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"abstract": "Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2 years (range 5.8-14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3 months (⩽ 10%) and of complete cytogenetic response and major molecular response at 1 year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57 years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.",
"affiliations": "Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.;Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.;Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.;Department of Statistical Sciences, Sapienza University, Rome, Italy.;Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.;Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.;Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.;Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), Rome, Italy.;Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.;Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.;Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy. breccia@bce.uniroma1.it.",
"authors": "Molica|Matteo|M|http://orcid.org/0000-0001-6391-4406;Colafigli|Gioia|G|;Scalzulli|Emilia|E|;Alunni Fegatelli|Danilo|D|;Chiatamone Ranieri|Sofia|S|;Rizzo|Lorenzo|L|;Diverio|Daniela|D|;Efficace|Fabio|F|;Latagliata|Roberto|R|;Foà|Robin|R|;Breccia|Massimo|M|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D007372:Interferons",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-019-03706-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "98(8)",
"journal": "Annals of hematology",
"keywords": "Chronic myeloid leukemia; Imatinib; Long-term follow-up; Real-life experience",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D002318:Cardiovascular Diseases; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D007372:Interferons; D015466:Leukemia, Myeloid, Chronic-Phase; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1891-1904",
"pmc": null,
"pmid": "31079264",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ten-year outcome of chronic-phase chronic myeloid leukemia patients treated with imatinib in real life.",
"title_normalized": "ten year outcome of chronic phase chronic myeloid leukemia patients treated with imatinib in real life"
} | [
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"companynumb": "IT-MYLANLABS-2019M1091954",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
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"actiondrug": "5",
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"activesubstancename": "IMATINIB MESYLATE"
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"abstract": "Proctosedyl® and Proctomyxin® are two commonly prescribed hemorrhoid therapies. Their topical application to the perianal region may be complicated by a local allergic contact dermatitis and subsequent autoeczematization reaction. We present three cases of an autoeczematization (ID) reaction to varying topical allergens found in Proctosedyl®/Proctomyxin®. It is our recommendation that physician and patient education, avoidance of allergens (or cross-reactants), and appropriate choice of topical corticosteroid is important in preventing and avoiding flares.",
"affiliations": "Department of Dermatology, Division of Medicine, University of Calgary, Calgary, Alberta, Canada.;Department of Dermatology, University of Ottawa, Ottawa, Ontario, Canada.",
"authors": "Hughes|J D Matthew|JDM|;Pratt|Melanie D|MD|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000486475",
"fulltext": "\n==== Front\nCase Rep DermatolCase Rep DermatolCDECase Reports in Dermatology1662-6567S. 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 10.1159/000486475cde-0010-0238Case SeriesAllergic Contact Dermatitis and Autoeczematization to Proctosedyl® Cream and Proctomyxin® Cream Hughes J.D. Matthew a*Pratt Melanie D. baDepartment of Dermatology, Division of Medicine, University of Calgary, Calgary, Alberta, CanadabDepartment of Dermatology, University of Ottawa, Ottawa, Ontario, Canada*J.D. Matthew Hughes, 1904-179 Metcalfe Street, Ottawa, ON K2P 0W1 (Canada), E-Mail jhugh017@uottawa.caSep-Dec 2018 24 10 2018 24 10 2018 10 3 238 246 16 1 2017 18 12 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.Proctosedyl® and Proctomyxin® are two commonly prescribed hemorrhoid therapies. Their topical application to the perianal region may be complicated by a local allergic contact dermatitis and subsequent autoeczematization reaction. We present three cases of an autoeczematization (ID) reaction to varying topical allergens found in Proctosedyl®/Proctomyxin®. It is our recommendation that physician and patient education, avoidance of allergens (or cross-reactants), and appropriate choice of topical corticosteroid is important in preventing and avoiding flares.\n\nKeywords\nAllergic contact dermatitisProctosedyl® creamProctomyxin® creamHemorrhoidsPatch testCross-reactivity\n==== Body\nIntroduction\nProctosedyl® cream (Sanofi-Aventis, Paris, France) and Proctomyxin® cream (Novartis, Basel, Switzerland) are common medications used to treat hemorrhoids. Framycetin, hydrocortisone, and dibucaine (cinchocaine) are 3 active ingredients in these creams. These ingredients are common in over-the-counter (OTC) medications and are potential allergens [1].\n\nWe present 3 cases of allergic contact dermatitis (ACD) in males who used Proctosedyl® cream and Proctomyxin® cream to treat their hemorrhoids; 2 of these men experienced an autoeczematization.\n\nCase Reports\nCase 1\nA 72-year-old man presented to the emergency department with a very pruritic, tender, erythematous eczematous dermatitis that started in the perianal area and then became more widespread. A diagnosis of ACD in his perianal region likely due to Proctosedyl®, a cream to treat his hemorrhoids, was made. He had previously used Lamisil® cream (Novartis), Benadryl® cream (Johnson & Johnson, New Brunswick, NJ, USA), and 2 hydrocortisone preparations (Imacort® [Spirig, Egerkingen, Switzerland] and Cortoderm® [Pharmacare Ltd., Port Elizabeth, South Africa]).\n\nHe was subsequently patch tested with readings completed at 48 and 96 h. His results were strongly positive (3+) for gentamicin sulfate 20% in pet, kanamycin sulfate 20% in pet, framycetin sulfate 10% in pet, rosin 20% in pet, tixocortol-21-pivalate 1% in pet, and hydrocortisone 1% in pet. Specific results at 96 h (true allergens) are shown in Table 1 (medication is listed in Table 2). Our patient was advised about all his contact allergies and potential cross-reactions. He was prescribed Betaderm® 0.1% ointment (a safe group 3 [D1] steroid) for potential future reactions and Protopic cream® (Astella/Fujisawa, Tokyo, Japan) for facial eruptions.\n\nCase 2\nA 27-year-old man presented with severe ACD in the perianal region followed by a widespread flare of his eczema (autoeczematization) to Proctomyxin® cream. He used Proctomyxin® cream, Proctozone® (Rising, Allendale, NJ, USA), Anusol HC® (Salix, Raleigh, NC, USA), Polysporin® Complete (Johnson & Johnson), and Proctofoam® cream (Meda, Somerset, NJ, USA) to treat his hemorrhoids (see Table 2 for ingredients). He was started on 50 mg of oral prednisone and weaned down over 3 weeks. He was also given topical betamethasone 0.1% ointment.\n\nHe was subsequently patch tested, and results were read at 48 and 120 h; the results are summarized in Table 1. He was strongly reactive (3+) to neomycin sulfate 20% in pet, gentamicin sulfate 20% in pet, kanamycin sulfate 10% in pet, framycetin sulfate 10% in pet, dibucaine HCl 5% in pet, lanolin alcohol (Amerchol L-101) 50% in pet, carba mix 3% in pet, Proctozone® cream, Anusol HC® cream, chlorhexidine digluconate 0.5% aq, and Proctomyxin® cream. He was educated regarding which safe skin products he could use (Lipikar® balm [F. Hoffmann-La Roche AG, Basel, Switzerland], Dove® for sensitive skin [Unilever, UK]). He was advised about all his contact allergies, their sources and cross-reactions.\n\nCase 3\nA 44-year-old man presented to the emergency room with a history of a pruritic, spreading perianal eczematous dermatitis, which developed 2 days after commencing Proctosedyl® cream treatment for his hemorrhoids. He also started 1% hydrocortisone cream. He developed an autoeczematization reaction in his body folds (axilla, antecubital fossa, and ankles); this reaction persisted for a few weeks. His pruritus was controlled with Claritin® (Schering-Plough, Kenilworth, NJ, USA) and Reactine® (Johnson & Johnson). Past history revealed the use of Kenacomb® cream (GlaxoSmithKline, Brentford, London, UK) for an axillary rash 12 years before, which resulted in a similar clinical picture of ACD. He was given Atarax® (GlaxoSmithKline) (hydroxyzine) to treat his Kenacomb cream-induced ACD. His ACD worsened and became generalized.\n\nTwo rounds of patch testing were completed and results were read at 48 h and the 120-h mark. Results are summarized in the corresponding Table 1 and Figure 1. He was positive for all tested cross-reacting aminoglycosides (neomycin sulfate, gentamycin sulfate, kanamycin sulfate, and framycetin sulfate) as well as the co-reacting bacitracin. He was also strongly positive for dibucaine (chichocaine HCl 5% in pet), tixocortol-21-pivalate 1% in pet (screens for group A [now group I] hydrocortisone allergy), ethylenediamine dihydrochloride 1% in pet, thiuram mix 1% in pet (rubber), fragrance mix 8% in pet, and triamcinolone acetonide and its screener for group B (now group II) corticosteroid allergy budesonide 0.1% in pet. Kenacomb® contains ethylenediamine, triamcinolone acetonide 1% in pet, and neomycin, to all of which the patient had a very strong reaction, in addition to the whole Kenacomb® cream preparation. Ethylenediamine dihydrochloride, an ingredient used as a stabilizer in Kenacomb® cream, cross-reacts with hydroxyzine (Atarax® and Reactine®) [2]. This caused a systemic contact dermatitis reaction when the patient took hydroxyzine for his original ACD to Proctosedyl® cream. Proctosedyl® cream contains hydrocortisone acetate and dibucaine HCl. Again, the patient had a strong reaction to both ingredients plus the whole preparation.\n\nIn all 3 cases, the patients were tested in accordance with the North American Contact Dermatitis Group (NACDG) [1] protocol and the NACDG standard screening series using Finn Chambers (allergEAZE; SmartPractice, Phoenix, AZ, USA) and Scanpor tape (Norgesplaster Alpharma, Vennesla, Norway), as well as the other series, which can be seen in Table 1.\n\nDiscussion\nIt is estimated that ACD affects 15–20% of the general population at some point [3]. ACD risk factors are divided into acquired and inherited categories. Acquired risk factors include stasis dermatitis, polysensitization, and irritant contact dermatitis. Inherited risk factors include genetic mutations (Table 3), young age (due to increased immune function), female gender, and possibly lighter skin color due to decreased barrier function [3].\n\nClinical Presentation\nACD classically presents acutely as a papulovesicular, edematous, erythematous spreading eruption. Scaling may occur in subacute lesions and thickened plaques; lichenification or fissuring may be seen in chronic cases [4]. As in our cases, sensitization to multiple allergens, or polysensitization, can occur. A detailed history, including the points in Table 4, is important to help elucidate allergen sources. Polysensitization is subcategorized into co-sensitization (co-reactivity) and cross-sensitization. Co-sensitization is when multiple sensitizations occur to immunologically distinct chemicals at the same time. Cross-sensitization is when the 2 different antigens appear similar to the immune system. As mentioned, autoeczematization is a full-body ACD flare from a topical agent, whereas a systemic reaction appears the same but occurs secondary to a parenteral exposure.\n\nPathophysiology\nACD is a classic T-cell-mediated hypersensitivity to exogenous agents. Initially, low-molecular-weight (< 500 Da) chemicals (haptens), which are nonimmunogenic, penetrate the stratum corneum and covalently bind to amino acid side chains [5]. Next, the sensitization phase occurs when the hapten-protein complex is engulfed by Langerhans cells and drained to the regional lymph node. Clonal expansion occurs and T cells circulate the body before the elicitation phase occurs [6]. The elicitation phase commences when a T-cell- (primarily CD8+ Tc1 cells) mediated inflammatory response ensues as a consequence of being re-exposed to a cross-reactive or previously sensitized agent [7].\n\nTreatment\nThe mainstay of ACD treatment is allergen identification through patch testing and avoidance, which needs to be clearly conveyed to the patient. Short-term management of acute flares may require the use of topical corticosteroids. The use of betamethasone valerate (group D1) or desoximetasone (group C) is recommended, as they are the least allergenic corticosteroids. Oral prednisone is added in more severe cases. Calcineurin inhibitors (tacrolimus or pimecrolimus) in place of corticosteroids are acceptable, especially in cases involving the face or eyelids. In rare systemic cases, immunosuppressive agents have been successfully used (i.e., unavoidable airborne allergens like dust).\n\nProctosedyl® cream (specifically its constituent dibucaine) as a vehicle for ACD allergens was first described in a case report published by Lee in 1998 [8]. A second case report by Kearney and Fewings [8] attributed ACD to dibucaine (aka cinchocaine) in 2001; but these remain 2 isolated case reports demonstrating a direct link. At times, lidocaine and dibucaine can cross-react. However, the NACDG patch test results from 2011 to 2012 demonstrate that 9.1% (n = 384) of patch-tested patients had a definitive ACD reaction to neomycin [9]; this substance commonly cross-reacts with framycetin (in our patients' hemorrhoid creams), since both are aminoglycoside topical antibiotics.\n\nBased on the history and patch testing results demonstrated by our cases, the following was surmised. These patients were sensitized to multiple distinct components. Their exposure to Proctosedyl® cream and Proctomyxin cream® caused a range of reactions along the ACD spectrum. The re-exposure to similar agents (cases 2 and 3) consequently created a widespread autoeczematization that required oral prednisone. It was concluded that Proctosedyl® cream and Proctomyxin® cream were responsible in all 3 cases of ACD. One case had systemic contact dermatitis from a parental exposure to hydroxyzine and Reactine®.\n\nFactors that contribute to sensitization include warm, moist, intertriginous areas that are fissured, such as the perianal region. Other high-risk sites are venous stasis dermatitis of the lower legs, otitis externa, perivulvar areas, eyelids, and legs.\n\nConclusions\nThese 3 ACD cases secondary to hemorrhoid treatment demonstrate several unique features. This report is an example of multiple patients with polysensitization to multiple unrelated allergies in hemorrhoid preparations (Proctosedyl® cream, Proctomyxin® cream, Anusol HC®, and Proctozone®). Second, it demonstrates the broad possible cross-reactivity to other medications which physicians and patients must be diligent to avoid. Finally, 2 of these cases showed autoeczematization, and 1 case is an example of a systemic reaction.\n\nKey Points\nACD requires sensitization prior to elicitation of clinical findings.\n\nWhen ACD findings are present, all offending agents should be stopped in order to prevent worsening of existing rashes or an autoeczematization reaction.\n\nWhen establishing a diagnosis, an accurate detailed history and patch testing helps determine the cause of ACD.\n\nThe management of allergic contact includes patient education, allergen avoidance, appropriate topical steroids (betamethasone) that are less allergic, and follow-up.\n\nAlso, avoiding multiple OTC products is necessary, such as wet wipes, OTC hydrocortisone cream, etc.\n\nSafe products include gentle bar soap (Aveno Bar®), plain Vaseline, and Betaderm ointment if perianal pruritis develops.\n\nStatement of Ethics\nAll patients in this study have consented to the use of nonidentifiable personal information for the purposes of this publication.\n\nDisclosure Statement\nNo author involved in this study has any conflicts of interest to disclose.\n\nFig. 1. Case 3. Patch test results at 120 h. Note the individual eczematous patches present at 120 h despite background erythema which persisted 72 h after the removal of his patches.\n\nTable 1 Summary of the patch test results for all 3 patients\n\nCompound\tCase 1\tCase 2\tCase 3\t\nAminoglycosides\t\nNeomycin sulfate 20% in pet\t–\t3+\t3+\t\nGentamicin sulfate 20% in pet\t3+\t3+\t3+\t\nKanamycin sulfate 10% in pet\t3+\t3+\t3+\t\nFramycetina sulfate 10% in pet\t3+\t3+\t3+\t\nBacitracin 20% in pet\t\t\t3+\t\n\t\nOther tested compounds\t\nRosinb (Colophonium) 20% in pet\t2+\t1+\t–\t\nTixocortol-21-pivalatec 1% in pet\t3+\t–\t3+\t\nCarba mix 3% in pet\t–\t3+\t–\t\nDiphenyl guanidined 1% in pet\t–\t1+\t–\t\nLanolin alcohol (Amerchol L-101) 50% in pet\t–\t3+\t–\t\nDibucaine or cinchocaine HCl 5% in pet\t–\t3+\t3+\t\nProctozone® cream\t–\t3+\t–\t\nAnusol HC® cream (Salix, Raleigh, NC, USA)\t–\t3+\t–\t\nBenzophenone-4e (Sulisobenzone)\t–\t2+\t–\t\nChlorhexidinef digluconate 0.5% aq\t–\t3+\t–\t\nHydrocortisone cream 1% (1)\t3+\t–\t3+\t\nProctosedyl cream\t3+\t–\t3+\t\nBenadryl cream (1)\t3+\t–\t–\t\nProctomyxin® cream (2)\t–\t3+\t–\t\nKenacomb cream\t–\t–\t3+\t\nThiuram mix 1% in pet\t–\t–\t3+\t\nEthylenediamine dihydrochloride 1% in pet\t–\t–\t3+\t\nFragrance I 8% in pet\t–\t–\t3+\t\nTriamcinolone acetonide 1% in pet\t–\t–\t3+\t\nAlclometasone-17,21-diproprionate 1% in pet\t–\t–\t2+\t\nBudesonide 0.1% in pet\t–\t–\t3+\t\nAll results were recorded at 96–120 h as per the NACDG guidelines. Results at 48 h are excluded for simplicity and accuracy.\n\na Framycetin: found in Proctosedyl®.\n\nb Rosin: sap/pitch from pine trees used in Band-Aids.\n\nc Tixocortol-21-pivalate: screen for hydrocortisone allergy.\n\nd Diphenyl guanidine: part of carba, a rubber accelerator.\n\ne Benzophenone (sulisobenzone): found in sunscreens and shampoos.\n\nf Chlorhexidine: antibacterial agent found in cleansers, toothpaste, and shampoos.\n\nTable 2 Topical medications used by our patients and their ingredients\n\nMedication\tIngredient\tIngredient\t\nProctosedyl® cream (in 1 g)\tHydrocortisone BP 5 mg (0.5%)\tEsculin 10 mg (1%)\t\n\tCinchocaine hydrochloride BP 5 mg (0.5%)\tAnhydrous lanolin\t\n\t\tFramycetin sulfate BP 10 mg\t\n\t\nProctomyxin® cream (in 1 g)\tHydrocortisone 5 mg (0.5%)\tCinchocaine hydrochloride 5 mg (0.5%)\t\n\tFramycetin sulfate 10 mg\tEsculin 10 mg (1%)\t\n\tAnhydrous lanolin\t\t\n\t\nProctozone® (in 1 g)\tHydrocortisone (as acetate) 5 mg\tLanolin\t\n\tFramycetin sulfate 10 mg\tLight mineral oil\t\n\tCinchocaine hydrochloride 5 mg\tPetrolatum\t\n\tEsculin 10 mg\t\t\n\t\nAnusol HC® (in 1 g)\tZinc sulfate monohydrate 0.5%\tOleth-2\t\n\tCalcium phosphate (dibasic)\tPetrolatum\t\n\tMethylparaben\tPropyl paraben\t\n\tMineral oil\t\t\nPolysporin® (in 1 g)\t10,000 units Polymyxin B (as sulfate)\tVitamin E\t\n\t500 units bacitracin zinc\tSodium pyruvate\t\n\tButylated hydroxytoluene\tOliv e oil, petrolatum\t\n\tCocoa butter\tCotton seed oil\t\n\t\nProctofoam® (in 375 mg)\t1% hydrocortisone acetate (3.75 mg/dose)\tWater\t\n\t1% pramoxine hydrochloride (3.75 mg/dose)\tTriethanolamine\t\n\tCetyl alcohol\tSteareth-10\t\n\tEmulsifying wax\tPropylparaben\t\n\tIsobutane\tPropylene glycol\t\n\t\tPropane\t\n\t\tMethylparaben\t\n\t\nKenacomb®a\tNystatin\tNeomycin\t\n\tGramicidin\tTriamcinolone acetonide\t\n\tEthylenediamine\t\t\n\t\nAtarax®\tHydroxyzine\tSoybean oil\t\n\tHydrocholoride (10 mg)\tLecithin\t\n\tWax mixture\t\t\na Bristol Myers Squibb could not directly comment on the ingredients in Kenacomb as it is discontinued.\n\nTable 3 Genetic risk factors for ACD and their effects\n\nGenetic mutation\tEffect\t\n\t\nMetabolism and activation of NATs\tPatients with ACD tend to have NATs with higher enzymatic activity\t\n\t\nHomogeneous deletion of glutathione S-transferases (GSTs) M1 and T1\tIncreased sensitization against preservative thimerosal\t\n\t\nCytokine polymorphisms\tChange immunologic response\t\n\t\nPromoter of TNF-α at position 308\tHigher susceptibility to chromate in cement workers\t\n\t\nHomozygous allele IL-16–295C\tHigher frequency in polysensitized individuals\t\n\t\nACD, allergic contact dermatitis; NAT, N-acetyltransferase.\t\nTable 4 Important history points\n\nDemographics and occupational history\tAge\tGender\t\n\tReligion\tEthnicity\t\n\tJob title\tSocial aspects (marital status)\t\n\tRegular exposures\tJob description\t\n\tOccasional exposures\tEmployment location\t\n\tTime at current job\tPrevious occupation\t\n\t\nFamily medical history\tGenetic factors\tPredisposition\t\n\t\nPast medical history\tDrug allergies\tConcomitant diseases\t\n\tMedications\tSurgeries\t\n\t\nDermatitis-specific history\tOnset\tLocation\t\n\tTemporal association (waxing/waning)\tTreatment\n==== Refs\nReferences\n1 Pratt MD Belsito DV DeLeo VA Fowler JF Jr Fransway AF Maibach HI North American Contact Dermatitis Group patch-test results, 2001–2002 study period Dermatitis 2004 12 15 (4) 176 83 15842061 \n2 Lew BL Haw CR Lee MH Cutaneous drug eruption from cetirizine and hydroxyzine J Am Acad Dermatol 2004 6 50 (6) 953 6 15153902 \n3 Peiser M Tralau T Heidler J Api AM Arts JH Basketter DA Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany Cell Mol Life Sci 2012 3 69 (5) 763 81 21997384 \n4 Bologna J Schaffer J Duncan K Ko C Dermatology Essentials 2014 China Elseview \n5 Divkovic M Pease CK Gerberick GF Basketter DA Hapten-protein binding: from theory to practical application in the in vitro prediction of skin sensitization Contact Dermat 2005 10 53 (4) 189 200 \n6 Vocanson M Hennino A Rozières A Poyet G Nicolas JF Effector and regulatory mechanisms in allergic contact dermatitis Allergy 2009 12 64 (12) 1699 714 19839974 \n7 Vocanson M Hennino A Cluzel-Tailhardat M Saint-Mezard P Benetiere J Chavagnac C CD8+ T cells are effector cells of contact dermatitis to common skin allergens in mice J Invest Dermatol 2006 4 126 (4) 815 20 16456532 \n8 Kearney CR Fewings J Allergic contact dermatitis to cinchocaine Australas J Dermatol 2001 5 42 (2) 118 9 11309035 \n9 Warshaw EM Maibach HI Taylor JS Sasseville D DeKoven JG Zirwas MJ North American contact dermatitis group patch test results: 2011–2012 Dermatitis 2015 Jan-Feb 26 (1) 49 59 25581671\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6567",
