pereira N, Sarmento A, Magro F. Nocardia infections among immunomodulated inflammatory bowel disease patients: a review. World J Gastroenterol. 2015;21(21):6491–8.\nAbreu C Rocha-Pereira N Sarmento A Magro F Nocardia infections among immunomodulated inflammatory bowel disease patients: a review World J Gastroenterol 2015 21 21 6491 8 26074688\n[3] Mazzaferri F, Cordioli M, Segato E, Adami I, Maccacaro L, Sette P, et al. Nocardia infection over 5 years (2011–2015) in an Italian tertiary care hospital. New Microbiol. 2018;41(2):136–40.\nMazzaferri F Cordioli M Segato E Adami I Maccacaro L Sette P Nocardia infection over 5 years (2011–2015) in an Italian tertiary care hospital New Microbiol 2018 41 2 136 40 29806691\n[4] Paige EK, Spelman D. Nocardiosis: 7-year experience at an Australian tertiary hospital. Intern Med J. 2019;49(3):373–9.\nPaige EK Spelman D Nocardiosis: 7-year experience at an Australian tertiary hospital Intern Med J 2019 49 3 373 9 30091232\n[5] Takiguchi Y, Ishizaki S, Kobayashi T, Sato S, Hashimoto Y, Suruga Y, et al. Pulmonary nocardiosis: a clinical analysis of 30 cases. Intern Med. 2017;56(12):1485–90.\nTakiguchi Y Ishizaki S Kobayashi T Sato S Hashimoto Y Suruga Y Pulmonary nocardiosis: a clinical analysis of 30 cases Intern Med 2017 56 12 1485 90 28626172\n[6] Rouzaud C, Rodriguez-Nava V, Catherinot E, Méchaï F, Bergeron E, Farfour E, et al. Clinical assessment of a Nocardia PCR-based assay for diagnosis of nocardiosis. J Clin Microbiol. 2018;56:6.\nRouzaud C Rodriguez-Nava V Catherinot E Méchaï F Bergeron E Farfour E Clinical assessment of a Nocardia PCR-based assay for diagnosis of nocardiosis J Clin Microbiol 2018 56 6\n[7] You Y, Chen W, Zhong B, Song Z, Yang X. Disseminated nocardiosis caused by Nocardia elegans: a case report and review of the literature. Infection. 2018;46(5):705–10.\nYou Y Chen W Zhong B Song Z Yang X Disseminated nocardiosis caused by Nocardia elegans: a case report and review of the literature Infection 2018 46 5 705 10 29737456\n[8] Datta R, Kramer E, Reinhart H, Campbell S, Wong E, Gupta S. Menace elbow: disseminated nocardiosis. Am J Med. 2018;131(11):1307–9.\nDatta R Kramer E Reinhart H Campbell S Wong E Gupta S Menace elbow: disseminated nocardiosis Am J Med 2018 131 11 1307 9 29729234\n[9] Ambrosioni J, Lew D, Garbino J. Nocardiosis: updated clinical review and experience at a tertiary center. Infection. 2010;38(2):89–97.\nAmbrosioni J Lew D Garbino J Nocardiosis: updated clinical review and experience at a tertiary center Infection 2010 38 2 89 97 20306281\n[10] Welsh O, Vera-Cabrera L, Salinas-Carmona MC. Current treatment for Nocardia infections. Expert Opin Pharmacother. 2013;14(17):2387–98.\nWelsh O Vera-Cabrera L Salinas-Carmona MC Current treatment for Nocardia infections Expert Opin Pharmacother 2013 14 17 2387 98 24093436\n[11] Larruskain J, Idigoras P, Marimón JM, Pérez-Trallero E. Susceptibility of 186 Nocardia sp. isolates to 20 antimicrobial agents. Antimicrob Agents Chemother. 2011;55(6):2995–8.\nLarruskain J Idigoras P Marimón JM Pérez-Trallero E Susceptibility of 186 Nocardia sp. isolates to 20 antimicrobial agents Antimicrob Agents Chemother 2011 55 6 2995 8 21402847\n[12] Hinson KR, Herres JA, Chow SK. Answer to July 2018 photo quiz. J Clin Microbiol. 2018;56:7.\nHinson KR Herres JA Chow SK Answer to July 2018 photo quiz J Clin Microbiol 2018 56 7\n[13] Ott SR, Meier N, Kolditz M, Bauer TT, Rohde G, Presterl E, et al. Pulmonary nocardiosis in Western Europe-clinical evaluation of 43 patients and population-based estimates of hospitalization rates. Int J Infect Dis. 2019;81:140–8.\nOtt SR Meier N Kolditz M Bauer TT Rohde G Presterl E Pulmonary nocardiosis in Western Europe-clinical evaluation of 43 patients and population-based estimates of hospitalization rates Int J Infect Dis 2019 81 140 8 30658169\n[14] Wayne PA. Susceptibility testing of mycobacteria, Nocardiae, and other aerobic actinomycetes; approved standard-second edition. CLSI document M24-A2. Pennsylvania: Clinical and Laboratory Standards Institute; 2011. p. 43.\nWayne PA Susceptibility testing of mycobacteria, Nocardiae, and other aerobic actinomycetes; approved standard-second edition CLSI document M24-A2 Pennsylvania Clinical and Laboratory Standards Institute 2011 p. 43\n[15] Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev. 2006;19(2):259–82.\nBrown-Elliott BA Brown JM Conville PS Wallace RJ Jr Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy Clin Microbiol Rev 2006 19 2 259 82 16614249\n[16] Clark NM, Reid GE. Nocardia infections in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):83–92.\nClark NM Reid GE Nocardia infections in solid organ transplantation Am J Transplant 2013 13 Suppl 4 83 92 23465002\n[17] Cattaneo C, Antoniazzi F, Caira M, Castagnola C, Delia M, Tumbarello M, et al. Nocardia spp infections among hematological patients: results of a retrospective multicenter study. Int J Infect Dis. 2013;17(8):e610–4.\nCattaneo C Antoniazzi F Caira M Castagnola C Delia M Tumbarello M Nocardia spp infections among hematological patients: results of a retrospective multicenter study Int J Infect Dis 2013 17 8 e610 4 23453714\n[18] de Montmollin E, Corcos O, Noussair L, Leflon-Guibout V, Belmatoug N, Joly F, et al. Retroperitoneal abscesses due to Nocardia farcinica: report of two cases in patients with malnutrition. Infection. 2012;40(1):93–6.\nde Montmollin E Corcos O Noussair L Leflon-Guibout V Belmatoug N Joly F Retroperitoneal abscesses due to Nocardia farcinica: report of two cases in patients with malnutrition Infection 2012 40 1 93 6 21861123\n[19] Flateau C, Jurado V, Lemaître N, Loïez C, Wallet F, Saiz-Jimenez C, et al. First case of cerebral abscess due to a novel Nocardia species in an immunocompromised patient. J Clin Microbiol. 2013;51(2):696–700.\nFlateau C Jurado V Lemaître N Loïez C Wallet F Saiz-Jimenez C First case of cerebral abscess due to a novel Nocardia species in an immunocompromised patient J Clin Microbiol 2013 51 2 696 700 23224088\n[20] Piau C, Kerjouan M, Le Mouel M, Patrat-Delon S, Henaux PL, Brun V, et al. First case of disseminated infection with Nocardia cerradoensis in a human. J Clin Microbiol. 2015;53(3):1034–7.\nPiau C Kerjouan M Le Mouel M Patrat-Delon S Henaux PL Brun V First case of disseminated infection with Nocardia cerradoensis in a human J Clin Microbiol 2015 53 3 1034 7 25568436\n[21] Chen N, Qin Q, Sun KD, Luo D, Cheng QH. An unusual successful treatment with non-sulfonamides: primary cutaneous nocardiosis caused by Nocardia brasiliensis. Ther Clin Risk Manag. 2018;14:1661–4.\nChen N Qin Q Sun KD Luo D Cheng QH An unusual successful treatment with non-sulfonamides: primary cutaneous nocardiosis caused by Nocardia brasiliensis Ther Clin Risk Manag 2018 14 1661 4 30237721\n\n",
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"title": "Clinical analysis of 11 cases of nocardiosis.",
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"abstract": "BACKGROUND\nTo illustrate the potential side effects and clinical efficacy of Botox injections in treating sialorrhoea.\n\n\nMETHODS\nA 26-year-old patient with cerebral palsy with dystonia had a long history of severe, distressing sialorrhoea. She was treated with three separate Botox injections into her salivary glands in December 2011, July 2012 and March 2013.\n\n\nCONCLUSIONS\nFollowing the Botox injections the patient developed dysphagia, began to expectorate thick mucus and developed a cough; she was treated for a chest injection and during this time her feeding deteriorated. Three injections were given as the patient had an objective and significant reduction in salivation. However, the side effect profile was deemed too great to continue with treatment.\n\n\nCONCLUSIONS\nBotox is a novel and effective treatment for reducing saliva production. Its clinical efficacy is supported by this case and correlates with the recent literature. Although rare, significant side effects can happen and the case presented illustrates the care needed when administering injections, particularly in a subgroup of patients.",
"affiliations": "University of Manchester, United Kingdom. Electronic address: thomas.layton@student.manchester.ac.uk.",
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"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(14)00323-X10.1016/j.ijscr.2014.10.072ArticleAn unusual complication of Botox treatment for sialorrhoea Layton Thomas Benjamin thomas.layton@student.manchester.ac.uk⁎University of Manchester, United Kingdom⁎ Tel.: +44 7703684378. thomas.layton@student.manchester.ac.uk04 11 2014 04 11 2014 2014 5 12 1072 1073 13 3 2014 18 10 2014 20 10 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Highlights\n• Illustrates the potential side effects of Botox injections.\n\n• Highlights the need to locate the salivary glands accurately before using Botox injections.\n\n• Supports the clinical efficacy of using Botox injections in treating sialorrhoea.\n\n\n\nINTRODUCTION\nTo illustrate the potential side effects and clinical efficacy of Botox injections in treating sialorrhoea.\n\nPRESENTATION OF CASE\nA 26-year-old patient with cerebral palsy with dystonia had a long history of severe, distressing sialorrhoea. She was treated with three separate Botox injections into her salivary glands in December 2011, July 2012 and March 2013.\n\nDISCUSSION\nFollowing the Botox injections the patient developed dysphagia, began to expectorate thick mucus and developed a cough; she was treated for a chest injection and during this time her feeding deteriorated. Three injections were given as the patient had an objective and significant reduction in salivation. However, the side effect profile was deemed too great to continue with treatment.\n\nCONCLUSION\nBotox is a novel and effective treatment for reducing saliva production. Its clinical efficacy is supported by this case and correlates with the recent literature. Although rare, significant side effects can happen and the case presented illustrates the care needed when administering injections, particularly in a subgroup of patients.\n\nKeywords\nMaxillofacialCerebral palsy\n==== Body\n1 Introduction\nPathological sialorrhoea can be due to intrinsic hypersalivation or occur secondary to neurological disorders such as amyotrophic lateral sclerosis (ALS), cerebral palsy (CP), Parkinson disease (PD), or as a side effect of medications.1 It can cause both psychological and physiological distress to patients. In children, the most common cause of sialorrhoea is CP with hypersalivation occurring in 10–38% of patients.2 In adults, PD is the most common cause with 70–80% of PD patients demonstrating sialorrhoea.3 Sialorrhoea resulting from neurological conditions has a complex aetiology and is produced by impaired swallowing as a result of compromised neuromuscular function and aberrant coordination of the oral, facial and lingual musculature.1\n\nBotulinum toxin (BoNT) is a neurotoxin that blocks the release of acetylcholine and a number of other neurotransmitters from synaptic vesicles.4 Its effect on drooling was first noticed in patients with Parkinson disease and has been reported to be effective in the treatment of sialorrhoea in numerous case studies, clinical trials and retrospective studies.4 At present, three type A and one type B toxins are in clinical use; onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB.1\n\n2 Case report\nA 26-year-old patient with cerebral palsy had suffered from sialorrhoea all her life. She was treated with three separate Botox injections into her salivary glands in December 2011, July 2012 and March 2013. After the first Botox injection she developed breathing difficulties, a nocturnal cough, produced thick mucus and seemed to choke whilst eating, suffering from dysphagia. Two courses of antibiotics were given, but they had no clinical effect. The patient gradually improved, but her appetite was still reduced.\n\nAfter the second injection the patient's feeding deteriorated again and she developed dysphagia and a distaste of her food. Also, she started to produce more thick mucus and choked at night. She was assessed by a speech and language therapist who advised a soft mash/pureed diet with thickened drinks. In addition to this she was prescribed carbocysteine that did have some effect. Over the next few months her feeding proved very difficult with frequent choking episodes and a general distaste for food leading to a reduced appetite and weight loss.\n\nDespite the side effects listed above the Botox injection were effective at treating the patient's sialorrhoea and she found this socially more acceptable and comfortable. Therefore a further Botox injection was administered. Within three days her feeding deteriorated alarmingly as noted by her parents. She began choking on all food and drinks, with severe episodes making her nauseous and pale. Moreover, taking her oral medication was difficult and she was expectorating thick viscous mucus.\n\nThe parents of the patient declared that there was no doubt in their minds that the side effects described above were associated with the administration of Botox into her salivary glands.\n\n3 Discussion\nBoNT is an established treatment option to treat hypersalivation. Fuster Torres et al.5 stated that a significant reduction was observed in the production of saliva following injections in a number of studies and the duration of the therapeutic effect was 1.5–6 months.5 Hay and Penn6 also noted a statistically significant decrease in drooling in a peadiatric population.5 The case presented here validates the clinical efficacy of Botox in treating sialorrhoea and the patient's carers acknowledged an objective reduction in drooling.\n\nBotox injections are a less invasive treatment strategy for sialorrhoea compared to surgery. Various surgical procedures are available, such as salivary gland duct ligation that is usually used as a last resort when other methods have failed and in severe refractory cases. Behaviour modification techniques, correction of situational factors and oral-motor therapy are other treatment options, but do not always produce a consistent improvement. Oral agents, such as glycopyrrolate, and topical agents are also offered with varying degrees of success. A potential disadvantage of Botox injections is the array of side effects that can be encountered as illustrated in this case. However, in a large scale study Amrita Lakraj et al.1 defined side effects as uncommon and manageable when injections were delivered at experienced centres.\n\nChan et al.7 recently performed a review of the long-term safety and efficacy of Botox injections for sialorrhoea in 69 children. They declared that postinjection complications occurred in 19 patients (23 events). This was fourteen patients (15 events) with minor and five (8 events) with major complications. Major complications included aspiration pneumonia (n = 3), severe dysphagia (n = 2), and loss of motor control of the head (n = 3), resulting in 5 hospitalizations and 2 nasogastric tube insertions. The patient in our report did suffer from dysphagia, and possibly a chest infection, but did not require hospitalization.\n\nIn contrast, Amrita Lakraj et al.1 concluded that along with a significant positive clinical effect in patients BoNT had a limited side effect profile. They stated hypersalivation in 3.9%, dysphagia in 3.3%, xerostomia in 3.3% and pneumonia in 2.2% of patients. The side effects listed here are only apparent in a small minority of the patient sample, but the adverse effect seem characteristic.\n\nAs Botox injections are frequently used in patients with pre-existing dysphagia and other oropharyngeal neurological deficits the side effect of dysphagia may be significant. Any exacerbation of swallowing difficulties could have the potential to cause aspiration pneumonia.8 Dysphagia may result from inaccurate injection of the Botox into the salivary glands signifying the importance of localizing the correct site before the drug is administered.\n\n4 Conclusions\nNumerous studies validate the clinical efficacy of Botox injections in sialorrhoea and the patient presented here supports this data. There is also a wealth of information describing potential side effects of Botox injections, but these are only experienced in a minority of patients. This case is an unusual example of significant side effects resulting from Botox treatment. Also, the cardinal side effects experienced by the patient correlate with reported side effects in the literature, notably dysphagia, increased mucus expectoration and possibly a chest infection. This illustrates the need to consider possible side effects when giving Botox injections as they have the potential to cause significant morbidity, particularly in patients with severe neurological disorders.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nFunding\nNone.\n\nEthical approval\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n==== Refs\nReferences\n1 Amrita Lakraj A. Moghimi N. Jabbari B. Sialorrhea: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins PN Department of Neurology, Case Western Toxins 5 5 2013 1010 1031 23698357 \n2 Hamdy S. Aziz Q. Rothwell J.C. Hobson A. Barlow J. Thompson D.G. Cranial nerve modulation of human cortical swallowing motor pathways Am. J. Physiol. 272 1997 G802 G808 9142911 \n3 Volonte M.A. Porta M. Comi G. Clinical assessment of dysphagia in early phases of Parkinson's disease Neurol. Sci. 23 2002 S121 S122 12548373 \n4 Pal P.K. Calne D.B. Calne S. Tsui J.K. Botulinum toxin a as treatment for drooling saliva in PD Neurology 54 2000 244 247 10636161 \n5 Fuster Torres M.A. Berini Aytés L. Gay Escoda C. Salivary gland application of botulinum toxin for the treatment of sialorrhea Med. Oral Patol. Oral Cir. Bucal 12 November (7) 2007 E511 E517 17978775 \n6 Hay N. Penn C. Botox (®) to reduce drooling in a paediatric population with neurological impairments: a phase I study Int. J. Lang. Commun. Disord. 46 September–October (5) 2011 550 563 21899672 \n7 Chan K.H. Liang C. Wilson P. Higgins D. Allen G.C. Long-term safety and efficacy data on botulinum toxin type A: an injection for sialorrhea JAMA Otolaryngol. Head Neck Surg. 139 February (2) 2013 134 138 23429943 \n8 Glickman S. Deaney C.N. Treatment of relative sialorrhoea with botulinum toxin type A: description and rationale for an injection procedure with case report Eur. J. Neurol. 8 2001 567 571 11784340\n\n",
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"abstract": "Sciatic nerve injury is one of the frequent mononeuropathies in children that occurs due to different causes such as nerve compression, trauma and stretch during surgery. Gluteal injection is an uncommon cause of sciatic injury in developed countries. Poor techniques and frequent injections are the common cause of injection palsy. Proneal division of the sciatic nerve is more prone to injury due to anatomic and structural characteristics. The diagnosis is based on electrophysiological studies and the recovery rate is poor. In this study, in a period of 2 years between 2012 and 2013, we report seven children under 6 years old (three females and four males) with abnormal gait and foot pain following gluteal injection in pediatric electrodiagnostic center. Five children had proneal component and two with tibial component injuries. Five children were followed for one year and only one showed good recovery.",
"affiliations": "Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Medical Philosophy and History Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.",
"authors": "Toopchizadeh|Vahideh|V|;Barzegar|Mohammad|M|;Habibzadeh|Afshin|A|",
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"fulltext": "\n==== Front\nIran J Child NeurolIran J Child NeurolIJCNIranian Journal of Child Neurology1735-46682008-0700Shahid Beheshti University of Medical Sciences Tehran, Iran ijcn-9-069Case ReportSciatic Nerve Injection Palsy in Children, Electrophysiologic Pattern and Outcome: A Case Series Study TOOPCHIZADEH Vahideh MD1BARZEGAR Mohammad MD2HABIBZADEH Afshin MD31 Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 2 Pediatric Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 3 Medical Philosophy and History Research Center, Tabriz University of Medical Sciences, Tabriz, IranCorresponding Author: Toopchizadeh V. MD , Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Sciences, Golgasht Ave., Tabriz, Iran; Zip code: 5166615556; Tel: +984113373967 , Fax: +984113373967 , E-mail: toopchi@tbzmed.ac.irSummer 2015 9 3 69 72 23 8 2014 7 11 2014 11 11 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Sciatic nerve injury is one of the frequent mononeuropathies in children that occurs due to different causes such as nerve compression, trauma and stretch during surgery. Gluteal injection is an uncommon cause of sciatic injury in developed countries. Poor techniques and frequent injections are the common cause of injection palsy. Proneal division of the sciatic nerve is more prone to injury due to anatomic and structural characteristics. The diagnosis is based on electrophysiological studies and the recovery rate is poor. In this study, in a period of 2 years between 2012 and 2013, we report seven children under 6 years old (three females and four males) with abnormal gait and foot pain following gluteal injection in pediatric electrodiagnostic center. Five children had proneal component and two with tibial component injuries. Five children were followed for one year and only one showed good recovery.\n\nKey Words\nGluteal injectionSciatic nerve injuryChildren\n==== Body\nIntroduction\nSciatic nerve injury is one of the frequent mononeuropathies in children that occurs due to different causes such as nerve compression, trauma and stretch during surgery (1-3). Intramuscular gluteal injection is the most common injury mechanism of iatrogenic traumatic sciatic nerve injury, which would cause significant health problems, especially in developing countries (1-3). In children similar to adults, sciatic nerve injury usually presents with clinical features of proneal nerve involvement and electrophysiological evaluations have the main role in its diagnosis. Recovery is minimal and depends on the etiology and the severity of the nerve lesion (3-5). In this study, we report a series of sciatic nerve injury due to gluteal injection, their electrophysiological pattern and outcome.\n\nCase report\nIn a period of 2 years between 2012 and 2013, 7 children (18 months to 6 years old) with pain in lower limb, foot drop and gait problem after gluteal injection were visited in Pediatric Electrodiagnostic Center of Tabriz children hospital. The injected drugs were antibiotics, diclofenac, phenobarbital and metoclopramide (Table 1). The main complaints in all children were pain and abnormal gait after injection. In physical examination, there was weakness in ankle dorsi flexion in five children and weakness in ankle plantar flexion and knee flexion in two cases in the involved limb. Deep tendon reflex of the knee was normal in all children and the Achilles reflex of the ankle was reduced. Sensory tests were not reliable because of children’s uncooperative; however, in two patients there was pain and tenderness in the foot. In electrophysiological studies in five patients, proneal nerve was involved as having reduced or unobtainable compound muscle action potential (CMAP) of deep proneal nerve and sensory nerve action potential (SNAP) of superficial proneal nerve and slight reduction in the CMAP amplitude of tibial nerve and SNAP of sural nerve compared to uninvolved limb. In two patients with injection of phenobarbital and metoclopramide, tibial nerve was mostly involved as significant reduction in CMAP amplitude of tibial nerve and SNAP of sural nerve. Needle electromyography showed neurogenic changes in related muscles (Table 1). Five patients were followed after 12 months with electrodiagnostic tests and good regeneration was observed only in one case (Table 1). The treatment in most cases was physiotherapy and use of splint.\n\nTable 1 Patients’ Characteristics with Sciatic Nerve Injection Palsy\n\n\nPatients\n\t\nAge (y)\n\t\nSex\n\t\nDrug\n\t\nProneal\n\n\nCMAP\n\t\nSPN\n\n\nSNAP\n\t\nTibial\n\n\nCMAP\n\t\nSural\n\n\nSNAP\n\t\nNeurogenic pattern in muscle\n\t\nRegeneration\n\n\nprocess\n\t\n1- AJ\t2\tF\tDiclofenac\tLow Amp.\tUnobtainable\tNormal\tMildly low Amp.\tPL, TA\tGood\t\n2- FR\t3\tF\tAntibiotic\tUnobtainable\tUnobtainable\tNormal\tMildly low Amp.\tPL, TA\tNo\t\n3- NB\t1.5\tM\tPhenobarbital\tMildly Low Amp.\tMildly Low Amp.\tLow Amp.\tunobtainable\tGCS\tPoor\t\n4- MA\t4\tF\tMetoclopramide\tNormal\tNormal\tLow Amp.\tLow Amp.\tGCS\tA few\t\n5- AA\t3\tM\tDiclofenac\tLow Amp\tUnobtainable\tNormal\tLow Amp.\tTA,PL\t---\t\n6- ME\t7\tM\tAntibiotic\tUnobtainable\tUnobtainable\tNormal\tMildly low Amp.\tPL,TA\t---\t\n7- EN\t2.5\tM\tAntibiotic\tLow Amp.\tUnobtainable\tNormal\tMildly low Amp.\tTA,PL\tA few\t\nDiscussion\nThe sciatic nerve is the longest and widest nerve in the body, which originates just distal to the lumbosacral plexus and is responsible for most of the function of the lower extremity. The sciatic nerve has two components, the common proneal nerve and the tibial nerve. Proneal nerve is usually more affected because of its posterolateral position and smaller amount of supporting connective tissue (5, 6). Although electrodiagnostic studies in children may be limited by poor tolerance, but they play a crucial role in establishing the diagnosis, recognizing the place, severity and type of lesion as well as recovery and prognosis of nerve injury (1, 3, 4, 7). Sciatic nerve injury due to gluteal injections is an iatrogenic injury in developing countries that could manifest as mild paresthesia to severe neurologic complications (6). In developed countries, this complication is reduced with less intramuscular injections and more attention in injection (7). The patient is usually complaining of the pain radiating to posterolateral of the limb and variable motor and sensory deficit such as parasthesia, numbness or weakness (6, 8). In this case series, we report seven children with sciatic nerve injury due to gluteal injection, including two patients with tibial nerve involvement and five patients with proneal nerve involvement. Pain and abnormal gait after injection were the chief complaint in most of the cases. In physical examination, there was weakness, pain and tenderness in sole of foot as well as reduced Achilles reflex, but normal deep tendon reflex of the knee. Srinivasan and colleagues also reported 53 sciatic nerve injuries in children in a period of 30 years and observed only one case with nerve injury due to gluteal injection (3). Unlike their study, in our series, we observed seven sciatic nerve injection injuries in two years. This case series is a report of patients in developing countries, while they reported their experience in a developed country. Understanding the anatomy of the gluteal site is important to prevent complications. In developing countries, it is possible that drugs be injected by an inexperienced person especially in private clinic, which would accompany with complications. In a recent review, Mishra et al. reported 1506 sciatic nerve injuries of which 80% were affected in childhood (9). Children are more often affected than adults because of less muscular and fat tissue relative to adults and are more prone to sciatic nerve injury (2, 3, 9). Some drugs, especially analgesics and antibiotics, have often been considered responsible for this complication; however, many other drugs were reported to cause sciatic injury (4, 9). Similarly, in our study, analgesics and antibiotics were responsible for five injuries of seven cases and metoclopramide plus phenobarbital were responsible for other two sciatic nerve injury. The reason for the injury still is not known. The thickness of subcutaneous tissue and gluteal musculature in children is a predisposing factor for the injury (6). It is presumed that allergic reaction, direct nerve fiber damage, neuronal ischemia, and constriction of scar tissue have role in the injury, besides, anatomic variations and neurotoxicity are important (1, 2). The nerve injury due to injection may cause axonal and myelin degeneration. It would also generate tissue inflammation and related inflammatory cascades which results in neuropathy and neuropathic pain (6). Recovery rate is related to the severity of the primary lesion and most of the patients had minimal recovery (3). We followed five patients for one year and recovery rate was good only in one patient. In other four cases, the recovery was minimal.\n\n\nIn conclusion, considering the high possibility of sciatic nerve injury due to gluteal injection and its poor recovery in children, it is recommended that injections be performed by an experienced person and if possible to have less intramuscular injections. In addition to proneal nerve, tibial nerve is also involved in sciatic nerve injury due to gluteal injection in children. Drugs other than antibiotics and analgesics could cause this injury.\n\nAcknowledgments\nThis research was financially supported by Physical Medicine and Rehabilitation Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.\n\n\n\nConflict of interest: None \n\nAuthors’ contribution\nDr Toopchizadeh contributed in sample selection, electrophysiologic studies and clinical revision of the article. \n\nDr Barzegar contributed in electrophysilogical studies and neurological examinations. \n\nDr Habibzadeh contributed in literature research, writing and critical revision.\n==== Refs\nReferences\n1 Yeremeyeva E Kline DG Kim DH Iatrogenic sciatic nerve injuries at but¬tock and thigh levels: the Louisiana State University experience review Neurosurgery 2009 65 4 Suppl A63 6 19927080 \n2 Bramhall RJ Deveraj VS Traumatic sciatic nerve palsy after gluteal injection Eur J Plastic Surg 2011 34 137 8 \n3 Srinivasan J Ryan MM Escolar DM Darras B Jones HR Pediatric sciatic neuropathies: A 30-year prospective study Neurology 2011 76 11 976 80 21403109 \n4 Fapojuwo OA Akinlade TS Gbiri CA A three-year review of sciatic nerve injection palsy in the Physiotherapy Department of a Nigerian Specialist Hospital Afr J Med Med Sci 2008 37 389 93 19301718 \n5 Maqbool W Sheikh S Ahmed A Clinical, electrophysiological, and prognostic study of postinjection sciatic nerve injury: an avoidable cause of loss of limb in the peripheral medical service Ann Indian Acad Neurol 12 116 9 20142858 \n6 Eker HE Cok OY Aribogan A A treatment option for post-injection sciatic neuropathy: transsacral block with methylprednisolone Pain Physician 2010 13 5 451 6 20859314 \n7 Yuen EC So YT Olney RK The electrophysiologic features of sciatic neuropathy in 100 patients Muscle Nerve 1995 18 414 20 7715627 \n8 Pandian JD Bose S Daniel V Singh Y Abraham AP Nerve injuries following intramuscular injections: a clinical and neurophysiological study from Northwest India J Peripher Nerv Syst 2006 11 165 71 16787515 \n9 Mishra P Stringer MD Sciatic nerve injury from intramuscular injection: a persistent and global problem Int J Clin Pract 2010 64 1573 9 20670272\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1735-4668",