"issue": "10(3)",
"journal": "Case reports in dermatology",
"keywords": "Allergic contact dermatitis; Cross-reactivity; Hemorrhoids; Patch test; Proctomyxin® cream; Proctosedyl® cream",
"medline_ta": "Case Rep Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101517685",
"other_id": null,
"pages": "238-246",
"pmc": null,
"pmid": "30519170",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "15842061;16191014;25581671;19839974;21997384;15153902;11309035;16456532",
"title": "Allergic Contact Dermatitis and Autoeczematization to Proctosedyl® Cream and Proctomyxin® Cream.",
"title_normalized": "allergic contact dermatitis and autoeczematization to proctosedyl cream and proctomyxin cream"
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"companynumb": "CA-STRIDES ARCOLAB LIMITED-2019SP001555",
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"activesubstancename": "LORATADINE"
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"drugadditional... |
{
"abstract": "To verify safety and efficacy of the corticosteroid-sparing drug azathioprine (AZA) in Rasmussen syndrome (RS), we retrospectively analyzed a cohort of patients with RS recruited in a single pediatric neuroscience center.\n\n\n\nWe compared outcomes in 30 patients with RS who received AZA with 23 patients who were not treated with this drug. We used a multimodal approach to correlate therapy with clinical features (seizures, epilepsia partialis continua [EPC], hemiparesis) and neuroimaging markers of progressive brain atrophy.\n\n\n\nAZA was well tolerated; only 1 patient discontinued treatment due to pancytopenia. In 27 of 30 patients receiving AZA, all of whom were corticosteroid responders, corticosteroid therapy could be weaned or reduced without worsening of seizures in 89%. Patients receiving AZA had a lower prevalence of EPC (42% vs 67% in controls) and hemiparesis (64% vs 92%, respectively). Cox regression showed for the AZA group compared to controls a delayed time to (1) EPC (≈2 years, exp[B] = 0.295, 95% confidence interval [CI] 0.108-0.807; p = 0.017), (2) hemiparesis (≈1 year, exp[B] = 0.315, 95% CI 0.137-0.724; p = 0.007), and (3) surgery (≈2 years, exp[B] = 2.068, 95% CI 1.012-4.227; p = 0.046). However, there were no group differences in cognitive decline over time (IQ change per year) or in hemispheric gray matter atrophy on serial MRI scans.\n\n\n\nAZA treatment appears to slow clinical progression of RS in steroid responders; this will give the greatest advantage in patients in the early stages of the disease in whom surgical decision-making may require further time.\n\n\n\nThis study provides Class III evidence that for pediatric patients with RS AZA is well tolerated and slows hemiparesis and appearance of EPC.",
"affiliations": "From the Developmental Neurosciences Programme (S.P., T.B., J.H.C.), Great Ormond Street Institute of Child Health, London, UK; Child Neuropsychiatry Unit (S.P., G.C.), University of Verona, Italy; and Great Ormond Street Hospital for Children NHS Foundation Trust (S.P., F.D., S.V., J.H.C.), London, UK.;From the Developmental Neurosciences Programme (S.P., T.B., J.H.C.), Great Ormond Street Institute of Child Health, London, UK; Child Neuropsychiatry Unit (S.P., G.C.), University of Verona, Italy; and Great Ormond Street Hospital for Children NHS Foundation Trust (S.P., F.D., S.V., J.H.C.), London, UK.;From the Developmental Neurosciences Programme (S.P., T.B., J.H.C.), Great Ormond Street Institute of Child Health, London, UK; Child Neuropsychiatry Unit (S.P., G.C.), University of Verona, Italy; and Great Ormond Street Hospital for Children NHS Foundation Trust (S.P., F.D., S.V., J.H.C.), London, UK.;From the Developmental Neurosciences Programme (S.P., T.B., J.H.C.), Great Ormond Street Institute of Child Health, London, UK; Child Neuropsychiatry Unit (S.P., G.C.), University of Verona, Italy; and Great Ormond Street Hospital for Children NHS Foundation Trust (S.P., F.D., S.V., J.H.C.), London, UK.;From the Developmental Neurosciences Programme (S.P., T.B., J.H.C.), Great Ormond Street Institute of Child Health, London, UK; Child Neuropsychiatry Unit (S.P., G.C.), University of Verona, Italy; and Great Ormond Street Hospital for Children NHS Foundation Trust (S.P., F.D., S.V., J.H.C.), London, UK.;From the Developmental Neurosciences Programme (S.P., T.B., J.H.C.), Great Ormond Street Institute of Child Health, London, UK; Child Neuropsychiatry Unit (S.P., G.C.), University of Verona, Italy; and Great Ormond Street Hospital for Children NHS Foundation Trust (S.P., F.D., S.V., J.H.C.), London, UK.;From the Developmental Neurosciences Programme (S.P., T.B., J.H.C.), Great Ormond Street Institute of Child Health, London, UK; Child Neuropsychiatry Unit (S.P., G.C.), University of Verona, Italy; and Great Ormond Street Hospital for Children NHS Foundation Trust (S.P., F.D., S.V., J.H.C.), London, UK. h.cross@ucl.ac.uk.",
"authors": "Pellegrin|Serena|S|0000-0001-9954-3053;Baldeweg|Torsten|T|0000-0002-5724-1679;Pujar|Suresh|S|0000-0002-9894-4194;D'Arco|Felice|F|0000-0001-7396-591X;Cantalupo|Gaetano|G|0000-0003-1343-8434;Varadkar|Sophia|S|0000-0001-7154-6738;Cross|J Helen|JH|0000-0001-7345-4829",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000011004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "96(2)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000293:Adolescent; D001379:Azathioprine; D002648:Child; D015331:Cohort Studies; D004660:Encephalitis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D056747:Immunomodulation; D007166:Immunosuppressive Agents; D007167:Immunotherapy; D008297:Male; D064847:Multimodal Imaging; D009483:Neuropsychological Tests; D012189:Retrospective Studies",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e267-e279",
"pmc": null,
"pmid": "33046614",
"pubdate": "2021-01-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Immunomodulation With Azathioprine Therapy in Rasmussen Syndrome: A Multimodal Evaluation.",
"title_normalized": "immunomodulation with azathioprine therapy in rasmussen syndrome a multimodal evaluation"
} | [
{
"companynumb": "GB-SEBELA IRELAND LIMITED-2020SEB00134",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nTo determine if a correlation exists between the number of previous enhanced magnetic resonance (MR) imaging examinations and high signal intensity in the globus pallidus (GP) and dentate nucleus (DN) in patients who received gadodiamide (Omniscan), a linear nonionic gadolinium-based contrast agent, and in those who received gadobenate dimeglumine (MultiHance), a linear ionic contrast agent.\n\n\nMETHODS\nInstitutional review board approval was obtained for this single-center retrospective study, with waiver of informed consent. The study population included 69 patients divided into two groups: Group 1 included patients who underwent gadodiamide-enhanced MR imaging, and group 2 included patients who underwent gadobenate dimeglumine-enhanced MR imaging. Two radiologists conducted a quantitative analysis of unenhanced T1-weighted images by using region of interest measurements. The GP-to-thalamus (TH) signal intensity ratio, DN-to-middle cerebellar peduncle (MCP) signal intensity ratio and relative percentage change (Rchange) between the first and last examinations for each patient were calculated. Relation between the signal intensity ratios and Rchange and the number of enhanced MR imaging examinations was analyzed by using a generalized additive model. Inter- and intraobserver agreement was evaluated with the Lin concordance correlation coefficient test.\n\n\nRESULTS\nGroup 1 included 23 patients (19 female), with a mean of 5.0 doses ± 2.4 (standard deviation) (range, 3-11 doses) administered. Group 2 included 46 patients (24 female) with a mean of 4.6 doses ± 2.2 (range, 3-11 doses) administered. The interval between the first and last examination was 1500.1 days ± 780.2 (range, 98-3097 days) for group 1 and 1086.2 days ± 582.9 (range, 94-2633) for group 2. All patients had normal liver and renal function. Gadodiamide showed a significant increase in DN:MCP and GP:TH (P < .001 for both) and in Rchange (P = .001 for GP:TH, P < .001 for DN:MCP). In group 2, there was no significant increase in DN:MCP or GP:TH over time or in Rchange for GP:TH, but there was a significant trend toward an increase in Rchange for DN:MCP (P = .013). Interobserver agreement was almost perfect (0.99; 95% confidence interval: 0.99, 0.99) for all evaluated structures. Intraobserver agreement was substantial to almost perfect for both readers.\n\n\nCONCLUSIONS\nA significant increase in GP:TH and DN:MCP is associated with multiple gadodiamide-enhanced studies but not with gadobenate dimeglumine-enhanced studies, likely reflecting differences in stability and elimination of both contrast agents. Rate-of-change data indirectly suggest gadolinium deposition in the DN with gadobenate dimeglumine use, although it is considerably less than that with gadodiamide use.",
"affiliations": "From the Department of Radiology, University of North Carolina at Chapel Hill, CB 7510, 2001 Old Clinic Bldg, Chapel Hill, NC 27599-7510 (J.R., M.C., M.A., R.H.N., M.R., R.C.S.); Department of Radiology. King Faisal Specialist Hospital & Research Center, Riyadh. Saudi Arabia (M.A.); and Siemens Healthcare, Cary, NC (B.M.D.).;From the Department of Radiology, University of North Carolina at Chapel Hill, CB 7510, 2001 Old Clinic Bldg, Chapel Hill, NC 27599-7510 (J.R., M.C., M.A., R.H.N., M.R., R.C.S.); Department of Radiology. King Faisal Specialist Hospital & Research Center, Riyadh. Saudi Arabia (M.A.); and Siemens Healthcare, Cary, NC (B.M.D.).;From the Department of Radiology, University of North Carolina at Chapel Hill, CB 7510, 2001 Old Clinic Bldg, Chapel Hill, NC 27599-7510 (J.R., M.C., M.A., R.H.N., M.R., R.C.S.); Department of Radiology. King Faisal Specialist Hospital & Research Center, Riyadh. Saudi Arabia (M.A.); and Siemens Healthcare, Cary, NC (B.M.D.).;From the Department of Radiology, University of North Carolina at Chapel Hill, CB 7510, 2001 Old Clinic Bldg, Chapel Hill, NC 27599-7510 (J.R., M.C., M.A., R.H.N., M.R., R.C.S.); Department of Radiology. King Faisal Specialist Hospital & Research Center, Riyadh. Saudi Arabia (M.A.); and Siemens Healthcare, Cary, NC (B.M.D.).;From the Department of Radiology, University of North Carolina at Chapel Hill, CB 7510, 2001 Old Clinic Bldg, Chapel Hill, NC 27599-7510 (J.R., M.C., M.A., R.H.N., M.R., R.C.S.); Department of Radiology. King Faisal Specialist Hospital & Research Center, Riyadh. Saudi Arabia (M.A.); and Siemens Healthcare, Cary, NC (B.M.D.).;From the Department of Radiology, University of North Carolina at Chapel Hill, CB 7510, 2001 Old Clinic Bldg, Chapel Hill, NC 27599-7510 (J.R., M.C., M.A., R.H.N., M.R., R.C.S.); Department of Radiology. King Faisal Specialist Hospital & Research Center, Riyadh. Saudi Arabia (M.A.); and Siemens Healthcare, Cary, NC (B.M.D.).;From the Department of Radiology, University of North Carolina at Chapel Hill, CB 7510, 2001 Old Clinic Bldg, Chapel Hill, NC 27599-7510 (J.R., M.C., M.A., R.H.N., M.R., R.C.S.); Department of Radiology. King Faisal Specialist Hospital & Research Center, Riyadh. Saudi Arabia (M.A.); and Siemens Healthcare, Cary, NC (B.M.D.).",
"authors": "Ramalho|Joana|J|;Castillo|Mauricio|M|;AlObaidy|Mamdoh|M|;Nunes|Renato H|RH|;Ramalho|Miguel|M|;Dale|Brian M|BM|;Semelka|Richard C|RC|",
"chemical_list": "D003287:Contrast Media; D009942:Organometallic Compounds; C064572:gadobenic acid; D008536:Meglumine; C064925:gadodiamide; D019786:Gadolinium DTPA",
"country": "United States",
"delete": false,
"doi": "10.1148/radiol.2015150872",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-8419",
"issue": "276(3)",
"journal": "Radiology",
"keywords": null,
"medline_ta": "Radiology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002529:Cerebellar Nuclei; D003287:Contrast Media; D005260:Female; D019786:Gadolinium DTPA; D005917:Globus Pallidus; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008536:Meglumine; D008875:Middle Aged; D009942:Organometallic Compounds; D012189:Retrospective Studies; D013788:Thalamus; D014018:Tissue Distribution; D055815:Young Adult",
"nlm_unique_id": "0401260",
"other_id": null,
"pages": "836-44",
"pmc": null,
"pmid": "26079490",
"pubdate": "2015-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents.",
"title_normalized": "high signal intensity in globus pallidus and dentate nucleus on unenhanced t1 weighted mr images evaluation of two linear gadolinium based contrast agents"
} | [
{
"companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OSCN-PR-1506L-0142",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADODIAMIDE"
},
... |
{
"abstract": "Cumulative evidence has shown that nonsteroidal anti-inflammatory drugs (NSAIDs) can induce acute renal failure and nephrotic-range proteinuria. Cyclooxygenase-2 (COX-2) inhibitors have less nephrotoxicity; however, recent data indicate that they may cause the same renal problems as NSAIDs do. Herein, we present a case of celecoxib-associated minimal change disease (MCD) with profound urinary protein loss and acute renal failure. Renal function and nephrotic syndrome in this patient resolved completely after discontinuation of celecoxib and treatment with methylprednisolone. Clinicians should keep high index of suspicions in patients developing nephrotic syndrome and acute renal failure after taking COX-2 inhibitors since secondary MCD responds well to timely cessation of COX-2 inhibitors and administration of steroid therapy.",
"affiliations": "Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11221, Taiwan, Republic of China.",
"authors": "Chen|Yu-Hsin|YH|;Tarng|Der-Cherng|DC|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D008565:Membrane Proteins; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0304-4920",
"issue": "54(4)",
"journal": "The Chinese journal of physiology",
"keywords": null,
"medline_ta": "Chin J Physiol",
"mesh_terms": "D058186:Acute Kidney Injury; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D006801:Humans; D007668:Kidney; D008565:Membrane Proteins; D013449:Sulfonamides",
"nlm_unique_id": "7804502",
"other_id": null,
"pages": "264-8",
"pmc": null,
"pmid": "22129825",
"pubdate": "2011-08-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Profound urinary protein loss and acute renal failure caused by cyclooxygenase-2 inhibitor.",
"title_normalized": "profound urinary protein loss and acute renal failure caused by cyclooxygenase 2 inhibitor"
} | [
{
"companynumb": "TW-PFIZER INC-2011182371",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CELECOXIB"
},
"drugadditional": "1",
... |
{
"abstract": "Acute myeloid leukemia has a poor outcome because of early deaths, high relapse rate and financial constraints. Our hospital provides care free of cost and this study assesses the short term outcome of acute myeloid leukemia in adults. The study was done from September 2013 to May 2015. All patients above 18 years of age were included. Cytarabine infusion 100 mg/m2 daily for 7 days and Daunorubicin 60 mg/m2 daily for 3 days was used for induction chemotherapy followed by three cycles of high dose cytarabine as post-remission therapy. One hundred and two patients were included in the study. 48% were males. The median age was 41 years. There was an intention to treat in 84 patients. 13 patients died before chemotherapy and 71 patients (57 non AML M3) received induction chemotherapy. 82% of them had a Eastern Cooperative Oncology Group performance score of ≤ 2. 28 (of 57 non AML M3) patients were alive after post-remission therapy (with 39% deaths during induction phase) and 15 of them were in remission after a median follow up of nine months. The overall event free survival at the end of the study was 22% (16 out of 71). Altogether, 63 out of 84 patients had died. Sepsis was considered as the cause of death in 46% of the patients, but the isolation of causative organism was limited (20%). The treatment outcomes of AML are poor at our centre and the current standard of care needs a significant improvement.",
"affiliations": "Samaritan Hospital, Pazhanganad, Ernakulam, 683562 India.;2Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, 605006 India.;3Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, 605006 India.;4Department of Medicine, Mahatma Gandhi Medical College and Research Institute, Pondicherry, 607403 India.",
"authors": "Jacob|Sherin|S|;Jacob|Sajini Elizabeth|SE|;Suryanarayana|Bettadpura Shamanna|BS|0000-0002-6715-1570;Dutta|Tarun Kumar|TK|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-018-1051-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0971-4502",
"issue": "35(3)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "Acute myeloid leukemia; Resource limited settings; Short term outcome",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "431-436",
"pmc": null,
"pmid": "31388253",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "14673054;14716122;15835484;25858293;26885243;29184070",
"title": "Clinical Profile and Short Term Outcome of Adult Patients with Acute Myeloid Leukemia.",
"title_normalized": "clinical profile and short term outcome of adult patients with acute myeloid leukemia"
} | [
{
"companynumb": "IN-PFIZER INC-2018505668",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS"
},
... |
{
"abstract": "Chemotherapy for lymphoma may be avoided in the presence of coincident cytopenia. In case of immune cytopenia secondary to lymphoma, treatment of cytopenia is the same for primary cases, however, chemotherapy for lymphoma may be effective at the cost of severe hematological toxicity. The present study reports a complex case of thrombocytopenia and direct antiglobulin test-negative hemolytic anemia, thus mimicking Evans syndrome, secondary to cluster of differentiation 5-positive B-cell lymphoma with massive splenomegaly, in a patient suffering from rheumatoid arthritis for two decades. Treatment with prednisolone, high-dose dexamethasone, eltrombopag and rituximab for cytopenia were not effective. Chemotherapy with bendamustine subsequently resolved the cytopenia, additionally resulting in a complete remission of lymphoma. Thus, bendamustine may have a role in the management of lymphoma complicated with severe cytopenia.",
"affiliations": "Division of Clinical Laboratory Medicine, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.;Division of Rehabilitation, Tottori University Hospital, Yonago, Tottori 683-8504, Japan.;Department of Hematology, Tottori University Hospital, Yonago, Tottori 683-8504, Japan.;Division of Clinical Laboratory Medicine, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.",
"authors": "Hosoda|Yuzuru|Y|;Hagino|Hiroshi|H|;Hino|Norihiko|N|;Motokura|Toru|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2017.1425",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "7(5)",
"journal": "Molecular and clinical oncology",
"keywords": "Evans syndrome; bendamustine; immune thrombocytopenia; rheumatoid arthritis; splenomegaly",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "855-858",
"pmc": null,
"pmid": "29181179",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": "22500164;27018242;25081899;12426661;28105347;19638626;21119113;2295057;23433739;23650408;27354722",
"title": "Efficacy of bendamustine on thrombocytopenia and hemolytic anemia secondary to CD5-positive B-cell lymphoma with massive splenomegaly in a patient with rheumatoid arthritis.",
"title_normalized": "efficacy of bendamustine on thrombocytopenia and hemolytic anemia secondary to cd5 positive b cell lymphoma with massive splenomegaly in a patient with rheumatoid arthritis"
} | [
{
"companynumb": "JP-TEVA-817387ACC",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE HYDROCHLORIDE"
},
"drugadditional": "3",... |
{
"abstract": "Predicting the incidence rate of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) and its prognosis in patients with non-small cell lung cancer (NSCLC) and IPF is difficult. The aim was to study the incidence of IPF-AE during the clinical course of the disease and its prognosis in patients with both NSCLC and IPF.\n\n\n\nIn this retrospective study, we compared the incidence rate of AE during the clinical course of the disease as well as the 1-year survival rate and overall survival (OS) of patients with NSCLC and IPF using a modified gender, age and physiology (mGAP) staging system based on gender, age and percent predicted forced vital capacity.\n\n\n\nOf 43 patients with NSCLC and IPF included in the final analysis, 17 patients (40%; 95% CI: 26-54%) experienced AE during the clinical course of the disease. One-year survival and median OS were 41.9% (95% CI: 28-57%) and 9.4 months, respectively. Further analysis showed that the incidence of IPF-AE gradually increased and that the 1-year survival rate and median OS gradually decreased with increasing mGAP index score and stage.\n\n\n\nOur study suggested that mGAP index score and cancer stage may predict IPF-AE and its prognosis in patients with NSCLC and IPF.",
"affiliations": "Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.",
"authors": "Kobayashi|Haruki|H|0000-0002-3386-8063;Omori|Shota|S|;Nakashima|Kazuhisa|K|;Wakuda|Kazushige|K|;Ono|Akira|A|;Kenmotsu|Hirotsugu|H|;Naito|Tateaki|T|;Murakami|Haruyasu|H|;Endo|Masahiro|M|;Takahashi|Toshiaki|T|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/resp.13075",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1323-7799",
"issue": "22(7)",
"journal": "Respirology (Carlton, Vic.)",
"keywords": "acute exacerbation; gender, age and physiology index; idiopathic pulmonary fibrosis; lung cancer; non-small cell lung cancer",
"medline_ta": "Respirology",
"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D018450:Disease Progression; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D014797:Vital Capacity",
"nlm_unique_id": "9616368",
"other_id": null,
"pages": "1379-1385",
"pmc": null,