"issue": "9(3)",
"journal": "Iranian journal of child neurology",
"keywords": "Children; Gluteal injection; Sciatic nerve injury",
"medline_ta": "Iran J Child Neurol",
"mesh_terms": null,
"nlm_unique_id": "101463836",
"other_id": null,
"pages": "69-72",
"pmc": null,
"pmid": "26401156",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "7715627;19927080;20142858;21403109;20670272;19301718;20859314;16787515",
"title": "Sciatic Nerve Injection Palsy in Children, Electrophysiologic Pattern and Outcome: A Case Series Study.",
"title_normalized": "sciatic nerve injection palsy in children electrophysiologic pattern and outcome a case series study"
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"activesubstance": {
"activesubstancename": "DICLOFENAC"
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{
"abstract": "BACKGROUND\nNon-medical prescription opioid use (NMPOU) has become a major public health issue in the USA and is also increasing in Europe. However, little is known about neuropsychological associations of NMPOU-specifically regarding social cognition, which is essential for social functioning and treatability of opioid dependence. Previous studies with heroin users and opioid-substituted patients reported deficits in various cognitive functions, but these results are likely confounded by comorbid physical and psychiatric diseases, overdose-associated hypoxia, and adulteration of street heroin. Therefore, the purpose of the present study was to investigate social and non-social cognition in a relatively pure NMPOU sample taking opioid analgesics or antitussives.\n\n\nMETHODS\nWe assessed 23 individuals with NMPOU objectively confirmed by hair analyses and 29 opioid-naïve, healthy controls, employing a comprehensive neuropsychological test battery.\n\n\nRESULTS\nSignificant impairments were found between NMPOU individuals and controls regarding the cognitive domains of attention (p < .01, Hedge's g = .85), declarative memory (p < .05, g = .66), and global cognitive empathy (p < .01, g = 0.99)-the latter included problems with emotion recognition from faces, voices, and complex scenes. Opioid hair concentrations transformed to morphine equivalents were negatively correlated with global cognitive empathy (r = - 0.52, p < .01), suggesting dose-dependent deficits.\n\n\nCONCLUSIONS\nIn contrast to stimulant users primarily displaying deficits in emotional empathy, opioid users showed relatively selective impairments in measures of cognitive empathy, with dose-dependent effects suggesting potential opioid-induced deficits and involvement of the opioid-system in processes of cognitive empathy. These results have important implications for future interventions of opioid dependence targeting social functioning and consequently enhancing therapy outcome and preventing relapse.",
"affiliations": "Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital of the University of Zurich, Lenggstrasse 31, PO Box 1931, 8008, Zurich, Switzerland. saraliane.kroll@bli.uzh.ch.;Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital of the University of Zurich, Lenggstrasse 31, PO Box 1931, 8008, Zurich, Switzerland.;Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital of the University of Zurich, Lenggstrasse 31, PO Box 1931, 8008, Zurich, Switzerland.;Psychiatric Hospital of the University of Munich, Nussbaumstrasse 7, 80336, Munich, Germany.;Center for Forensic Hair Analysis, Institute of Forensic Medicine, University of Zurich, Kurvenstrasse 17, 8006, Zurich, Switzerland.;Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital of the University of Zurich, Lenggstrasse 31, PO Box 1931, 8008, Zurich, Switzerland. quednow@bli.uzh.ch.",
"authors": "Kroll|Sara L|SL|http://orcid.org/0000-0001-9823-5171;Nikolic|Emilija|E|;Bieri|Franziska|F|;Soyka|Michael|M|;Baumgartner|Markus R|MR|;Quednow|Boris B|BB|",
"chemical_list": "D000701:Analgesics, Opioid; D003932:Heroin; D009020:Morphine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00213-018-5060-z",
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"issn_linking": "0033-3158",
"issue": "235(12)",
"journal": "Psychopharmacology",
"keywords": "Codeine; Cognition; Emotion recognition; Empathy; Morphine; Opioid addiction; Prescription opioid",
"medline_ta": "Psychopharmacology (Berl)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D003071:Cognition; D004645:Empathy; D005260:Female; D003932:Heroin; D006801:Humans; D008297:Male; D009020:Morphine; D009483:Neuropsychological Tests; D009293:Opioid-Related Disorders; D012919:Social Behavior; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "7608025",
"other_id": null,
"pages": "3451-3464",
"pmc": null,
"pmid": "30310961",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "28761945;22245006;21586330;21531077;23703315;21049527;24046750;10885043;10882838;19011441;29087534;20558415;15537986;28473157;24179316;24115776;26492929;21216272;24094294;21592584;25555525;25976511;16160707;21854644;23453713;1932883;19087898;13688369;28149649;16337817;12439832;22088946;28493364;22771335;23446056;21466500;22715878;12914896;17990089;19608356;29268271;16112148;28095255;23164063;20974173;19338504;23988582;14970829;23800218;3687892;28394427;27069803;23796238;16157488;27660698;20554115;24932875;19395359;26974713;16755332;28281909",
"title": "Cognitive and socio-cognitive functioning of chronic non-medical prescription opioid users.",
"title_normalized": "cognitive and socio cognitive functioning of chronic non medical prescription opioid users"
} | [
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"companynumb": "CH-JNJFOC-20181043295",
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"activesubstancename": "MORPHINE"
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"abstract": "Systemic mastocytosis results from proliferation and activation of an abnormal mast cell clone. It is a heterogeneous disorder with clinical manifestations ranging from skin lesions alone to aggressive multi-organ infiltration and decreased survival. Given these varied manifestations, diagnosis can be difficult. We describe the case of a woman who presented with rash and diarrhoea and had a history of anaphylactic reactions. Over a protracted period, the patient's symptoms were investigated by a number of specialties including gastroenterology, dermatology, immunology and haematology. Morphological, immunohistochemical and molecular analysis of bone marrow samples ultimately led to a diagnosis of systemic mastocytosis. Management with leukotriene and histamine antagonists resulted in significant improvement in symptoms and quality of life. The case serves to highlight the protean manifestations of systemic mastocytosis, the tests available to diagnose it and the agents available to treat it.",
"affiliations": "Haematology, University College London Hospitals NHS Foundation Trust, London, UK.;Haematology, University College London Hospitals NHS Foundation Trust, London, UK.;Haematology, University College London Hospitals NHS Foundation Trust, London, UK.;Haematology, University College London Hospitals NHS Foundation Trust, London, UK.;Haematology, University College London Hospitals NHS Foundation Trust, London, UK.",
"authors": "Nallamilli|Susanna|S|http://orcid.org/0000-0002-6080-601X;O'Neill|Aideen|A|;Wilson|Andrew|A|;Sekhar|Mallika|M|;Lambert|Jonathan|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229967",
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"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "gastrointestinal system; haematology (incl blood transfusion); skin",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000707:Anaphylaxis; D003937:Diagnosis, Differential; D003967:Diarrhea; D005076:Exanthema; D005260:Female; D006801:Humans; D034721:Mastocytosis, Systemic",
"nlm_unique_id": "101526291",
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"pmc": null,
"pmid": "31471359",
"pubdate": "2019-08-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28069279;22012443;24761987;26154789;27507661;17063092;30007464",
"title": "Systemic mastocytosis: variable manifestations can lead to a challenging diagnostic process.",
"title_normalized": "systemic mastocytosis variable manifestations can lead to a challenging diagnostic process"
} | [
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"companynumb": "GB-MICRO LABS LIMITED-ML2019-02654",
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"activesubstancename": "MONTELUKAST SODIUM"
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"abstract": "A complicated case of female genital mutilation (FGM) type 2b done in late-pregnancy is presented and the interplay of Yoruba and Kwale culture, in this case, is discussed. A Yoruba who grew up among Kwales/Urhobos had FGM at 38 weeks and 4 days gestation (to assure vaginal delivery) and presented with vulvar hematoma, septicemia, obstructed labor, and a distressed fetus. 5 days after FGM procedure, she had an emergency cesarean section (EmCS), repair of FGM site and baby was admitted in special care. There was the obvious synergy of the Yoruba culture of FGM in infancy and Kwale/Urhobo culture of FGM in pregnancy. The patient and her fetus/baby almost became mortalities but for prompt intervention. The role of sociocultural factors in the practice of FGM is recommended to be further investigated as FGM even in educated women and at the dangerous stage of term pregnancy is still prevalent.",
"affiliations": "Department of Obstetrics and Gynaecology, University of Benin; Department of Obstetrics and Gynaecology, University of Benin Teaching Hospital, Benin City, Nigeria.;Department of Obstetrics and Gynaecology, University of Benin Teaching Hospital, Benin City, Nigeria.",
"authors": "Sodje|J Dk|JD|;Ilevbare|F O|FO|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins; D013745:Tetanus Toxoid; D008795:Metronidazole; D002443:Ceftriaxone",
"country": "India",
"delete": false,
"doi": "10.4103/njcp.njcp_372_18",
"fulltext": null,
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"issue": "23(6)",
"journal": "Nigerian journal of clinical practice",
"keywords": "Complications; FGM; culture; pregnancy; rights",
"medline_ta": "Niger J Clin Pract",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D002585:Cesarean Section; D019093:Circumcision, Female; D004322:Drainage; D004638:Emergency Treatment; D005260:Female; D005839:Gentamicins; D006406:Hematoma; D006801:Humans; D008795:Metronidazole; D007744:Obstetric Labor Complications; D011247:Pregnancy; D011256:Pregnancy Outcome; D018805:Sepsis; D013745:Tetanus Toxoid; D016896:Treatment Outcome; D014845:Vulvar Diseases; D055815:Young Adult",
"nlm_unique_id": "101150032",
"other_id": null,
"pages": "883-886",
"pmc": null,
"pmid": "32525127",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Transcultural influence on female genital mutilation done in late pregnancy: A case report.",
"title_normalized": "transcultural influence on female genital mutilation done in late pregnancy a case report"
} | [
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"companynumb": "NVSC2020NG233479",
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"activesubstancename": "GENTAMICIN"
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{
"abstract": "BACKGROUND\nChemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response.\n\n\nMETHODS\nA 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life.\n\n\nCONCLUSIONS\nThis case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.",
"affiliations": "Department of Oncology, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain. pmromano@unav.es.;Department of Gynecology, Clínica Universidad de Navarra, Pamplona, Spain.;Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain.;Department of Oncology, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain.;Department of General Surgery, Clínica Universidad de Navarra, Pamplona, Spain.;Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain.;Hematology Service, Clínica Universidad de Navarra, Pamplona, Spain.;Department of Oncology, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain.",
"authors": "Martin-Romano|P|P|;Jurado|M|M|;Idoate|M A|MA|;Arbea|L|L|;Hernandez-Lizoain|J L|JL|;Cano|D|D|;Paramo|J A|JA|;Martin-Algarra|S|S|",
"chemical_list": "D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1262-y",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 126210.1186/s13256-017-1262-yCase ReportDurable complete remission with aromatase inhibitor therapy in a patient with metastatic uterine carcinosarcoma with poor performance status and coagulation disorders: a case report Martin-Romano P. +34 948 275400pmromano@unav.es 1Jurado M. mjurado@unav.es 2Idoate M. A. maidoate@unav.es 3Arbea L. larbea@unav.es 1Hernandez-Lizoain J. L. jlhernande@unav.es 4Cano D. dcanor@unav.es 5Paramo J. A. japaramo@unav.es 6Martin-Algarra S. smalgarra@unav.es 11 0000 0001 2191 685Xgrid.411730.0Department of Oncology, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008 Pamplona, Spain 2 0000 0001 2191 685Xgrid.411730.0Department of Gynecology, Clínica Universidad de Navarra, Pamplona, Spain 3 0000 0001 2191 685Xgrid.411730.0Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain 4 0000 0001 2191 685Xgrid.411730.0Department of General Surgery, Clínica Universidad de Navarra, Pamplona, Spain 5 0000 0001 2191 685Xgrid.411730.0Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain 6 0000 0001 2191 685Xgrid.411730.0Hematology Service, Clínica Universidad de Navarra, Pamplona, Spain 19 4 2017 19 4 2017 2017 11 11529 9 2016 6 3 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nChemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response.\n\nCase presentation\nA 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life.\n\nConclusions\nThis case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.\n\nKeywords\nUterine carcinosarcomaHormonal receptorsAromatase inhibitorsComplete pathological responseLong-term survivorissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nUterine sarcomas are rare diseases with poor outcomes and a diverse histopathological classification. Taken together, these facts hamper a consensus on risk factors and treatment guidelines [1–3]. Despite its limited efficacy, chemotherapy appears to be the optimal regimen for metastatic disease. However, this approach remains controversial, especially in patients with poor performance status (PS) at the time of diagnosis. On the other hand, targets of the estrogen and progesterone receptor have been successfully employed in small series of patients [4, 5].\n\nUterine sarcomas account for nearly 3% of all uterine cancers. Histological categorization according to the World Health Organization Classification of Tumours is represented in Table 1 [6]. The most frequent histological type is leiomyosarcoma, responsible for almost 40% of all cases, followed by endometrial stromal tumors, and undifferentiated sarcomas (15% and 5%, respectively) [1, 7, 8]. Malignant mixed Müllerian tumor or carcinosarcoma of the uterus represents almost 40% of uterine sarcomas. Furthermore, it is now contemplated as a dedifferentiated form of endometrial carcinoma with epithelial and sarcomatous/mesenchymal components [1].Table 1 World Health Organization classification of tumors 2003. Pathology and genetics of tumors of the breast and female genital organs. Uterine sarcomas [6]\n\nMesenchymal tumors\t\n Endometrial stromal and related tumors\t\n Endometrial stromal sarcoma, low grade\t10–15%\t\n Undifferentiated endometrial sarcoma\t5–10%\t\n Smooth muscle tumors\t\n Leiomyosarcoma\t40%\t\n Mixed epithelial and mesenchymal tumors\t\n Carcinosarcoma (malignant Müllerian mixed tumor; metaplastic carcinoma)\t40%\t\n\n\n\nEpidemiology and prognosis are both very different according to each uterine sarcoma subgroup. Leiomyosarcoma and endometrial stromal tumor normally occur in premenopausal women and localized disease is the most common stage at diagnosis. Regardless of the stage at diagnosis, leiomyosarcoma is an aggressive illness with a poor outcome [7, 9] compared to endometrial stromal tumors [10]. Although early stages of both tumors are usually treated with hysterectomy and bilateral salpingo-oophorectomy without lymphadenectomy, there are no standard recommendations for adjuvant therapy or advanced disease treatment due to the absence of randomized clinical trials [5].\n\nUterine carcinosarcoma (UCS) is typically diagnosed in post-menopausal women and usually presents extrauterine spread at the time of diagnosis. The following were suggested as prognostic factors favoring survival: age <40, white race, early stage disease, lymphadenectomy, and adjuvant radiotherapy (RT) [11]. Patients with UCS present a 5-year actuarial survival rate of approximately 30%, mainly due to the high rates of both local and distant relapses [1]. An association between elevated cancer antigen-125 (Ca-125) levels, extrauterine disease, and poor survival has been suggested in a single institution study [12]. When diagnosed at an early stage, the most accepted approach includes total hysterectomy, bilateral oophorectomy, pelvic and aortic lymphadenectomy, omentectomy, and peritoneal cytology, followed by adjuvant pelvic RT [13]. Lymph node dissection has demonstrated an upstaging in 20% of patients with early stage disease [1]. On the other hand, surgical cytoreduction has been investigated in advanced stage, showing increased survival when patients with UCS underwent a complete resection [14]. The role of adjuvant chemotherapy has been studied in small series of patients. The combination of cisplatin and ifosfamide has shown an improvement in both disease-free and overall survival in resected UCS [8, 15]. For advanced disease, paclitaxel-based regimens have promising results in terms of response rates and long-term survival [16, 17]. A phase III randomized trial of ifosfamide and paclitaxel versus carboplatin and paclitaxel could clarify this issue. On the other hand, adjuvant RT decreases the risk of pelvic recurrence [18]. Although multimodal treatment seems to be the appropriate approach, the optimal combination and sequence has yet to be defined [19].\n\nWe present the case of a patient with an unresectable and metastatic UCS with positive hormone receptors, and a poor PS due to vaginal bleeding and a pulmonary thromboembolism, that subsequently improves radically and achieves a complete response with aromatase inhibitor therapy (AIT). Currently, the patient remains free of disease after completing 5 years of treatment.\n\nCase presentation\nThe case of a 54-year-old white postmenopausal woman with an unremarkable past medical history except for a tobacco smoking habit and a few weeks of weight loss, weakness, anorexia, and abdominal mass is described.\n\nThe patient presented to our emergency room in April 2009 after a 5-day history of severe vaginal bleeding and progressive dyspnea, with hypovolemic shock, and confusional status. A physical examination showed hypoxemia, a large abdominal mass, intense abdominal discomfort, and left lower extremity edema. A hemogram showed a severe anemia (hemoglobin 5.5 g/dl). An abdominal computed tomography (CT) scan demonstrated a 20-cm ill-defined heterogeneous hypogastria mass that originated in her uterus with several inner bleeding and necrotic areas, invasion of her right ureter, and both her right iliac artery and vein (Fig. 1a, d); para-aortic and left iliac lymphadenopathy along with bone distortion of L3 and L4 vertebrae were also present (Fig. 1b), as well as a right hydronephrosis (Fig. 1c) due to tumor invasion of her distal ureter, and pulmonary thromboembolism. Admission to the intensive care unit was required for continuous monitoring along with fluid resuscitation, blood transfusion, and anticoagulation treatment. A right ureteral stent placement was also required. As soon as she was stabilized, a biopsy of the pelvic mass was carried out. The pathological diagnosis of a high grade endometrial carcinosarcoma was obtained (Fig. 2a). Intense immunoreactivity to vimentin and keratin was observed in 100% of the tumor within the original biopsy (Fig. 2b, c). Immunohistochemical positive results were also detected for estrogen and progesterone (Fig. 2d). A positron emission tomography (PET) scan confirmed the presence of a large, heterogeneous, and highly metabolic pelvic mass with a maximum standardized uptake value (SUV max) of 17.33, with extension to her lower abdominal cavity. Other pathological deposits were present at her left para-aortic ganglia and L3 to L4 vertebral bodies (Fig. 3). At diagnosis, her Ca-125 was 522.8 UI/ml (Fig. 4a), carcinoembryonic antigen (CEA) was normal, and alkaline phosphatase was 767 UI/L.Fig. 1 \na Computed tomography scan at diagnosis showing the pelvic mass (arrows). b Computed tomography scan at diagnosis showing the bone metastasis in L3 (arrows). c Computed tomography scan at diagnosis displaying a right hydronephrosis (arrows). d Computed tomography scan at diagnosis showing the pelvic mass\n\n\nFig. 2 Positron emission tomography scan at diagnosis\n\n\nFig. 3 \na and b Computed tomography scan showing partial response after 3 months of treatment. Arrows on panel a are pointing to the pelvic mass\n\n\nFig. 4 Positron emission tomography scan after 10 months of therapy\n\n\n\n\nGiven the existence of metastatic disease and an Eastern Cooperative Oncology Group (ECOG) PS of 3, the illness was deemed terminal and non-curable. The patient and her closest relatives confronted the dismal prognosis and, therefore, initiation of chemotherapy was declined.\n\nDue to the presence of a large mass responsible for her vaginal bleeding and severe anemia, as well as the high risk of renal complications as a result of the extrinsic compression of her ureter, palliative radiation was considered. She was then referred to our radiation oncology department for external beam radiation therapy of the abdominopelvic mass, with hemostatic intention. Tridimensional external beam RT with parallel opposed anterior to posterior-posterior to anterior (AP-PA) fields was administered (ten fractions of 2.5 Gy) with complete control of her hemorrhagic symptoms and PS improvement to ECOG 2.\n\nOnce the radiation treatment was completed, based on her immunohistochemical findings and prior reports [4, 20–22], treatment with an oral non-steroidal aromatase inhibitor (letrozole 2.5 mg/daily) was initiated. In May 2009, 5 days after the initiation of AIT, she was discharged and scheduled to be followed on an ambulatory basis. On the first visit, after 1 month of AIT, she displayed PS progress to 1 without any side effects, including hot flashes or joint pain.