"pmid": "28543987",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Modified GAP index for prediction of acute exacerbation of idiopathic pulmonary fibrosis in non-small cell lung cancer.",
"title_normalized": "modified gap index for prediction of acute exacerbation of idiopathic pulmonary fibrosis in non small cell lung cancer"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20171105220",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "We conducted a phase I/II study to investigate the safety and efficacy of nivolumab with paclitaxel plus ramucirumab.\n\n\n\nPatients with advanced gastric cancer (AGC) refractory to first-line chemotherapy were included. Patients received nivolumab (3 mg/kg on days 1 and 15) combined with paclitaxel (80 mg/m2 on days 1, 8, and 15) and ramucirumab (8 mg/kg on days 1 and 15) every 4 weeks. After feasibility evaluation in six patients (phase I), 37 additional patients were enrolled in the phase II part with the primary endpoint of 6-month progression-free survival (PFS) rate with two-sided 80% confidence interval (CI). The combined positive score (CPS) was defined as the number of programmed death-ligand 1-positive cells divided by the total number of viable tumor cells multiplied by 100.\n\n\n\nForty-three patients were enrolled. Of these, 60.5% had CPS ≥ 1. Dose-limiting toxicities were observed in two patients, and the recommended dose was determined as level 1. Thirty-nine (90.7%) patients experienced treatment-related adverse events (AEs) grade ≥3 and 14 (32.6%) patients experienced immune-related AEs grade ≥3. The overall response rate was 37.2% (95% CI, 23.0%-53.5%) and the 6-month PFS rate was 46.5% (80% CI, 36.4%-55.8%; P = 0.067). Median survival time was 13.1 months (95% CI, 8.0-16.6 months): 13.8 months (95% CI, 8.0-19.5 months) in patients with CPS ≥ 1 and 8.0 months (95% CI, 4.8-24.1 months) in patients with CPS < 1.\n\n\n\nNivolumab with paclitaxel plus ramucirumab demonstrated promising antitumor activity with manageable toxicities as second-line treatment for AGC.",
"affiliations": "Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. tnakajima@kuhp.kyoto-u.ac.jp.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.;Department of Clinical Trial Promotion, Chiba Cancer Center, Chuo, Chiba, Japan.;Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan.;Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.;Division of Pathology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.;Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.;Department of Clinical Trial Promotion, Chiba Cancer Center, Chuo, Chiba, Japan.;Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan.;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku, Tokyo, Japan.",
"authors": "Nakajima|Takako Eguchi|TE|;Kadowaki|Shigenori|S|;Minashi|Keiko|K|;Nishina|Tomohiro|T|;Yamanaka|Takeharu|T|;Hayashi|Yuichiro|Y|;Izawa|Naoki|N|;Muro|Kei|K|;Hironaka|Shuichi|S|0000-0001-9714-231X;Kajiwara|Takeshi|T|;Kawakami|Yutaka|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-20-3559",
"fulltext": null,
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"issn_linking": "1078-0432",
"issue": "27(4)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "1029-1036",
"pmc": null,
"pmid": "33262133",
"pubdate": "2021-02-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Multicenter Phase I/II Study of Nivolumab Combined with Paclitaxel Plus Ramucirumab as Second-line Treatment in Patients with Advanced Gastric Cancer.",
"title_normalized": "multicenter phase i ii study of nivolumab combined with paclitaxel plus ramucirumab as second line treatment in patients with advanced gastric cancer"
} | [
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"abstract": "Evaluate the type and severity of potential drug-drug interactions and identify risk factors involved, in pediatric patients admitted in a hospital setting.\n\n\n\nTransversal retrospective analytical study was carried out with hospitalized pediatric patients from a Hospital in the West of Mexico, second and third level. The patients included were ≤18 years old hospitalized in the children wards; those admitted at the emergency room, neonatal intermediate and intensive therapy units were not included. Medical prescriptions were reviewed taking into consideration anthropometric characteristics, diagnosis and number of drugs prescribed to identify potential drug-drug interactions using Micromedex 2.0 database.\n\n\n\n88 patients were included, an average of 4.6 ± 2.8 of drugs were prescribed per patient. 37 subjects (42%) presented some degree of potential drug-drug interactions of which 25.5% were major and 27.7% moderate according to the software. Identified risk factors were: age ≥ 4 years (OR 1.917; 95% CI 1.081-3.399), BSA ≥ 0.8m2(OR 1.825; 95% CI 1.021-3.263), height ≥ 1 m (OR 2.556;95% CI 1.322 - 4.941), and number of prescribed medications ≥ 4 (OR 2.106;95% CI 1.248 - 3.556).\n\n\n\nSome of the interactions found were for the benefit of the patient, but others were considered undesirable because they altered the pharmacokinetics of some of the medications administered. Detecting in time the harmful interactions for a patient may favor the patient's safety.",
"affiliations": "Pharmacy Service, Nuevo Hospital Civil de Guadalajara \"Dr. Juan I. Menchaca\", 750 Salvador Quevedo y Zubieta St., 44340, Guadalajara, Mexico. Electronic address: favyri.sp@gmail.com.;Medical and Pharmaceutical Biotechnology Department, Centro de Asistencia en Tecnología y Diseño del Estado de Jalisco, 800 Normalistas Av., 44270, Guadalajara, Mexico. Electronic address: sttephie@hotmail.com.;Molecular Biology and Genomics Department, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 950 Sierra Mojada St., 44340, Guadalajara, Mexico. Electronic address: edsaul.perez@gmail.com.;Pharmacovigilance Department, Laboratorios PiSA, 1840 España Ave., 44190, Guadalajara, Mexico. Electronic address: aleyda_sanmis7@hotmail.com.;Microbiology Department, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 950 Sierra Mojada St., 44340, Guadalajara, Mexico. Electronic address: ivanhzc21@yahoo.com.mx.;Centro integral de Medicina Ambiental y Toxicología CIMATOX S.A.S, de C.V. María Reyes 2, Guadalajara, Mexico. Electronic address: contacto@cimatox.com.;Medical and Life Sciences Department, Centro Universitario de la Ciénega, Universidad de Guadalajara, 1115 Universidad Av., 47820, Ocotlán, Mexico. Electronic address: selene.huerta@academicos.udg.mx.",
"authors": "Medina-Barajas|Fabiola|F|;Vázquez-Méndez|Estefanía|E|;Pérez-Guerrero|Edsaúl Emilio|EE|;Sánchez-López|Virginia Aleyda|VA|;Hernández-Cañaveral|Iván I|II|;Gabriel A|Real-Ornelas|RO|;Huerta-Olvera|Selene G|SG|",
"chemical_list": null,
"country": "Singapore",
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"doi": "10.1016/j.pedneo.2019.11.006",
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"issn_linking": "1875-9572",
"issue": "61(3)",
"journal": "Pediatrics and neonatology",
"keywords": "drug-drug interactions; medication errors; pediatric patients; potential drug-drug interactions",
"medline_ta": "Pediatr Neonatol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005260:Female; D006760:Hospitalization; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010865:Pilot Projects; D012189:Retrospective Studies",
"nlm_unique_id": "101484755",
"other_id": null,
"pages": "279-289",
"pmc": null,
"pmid": "31866496",
"pubdate": "2020-06",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pilot study: Evaluation of potential drug-drug interactions in hospitalized pediatric patients.",
"title_normalized": "pilot study evaluation of potential drug drug interactions in hospitalized pediatric patients"
} | [
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"companynumb": "MX-LUNDBECK-DKLU3021540",
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"abstract": "Oxaliplatin is a third-generation platinum derivative used for metastatic or advanced colorectal cancer treatment. Although myelosuppression is the most common cause of oxaliplatin-induced thrombocytopenia, rare cases of oxaliplatin-induced immune-mediated thrombocytopenia are reported. We report a case of a 57-year-old woman with colon cancer who developed gum bleeding and petechiae after oxaliplatin infusion. Laboratory tests revealed grade 4 thrombocytopenia and grade 4 neutropenia. She recovered from the thrombocytopenia and accompanying neutropenia within 4 days with no recurrence following discontinuation of oxaliplatin. Physicians need to be aware of the risk of severe acute thrombocytopenia following oxaliplatin administration.",
"affiliations": "Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.",
"authors": "Woo|Hyun Sun|HS|;Lee|Kyoung Hwa|KH|;Yoon|Phill Hoon|PH|;Kim|Su Ji|SJ|;Park|Inkeun|I|;Kim|Young Saing|YS|;Ahn|Hee Kyung|HK|;Hong|Junshik|J|;Shin|Dong Bok|DB|;Sym|Sun Jin|SJ|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016179:Granulocyte Colony-Stimulating Factor",
"country": "Korea (South)",
"delete": false,
"doi": "10.4143/crt.2014.052",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 2554458010.4143/crt.2014.052crt-2014-052Case ReportOxaliplatin-Induced Immune-Mediated Thrombocytopenia: A Case Report Woo Hyun Sun MDLee Kyoung Hwa MDYoon Phill Hoon MDKim Su Ji MDPark Inkeun MDKim Young Saing MDAhn Hee Kyung MDHong Junshik MDShin Dong Bok MDSym Sun Jin MD\nDivision of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, KoreaCorrespondence: Sun Jin Sym, MD Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon 21565, Korea Tel: 82-32-460-8507 Fax: 82-32-460-2391 E-mail: sympson@gilhospital.com10 2015 28 10 2014 47 4 949 953 26 2 2014 15 6 2014 Copyright © 2015 by the Korean Cancer Association2015This 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.Oxaliplatin is a third-generation platinum derivative used for metastatic or advanced colorectal cancer treatment. Although myelosuppression is the most common cause of oxaliplatin-induced thrombocytopenia, rare cases of oxaliplatin-induced immune-mediated thrombocytopenia are reported. We report a case of a 57-year-old woman with colon cancer who developed gum bleeding and petechiae after oxaliplatin infusion. Laboratory tests revealed grade 4 thrombocytopenia and grade 4 neutropenia. She recovered from the thrombocytopenia and accompanying neutropenia within 4 days with no recurrence following discontinuation of oxaliplatin. Physicians need to be aware of the risk of severe acute thrombocytopenia following oxaliplatin administration.\n\nOxaliplatinColorectal neoplasmsThrombocytopeniaNeutropenia\n==== Body\nIntroduction\nOxaliplatin is a third generation platinum analog given to patients with metastatic or advanced colorectal cancer. The combination of oxaliplatin, fluorouracil, and leucovorin improves disease-free survival in patients with metastatic and stage II or III colorectal cancer [1-3].\n\nThrombocytopenia, a common side effect of oxaliplatin, occurs in more than 70% of patients with colorectal cancer receiving oxaliplatin. However, grade 3-4 thrombocytopenia causing life-threatening bleeding presents in only 3%-4% of patients [4]. According to Jardim et al. [5], oxaliplatin-related thrombocytopenia can occur by three mechanisms. The main cause of thrombocytopenia related to oxaliplatin is myelosuppression, which represents asymptomatic thrombocytopenia. In some patients, hepatic sinusoid damage by oxaliplatin leads to portal hypertension and resultant splenic sequestration of platelets. The third mechanism, immune-mediated thrombocytopenia, rarely occurs during oxaliplatin infusion [6]. Although rare, this immune-mediated mechanism can result in grade 3-4 thrombocytopenia with life-threatening bleeding, hypersensitivity reactions, or hemolysis [6]. These symptoms and thrombocytopenia occur suddenly after administration of oxaliplatin and are easily treated by stopping oxaliplatin infusion. However, because of its rarity, physicians are usually not familiar with this oxaliplatin-induced immune-mediated thrombocytopenia. We report a case of immune-mediated thrombocytopenia associated with oxaliplatin.\n\nCase Report\nA 56-year-old female without relevant comorbidities was diagnosed with colon adenocarcinoma located in the ascending colon in May 2008. Right hemicolectomy was performed, and the pathologic stage was stage III-C (pT3N2M0). She underwent 12 cycles of adjuvant chemotherapy with mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 on day 1, 5-fluorouracil 400 mg/m2 as an intravenous bolus on day 1 followed by continuous infusion of 1,200 mg/m2/day on days 1 and 2). In December 2009, abdomen-pelvis computed tomography (A-PCT) scan showed recurrent right retrocaval and right renal hilar lymph nodes (LNs). She received three cycles of palliative FOLFIRI (irinotecan 180 mg/m2 on day 1, leucovorin 200 mg/m2 on day 1, 5-fluorouracil 400 mg/m2 as an intravenous bolus on day 1, followed by 1,200 mg/m2 on day 1 and 2). She had palliative right nephrectomy with LNs dissection for a salvage surgery in April 2010. We then gave eight cycles of palliative capecitabine and oxaliplatin because the pathology report mentioned metastasis to two out of 19 LNs around the right kidney.\n\nIn October 2011, disease recurrence in a pericaval LN was noted in 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT). Therefore the patient again received 12 cycles of palliative mFOLFOX6, resulting in stable disease. There was no hypersensitivity reaction associated with oxaliplatin during these chemotherapy cycles.\n\nIn January 2013, PET-CT showed progression of metastatic lesions in left hilar and paravertebral area, and palliative mFOLFOX6 was resumed. On the sixth cycle, she felt a squeezing pain along the spine from her head to the lumbar area after oxaliplatin administration. Nine hours after oxaliplatin infusion, she developed mild gum bleeding and petechiae spreading from the needle site over her entire left arm. At this time, complete blood count (CBC) revealed thrombocytopenia and neutropenia: platelet count of 4,000/m3, white blood cell (WBC) count of 210/m3, and absolute neutrophil count (ANC) of 80/m3. The platelet and WBC levels were in the normal range on admission: platelet count of 129,000/m3, WBC count of 3,440/m3, and ANC of 1,850/m3. The bicytopenia resolved in a few days after platelet transfusion and granulocyte-colony stimulating factor (G-CSF) administration (Fig. 1). We thought it better to reduce the dose of oxaliplatin on the next cycle than stop the mFOLFOX6 cycles, because the side effects were not severe and resolved easily.\n\nOn the seventh cycle of mFOLFOX6, the dose of oxaliplatin was reduced to 70 mg/m2. On admission, the laboratory test showed normal WBC and platelet counts: platelet count of 207,000/m3, WBC count of 3,800/m3, and ANC of 1,599/m3. During oxaliplatin administration, she felt squeezing back pain again. After 5 hours, gum bleeding and petechiae over her entire arm developed. Laboratory test revealed acute-onset thrombocytopenia and neutropenia (platelet 2,000/m3, WBC 670/m3, and ANC 299/m3) (Fig. 2). After three days of supportive care with platelet transfusion and G-CSF injection, the platelet and WBC count recovered to 77,000/m3 and 6,270/m3 respectively, and back pain, gum bleeding and petechiae also improved. She was discharged from the hospital on the fourth day after oxaliplatin administration. We decided to stop the palliative mFOLFOX6 chemotherapy. She receives regular check-ups, and the disease has not progressed further at this time.\n\nDiscussion\nThrombocytopenia of all grades is reported in up to 70% of patients exposed to oxaliplatin. However, only 3%-4% of patients present with grade 3-4 thrombocytopenia with the risk of life-threatening bleeding [1,2,4]. We report a rare case of oxaliplatin-related thrombocytopenia with bleeding.\n\nThe most common cause of oxaliplatin-induced thrombocytopenia is bone marrow suppression, which develops in 45%-77% of colorectal cancer patients who receive oxaliplatin [1,2,7]. In these cases, bleeding is not common, and concomitant anemia and neutropenia are frequent. Chemotherapyinduced myelosuppression usually reaches nadir 10-14 days after chemotherapy administration and does not cause extreme thrombocytopenia within several hours of oxaliplatin administration [5]. In the present case, myelosuppression was excluded, as oxaliplatin-dependent thrombocytopenia developed within several hours, accompanied by gum bleeding.\n\nAnother mechanism of oxaliplatin-induced thrombocytopenia is splenic sequestration. The hepatic sinusoid can be injured by chemotherapy including oxaliplatin, resulting in portal hypertension leading to splenic sequestration of platelets. This phenomenon is characterized by prolonged thrombocytopenia and splenomegaly [8]. Our patient did not have splenomegaly in A-PCT and recovered from acute thrombocytopenia immediately after platelet transfusion.\n\nDrug-induced immune-mediated thrombocytopenia is also a possible mechanism of oxaliplatin-induced thrombocytopenia. Several studies identified oxaliplatin-dependent platelet glycoprotein IIb/IIIa complex-specific antibodies in patients who developed severe acute thrombocytopenia in only one or two days after oxaliplatin administration [8-10]. A definitive diagnosis of oxaliplatin-induced immune-mediated thrombocytopenia can be established by detection of oxaliplatin-dependent IgG antibodies in patients’ sera [9]. However, it can be diagnosed clinically by acute thrombocytopenia occurring within several hours of oxaliplatin infusion, frequently accompanied by hemolysis or neutropenia. Platelet counts recover rapidly after discontinuation of oxaliplatin and transfusion [5].\n\nThese three mechanisms of thrombocytopenia are summarized and compared with the thrombocytopenia in our case (Table 1). Our case was similar to oxaliplatin immune-mediated thrombocytopenia [5]. In our case, the patient presented with symptomatic thrombocytopenia developing several hours after oxaliplatin administration and resolving rapidly after discontinuation of oxaliplatin. Therefore, we diagnosed oxaliplatin-induced immune-mediated thrombocytopenia without a laboratory test for oxaliplatin-dependent IgG antibodies. Accompanying neutropenia in the present case is in line with the previous two case reports of oxaliplatin-related acute pancytopenia [8,11]. In these reports, acute pancytopenia occurred by production of oxaliplatin-dependent antibodies to platelets, red blood cells and neutrophils, respectively.\n\nSuzuki et al. [12] reviewed 24 cases of published oxaliplatin-induced acute thrombocytopenia and Ohta et al. [13] reviewed 20 cases. Sixteen of 20 cases in Ohta et al.'s study [13] were also included in Suzuki et al.'s study [12]. These cases suggested that female gender and prolonged exposure to oxaliplatin were risk factors for developing immune-mediated thrombocytopenia. With the exception of symptoms related to thrombocytopenia, patients presented with hypersensitivity reactions such as chills, fever, rash, abdominal or back pain, and bronchospasm. The average number of cycles prior to onset of thrombocytopenia was 16.8 (range, 3 to 25 cycles) in 25 cases in these two studies [12,13]. Most of these oxaliplatin immune-mediated thrombocytopenia cases were induced after 10 cycles of chemotherapy (76% of patients in Suzuki et al. [12] and Ohta et al.’s [13] reports). In the current case, thrombocytopenia occurred in the 40th cycle of oxaliplatin chemotherapy. Our patient had been exposed to oxaliplatin even longer than other cases, although she had not received 40 continuous cycles of oxaliplatin-containing chemotherapy.\n\nWe did not realize that the first episode of acute thrombocytopenia in the present case was oxaliplatin-dependent immune-mediated thrombocytopenia, and considered it transient thrombocytopenia of unknown etiology. When the patient received oxaliplatin again, the gum-bleeding and thrombocytopenia developed more rapidly. The possibilities of disseminated intravascular coagulation and idiopathic thrombocytopenia were excluded because prothrombin time and partial thromboplastin time levels were in the normal range and evidence of hemolysis was not found on peripheral blood smear. Myelosuppression was also excluded due to normal range of CBC on admission. Since the platelet and WBC levels decreased suddenly during oxaliplatin administration and recovered following interruption of oxaliplatin, platelet transfusion and G-CSF administration, a diagnosis of oxaliplatin-associated immune-mediated thrombocytopenia was made. Reflecting on our experience, if a physician is not aware of oxaliplatin-induced immune-mediated thrombocytopenia, proper management may be delayed. Currently, there are no specific preemptive measures to prevent or predict oxaliplatin-induced immune-mediated thrombocytopenia. The only method for early detection is a high level of suspicion. There are also no specific management guidelines. Platelet count usually recovers rapidly after discontinuation of oxaliplatin, but platelet transfusion is helpful for increasing platelet levels in case of clinically meaningful bleeding. The value of corticosteroid is not certain yet [5]. Because of the rarity of the condition and lack of uniformity of previous case reports regarding corticosteroid administration, there is currently insufficient evidence for using corticosteroid. The most important countermeasure is not giving oxaliplatin again.\n\nIn conclusion, oxaliplatin-induced immune-mediated thrombocytopenia is a rare but important complication of oxaliplatin-containing chemotherapy that presents with acute symptomatic thrombocytopenia accompanied by fever, rash, and abdominal or back pain. A physician who treats patients with oxaliplatin should keep in mind the possibility of oxaliplatin-induced immune thrombocytopenia that may cause life-threatening bleeding, and consider discontinuing oxaliplatin administration and checking complete blood cell counts.\n\nConflict of interest relevant to this article was not reported.\n\nFig. 1. Acute bicytopenia on the sixth cycle of FOLFOX. WBC, white blood cell.\n\nFig. 2. Acute bicytopenia on the seventh cycle of FOLFOX. WBC, white blood cell.\n\nTable 1. Three oxaliplatin-induced thrombocytopenia mechanisms compared with our case\n\n\tMyelosuppression\tSplenic sequestration\tImmune-mediated\tPresent case\t\nThrombocytopenia characteristics\tSubacute, after about 1 week following chemotherapy\tInsidious onset\tSudden onset\tSudden onset\t\nUsually recovers by the next cycle of chemotherapy\tProlonged thrombocytopenia even after oxaliplatin cessation\tFast and complete recovery after discontinuation of the drug\tComplete recovery after discontinuation of the drug\t\nBleeding\tNot common\tNot common\tUsual\nMight be life-threatening\tGum bleeding\nPetechiae\t\nAccompanied anemia and neutropenia\tUsual\tNot common\tNot common\tSudden-onset neutropenia\t\nPortal HTN and splenomegaly\tNo\tYes\tNo\tNo\t\nCombined hypersensitivity reactions\tNot common\tNot common\tCommon (chills, fever, rash, abdominal or back pain, and bronchospasm)\tNo hypersensitivity reactions\t\nOxaliplatin-dependent IgG Ab\tNo\tNo\tYes\tTest not done\t\nBone marrow aspirates\tToxicity to megakaryocytic progenitors\t-\tIncreased numbers of megakaryocytes\tTest not done\t\nHTN, hypertension; IgG Ab, immunoglobulin G antibody.\n==== Refs\nReferences\n1 Andre T Boni C Mounedji-Boudiaf L Navarro M Tabernero J Hickish T Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer N Engl J Med 2004 350 2343 51 15175436 \n2 de Gramont A Figer A Seymour M Homerin M Hmissi A Cassidy J Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer J Clin Oncol 2000 18 2938 47 10944126 \n3 Kanemitsu Y Kato T Shimizu Y Inaba Y Shimada Y Nakamura K A randomized phase II/III trial comparing hepatectomy followed by mFOLFOX6 with hepatectomy alone as treatment for liver metastasis from colorectal cancer: Japan Clinical Oncology Group Study JCOG0603 Jpn J Clin Oncol 2009 39 406 9 19389795 \n4 Wu Y Aravind S Ranganathan G Martin A Nalysnyk L Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: a descriptive study of a large \n5 Jardim DL Rodrigues CA Novis YA Rocha VG Hoff PM Oxaliplatin-related thrombocytopenia Ann Oncol 2012 23 1937 42 22534771 \n6 Bautista MA Stevens WT Chen CS Curtis BR Aster RH Hsueh CT Hypersensitivity reaction and acute immune-mediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature J Hematol Oncol 2010 3 12 20346128 \n7 Colucci G Gebbia V Paoletti G Giuliani F Caruso M Gebbia N Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale J Clin Oncol 2005 23 4866 75 15939922 \n8 Taleghani BM Meyer O Fontana S Ahrens N Novak U Borner MM Oxaliplatin-induced immune pancytopenia Transfusion 2005 45 704 8 15847658 \n9 Curtis BR Kaliszewski J Marques MB Saif MW Nabelle L Blank J Immune-mediated thrombocytopenia resulting from sensitivity to oxaliplatin Am J Hematol 2006 81 193 8 16493620 \n10 Pavic M Moncharmont P Seve P Rigal D Broussolle C Oxaliplatin-induced immune thrombocytopenia Gastroenterol Clin Biol 2006 30 797 8 16801909 \n11 Fontao-Wendel R Hoff PM Lazar A Freitas D Novis Y Patah P Immune-mediated pancytopenia induced by oxaliplatin: a case report Transfusion 2010 50 1453 9 20210930 \n12 Suzuki K Oda H Sugawara Y Masuya M Nakase K Fujioka M Oxaliplatin-induced acute thrombocytopenia: a case report and review of the literature Intern Med 2013 52 611 5 23448774 \n13 Ohta S Cho Y Oshima S Hosoya O Juni K Kojima H Oxaliplatin-induced acute-onset thrombocytopenia and hemorrhage: case report and review of the literature Oncol Lett 2012 3 1297 300 22783437\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-2998",
"issue": "47(4)",
"journal": "Cancer research and treatment",
"keywords": "Colorectal neoplasms; Neutropenia; Oxaliplatin; Thrombocytopenia",
"medline_ta": "Cancer Res Treat",
"mesh_terms": "D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017713:Platelet Transfusion; D016553:Purpura, Thrombocytopenic, Idiopathic",
"nlm_unique_id": "101155137",
"other_id": null,
"pages": "949-53",
"pmc": null,
"pmid": "25544580",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22534771;20210930;15847658;20110050;16493620;23448774;15939922;22783437;16801909;10944126;15175436;20346128;19389795",
"title": "Oxaliplatin-Induced Immune-Mediated Thrombocytopenia: A Case Report.",
"title_normalized": "oxaliplatin induced immune mediated thrombocytopenia a case report"
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"activesubstancename": "OXALIPLATIN"
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"d... |
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"abstract": "Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death-1 antibodies are effective against malignant tumors. However, they induce unique adverse events known as immune-related adverse events. Hypophysitis is one of the most frequent immune-related adverse events of anti-cytotoxic T-lymphocyte antigen-4 therapies. However, there have been few reports describing the pathological findings of hypophysitis induced by anti-programmed death-1 antibodies. The present case is the first autopsy case of hypophysitis induced by nivolumab monotherapy, an anti-programmed death-1 antibody. Pathologically, lymphocytes infiltrated the anterior lobe of the pituitary gland, and the number of pituitary cells, especially adrenocorticotropic hormone-positive cells, decreased. However, necrosis and remarkable fibrosis were not observed. Immunohistologically, some pituitary cells expressed programmed death-ligand 1. Lymphocytes were predominantly CD8-positive T cells, and CD68-positive macrophages and CD20-positive B-cells were also observed. IgG and C4d were deposited on pituitary cells, but IgG4 (a subclass of nivolumab) was not detected. These findings indicate that type IVc and type II hypersensitivity mechanisms may occur in hypophysitis induced by anti-programmed death-1 antibodies and that the inflammatory mechanisms underlying hypophysitis induced by anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen-4 antibodies are different.",
"affiliations": "Department of Diagnostic Pathology, Jichi Medical University Saitama Medical Center, Omiya, Saitama, Japan.;Home Clinic for Everyone, Fuchu, Tokyo, Japan.;Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.;Department of Pathology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.;Department of Pathology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.",
"authors": "Okabe|Naota|N|http://orcid.org/0000-0001-7683-9716;Kobayashi|Takaaki|T|;Furuse|Junji|J|;Fujiwara|Masachika|M|;Kamma|Hiroshi|H|http://orcid.org/0000-0002-8985-4154",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/pin.13161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1320-5463",
"issue": null,
"journal": "Pathology international",
"keywords": "hypophysitis; immune-related adverse events; melanoma; nivolumab",
"medline_ta": "Pathol Int",
"mesh_terms": null,
"nlm_unique_id": "9431380",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34506687",
"pubdate": "2021-09-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "An autopsy case study of lymphocytic hypophysitis induced by nivolumab treatment for esophageal malignant melanoma.",
"title_normalized": "an autopsy case study of lymphocytic hypophysitis induced by nivolumab treatment for esophageal malignant melanoma"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-097669",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Diabetic patients with hypertension are approximately twice as likely to develop cardiovascular disease as non-diabetic patients with hypertension. Given that hypertension affects ∼60% of patients with diabetes, effective blood pressure (BP) management is important in this high-risk population. This post-hoc analysis pooled data from six clinical studies to quantify additional BP efficacy achieved when titrating hypertensive diabetic patients from amlodipine 5 mg to 10 mg. Approximately half of the diabetic patients were male (44/98; 44.9%) with a mean (standard deviation [SD]) age of 60.6 (9.6) years and a baseline mean (standard error [SE]) systolic blood pressure/diastolic blood pressure (SBP/DBP) of 150.8 (1.30)/87.5 (0.94) mmHg while on amlodipine 5 mg (159.1 [1.40]/92.6 [0.94] mmHg prior to treatment). In comparison, 350/610 (57.4%) non-diabetic patients were male with a mean (SD) age of 58.7 (11.1) years and baseline mean (SE) SBP/DBP of 150.3 (0.62)/90.9 (0.41) mmHg while on amlodipine 5 mg (160.0 [0.67]/96.2 [0.45] mmHg prior to treatment). Increasing amlodipine from 5 mg to 10 mg lowered sitting SBP by -12.5 mmHg (95% confidence interval (CI): -15.5, -9.5; P<0.0001) and DBP by -6.0 mmHg (-7.4, -4.6; P<0.0001) in diabetic patients; and SBP by -12.4 mmHg (-13.5, -11.3; P<0.0001) and DBP by -7.3 mmHg (-8.0, -6.7; P<0.0001) in non-diabetic patients. In total, 12.0% (95% CI: 6.4, 20.0) of diabetic patients achieved their BP goal versus 46.4% (42.4, 50.4) of non-diabetic patients after titration to amlodipine 10 mg. Overall, 22.0% of diabetic patients experienced 31 adverse events (AEs) and 28.9% of non-diabetic patients experienced 282 AEs. Serious AEs were reported by one (1.0%) diabetic and five (0.8%) non-diabetic patients. In this analysis, increasing amlodipine from 5 mg to 10 mg produced a clinically significant reduction in the BP of diabetic hypertensive patients, similar to non-diabetic patients, highlighting the importance of optimizing amlodipine titration in this high-risk population.",
"affiliations": "Pfizer Inc., New York, NY, USA.;Pfizer Inc., New York, NY, USA.;Pfizer Inc., New York, NY, USA.",
"authors": "Jeffers|Barrett W|BW|;Bhambri|Rahul|R|;Robbins|Jeffery|J|",
"chemical_list": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/VHRM.S64511",
"fulltext": "\n==== Front\nVasc Health Risk ManagVasc Health Risk ManagVascular Health and Risk ManagementVascular Health and Risk Management1176-63441178-2048Dove Medical Press 10.2147/VHRM.S64511vhrm-10-651Original ResearchUptitrating amlodipine significantly reduces blood pressure in diabetic patients with hypertension: a retrospective, pooled analysis Jeffers Barrett W Bhambri Rahul Robbins Jeffery Pfizer Inc., New York, NY, USACorrespondence: Barrett W Jeffers, Pfizer Inc., 235 East 42nd Street, New York, NY 10017, USA, Tel +1 908 901 7231, Email barrett.jeffers@pfizer.com2014 14 11 2014 10 651 659 © 2014 Jeffers et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Diabetic patients with hypertension are approximately twice as likely to develop cardiovascular disease as non-diabetic patients with hypertension. Given that hypertension affects ∼60% of patients with diabetes, effective blood pressure (BP) management is important in this high-risk population. This post-hoc analysis pooled data from six clinical studies to quantify additional BP efficacy achieved when titrating hypertensive diabetic patients from amlodipine 5 mg to 10 mg. Approximately half of the diabetic patients were male (44/98; 44.9%) with a mean (standard deviation [SD]) age of 60.6 (9.6) years and a baseline mean (standard error [SE]) systolic blood pressure/diastolic blood pressure (SBP/DBP) of 150.8 (1.30)/87.5 (0.94) mmHg while on amlodipine 5 mg (159.1 [1.40]/92.6 [0.94] mmHg prior to treatment). In comparison, 350/610 (57.4%) non-diabetic patients were male with a mean (SD) age of 58.7 (11.1) years and baseline mean (SE) SBP/DBP of 150.3 (0.62)/90.9 (0.41) mmHg while on amlodipine 5 mg (160.0 [0.67]/96.2 [0.45] mmHg prior to treatment). Increasing amlodipine from 5 mg to 10 mg lowered sitting SBP by −12.5 mmHg (95% confidence interval (CI): −15.5, −9.5; P<0.0001) and DBP by −6.0 mmHg (−7.4, −4.6; P<0.0001) in diabetic patients; and SBP by −12.4 mmHg (−13.5, −11.3; P<0.0001) and DBP by −7.3 mmHg (−8.0, −6.7; P<0.0001) in non-diabetic patients. In total, 12.0% (95% CI: 6.4, 20.0) of diabetic patients achieved their BP goal versus 46.4% (42.4, 50.4) of non-diabetic patients after titration to amlodipine 10 mg. Overall, 22.0% of diabetic patients experienced 31 adverse events (AEs) and 28.9% of non-diabetic patients experienced 282 AEs. Serious AEs were reported by one (1.0%) diabetic and five (0.8%) non-diabetic patients. In this analysis, increasing amlodipine from 5 mg to 10 mg produced a clinically significant reduction in the BP of diabetic hypertensive patients, similar to non-diabetic patients, highlighting the importance of optimizing amlodipine titration in this high-risk population.\n\nKeywords\nhypertensiondiabetescalcium channel blockerscardiovascular disease preventionefficacy\n==== Body\nBackground\nHypertension and diabetes each represent a major public health challenge worldwide. They frequently co-exist, thus compounding the risk of vascular morbidity and mortality associated with these conditions individually. The worldwide prevalence of hypertension in the year 2000 was estimated to be 26.4% (972 million adults), with a predicted rise of approximately 60% to a total of 1.56 billion adults (29.2%) by 2025.1 Recent estimates put global diabetes prevalence in the year 2011 at 8.3% (366 million adults), increasing to 9.9% (552 million adults; approximately 50% rise) by 2030.2\n\nHigher levels of blood pressure (BP) are a powerful predictor of cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke.3,4 Hypertension affects approximately 60% of patients with diabetes,5 and is twice as likely to occur in diabetic patients compared with their age-matched non-diabetic counterparts.6 Compared with diabetic individuals who are normotensive, those with concomitant hypertension exhibit about a two-fold increase in the risk of cardiovascular events and death.7–9 Moreover, hypertension has been found to be a stronger predictor of cardiovascular events as compared with diabetes.9\n\nGiven the high prevalence of hypertension in diabetic patients, combined with the observed increased cardiovascular risk attributable to hypertension, appropriate BP management strategies should be employed to mitigate the risk of future CVD events. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) advocate a sitting BP goal of 140/90 mmHg for hypertensive patients with diabetes and/or chronic kidney disease patients.10 Similarly, the American Diabetes Association (ADA) guidelines and joint guidelines from the European Society of Hypertension (ESH)/European Society of Cardiology (ESC) recommend a BP goal of <140/80 mmHg11 and <140/85 mmHg,12 respectively, for patients with diabetes. The caveat is that a lower systolic blood pressure (SBP) target (ie, <130 mmHg) may be appropriate for some diabetic individuals, such as younger patients or those at higher risk of stroke, if it can be achieved with fewer drugs and without adverse effects.11 A similarly revised BP goal of <140/85 mmHg has been proposed for those with diabetes in the latest joint guidelines for hypertension management from the ESH/ESC.12 However, effective therapeutic control of BP in patients with concomitant diabetes and hypertension can be challenging, and many patients are not achieving desired BP goals despite antihypertensive medication use.13–18\n\nAntihypertensive regimens based on angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics/beta-blockers are all broadly comparable for reducing cardiovascular risk in patients with and without diabetes.19 Amlodipine (Pfizer Inc., New York, NY, USA) is a well-established, long-acting CCB for the treatment of hypertension, including patients with diabetes.20–22 Studies in hypertensive patients have highlighted the additional benefit of titrating amlodipine from 5 mg to 10 mg once daily with regard to lowering BP,23–27 including Asian patients.26 However, because the efficacy of increasing amlodipine dose from 5 mg to 10 mg has thus far only been evaluated in a small number of patients with hypertension and diabetes, we conducted this post-hoc analysis of 710 patients with known diabetic status from six clinical trials, which included 100 diabetic patients. The objective of this analysis was to assess the incremental effect of amlodipine titration to 10 mg daily on BP-lowering efficacy in patients with concomitant diabetes and hypertension who had not responded sufficiently to treatment with the 5 mg dose.\n\nMethods\nStudy selection criteria\nStudies selected for this analysis were all Pfizer-sponsored studies of amlodipine treatment for mild to moderate hypertension for which there was patient-level data, diabetic status was known, and dose was titrated from 5 mg to 10 mg.\n\nStudy design and participants\nThis post-hoc analysis used pooled data from six randomized controlled or open-label clinical studies assessing the efficacy and safety of amlodipine 5 mg daily titrated to 10 mg daily in patients with mild or moderate hypertension (Table 1). Although total study durations varied depending on the design, patients in this analysis received amlodipine at a dose of 5 mg daily for 4–8 weeks followed by titration up to 10 mg daily as required for an additional 4–8 weeks. Patients were stratified into two subgroups based on their diabetes status at the time of entry into the study (those with diabetes versus those without diabetes), derived from their medical history.\n\nStudy endpoints and assessments\nEfficacy endpoints were change from baseline in sitting SBP and diastolic blood pressure (DBP) to the specified time point, and proportion of patients who achieved the sitting BP goal at follow-up. Depending on the study, sitting BP was measured once or twice at each visit. Each patient’s response for a given visit was the average of the multiple measurements, or the single measurement if only one sitting BP was available. The sitting BP goal was <130/80 mmHg for patients with diabetes and <140/90 mmHg for patients without diabetes. The BP goal was also assessed according to recently revised guidelines of a sitting BP goal of <140/80 mmHg (ADA guidelines)11 and a sitting BP goal for age <60 years, 140/90 mmHg; age ≥60 years, 150/90 mmHg (JNC 8 guidelines)10 for both subgroups.\n\nSafety endpoints were frequency of treatment-emergent adverse events (AEs) (all causality), treatment-emergent serious AEs (all causality), and AEs resulting in withdrawal from treatment (all causality).\n\nStatistical analyses\nPatients without a diabetes status at study entry were excluded from the analysis. The efficacy analysis included all patients in the intent-to-treat population who received at least one dose of amlodipine, were titrated from 5 mg to 10 mg daily, and had both a baseline and at least one follow-up BP measurement (last observation carried forward analysis). The safety analysis included all patients who received a least one dose of amlodipine and were titrated from 5 mg to 10 mg daily.\n\nBaseline values were established while patients were on amlodipine 5 mg treatment (ie, prior to amlodipine titration). Baseline characteristics were compared between the two subgroups using analysis of variance for numeric variables with study and subgroup in the model, and using the Cochran–Mantel–Haenszel statistic stratified by study for dichotomous variables. Blood pressure data were analyzed using descriptive statistics, paired Student’s t-tests, and corresponding confidence intervals (CIs). An exact CI based on the binomial distribution was used for the proportion of responders. The proportion of common AEs was compared between subgroups using the Cochran–Mantel–Haenszel statistic stratified by study. Given the sparseness of events across studies, a corresponding unconditional exact CI was calculated on the pooled data using the statistical software StatXact Version 10 by Cytel (Cambridge, MA, USA).28 All tests used an alpha of 0.05 with corresponding 95% CIs.\n\nResults\nStudy population\nA total of 710 patients with known diabetic status were included in this analysis (693 with complete BP data). Of the 100 patients (14.1%) with diabetes at study entry, four patients (4.0%) discontinued from the study; all four discontinuations were due to AEs. Of the 610 patients (85.9%) without diabetes at study entry, 44 patients (7.2%) discontinued from the study. Reasons for discontinuation among non-diabetic patients included: AEs (n=33; 5.4%), no longer willing to participate (n=4; 0.7%), protocol violation (n=2; 0.3%), insufficient clinical response (n=1; 0.2%), and other reason (n=4; 0.7%).\n\nPatients with diabetes were mostly female (55.1%) with a mean (standard deviation [SD]) age of 60.6 (9.6) years and a baseline mean (standard error [SE]) SBP/DBP prior to amlodipine treatment of 159.1 (1.40)/92.6 (0.94) mmHg (Table 2); mean (SE) SBP/DBP was 150.8 (1.30)/87.5 (0.94) mmHg while on amlodipine 5 mg treatment. Patients without diabetes were mostly male (57.4%) with a mean (SD) age of 58.7 (11.1) years and a baseline mean (SE) SBP/DBP prior to amlodipine treatment of 160.0 (0.67)/96.2 (0.45) mmHg (Table 2); mean (SE) SBP/DBP was 150.3 (0.62)/90.9 (0.41) mmHg while on amlodipine 5 mg treatment. Patients with diabetes weighed more and had a higher body mass index than their non-diabetic counterparts (Table 2).\n\nBlood pressure levels and goal attainment\nIn patients with diabetes, titration of amlodipine 5 mg to 10 mg lowered sitting SBP by –12.5 mmHg (95% CI: −15.5, −9.5; P<0.0001) and DBP by −6.0 mmHg (95% CI: −7.4, −4.6; P<0.0001) from baseline (established while patients were on amlodipine 5 mg treatment) to follow-up (Figure 1A). Mean (SE) SBP/DBP at follow-up in diabetic patients was 138.3 (1.35)/81.5 (0.86) mmHg. Similarly, in patients without diabetes, titration to amlodipine 10 mg lowered sitting SBP by −12.4 mmHg (95% CI: −13.5, −11.3; P<0.0001) and DBP by −7.3 mmHg (95% CI: −8.0, −6.7; P<0.0001) from baseline (established on amlodipine 5 mg treatment) to follow-up (Figure 1B). Mean (SE) SBP/DBP at follow-up in non-diabetic patients was 137.9 (0.56)/83.5 (0.36) mmHg.\n\nNot surprisingly, fewer patients with diabetes achieved their desired BP goal compared with non-diabetic patients. In total, 12/100 patients with diabetes (12.0%; 95% CI: 6.4, 20.0) attained a BP <130/80 mmHg; 283/610 patients without diabetes (46.4%; 95% CI: 42.4, 50.4) attained a BP <140/90 mmHg. Slightly more diabetic patients (25/100 [25%; 95% CI: 16.9, 34.7]) achieved the newly revised ADA target BP levels of <140/80 mmHg. Even more diabetic patients (64/100 [64%; 95% CI: 53.8, 73.4]) achieved the new JNC 8 target BP goals of 140/90 (aged <60 years) or 150/90 (aged ≥60 years) mmHg.