\n\nThree months after AIT initiation, a hospital admission was required due to urinary infection. An abdominopelvic CT scan demonstrated a partial response (Fig. 5a, b) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (7.6 cm, previous 20 cm) and a fistula between her small intestine and vagina. Given the good radiological response, and her general improvement, an intestinal bypass was performed and AIT was maintained at the same dose for 8 additional months, without side effects.Fig. 5 \na Pathological staging at diagnosis and before treatment. b Vimentin expression at diagnosis. c Keratin expression at diagnosis. d Estrogen expression at diagnosis. e Pathologic complete response (ypT0)\n\n\n\n\nTen months after the initiation of AIT, she was re-evaluated with a PET/CT scan. A decrease in the size and metabolic activity of the pelvic tumor uptake was observed (SUV max = 5.58), as well as a disappearance of metastatic lymph nodes in the para-aortic region and the uptake of L3 to L4 vertebral bodies (Fig. 6). Her Ca-125 and alkaline phosphatase were 12.6 UI/ml and 141 UI/L, respectively.Fig. 6 \na Evolution of Ca-125 levels. b Evolution of bilirubin levels\n\n\n\n\nOnce the excellent objective primary lesion response, the absence of secondary disease, and the significant improvement in PS were established, she was deemed to be a candidate for salvage surgery and an exploratory laparoscopy was performed. During the surgical procedure, the complete removal of the residual mass was considered feasible. The intervention was then converted to a laparotomy and a total hysterectomy with oophorectomy, external iliac lymphadenectomy, a partial cystectomy, excision of small intestine segment, as well as partial debulking of a pelvic residual mass was accomplished. Pathologic examination reported marked bleeding and necrotic changes due to prior treatment, without evidence of tumor disease, and tumor-free lymph nodes (ypT0 ypN0), along with ovarian fibrotic changes secondary to previous AIT, and small bowel atrophy and fibrosis (Fig. 2e).\n\nAfter the surgery, adjuvant letrozole was restarted with the plan to complete 5 years. Nine months after resection, she presented a major midline abdominal hernia. She required an abdominal eventroplasty. During surgery the right ureteral stent was also removed.\n\nIn the following months, she developed a slight but progressive increase in bilirubin levels (from 1.6 to 2.2 mg/dl), which was attributed to the AIT. Therefore, her AIT dose was reduced to 50% and administered every 48 hours, with subsequent normalization of bilirubin levels (Fig. 4b). Letrozole at the reduced dose was maintained until completion of 5 years with good tolerance and an excellent PS, and AIT was discontinued.\n\nAfter more than 7 years of follow-up, she remains free of disease, with negative Ca-125 tumor marker and without symptoms related to the prior illness or the local and systemic treatments received.\n\nDiscussion\nWe describe the case of a patient with a metastatic UCS and a dreadful medical condition who not only recovers from the critical initial situation, but also achieves a pathological complete response. Moreover, she maintained long-term disease control without limiting side effects after completing a multimodality therapy with RT, surgery, and 5 years of treatment with AIT.\n\nIt must be emphasized that the RT dose administered was 25 Gy. This treatment was given with a palliative intention, and its therapeutic goal was merely hemostatic. To the best of our knowledge, such a low radiation dose has never been demonstrated to have any relevant antitumor activity in uterine sarcoma. Results from evaluation of RT in the adjuvant setting have reported superior local control rates, although no survival advantage has been demonstrated [11]. Moreover, when given postoperatively, the recommended dose for external beam RT is usually 45 Gy. Consequently, it is difficult to assume that a RT dose of 25 Gy may induce the response attained in the massive uterine disease, as well as the lymph nodes, and bone metastases.\n\nAfter achieving partial remission of uterine disease, our patient underwent salvage surgery. The intervention was limited to the primary uterine tumor. A pathological report did not show any residual tumor and a complete response was concluded from the resected specimen evaluation. Based on these results as well as on the metabolic response observed in the PET/CT scan, no additional RT was administered on the surgical bed, pelvic nodes, and bone metastases.\n\nIn metastatic uterine sarcomas, chemotherapy is the most commonly accepted treatment, regardless of its histological type [4, 5, 8]. Other approaches like endocrine therapy can be considered a reasonable management due to the occasional presence of estrogen and progesterone receptors in the neoplastic cells, as well as to the results obtained with AIT as previously described [20–22]. However, it must be taken into consideration that some stablished guidelines for sarcoma treatment like the ESMO Clinical Practice Guidelines indicate that tamoxifen must not be recommended in women with uterine sarcoma, due to its clearly stablished side effects [23]. Likewise, the development of UCS has been reported in series of patients with breast cancer treated with long-term tamoxifen [24]. Other agents including progestins have been successfully used in the treatment of patients with endometrial stromal cell cancer, with response rates ranging from 76 to 88% in different clinical studies on uterine sarcoma using aromatase inhibitors [5]. Patients with metastatic leiomyosarcoma have also been treated with aromatase inhibitors, showing encouraging results [22]. Estrogen receptor expression by tissue microarray analysis in advanced UCS has been found to be enlarged and there was increased disease progression [25]. Despite these facts, aromatase inhibitors have not been demonstrated to improve survival and therefore additional clinical and translational research must be completed to consider these agents active in UCS therapy.\n\nThe prognosis of our patient was dismal due to the aggressiveness of the disease and its extension. The administration of systemic chemotherapy was totally contraindicated due to her poor PS and concurrent medical condition, including bleeding, hypovolemic shock, pulmonary thromboembolism, and renal insufficiency. In this context, and given the positivity of estrogen and progesterone receptors in the tumoral cells, the option to initiate oral hormonal therapy with palliative intention seemed reasonable.\n\nConclusions\nUterine sarcoma requires a multidisciplinary approach, but the gold standard in advanced disease still has to be defined. Future studies are required to elucidate whether biological and/or targeted therapy has a role in the treatment of these tumors. In the case of metastatic UCS, chemotherapy and palliative symptomatic RT might be helpful in selected cases but, as our case illustrates, aromatase inhibitors should also be considered an active option in these patients.\n\nAbbreviations\nAITAromatase inhibitor therapy\n\nCa-125Cancer antigen-125\n\nCTComputed tomography\n\nECOGEastern Cooperative Oncology Group\n\nPETPositron emission tomography\n\nPSPerformance status\n\nRTRadiotherapy\n\nSUV maxMaximum standardized uptake value\n\nUCSUterine carcinosarcoma\n\nAcknowledgements\nWe thank Lourdes Soria, NR for her excellent work in the clinical care and management of the patient during the treatment and follow-up period. We also want to express our gratitude to the patient and her family for their desire to share the information about the case, with the hope to be of help to other patients with advanced uterine sarcoma.\n\nFunding\nThere was no funding for this study.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nSM-A and PMR were responsible for the acquisition of data, drafting the manuscripts, and scientific revision. SM-A was responsible for the clinical management of the patient and was supervisor of the discussion and editing of the manuscript. SM-A, PMR, JAP, LA, MJ, JLH-L, and DC were involved in clinical management of the patient and interpretation of data. MAI was responsible for the interpretation of pathology. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Major FJ Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study Cancer 1993 71 4 Suppl 1702 9 10.1002/cncr.2820710440 8381710 \n2. Giuntoli RL 2nd Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy Gynecol Oncol 2003 89 3 460 9 10.1016/S0090-8258(03)00137-9 12798712 \n3. D’Angelo E Prat J Uterine sarcomas: a review Gynecol Oncol 2010 116 1 131 9 10.1016/j.ygyno.2009.09.023 19853898 \n4. Pink D Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: single center experience with 10 cases and review of the literature Gynecol Oncol 2006 101 3 464 9 10.1016/j.ygyno.2005.11.010 16368128 \n5. Amant F Clinical management of uterine sarcomas Lancet Oncol 2009 10 12 1188 98 10.1016/S1470-2045(09)70226-8 19959075 \n6. Tavassoli F Devilee P Organization WH Tumours of the Breast and Female Genital Organs – Pathology and Genetics. World Health Organization Classification of Tumours 2003 Lyon IARC Press \n7. D’Angelo E Spagnoli LG Prat J Comparative clinicopathologic and immunohistochemical analysis of uterine sarcomas diagnosed using the World Health Organization classification system Hum Pathol 2009 40 11 1571 85 10.1016/j.humpath.2009.03.018 19540555 \n8. Reichardt P The treatment of uterine sarcomas Ann Oncol 2012 23 Suppl 10 x151 7 10.1093/annonc/mds359 22987952 \n9. Abeler VM Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients Histopathology 2009 54 3 355 64 10.1111/j.1365-2559.2009.03231.x 19236512 \n10. Dionigi A Endometrial stromal nodules and endometrial stromal tumors with limited infiltration: a clinicopathologic study of 50 cases Am J Surg Pathol 2002 26 5 567 81 10.1097/00000478-200205000-00003 11979087 \n11. Wright JD The role of radiation in improving survival for early-stage carcinosarcoma and leiomyosarcoma Am J Obstet Gynecol 2008 199 5 536. e1 8 10.1016/j.ajog.2008.04.019 18511017 \n12. Huang GS Serum CA125 predicts extrauterine disease and survival in uterine carcinosarcoma Gynecol Oncol 2007 107 3 513 7 10.1016/j.ygyno.2007.08.060 17935762 \n13. Callister M Malignant mixed Mullerian tumors of the uterus: analysis of patterns of failure, prognostic factors, and treatment outcome Int J Radiat Oncol Biol Phys 2004 58 3 786 96 10.1016/S0360-3016(03)01561-X 14967435 \n14. Tanner EJ The role of cytoreductive surgery for newly diagnosed advanced-stage uterine carcinosarcoma Gynecol Oncol 2011 123 3 548 52 10.1016/j.ygyno.2011.08.020 21945551 \n15. Gonzalez Bosquet J The impact of multi-modal therapy on survival for uterine carcinosarcomas Gynecol Oncol 2010 116 3 419 23 10.1016/j.ygyno.2009.10.053 19896181 \n16. Sutton G A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study Gynecol Oncol 2000 79 2 147 53 10.1006/gyno.2000.6001 11063636 \n17. Lacour RA A phase II trial of paclitaxel and carboplatin in women with advanced or recurrent uterine carcinosarcoma Int J Gynecol Cancer 2011 21 3 517 22 10.1097/IGC.0b013e31820da9e2 21436700 \n18. Gerszten K The impact of adjuvant radiotherapy on carcinosarcoma of the uterus Gynecol Oncol 1998 68 1 8 13 10.1006/gyno.1997.4901 9454652 \n19. Cantrell LA Blank SV Duska LR Uterine carcinosarcoma: A review of the literature Gynecol Oncol 2015 137 3 581 8 10.1016/j.ygyno.2015.03.041 25805398 \n20. Spano JP Long-term survival of patients given hormonal therapy for metastatic endometrial stromal sarcoma Med Oncol 2003 20 1 87 93 10.1385/MO:20:1:87 12665689 \n21. Reich O Regauer S Hormonal therapy of endometrial stromal sarcoma Curr Opin Oncol 2007 19 4 347 52 10.1097/CCO.0b013e3281a7ef3a 17545798 \n22. O’Cearbhaill R Treatment of advanced uterine leiomyosarcoma with aromatase inhibitors Gynecol Oncol 2010 116 3 424 9 10.1016/j.ygyno.2009.10.064 19932916 \n23. ESMO/European Sarcoma Network Working Group Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2014 25 Suppl 3 iii102 12 10.1093/annonc/mdu254 25210080 \n24. McCluggage WG Uterine carcinosarcoma in association with tamoxifen therapy Br J Obstet Gynaecol 1997 104 6 748 50 10.1111/j.1471-0528.1997.tb11992.x 9197885 \n25. Huang GS Tissue microarray analysis of hormonal signaling pathways in uterine carcinosarcoma Am J Obstet Gynecol 2009 200 4 457. e1 5 10.1016/j.ajog.2008.12.012 19200930\n\n",
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"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Aromatase inhibitors; Complete pathological response; Hormonal receptors; Long-term survivor; Uterine carcinosarcoma",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D047072:Aromatase Inhibitors; D001778:Blood Coagulation Disorders; D001859:Bone Neoplasms; D002296:Carcinosarcoma; D005260:Female; D006801:Humans; D000077289:Letrozole; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009570:Nitriles; D012074:Remission Induction; D012769:Shock; D014230:Triazoles; D014592:Uterine Hemorrhage; D014594:Uterine Neoplasms",
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"pubdate": "2017-04-19",
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"title": "Durable complete remission with aromatase inhibitor therapy in a patient with metastatic uterine carcinosarcoma with poor performance status and coagulation disorders: a case report.",
"title_normalized": "durable complete remission with aromatase inhibitor therapy in a patient with metastatic uterine carcinosarcoma with poor performance status and coagulation disorders a case report"
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"abstract": "Drug-induced acute pancreatitis (DIAP) is a rare gastrointestinal condition but well-known in the medical literature. The medications have been classified into four subgroups (Classes I-IV) depending upon the propensity of the cases discussed in the literature, interval time period between drug initiation to pancreatitis, and reaction to the drug with reintroduction. Our clinical case is one such example where losartan was described as the agent of recurrent pancreatitis after excluding all other possible causes with laboratory and imaging studies.",
"affiliations": "Internal Medicine, Staten Island University Hospital, Staten Island, USA.;Internal Medicine, Staten Island University Hospital, Staten Island, USA.;Internal Medicine, Staten Island University Hospital, Staten Island, USA.",
"authors": "Anwar|Shamsuddin M|SM|;Aqsa|Anum|A|;Shaukat|Rameez|R|",
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"doi": "10.7759/cureus.6253",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.6253GastroenterologyMedical EducationLosartan-induced Pancreatitis Muacevic Alexander Adler John R Anwar Shamsuddin M 1Aqsa Anum 1Shaukat Rameez 1\n1 \nInternal Medicine, Staten Island University Hospital, Staten Island, USA \nShamsuddin M. Anwar shamsduhs15@gmail.com28 11 2019 11 2019 11 11 e625321 11 2019 28 11 2019 Copyright © 2019, Anwar et al.2019Anwar et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/25318-losartan-induced-pancreatitisDrug-induced acute pancreatitis (DIAP) is a rare gastrointestinal condition but well-known in the medical literature. The medications have been classified into four subgroups (Classes I-IV) depending upon the propensity of the cases discussed in the literature, interval time period between drug initiation to pancreatitis, and reaction to the drug with reintroduction. Our clinical case is one such example where losartan was described as the agent of recurrent pancreatitis after excluding all other possible causes with laboratory and imaging studies.\n\npancreatitisace inhibitorsangiotensin receptor blockadeThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nAcute pancreatitis is a frequently seen gastrointestinal condition in clinical settings, and its common causes include gallstones, hypertriglyceridemia, excess alcohol usage, iatrogenic causes, such as endoscopic retrograde cholangiopancreatography (ERCP), hypercalcemia, and drugs such as certain antiretrovirals, immunosuppressants, diuretics, and antibiotics. We intend to describe one such case of drug-induced acute pancreatitis (DIAP) with renin-angiotensinogen system inhibitor-losartan.\n\nCase presentation\nA 71-year-old female with a pertinent history of essential hypertension, anxiety, and hypothyroidism presented with acute-onset abdominal pain. The pain described the typical characteristics of pancreatitis, with sharp mid-gastric pain radiating towards the back, without any significant relieving factors, accompanied by unremitting nausea and vomiting. The patient did not have any recent history of smoking, drinking, or any recreational drug use. Her home medications included losartan, Synthroid, Xanax, and bupropion.\n\nClinical history did not yield any relevant information, apart from the fact that the patient had presented with similar acute symptoms of pancreatitis approximately four weeks prior to this episode. She was conservatively managed with intravenous fluids and pain control with the resolution of symptoms. The patient was investigated for common causes of pancreatitis, including ultrasound and computed tomography (CT) of the abdomen, lipid profile, drug screen, and hepatitis panel. The workup to rule out the common causes of pancreatitis was negative.\n\nThe patient subsequently improved and was discharged home to be followed by the gastroenterology for further investigations, including magnetic resonance imaging (MRI) of the abdomen and immunoglobulin (IgG4) levels, to rule out uncommon causes of pancreatitis. Of note, before discharge home, she was resumed on losartan at the same dose.\n\nIn this admission, the patient presented with similar complains and the repeat CT abdomen with intravenous (IV) contrast redemonstrated acute pancreatic inflammation with mild peri-pancreatic fluid accumulation without any evidence of necrosis and ductal dilatation (Figure 1). The ultrasound of the abdomen was also repeated, which did not yield any evidence of cholelithiasis and the common bile duct measured 4 mm in size. The patient was evaluated by gastroenterology and was managed symptomatically. MRI the abdomen did not demonstrate intra or extrahepatic biliary ductal pathology, cholelithiasis, or choledocholithiasis. No evidence of abnormal pancreatic ductal pathology was noted. The patient was ultimately taken off losartan and started on calcium channel blocker for hypertension. The patient ultimately improved and was discharged home to do a follow-up with her primary care physician and gastroenterology as needed.\n\nFigure 1 CT abdomen\nThe arrowhead points at the inflamed pancreas.\n\nThe patient had no evidence of abnormal biliary tract or pancreatic duct pathology on relevant imaging studies. Repeat lipid profile, hepatitis panel and liver function tests were within normal limits. The patient did not have alcohol use disorder, and blood alcohol levels were also negative on both admissions. Losartan was deemed as the causative agent for recurrent pancreatitis, a rare phenomenon to be described in the medical literature.\n\nDiscussion\nThe aforementioned clinical case describes drug-induced acute pancreatitis (DIAP) with the causative agent being losartan. The literature review has shown that DIAP is rare and has seldom been reported. It is mainly due to a lack of recognition as most of these medications are used frequently. There are no compartmentalizing features and proving the association of the drug with pancreatitis also requires a high degree of suspicion. Drug discontinuation followed by monitoring for the resolution of symptoms of the drug and re-exposure to the same drug causing another episode of acute pancreatitis leads to the diagnosis. Its prevention requires a current knowledge of medications and their possible side-effects. \n\nFive hundred and fifty drugs are recognized by the World Health Organization (WHO) database to be suspected as a cause of DIAP [1]. Out of these, 525 have been confirmed reported to be associated. It is estimated that DIAP comprises 2% of all cases of acute pancreatitis overall [2]. However, its true incidence is unknown. Causality has been established based on reported cases.\n\nFour categories of medicines have been formulated known to be associated with DIAP. Class I has the list of medications that have at least one case reported as the cause of DIAP. Class IA includes medications that were suspected to be the cause after the most common causes of acute pancreatitis have been excluded. Class IB includes medications that were found to be the cause of DIAP after the rec-challenge of the drug when the common causes could not be ruled out. Class II includes medications that were found to have 75% latency. Class III was not found to have latency and Class IV included medications with very few reported cases and not fitting into other classes [3]. Among inhibitors of the renin-angiotensin system (RAS), reported cases of DIAP are mainly related to the use of captopril, ramipril, enalapril, lisinopril, quinapril, benazepril, losartan, and telmisartan and they are classified as Class IB.\n\nAngiotensin receptor blockers (ARBs) inhibit the binding of molecule angiotensin II at angiotensin type 1 (AT-1) receptors. These receptors are the G-protein coupled receptors with the three other types being AT-2, AT-4, and MAS. All these receptors help regulate cardiovascular, hemodynamic, renal, and endothelial functions in a harmonious way, including cell proliferation, survival, fibroblast proliferation, and inflammation [4]. The net effect is an increase in blood pressure and salt and water retention by vasoconstriction, catecholamine release, increased aldosterone synthesis, vasopressin release, and renal actions [5]. Angiotensin II also exerts its effects by inactivating bradykinin and by the production of prostaglandins. Bradykinin usually causes vasodilation and increased vascular permeability of the post-capillary venules. It leads to extravasation into tissue space, causing angioedema [6-7]. So, ARBs are mainly used to control blood pressure and the common side effects noted are cough, angioedema, hyperkalemia, acute kidney injury, and hypotension.\n\nIt is known that AT-I and AT-II receptors are found in pancreatic ducts and acinar cells, which regulate physiological pancreatic functions. Different mechanisms have been proposed through which renin angiotensinogen system inhibitors can induce pancreatitis. The usage of these classes of medications results in decreased bradykinin degradation and increased endothelin 1 affecting the microcirculation of the pancreas and dysregulating the exocrine secretions [8]. Other proposed mechanisms include angioedema of the pancreatic duct and a direct toxic effect on pancreatic cells [9].\n\nDrug-induced acute pancreatitis is always diagnosed after the common causes of acute pancreatitis have been ruled out. Common causes include gallstones, alcoholism, post-trauma, and post-endoscopic retrograde cholangiopancreatography (ERCP). Once these common causes are excluded, drug-induced pancreatitis is diagnosed based on clinical symptoms, elevated levels of serum lipase, amylase, abdominal imaging, and recurrence of symptoms with the reintroduction of the medication [10]. In our clinical case, abdominal imaging studies, including CT abdomen, ultrasound, and MRI, were found to be negative for intra-abdominal pathology. The patient did not have any dyslipidemia, liver function test abnormalities, abnormal hepatitis panel, or elevated blood alcohol levels. The patient was challenged with the reintroduction of losartan and within four weeks of resuming the medication, she developed similar symptoms again, making this highly suspicious for DIAP.\n\nEland et al., via a prospective case-control study, stated that the risk of DIAP increases with higher loading and maintenance doses [11]. Its incidence is considered highest in the first few months of the onset of therapy. As observed in our case, there was a recurrence within four weeks of restarting losartan therapy. Symptoms resolved on both occasions after losartan discontinuation. A retrospective study conducted by Kuoppala et al. showed a moderately increased risk of DIAP with ACEI [12]. Similarly, Burak et al. described a case of recurrence of pancreatitis on resuming valsartan in a 58-year-old male [13]. He developed the second episode of pancreatitis within six weeks of resuming 160 mg valsartan. It was later discontinued, and the patient then remained symptom-free. In addition, Kanbay et al. shared a case of two episodes of ramipril-induced pancreatitis within 26 months of starting treatment [14]. Upon recognition, it was then replaced by atenolol, and the patient did not have another pancreatitis attack afterward. \n\nTo the best of our knowledge and after thorough literature research, we found three previous case reports of losartan-induced pancreatitis [15-17]. In all these cases, patients were rechallenged with Losartan, which resulted in the recurrence of acute pancreatitis. Pancreatitis being a serious medical condition that can be severe, leading to mortality in about 45% of cases, efforts should be made to further investigate the drug's safety [18]. Given the fact that DIAP is very rare to come across, physicians should have a strong clinical suspicion and insight about these uncommon side effects of commonly prescribed medications including losartan.\n\nConclusions\nLosartan is a commonly prescribed angiotensinogen receptor blocker used for controlling blood pressure. Drug-induced acute pancreatitis is a rare side-effect associated with this medication and the primary means of its diagnosis is by the exclusion of the common causes of pancreatitis.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Drug induced pancreatitis Best Pract Res Clin Gastroenterol Nitsche CJ Jamieson N Lerch MM Mayerle JV 143 155 24 2010 20227028 \n2 Drug-induced pancreatitis Drug Saf Wilmink T Frick TW 406 423 14 1996 8828018 \n3 Drug-induced acute pancreatitis: an evidence-based review Clin Gastroenterol Hepatol Badalov N Baradarian R Iswara K Li J Steinberg W Tenner S 648 661 5 2007 17395548 \n4 Angiotensin receptors: structure, function, signaling and clinical applications [EPub] J Cell Signal Singh KD Karnik SS 111 1 2016 https://www.ncbi.nlm.nih.gov/pubmed/27512731 27512731 \n5 Role of angiotensin II in blood pressure regulation and in the pathophysiology of cardiovascular disorders J Hum Hypertens Fyhrquist F Metsarinne K Tikkanen I 19 24 9 1995 https://www.ncbi.nlm.nih.gov/pubmed/8583476 \n6 Plasma bradykinin in angio-oedema Lancet Nussberger J Cugno M Amstutz C Cicardi M Pellacani A Agostoni A 1693 1697 351 1998 9734886 \n7 The plasma bradykinin-forming pathways and its interrelationships with complement Mol Immunol Kaplan AP Ghebrehiwet B 2161 2169 47 2010 20580091 \n8 Angiotensin-converting enzyme (ACE) inhibitor-induced acute pancreatitis: in search of the evidence South Med J Singh S 1327 1328 99 2006 https://sma.org/southern-medical-journal/article/angiotensin-converting-enzyme-ace-inhibitor-induced-acute-pancreatitis-in-search-of-the-evidence/ 17233187 \n9 Contemporary review of drug-induced pancreatitis: a different perspective World J Gastrointest Pathophysiol Hung WY Abreu Lanfranco O 405 415 5 2014 25400984 \n10 Drug-induced acute pancreatitis: a review Ochsner J Jones MR Hall OM Kaye AM Kaye AD 45 51 15 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365846/ 25829880 \n11 Antihypertensive medication and the risk of acute pancreatitis: the European case-control study on drug-induced acute pancreatitis (EDIP) Scand J Gastroenterol Eland IA Sundstrom A Velo GP 1484 1490 41 2006 17101581 \n12 ACE inhibitors and the risk of acute pancreatitis-a population-based case-control study Pharmacoepidemiol Drug Saf Kuoppala J Enlund H Pulkkinen J Kastarinen H Jyrkkä J Happonen P Paajanen H 853 857 26 2017 28247528 \n13 Valsartan-induced acute pancreatitis Intern Med Can B Sali M Batman A 703 705 53 2014 24694480 \n14 Acute pancreatitis due to ramipril therapy Postgrad Med J Kanbay M Korkmaz M Yilmaz U Gur G Boyacioglu S 617 618 80 2004 15467001 \n15 Acute pancreatitis in a patient treated with losartan [Article in Spanish] Aten Primaria Arellano L Altaba A Santamaria C Garcia-Vicente JA 316 317 46 2014 24690523 \n16 Pancreatitis after losartan Lancet Birck R Keim V Fiedler F van der Woude FJ Rohmeiss P 1178 351 1998 9643695 \n17 Losartan-induced acute pancreatitis Ann Intern Med Bosch X 1043 1044 127 1997 https://annals.org/aim/article-abstract/711012/losartan-induced-acute-pancreatitis \n18 Mortality prognostic factors in acute pancreatitis J Med Life Popa CC Badiu DC Rusu OC Grigorean VT Neagu SI Strugaru CR 413 418 9 2016 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141403/ 27928447\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(11)",