\n\nSafety\nOverall, 22/100 patients with diabetes (22.0%) experienced 31 AEs and 176/610 patients without diabetes (28.9%) experienced 282 AEs (Table 3). The AEs most frequently reported by patients with diabetes were: peripheral edema (n=4; 4.0%), sinusitis (n=2; 2.0%), and upper respiratory tract infection (n=2; 2.0%). The AEs most frequently reported by patients without diabetes were: peripheral edema (n=46; 7.5%), nasopharyngitis (n=24; 3.9%), back pain (n=8; 1.3%), and upper respiratory tract infection (n=6; 1.0%).\n\nSerious AEs were reported by one patient (0.1%) with diabetes (event: ankle fracture) and five patients (0.8%) without diabetes (events: cardiomyopathy, pneumonia, facial bone fracture, intervertebral disk protrusion, gingival cancer, cerebrovascular accident, cerebrovascular disorder, Table 3). Three patients with diabetes (3.0%) and 20 patients without diabetes (3.3%) withdrew from treatment due to an AE (Table 3). Adverse events that led to treatment withdrawal in patients with diabetes included: peripheral edema (n=1; 1.0%), headache (n=1; 1.0%), and hypertension (n=1; 1.0%). AEs that led to treatment withdrawal in patients without diabetes included: peripheral edema (n=8; 1.3%), joint swelling (n=2; 0.3%), and dyspnea (n=2; 0.3%).\n\nDiscussion\nThis retrospective, pooled analysis has shown that increasing amlodipine from 5 mg to 10 mg daily provided a clinically and statistically significant incremental reduction in sitting SBP and DBP in patients with concomitant diabetes and hypertension who had not responded sufficiently to treatment with the 5 mg dose. Furthermore, the incremental benefit on BP lowering achieved with amlodipine titration was similar in both diabetic and non-diabetic patient populations. This is similar to what has previously been observed in other patient populations, such as Asian patients with hypertension.26 Amlodipine 10 mg was also well tolerated in patients with diabetes, demonstrating a safety profile similar to that observed in the non-diabetic patient group and previous studies involving high-dose amlodipine.23,24,26,29,30\n\nThe age-adjusted prevalence of diagnosed diabetes in the general US adult population has recently been estimated at 8.5%.31 However, in this analysis, diabetes prevalence in this patient population with mild or moderate hypertension was nearly double that of the current national estimate, at 14.1%. Patients with hypertension have been shown to have a 2.5-fold excess risk of developing diabetes over 6 years of follow-up compared with non-hypertensive individuals (relative risk: 2.43; 95% CI: 2.16, 2.73).32 Similarly, hypertension is twice as likely to occur in patients with diabetes versus those without diabetes, with prevalence in diabetic patients of approximately 60%.5,6 Although hypertension and diabetes individually predict cardiovascular morbidity and mortality, the concomitance of these two conditions only serves to exacerbate the cardiovascular risk associated with either condition in isolation.7–9 Hence, appropriate management of cardiovascular risk factors, with particular emphasis on the early detection and effective treatment of hypertension in patients with diabetes, is paramount to reduce CVD burden in these high-risk individuals.\n\nEven modest reductions in BP have the potential to substantially reduce cardiovascular morbidity and mortality. A meta-analysis of data from 61 prospective observational studies on deaths from vascular disease among individuals with no known vascular disease at baseline found that a 2 mmHg reduction in SBP could lower mortality from stroke by 10% and from ischemic heart disease or other vascular causes by 7%.4 Similarly, the results of a prospective, observational study in patients with diabetes showed that a 10 mmHg decrease in SBP was associated with reductions in the risk of diabetes-related complications (including myocardial infarction, sudden death, angina, and stroke; relative risk reduction: 12%; 95% CI: 10%, 14%; P<0.0001), diabetes-related deaths (including death from myocardial infarction, sudden death, and stroke; relative risk reduction: 15%; 95% CI: 12%, 18%; P<0.0001), and myocardial infarction (relative risk reduction: 11%; 95% CI: 7%, 14%; P<0.0001).33 Thus, the observed incremental reduction in BP by uptitrating amlodipine to 10 mg (−12.5 mmHg in SBP, −6.0 mmHg in DBP) in diabetic patients would be expected to drastically reduce the occurrence of diabetes-related complications.\n\nNumerous clinical trials of antihypertensive agents have demonstrated the benefit of BP lowering on cardiovascular outcomes in a range of patient populations, including patients with diabetes.34–36 The UK Prospective Diabetes Study compared tight control of BP to <150/85 mmHg with less rigorous control of BP to <180/105 mmHg in hypertensive patients with diabetes.34 Patients allocated to tight BP control experienced a 24% reduction in the relative risk of diabetes-related endpoints (including sudden death, myocardial infarction, angina, and stroke; 95% CI: 8%, 38%; P=0.0046), a 32% reduction in diabetes-related deaths (including death from myocardial infarction, sudden death, and stroke; 95% CI: 6%, 51%; P=0.019), and a 44% reduction in the risk of stroke (95% CI: 11%, 65%; P=0.013) compared with patients allocated to less rigorous BP control. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial demonstrated that significant reductions in SBP and DBP (−5.6 mmHg and −2.2 mmHg, respectively; both P<0.001) to mean follow-up levels of 134.7/74.8 mmHg reduced the relative risk of major macrovascular or microvascular events (including CVD death, non-fatal stroke, and non-fatal myocardial infarction) by 9% (hazard ratio [HR]: 0.91; 95% CI: 0.83, 1.00; P=0.04), and CVD death by 18% (HR: 0.82; 95% CI: 0.68, 0.98; P=0.03).35 A subgroup analysis of 1,501 patients with diabetes enrolled in the Hypertension Optimal Treatment (HOT) trial, where hypertensive patients were randomly assigned to a target DBP, showed that the risk of major cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) was halved in those randomized to a DBP ≤80 mmHg compared with ≤90 mmHg (relative risk for 90 mmHg versus 80 mmHg: 2.06; 95% CI: 1.24, 3.44; P for trend =0.005).36\n\nHowever, recent results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD)37 and International Verapamil SR-Trandolapril Study (INVEST)38 trials have questioned the clinical benefit obtained with aggressive control of SBP levels to <120 mmHg, or even <130 mmHg. For example, the ACCORD trial, where patients with diabetes were randomized to a SBP <120 mmHg versus <140 mmHg, failed to demonstrate a significant reduction in the relative risk of major cardiovascular events, although a significant reduction in the relative risk of stroke was observed (HR: 0.59; 95% CI: 0.39, 0.89; P=0.01).37 Moreover, the incidence of serious AEs attributed to antihypertensive treatment was significantly higher in the intensive-therapy group (3.3%) compared with the standard-therapy group (1.3%; P<0.001), indicating the potential for harm with aggressive BP lowering to within the normotensive range in this patient population. With this in mind, recent updates to treatment guidelines for the management of BP in patients with diabetes have seen therapeutic targets revised to <140/80 mmHg (ADA),11 or <140/85 mmHg (ESH/ESC),12 with the option of a lower SBP goal (ie, <130 mmHg) for some individuals, such as younger patients or those at very high risk of stroke, if it can be achieved with few drugs and without adverse effects.11\n\nFor patients with diabetes, current clinical practice guidelines advocate the use of renin–angiotensin system (RAS) inhibitors such as an ACEI or an ARB, with the addition of a CCB such as amlodipine, and/or hydrochlorothiazide, as needed to achieve BP goals.11 Studies in hypertensive patients have highlighted the incremental benefit of titrating amlodipine up to 10 mg on BP lowering.23–26 Moreover, higher doses of amlodipine have been shown to be equally effective or superior, either as monotherapy or in combination with another agent, in reducing cardiovascular outcomes compared with other treatment regimens,39–42 even in patients with diabetes.16 The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial16 demonstrated that combination therapy with benazepril and amlodipine (mean achieved BP: 131.5/72.6 mmHg) reduced the relative risk of a cardiovascular event (cardiovascular death, myocardial infarction, stroke, hospitalization for angina, resuscitated arrest, and coronary revascularization) by 21% compared with benazepril and hydrochlorothiazide (mean achieved BP: 132.7/73.7 mmHg) in patients with concomitant diabetes and hypertension (HR: 0.79; 95% CI: 0.68, 0.92; P<0.003).\n\nThis analysis of pooled data from trials investigating the incremental effect of amlodipine titration to 10 mg daily on BP-lowering efficacy in patients with concomitant diabetes and hypertension has revealed that increasing amlodipine from 5 mg to 10 mg daily significantly lowered sitting SBP by −12.5 mmHg and DBP by −6.0 mmHg. Reductions in SBP and DBP of this magnitude are likely to translate to meaningful clinical reductions in cardiovascular outcomes in this high-risk patient group, however, the lack of information on cardiovascular events is an obvious limitation of this study. Nevertheless, the ability to increase amlodipine dose may provide a safe and effective strategy through which to achieve an incremental improvement in BP levels before adding to the medication burden of this patient group, where the average number of antihypertensive medications used to achieve BP goals may be as high as 4.3.43\n\nConclusion\nThis retrospective, pooled analysis demonstrates that a significant, incremental improvement in sitting SBP and DBP levels can be safely achieved in patients with and without concomitant diabetes and hypertension by increasing amlodipine dose from 5 mg to 10 mg once daily. Thus, the use of amlodipine as a therapeutic option can be extended in the effective management of hypertension in patients with diabetes.\n\nAcknowledgments\nEditorial support was provided by Michelle Jenvey, PhD, Shirley Smith, PhD, Sarah Knott and Alexandra Bound, PhD of Engage Scientific and was funded by Pfizer Inc.\n\nAuthor contributions\n\nBarrett W Jeffers, Rahul Bhambri, and Jeffery Robbins were involved in the design of the study. Jeffery Robbins performed the statistical analysis of the data. Barrett W Jeffers, Rahul Bhambri, and Jeffery Robbins interpreted the data, were involved in the drafting of the manuscript, and critically reviewed the manuscript for important intellectual content and accuracy, and made revisions. All authors have approved the final version to be published.\n\nDisclosure\n\nThis study was funded by Pfizer Inc. Barrett W Jeffers, Rahul Bhambri, and Jeffery Robbins are employees of Pfizer Inc.\n\nFigure 1 Sitting blood pressure at baseline and follow-up in (A) patients with diabetes and (B) patients without diabetes titrated from amlodipine 5 mg to 10 mg.\n\nNotes: Analyses were conducted using the intent-to-treat population. Baseline was established while patients were on amlodipine 5-mg treatment; follow-up was determined using a last-observation-carried-forward analysis.\n\nAbbreviations: BP, blood pressure; CI, confidence interval.\n\nTable 1 Studies used in the pooled analysisa\n\nStudy\tDesign\tStudy number/NCT number (if applicable)\tWith diabetes (N=100)\tWithout diabetes (N=610)\tPatient population\tTotal study durationb\tStudy dates\t\n1\tRandomized, multicenter, double-blind, parallel group\tA0531004c\t10\t70\tWashed out of antihypertensives or treatment naïve\t18 weeks\t6 March 2001–14 October 2003\t\n2\tSingle arm, multicenter, open, non-interventional\tA0531044c\t38\t134\tWashed out of antihypertensives or treatment naïve\t12 weeks\t1 November 2001–31 March 2002\t\n3\tRandomized, multicenter, double-blind, parallel group\tA0531085\nNCT00415623\t26\t125\tUncontrolled on current antihypertensive at screening, doses stable throughout the study\t16 weeks\t6 January 2007–20 October 2007\t\n4\tSingle arm, long-term extension for NCT00415623\tA0531086\nNCT00443456\t12\t57\tUncontrolled on current antihypertensive at screening, doses stable throughout the study\t44 weeks\t2 May 2007–11 June 2008\t\n5\tRandomized, multicenter, double- blind, parallel group\tA053R0510c\t12\t121\tWashed out of antihypertensives or treatment naïve\t18 weeks\tStudy dates unavailable\t\n6\tSingle arm, multicenter, open, non-interventional\tAML-NY-93002c\t2\t103\tUncontrolled on current antihypertensive at screening, doses stable throughout the study, or treatment naïve\t14 weeks\t20 November 1993–30 April 1995\t\nNotes:\n\na All Pfizer-sponsored studies of amlodipine treatment for mild to moderate hypertension for which there were patient-level data, diabetic status was known, and dose was titrated from 5 mg to 10 mg\n\nb where applicable, total study duration included screening, baseline, and multiple study phases\n\nc these trials started before September 2008, before clinical studies were registered at http://www.clinicaltrials.gov; NCT Number, ClinicalTrials.gov Identifier.\n\nTable 2 Baseline characteristics of the study population stratified by diabetes status\n\nCharacteristic\tWith diabetes (N=100)\tWithout diabetes (N=610)\t\nMale, n (%)\t44 (44.9)a,*\t350 (57.4)\t\nMean age, years (SD)\t60.6 (9.64)\t58.7 (11.08)\t\nMean SBP/DBP, mmHg (SE)\t159.1 (1.40)/92.6 (0.94)*\t160.0 (0.67)/96.2 (0.45)\t\nMean weight, kg (SD)\t82.1 (16.80)*\t75.4 (16.68)\t\nMean BMI, kg/m2 (SD)\t30.3 (4.60)*\t27.0 (4.36)\t\nHistory of CHD, n (%)\t7 (7.0)\t24 (3.9)\t\nPrior antihypertensive use, n (%)\t64 (64.0)\t312 (51.1)\t\n Prior antihypertensive use by class, n (%)b\t\n ACEI\t42 (42.0)\t139 (22.8)\t\n ARB\t4 (4.0)\t49 (8.0)\t\n Alpha receptor agonist/antagonist\t2 (2.0)\t10 (1.6)\t\n Alpha2-Adrenergic Agonist\t\t1 (0.2)\t\n BB\t14 (14.0)\t64 (10.5)\t\n CCB\t37 (37.0)\t140 (23.0)\t\n Centrally-acting antihypertensive\t5 (5.0)\t8 (1.3)\t\n Diuretics\t10 (10.0)\t80 (13.1)\t\n Ergot alkaloid\t\t1 (0.2)\t\n Vasodilator\t\t1 (0.2)\t\nNotes:\n\na N=98 (two patients with sex not specified)\n\nb patients could have been taking more than one medication\n\n* P<0.05.\n\nAbbreviations: BMI, body mass index; CHD, coronary heart disease; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation; SE, standard error; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta blocker; CCB, calcium channel blocker.\n\nTable 3 Incidence of all-cause adverse events in patients with and without diabetes titrated from amlodipine 5 mg to 10 mg\n\nParameter\tWith diabetes (N=100)\tWithout diabetes (N=610)\tDifference (%)b\t95% CIb\t\nNumber of AEs\t31\t282\t\t\t\nPatients with AEs, n (%)\t22 (22.0)\t176 (28.9)\t\t\t\nPatients with serious AEs, n (%)\t1 (1.0)\t5 (0.8)\t\t\t\nPatients withdrawn from treatment due to AEs, n (%)\t3 (3.0)\t20 (3.3)\t\t\t\nMost common AEsa, n (%)\t\n Back pain\t0 (0.0)\t8 (1.3)\t−1.3\t[−2.7, 2.1]\t\n Nasopharyngitis\t0 (0.0)\t24 (3.9)\t−3.9*\t[−5.9, −0.5]\t\n Peripheral edema\t4 (4.0)\t46 (7.5)\t−3.5\t[−7.3, 2.3]\t\n Sinusitis\t2 (2.0)\t0 (0.0)\t2.0*\t[ 0.2, 7.0]\t\n Upper respiratory tract infection\t2 (2.0)\t6 (1.0)\t1.0\t[−1.0, 5.6]\t\nNotes: Analyses were conducted using the safety population. Baseline was established while patients were on amlodipine 5 mg treatment.\n\n* P<0.05, null hypothesis is that the percentage of patients with the given AE is equal between the two subgroups, versus not equal\n\na those with an incidence >1.0% in either subgroup\n\nb difference between the two subgroups in the percentage of most common AEs (those with diabetes minus those without), and associated 95% confidence interval.\n\nAbbreviations: AEs, adverse events; CI, confidence interval.\n==== Refs\nReferences\n1 Kearney PM Whelton M Reynolds K Muntner P Whelton PK He J Global burden of hypertension: analysis of worldwide data Lancet 2005 365 9455 217 223 15652604 \n2 Whiting DR Guariguata L Weil C Shaw J IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030 Diabetes Res Clin Pract 2011 94 3 311 321 22079683 \n3 Kannel WB Blood pressure as a cardiovascular risk factor: prevention and treatment JAMA 1996 275 20 1571 1576 8622248 \n4 Lewington S Clarke R Qizilbash N Peto R Collins R Prospective Studies Collaboration Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies Lancet 2002 360 9349 1903 1913 12493255 \n5 Centers for Disease Control and Prevention Age-Adjusted Percentage of Adults Aged 18 Years or Older with Diagnosed Diabetes Who have Hypertension, United States, 1995–2009 Available from: http://www.cdc.gov/diabetes/statistics/comp/fig8.htm Accessed June 30, 2014 \n6 Chokshi NP Grossman E Messerli FH Blood pressure and diabetes: vicious twins Heart 2013 99 8 577 585 23434624 \n7 [No authors listed] Hypertension in Diabetes Study (HDS). II. Increased risk of cardiovascular complications in hypertensive type 2 diabetic patients J Hypertens 1993 11 3 319 325 8387090 \n8 Turner RC Millns H Neil HA Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23) BMJ 1998 316 7134 823 828 9549452 \n9 Chen G McAlister FA Walker RL Hemmelgarn BR Campbell NR Cardiovascular outcomes in Framingham participants with diabetes: the importance of blood pressure Hypertension 2011 57 5 891 897 21403089 \n10 James PA Oparil S Carter BL Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8) JAMA 2014 311 5 507 520 24352797 \n11 American Diabetes Association Standards of medical care in diabetes – 2013 Diabetes Care 2013 36 Suppl 1 S11 S66 23264422 \n12 Mancia G Fagard R Narkiewicz K 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) J Hypertens 2013 31 7 1281 1357 23817082 \n13 Brown MJ Castaigne A de Leeuw PW Influence of diabetes and type of hypertension on response to antihypertensive treatment Hypertension 2000 35 5 1038 1042 10818061 \n14 Amar J Chamontin B Genes N Cantet C Salvador M Cambou JP Why is hypertension so frequently uncontrolled in secondary prevention? J Hypertens 2003 21 6 1199 1205 12777958 \n15 Mancia G Ambrosioni E Rosei EA Blood pressure control and risk of stroke in untreated and treated hypertensive patients screened from clinical practice: results of the ForLife study J Hypertens 2005 23 8 1575 1581 16003185 \n16 Weber MA Bakris GL Jamerson K Cardiovascular events during differing hypertension therapies in patients with diabetes J Am Coll Cardiol 2010 56 1 77 85 20620720 \n17 Kuznik A Mardekian J Trends in utilization of lipid- and blood pressure-lowering agents and goal attainment among the US diabetic population, 1999–2008 Cardiovasc Diabetol 2011 10 31 21496321 \n18 Stark Casagrande S Fradkin JE Saydah SH Rust KF Cowie CC The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988–2010 Diabetes Care 2013 36 8 2271 2279 23418368 \n19 Turnbull F Neal B Algert C Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials Arch Intern Med 2005 165 12 1410 1419 15983291 \n20 Norvasc® (amlodipine besylate) tablets [prescribing information] United States Pfizer Inc., New York, NY, USA 2013 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019787s053lbl.pdf Accessed May 8, 2014 \n21 Tatti P Pahor M Byington RP Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM Diabetes Care 1998 21 4 597 603 9571349 \n22 Sharma AM Bakris G Neutel JM Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients: an 8-week randomized, parallel-group, double-blind trial Clin Ther 2012 34 3 537 551 22386829 \n23 Varrone J Investigators of Study AML-NY-86-002 The efficacy and safety of amlodipine in the treatment of mild and moderate essential hypertension in general practice J Cardiovasc Pharmacol 1991 17 Suppl 1 S30 S33 16296705 \n24 Fujiwara T Ii Y Hatsuzawa J The Phase III, double-blind, parallel-group controlled study of amlodipine 10 mg once daily in Japanese patients with essential hypertension who insufficiently responded to amlodipine 5 mg once daily J Hum Hypertens 2009 23 8 521 529 19148107 \n25 Fukutomi M Hoshide S Eguchi K Watanabe T Shimada K Kario K Differential effects of strict blood pressure lowering by losartan/hydrochlorothiazide combination therapy and high-dose amlodipine monotherapy on microalbuminuria: the ALPHABET study J Am Soc Hypertens 2012 6 1 73 82 22054782 \n26 Kario K Robbins J Jeffers BW Titration of amlodipine to higher doses: a comparison of Asian and Western experience Vasc Health Risk Manag 2013 9 695 701 24235839 \n27 Hong SJ Ahn TH Baek SH Comparison of efficacy and tolerability of amlodipine orotate versus amlodipine besylate in adult patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week follow-up, noninferiority trial Clin Ther 2006 28 4 537 551 16750465 \n28 Chan IS Zhang Z Test-based exact confidence intervals for the difference of two binomial proportions Biometrics 1999 55 4 1202 1209 11315068 \n29 Bobrie G I-COMBINE Study Investigators I-COMBINE study: assessment of efficacy and safety profile of irbesartan/amlodipine fixed-dose combination therapy compared with amlodipine monotherapy in hypertensive patients uncontrolled with amlodipine 5 mg monotherapy: a multicenter, phase III, prospective, randomized, open-label with blinded-end point evaluation study Clin Ther 2012 34 8 1705 1719 22853848 \n30 Kang SM Youn JC Chae SC Comparative efficacy and safety profile of amlodipine 5 mg/losartan 50 mg fixed-dose combination and amlodipine 10 mg monotherapy in hypertensive patients who respond poorly to amlodipine 5 mg monotherapy: an 8-week, multicenter, randomized, double-blind phase III noninferiority study Clin Ther 2011 33 12 1953 1963 22136978 \n31 Centers for Disease Control and Prevention National Center for Health Statistics Division of Health Interview Statistics Crude and Age-Adjusted Percentage of Civilian, Noninstitutionalized Adults with Diagnosed Diabetes, United States, 1980–2011 Available from: http://www.cdc.gov/diabetes/statistics/prev/national/figageadult.htm Accessed June 30, 2014 \n32 Gress TW Nieto FJ Shahar E Wofford MR Brancati FL Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study N Engl J Med 2000 342 13 905 912 10738048 \n33 Adler AI Stratton IM Neil HA Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study BMJ 2000 321 7258 412 419 10938049 \n34 [No authors listed] Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group BMJ 1998 317 7160 703 713 9732337 \n35 Patel A ADVANCE Collaborative Group MacMahon S Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial Lancet 2007 370 9590 829 840 17765963 \n36 Hansson L Zanchetti A Carruthers SG Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group Lancet 1998 351 9118 1755 1762 9635947 \n37 ACCORD Study Group Cushman WC Evans GW Effects of intensive blood-pressure control in type 2 diabetes mellitus N Engl J Med 2010 362 17 1575 1585 20228401 \n38 Cooper-DeHoff RM Gong Y Handberg EM Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease JAMA 2010 304 1 61 68 20606150 \n39 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA 2002 288 23 2981 2997 12479763 \n40 Julius S Kjeldsen SE Weber M Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial Lancet 2004 363 9426 2022 2031 15207952 \n41 Dahlof B Sever PS Poulter NR Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial Lancet 2005 366 9489 895 906 16154016 \n42 Jamerson K Weber MA Bakris GL Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients N Engl J Med 2008 359 23 2417 2428 19052124 \n43 Bakris GL Maximizing cardiorenal benefit in the management of hypertension: achieve blood pressure goals J Clin Hypertens (Greenwich) 1999 1 2 141 147 11416606\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6344",