"journal": "Cureus",
"keywords": "ace inhibitors; angiotensin receptor blockade; pancreatitis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e6253",
"pmc": null,
"pmid": "31893179",
"pubdate": "2019-11-28",
"publication_types": "D002363:Case Reports",
"references": "25829880;8828018;9643695;27928447;17395548;17101581;24690523;17233187;20227028;28247528;20580091;25400984;27512731;15467001;9412296;8583476;9734886;24694480",
"title": "Losartan-induced Pancreatitis.",
"title_normalized": "losartan induced pancreatitis"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP007578",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE SODIUM"
},
"drug... |
{
"abstract": "RNA screening for HEV in 22 liver-transplanted children with chronic graft hepatitis out of a cohort of 267 liver-transplanted children detected a single patient with chronic HEV infection. Although this patient remained viremic for 33 months, anti-HEV-IgG was not detectable with MP assay but with Wantai assay. We present the first case of successful ribavirin therapy in an immunosuppressed child with chronic HEV infection. In conclusion, chronic HEV infection in immunosuppressed children may not be detectable employing serological assays. Therefore, the most reliably screening method is screening for HEV-RNA. Chronic HEV infection in children can successfully be treated with ribavirin.",
"affiliations": "Pediatric Gastroenterology and Hepatology, Children's Hospital, Hannover Medical School, Hannover, Germany. Junge.Norman@mh-hannover.de",
"authors": "Junge|Norman|N|;Pischke|Sven|S|;Baumann|Ulrich|U|;Goldschmidt|Imeke|I|;Manns|Michael|M|;Wedemeyer|Heiner|H|;Pfister|Eva-Doreen|ED|",
"chemical_list": "D000914:Antibodies, Viral; D000998:Antiviral Agents; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D012367:RNA, Viral; D012254:Ribavirin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12077",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "17(4)",
"journal": "Pediatric transplantation",
"keywords": null,
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D000914:Antibodies, Viral; D000998:Antiviral Agents; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006505:Hepatitis; D016751:Hepatitis E; D006801:Humans; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007223:Infant; D017093:Liver Failure; D016031:Liver Transplantation; D008297:Male; D016133:Polymerase Chain Reaction; D011183:Postoperative Complications; D012367:RNA, Viral; D012189:Retrospective Studies; D012254:Ribavirin",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "343-7",
"pmc": null,
"pmid": "23551547",
"pubdate": "2013-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Results of single-center screening for chronic hepatitis E in children after liver transplantation and report on successful treatment with ribavirin.",
"title_normalized": "results of single center screening for chronic hepatitis e in children after liver transplantation and report on successful treatment with ribavirin"
} | [
{
"companynumb": "DE-KADMON PHARMACEUTICALS, LLC-KAD201306-000759",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugaddi... |
{
"abstract": "Clinical studies have demonstrated that subclinical actinic keratoses (AKs) may be clinically evidenced following treatment of multiple AKs with a topical immunotherapy agent known to reveal a \"field cancerization\". The aim of our study was to investigate if subclinical AKs may be evidenced also in case of single AKs. Ten patients with single, solitary AKs were treated with IQ 3.75% cream applied on the lesion and on a 5 × 5 cm surrounding area once daily for two 2-week treatment cycles separated by a 2-week treatment-free period. Lesions were evaluated by clinical, dermoscopic and RCM examination. At the end of treatment, subclinical lesions were evidenced in 8 of 10 patients revealing the presence of a field cancerization. If larger studies will confirm these results, field cancerization could likely be considered also in case of solitary AKs, resulting in a different approach in terms of disease evolution and treatment.",
"affiliations": "Dermatology Clinic, University of Catania, Catania, Italy.;Dermatology Clinic, University of Catania, Catania, Italy.;Dermatology Clinic, University of Catania, Catania, Italy.;Centroderm Clinic, Wuppertal, Germany.;Dermatology Clinic, University of Catania, Catania, Italy.",
"authors": "Micali|Giuseppe|G|0000-0002-5157-3939;Verzì|Anna Elisa|AE|0000-0002-3274-6099;Barresi|Sebastiano|S|;Dirschka|Thomas|T|;Lacarrubba|Francesco|F|0000-0002-0860-2060",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/dth.14607",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "34(1)",
"journal": "Dermatologic therapy",
"keywords": "actinic keratosis; dermoscopy; field cancerization; imiquimod; reflectance confocal microscopy",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D006801:Humans; D055623:Keratosis, Actinic; D010865:Pilot Projects",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e14607",
"pmc": null,
"pmid": "33249729",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Field cancerization in clinically solitary actinic keratosis: A pilot study.",
"title_normalized": "field cancerization in clinically solitary actinic keratosis a pilot study"
} | [
{
"companynumb": "IT-TOLMAR, INC.-20IT024370",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMIQUIMOD"
},
"drugadditional": "3",
... |
{
"abstract": "We successfully used a haploidentical transplantation protocol with posttransplant cyclophosphamide (CY) (50 mg/kg/d on days +3 and +4) for in vivo T-cell depletion in patients with mucopolysaccharidosis using reduced-intensive conditioning regimens, followed by a busulfan-based conditioning regimen, which included busulfan (12 to 16 mg/kg) and fludarabine(150 to 200 mg/m)+rabbit antihuman thymocyte globulin (7.5 to 10 mg/kg) as a conditioning regimen. Cyclosporine or tacrolimus, methotrexate, mycophenolate mofetil, and methylprednisolone were administered to prevent graft-versus-host disease (GVHD). After follow-up for a median period of 1.5 years, all 8 patients without preexisting severe comorbidities and early transplant referrals are alive, with 100% donor chimerism and excellent performance status. Only 1 patient developed chronic GVHD(II). We conclude that posttransplant CY is effective in vivo for T-cell depletion to promote full donor engraftment in patients with mucopolysaccharidosis. In addition, with posttransplant CY, the procedure reduced the rate of GVHD and the cost of transplant and improved the patients' quality of life.",
"affiliations": "Department of Hematology and Oncology, Hospital of Capital Institute of Pediatrics, Chaoyang District, Beijing, China.",
"authors": "Yue|Yan|Y|;Song|Zeliang|Z|;Li|Junhui|J|;Feng|Shunqiao|S|;Liu|Rong|R|;Shi|Xiaodong|X|",
"chemical_list": "D000961:Antilymphocyte Serum; D006680:HLA Antigens; D003520:Cyclophosphamide; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001157",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "40(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D064591:Allografts; D000961:Antilymphocyte Serum; D002066:Busulfan; D002675:Child, Preschool; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D009083:Mucopolysaccharidoses; D015996:Survival Rate; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e350-e354",
"pmc": null,
"pmid": "29621063",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Posttransplant Cyclophosphamide for HLA-haploidentical Transplantation in Patients With Mucopolysaccharidosis.",
"title_normalized": "posttransplant cyclophosphamide for hla haploidentical transplantation in patients with mucopolysaccharidosis"
} | [
{
"companynumb": "CN-ALKEM LABORATORIES LIMITED-CN-ALKEM-2018-07003",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "We present the first reported cases of delayed inflammatory reactions (DIR) to hyaluronic acid (HA) dermal fillers after exposure to the COVID-19 spike protein. DIR to HA is reported to occur in the different scenarios including: secondary to poor injection technique, following dental cleaning procedures, following bacterial/viral illness, and after vaccination. In this report of 4 cases with distinct clinical histories and presentations: one case occured following a community acquired COVID-19 infection, one case occured in a study subject in the mRNA-1273 clinical phase III trial, one case occurred following the first dose of publically available mRNA-1273 vaccine (Moderna, Cambridge MA), and the last case occurred after the second dose of BNT162b2 vaccine (Pfizer, New York, NY). Injectable HA dermal fillers are prevalent in aesthetic medicine for facial rejuvenation. Structural modifications in the crosslinking of HA fillers have enhanced the products' resistance to enzymatic breakdown and thus increased injected product longevity, however, have also led to a rise in DIR. Previous, DIR to HA dermal fillers can present clinically as edema with symptomatic and inflammatory erythematous papules and nodules. The mechanism of action for the delayed reaction to HA fillers is unknown and is likely to be multifactorial in nature. A potential mechanism of DIR to HA fillers in COVID-19 related cases is binding and blockade of angiotensin 2 converting enzyme receptors (ACE2), which are targeted by the SARS-CoV-2 virus spike protein to gain entry into the cell. Spike protein interaction with dermal ACE2 receptors favors a pro-inflammatory, loco-regional TH1 cascade, promoting a CD8+T cell mediated reaction to incipient granulomas, which previously formed around residual HA particles. Management to suppress the inflammatory response in the native COVID-19 case required high-dose corticosteroids (CS) to suppress inflammatory pathways, with concurrent ACE2 upregulation, along with high-dose intralesional hyaluronidase to dissolve the inciting HA filler. With regards to the two vaccine related cases; in the mRNA-1273 case, a low dose angiotensin converting enzyme inhibitor (ACE-I) was utilized for treatment, to reduce pro-inflammatory Angiotensin II. Whereas, in the BNT162b2 case the filler reaction was suppressed with oral corticosteroids. Regarding final disposition of the cases; the vaccine-related cases returned to baseline appearance within 3 days, whereas the native COVID-19 case continued to have migratory, evanescent, periorbital edema for weeks which ultimately subsided.",
"affiliations": "Dermatology, Laser, and Vein Specialists of the Carolinas, PLLC, Charlotte, NC, USA. gmunavalli@carolinaskin.com.;Dermatology, Laser, and Vein Specialists of the Carolinas, PLLC, Charlotte, NC, USA.;South Dakota Sanford School of Medicine, Vermillion, SD, USA.;The Derm-Glenview, Glenview, IL, USA.;South Dakota Sanford School of Medicine, Vermillion, SD, USA.;Arena Dermatology, Herzliya, Israel.",
"authors": "Munavalli|Girish Gilly|GG|http://orcid.org/0000-0002-5061-8314;Guthridge|Rachel|R|;Knutsen-Larson|Siri|S|;Brodsky|Amy|A|;Matthew|Ethan|E|;Landau|Marina|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00403-021-02190-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-3696",
"issue": null,
"journal": "Archives of dermatological research",
"keywords": "ACE receptor; ACE receptor inhibitor; ACE2; COVID-19; Delayed inflammatory reaction; Hyaluronic acid fillers; mRNA vaccine",
"medline_ta": "Arch Dermatol Res",
"mesh_terms": null,
"nlm_unique_id": "8000462",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33559733",
"pubdate": "2021-02-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "31592917;32760206;32390279;30789508;32547150;22938010;32880613;23642806;26655699;32035107;32345362;32660650;32336612;33002985;33306989;12646655;32663912;23361999;29952893;32594572;29632758;31118731;33058948;26166260;32785213;32685191;33378609;20606987;33220855;33053279;29636450",
"title": "\"COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment\".",
"title_normalized": "covid 19 sars cov 2 virus spike protein related delayed inflammatory reaction to hyaluronic acid dermal fillers a challenging clinical conundrum in diagnosis and treatment"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-337339",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "A 68-year-old woman presenting with rheumatoid arthritis was admitted due to pancytopenia caused by methotrexate. Pneumocystis jirovecii pneumonia was diagnosed based on the abnormal shadows observed on chest computed tomography, the presence of serum β-D-glucan, and positive P. jirovecii-DNA results in a sputum analysis. Subsequently, after treatment with leucovorin and trimethoprim-sulfamethoxazole, lung consolidation was found to be aggravated, along with a rapidly increasing leukocyte count. In addition, cytomegalovirus colitis was diagnosed. Both conditions were associated with immune reconstitution inflammatory syndrome caused by recovery from leukopenia. The patient was successfully treated with intravenous methylprednisolone pulse therapy and ganciclovir.",
"affiliations": "Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan.;Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan.",
"authors": "Shima|Natsuki|N|;Kokuzawa|Ayako|A|;Saito|Keisuke|K|;Kamata|Yasuyuki|Y|;Nagashima|Takao|T|;Sato|Kojiro|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.7176-21",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34248117\n10.2169/internalmedicine.7176-21\nCase Report\nImmune Reconstitution Inflammatory Syndrome Associated with Pneumocystis jirovecii Pneumonia and Cytomegalovirus Colitis in a Patient with Rheumatoid Arthritis\nShima Natsuki 1\nKokuzawa Ayako 1\nSaito Keisuke 1\nKamata Yasuyuki 1\nNagashima Takao 1\nSato Kojiro 1\n1 Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Japan\nCorrespondence to Dr. Takao Nagashima, naga4ma@jichi.ac.jp\n\n10 7 2021\n15 1 2022\n61 2 245248\n27 1 2021\n27 5 2021\nCopyright © 2022 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 68-year-old woman presenting with rheumatoid arthritis was admitted due to pancytopenia caused by methotrexate. Pneumocystis jirovecii pneumonia was diagnosed based on the abnormal shadows observed on chest computed tomography, the presence of serum β-D-glucan, and positive P. jirovecii-DNA results in a sputum analysis. Subsequently, after treatment with leucovorin and trimethoprim-sulfamethoxazole, lung consolidation was found to be aggravated, along with a rapidly increasing leukocyte count. In addition, cytomegalovirus colitis was diagnosed. Both conditions were associated with immune reconstitution inflammatory syndrome caused by recovery from leukopenia. The patient was successfully treated with intravenous methylprednisolone pulse therapy and ganciclovir.\n\ndisease-modifying anti-rheumatic drugs\nleukopenia\nmethotrexate\nmyelosuppression\npancytopenia\n==== Body\npmcIntroduction\n\nImmune reconstitution inflammatory syndrome (IRIS) is defined as an aggravated immune response generated against various pathogens during recovery of the immune system in patients infected with human immunodeficiency virus (HIV) and treated with antiretroviral therapy (1). The pathogenesis of IRIS remains unclear, but an imbalance in the Th1/Th2 cytokine levels has been partly attributed to its pathogenesis (2-4). A young age of the patients at the initiation of anti-HIV therapy, low CD4+ cell count, and low ratio of CD4+/CD8+ cells are predictors of IRIS in HIV-positive patients (5).\n\nIRIS can also occur in immunocompromised non-HIV patients, such as those who have undergone organ transplantation; those with connective tissue diseases, malignancy, and neutropenia; and women during the postpartum period (2,6-8). Potential mechanisms that promote recovery from immunodeficiency include discontinuation or rapid tapering of glucocorticoids or immunosuppressants or both, withdrawal of or reduction in the effects of anti-tumor necrosis factor (TNF)-α antibodies, and the use of immune-checkpoint antagonists (6).\n\nWe herein report a patient with rheumatoid arthritis (RA) who developed IRIS associated with Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) colitis immediately after discontinuation of methotrexate (MTX) because of pancytopenia.\n\nCase Report\n\nA 68-year-old woman presenting with a 20-year history of RA was admitted to our hospital because of pancytopenia development and the presence of an abnormal shadow on chest computed tomography (CT). She had been treated with MTX (6 mg; weekly) and actarit (100 mg; daily). Her vital signs on arrival in the hospital were as follows: body temperature, 38.9 °C; pulse rate, 122 beats/min; blood pressure, 104/58 mmHg; respiratory rate, 20 breaths/min; and percutaneous oxygen saturation, 95% (2 L/min via nasal cannula). Lung auscultation revealed the presence of coarse crackles at the left lung base. Intermittent abdominal pain was present in the left lower abdomen.\n\nLaboratory findings were as follows: leukocyte count, 1,100 /μL (myelocytes, 2%; metamyelocytes, 1%; neutrophils, 9%; eosinophils, 4%; basophils, 1%; monocytes, 37%; and lymphocytes, 46%); hemoglobin level, 7.7 g/dL; platelet count, 3.8×104/μL; serum albumin, 2.2 g/dL; lactate dehydrogenase level, 149 U/L; urea nitrogen level, 24 mg/dL; creatinine level, 1.67 mg/dL (estimated glomerular filtration rate was 24 mL/min/1.73 m2); C-reactive protein level, 35.85 mg/dL; and IgG level, 824 mg/dL. Liver function test results were nearly within normal ranges. The anti-HIV antibody test result was negative. Chest radiography and plain chest CT revealed the presence of ground-glass opacity in the bilateral lungs and consolidation in the left lower lobe (Fig. 1).\n\nFigure 1. (a) Chest radiography and (b) chest computed tomography (CT) findings on admission. There was a ground-glass opacity in the right lung and consolidation in the left lower lobe.\n\nBacterial pneumonia was suspected, and she was treated with intravenously administered piperacillin/tazobactam (13.5 g; daily). Furthermore, leucovorin administration was commenced for MTX-induced pancytopenia. As the level of serum β-D-glucan was found to be elevated at 156 pg/mL, PCP was clinically diagnosed, and trimethoprim-sulfamethoxazole plus prednisolone (80 mg; daily) was added to the treatment regimen. On the fifth day after admission, repeated chest radiography and chest CT showed the presence of extensive consolidations in the bilateral lungs, suggesting exacerbation of PCP (Fig. 2). The leukocyte count increased and was found to be 24,200 /μL (neutrophils, 59%; lymphocytes, 13%) on that day. As worsening of the consolidations coincided with the rapid recovery of the leukocyte count, the presence of IRIS associated with PCP was considered. Methylprednisolone pulse therapy was commenced, and her general conditions improved. The presence of DNA of P. jirovecii in the sputum was confirmed by polymerase chain reaction.\n\nFigure 2. (a) Repeated chest radiograph and (b) chest CT on day 5 after admission. Consolidation and pleural effusion developed, particularly in the right lung.\n\nOn the 6th day after admission, she developed hematochezia. Colonoscopy revealed the presence of a deep punched-out ulcer in the sigmoid colon (Fig. 3). A histopathological examination of the biopsied mucosa revealed the presence of granulation tissue with inflammatory cell infiltration. An immunohistochemical analysis showed positive results for the CMV antigen. CMV colitis was diagnosed via a macroscopic examination of the colon ulcer and colon histology. Intravenous ganciclovir was administered, and her abdominal symptoms subsided. The clinical course of the patient is shown in Fig. 4.\n\nFigure 3. Macroscopic findings of the sigmoid colon on colonoscopy. Immunohistochemical staining demonstrated positivity for cytomegalovirus antigen (Inset).\n\nFigure 4. Clinical course of the patient. Black triangles indicate mPSL pulse treatment. GCV: ganciclovir, L: leucovorin, Lym: lymphocyte, mPSL: methylprednisolone, PSL: prednisolone, TAZ/PIPC: tazobactam/piperacillin, TMP-SMX: trimethoprim-sulfamethoxazole, WBC: white blood cell\n\nDiscussion\n\nA patient with RA developed IRIS as a manifestation of exacerbated PCP. Rapid recovery of the leukocyte count might have triggered IRIS development. Treatment with methylprednisolone pulse therapy showed improved results. She presented with concomitant CMV colitis, which could also be considered an IRIS.\n\nTo our knowledge, IRIS associated with PCP has never been reported in patients who discontinued MTX alone. IRIS associated with tuberculosis has been reported in a patient with RA when both adalimumab and MTX were discontinued; however, the main immunosuppressive agent was adalimumab (9). IRIS associated with PCP shows acute manifestation compared with that triggered by other microorganisms, such as Mycobacterium tuberculosis or Cryptococcus (10). The interval between admission and worsening of the radiography findings was short (five days) in the patient discussed in this report. PCP-IRIS can develop within a week in HIV-positive patients receiving antiviral therapy (10,11). The prognosis of PCP-IRIS is worse in HIV-negative patients than that in HIV-positive patients; indeed, approximately half of non-HIV patients succumbed to PCP, whereas PCP-associated death was not reported in HIV-positive patients (11,12). More potent immunosuppressive therapy is required for PCP-IRIS in HIV-negative patients than in HIV-positive patients.\n\nThe rapid recovery of the leukocyte count was a trigger for PCP-IRIS development. Regarding IRIS triggered during neutrophil recovery after chemotherapy, invasive aspergillosis and chronic disseminated candidiasis, not PCP, have been reported as causative factors (13). A strong influx of CD4+ and CD8+ cells in the lungs was demonstrated in a patient with HIV after PCP-IRIS had developed (14). In HIV-positive patients, CD4+ cells may be central mediators of IRIS (15). Thus, the rapid recovery of lymphocytes, rather than the recovery of neutrophils, may have contributed to the development of PCP-IRIS in the present patient. The absolute lymphocyte count increased markedly from 506 /μL to 3,146 /μL on the day after admission. Notably, an increased lymphocyte count is a marker for PCP-IRIS in patients who are HIV-negative immunosuppressed hosts (16). However, as the present patient did not undergo a bronchoalveolar lavage examination, there is no direct evidence that the lymphocytes had accumulated in the lungs.\n\nFurthermore, the marked increase in the lymphocyte count may have exacerbated the CMV colitis. CMV colitis rarely manifests as an IRIS; however, it has been reported as an unmasked IRIS in a patient infected with HIV (17-19). The present patient developed hematochezia, which coincided with the exacerbation of PCP. We speculated that CMV colitis was present before admission, and it markedly manifested along with the rapid recovery of lymphocyte count, causing IRIS development (a paradoxical manifestation of IRIS). One case of CMV-IRIS presenting with a skin ulcer has been reported in a patient with rheumatoid vasculitis with tapering doses of prednisolone and MTX (20).\n\nIn conclusion, concurrent development of PCP-IRIS and CMV-IRIS was observed in a patient with RA. The trigger for IRIS development was the rapid recovery of the lymphocyte count from pancytopenia caused by MTX. Since myelosuppression is a major complication observed in patients with RA treated with MTX, clinicians should be alert for IRIS when the lymphocyte count rapidly recovers.\n\nThe patient and her family provided their written informed consent.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Gopal R , Rapaka RR , Kolls JK . Immune reconstitution inflammatory syndrome associated with pulmonary pathogens. Eur Respir Rev 26 : 2017.\n2. Sun HY , Singh N . Immune reconstitution inflammatory syndrome in non-HIV immunocompromised patients. Curr Opin Infect Dis 22 : 394-402, 2009.19483618\n3. Zheng Y , Zhou H , He Y , Chen Z , He B , He M . The immune pathogenesis of immune reconstitution inflammatory syndrome associated with highly active antiretroviral therapy in AIDS. AIDS Res Hum Retroviruses 30 : 1197-1202, 2014.25131160\n4. Grant PM , Komarow L , Lederman MM , et al . Elevated interleukin 8 and T-helper 1 and T-helper 17 cytokine levels prior to antiretroviral therapy in participants who developed immune reconstitution inflammatory syndrome during ACTG A5164. J Infect Dis 206 : 1715-1723, 2012.23002445\n5. Ratnam I , Chiu C , Kandala NB , Easterbrook PJ . Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort. Clin Infect Dis 42 : 418-427, 2006.16392092\n6. Sueki H , Mizukawa Y , Aoyama Y . Immune reconstitution inflammatory syndrome in non-HIV immunosuppressed patients. J Dermatol 45 : 3-9, 2018.28944502\n7. Gupta M , Jafri K , Sharim R , et al . Immune reconstitution inflammatory syndrome associated with biologic therapy. Curr Allergy Asthma Rep 15 : 499, 2015.25504263\n8. Sun HY , Singh N . Opportunistic infection-associated immune reconstitution syndrome in transplant recipients. Clin Infect Dis 53 : 168-176, 2011.21690625\n9. Wallis RS , van Vuuren C , Potgieter S . Adalimumab treatment of life-threatening tuberculosis. Clin Infect Dis 48 : 1429-1432, 2009.19364287\n10. Mok HP , Hart E , Venkatesan P . Early development of immune reconstitution inflammatory syndrome related to Pneumocystis pneumonia after antiretroviral therapy. Int J STD AIDS 25 : 373-377, 2014.24122663\n11. Wu AK , Cheng VC , Tang BS , et al . The unmasking of Pneumocystis jiroveci pneumonia during reversal of immunosuppression: case reports and literature review. BMC Infect Dis 4 : 57, 2004.15588295\n12. Roade Tato L , Burgos Cibrian J , Curran Fabregas A , et al . Immune reconstitution inflammatory syndrome in HIV-infected patients with Pneumocystis jirovecii pneumonia. Enferm Infecc Microbiol Clin (Engl Ed) 36 : 621-626, 2018.29187293\n13. Dellière S , Guery R , Candon S , et al . Understanding pathogenesis and care challenges of immune reconstitution inflammatory syndrome in fungal infections. J Fungi (Basel) 4 : 139, 2018.\n14. Barry SM , Lipman MC , Deery AR , Johnson MA , Janossy G . Immune reconstitution pneumonitis following Pneumocystis carinii pneumonia in HIV-infected subjects. HIV Med 3 : 207-211, 2002.12139660\n15. Barber DL , Andrade BB , Sereti I , Sher A . Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. Nat Rev Microbiol 10 : 150-156, 2012.22230950\n16. Cheng VC , Hung IF , Wu AK , Tang BS , Chu CM , Yuen KY . Lymphocyte surge as a marker for immunorestitution disease due to Pneumocystis jiroveci pneumonia in HIV-negative immunosuppressed hosts. Eur J Clin Microbiol Infect Dis 23 : 512-514, 2004.15141339\n17. von Both U , Laffer R , Grube C , Bossart W , Gaspert A , Günthard HF . Acute cytomegalovirus colitis presenting during primary HIV infection: an unusual case of an immune reconstitution inflammatory syndrome. Clin Infect Dis 46 : e38-e40, 2008.18199043\n18. Yoshida S , Mori N , Honda M . Cytomegalovirus colitis in a patient with HIV infection shortly after initiation of antiretroviral therapy. IDCases 17 : e00552, 2019.31193047\n19. Alukal J , Asif M , Mundada R , McNamee WB . Recurrent cytomegalovirus colitis: a rare case of immune reconstitution inflammatory syndrome. BMJ Case Rep 2018 : bcr2017221121, 2018.\n20. Katsuta M , Shiohara T , Asahina A . Refractory rheumatoid vasculitis complicated by cytomegalovirus reactivation as a manifestation of immune reconstitution inflammatory syndrome. JAAD Case Rep 6 : 652-655, 2020.32613063\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": null,
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "disease-modifying anti-rheumatic drugs; leukopenia; methotrexate; myelosuppression; pancytopenia",
"medline_ta": "Intern Med",
"mesh_terms": null,
"nlm_unique_id": "9204241",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34248117",
"pubdate": "2021-07-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immune Reconstitution Inflammatory Syndrome Associated with Pneumocystis Jirovecii Pneumonia and Cytomegalovirus Colitis in a Patient with Rheumatoid Arthritis.",
"title_normalized": "immune reconstitution inflammatory syndrome associated with pneumocystis jirovecii pneumonia and cytomegalovirus colitis in a patient with rheumatoid arthritis"
} | [
{
"companynumb": "JP-AZURITY PHARMACEUTICALS, INC.-2021AZY00081",
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"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadd... |
{
"abstract": "To describe the impact of hospitalization with COVID-19 infection on warfarin dose requirements in adult inpatients.\nA retrospective chart review of 8 adults on warfarin admitted to Michigan Medicine with COVID-19 infection was conducted and reported as a case series. Outcomes of interest were difference in average daily dose of warfarin prior to admission (PTA) and while inpatient (IP), warfarin sensitivity, time in therapeutic range (TTR), confirmed or suspected thromboembolic event, any major or clinically significant bleeding episodes, and in-hospital mortality. IP average daily warfarin doses were lower when compared to PTA average daily doses [1.3 mg (1.3) vs. 6.2 mg (4.1)]. The mean percentage decrease in dose was 68.8% (23) and the mean absolute dose difference was 4.8 mg (4.3). Mean IP percentage tests in range was 30.8% (24.6) and mean IP warfarin sensitivity was 4.2 (3.8), both of which differed from PTA TTR and warfarin sensitivity for those with data available (n = 3, n = 6, respectively). One patient was treated for suspected acute pulmonary embolism while on warfarin and one patient experienced clinically relevant bleeding. In-hospital mortality was zero, mean length of stay (LOS) was 17 days (14.4), and mean intensive care unit (ICU) LOS for the 3 patients requiring ICU level care was 14.3 days (4.5).\nDecreased warfarin dose requirements were evident in this group of adults hospitalized with COVID-19 infection. These findings suggest lower doses of warfarin may be needed to achieve therapeutic anticoagulation while inpatient.",
"affiliations": "Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA.;Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA.;Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA.;University of Michigan College of Pharmacy, Ann Arbor, MI, USA.;Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA.",
"authors": "Irwin|Madison N|MN|https://orcid.org/0000-0003-3769-7035;Adie|Sarah|S|;Sandison|Katherine|K|;Alsomairy|Sarah A|SA|;Brancaccio|Adamo|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/08971900211000705",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": null,
"journal": "Journal of pharmacy practice",
"keywords": "SARS virus; anticoagulants; coronavirus; international normalized ratio (INR); warfarin",
"medline_ta": "J Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "8971900211000705",
"pmc": null,
"pmid": "33719699",
"pubdate": "2021-03-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Warfarin Dose Requirements in Adults Hospitalized With COVID-19 Infection: A Retrospective Case Series.",
"title_normalized": "warfarin dose requirements in adults hospitalized with covid 19 infection a retrospective case series"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-030708",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "Calcium channel blockers (CCBs) are medications often used in the clinical management of hypertension and coronary artery disease. Gingival enlargement is a common side effect of CCB administration with no other oral tissue hyperplasia being reported. Thus, gingival enlargement is considered to be a tissue-specific side effect of CCBs. Here, we report for the first time a case of CCB-related palate hyperplasia in a patient suffering from oral lichen planus and the possible reasons for its occurrence.",
"affiliations": null,
"authors": "Wang|Xinwen|X|;Liu|Qing|Q|;Dong|Guangying|G|;Wang|Qintao|Q|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP202541",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "54(9)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D017311:Amlodipine; D002121:Calcium Channel Blockers; D005260:Female; D006801:Humans; D006965:Hyperplasia; D017676:Lichen Planus, Oral; D008875:Middle Aged; D021362:Palate, Hard",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "712-5",
"pmc": null,
"pmid": "27251408",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible hard palate hyperplasia associated with amlodipine use: case report.",
"title_normalized": "reversible hard palate hyperplasia associated with amlodipine use case report"
} | [
{
"companynumb": "CN-ACCORD-041673",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nOsmotic demyelination syndrome (ODS), which embraces central pontine and extrapontine myelinolysis, is an uncommon neurological disorder that occurs due to plasma osmotic changes.\n\n\nMETHODS\nWe present the case of a 55-year-old man, who presented with severe hyponatremia due to repeated vomiting, antidepressant treatment and consumption of large amounts of water. Fifteen days after sodium correction, the patient showed fluctuation of vigilance, dysarthria and dysphagia, tremor, cogwheel rigidity, bilateral facial palsy, ophthalmoplegia and tetraparesis. A brain MRI scan revealed extrapontine and later on pontine myelinolysis. He received intravenous steroids and subsequently immunoglobulin. His status began to improve gradually after completion of immunoglobulin and at three month-follow-up had no neurological deficit.\n\n\nMETHODS\nA comprehensive literature search of all reported ODS cases that received immunoglobulin, steroids or plasmapheresis was conducted in the electronic databases PubMed and Web of science.\n\n\nCONCLUSIONS\nImprovement was seen in most cases that received immunoglobulin either during treatment or in the first days after treatment. With regard to steroids, although most cases reported improvement in the following months their effect on the outcome is unclear. Most cases treated with plasmapheresis reported favorable outcome at variable follow-up time. Immunoglobulin and steroids have immunomodulatory effects, which could contribute to promotion of myelin repair in ODS. Plasmapheresis has effects on the immune system beyond removing myelinotoxins from the circulation. More evidence is required to support their use in ODS. However, in view of the disease severity, these therapeutic choices should be considered in the clinical management of ODS.",
"affiliations": "Medical School, University of Cyprus, Nicosia, Cyprus; Department of Neurology, Nicosia General Hospital, Nicosia, Cyprus. Electronic address: stkalampok@gmail.com.;Medical School, University of Cyprus, Nicosia, Cyprus; Department of Neurology, Nicosia General Hospital, Nicosia, Cyprus.;Medical School, University of Cyprus, Nicosia, Cyprus; Department of Neurology, Nicosia General Hospital, Nicosia, Cyprus.;Department of Internal medicine, Nicosia General Hospital, Nicosia, Cyprus.;Department of Internal medicine, Nicosia General Hospital, Nicosia, Cyprus.;Department of Internal medicine, Nicosia General Hospital, Nicosia, Cyprus.;Medical School, University of Cyprus, Nicosia, Cyprus; Department of Neurology, Nicosia General Hospital, Nicosia, Cyprus.",
"authors": "Kalampokini|Stefania|S|;Artemiadis|Artemios|A|;Zis|Panagiotis|P|;Hadjihannas|Linos|L|;Parpas|Giorgos|G|;Kyrri|Artemis|A|;Hadjigeorgiou|Georgios M|GM|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2021.106811",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "208()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Immunoglobulin; Myelinolysis; Osmotic demyelination syndrome; Plasmapheresis; Steroids",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "106811",
"pmc": null,
"pmid": "34358802",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Osmotic demyelination syndrome improving after immune-modulating treatment: Case report and literature review.",
"title_normalized": "osmotic demyelination syndrome improving after immune modulating treatment case report and literature review"
} | [
{
"companynumb": "CY-AUROBINDO-AUR-APL-2022-006584",
"fulfillexpeditecriteria": "1",
"occurcountry": "CY",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "While epistaxis is self-limiting in most cases, patients who are anticoagulated are at increased risk for life-threatening hemorrhage. The management of epistaxis in patients with a left ventricular assist device is further complicated by an increased risk for hemodynamic instability. Here, we detail the successful treatment of massive epistaxis in a left ventricular assist device patient by endovascular particle embolization. We hope to increase awareness in the cardiovascular community of this minimally invasive, potentially life-saving procedure.",
"affiliations": "From the Section of Cardiac Surgery, Yale School of Medicine, New Haven, Connecticut.",
"authors": "Letzen|Brian S|BS|;Matouk|Charles C|CC|;Bonde|Pramod|P|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1097/MAT.0000000000000153",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-2916",
"issue": "61(1)",
"journal": "ASAIO journal (American Society for Artificial Internal Organs : 1992)",
"keywords": null,
"medline_ta": "ASAIO J",
"mesh_terms": "D000368:Aged; D000792:Angiography; D000925:Anticoagulants; D004621:Embolization, Therapeutic; D004844:Epistaxis; D005260:Female; D006353:Heart-Assist Devices; D006801:Humans; D009297:Nasal Mucosa; D009305:Nasopharynx",
"nlm_unique_id": "9204109",
"other_id": null,
"pages": "102-3",
"pmc": null,
"pmid": "25248039",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Particle embolization for the treatment of life-threatening epistaxis in a left ventricular assist device patient.",
"title_normalized": "particle embolization for the treatment of life threatening epistaxis in a left ventricular assist device patient"
} | [
{
"companynumb": "US-BAYER-2015-378986",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"d... |
{
"abstract": "Sweet syndrome (SS) is an acute febrile neutrophilic dermatosis that can be associated with malignancy and medications. A 60-year-old man presented with erythematous, edematous, and ulcerated plaques in the extensor surface of the upper extremities, after a ketoconazole course due to pityrosporum folliculitis. Skin biopsy showed a dense dermal neutrophilic infiltrate, associated with marked papillary dermal edema. Blood count showed leukocytosis and neutrophilia. Skin lesions resolved spontaneously with discoloration after 2 weeks of discontinuation of ketoconazole. Although most cases of drug-induced SS are associated with granulocyte colony-stimulating factor, other medications need to be considered. This is the first reported case of ketoconazole-induced SS despite its widespread use.",
"affiliations": "Departments of *Dermatology and Cutaneous Surgery, and †Pathology, Miller School of Medicine, University of Miami, Miami, FL.",
"authors": "Baquerizo Nole|Katherine L|KL|;Lee|Eric|E|;Villada|Gabriel|G|;Romanelli|Paolo|P|",
"chemical_list": "D000935:Antifungal Agents; D007654:Ketoconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000000252",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "37(5)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000935:Antifungal Agents; D001706:Biopsy; D003875:Drug Eruptions; D006801:Humans; D007654:Ketoconazole; D008297:Male; D008875:Middle Aged; D012867:Skin; D016463:Sweet Syndrome",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "419-22",
"pmc": null,
"pmid": "25590289",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ketoconazole-induced Sweet syndrome: a new association.",
"title_normalized": "ketoconazole induced sweet syndrome a new association"
} | [
{
"companynumb": "US-JNJFOC-20150424623",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "KETOCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "The gabapentinoid drugs gabapentin and pregabalin were originally developed as antiseizure drugs but now are prescribed mainly for treatment of pain. For gabapentin, the only pain-related indication approved by the US Food and Drug Administration (FDA) is postherpetic neuralgia. For pregabalin, FDA-approved indications related to pain are limited to postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy or spinal cord injury, and fibromyalgia. Despite these limited indications, gabapentin and pregabalin are widely prescribed off-label for various other pain syndromes. Such use is growing, possibly because clinicians are searching increasingly for alternatives to opioids.\n\n\n\nThis report summarizes the limited published evidence to support off-label gabapentinoid uses, describes clinical cases in which off-label use is problematic, and notes how review articles and guidelines tend to overstate gabapentinoid effectiveness.\n\n\n\nClinicians who prescribe gabapentinoids off-label for pain should be aware of the limited evidence and should acknowledge to patients that potential benefits are uncertain for most off-label uses.",
"affiliations": "Department of Medicine, University of South Carolina School of Medicine, Columbia.;Department of Medicine, University of South Carolina School of Medicine, Columbia.",
"authors": "Goodman|Christopher W|CW|;Brett|Allan S|AS|",
"chemical_list": "D000700:Analgesics; D000069583:Pregabalin; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1001/jamainternmed.2019.0086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6106",
"issue": "179(5)",
"journal": "JAMA internal medicine",
"keywords": null,
"medline_ta": "JAMA Intern Med",
"mesh_terms": "D000700:Analgesics; D003929:Diabetic Neuropathies; D017277:Drug Approval; D005356:Fibromyalgia; D000077206:Gabapentin; D006801:Humans; D017116:Low Back Pain; D000071081:Minimal Clinically Important Difference; D009437:Neuralgia; D051474:Neuralgia, Postherpetic; D056687:Off-Label Use; D010146:Pain; D010147:Pain Measurement; D000069583:Pregabalin; D011843:Radiculopathy; D012585:Sciatica; D013119:Spinal Cord Injuries",
"nlm_unique_id": "101589534",
"other_id": null,
"pages": "695-701",
"pmc": null,
"pmid": "30907944",
"pubdate": "2019-05-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Clinical Overview of Off-label Use of Gabapentinoid Drugs.",
"title_normalized": "a clinical overview of off label use of gabapentinoid drugs"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-03583",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"druga... |
{
"abstract": "OBJECTIVE\nTo assess the clinical experience of tigecycline-based salvage therapy in patients presenting with Bone and Joint Infections (BJI).\n\n\nMETHODS\nMulticenter retrospective cohort study in France and Turkey (2007-2014).\n\n\nRESULTS\nThirty-six patients (age 58.2±17.8 years; 21 men) were included. The most frequently isolated bacteria were Enterobacteriaceae and staphylococci. Tigecycline (50mg BID, mainly in combination (69.4%), mean duration of 58 days) was indicated for multidrug resistance (90.6%) and/or previous antibiotic intolerance (36.1%), and/or as second- or third-line therapy (69.4%). Six patients (16.7%) experienced early treatment discontinuation for adverse event (4 severe vomiting, 1 pancreatitis, 1 asymptomatic lipase increase). Clinical success was observed in 23 of 30 assessable patients who completed the tigecycline therapy (mean follow-up: 54.1±57.7 weeks).\n\n\nCONCLUSIONS\nProlonged tigecycline-based therapy could be an alternative in patients presenting with BJI requiring salvage therapy, especially if multidrug-resistant Enterobacteriaceae and/or staphylococci are involved.",
"affiliations": "Service de rhumatologie, centre hospitalier Lyon-Sud, hospices civils de Lyon, 69310 Pierre-Bénite, France.;Service des maladies infectieuses, hôpital Raymond-Poincaré, Assistance publique-hôpitaux de Paris, 92380 Garches, France.;Service des maladies infectieuses, CHU de Bordeaux, 33000 Bordeaux, France.;Ege University, Izmir, Turkey.;Çukurova University, Adana, Turkey.;Service des maladies infectieuses, hospices civils de Lyon, 69004 Lyon, France; Université Claude-Bernard Lyon 1, 69100 Lyon, France; Centre de référence des IOA complexes de Lyon, Lyon, France; Inserm U1111, centre international de recherche en infectiologie, CIRI, CNRS UMR5308, ENS de Lyon, UCBL1, 21, avenue Tony-Garnier, 69007 Lyon, France.;Centre de référence des IOA complexes, hôpital Diaconesses-Croix-Saint-Simon, groupe hospitalier, 75012 Paris, France.;Université Claude-Bernard Lyon 1, 69100 Lyon, France; Centre de référence des IOA complexes de Lyon, Lyon, France; Service de chirurgie orthopédique, centre Albert-Trillat, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France.;Université Claude-Bernard Lyon 1, 69100 Lyon, France; Centre de référence des IOA complexes de Lyon, Lyon, France; Laboratoire de bactériologie, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France.;Service des maladies infectieuses, hospices civils de Lyon, 69004 Lyon, France; Université Claude-Bernard Lyon 1, 69100 Lyon, France; Centre de référence des IOA complexes de Lyon, Lyon, France; Inserm U1111, centre international de recherche en infectiologie, CIRI, CNRS UMR5308, ENS de Lyon, UCBL1, 21, avenue Tony-Garnier, 69007 Lyon, France.;Service des maladies infectieuses, hospices civils de Lyon, 69004 Lyon, France; Université Claude-Bernard Lyon 1, 69100 Lyon, France; Centre de référence des IOA complexes de Lyon, Lyon, France; Inserm U1111, centre international de recherche en infectiologie, CIRI, CNRS UMR5308, ENS de Lyon, UCBL1, 21, avenue Tony-Garnier, 69007 Lyon, France. Electronic address: tristan.ferry@univ-lyon1.fr.",
"authors": "Wach|J|J|;Dinh|A|A|;Dutronc|H|H|;Sipahi|O R|OR|;Candevir|A|A|;Valour|F|F|;Zeller|V|V|;Lustig|S|S|;Laurent|F|F|;Chidiac|C|C|;Ferry|T|T|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline",
"country": "France",
"delete": false,
"doi": "10.1016/j.medmal.2017.09.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0399-077X",
"issue": "48(1)",
"journal": "Medecine et maladies infectieuses",
"keywords": "Bone and joint infection; Infection ostéoarticulaire; Tigecycline; Tigécycline",
"medline_ta": "Med Mal Infect",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D015331:Cohort Studies; D004341:Drug Evaluation; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D010000:Osteitis; D010195:Pancreatitis; D012189:Retrospective Studies; D016879:Salvage Therapy; D000078304:Tigecycline; D014421:Turkey; D014839:Vomiting",
"nlm_unique_id": "0311416",
"other_id": null,
"pages": "53-57",
"pmc": null,
"pmid": "29031650",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Tigecycline-based prolonged salvage therapy in patients presenting with complex bone and joint infection.",
"title_normalized": "tigecycline based prolonged salvage therapy in patients presenting with complex bone and joint infection"
} | [
{
"companynumb": "FR-PFIZER INC-2017455043",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
},
"drugadditional": "1",
... |
{
"abstract": "Two multiple myeloma (MM) patients developed venous thromboembolism (VTE) while being treated with lenalidomide and low-dose dexamethasone. Aspirin is recommended for VTE prophylaxis when using lenalidomide/dexamethasone for MM patients with a standard risk of VTE. Despite aspirin administration, however, these two patients experienced VTE. Following VTE development, warfarin and then a Factor Xa inhibitor, edoxaban, were administered. The edoxaban treatment, especially, resulted in favorable and effective control of VTE. Considering these observations, Factor Xa inhibitors may in future become a preferred option for prevention and treatment of VTE when managing MM patients.",
"affiliations": "Department of Internal Medicine, JCHO Tokyo Kamata Medical Center.",
"authors": "Kawaguchi|Masato|M|;Uchimura|Norio|N|;Okuda|Yuko|Y|;Konuma|Satomi|S|;Nehashi|Yoshio|Y|",
"chemical_list": "D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; D013792:Thalidomide; D000077269:Lenalidomide; C552171:edoxaban",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.56.1096",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "56(8)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D009101:Multiple Myeloma; D011725:Pyridines; D013792:Thalidomide; D013844:Thiazoles; D014057:Tomography, X-Ray Computed; D054556:Venous Thromboembolism",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "1096-9",
"pmc": null,
"pmid": "26345573",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of venous thromboembolism with a Factor Xa inhibitor, edoxaban, in patients with lenalidomide-treated multiple myeloma.",
"title_normalized": "successful treatment of venous thromboembolism with a factor xa inhibitor edoxaban in patients with lenalidomide treated multiple myeloma"
} | [
{
"companynumb": "JP-BAYER-2015-457955",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nR-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is standard care for aggressive B-cell lymphoma. A prospective trial was conducted to investigate the role of additive radiotherapy (RT) to bulky and extralymphatic disease.\n\n\nMETHODS\nThe best arm of the RICOVER-60 trial (6×R-CHOP-14+2R [R-CHOP administered once every 2 weeks plus two additional applications of rituximab] plus involved-field RT [36 Gy] to sites of initial bulky [≥ 7.5 cm] disease and extralymphatic involvement) was compared with a cohort receiving the same immunochemotherapy but without RT in an amendment to the RICOVER-60 trial (RICOVER-noRTh) in a prospective fashion.\n\n\nRESULTS\nAfter a median observation time of 39 months, 164 of 166 RICOVER-noRTh patients were evaluable. In a multivariable analysis of the intention-to-treat population adjusting for International Prognostic Index risk factors and age (> 70 years), event-free survival (EFS) of patients with bulky disease was inferior without additive RT (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.5; P = .005), with trends for inferior progression-free (PFS; HR, 1.8; 95% CI, 1.0 to 3.3; P = .058) and overall survival (OS; HR, 1.6; 95% CI, 0.9 to 3.1; P = .127). In a per-protocol analysis with 11 patients in RICOVER-noRTh excluded for receiving unplanned RT, multivariable analysis revealed HRs of 2.7 (95% CI, 1.3 to 5.9; P = .011) for EFS, 4.4 (95% CI, 1.8 to 10.6; P = .001) for PFS, and 4.3 (95% CI, 1.7 to 11.1; P = .002) for OS for patients not receiving RT to bulky disease.\n\n\nCONCLUSIONS\nAdditive RT to bulky sites abrogates bulky disease as a risk factor and improves outcome of elderly patients with aggressive B-cell lymphoma. Whether RT can be spared in patients with (metabolic) complete remission after immunochemotherapy must be addressed in appropriately designed prospective trials.",
"affiliations": "Gerhard Held, Niels Murawski, Jochen Fleckenstein, Viola Pöschel, Carsten Zwick, Jörg Bittenbring, Jörg Schubert, Christian Rübe, and Michael Pfreundschuh, Universitätsklinikum des Saarlandes, Homburg; Marita Ziepert and Markus Löffler, Universität Leipzig, Leipzig; Mathias Hänel, Klinikum Chemnitz, Chemnitz; Sibylla Wilhelm, Städtisches Klinikum Karlsruhe, Karlsruhe; and Norbert Schmitz, Asklepios-Klinik St Georg, Hamburg, Germany.",
"authors": "Held|Gerhard|G|;Murawski|Niels|N|;Ziepert|Marita|M|;Fleckenstein|Jochen|J|;Pöschel|Viola|V|;Zwick|Carsten|C|;Bittenbring|Jörg|J|;Hänel|Mathias|M|;Wilhelm|Sibylla|S|;Schubert|Jörg|J|;Schmitz|Norbert|N|;Löffler|Markus|M|;Rübe|Christian|C|;Pfreundschuh|Michael|M|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2013.51.4505",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "32(11)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "1112-8",
"pmc": null,
"pmid": "24493716",
"pubdate": "2014-04-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma.",
"title_normalized": "role of radiotherapy to bulky disease in elderly patients with aggressive b cell lymphoma"
} | [
{
"companynumb": "DE-JNJFOC-20140811995",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aim was to evaluate the safety of bilateral same-day injections with intravitreal antiangiogenic drugs for macular diseases.\n\n\nMETHODS\nCross-sectional retrospective review of unilateral and bilateral same-day antiangiogenic injections was conducted between January 2011 and March 2016 in the Unit of Macula, University and Polytechnic Hospital La Fe (Valencia, Spain). A total of 8,172 injections were administered, among which 6,560 were unilateral and 1,612 were bilateral injections. Patients were included in the study regardless of the diagnosis. Ranibizumab and aflibercept were the antiangiogenic drugs used. The presence of endophthalmitis or retinal detachment was evaluated.\n\n\nRESULTS\nA total of 1 (0.012%) culture-proven endophthalmitis and 19 (0.233%) acute intraocular inflammations were registered. In the unilateral injections group, there were 18 (0.274%) acute intraocular inflammations and 1 (0.015%) culture-proven endophthalmitis. One (0.062%) of the 1,612 bilateral same-day injections had a unilateral acute intraocular inflammation, and there were no culture-proven endophthalmitis in this group.\n\n\nCONCLUSIONS\nBilateral same-day injections are more convenient for patients and their caregivers than the unilateral injections administered on different days. In our study, the prevalence of culture-proven endophthalmitis and acute intraocular inflammation was lower in the bilateral injections than in the unilateral group. These data support the idea that bilateral same-day injections are a safe and valid treatment to use in our clinical practice.",
"affiliations": "Department of Ophthalmology, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal.;Unit of Macula, Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, spain.;Unit of Macula, Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, spain.;Unit of Macula, Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, spain.",
"authors": "Ruão|Miguel|M|;Andreu-Fenoll|María|M|;Dolz-Marco|Rosa|R|;Gallego-Pinazo|Roberto|R|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OPTH.S124282",