"issue": "10()",
"journal": "Vascular health and risk management",
"keywords": "calcium channel blockers; cardiovascular disease prevention; diabetes; efficacy; hypertension",
"medline_ta": "Vasc Health Risk Manag",
"mesh_terms": "D000328:Adult; D000368:Aged; D017311:Amlodipine; D000959:Antihypertensive Agents; D001794:Blood Pressure; D002121:Calcium Channel Blockers; D015897:Comorbidity; D003920:Diabetes Mellitus; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101273479",
"other_id": null,
"pages": "651-9",
"pmc": null,
"pmid": "25484592",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't",
"references": "15652604;23264422;21496321;20228401;15207952;23418368;22386829;19148107;12479763;22054782;23434624;16296705;10738048;9549452;22853848;10818061;8622248;17765963;11416606;22136978;8387090;10938049;12777958;9571349;21403089;12493255;9635947;15983291;16003185;23817082;11315068;24352797;9732337;16154016;22079683;24235839;16750465;20606150;20620720;19052124",
"title": "Uptitrating amlodipine significantly reduces blood pressure in diabetic patients with hypertension: a retrospective, pooled analysis.",
"title_normalized": "uptitrating amlodipine significantly reduces blood pressure in diabetic patients with hypertension a retrospective pooled analysis"
} | [
{
"companynumb": "US-ZYDUS-014102",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "Gadoxetate disodium, utilized in hepatobiliary magnetic resonance (MR) imaging, has been associated with transient respiratory motion during the arterial phase in adults.\n\n\n\nThe purpose of this study was to determine the presence and severity of this phenomenon in children imaged awake versus under general anesthesia.\n\n\n\nThis retrospective cohort study was approved by the institutional review board; informed consent was waived. One hundred thirty exams of children ≤18 years old who underwent dynamic liver MR imaging with gadoxetate disodium between October 2010 and January 2018 were reviewed. Three pediatric radiologists scored respiratory motion artifacts on all imaging phases using a 5-point Likert scale. Differences in mean motion scores were assessed with analysis of variance and Tukey's multiple comparisons test, and multivariable regression was used to identify predictors of arterial phase motion in awake patients.\n\n\n\nOne hundred thirty patients (50% [n=65] female; mean age: 9.8±3.7 years, 48.5% [n=63] awake) were included. There were significant differences in mean motion scores between phases in the awake cohort (P<0.0001) but not in the general anesthesia cohort (P=0.051). In the awake cohort, arterial phase motion score (mean: 3.52±0.83) was significantly higher than mean motion score in all other phases (P≤0.0003). There were no significant patient-specific predictors of arterial phase motion score in the awake cohort.\n\n\n\nSignificantly increased arterial phase respiratory motion artifact in awake children undergoing dynamic liver MR imaging with gadoxetate disodium suggests that transient respiratory motion occurs in children. General anesthesia may suppress this phenomenon.",
"affiliations": "Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 5031, Cincinnati, OH, 45229, USA. Leah.Gilligan@cchmc.org.;Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 5031, Cincinnati, OH, 45229, USA.;Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 5031, Cincinnati, OH, 45229, USA.;Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 5031, Cincinnati, OH, 45229, USA.;Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 5031, Cincinnati, OH, 45229, USA.;Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 5031, Cincinnati, OH, 45229, USA.",
"authors": "Gilligan|Leah A|LA|0000-0002-4632-7004;Trout|Andrew T|AT|;Anton|Christopher G|CG|;Schapiro|Andrew H|AH|;Towbin|Alexander J|AJ|;Dillman|Jonathan R|JR|",
"chemical_list": "D003287:Contrast Media; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00247-019-04437-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0449",
"issue": "49(9)",
"journal": "Pediatric radiology",
"keywords": "Children; Dyspnea; Gadoxetate disodium; Magnetic resonance imaging; Motion artifact; Transient severe motion",
"medline_ta": "Pediatr Radiol",
"mesh_terms": "D000293:Adolescent; D016477:Artifacts; D002648:Child; D002675:Child, Preschool; D003287:Contrast Media; D005260:Female; D019786:Gadolinium DTPA; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008107:Liver Diseases; D008279:Magnetic Resonance Imaging; D008297:Male; D012119:Respiration; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "0365332",
"other_id": null,
"pages": "1171-1176",
"pmc": null,
"pmid": "31203405",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": "21701987;19959517;17453513;30078042;27736700;27929673;26048848;21553038;22334493;16098345;25246096;26473642;27478381;25055154;24617733;23192781;27509544",
"title": "Respiratory motion in children and young adults undergoing liver magnetic resonance imaging with intravenous gadoxetate disodium contrast material.",
"title_normalized": "respiratory motion in children and young adults undergoing liver magnetic resonance imaging with intravenous gadoxetate disodium contrast material"
} | [
{
"companynumb": "US-BAYER-2019-130827",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOXETATE DISODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Background Various pathophysiological mechanisms such as microvascular and endothelial dysfunction, small vessel disease, diffuse atherosclerosis, and inflammation have been held responsible in the etiology of coronary slow flow. It is also thought to be a reflection of a systemic slow-flow phenomenon in the coronary arterial tree. Case Report A 44-year-old man presented with chest pain causing fatigue, together with blurred vision for the last 2 years, which disappeared after resting. He had used corticosteroid therapy for facial paralysis 1 month ago. Coronary slow flow was detected in all 3 major coronary arteries on coronary angiography. TIMI measurements for the left anterior descending artery, circumflex, and right coronary artery were 64, 72, and 55, respectively. In fundus fluorescein angiography, retinal vascularity was normal, the arm-to-retina circulation time was 21.8 s, and the arteriovenous transit time was 4.3 s. In the early arteriovenous phase, choroidal filling was long, with physiological patchy type. Diltiazem 90 mg/day and acetylsalicylic acid 100 mg/day were given. His chest pain and visual symptoms disappeared after medical treatment. Conclusions Physicians should be aware that glucocorticoids might cause an increase in the symptoms of coronary slow flow and some circulation problems, which might lead to systematic symptoms.",
"affiliations": "Department of Cardiology, Kırıkkale Yüksek İhtisas State Hospital, Kırıkkale, Turkey.;Department of Cardiology, Giresun University, Giresun, Turkey.;Department of Cardiology, Kırıkkale Yüksek İhtisas State Hospital, Kırıkkale, Turkey.;Department of Cardiology, Kırıkkale Yüksek İhtisas State Hospital, Kırıkkale, Turkey.;Department of Cardiology, Giresun University, Giresun, Turkey.;Department of Cardiology, Ordu University, Ordu, Turkey.;Department of Cardiology, Ordu University, Ordu, Turkey.",
"authors": "Koç|Şahbender|Ş|;Vural|Aslı|A|;Aksoy|Hakan|H|;Dindar|Barış|B|;Karagöz|Ahmet|A|;Günaydın|Zeki Yüksel|ZY|;Bektaş|Osman|O|",
"chemical_list": "D005938:Glucocorticoids; D003900:Desoxycorticosterone",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.893461",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "16()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D050197:Atherosclerosis; D001783:Blood Flow Velocity; D017023:Coronary Angiography; D003326:Coronary Circulation; D003331:Coronary Vessels; D003900:Desoxycorticosterone; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D017566:Microvascular Angina; D015354:Vision, Low",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "315-8",
"pmc": null,
"pmid": "26008865",
"pubdate": "2015-05-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12384470;12655279;5080284;9591894;9635901;16288834;17984234;18448380;19239478;23538021;23892686",
"title": "Coronary slow flow accompanying exertional blurred vision and effects of corticosteroids.",
"title_normalized": "coronary slow flow accompanying exertional blurred vision and effects of corticosteroids"
} | [
{
"companynumb": "TR-ROXANE LABORATORIES, INC.-2015-RO-01312RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugaddit... |
{
"abstract": "To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC).\nTwenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed.\nThe tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively.\nCombined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.",
"affiliations": "Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.;Department of Radiology, Nara Medical University, Kashihara, Japan.",
"authors": "Hidaka|Teruyuki|T|;Anai|Hiroshi|H|;Sakaguchi|Hiroshi|H|;Sueyoshi|Satoru|S|;Tanaka|Toshihiro|T|;Yamamoto|Kiyosei|K|;Morimoto|Kengo|K|;Nishiofuku|Hideyuki|H|;Maeda|Shinsaku|S|;Nagata|Takeshi|T|;Kichikawa|Kimihiko|K|",
"chemical_list": "D000970:Antineoplastic Agents; D004998:Ethiodized Oil",
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"keywords": "bland embolization; huge hepatocellular carcinoma; transarterial chemoembolization",
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"title": "Efficacy of combined bland embolization and chemoembolization for huge (≥10 cm) hepatocellular carcinoma.",
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"abstract": "A 14-month-old infant presented with gastroenteritis with febrile pancytopenia and was diagnosed with acute lymphocytic leukemia (ALL). Ten days post induction therapy, the patient developed hypertension that was ascribed to steroid therapy and treated with metoprolol and amlodipine. As leukocyte numbers began to recover the asymptomatic patient became anuric. Ultrasound showed echoic floating structures in the bladder. Following cystoscopy and retrograde pyelography examination, purulent debris was irrigated from the bladder and grew Pseudomonas aeruginosa. Ciprofloxacin therapy was initiated and renal function was restored within 2 days. The case highlights the potential for renal obstruction after neutropenia recovery in children undergoing induction therapy for ALL.",
"affiliations": "Faculty of Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.",
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"title": "Pseudomonas aeruginosa infection: an uncommon cause of post-renal obstruction following induction therapy for acute lymphoblastic leukemia.",
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"abstract": "Combined methylmalonic acidemia (MMA) and homocysteinemia are a group of autosomal recessive disorders caused by inborn errors of cobalamin metabolism, including CblC, D, F, and J, with cblC being the most common subtype. The clinical manifestations of combined MMA and homocysteinemia vary, but typically include neurologic, developmental and hematologic abnormalities.We report 4 children with combined MMA and homocysteinemia who presented predominantly with late-onset diffuse lung diseases (DLD). Of these, 3 accompanied by pulmonary arterial hypertension (PAH), 1 accompanied by hypertension, and 2 accompanied by renal thrombotic microangiopathy (TMA), which was confirmed by renal biopsy. This confirms combined MMA and homocysteinemia should be considered in the differential diagnosis of DLD with or without PAH or renal TMA.",
"affiliations": "Department of Respiratory Medicine, Beijing Children's Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People's Republic of China.;Imaging Center, Beijing Children's Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People's Republic of China.;Department of Nephrology, Beijing Children's Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People's Republic of China.;Department of Nephrology, Beijing Children's Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People's Republic of China.;Department of Nephrology, Beijing Children's Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People's Republic of China.;Department of Respiratory Medicine, Beijing Children's Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People's Republic of China.;Department of Respiratory Medicine, Beijing Children's Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People's Republic of China. zhaoshunyingdoc@sina.com.",
"authors": "Liu|Jinrong|J|;Peng|Yun|Y|;Zhou|Nan|N|;Liu|Xiaorong|X|;Meng|Qun|Q|;Xu|Hui|H|;Zhao|Shunying|S|",
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"fulltext": "\n==== Front\nOrphanet J Rare DisOrphanet J Rare DisOrphanet Journal of Rare Diseases1750-1172BioMed Central London 61010.1186/s13023-017-0610-8Letter to the EditorCombined methylmalonic acidemia and homocysteinemia presenting predominantly with late-onset diffuse lung disease: a case series of four patients Liu Jinrong liujinrong2006@163.com 1Peng Yun ppengyun@yahoo.com 2Zhou Nan zhounan11@sina.com 3Liu Xiaorong desin2000@sina.com 3Meng Qun 13651135778@163.com 3Xu Hui 5145823@qq.com 1Zhao Shunying zhaoshunyingdoc@sina.com 11 0000 0004 0369 153Xgrid.24696.3fDepartment of Respiratory Medicine, Beijing Children’s Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People’s Republic of China 2 0000 0004 0369 153Xgrid.24696.3fImaging Center, Beijing Children’s Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People’s Republic of China 3 0000 0004 0369 153Xgrid.24696.3fDepartment of Nephrology, Beijing Children’s Hospital, Capital Medical University, Nanlishi Road 56, Xicheng District, Beijing, People’s Republic of China 21 3 2017 21 3 2017 2017 12 5815 6 2016 8 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.Combined methylmalonic acidemia (MMA) and homocysteinemia are a group of autosomal recessive disorders caused by inborn errors of cobalamin metabolism, including CblC, D, F, and J, with cblC being the most common subtype. The clinical manifestations of combined MMA and homocysteinemia vary, but typically include neurologic, developmental and hematologic abnormalities.\n\nWe report 4 children with combined MMA and homocysteinemia who presented predominantly with late-onset diffuse lung diseases (DLD). Of these, 3 accompanied by pulmonary arterial hypertension (PAH), 1 accompanied by hypertension, and 2 accompanied by renal thrombotic microangiopathy (TMA), which was confirmed by renal biopsy. This confirms combined MMA and homocysteinemia should be considered in the differential diagnosis of DLD with or without PAH or renal TMA.\n\nKeywords\nMethylmalonic acidemiaHomocysteinemiaHomocystinuriaDiffuse Lung diseaseHypertension arterial pulmonaryChildrenBeijing Municipal and Commission Health and Family Planning2015-3-076Liu Jinrong issue-copyright-statement© The Author(s) 2017\n==== Body\nLetter to the editor\nIn adults, it is reported that isolated hyperhomocysteinemia may damage blood vessels, causing pulmonary arterial hypertension (PAH) and/or pulmonary thromboembolism [1, 2]. Both microangiopathy and thromboembolism can be the underlying mechanisms for pulmonary hypertension in CblC deficiency [3–8], but an association between MMA and/or homocysteinemia and diffuse lung disease (DLD) has not been broadly reported.\n\nHere, we report a series of 4 pediatric patients with combined MMA and homocysteinemia who developed late-onset DLD. Of these, 3 presented with concomitant PAH, 1 presented with concomitant hypertension, and 2 presented with concomitant renal thrombotic microangiopathy (TMA), which was confirmed by renal biopsy. The main novelty of these cases was the predominantly pulmonary symptomatology at presentation (i.e., chronic wet cough or respiratory failure), with or without PAH (as in the first episode of “pneumonia” or “asthma” of patient 1, 3 and 4), the HRCT imaging findings, and the lack of typical neurological sequelae and ophthalmological findings. We speculate that pulmonary microangiopathy secondary to combined MMA and homocysteinemia was the primary cause of DLD in all 4 cases. Therefore, combined MMA and homocysteinemia should be considered in the differential diagnosis of DLD with or without PAH or renal TMA. This diagnosis should be investigated promptly with the proper metabolic investigations (total plasma homocysteine, plasma acylcarnitine and urine organic acid profiles), so that treatment can be initiated in a timely fashion, as lung disease secondary to this metabolic disorder will respond to appropriate treatment but may not respond to symptomatic treatment.\n\nCase reports\nPatient 1\nA 21-month-old girl was transferred to our department with a 6-month history of slight productive cough and a 2-month history of shortness of breath. She had previously been treated with intermittent antibiotics but the cough was not resolved. Two months before admission, she had developed shortness of breath and fever, and been diagnosed with pneumonia. Echocardiography showed mild tricuspid and pulmonary valve regurgitation with a tricuspid regurgitation pressure gradient (TRPG, an estimate of pulmonary artery pressure) of 26 mmHg, which suggested that pulmonary artery (PA) pressure was normal. High-resolution computed tomography (HRCT) showed diffuse interstitial pneumonia, consolidation and pleural effusions. Fever, pulmonary consolidation and pleural effusions were resolved after treatment with antibiotics and glucocorticoids at her local hospital, but her shortness of breath and productive cough got worse.\n\nOn admission to our hospital, the patient was dyspneic, with nasal alar flaring and retraction, cyanosis in the lips and nail beds. There were no rales or cardiac murmurs on auscultation of the chest. The laboratory investigations showed a white blood cell count of 14,090/mL with 66.6% neutrophils, hemoglobin (Hb) 9.8 ~ 12.6 g/dL, platelet 322 ~ 387 × 109/L, serum lactate dehydrogenase (LDH) 563 IU/L and indirect bilirubin (IBIL) 33.5 μmol/L; and normal serum C-reactive protein concentration and renal function. The urinalysis showed protein in urine ranging from negative to 2+ and red blood cells (RBCs) from 0 ~ 2/HP to 2 ~ 6/HP. Arterial blood gas analysis showed type 1 respiratory failure and a mild metabolic acidosis. Sputum cultures were negative for bacterial, fungal and mycobacterial infection. An HRCT scan of her chest showed diffuse ground-glass opacification in the lower regions of the lungs, areas of smooth thickening of the interlobular septum and increased PA diameter (Fig. 1a). Echocardiography showed moderate PAH (TRPG 68 mmHg) with moderate dilation of the right atrium and ventricle, mild tricuspid and pulmonary valve regurgitation, and an ejection fraction (EF) of 74%. Based on the bilateral diffuse lung lesion of unknown reasons, mild metabolic acidosis, and her low BMI, we suspected she suffered from metabolic disease. Laboratory testing showed elevated concentration of methylmalonic acid in the serum (0.218 mg/dL) and urine (0.428 mg/dL, >420 times the reference value), and a high plasma homocysteine (Hcy) concentration (>50.0 μmol/L, reference range 5~15 μmol/L). Magnetic resonance imaging (MRI) of the brain was performed, which revealed dilated lateral ventricles with mild hydrocephalus, although she had no sigh of neurologic abnormalities. Genetic analysis confirmed a compound heterozygosity in MMACHC, with c.80A > G(p.Q27R) and c.331C > T(p.R111Ter) sequence variants, inherited from the patient’s mother and father, respectively. Combined MMA with homocysteinemia, CblC type/CblC defect/CblC deficiency was confirmed.Fig. 1 Lung CT showing the presence in both lungs of 1a diffuse ground-glass opacification predominant in lower region of lung and areas with smooth thickening of interlobular septum (on admission; Patient 1), 1b absence of abnormal pulmonary feature(after 1 month of treatment; Patient 1), 2a interlobular septal thickening and bilateral pleural effusion (1 year before admission; Patient 2), 2b diffuse poorly defined centrilobular nodules(5 days after treatment; Patient 2), 2c pulmonary artery (PA) with an enlarged diameter exceeding the aorta(5 days after treatment; Patient 2), and 3 diffuse poorly defined ground-glass centrilobular nodules(on admission; Patient 3)\n\n\n\n\nAt diagnosis on day 7 of her admission to our hospital, treatment with captopril (3.125 mg twice daily orally) and vitamin B12 (cyanocobalamin, 0.5 mg daily intramuscularly) was started. She had improved significantly by day 10. On day 13, we added folate (5 mg once daily orally), betaine (250 mg/kg once daily orally), levocarnitine (100 mg/kg once daily orally) and vitamin B6 (10 mg/kg twice daily orally) to her therapeutic regime. Her symptoms improved gradually. One month later, HRCT of the lung showed significant improvement (Fig. 1b), but she continued to require intermittent low-flow supplemental oxygen for a further 4 months. At follow-up 1 year later, echocardiography found normal PA pressures and lung CT findings were normal. She was asymptomatic at 3 years’ follow-up.