"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S124282opth-11-299Original ResearchSafety of bilateral same-day intravitreal injections of anti-vascular endothelial growth factor agents Ruão Miguel 1Andreu-Fenoll María 2Dolz-Marco Rosa 2Gallego-Pinazo Roberto 21 Department of Ophthalmology, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal2 Unit of Macula, Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, spainCorrespondence: Miguel Ruão, Department of Ophthalmology, Centro Hospitalar Entre Douro e Vouga, Rua Dr Cândido de Pinho 4520-211 – Santa Maria da Feira, Portugal, Tel +351 91417 2638, Email miguelruaocastro@gmail.com2017 01 2 2017 11 299 302 © 2017 Ruão et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Purpose\nThe aim was to evaluate the safety of bilateral same-day injections with intravitreal antiangiogenic drugs for macular diseases.\n\nMethods\nCross-sectional retrospective review of unilateral and bilateral same-day antiangiogenic injections was conducted between January 2011 and March 2016 in the Unit of Macula, University and Polytechnic Hospital La Fe (Valencia, Spain). A total of 8,172 injections were administered, among which 6,560 were unilateral and 1,612 were bilateral injections. Patients were included in the study regardless of the diagnosis. Ranibizumab and aflibercept were the antiangiogenic drugs used. The presence of endophthalmitis or retinal detachment was evaluated.\n\nResults\nA total of 1 (0.012%) culture-proven endophthalmitis and 19 (0.233%) acute intraocular inflammations were registered. In the unilateral injections group, there were 18 (0.274%) acute intraocular inflammations and 1 (0.015%) culture-proven endophthalmitis. One (0.062%) of the 1,612 bilateral same-day injections had a unilateral acute intraocular inflammation, and there were no culture-proven endophthalmitis in this group.\n\nConclusion\nBilateral same-day injections are more convenient for patients and their caregivers than the unilateral injections administered on different days. In our study, the prevalence of culture-proven endophthalmitis and acute intraocular inflammation was lower in the bilateral injections than in the unilateral group. These data support the idea that bilateral same-day injections are a safe and valid treatment to use in our clinical practice.\n\nKeywords\nbilateralintravitrealinjectionsanti-VEGFendophthalmitis\n==== Body\nIntroduction\nIntravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) are extensively used in the treatment of several ophthalmic diseases, including neovascular age-related macular degeneration, diabetic macular edema, macular edema secondary to retinal venous occlusive diseases, and other causes of choroidal neovascularization such as myopia.1–3\n\nPatients often require bilateral treatment. Several physicians administer the first injection in one eye, followed by the second injection in the fellow eye a week later. In these ophthalmic diseases, monthly examinations are frequent, and this second injection increases the patients’ and caregivers’ burden, and the physicians’ as well.4 In order to avoid this burden, bilateral same-day injections are a very common practice in many countries. In a survey made in the United States, 46% of the retina specialists use bilateral injections.5\n\nBilateral same-day injections are usually well tolerated, but patients should be properly advised of the risks, as well as of the symptoms of endophthalmitis.4,6–10\n\nThe rate of infectious endophthalmitis after anti-VEGF intravitreal injections has been described to be between 1 in 1,291 (0.078%) and 1 in 4,500 (0.022%).11,12 McCannel et al13 in a meta-analysis reported a rate of 0.049% of endophthalmitis after intravitreal anti-VEGF.\n\nIn a bilateral same-day injection study, the incidence of culture-proven endophthalmitis was 0.065%, and the incidence of acute intraocular inflammation was 0.033%.1\n\nAcute myocardial infarction, strokes, and thromboembolic events are systemic adverse side effects reported with the intravitreal injections of anti-VEGF,2,14 but it is still unknown if bilateral same-day injections have an increased risk of systemic side effects.6\n\nThe MARINA2 trial showed that patients who received unilateral intravitreal injections of ranibizumab 0.3 mg and 0.5 mg had myocardial infarction rates of 2.5% and 1.3% respectively, and the sham treatment group of 1.7%. The rate of stroke was 1.3% with 0.3 mg, 2.5% with 0.5 mg, and 0.8% in the sham group. None of these were statistically significant.\n\nSeveral recommendations have been made for perioperative care in intravitreal injections. Topical antibiotics pre- or postinjection have not been shown to be effective in the prevention of endophthalmitis, and these could select more virulent microorganism. This way, preinjection antisepsis becomes even more significant and should be applied both before and after topical or subconjunctival anaesthesia. Recommendations on the use of face masks, or maintaining silence, have been made too.15\n\nThe purpose of this study was to evaluate the safety of unilateral and bilateral same-day injections, administered in the same hospital by the same two surgeons (RGP and RDM).\n\nMethods\nCross-sectional retrospective review of medical records of unilateral and bilateral same-day anti-VEGF injections was conducted in the Macula Unit of the University and Polytechnic Hospital La Fe (Valencia) between January 2011 and March 2016. A total of 8,172 injections were administered in 1,024 patients. Only ranibizumab and aflibercept were used. Patients were included regardless the diagnosis. Age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, and myopic choroidal neovascularization were the major indications for injections. All injections were administered by two ophthalmologists (RGP and RDM). None of the exclusion criteria were used. The number of postinjection endophthalmitis was evaluated.\n\nThis study was approved by Instituto de Investigaciones Sanitarias La Fe. Informed consent was included in the study protocol and signed by each patient.\n\nIntravitreal anti-VEGF injection method\nThe Unit of Macula of the Department of Ophthalmology of the University Hospital La Fe (Valencia, Spain) administers intravitreal injections in a controlled ambient surgery cabin, the Arc Steril (Carl Zeiss Meditec, Inc., Jena, Germany). This unit creates ambient with an extremely low level of particles and microorganisms suspended in the air in a standard consultation room, due to the sterile laminar flow system present in the equipment.16\n\nThe preparation of the products was made in a laminar flow chamber in the hospital pharmacy. Individual doses were then transported to the Macula Unit.\n\nThe ophthalmologist administered the injection without surgical scrubs or face mask, but we washed our hands before each procedure. Patients used their own clothes, without hospital gown or face masks. Before the procedure, topical anesthetic and diluted povidone-iodine were instilled in the conjunctiva and cornea. No speculum was used. The intravitreal injection was made in the sclera 3–3.5 mm from the limbus with a 30-gauge needle containing 0.05 mL of anti-VEGF. Care was taken to maintain silence during the injection. Then, a new sterilize set of needle and syringe were used for the fellow eye. Diluted povidone-iodine was again instilled in the conjunctiva, as well as ofloxacin ointment.\n\nAll data were analyzed between March and April of 2016 and collected in an Microsoft® Excel® (Microsoft Corporation, Redmond, WA, USA) document.\n\nResults\nA total of 1,024 patients were administered with 8,172 injections. Six thousand five hundred and sixty unilateral injections were administered, 5,805 with ranibizumab and 755 with aflibercept. One thousand six hundred and twelve bilateral injections were made, 1,495 with ranibizumab and 117 with aflibercept. Table 1 exposes the distribution of injections per year.\n\nThe most common injection cause was age-related macular degeneration, responsible for 4,557 injections, followed by diabetic retinopathy, retinal vein occlusion, and myopic choroidal neovascularization. The different causes for intravitreal injections are shown in Table 2.\n\nIn the 8,172 injections, one culture-proven endophthalmitis and 19 acute intraocular inflammations were diagnosed. This gives us a global endophthalmitis’ prevalence of 0.012% and acute intraocular inflammation of 0.233%. Only one (0.062%) of the 1,612 bilateral same-day injections had a unilateral acute intraocular inflammation, and there were no culture-proven endophthalmitis in this group. In the unilateral injections group, there were 18 (0.274%) acute intraocular inflammations and 1 (0.015%) culture-proven endophthalmitis. Ranibizumab had a lower rate of acute intraocular inflammation, when compared with aflibercept, but the only case of culture-proven endophthalmitis was in a Ranibizumab patient. Table 3 shows the distribution of endophthalmitis per year and anti-VEGF used.\n\nThe only patient with a culture-proven endophthalmitis was an 83-year-old male, without imunosupression or other relevant comorbidity, and was injected with ranibizumab for a neovascular age-related macular degeneration. Culture was positive to Streptococcus pneumoniae. Intravitreal antibiotics and pars plana vitrectomy were performed, and the final visual acuity was 20/500.\n\nFive cases (0.076%) of retinal detatchment were diagnosed in the unilateral injections group. There were no cases of retinal detachment in the bilateral group.\n\nDiscussion\nBilateral same-day injections are common in many countries and are our choice in patients who need injections in both eyes. They are time-saving for the patients, their family, and the physician. The convenience is unquestionable, but safety concerns have been raised. In current literature, many articles have been written in this topic, but no conclusion has been reached.\n\nA large study with 1,534 same-day bilateral intravitreal anti-VEGF (in 367 patients) explored the incidence of complications after this procedure. Three complications were acknowledged: two unilateral culture-proven endophthalmitis (0.065%) and one unilateral acute intraocular inflammation (0.033%).1 These rates seem comparable to those found for unilateral injections (0.078%–0.022%).11,12 But this kind of comparison from different studies, with different conditions, can be misleading. In this study, we minimize this bias, evaluating injections made in the same hospital, by the same two surgeons, with two anti-VEGFs. No culture-proven endophthalmitis was diagnosed in the bilateral injections group, and the rate of acute intraocular inflammation was lower in the same-day bilateral injection group when compared with the unilateral group (0.062% vs 0.152%). The patient diagnosed with acute intraocular inflammation in the bilateral injections group had no signs of inflammation in the fellow eye.\n\nInterestingly, aflibercept had a higher rate of acute intraocular inflammation than ranibizumab (0.688% vs 0.178%). It has a substantial difference that should be taken into account in future studies.\n\nWe had a higher culture-proven endophthalmitis rate than we expected (0.110%). The year 2014 contributed significantly with seven of the nine cases, but we do not find any reasons for this discrepancy. Also, aflibercept injections had an unexpected higher rate.\n\nThe levels of serum VEGF after bilateral injections are also a concern, but Wang et al17 found no significant difference in pre- and postinjection serum levels of VEGF between unilateral and bilateral intravitreal anti-VEGF. This way, similar systemic effects of unilateral and bilateral injections are expected. But, since serum half-life of bevacizumab is known to be less than 1 week,17,18 and the measurements were made 1 month postinjection, an earlier postoperative observation could have bigger differences.\n\nConclusion\nIn our opinion, bilateral same-day injections are very well tolerated by patients, time-saving, and economically more favorable. In our study, the rate of endophthalmitis was lower in the bilateral injection group.\n\nDespite being a retrospective study, these results add some important information for our daily practice and help us to make a more informed choice.\n\nDisclosure\n\nThe authors do not have any financial interest or competing interests in the methods and devices mentioned in this presentation. The authors report no conflicts of interest in this work.\n\nTable 1 Number of unilateral/bilateral injections per year and anti-VEGF used\n\nYear\tRanibizumab\tAflibercept\tUnilateral\tBilateral\tTotal\t\n2011\t738\t0\t586\t152\t738\t\n2012\t571\t0\t497\t74\t571\t\n2013\t1,652\t197\t1,367\t482\t1,849\t\n2014\t2,125\t280\t1,927\t478\t2,405\t\n2015\t1,777\t346\t1,753\t370\t2,123\t\n2016\t437\t49\t430\t56\t486\t\nTotal\t7,300\t872\t6,560\t1,612\t8,172\t\nAbbreviation: anti-VEGF, anti-vascular endothelial growth factor.\n\nTable 2 Indications for injections\n\nYear\tAge-related macular degeneration\tDiabetic retinopathy\tRetinal vein occlusion\tMyopic choroidal neovascularization\tOther\t\n2011\t341\t159\t48\t66\t124\t\n2012\t321\t103\t70\t37\t40\t\n2013\t1,036\t441\t186\t84\t102\t\n2014\t1,339\t559\t303\t128\t76\t\n2015\t1,228\t380\t265\t164\t86\t\n2016\t292\t83\t50\t41\t20\t\nTotal\t4,557\t1,725\t922\t520\t448\t\nTable 3 Distribution of endophthalmitis per year and anti-angiogenic\n\nYear\tAcute intraocular inflammation\n\tCulture-proven endophthalmitis\n\tTotal\t\nRanibizumab\tAflibercept\tRanibizumab\tAflibercept\t\n2011\t1\t–\t–\t–\t1 (0.135%)\t\n2012\t–\t–\t–\t–\t0 (0%)\t\n2013\t1\t2\t–\t–\t3 (0.125%)\t\n2014\t9\t2\t–\t–\t11 (0.595%)\t\n2015\t2\t2\t1\t–\t5 (0.876%)\t\n2016\t–\t–\t–\t–\t0 (0%)\t\nTotal\t13 (0.178%)\n19 (0.233%)\t6 (0.688%)\t1 (0.014%)\n1 (0.012%)\t0 (0%)\t20 (0.245%)\n==== Refs\nReferences\n1 Lima LH Zweifel SA Engelbert M Evaluation of safety for bilateral same-day intravitreal injections of antivascular endothelial growth factor therapy Retina 2009 29 9 1213 1217 19934815 \n2 Rosenfeld PJ Brown DM Heier JS Ranibizumab for neovascular age-related macular degeneration N Engl J Med 2006 355 14 1419 1431 17021318 \n3 Wolf S Balciuniene VJ Laganovska G RADIANCE: a randomized controlled study of ranibizumab in patients with choroidal neovascularization secondary to pathologic myopia Ophthalmology 2014 121 3 682 692.e2 24326106 \n4 Bakri SJ Risco M Edwards AO Pulido JS Bilateral simultaneous intravitreal injections in the office setting Am J Ophthalmol 2009 148 1 66 69.e1 19403114 \n5 Green-Simms AE Ekdawi NS Bakri SJ Survey of intravitreal injection techniques among retinal specialists in the United States Am J Ophthalmol 2011 151 2 329 332 21168821 \n6 Abu-Yaghi NE Shokry AN Abu-Sbeit RH Bilateral same-session intravitreal injections of anti-vascular endothelial growth factors Int J Ophthalmol 2014 7 6 1017 1021 25540758 \n7 Chao DL Gregori NZ Khandji J Goldhardt R Safety of bilateral intravitreal injections delivered in a teaching institution Expert Opin Drug Deliv 2014 11 7 991 993 24815986 \n8 Davis RP Schefler AC Murray TG Concomitant bilateral intravitreal anti-VEGF injections for the treatment of exudative age-related macular degeneration Clin Ophthalmol 2010 4 703 707 20689785 \n9 Mahajan VB Elkins KA Russell SR Bilateral intravitreal injection of antivascular endothelial growth factor therapy Retina 2011 31 1 31 35 21187731 \n10 Woo SJ Han JM Ahn J Bilateral same-day intravitreal injections using a single vial and molecular bacterial screening for safety surveillance Retina 2012 32 4 667 671 22307220 \n11 Diago T McCannel CA Bakri SJ Pulido JS Edwards AO Pach JM Infectious endophthalmitis after intravitreal injection of antiangiogenic agents Retina 2009 29 5 601 605 19357558 \n12 Fintak DR Shah GK Blinder KJ Incidence of endophthalmitis related to intravitreal injection of bevacizumab and ranibizumab Retina 2008 28 10 1395 1399 18827737 \n13 McCannel CA Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies Retina 2011 31 4 654 661 21330939 \n14 Martin DF Maguire MG Ying GS Grunwald JE Fine SL Jaffe GJ Ranibizumab and bevacizumab for neovascular age-related macular degeneration N Engl J Med 2011 364 20 1897 1908 21526923 \n15 Merani R Hunyor AP Endophthalmitis following intravitreal antivascular endothelial growth factor (VEGF) injection: a comprehensive review Int J Retina Vitreous 2015 1 9 27847602 \n16 Fenoll MA ARCSTERILE: A COST-EFFECTIVE LUXURY Rev Enferm 2015 38 5 8 12 Spanish \n17 Wang D Choi KS Lee SJ Serum concentration of vascular endothelial growth factor after bilateral intravitreal injection of bevacizumab Korean J Ophthalmol 2014 28 1 32 38 24505199 \n18 Davidovic SP Nikolic SV Curic NJ Changes of serum VEGF concentration after intravitreal injection of Avastin in treatment of diabetic retinopathy Eur J Ophthalmol 2012 22 5 792 798 22344470\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "11()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "anti-VEGF; bilateral; endophthalmitis; injections; intravitreal",
"medline_ta": "Clin Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101321512",
"other_id": null,
"pages": "299-302",
"pmc": null,
"pmid": "28203056",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "24326106;25540758;26540890;22344470;21330939;19934815;18827737;21187731;19357558;24505199;21526923;19403114;17021318;20689785;24815986;21168821;22307220;27847602",
"title": "Safety of bilateral same-day intravitreal injections of anti-vascular endothelial growth factor agents.",
"title_normalized": "safety of bilateral same day intravitreal injections of anti vascular endothelial growth factor agents"
} | [
{
"companynumb": "PT-ROCHE-1906406",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
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"abstract": "The beta-herpesviruses, human herpesviruses-6 and -7 (HHV-6 and HHV-7), are closely related and have very similar biological behaviour. While HHV-6 is associated with encephalitis in immunosuppressed adults, HHV-7 is not recognised as a cause of neurological disease in such patients. This report describes the identification of a reactivated HHV-7 infection in the cerebrospinal fluid of an adult who presented with an acute myelitis 11 months after unrelated donor bone marrow transplant.",
"affiliations": "Department of Virology, Royal Free and University College Medical School, Windeyer Institute of Medical Sciences, London, UK.",
"authors": "Ward|K N|KN|;White|R P|RP|;Mackinnon|S|S|;Hanna|M|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1038/sj.bmt.1703774",
"fulltext": null,
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"issn_linking": "0268-3369",
"issue": "30(12)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D016026:Bone Marrow Transplantation; D002555:Cerebrospinal Fluid; D006086:Graft vs Host Disease; D016199:Herpesvirus 7, Human; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D017710:Lymphocyte Transfusion; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009101:Multiple Myeloma; D009187:Myelitis; D020336:Paraparesis, Spastic; D019349:Roseolovirus Infections; D014184:Transplantation, Homologous; D001750:Urinary Bladder, Neurogenic; D014775:Virus Activation",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "983-5",
"pmc": null,
"pmid": "12476296",
"pubdate": "2002-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Human herpesvirus-7 infection of the CNS with acute myelitis in an adult bone marrow recipient.",
"title_normalized": "human herpesvirus 7 infection of the cns with acute myelitis in an adult bone marrow recipient"
} | [
{
"companynumb": "GB-CONCORDIA PHARMACEUTICALS INC.-E2B_00018878",
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"activesubstancename": "CYCLOSPORINE"
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"abstract": "Erythroderma is a rare, potentially life-threatening presentation of psoriasis that can be triggered by medication reactions. Bupropion is indicated for major depressive disorder (Wellbutrin®, GlaxoSmithKline, Research Triangle Park, NC), smoking cessation (Zyban®, GlaxoSmithKline, Research Triangle Park, NC), and weight loss (when in formulation with naltrexone ER; Contrave®, Orixegen Therapeutics, La Jolla, CA). Bupropion can exacerbate psoriasis, however, this is an under-recognized side effect of the medication, particularly in the United States. We report a case of bupropion-induced erythrodermic psoriasis in a 62-year-old female who was prescribed the medication for depression. Due to the common comorbidities of depression, obesity, and tobacco abuse in psoriatic patients, all for which treatment with bupropion is indicated, it is important for physicians to be aware of the potential for a life-threatening medication reaction in this patient population.",
"affiliations": "Dermatology, Kansas City University-Graduate Medical Education Consortium/Advanced Dermatology and Cosmetic Surgery Orlando Dermatology Residency Program, Orlando, USA.;Dermatology, Kansas City University-Graduate Medical Education Consortium/Advanced Dermatology and Cosmetic Surgery Orlando Dermatology Residency Program, Orlando, USA.;Dermatology, Kansas City University-Graduate Medical Education Consortium/Advanced Dermatology and Cosmetic Surgery Orlando Dermatology Residency Program, Orlando, USA.",
"authors": "Foss|Michael G|MG|;Nyckowski|Timothy|T|;Steffes|William|W|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.18460",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.18460\nDermatology\nPsychiatry\nErythrodermic Psoriasis Exacerbated by Bupropion\nMuacevic Alexander\nAdler John R\nFoss Michael G 1\nNyckowski Timothy 1\nSteffes William 1\n1 Dermatology, Kansas City University-Graduate Medical Education Consortium/Advanced Dermatology and Cosmetic Surgery Orlando Dermatology Residency Program, Orlando, USA\nMichael G. Foss mikefoss27@gmail.com\n3 10 2021\n10 2021\n13 10 e184601 10 2021\nCopyright © 2021, Foss et al.\n2021\nFoss et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/72476-erythrodermic-psoriasis-exacerbated-by-bupropion\nErythroderma is a rare, potentially life-threatening presentation of psoriasis that can be triggered by medication reactions. Bupropion is indicated for major depressive disorder (Wellbutrin®, GlaxoSmithKline, Research Triangle Park, NC), smoking cessation (Zyban®, GlaxoSmithKline, Research Triangle Park, NC), and weight loss (when in formulation with naltrexone ER; Contrave®, Orixegen Therapeutics, La Jolla, CA). Bupropion can exacerbate psoriasis, however, this is an under-recognized side effect of the medication, particularly in the United States. We report a case of bupropion-induced erythrodermic psoriasis in a 62-year-old female who was prescribed the medication for depression. Due to the common comorbidities of depression, obesity, and tobacco abuse in psoriatic patients, all for which treatment with bupropion is indicated, it is important for physicians to be aware of the potential for a life-threatening medication reaction in this patient population.\n\nerythrodermic psoriasis\ndrug rash\ndrug reaction\nbupropion\nerythroderma\npsoriasis\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nPsoriasis affects up to 4.6% of the United States (US) population, and up to 2.25% of psoriatic patients may develop the erythrodermic variant, involving >80% of the body surface area (BSA) [1-4]. We report a case of a 62-year-old female with an acute eruption of erythrodermic psoriasis, four days after initiation of bupropion, a popularly prescribed antidepressant (Wellbutrin®, GlaxoSmithKline, Research Triangle Park, NC), smoking cessation aid (Zyban®, GlaxoSmithKline, Research Triangle Park, NC), and weight loss adjunct (when in combination with naltrexone ER; Contrave®, Orixegen Therapeutics, La Jolla, CA). Though rare, there have been increasing reports of bupropion inducing erythrodermic psoriasis, and the clinician should be aware of this association and elicit a history of psoriasis when prescribing this medication.\n\nCase presentation\n\nA 62-year-old female was brought to the hospital emergency department by ambulance for a diffuse skin eruption. Four days prior to presentation, she was initiated on bupropion for depression, which was previously treated with mirtazapine. Her medication list also included clobetasol ointment, calcipotriene ointment, levothyroxine, metformin, and mirabegron. She had a long-standing history of psoriasis affecting her scalp, extensor extremities, lower back, and chest. Additional medical history included hypothyroidism, diabetes, and urinary incontinence. \n\nTwo days after beginning bupropion, her psoriasis spread to involve flexural skin areas, with a further spread in the following two days. On day four, she presented to the hospital because her psoriasis covered the majority of her body surface, accompanied by mucosal changes, subjective fever, and fatigue (Figure 1).\n\nFigure 1 Erythrodermic psoriasis\n\nDiffuse erythema and scaling involving >80% of the patient’s body surface area (A and B), with concomitant mucosal changes consistent with geographic tongue (A).\n\nUpon arrival to the emergency room, she was found to be tachycardic, tachypneic, hypotensive, and febrile. Laboratory evaluation revealed a leukocytosis of 22 x109/L (reference range: 4.5-11.0 × 109/L) and an elevated creatinine of 1.74 mg/dL (reference range: 0.60-1.10 mg/dL), consistent with acute kidney injury, prompting an initial concern for sepsis along with erythroderma. Dermatology was consulted for further assessment. After obtaining relevant history, performing physical examination, and eliminating the possibility of other potential causes of erythroderma, a provisional diagnosis of bupropion-induced erythrodermic psoriasis was made. Biopsy confirmed the initial clinical diagnosis, showing hyperkeratosis, parakeratosis, and neutrophils in the stratum corneum forming Munro microabscesses (Figure 2).\n\nFigure 2 Erythrodermic psoriasis (H&E original magnification x 100)\n\nHyperkeratosis, parakeratosis, and acanthosis with elongation of rete ridges. Neutrophils are present in the stratum corneum, forming Munro microabscesses. The papillary dermis is edematous with dilated capillaries.\n\nBupropion was promptly discontinued. Due to improvement in renal function following fluid resuscitation, the patient was begun on cyclosporine 2.5 mg/kg/day. Her erythroderma cleared within five days, and she followed up in our outpatient clinic for further long-term management including transitioning from cyclosporine to secukinumab, with near resolution of her psoriasis at five-week follow-up.\n\nDiscussion\n\nErythroderma is generalized erythema and scale involving >80% of the body surface area that can be life-threatening due to systemic manifestations of impaired skin barrier [3,5]. Psoriasis is the most commonly identified trigger of erythroderma, causing up to 25% of cases [3]. It is important to recognize and address the causes of erythrodermic psoriasis, including rapid withdrawal of systemic immunosuppressive therapy, underlying systemic infections, or drug reactions [3,6]. This is the fourth report and sixth case of bupropion-associated erythrodermic psoriasis [1,7,8]. In addition to erythroderma, Stevens-Johnson syndrome and morbilliform drug eruption have also occurred following bupropion initiation, both with concomitant psoriasis exacerbation secondary to koebnerization [9,10].\n\nBupropion causes reuptake inhibition of both norepinephrine and dopamine, without affecting serotonin [11]. Initially approved in 1985 for major depressive disorder, it has since received approval for seasonal affective disorder and smoking cessation [11-13]. Psychiatrists prescribe bupropion for depression with symptoms of lethargy, sexual dysfunction, and/or weight gain due to its unique side effect profile [11]. Bupropion may even lead to weight loss, an indication for which it was re-branded in combination with naltrexone ER in 2014 [11,14]. \n\nMinor dermatologic side effects including urticarial and morbilliform rashes are not uncommon with bupropion use, occurring in up to 10% of users [12,13]. Commonly reported serious cutaneous adverse reactions associated with bupropion, although relatively rare, include angioedema and serum-sickness-like reactions [15]. Flaring of psoriasis is an under-recognized side effect of bupropion, particularly in the United States. The manufacturer for bupropion reports worsening of psoriasis among 1 in 1000 people in the United Kingdom (UK) patient leaflet, but this information is conspicuously absent in the US prescribing information [12,13,16].\n\nPsoriasis is a multisystem inflammatory disorder with a number of related comorbidities relevant to populations treated with bupropion, including obesity, cigarette smoking, and depression [17,18]. Psoriasis, obesity, and mood changes are comorbidities unified by elevated tumor necrosis factor (TNF)-alpha levels that may result in a self-amplifying feedback loop [19,20]. This cascade poses an attractive target for treatment with bupropion given its comparative weight-loss properties versus other anti-depressants that can lead to weight gain [11]. Although it may seem logical to prescribe bupropion in the depressed, obese, psoriatic smoker, we suggest doing so with caution. In patients who are candidates for bupropion treatment, we recommend eliciting a history of psoriasis, accompanied by physical examination with attention to cutaneous findings. If bupropion is ultimately prescribed, psoriatic patients should be counseled on the potential for erythroderma and immediate discontinuation if these symptoms occur.\n\nConclusions\n\nWe report the sixth case of erythrodermic psoriasis related to bupropion initiation. With obesity and depressive disorders in the United States steadily rising, and the recent FDA indication for weight loss, bupropion prescriptions will likely parallel this increase. Prescribers should be aware of the relationship between bupropion and psoriasis, including the dangerous erythrodermic variant. Ultimately, prescribers should take a thorough history of psoriasis and if they confirm, then counsel the patient to immediately stop therapy if they notice significant worsening or spreading of the disease.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Acute generalized erythrodermic pustular psoriasis associated with bupropion/naltrexone (Contrave®) J Emerg Med Singh PA Cassel KP Moscati RM Eckersley D 111 113 52 2017\n2 Psoriasis Dermatology van de Kerkhof PC Nestlé FO 138 160 Philadelphia, PA Elsevier 4th ed. 2017\n3 Erythroderma Dermatology Whittaker S 175 187 Philadelphia, PA Elsevier 4th ed. 2017\n4 Treatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation J Am Acad Dermatol Rosenbach M Hsu S Korman NJ Lebwohl MG Young M Bebo BF Jr Van Voorhees AS 655 662 62 2010 19665821\n5 Infectious complications of erythrodermic psoriasis J Am Acad Dermatol Green MS Prystowsky JH Cohen SR Cohen JI Lebwohl MG 911 914 34 1996 8621827\n6 Treatment of erythrodermic psoriasis with biologics: a systematic review J Am Acad Dermatol Carrasquillo OY Pabón-Cartagena G Falto-Aizpurua LA Santiago-Vázquez M Cancel-Artau KJ Arias-Berrios G Martín-García RF 151 158 83 2020 32247872\n7 Generalized pustular and erythrodermic psoriasis associated with bupropion treatment Br J Dermatol Cox NH Gordon PM Dodd H 1061 1063 146 2002 12072078\n8 Erythrodermic psoriasis induced by bupropion J Eur Acad Dermatol Venereol Matos-Pires E Campos S Mendes-Bastos P João A Fernandes C 129 130 31 2017\n9 A case of bupropion-induced Stevens-Johnson syndrome with acute psoriatic exacerbation J Drugs Dermatol Surovik J Riddel C Chon SY 1010 1012 9 2010 https://pubmed.ncbi.nlm.nih.gov/20684153/ 20684153\n10 Drug eruption and exacerbation of psoriasis related to bupropion Eur J Dermatol Gómez-Fernández C Herranz Pinto P Casado Verrier B Sendagorta Cudós E Beato-Merino MJ Jiménez MC 120 121 21 2011 21233071\n11 Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant Ther Adv Psychopharmacol Patel K Allen S Haque MN Angelescu I Baumeister D Tracy DK 99 144 6 2016 27141292\n12 Wellbutrin® (bupropion hydrochloride) tablets Research Triangle Park, North Carolina:GlaxoSmithKline 8 2021 https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018644s043lbl.pdf\n13 Zyban® (bupropion hydrochloride) sustained-release tablets Research Triangle Park, North Carolina:GlaxoSmithKline 8 2021 2011 https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020711s026lbl.pdf\n14 Contrave® (naltrexone HCl and bupropion HCl) extended release tablets La Jolla, California:Orexigon Therapeutics 8 2021 2014 https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf\n15 Serious adverse reactions of bupropion for smoking cessation: analysis of the French Pharmacovigilance Database from 2001 to 2004 Drug Saf Beyens MN Guy C Mounier G Laporte S Ollagnier M 1017 1026 31 2008 18840021\n16 Package leaflet: Information for the user: Zyban® Zyban®. Uxbridge, Middlesex, United Kingdom:GlaxoSmithKline 8 2021 2021 https://www.medicines.org.uk/emc/files/pil.3827.pdf\n17 Psoriasis: classical and emerging comorbidities An Bras Dermatol De Oliveira M de Oliveira Rocha B Duarte GV 9 20 90 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323693/ 25672294\n18 Psoriasis and comorbid diseases: epidemiology J Am Acad Dermatol Takeshita J Grewal S Langan SM Mehta NN Ogdie A Van Voorhees AS Gelfand JM 377 390 76 2017 28212759\n19 Depression and suicidality in psoriasis: review of the literature including the cytokine theory of depression J Eur Acad Dermatol Venereol Koo J Marangell LB Nakamura M Armstrong A Jeon C Bhutani T Wu JJ 1999 2009 31 2017 28681405\n20 An update on the role of adipose tissues in psoriasis Front Immunol Wong Y Nakamizo S Tan KJ Kabashima K 10 2019\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(10)",
"journal": "Cureus",
"keywords": "bupropion; drug rash; drug reaction; erythroderma; erythrodermic psoriasis; psoriasis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e18460",
"pmc": null,
"pmid": "34745784",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "27141292;18840021;28212759;25672294;8621827;28130024;27519979;12072078;21233071;28681405;20684153;32247872;31316526;19665821",
"title": "Erythrodermic Psoriasis Exacerbated by Bupropion.",
"title_normalized": "erythrodermic psoriasis exacerbated by bupropion"
} | [
{
"companynumb": "US-ALVOGEN-2021-ALVOGEN-117824",
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"abstract": "Hematopoietic stem cell transplantation (HSCT) recipients are vulnerable to invasive pneumococcal disease (IPD), with reported IPD rates ranging from 3.81 to 22.5/1000 HSCT. This IPD risk could relate to immunodeficiency, low vaccination uptake, and poor immunogenicity of pneumococcal polysaccharide vaccine (PPV). Literature comparing the clinical effectiveness of pneumococcal conjugate vaccination (PCV) and PPV after HSCT is limited. In this retrospective analysis of HSCT recipients at our center from 2004 to 2015, we evaluated vaccination uptake and compared IPD rates in patients receiving PPV (pre-2010 group) and PCV (post-2010 group). IPD was determined from microbiological results for all HSCT recipients from January 2004 to June 30, 2019. Eight hundred patients had a total of 842 HSCT events, including autologous HSCT (auto-HSCT; n = 562) and allogeneic HSCT (allo-HSCT; n = 280). More than 90% of the HSCT recipients were enrolled, and >93% of surviving HSCT recipients completed the vaccination protocol. Fifteen IPD episodes occurred in 13 patients between 2004 and June 30, 2019. Thirteen episodes occurred in the pre-2010 group, even though 9 of 13 (69%) serotyped isolates were covered by PPV. Two episodes occurred in the post-2010 group; neither serotype was covered by PCV. Thus, with PCV introduction, IPD rate was significantly reduced from 38.5/1000 unique HSCTs pre-2010 to 4.0/1000 unique HSCTs post-2010 (P < .001). A significant reduction was seen in both auto-HSCTs (from 29.4 to 3.1 /1000 unique auto-HSCTs; P = .011) and allo-HSCTs (from 58.3 to 5.6/1000 unique allo-HSCTs; P = .011). PCV demonstrated superior clinical effectiveness over PPV, highlighting its importance in preventing infectious complications after HSCT. Robust vaccination programs at transplantation centers are needed to optimize vaccination uptake and completion.",
"affiliations": "Infectious Diseases Unit, Royal Adelaide Hospital, Adelaide, Australia.;Infectious Diseases Unit, Royal Adelaide Hospital, Adelaide, Australia.;Royal Adelaide Hospital, Adelaide, Australia; Cancer Theme, South Australian Health and Medical Research Institute. Department of Medicine, University of Adelaide, Adelaide, Australia.;Royal Adelaide Hospital, Adelaide, Australia; Cancer Theme, South Australian Health and Medical Research Institute. Department of Medicine, University of Adelaide, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia.;Royal Adelaide Hospital, Adelaide, Australia; Cancer Theme, South Australian Health and Medical Research Institute. Department of Medicine, University of Adelaide, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia.;School of Medicine, University of Adelaide, Adelaide, Australia.;Royal Adelaide Hospital, Adelaide, Australia; Cancer Theme, South Australian Health and Medical Research Institute. Department of Medicine, University of Adelaide, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia. Electronic address: devendra.hiwase@sa.gov.au.",
"authors": "Roberts|Matthew B|MB|;Bak|Narin|N|;Wee|Li Yan A|LYA|;Chhetri|Rakchha|R|;Yeung|David T|DT|;Lewis|Ian|I|;Hiwase|Devendra K|DK|",
"chemical_list": "D022242:Pneumococcal Vaccines",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2019.10.006",
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"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "26(2)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Hematopoietic stem cell transplantation; Invasive pneumococcal disease; Pneumococcal vaccines",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D022242:Pneumococcal Vaccines; D012189:Retrospective Studies; D016896:Treatment Outcome; D014611:Vaccination",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "421-427",
"pmc": null,
"pmid": "31627016",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical Effectiveness of Conjugate Pneumococcal Vaccination in Hematopoietic Stem Cell Transplantation Recipients.",
"title_normalized": "clinical effectiveness of conjugate pneumococcal vaccination in hematopoietic stem cell transplantation recipients"
} | [
{
"companynumb": "AU-TAKEDA-2020TUS037323",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditi... |
{
"abstract": "Clinical and laboratory features of 99 patients receiving long-term amiodarone therapy were analyzed to determine which individuals may be at a high risk for developing amiodarone-induced thyroid dysfunction. The group of 68 men and 31 women was followed up for an average of 27 months (range 3 to 60). There were no differences in age, sex, dose of amiodarone, type or severity of underlying heart disease or baseline serum thyroxine levels in patients who developed hypothyroidism (n = 32) or hyperthyroidism (n = 5) or remained euthyroid (n = 62). Baseline serum thyrotropin levels were statistically higher in patients who became hypothyroid, but there was considerable overlap with the other patient groups. Serum reverse triiodothyronine (reverse T3), which has been suggested to be a marker of amiodarone efficacy, correlated directly with serum thyroxine levels, and was not an independent variable. There was no pattern to the time course for development of thyroid dysfunction, which occurred in 49% of those followed up and developed as early as 1 month or, in one individual, as late as after 3 years of amiodarone therapy. There are few guidelines for replacement therapy in patients with amiodarone-induced hypothyroidism. L-thyroxine dosage was adjusted cautiously in these high risk individuals to achieve serum thyroxine levels within the reference range of euthyroid individuals taking amiodarone: the mean dosage required was 136 micrograms/day. Normalization of serum thyrotropin (TSH) would have required doses of L-thyroxine that were judged to be excessively high.(ABSTRACT TRUNCATED AT 250 WORDS)",
"affiliations": null,
"authors": "Albert|S G|SG|;Alves|L E|LE|;Rose|E P|EP|",
"chemical_list": "D013972:Thyrotropin; D002784:Cholesterol; D000638:Amiodarone; D013974:Thyroxine",
"country": "United States",
"delete": false,
"doi": "10.1016/s0735-1097(87)80098-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1097",
"issue": "9(1)",
"journal": "Journal of the American College of Cardiology",
"keywords": null,
"medline_ta": "J Am Coll Cardiol",
"mesh_terms": "D000368:Aged; D000638:Amiodarone; D001145:Arrhythmias, Cardiac; D002784:Cholesterol; D005260:Female; D006801:Humans; D006980:Hyperthyroidism; D007037:Hypothyroidism; D008297:Male; D012306:Risk; D013960:Thyroid Function Tests; D013972:Thyrotropin; D013974:Thyroxine",
"nlm_unique_id": "8301365",
"other_id": null,
"pages": "175-83",
"pmc": null,
"pmid": "3794094",
"pubdate": "1987-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thyroid dysfunction during chronic amiodarone therapy.",
"title_normalized": "thyroid dysfunction during chronic amiodarone therapy"
} | [
{
"companynumb": "US-PFIZER INC-2015198735",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
... |
{
"abstract": "Lymphoepithelioma-like carcinoma (LELC) of lung is a rare tumor that is mostly reported in south-east Asian countries. The surgical removal is curative in the early stages but there is no consensus on the choice of chemotherapy for the treatment of advanced stage tumors. Most of the data on chemotherapy are based on small case series and retrospective studies. As per available data, this tumor responds to chemotherapy initially but recurrences are common. The use of conventional chemotherapy in recurrent tumors leads to cumulative toxicities in the long term. Due to lack of actionable mutations, targeted therapies are also not very useful. Immune check point inhibitors immune checkpoint inhibitors have shown survival benefit in patients with advanced stage non-small-cell and small cell carcinoma with better side effect profile than conventional chemotherapy. The role of immune checkpoint inhibitors in LELC is unknown. Though several studies have reported high expression of programmed cell death-1 (PD-1)/or its -ligand (PD-L1) in LELC providing a rationale for trial of these agents, the actual benefit of these agents in LELC has not been reported so far. In this case series, we report two cases of advanced stage LELC that progressed despite multiple lines of chemotherapy but responded favorably to a PD-1 inhibitor, nivolumab.",
"affiliations": "Department of Internal Medicine, Maimonides Medical Center, Brooklyn, NY 11219, USA.;Hematology & Oncology, Maimonides Medical Center, Brooklyn, NY 11219, USA.;Department of Pathology, Maimonides Medical Center, Brooklyn, NY 11219, USA.;Hematology & Oncology, Maimonides Medical Center, Brooklyn, NY 11219, USA.",
"authors": "Kumar|Vivek|V|;Dave|Vishangi|V|;Harris|Jonathan|J|;Huang|Yiwu|Y|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.2217/imt-2017-0067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "9(12)",
"journal": "Immunotherapy",
"keywords": "EBV; ICIs; LELC; lymphoepithelial-like carcinoma; nivolumab",
"medline_ta": "Immunotherapy",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002277:Carcinoma; D002289:Carcinoma, Non-Small-Cell Lung; D018450:Disease Progression; D005260:Female; D006801:Humans; D008168:Lung; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D000077594:Nivolumab; D012189:Retrospective Studies",
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "955-961",
"pmc": null,
"pmid": "28971752",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Response of advanced stage recurrent lymphoepithelioma-like carcinoma to nivolumab.",
"title_normalized": "response of advanced stage recurrent lymphoepithelioma like carcinoma to nivolumab"
} | [
{
"companynumb": "US-PFIZER INC-2017473038",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo assess the effectiveness of the newer antiepileptic drugs (AEDs)-in particular lamotrigine, topiramate, and levetiracetam-in controlling epileptic seizures in pregnant women.\n\n\nMETHODS\nAnalysis of data in the Australian Register of Antiepileptic Drugs in Pregnancy concerning seizure control in 1,534 pregnancies in women with AED-treated epilepsies.\n\n\nRESULTS\nIn AED monotherapy (1,111 pregnancies), use of levetiracetam in pregnancies in the Australian Register was associated with levels of seizure control similar to those that applied for the major older AEDs carbamazepine and valproate, but with levels of seizure control superior to those associated with use of lamotrigine and topiramate.\n\n\nCONCLUSIONS\nLevetiracetam shows promise as a satisfactory drug for controlling seizures in pregnancy.",
"affiliations": "Departments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.",
"authors": "Vajda|Frank J E|FJ|;O'Brien|Terrence|T|;Lander|Cecilie|C|;Graham|Janet|J|;Eadie|Mervyn|M|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D000077287:Levetiracetam; D000077213:Lamotrigine; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.12711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "55(8)",
"journal": "Epilepsia",
"keywords": "Antiepileptic drugs; Lamotrigine; Levetiracetam; Pregnancy; Seizures; Topiramate",
"medline_ta": "Epilepsia",
"mesh_terms": "D000927:Anticonvulsants; D005260:Female; D005632:Fructose; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D010889:Piracetam; D011247:Pregnancy; D012042:Registries; D012640:Seizures; D000077236:Topiramate; D016896:Treatment Outcome; D014227:Triazines; D014739:Victoria",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1229-34",
"pmc": null,
"pmid": "24995555",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The efficacy of the newer antiepileptic drugs in controlling seizures in pregnancy.",
"title_normalized": "the efficacy of the newer antiepileptic drugs in controlling seizures in pregnancy"
} | [
{
"companynumb": "AU-JNJFOC-20140811856",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aim of the study is to evaluate the therapeutic efficacy and safety of Yttrium- 90 radiolabelled chimeric anti CD20 antibody-Rituximab in the treatment of patients with relapsed/ refractory B cell Non-Hodgkins Lymphoma (NHL).\n\n\nMETHODS\nTwenty patients with relapsed/refractory CD20+ NHL in progressive state were included in the study. These patients had undergone a median of 2 (range 2-5) prior standard chemotherapy ± immunotherapy regimens. All the patients received rituximab 250 mg/m2 on days 1 and 8, and either 14 MBq/kg (0.4 mCi/kg) or 11 MBq/kg (0.3 mCi/kg) of Y-90 Rituximab on day 8 (maximum dose, 32 mCi) depending upon their platelet count. The patients were observed for systemic toxicity and response for at least 12 weeks after therapy.\n\n\nRESULTS\nNo acute adverse effects were observed after the administration of 90Y-Rituximab. Overall response rate (ORR) was 45% of which complete response (CR) was observed in 2 patients, stable disease in 1 patient and partial response in 6 patients. The therapy was well tolerated with grade IV thrombocytopenia, neutropenia and anemia observed in 3, 4 and 2 patients respectively.\n\n\nCONCLUSIONS\n90Y-Rituximab therapy is safe and well tolerated in high risk extensively pretreated NHL patients. Toxicity is primarily hematologic, transient and reversible.",
"affiliations": "Room No-57A, Department of Nuclear Medicine, AIIMS, Ansari Nagar, New Delhi, India. thakralparul@gmail.com.",
"authors": "Thakral|Parul|P|;Singla|Suhas|S|;Vashist|Atul|A|;Yadav|Madhav P|MP|;Gupta|Santosh K|SK|;Tyagi|Jaya S|JS|;Sharma|Atul|A|;Bal|Chandra S|CS|;Snehlata|EmptyYN Y|EY|;Malhotra|Arun|A|",
"chemical_list": "D018951:Antigens, CD20; D000970:Antineoplastic Agents; D015021:Yttrium Radioisotopes; D000069283:Rituximab",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1874471009999160625110400",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1874-4710",
"issue": "9(2)",
"journal": "Current radiopharmaceuticals",
"keywords": null,
"medline_ta": "Curr Radiopharm",
"mesh_terms": "D000328:Adult; D000368:Aged; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016499:Radioimmunotherapy; D000069283:Rituximab; D016896:Treatment Outcome; D055815:Young Adult; D015021:Yttrium Radioisotopes",
"nlm_unique_id": "101468718",
"other_id": null,
"pages": "160-8",
"pmc": null,
"pmid": "27593256",
"pubdate": "2016",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Preliminary Experience with Yttrium-90-labelled Rituximab (Chimeric Anti CD-20 Antibody) in Patients with Relapsed and Refractory B Cell Non-Hodgkins Lymphoma.",
"title_normalized": "preliminary experience with yttrium 90 labelled rituximab chimeric anti cd 20 antibody in patients with relapsed and refractory b cell non hodgkins lymphoma"
} | [
{
"companynumb": "IN-ROCHE-1835834",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "This study aimed to describe the utility of the neutrophil-to-lymphocyte ratio (NLR) for predicting bacterial infections in patients with rheumatoid arthritis (RA) treated with Tocilizumab (TCZ). We extracted RA patients treated with TCZ in whom an infection developed between April 2008 and March 2018 from our hospital database. We divided these patients into the bacterial infection and non-bacterial infection groups and compared their background, C-reactive protein (CRP) values, white blood cell count (WBC), the NLR at the time of infection diagnosis, and the ratio of the NLR at the time of infection diagnosis (post-NLR) to the NLR at baseline (pre-NLR). Of the 196 patients who received TCZ, 21 experienced a bacterial infection and 20 had a non-bacterial infection. The median CRP level, WBC count, post-NLR, and post-NLR/pre-NLR ratio in the bacterial infection group were significantly higher than in the non-bacterial infection group. In receiver operating characteristics (ROC) curve analysis for predicting bacterial infection, the area under the curve (AUC) for CRP, WBC, NLR, and the post-NLR/pre-NLR ratio were 0.787, 0.857, 0.887, and 0.975, respectively. The cut-off value of 2.25 for the post-NLR/pre-NLR ratio showed the greatest sensitivity (90.5%) and specificity (100%). The post-NLR/pre-NLR ratio may be a useful surrogate marker for predicting bacterial infections in patients with RA treated with TCZ.",
"affiliations": "Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan. yoshiki_nagai@tmhp.jp.;Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.;Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.;Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo, 183-8524, Japan.",
"authors": "Nagai|Yoshiki|Y|http://orcid.org/0000-0002-4535-8933;Yokogawa|Naoto|N|http://orcid.org/0000-0002-7814-443X;Shimada|Kota|K|;Sugii|Shoji|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D002097:C-Reactive Protein; C502936:tocilizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-020-04705-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "40(12)",
"journal": "Rheumatology international",
"keywords": "Infection; Neutrophil-to-lymphocyte ratio (NLR); Rheumatoid arthritis; Tocilizumab",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001424:Bacterial Infections; D015415:Biomarkers; D002097:C-Reactive Protein; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D012189:Retrospective Studies; D012680:Sensitivity and Specificity",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "2039-2046",
"pmc": null,
"pmid": "32965587",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Utility of the neutrophil-to-lymphocyte ratio for predicting bacterial infection in patients with rheumatoid arthritis receiving Tocilizumab.",
"title_normalized": "utility of the neutrophil to lymphocyte ratio for predicting bacterial infection in patients with rheumatoid arthritis receiving tocilizumab"
} | [
{
"companynumb": "JP-ROCHE-2687667",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Disseminated Scedosporium prolificans infection occurs mainly in immunocompromised patients. The mortality rate is high, as the fungus is resistant to most antifungal agents. Here, we present the case of a 66-year-old female with acute myeloid leukemia who developed infective endocarditis caused by S. prolificans infection during induction chemotherapy. Her 1,3-β-D-glucan levels were elevated and computed tomography revealed bilateral sinusitis and disseminated small nodular masses within the lungs and spleen; it nonetheless took 6 days to identify S. prolificans by blood culture. The patient died of multi-organ failure despite the combined use of voriconazole and terbinafine. Autopsy revealed numerous mycotic emboli within multiple organs (caused by mitral valve vegetation) and endocarditis (caused by S. prolificans). The geographic distribution of this infection is limited to Australia, the United States, and southern Europe, particularly Spain. The first Japanese case was reported in 2011, and four cases have been reported to date, including this one. Recently, the incidence of S. prolificans-disseminated infection in immunocompromised patients has increased in Japan. Therefore, clinicians should consider S. prolificans infection as a differential diagnosis when immunocompromised patients suffer disseminated infections with elevated 1,3-β-D-glucan levels.",
"affiliations": "Department of Hematology, Kobe City Medical Center General Hospital, 2-2, Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.",
"authors": "Ochi|Yotaro|Y|;Hiramoto|Nobuhiro|N|;Takegawa|Hiroshi|H|;Yonetani|Noboru|N|;Doi|Asako|A|;Ichikawa|Chihiro|C|;Imai|Yukihiro|Y|;Ishikawa|Takayuki|T|",
"chemical_list": "D000935:Antifungal Agents; D009281:Naphthalenes; D011509:Proteoglycans; D047071:beta-Glucans; C010770:polysaccharide-K; D000077291:Terbinafine; D065819:Voriconazole",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-015-1752-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "101(6)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D004696:Endocarditis; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute; D009102:Multiple Organ Failure; D009181:Mycoses; D009281:Naphthalenes; D011509:Proteoglycans; D021681:Scedosporium; D000077291:Terbinafine; D065819:Voriconazole; D047071:beta-Glucans",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "620-5",
"pmc": null,
"pmid": "25630434",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19337880;19005145;24462439;19301173;23908944;19031336;9236303;21441711;12499177;19549223;14708963;22416481;19085456;12627286;18202441;11731939;11797173;11418156;11340550;19058049;17366022;15529309;15614697;12801370",
"title": "Infective endocarditis caused by Scedosporium prolificans infection in a patient with acute myeloid leukemia undergoing induction chemotherapy.",
"title_normalized": "infective endocarditis caused by scedosporium prolificans infection in a patient with acute myeloid leukemia undergoing induction chemotherapy"