\n\nPatient 2\nA girl aged 4 years and 7 months presented with a 1-year history of slight cough and shortness of breath. She had been observed to have lower than expected levels of physical activity, and slightly delayed intellectual and language development since birth. Echocardiography and MRI of the brain undertaken when she was 1 year old had been normal. She had been admitted to her local hospital 1 year previously due to bilateral palpebral edema, and slight cough and shortness of breath. Echocardiography undertaken at the time showed PAH, blood routine test showed a hemoglobin level of 7.7 g/dL and a platelet count of 161 × 109/L, urinalysis showed proteinuria (2+) and microscopic hematuria, and HRCT showed interlobular septal thickening and bilateral pleural effusions (Fig. 1c). After treatment with bosentan, a diuretic and captopril, the palpebral edema, proteinuria and pleural effusions resolved gradually, but her cough, dyspnea and PAH did not improve, and HRCT revealed multiple nodular lesions in both lungs, so she was referred to our department.\n\nOn admission to our hospital, physical examination revealed she had cyanosis of the lips and nail beds. Chest auscultation revealed a second-degree systolic heart murmur but no rales in the lungs. Laboratory investigations detected increased serum LDH (384 IU/L) and blood urea nitrogen (BUN) concentration (11.64 mmol/L, normal range 1.7~ 7.1 mmol/L). Urinalysis revealed protein in urine 2+ and RBCs ranging from 0 ~ 2/HP to 4 ~ 6/HP. We undertook metabolic studies for her slight development delay and renal injury. Methylmalonic acid concentrations were elevated in the serum (0.294 mg/dL) and urine (0.354 mg/dL, >350 times the reference value), and a plasma Hcy concentration was >50.0 μmol/L. Therefore ophthalmologic examination was performed, which revealed bilateral macular coloboma. Echocardiography showed severe PAH (TRPG 81 mmHg) with moderate dilation of the right atrium and ventricle, EF 68%, moderate tricuspid regurgitation and mild pulmonary regurgitation. Her parents did not consent to her undergoing genetic testing. Combined MMA with homocysteinemia was clinically diagnosed.\n\nAfter diagnosis on day 5 of her admission to our hospital, she was started on treatment with parenteral cyanocobalamin, levocarnitine, vitamin B6 and betaine. Her symptoms improved gradually. On day 10, contrast-enhanced lung CT showed diffuse poorly defined centrilobular nodules, and dilation of the PA to a diameter exceeding that of the aorta (Fig. 1d, e). By day 13, she was more active and was able to get out of bed. On day 15, oxygen treatment was discontinued. On day 22, echocardiography showed mild to moderate PAH (TRPG 60 mmHg) with mild dilatation of the right atrium and ventricle, mild tricuspid regurgitation and mild pulmonary regurgitation. At follow-up 2 months later at her local hospital, lung CT and echocardiography showed further substantial improvements. Unfortunately, she died suddenly 6 months later without an autopsy.\n\nPatient 3\nA girl aged 8 years and 5 months was admitted to our hospital for investigation after a 6-year history of decreased activity and intermittent vomiting and diarrhea, and a 2-year history of renal impairment and slight productive cough. Two years before admission, she had been diagnosed with renal failure, hypertension and moderate anemia. Based on her clinical characteristics, she was suspected of having Goodpasture syndrome or vasculitis at her local hospital. At that time, urinalysis showed proteinuria 2+ and microscopic hematuria, and the lung CT revealed diffuse interstitial and parenchymal infiltration.\n\nOn admission to our hospital, physical examination revealed she had mild cyanosis of the nail beds. There were no rales or heart murmurs on auscultation of the chest. In laboratory investigations she had elevated BUN (7.73 mmol/L), serum creatinine (115 μmol/L) and IBIL (21.9 μmol/L) concentrations. Routine blood tests showed low hemoglobin (9.6 ~ 11.5 g/dL) without thrombocytopenia. The urinalysis revealed protein in urine ranging from negative to 2+ and RBCs from 0 ~ 2/HP to 2 ~ 4/HP. Diffuse poorly defined ground-glass centrilobular nodules were seen on HRCT (Fig. 1f). Echocardiography was normal, with no evidence of PAH. We undertook metabolic studies for her renal failure of unknown reasons. Methylmalonic acid concentration in the serum was 0.299 mg/dL and in the urine was 0.127 mg/dL (>120 times the reference value); plasma Hcy concentration was >50.0 μmol/L. Therefore brain MRI was performed, which revealed evident demyelinating lesions, although she had no sign of neurologic abnormalities. Genetic analyses confirmed a compound heterozygosity in MMACHC, with c.80A > G(p.Q27R) and c.609G > A(p.W203X) sequence variants, inherited from the patient’s mother and father, respectively. Mutation screening of atypical hemolytic uremic syndrome (HUS) associated genes (CFHR1, CFHR3, CFH, CD46, CFI, CFB, C3 and THBD), PAH associated genes (SMAD9, CAV1, KCNK3, CTEPH1, CPS1 and SARS2), pulmonary venous occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) associated genes (BMPR2, EIF2AK4) showed no abnormalities. Combined MMA with homocysteinemia, CblC type was confirmed.\n\nOn day 1 after admission, she was treated with oral amlodipine besylate and fosinopril. On day 6, after diagnosis, treatment with parenteral cyanocobalamin, folate, levocarnitine, vitamin B6 and betaine was initiated. Renal biopsy undertaken on day 7 subsequently revealed mesangioproliferative glomerulonephritis and TMA with stenotic and occlusive capillaries and ischemic sclerosis. By day 10, her physical strength was improving. On day 11, bronchoscopy was performed and there was no evidence of hemosiderin-laden alveolar macrophages in the bronchoalveolar lavage fluid (BALF). She improved significantly at 9 months’ follow-up.\n\nPatient 4\nA boy aged 7 years and 8 months was referred to our respiratory department because of a month period of mild wet cough particularly in the morning and shortness of breath. The HRCT showed mild diffuse ground-glass opacification in both lungs. Echocardiography revealed severe PAH. Asthma was suspected. After receiving a treatment with montelukast and repeated antibiotics for 1 month, and sildenafil and captopril for 15 days, his shortness of breath and PAH (mild to moderate) dramatically improved, but the cough was not resolved. When he was 4 months of age, he had hemolytic anemia without thrombocytopenia or kidney damage. Additionally, he had been diagnosed with acute glomerulonephritis with mild microscopic hematuria 1 year earlier.\n\nOn admission to our department, physical examination revealed no rales or heart murmurs on auscultation of the chest. We highly suspected he had combined MMA with homocysteinemia. Laboratory investigations showed a hemoglobin of 10.4 g/dL and mildly elevated LDH (330 IU/L), BUN (9.67 mmol/L), and Cr (71 μmol/L). Urinalysis only revealed sparse RBCs. Blood smear examination revealed sparse fragmented and deformed RBC. The serum and urinary methylmalonic acid concentrations were 0.383 mg/dL and 0.1034 mg/dL (>103 times the reference value) respectively, and plasma Hcy concentration was 193.76 μmol/L. Brain MRI revealed evident demyelinating lesions, although he had no sign of neurologic abnormalities. Genetic analyses confirmed a compound heterozygosity in MMACHC, with c.80A > G(p.Q27R) and c.609G > A(p.W203X) sequence variants, inherited from the patient’s father and mother, respectively. Mutation screening of atypical HUS and PAH associated genes showed no abnormalities. Combined MMA with homocysteinemia, CblC type was confirmed.\n\nAfter admission, he was continuously treated with oral sildenafil and captopril. On day 4, treatment with parenteral cyanocobalamin, folate, levocarnitine, vitamin B6 and betaine was initiated. Renal biopsy undertaken on day 6 subsequently revealed TMA with stenotic capillaries, ischemic sclerosis, and membranoproliferative glomerulonephritis. Transbronchoscopic lung biopsy undertaken on day 9 subsequently revealed a thickening of the alveolar septum with a small quantity lymphatic tissue and lymphocytes. There was no evidence of hemosiderin-laden alveolar macrophages in the BALF. On day 15, his cough improved significantly and echocardiography just showed mild PAH.\n\nIn all 4 patients, metabolic investigations were suggestive of cobalamin deficiency, with elevated blood propionylcarnitine (C3) concentration as well as an elevated propionylcarnitine–acetylcarnitine (C3/C2) ratio, in the context of low or normal concentrations of methionine. Clinical characteristics and results of auxiliary examination of the 4 patients are summarized in Tables 1, 2 and 3.Table 1 Demographic and clinical features, genetic evaluation and prognosis of 4 Chinese patients with combined MMA and homocysteinemia\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\t\nGender\tFemale\tFemale\tFemale\tMale\t\nAge\t21 months\t4-years-7-months\t8-years-5-months\t7-years-8-months\t\nPresentation\tCough,dyspnea\tSlightly delayed intellectual and language development, cough,\nshort of breath\tDecreased activity, vomiting,diarrhea, abnormal renal function,cough\tMild wet cough and shortness of breath\t\nWeight(kg)/PCSAG\t9.0/<3rd percentile\t14.0/3rd percentile\t18.5/<3rd percentile\t16.0/<3rd percentile\t\nHeight(cm)/PCSAG\t83/30th percentile\t112/90th percentile\t118/<3rd percentile\t123/23th percentile\t\nHead circumference(cm)\t45.1/(normal)\tNo record\tNo record\t50.2/(normal)\t\nBMI(kg/m2)/PCSAG\t13.0/<3rd percentile\t11.16/<3rd percentile\t13.29/8th percentile\t10.58 < 3rd percentile\t\nRespiratory rate(breaths/min)\t40\t28\t22\t20\t\nHeart rate(beats/min)\t145\t102\t110\t90\t\nBlood pressure(mmHg)\t90/55\t90/60\t130/100\t95/60\t\nClubbed fingers\t+\t+\t+\t+\t\nFundus examination\tNormal\tBilateral macular coloboma\tNormal\tNormal\t\nMMACHC gene\tc.80A > G(p.Q27R),\nc.331C > T(p.R111Ter)\tNot available\tc.80A > G(p.Q27R),\nc.609G > A(p.W203X)\tc.80A > G(p.Q27R),\nc.609G > A(p.W203X)\t\nGenotype\tCblC\tNot available\tCblC\tCblC\t\nFollow-up\t3 years\t6 months\t9 months\t1 month\t\nPrognosis\tAsymptomatic\tImprovement, but died suddenly\tImprovement\tImprovement\t\n\nAbbreviations: BMI body mass index; CblC cobalamin C; PCSAG percentile of the children with same age and gender\n\n\nTable 2 Laboratory features of 4 Chinese patients with combined MMA and homocysteinemia\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\t\nHemoglobin(g/dL)\t9.8 ~ 11.6\t11.5 ~ 12.5\t9.6 ~ 11.5\t104\t\nMCV(fL)\t113.4 ~ 118.6\t91.3 ~ 92.5\t89.4 ~ 94.6\t103.8\t\nPlatelet(×109/L)\t322 ~ 387\t161 ~ 317\t249 ~ 332\t502\t\nUrine protein\tNegative ~ 2+\t2+\tNegative ~ 2+\tNegative\t\nUrinary erythrocytes\t0-2/HP ~ 2-6/HP\t0-2/HP ~ 4-6/HP\t0-2/HP ~ 2-4/HP\tsparse\t\nArterial blood gas analysis\tPaO2: 27 mmHg, mild metabolic acidosis\tPaO2: 49 mmHg\tPaO2: 60 mmHg\tPaO2: 83 mmHg\t\nLiver function,serum albumin, cholesterol, triglyceride\tNormal\tNormal\tNormal\tNormal\t\nIBIL (μmol/L)\t33.5\t10.5\t21.9\t8.69\t\nBUN(mmol/L)\t7.1\t12.37\tBUN7.73\tBUN9.67\t\nCr (μmol/L)\t38\t67\t115\t71\t\neGFR (80–120 mL/min/1.73 m2)\t81\t61\t37\t64\t\nSerum LDH(IU/L)\t563(normal range:50 ~ 240)\t384(normal range:50 ~ 240)\t286(normal range:110 ~ 295)\t330((normal range: 110 ~ 295)\t\nMethionine concentrations (normal range:8.6 ~ 23.3 μmol/L)\t7.6\t22.6\t8.4\t11.1\t\nSerous vitamin B12\tNormal\tNormal\tNormal\tNormal\t\nSerous folate\tNormal\tNormal\tNormal\tNormal\t\nComplement C3,C4\tNormal\tNormal\tNormal\tNormal\t\nThyroid hormones\tNormal\tNormal\tNormal\tNormal\t\nImmune globulin\tNormal\tNormal\tNormal\tNormal\t\nLymphocyte subsets\tNormal\tNormal\tNormal\tNormal\t\nSerum ceruloplasmin\tNormal\tNormal\tNormal\tNormal\t\nANA,dsDNA,ACA, ANCA\tNegative\tNegative\tNegative\tNegative\t\nAnti-GBM Ab\tNegative\tNegative\tNegative\tNegative\t\nCoombs test\tNegative\tNegative\tNegative\t±\t\nBone marrow examination\tMegaloblastic anemia\tNormal\tMegaloblastic anemia\tNormal\t\n\nAbbreviations: ANA antinuclear antibody; ACA anticardiolipin antibody; ANCA antineutrophil cytoplasmic antibody; anti-GBM Ab-Anti-glomerular basement membrane antibody; BUN blood urea nitrogen; Cr creatinine; dsDNA double stranded DNA antibody; eGFR estimated glomerular filtration rate; LDH lactate dehydrogenase; IBIL indirect bilirubin concentration; MCV Mean Corpuscular Volume\n\n\nTable 3 Imaging features of 4 Chinese patients with combined MMA and homocysteinemia\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\t\nPAH\t+\t+\t—\t+\t\nEF(%)\t74\t68\t75\t77\t\nAbdominal ultrasonography\tEcho enhancement of the renal parenchyma on both sides\tMild enlargement of both kidneys\tEcho enhancement and diffuse injury to the renal parenchyma on both sides\tNormal\t\nBrain MRI\tDilated lateral ventricles with mild hydrocephalus\tNormal\tDemyelinating lesions\tDemyelinating lesions\t\nLung CT\tDiffuse ground-glass opacification, interlobular septal thickening\tDiffuse poorly defined centrilobular nodules, interlobular septal thickening\tDiffuse poorly defined ground-glass centrilobular nodules\tMild diffuse ground-glass opacification,\t\n\nAbbreviations: EF ejection fraction; MRI magnetic resonance imaging; PAH pulmonary arterial hypertension\n\n\n\n\nDiscussion\nIn this case series of children with combined MMA and homocysteinemia presenting predominantly with late-onset DLD, 3 cases also had PAH and 1 had hypertension. The diagnosis was made in each of the patients mainly on the basis of clinical features of multisystem damage, elevated serum and urine methylmalonic acid concentrations, elevated plasma homocysteine concentration, and elevated blood C3 concentration and C3/C2 ratio. Combined MMA with homocysteinemia results from deficient synthesis of the coenzymes derived from vitamin B12. So far, eight variants have been described, cobalamin C (CblC) being the most prevalent. The Cb1C defect was confirmed in patients 1 (c.80A > G, c.331C > T), 3(c.80A > G, c.609G > A) and 4 (c.80A > G, c.609G > A). Patient 2 had macular coloboma, which is supportive of a cblC defect, however her parents refused to give consent for the genotyping analysis. All 3 patients carried the c.80A > G mutation which has been reported in 4 Chinese patients with TMA or PAH [9]. The c.331C > T mutation was associated with the early-onset form mainly in the French, Canadian, Acadian and Cajun populations [10, 11], and has been reported in 1 Chinese patient [12]. The c.609G > A mutation is a hot spot mutation in Chinese patients with CblC defect [12, 13] and has been reported in 2 Chinese patients with HUS [14]. Patient 3 and 4 carried compound heterozygous mutations (c.80A > G, c.609G > A), which have been reported in eight Chinese patients with early-onset of the condition [12, 13], and 1 late-onset Chinese patient with PAH and renal TMA [9]. However, to date, the most frequent MMACHC mutations associated with PAH and renal TMA were c.271dupA, c.276G > T, and c.565C > A in Western countries [4–7, 15, 16].\n\nCombined MMA and homocysteinemia is a multisystemic disorder that can lead to damage to the central nervous system, retina, liver, kidneys and bone marrow (http://www.ncbi.nlm.nih.gov/books/NBK1328/). In our series, all patients had evidence of renal injury, hematologic and neurologic abnormalities to some extent;patient 2 also had bilateral macular coloboma, which are also common in combined MMA and homocysteinemia. Cardiomyopathy, both dilated, hypertrophic and non compaction, as well as microangiopathy have been described in patients affected with this group of conditions [17]. There have been 2 reports of pulmonary embolism and PAH in children with cobalamin C defect [3, 18], 7 of PAH in patients(including 1 adult) with cobalamin C defect [4–7, 9, 15, 16], 1 of PAH in newborn with MMA [19]. PVOD has been described as histological diagnosis in 3 patients with CblC defect [6, 16]. Contrast-enhanced lung CT was performed in patient 2 and didn’t show thin pulmonary venous or pulmonary artery embolism. DLD improved significantly after treatment in all patients, which didn’t suggest PVOD. In addition the lung abnormalities identified on imaging were not sufficiently severe to have caused PAH. Therefore we consider PAH was caused by combined MMA and homocysteinemia.\n\nIn this study, we aimed to show that there may be a relationship between combined MMA and homocysteinemia and DLD in children, although interstitial lung disease has been reported in association with other syndromes such as Niemann-Pick disease, as well as pulmonary alveolar proteinosis. No other causes of DLD, such as connective tissue disease, alveolar hemorrhage syndromes, pulmonary vasculitis, hypersensitivity pneumonitis, drug induced interstitial pneumonia, or infection were detected in any of the patients. Thus we think that in these cases, it is highly possible that DLD was caused by combined MMA and homocysteinemia, and not by PAH, based on the following reasons. Respiratory symptoms arose before or at the time of PAH diagnosis in the first 2 patients and in patient 4. Additionally, DLD existed in the absence of PAH in patient 3, despite lung imaging being similar to that in patient 2. Furthermore, DLD improved substantially in all patients when they were treated for MMA and homocysteinemia, but patient 2 did not improve when she was treated with bosentan.\n\n\nPost mortem examination of 4 patients with combined MMA and homocysteinemia found severe vascular lesions, with renal damage characteristic of TMA [20, 21], thromboemboli in the pulmonary circulation [18, 21], and massive endothelial proliferation in pulmonary post-capillary venules [16]. In the renal biopsy undertaken in the last 2 patients we observed TMA with stenotic and occlusive capillaries. Further, there have been reports showing this association [6, 7, 15, 16]. Additionally, the first 2 patients also had renal injury (including proteinuria and microscopic hematuria) and anemia. Furthermore patient 1 had an elevated level of serum LDH and IBIL, and patient 2 had an elevated level of serum LDH, which suggested that both of them might have atypical renal TMA especially patient 1. Renal TMA may be underestimated especially in China because its features are too subtle. None of the 4 patients presented with thrombocytopenia, which was consistent with the report by Komhoff M [6]. There was also imaging evidence of diffuse pulmonary microangiopathic lesions in all 4 of our patients. Therefore, we also speculate that the damage of vascular endothelial cell function (including pulmonary vessels) was triggered by intracellular and systemic changes by MMACHC variants. This was particularly marked in the presence of increased serum homocysteine concentration and could increase the permeability of pulmonary capillaries. The resulting vasoconstriction, vascular smooth muscle cell proliferation, and microthrombus formation, especially pulmonary TMA [1, 7], caused the presence of diffuse ground-glass opacification and centrilobular nodules in the lungs.\n\nIn this paper, DLD was diagnosed by lung imaging. DLD is consist of many kinds of lung diseases, including pulmonary vasculopathy.\n\nOur study has several limitations. We did not undertake blood smear examination in the first 3 patients, because of our poor awareness of TMA. Additionally, we did not undertake lung biopsy in the first 3 patients, as it was not warranted by the severity of patients 1 and 2, and the parents of patient 3 declined to give consent. Patient 4 underwent transbronchoscopic lung biopsy, and the histologic findings only showed a thickening of the alveolar septum without vascular structure, owing to the small tissue sample. These patients were not treated with hydroxocobalamin, which was unavailable in mainland China. We used TRPG to estimate PA pressures rather than undertake right heart catheterization, which is substantially more invasive.\n\nConclusions\nCblC defect has biochemical (combined MMA and homocysteinemia), radiological (DLD) and cardiological (PAH) characteristics. Our study suggested combined MMA and homocysteinemia be considered a potential reversible cause of DLD and PAH. Prompt recognition, diagnosis and treatment of CblC defect may reverse not only lung damage, but may prevent other complications associated with CblC defect (renal microangiopathy), and that it should be suspected not only in children, but in adults with similar findings.\n\nAbbreviations\nBALFBronchoalveolar lavage fluid\n\nBMIBody mass index\n\nBUNBlood urea nitrogen\n\ncblCCobalamin C\n\nDLDDiffuse lung diseases\n\nEFEjection fraction\n\nHcyHomocysteine\n\nHRCTHigh-resolution computed tomography\n\nHUSHemolytic uremic syndrome\n\nIBILIndirect bilirubin\n\nLDHLactate dehydrogenase\n\nMMAMethylmalonic Acidemia\n\nMRIMagnetic resonance imaging\n\nPAPulmonary arterial\n\nPAHPulmonary arterial hypertension\n\nPCHPulmonary capillary hemangiomatosis\n\nPVODPulmonary venous occlusive disease\n\nRBCsRed blood cells\n\nTMAThrombotic microangiopathy\n\nTRPGTricuspid regurgitation pressure gradient\n\nAcknowledgements\nWe would like to thank Prof. Kaifeng Xu (Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences) and Prof. Chunhua Zhang (Department of Research and Development, MILS International, Kanazawa 921-8105, Japan) for the help in revising the manuscript, the staff at Joy Orient Translational Medicine Research Center for their expert technical assistance. We also thank all of the patients and their families for their kind cooperation.\n\nFunding\nThis work was supported by Beijing Municipal and Commission Health and Family Planning[2015-3-076]. The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\n\nAvailability of data and materials\nPlease contact author for data requests.\n\nAuthors’ contributions\nJL supervised the patient care, conceptualized and designed the report, collected the data, and drafted the initial manuscript; YP supervised the radiological images and revised the article;NZ supervised the patient care and collected the data; XL supervised the patient care; QM supervised the patient care; HX supervised the patient care and collected the data; SZ supervised the patient care, conceptualized the report, and reviewed and revised the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nAll patient guardians gave informed consent to the publication of this study.