} | [
{
"companynumb": "PHHY2015JP076572",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DORIPENEM"
},
"drugadditional": null,
"drug... |
{
"abstract": "We present three cases of cerebral aneurysms (1 unruptured; 2 ruptured) treated with endovascular techniques in pregnancies. The first ruptured case is a 28-year-old female on 20th gestational week. After the endovascular coiling, the patient suffered persistent hemiparesis and delivered a healthy baby by cesarean section. The second ruptured case is a 25-year-old female on 36th week of pregnancy. She died of aneurysm re-rupture after delivery of a healthy baby by cesarean section. The third unruptured case is a 31-year-old woman on the 26th gestational week of pregnancy who died of a giant basilar tip aneurysm after stent-assisted coiling. Ruptured aneurysm obliteration should be prioritized followed by vaginal delivery or cesarean section. The decision regarding the treatment of unruptured aneurysms should be carefully considered on a case-by-case basis. Stent-assisted coiling may be applicable to aneurysm during pregnancy.",
"affiliations": "Interventional Neuroradiology Department, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, China.;Interventional Neuroradiology Department, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, China.;Interventional Neuroradiology Department, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, China liyouxiang@263.net.;Interventional Neuroradiology Department, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, China.",
"authors": "Liu|Peng|P|;Lv|Xianli|X|;Li|Youxiang|Y|;Lv|Ming|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1591019915609134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "21(6)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Aneurysm; endovascular management; pregnancy",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D000328:Adult; D017542:Aneurysm, Ruptured; D002585:Cesarean Section; D003952:Diagnostic Imaging; D057510:Endovascular Procedures; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D015607:Stents",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "654-8",
"pmc": null,
"pmid": "26472635",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24256763;11779521;9668186;19921289;11838740;7762040;9167776;11711158;11717668;25132934;20465907;7789594;1919702;2274125;14504879;19211489;23979051;4858207;21799174;16135580;8703181;10954284;22209508;12895402;18559459;21334622",
"title": "Endovascular management of intracranial aneurysms during pregnancy in three cases and review of the literature.",
"title_normalized": "endovascular management of intracranial aneurysms during pregnancy in three cases and review of the literature"
} | [
{
"companynumb": "CN-BAYER-2015-490219",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Vancomycin is a widely used antibiotic in hemodialysis patients. The main complications include renal toxicity and skin lesions. Herein, we report the case of a 29-year-old hemodialysis patient who presented a bullous pruriginous dermatosis after vancomycin treatment. A skin biopsy revealed a linear IgA bullous dermatosis (LABD). This is a rare form of dermatosis and is either idiopathic or more likely vancomycin-induced. Similarities in the molecular structure of vancomycin and epidermal basement membrane glycoproteins could explain the auto-immune response. The overall prognosis after drug discontinuation and dermocorticoid treatment was good.",
"affiliations": "AURA Paris Plaisance, Paris, France.;AURA Paris Plaisance, Paris, France.;Service dermatologie, Hôpital Saint-joseph, Paris, France.;AURA Paris Plaisance, Paris, France.;AURA Paris Plaisance, Paris, France.;AURA Paris Plaisance, Paris, France.",
"authors": "Schurder|Juliet|J|;Morel|Pauline|P|;Blanc|Julie|J|;Clerté|Maëva|M|;Ridel|Christophe|C|;Touzot|Maxime|M|0000-0002-0510-2431",
"chemical_list": "D014640:Vancomycin",
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12786",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "23(4)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "dialysis; skin; toxicity; vancomycin",
"medline_ta": "Hemodial Int",
"mesh_terms": "D000328:Adult; D006801:Humans; D062027:Linear IgA Bullous Dermatosis; D008297:Male; D011379:Prognosis; D006435:Renal Dialysis; D014640:Vancomycin",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "E127-E129",
"pmc": null,
"pmid": "31579994",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Skin lesions and vancomycin use in a hemodialysis patient.",
"title_normalized": "skin lesions and vancomycin use in a hemodialysis patient"
} | [
{
"companynumb": "FR-AMGEN-FRASP2019193824",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": "3",
... |
{
"abstract": "Intense pulsed light (IPL) is a good option for erythema and telangiectasia of rosacea. Demodex, which is light and heat sensitive, is an important risk of Rosacea. Sometimes, IPL can induce rosacea aggravation. Here, we show two cases of erythema rosacea aggravated as pustule in several hours after IPL. Both cases show high density of Demodex after IPL. Neither of them had photosensitivity, systemic disease, or any other contraindication for IPL. One of the patients received IPL again after Demodex infection relieved and this time there was no inflammation induction. We need to attract more attention to IPL-induced rosacea aggravation and latent Demodex infection may act as a cofactor.",
"affiliations": "a The Institute of Photomedicine, Shanghai skin diseases Hospital , Tongji University School of Medicine , Shanghai , China.;a The Institute of Photomedicine, Shanghai skin diseases Hospital , Tongji University School of Medicine , Shanghai , China.;a The Institute of Photomedicine, Shanghai skin diseases Hospital , Tongji University School of Medicine , Shanghai , China.;a The Institute of Photomedicine, Shanghai skin diseases Hospital , Tongji University School of Medicine , Shanghai , China.;a The Institute of Photomedicine, Shanghai skin diseases Hospital , Tongji University School of Medicine , Shanghai , China.;a The Institute of Photomedicine, Shanghai skin diseases Hospital , Tongji University School of Medicine , Shanghai , China.",
"authors": "Wang|Peiru|P|;Zhang|Linglin|L|;Shi|Lei|L|;Yuan|Chao|C|;Zhang|Guolong|G|;Wang|Xiuli|X|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D008911:Minocycline; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1080/14764172.2018.1502448",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4172",
"issue": "21(3)",
"journal": "Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology",
"keywords": "Demodex; Rosacea; intense pulsed light",
"medline_ta": "J Cosmet Laser Ther",
"mesh_terms": "D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents; D001706:Biopsy; D004890:Erythema; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D062325:Intense Pulsed Light Therapy; D008875:Middle Aged; D008911:Minocycline; D008924:Mite Infestations; D012189:Retrospective Studies; D012393:Rosacea; D012867:Skin; D063465:Skin Cream; D016559:Tacrolimus; D013684:Telangiectasis; D016896:Treatment Outcome",
"nlm_unique_id": "101136419",
"other_id": null,
"pages": "163-165",
"pmc": null,
"pmid": "30040520",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Latent Demodex infection contributes to intense pulsed light aggravated rosacea: cases serial.",
"title_normalized": "latent demodex infection contributes to intense pulsed light aggravated rosacea cases serial"
} | [
{
"companynumb": "CN-ACCORD-128116",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Decremental responses in repetitive nerve stimulation have been reported in a few hereditary myopathies. We examined the frequency of decrement in a cohort of myopathy patients.\n\n\n\nWe reviewed all patients referred for myopathy who underwent repetitive nerve stimulation between January 2007 and May 2017. We included patients with decrement (>10%) and either a pathological or molecular diagnosis of myopathy.\n\n\n\nAmong 157 patients with myopathies, 4 patients had decrement (2 hydroxychloroquine-associated vacuolar myopathy, 1 centronuclear myopathy, and 1 distal myopathy). One hydroxychloroquine-associated vacuolar myopathy patient also had inflammatory myopathy. Pyridostigmine improved weakness in the centronuclear myopathy patient, but not in the distal myopathy patient. No patient with an acquired myopathy received pyridostigmine.\n\n\n\nDespite the rare occurrence of decrement in myopathy, its presence may urge consideration of pharmacological intervention. Muscle Nerve 59:475-478, 2019.",
"affiliations": "Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.;Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.;Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.;Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.;Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.",
"authors": "Elahi|Behzad|B|0000-0002-4397-4935;Laughlin|Ruple S|RS|;Litchy|William J|WJ|;Milone|Margherita|M|;Liewluck|Teerin|T|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D006886:Hydroxychloroquine; D011729:Pyridostigmine Bromide",
"country": "United States",
"delete": false,
"doi": "10.1002/mus.26393",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-639X",
"issue": "59(4)",
"journal": "Muscle & nerve",
"keywords": "centronuclear myopathy; congenital myasthenic syndrome; decrement; distal myopathy; hydroxychloroquine-associated myopathy; multiminicore disease; neuromuscular transmission defect",
"medline_ta": "Muscle Nerve",
"mesh_terms": "D002800:Cholinesterase Inhibitors; D015331:Cohort Studies; D004568:Electrodiagnosis; D004576:Electromyography; D005260:Female; D040181:Genetic Diseases, X-Linked; D006801:Humans; D006886:Hydroxychloroquine; D007167:Immunotherapy; D016464:Lysosomal Storage Diseases; D008297:Male; D009046:Motor Neurons; D018482:Muscle, Skeletal; D009135:Muscular Diseases; D020914:Myopathies, Structural, Congenital; D011729:Pyridostigmine Bromide; D009435:Synaptic Transmission",
"nlm_unique_id": "7803146",
"other_id": null,
"pages": "475-478",
"pmc": null,
"pmid": "30536954",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neuromuscular transmission defects in myopathies: Rare but worth searching for.",
"title_normalized": "neuromuscular transmission defects in myopathies rare but worth searching for"
} | [
{
"companynumb": "US-TEVA-2019-US-1046762",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": "3",
... |
{
"abstract": "We describe here a rare case of a 74-year-old man with essential thrombocythemia who presented an early nonobstructive thrombosis of aortic porcine bioprosthesis complicated by multiple ischemic strokes 14 days after the primary operation. Transesophageal echocardiography on the postoperative day (POD) 17 revealed a mobile, nonobstructive thrombosis inserted on the anterior cusp right of the bioprosthesis. Anticoagulation by intravenous unfractionated heparin was effective with disappearance of the thrombus with good aortic prosthesis function on the POD 20 without requiring reoperation. The patient had a complete recovery of neurological disorders and was discharged on POD 26.",
"affiliations": "Department of Cardiology, Saint Joseph's Hospital, Paris, France.;Department of Cardiology, Saint Joseph's Hospital, Paris, France.",
"authors": "Fischer|Quentin|Q|;Garçon|Philippe|P|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/2211-4122.187962",
"fulltext": "\n==== Front\nJ Cardiovasc EchogrJ Cardiovasc EchogrJCEJournal of Cardiovascular Echography2211-41222347-193XMedknow Publications & Media Pvt Ltd India 28465971JCE-26-9710.4103/2211-4122.187962Case ReportMultiple Strokes Secondary to an Early Thrombosis of Aortic Bioprosthesis on Aspirin Therapy Fischer Quentin Garçon Philippe Department of Cardiology, Saint Joseph's Hospital, Paris, FranceAddress for correspondence Dr. Quentin Fischer, Groupe Hospitalier Paris Saint Joseph, 185 Rue Raymond Losserand, 75014 Paris, France. E-mail: q.fischer75@gmail.comJul-Sep 2016 26 3 97 99 Copyright: © 2016 Journal of Cardiovascular Echography2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.We describe here a rare case of a 74-year-old man with essential thrombocythemia who presented an early nonobstructive thrombosis of aortic porcine bioprosthesis complicated by multiple ischemic strokes 14 days after the primary operation. Transesophageal echocardiography on the postoperative day (POD) 17 revealed a mobile, nonobstructive thrombosis inserted on the anterior cusp right of the bioprosthesis. Anticoagulation by intravenous unfractionated heparin was effective with disappearance of the thrombus with good aortic prosthesis function on the POD 20 without requiring reoperation. The patient had a complete recovery of neurological disorders and was discharged on POD 26.\n\nKey Words\nAortic bioprosthetic valvenonobstructive thrombosisstroke\n==== Body\nINTRODUCTION\nThrombosis of aortic bioprosthesis early after cardiac surgery is a rare but serious complication not really known and documented. This report is about a 74-year-old man with early nonobstructive thrombosis treated by a St. Jude Epic (St. Jude Medical, Inc., St. Paul, Minn) aortic porcine bioprosthesis 14 days after the primary operation.\n\nCASE REPORT\nA 74-year-old-man with severe aortic stenosis without coronary artery disease underwent aortic valve replacement (AVR) with a 23-mm St. Jude Medical Epic heart valve at the supra-annular position.\n\nThe only medical history is essential thrombocythemia treated with clopidogrel, without any background of bleeding or previous thromboembolism.\n\nThere was no complication during the surgery, but the patient presented an important bleeding in the early postoperative suites with requiring 3 red blood cell units and 1250 cc of fresh frozen plasma on the postoperative day (POD) 0.\n\nDuring the hospitalization, transthoracic echocardiography (TTE) performed on POD 5 showed mean transvalvular pressure gradient (PG) of 12 mmHg, effective orifice area of 1.1 cm2, and normal prosthetic valve function without thrombosis.\n\nFor these reasons, the patient was discharged from the hospital on POD 11, with a bitherapy by aspirin 100 mg/day and enoxaparin 0.4 ml/day.\n\nOn POD 14, the patient suddenly developed severe left-sided weakness and speech difficulty revealing multiple ischemic strokes (left and right middle and posterior cerebral arteries), splenic infarction, and lateral myocardial infarction of embolic origin.\n\nTransesophageal echocardiography (TEE) on POD 17 revealed a good aortic prosthesis function (mean PG, 16 mm Hg; effective orifice area, 1.03 cm2; and permeability index at 0.3) with good cusps mobility and no structural valve deterioration, but visualization of a mobile isoechoic mass bell clapper inserted on the anterior cusp right of the bioprosthesis suggestive of a nonobstructive thrombosis [Figure 1].\n\nFigure 1 Transesophageal echocardiography on the postoperative day 17 showing a mobile isoechoic mass bell clapper inserted on the anterior cusp right of the aortic bioprosthesis (“white arrow”)\n\nAccording to guidelines,[12] anticoagulation by intravenous unfractionated heparin was started with continuation of aspirin therapy. On POD 20, TEE control showed the disappearance of the thrombus with good aortic prosthesis function [Figure 2].\n\nFigure 2 Transesophageal echocardiography on the postoperative day 20 showing disappearance of the mass, with good aortic prosthesis function\n\nThrombophilia testing confirmed essential thrombocythemia with JAK2 mutation and showed hyperhomocysteinemia with MTHFR gene mutation.\n\nAfter multidisciplinary meeting, it was decided to introduce a treatment by hydroxyurea and pursue long-term fluindione and aspirin therapy.\n\nThe patient had a complete recovery of neurological disorders and was discharged on POD 26.\n\nAfter this episode, the patient presented none disturbs neurological or cardiovascular complications and is still alive after 9 years with a good functioning of the bioprosthesis.\n\nDISCUSSION\nWhile thrombosis of porcine bioprosthesis early after mitral valve replacement has been often described, thrombosis of aortic bioprosthesis is more anecdotic.\n\nBecause of the possible catastrophic consequences of unrecognized left ventricular outflow obstruction in conjunction with early thrombosis, some investigators have recommended anticoagulant therapy for all patients for 3 months after they have undergone AVR with a porcine bioprosthesis.\n\nHowever, because many patients who undergo AVR are elderly and frail, complete anticoagulant therapy in some such patients may be inappropriate in consideration of the possible risk of anticoagulant-related hemorrhage. Therefore, antithrombotic therapy during the early postoperative period after bioprosthetic AVR is controversial and needs evaluation of the patient's age and the adequacy of supervision.\n\nACC/AHA and ESC guidelines[1] recommended a low-dose aspirin for the first 3 months after implantation of an aortic bioprosthesis rather than an oral anticoagulation because the thromboembolic risk for epic valves and other types of bioprosthetic valves in the aortic position are reportedly low.[2]\n\nIn a study by Jamieson et al.,[2] no patient showed valve thrombosis after AVR with epic valves. The incidence of thrombosis associated with bioprosthesis is estimated to be only 0.03–0.7% per patient-year.[3]\n\nHowever, several studies have reported early thrombosis of bioprosthesis in the aortic position.\n\nBy comparing the incidence of thrombosis among valve types, there is a significant difference between stented porcine valves, pericardial valves, and stentless porcine valves with increased risk in stented porcine valve.\n\nIndeed, Brown et al. showed that all patients with aortic valve thrombosis received a stented porcine valve, with greater risk in epic valves (calculated incidence was 1.26% [confidence interval, 0.56–1.96]).[3]\n\nHowever, overall incidence of aortic bioprosthesis thrombosis is low except in any hypercoagulable state as in our case report.\n\nHence, previous studies found risk factors for thrombus formation depending of the type of bioprosthetic valves and risk factor of thromboembolic complications such as left ventricular dysfunction, endocarditis, use of steroids or hormones or thrombophilia.[3]\n\nIn bioprosthetic valves in the aortic position, the incidence of thromboembolic episodes is probably greatest during the first 3 months after operation, but literature review found that approximately half of the cases occurred after 13 months.[4]\n\nRecent studies showed that thrombosis are often hemodynamically subclinical with reduced leaflet motion and normal aortic-valve gradients on echocardiography.[5]\n\nHence, diagnosis was frequently performed on computerized tomography (CT) or TEE but was missed on TTE.\n\nOnly five cases of subclinical leaflet thrombosis in transcatheter aortic valves have been reported, but reduced leaflet motion was found in 40% of patients in a recent trial, suggesting that this phenomenon is not uncommon.[5]\n\nCONCLUSION\nSo far, in case of hypercoagulable state, thrombosis of aortic bioprosthetic valve may occur on aspirin therapy. Even if leaflet thrombosis is often subclinical, incidence of nonobstructive thrombosis in porcine bioprosthetic valves within 3 months after implantation is probably underestimated, and this raises the interest of a systematic CT after surgery and curative anticoagulation, especially in patients, with high risk of thromboembolic complication.\n\nTherefore, we need others studies to determine which patient must be treated by anticoagulation during 3 months after aortic bioprosthetic valve implantation.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Vahanian A Alfieri O Andreotti F Antunes MJ Barón-Esquivias G Baumgartner H Guidelines on the management of valvular heart disease (version 2012): The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Eur J Cardiothorac Surg 2012 42 S1 44 22922698 \n2 Jamieson WR Lewis CT Sakwa MP Cooley DA Kshettry VR Jones KW St Jude Medical Epic porcine bioprosthesis: Results of the regulatory evaluation J Thorac Cardiovasc Surg 2011 141 1449 54.e2 21277603 \n3 Brown ML Park SJ Sundt TM Schaff HV Early thrombosis risk in patients with biologic valves in the aortic position J Thorac Cardiovasc Surg 2012 144 108 11 21864857 \n4 Pislaru SV Hussain I Pellikka PA Maleszewski JJ Hanna RD Schaff HV Misconceptions, diagnostic challenges and treatment opportunities in bioprosthetic valve thrombosis: Lessons from a case series Eur J Cardiothorac Surg 2015 47 725 32 24829402 \n5 Makkar RR Fontana G Jilaihawi H Chakravarty T Kofoed KF de Backer O Possible subclinical leaflet thrombosis in bioprosthetic aortic valves N Engl J Med 2015 373 2015 24 26436963\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2211-4122",
"issue": "26(3)",
"journal": "Journal of cardiovascular echography",
"keywords": "Aortic bioprosthetic valve; nonobstructive thrombosis; stroke",
"medline_ta": "J Cardiovasc Echogr",
"mesh_terms": null,
"nlm_unique_id": "101562228",
"other_id": null,
"pages": "97-99",
"pmc": null,
"pmid": "28465971",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "22922698;21277603;24829402;26436963;21864857",
"title": "Multiple Strokes Secondary to an Early Thrombosis of Aortic Bioprosthesis on Aspirin Therapy.",
"title_normalized": "multiple strokes secondary to an early thrombosis of aortic bioprosthesis on aspirin therapy"
} | [
{
"companynumb": "FR-SA-2016SA170346",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Eosinophilic otitis media (EOM), which is characterized by the accumulation of eosinophils in middle ear effusion and the middle ear mucosa, is a refractory type of otitis media that is often associated with asthma. Although an early diagnosis and appropriate treatment are necessary to prevent the progression of hearing loss in patients with EOM, there are currently no well-established treatments for this condition. We treated a 60-year-old male patient with asthma and EOM. The patient's asthma was poorly controlled, despite the use of high-dose inhaled corticosteroids, long-acting beta-agonist treatment, and the regular use of systemic corticosteroids. Mepolizumab, an anti-IL-5 monoclonal antibody, was started to treat the patient's refractory asthma. At 4 months after the initiation of mepolizumab treatment, the patient's asthma, hearing, and middle ear effusion improved. The present case suggests that mepolizumab therapy can control EOM and asthma.",
"affiliations": "Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan. Electronic address: i-suzaki@med.showa-u.ac.jp.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan; Tokyo Metropolitan Health and Medical Treatment Corporation, Ebara Hospital, Tokyo, Japan.;Department of Medicine, Division of Respiratory Medicine and Allergology, Showa University, School of Medicine, Tokyo, Japan.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan; Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan; Kamio Memorial Hospital, Tokyo, Japan.;Department of Otorhinolaryngology, School of Medicine, Showa University, Tokyo, Japan.",
"authors": "Suzaki|Isao|I|;Kimura|Yurika|Y|;Tanaka|Akihiko|A|;Hirano|Kojiro|K|;Ishibashi|Atsushi|A|;Mizuyoshi|Tomomi|T|;Ando|Izumi|I|;Kitajima|Tatsuya|T|;Watanabe|So|S|;Hinohira|Yasuyuki|Y|;Kobayashi|Hitome|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C434107:mepolizumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.anl.2018.05.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-8146",
"issue": "46(1)",
"journal": "Auris, nasus, larynx",
"keywords": "Asthma; Eosinophilic otitis media; IL-5; Mepolizumab",
"medline_ta": "Auris Nasus Larynx",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001249:Asthma; D004802:Eosinophilia; D034381:Hearing Loss; D006801:Humans; D008297:Male; D008875:Middle Aged; D010034:Otitis Media with Effusion; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "7708170",
"other_id": null,
"pages": "141-146",
"pmc": null,
"pmid": "29909018",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of eosinophilic otitis media associated with severe bronchial asthma with an anti-IL-5 monoclonal antibody, mepolizumab.",
"title_normalized": "successful treatment of eosinophilic otitis media associated with severe bronchial asthma with an anti il 5 monoclonal antibody mepolizumab"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-006100",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute"... |
{
"abstract": "The aim was to evaluate the safety of intravenous lidocaine for postoperative pain and the impact on opioid requirements and pain scores.\n\n\n\nThis was a single-center, retrospective, single-arm analysis of adult patients who received intravenous lidocaine for postoperative pain from January 2016 to December 2019. Patients were excluded if they received lidocaine for any indication other than pain or if lidocaine was only given intraoperatively. The primary outcome of this analysis was to determine the incidence of adverse effects (AEs) and the reason for discontinuation of lidocaine. Secondary outcomes included median daily pain scores (visual analog scale and Critical-Care Pain Observation Tool) and opioid consumption (daily morphine milligram equivalents) 24 hours before infusion and during day 1.\n\n\n\nA total of 452 patients were evaluated of which 298 (65.9%) patients met inclusion criteria. Of the 154 patients excluded, 153 did not receive lidocaine postoperatively. The median duration of infusion was 34 [20:48] hours with a median initial and maintenance rate of 1 mg/kg/h dosed on ideal body weight. In our analysis, 174 (58.4%) patients had a documented AE during infusion and 38 (12.8%) had lidocaine discontinued because of an AE. The most common AE was nausea in 62 (20.8%) patients and the most common reason for discontinuation was confusion in 8 (2.7%) patients. Daily morphine milligram equivalents (P<0.001) and visual analog scale (P<0.001) significantly decreased when comparing 24 hours before infusion and day 1.\n\n\n\nAlthough a majority of patients receiving lidocaine for postoperative pain experienced an AE, this did not result in discontinuation in most patients.",
"affiliations": "Department of Pharmacy, Brigham and Women's Hospital, Boston, MA.",
"authors": "Schuler|Brian R|BR|;Lupi|Kenneth E|KE|;Szumita|Paul M|PM|;Kovacevic|Mary P|MP|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/AJP.0000000000000960",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-8047",
"issue": "37(9)",
"journal": "The Clinical journal of pain",
"keywords": null,
"medline_ta": "Clin J Pain",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D004311:Double-Blind Method; D006801:Humans; D007262:Infusions, Intravenous; D008012:Lidocaine; D010147:Pain Measurement; D010149:Pain, Postoperative; D012189:Retrospective Studies",
"nlm_unique_id": "8507389",
"other_id": null,
"pages": "657-663",
"pmc": null,
"pmid": "34265786",
"pubdate": "2021-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluating the Safety of Continuous Infusion Lidocaine for Postoperative Pain.",
"title_normalized": "evaluating the safety of continuous infusion lidocaine for postoperative pain"
} | [
{
"companynumb": "US-DENTSPLY PHARMACEUTICAL-2021SCDP000138",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional... |
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