\n\nEthics approval and consent to participate\nThe research was approved by the Ethics Committee of Beijing Children’s Hospital. All patient guardians gave informed consent to the study.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Arroliga AC Sandur S Jacobsen DW Tewari S Mustafa M Mascha EJ Association between hyperhomocysteinemia and primary pulmonary hypertension Respir Med 2003 97 7 825 9 10.1016/S0954-6111(03)00038-6 12854633 \n2. Wuillemin WA Solenthaler M Hyperhomocysteinemia: a risk factor for arterial and venous thrombosis Vasa 1999 28 3 151 5 10.1024/0301-1526.28.3.151 10483317 \n3. Profitlich L Kirmse B Wasserstein MP Diaz G Srivastava S Resolution of cor pulmonale after medical management in a patient with cblC-type methylmalonic aciduria and homocystinuria: a case report Cases J 2009 2 8603 10.4076/1757-1626-2-8603 19830091 \n4. Gunduz M Ekici F Ozaydin E Ceylaner S Perez B Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene Eur J Pediatr 2014 173 12 1707 10 10.1007/s00431-014-2330-6 24853097 \n5. Iodice FG Di Chiara L Boenzi S Aiello C Monti L Cogo P Cobalamin C defect presenting with isolated pulmonary hypertension Pediatrics 2013 132 1 e248 51 10.1542/peds.2012-1945 23753090 \n6. Komhoff M Roofthooft MT Westra D Teertstra TK Losito A van de Kar NC Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency Pediatrics 2013 132 2 e540 44 10.1542/peds.2012-2581 23837176 \n7. Grangé S Bekri S Artaud-Macari E Francois A Girault C Poitou AL Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C deficiency Lancet 2015 386 9997 1011 2 10.1016/S0140-6736(15)00076-8 26369474 \n8. George JN Cobalamin C, deficiency-associated thrombotic microangiopathy: uncommon or unrecognised? Lancet 2015 386 9997 1012 10.1016/S0140-6736(15)00077-X 26369475 \n9. Qi YH Qi JG Liu YP Yan H Liu XQ Zhang X Clinical analysis and follow-up study of cardiavascular system involvement in 10 children withmethylmalonic aciduria combined with hyperhomocysteinemia Zhongguo Dang Dai Er Ke Za Zhi 2015 17 9 965 70 26412180 \n10. Lerner-Ellis JP Tirone JC Pawelek PD Doré C Atkinson JL Watkins D Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type Nat Genet 2006 38 1 93 100 10.1038/ng1683 16311595 \n11. Huemer M Scholl-Bürgi S Hadaya K Kern I Beer R Seppi K Three new cases of late onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy Orphanet J Rare Dis 2014 9 161 10.1186/s13023-014-0161-1 25398587 \n12. Wang F Han L Yang Y Gu X Ye J Qiu W Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China J Inherit Metab Dis 2010 33 Suppl 3 S435 42 10.1007/s10545-010-9217-0 20924684 \n13. Liu MY Yang YL Chang YC Chiang SH Lin SP Han LS Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria J Hum Genet 2010 55 9 621 6 10.1038/jhg.2010.81 20631720 \n14. Li QL Song WQ Peng XX Liu XR He LJ Fu LB Clinical characteristics of hemolytic uremic syndrome secondary to cobalamin C disorder in Chinesechildren World J Pediatr 2015 11 3 276 80 10.1007/s12519-015-0032-4 26253414 \n15. Beck BB, van Spronsen F, Diepstra A, Berger RM, Kömhoff M. Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity. Pediatr Nephrol. 2016 Jun 11. [Epub ahead of print]\n16. Bouts AH Roofthooft MT Salomons GS Davin JC CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency Pediatr Nephrol 2010 25 12 2547 8 10.1007/s00467-010-1609-8 20652818 \n17. De Bie I Nizard SD Mitchell GA Fetal dilated cardiomyopathy: an unsuspected presentation of methylmalonic aciduria and hyperhomocystinuria, cblC type Prenat Diagn 2009 29 3 266 70 10.1002/pd.2218 19248038 \n18. Brandstetter Y Weinhouse E Splaingard ML Tang TT Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cbl-C type) Am J Med Genet 1990 36 2 167 71 10.1002/ajmg.1320360208 2368803 \n19. Agarwal R Feldman GL Poulik J Stockton DW Sood BG Methylmalonic acidemia presenting as persistent pulmonary hypertension of the newborn J Neonatal Perinatal Med 2014 7 3 247 51 25322992 \n20. Baumgartner ER Wick H Maurer R Egli N Steinmann B Congenital defect in intracellular cobalamin metabolism resulting in homocysteinuria and methylmalonic aciduria. I. Case report and histopathology Helv Paediatr Acta 1979 34 5 465 82 528229 \n21. Russo P Doyon J Sonsino E Ogier H Saudubray JM A congenital anomaly of vitamin B12 metabolism: a study of three cases Hum Pathol 1992 23 5 504 12 10.1016/0046-8177(92)90127-O 1568746\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1750-1172",
"issue": "12(1)",
"journal": "Orphanet journal of rare diseases",
"keywords": "Children; Diffuse Lung disease; Homocysteinemia; Homocystinuria; Hypertension arterial pulmonary; Methylmalonic acidemia",
"medline_ta": "Orphanet J Rare Dis",
"mesh_terms": "D001622:Betaine; D002648:Child; D002675:Child, Preschool; D005260:Female; D005492:Folic Acid; D006712:Homocystinuria; D006801:Humans; D007223:Infant; D008171:Lung Diseases; D008297:Male; D014805:Vitamin B 12; D014806:Vitamin B 12 Deficiency; D025101:Vitamin B 6",
"nlm_unique_id": "101266602",
"other_id": null,
"pages": "58",
"pmc": null,
"pmid": "28327205",
"pubdate": "2017-03-21",
"publication_types": "D002363:Case Reports; D016422:Letter; D013485:Research Support, Non-U.S. Gov't",
"references": "23837176;25322992;26369475;26412180;25398587;1568746;19830091;528229;23753090;2368803;27289364;26369474;16311595;24853097;12854633;20631720;20924684;10483317;20652818;26253414;19248038",
"title": "Combined methylmalonic acidemia and homocysteinemia presenting predominantly with late-onset diffuse lung disease: a case series of four patients.",
"title_normalized": "combined methylmalonic acidemia and homocysteinemia presenting predominantly with late onset diffuse lung disease a case series of four patients"
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"abstract": "OBJECTIVE\nFollowing preoperative chemoradiation and surgery, many patients with stage II to III rectal cancer are unable to tolerate full-dose adjuvant chemotherapy. BrUOG R-224 was designed to assess the impact of COmplete Neoadjuvant Treatment for REctal cancer (CONTRE), primary chemotherapy followed by chemoradiation and surgery, on treatment delivery, toxicities, and pathologic response at surgery.\n\n\nMETHODS\nPatients with clinical stage II to III (T3 to T4 and/or N1 to N2) rectal cancer received 8 cycles of modified FOLFOX6 followed by capecitabine 825 mg/m bid concurrent with 50.4 Gy intensity-modulated radiation therapy. Surgery was performed 6 to 10 weeks after chemoradiation.\n\n\nRESULTS\nThirty-nine patients were enrolled between August 2010 and June 2013. Median age was 61 years (30 to 79 y); 7 patients (18%) were clinical stage II and 32 (82%) stage III. Thirty-six patients (92%) received all 8 cycles of mFOLFOX6, of whom 35 completed subsequent chemoradiation; thus 89% of patients received CONTRE as planned. No unexpected toxicities were reported. All patients had resolution of bleeding and improvement of obstructive symptoms, with no complications requiring surgical intervention. Pathologic complete response (ypT0N0) was demonstrated in 13 patients (33%; 95% CI, 18.24%-47.76%).\n\n\nCONCLUSIONS\nCONTRE seems to be a well-tolerated alternative to the current standard treatment sequence. Evaluating its impact on long-term outcomes would require a large randomized trial, but using pathologic response as an endpoint, it could serve as a platform for assessing the addition of novel agents to preoperative treatment in stage II to III rectal cancer.",
"affiliations": "Brown University Oncology Research Group, Providence, RI.",
"authors": "Perez|Kimberly|K|;Safran|Howard|H|;Sikov|William|W|;Vrees|Matthew|M|;Klipfel|Adam|A|;Shah|Nishit|N|;Schechter|Steven|S|;Oldenburg|Nicklas|N|;Pricolo|Victor|V|;Rosati|Kayla|K|;Dipetrillo|Thomas|T|",
"chemical_list": "D009944:Organoplatinum Compounds; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
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"issn_linking": "0277-3732",
"issue": "40(3)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D059248:Chemoradiotherapy; D017024:Chemotherapy, Adjuvant; D013505:Digestive System Surgical Procedures; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D060828:Induction Chemotherapy; D002955:Leucovorin; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D050397:Radiotherapy, Intensity-Modulated; D012004:Rectal Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "283-287",
"pmc": null,
"pmid": "25374145",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Complete Neoadjuvant Treatment for Rectal Cancer: The Brown University Oncology Group CONTRE Study.",
"title_normalized": "complete neoadjuvant treatment for rectal cancer the brown university oncology group contre study"
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"companynumb": "US-SA-2014SA170828",
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"abstract": "Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10(-8); odds ratio=66.8; 95% confidence interval, 19.8-225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.",
"affiliations": "Department of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan. tohkin@phar.nagoya-cu.ac.jp",
"authors": "Tohkin|M|M|;Kaniwa|N|N|;Saito|Y|Y|;Sugiyama|E|E|;Kurose|K|K|;Nishikawa|J|J|;Hasegawa|R|R|;Aihara|M|M|;Matsunaga|K|K|;Abe|M|M|;Furuya|H|H|;Takahashi|Y|Y|;Ikeda|H|H|;Muramatsu|M|M|;Ueta|M|M|;Sotozono|C|C|;Kinoshita|S|S|;Ikezawa|Z|Z|;|||",
"chemical_list": "D015415:Biomarkers; D006680:HLA Antigens; D000493:Allopurinol",
"country": "United States",
"delete": false,
"doi": "10.1038/tpj.2011.41",
"fulltext": null,
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"issn_linking": "1470-269X",
"issue": "13(1)",
"journal": "The pharmacogenomics journal",
"keywords": null,
"medline_ta": "Pharmacogenomics J",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000493:Allopurinol; D044466:Asians; D015415:Biomarkers; D002896:Chromosomes, Human, Pair 6; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D055106:Genome-Wide Association Study; D006680:HLA Antigens; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012867:Skin; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "101083949",
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"pages": "60-9",
"pmc": null,
"pmid": "21912425",
"pubdate": "2013-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients.",
"title_normalized": "a whole genome association study of major determinants for allopurinol related stevens johnson syndrome and toxic epidermal necrolysis in japanese patients"
} | [
{
"companynumb": "JP-RANBAXY-2008RR-19901",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo describe 2.5 years of exposure to sitagliptin on glycemic control, immunosuppressive therapy, and adverse events following solid organ transplantation.\n\n\nMETHODS\nA 63-year-old Caucasian male received an orthotopic heart transplantation in June of 2006 secondary to idiopathic nonischemic cardiomyopathy. He was diagnosed with new-onset diabetes mellitus after transplantation (NODAT). Sitagliptin monotherapy was initiated in August 2007 and continued for 2.5 years.\n\n\nRESULTS\nHemoglobin A(1c) increased from 5.8% to 6.1%, but the recommended glycemic target of <7% was maintained over time and improvements in fasting home blood glucose monitoring values were achieved. Tacrolimus concentrations were not altered. Only minor dose adjustments to tacrolimus and mycophenolate mofetil were required. Maintenance corticosteroid dose remained unchanged and there was no evidence of biopsy-proven acute rejection. No adverse events were reported.\n\n\nCONCLUSIONS\nThis case report demonstrates that long-term sitagliptin treatment for NODAT may be effective, safe, and well tolerated in solid organ transplant recipients.",
"affiliations": "Department of Pharmacy Practice, Wayne State University, Detroit, Michigan 48201, USA. nickipinelli@wayne.edu",
"authors": "Pinelli|N R|NR|;Nemerovski|C W|CW|;Koelling|T M|TM|",
"chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D000068900:Sitagliptin Phosphate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2011.02.059",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "43(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D003920:Diabetes Mellitus; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D014230:Triazoles",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2113-5",
"pmc": null,
"pmid": "21693339",
"pubdate": "2011-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful long-term use of sitagliptin for the treatment of new-onset diabetes mellitus after solid organ transplantation: a case report.",
"title_normalized": "successful long term use of sitagliptin for the treatment of new onset diabetes mellitus after solid organ transplantation a case report"
} | [
{
"companynumb": "PHHY2019US226317",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "OBJECTIVE\nTo present 4 patients that developed hemorrhagic retinal infarction attributable to inadvertent overdose of cefuroxime after cataract surgery.\n\n\nMETHODS\nCase series.\n\n\nMETHODS\nSurgery in 4 patients was complicated-the posterior capsule was absent or torn-and anterior vitrectomy was performed. Cefuroxime was inadvertently injected at a dose higher than recommended in all 4 cases.\n\n\nRESULTS\nCase 1 had hemorrhage in the central and inferior retinal regions, as well as optic atrophy. Case 2 had hemorrhage in the peripapillary and macular regions, as well as optic atrophy. Case 3 had hemorrhage in the peripapillary and inferior retinal regions, as well as macular pucker attributable to fibrovascular formation in the central retinal region. Case 4 had hemorrhage in the peripapillary, macular, and inferior retinal regions. The cefuroxime doses administered to the presented patients were much higher than reported in other cases and resulted in a higher concentration in the vitreous. Consequently, the severity of toxicity was much higher than in other reported cases of cefuroxime-induced toxicity.\n\n\nCONCLUSIONS\nIn cases of intracameral cefuroxime overdose, hemorrhagic retinal infarction can develop after cataract surgery.",
"affiliations": "Department of Ophthalmology, Diyarbakır Training and Research Hospital, Diyarbakır, Turkey. Electronic address: ciftci1977@hotmail.com.;Department of Cardiology, Dicle University, School of Medicine, Diyarbakır, Turkey.;Department of Ophthalmology, Diyarbakır Training and Research Hospital, Diyarbakır, Turkey.",
"authors": "Çiftçi|Süleyman|S|;Çiftçi|Leyla|L|;Dağ|Umut|U|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002444:Cefuroxime",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "157(2)",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000867:Anterior Chamber; D000900:Anti-Bacterial Agents; D002387:Cataract Extraction; D002444:Cefuroxime; D062787:Drug Overdose; D006801:Humans; D007238:Infarction; D019654:Lens Implantation, Intraocular; D008297:Male; D009896:Optic Atrophy; D057851:Posterior Capsular Rupture, Ocular; D012166:Retinal Hemorrhage; D012171:Retinal Vessels; D012189:Retrospective Studies; D014821:Vitrectomy",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "421-425.e2",
"pmc": null,
"pmid": "24211862",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemorrhagic retinal infarction due to inadvertent overdose of cefuroxime in cases of complicated cataract surgery: retrospective case series.",
"title_normalized": "hemorrhagic retinal infarction due to inadvertent overdose of cefuroxime in cases of complicated cataract surgery retrospective case series"
} | [
{
"companynumb": "TR-LUPIN PHARMACEUTICALS INC.-2014-01605",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFUROXIME"
},
"drugadditional... |
{
"abstract": "Proximal-type epithelioid sarcoma is an ultra-rare, high-grade soft tissue malignancy usually presenting as a deep-seated painless mass in the proximal extremities. Most patients are diagnosed as young adults, between 20 and 40 years of age. Perineal and genital masses do occur but are extremely rare and represent a challenging tumour to diagnose and treat. Early radical excision is recommended due to its aggressive behaviour and poor prognosis. Median overall survival from initial diagnosis is 30 months. We present the case of a 22-year-old man with a left groin proximal-type epithelioid sarcoma who is sadly deceased 12 months after initial presentation despite early surgical excision, completion of both first-line and palliative chemotherapy, and palliative radiotherapy.",
"affiliations": "Department of Urology, Craigavon Area Hospital, Portadown, UK.;Department of Urology, Craigavon Area Hospital, Portadown, UK.;Department of Urology, Craigavon Area Hospital, Portadown, UK derek.hennessey@gmail.com.",
"authors": "Farnan|Jessica|J|;Morrison|Ellen|E|;Hennessey|Derek Barrry|DB|http://orcid.org/0000-0002-7372-0100",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232385",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "oncology; surgery; urology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D005834:Genital Neoplasms, Male; D006801:Humans; D008297:Male; D012509:Sarcoma; D013085:Spermatic Cord; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33414109",
"pubdate": "2021-01-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Para-spermatic cord proximal-type epithelioid sarcoma.",
"title_normalized": "para spermatic cord proximal type epithelioid sarcoma"
} | [
{
"companynumb": "IE-ACCORD-226825",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nThis observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27-83).\n\n\nMETHODS\nThe primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed.\n\n\nRESULTS\n10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group.\n\n\nCONCLUSIONS\nIn this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery.",
"affiliations": "Department of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.",
"authors": "Schnitzler|F|F|;Fidder|H|H|;Ferrante|M|M|;Noman|M|M|;Arijs|I|I|;Van Assche|G|G|;Hoffman|I|I|;Van Steen|K|K|;Vermeire|S|S|;Rutgeerts|P|P|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1136/gut.2008.155812",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-5749",
"issue": "58(4)",
"journal": "Gut",
"keywords": null,
"medline_ta": "Gut",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D005938:Glucocorticoids; D006760:Hospitalization; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "2985108R",
"other_id": null,
"pages": "492-500",
"pmc": null,
"pmid": "18832518",
"pubdate": "2009-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort.",
"title_normalized": "long term outcome of treatment with infliximab in 614 patients with crohn s disease results from a single centre cohort"
} | [
{
"companynumb": "BE-JNJFOC-20070501759",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "We herein report a case of fatal fulminant hepatitis secondary to crizotinib administration. The patient was 54-year-old female with a history of Hepatitis C infection (not current), dermatomyositis and steroid-induced diabetes mellitus. She was diagnosed with advanced lung adenocarcinoma with anaplastic lymphoma kinase rearrangement. We began 400 mg of crizotinib as first-line therapy. No adverse effects were seen until Day 16. On Day 29, she was admitted to hospital with elevated liver enzymes (aspartate aminotransferase 3236 IU/l, alanine aminotransferase 5201 IU/l) and coagulopathy (prothrombin time <10%), and was diagnosed with crizotinib-induced fulminant hepatitis. We started intensive care, using plasma exchange, continuous hemodiafiltration and high-dose steroid therapy. Unfortunately, she did not respond to therapies, and died on Day 36. The mechanism and risk factors of crizotinib-induced hepatotoxicity are uncertain. Physicians should be aware of possible adverse effects of crizotinib. A systemic survey is imperative to identify possible risk factors of crizotinib-related hepatotoxicity.",
"affiliations": "Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe daichianzen@yahoo.co.jp.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe.;Department of Anesthesiology, Kobe City Medical Center General Hospital, Kobe.;Department of Gastroenterology, Kobe City Medical Center General Hospital, Kobe.;Department of Pathology, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe.",
"authors": "Sato|Yuki|Y|;Fujimoto|Daichi|D|;Shibata|Yumi|Y|;Seo|Ryutaro|R|;Suginoshita|Yoshiki|Y|;Imai|Yukihiro|Y|;Tomii|Keisuke|K|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyu086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "44(9)",
"journal": "Japanese journal of clinical oncology",
"keywords": "anaplastic lymphoma kinase; crizotinib; drug induced liver toxicity; fulminant hepatitis; tyrosine kinase inhibitor",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000410:Alanine Transaminase; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D001219:Aspartate Aminotransferases; D002289:Carcinoma, Non-Small-Cell Lung; D056486:Chemical and Drug Induced Liver Injury; D000077547:Crizotinib; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases; D012307:Risk Factors",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "872-5",
"pmc": null,
"pmid": "24966207",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fulminant hepatitis following crizotinib administration for ALK-positive non-small-cell lung carcinoma.",
"title_normalized": "fulminant hepatitis following crizotinib administration for alk positive non small cell lung carcinoma"
} | [
{
"companynumb": "JP-PFIZER INC-2013278576",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SITAGLIPTIN PHOSPHATE"
},
"drugadditional": n... |
{
"abstract": "Bullous pemphigoid is an autoimmune blistering dermatosis with separation of the epidermis from the dermis. This disease process is common among elderly patients and manifests with subepidermal vesicles and tense bullae. Patients with bullous pemphigoid are more likely to have also received a previous diagnosis of a neurologic disorder. Gabapentin is an antiepileptic that is used to manage neuropathic pain. The authors describe, to their knowledge, the first report of gabapentin-induced bullous pemphigoid in an elderly man with no history of rashes or reactions to other medications.",
"affiliations": null,
"authors": "Flamm|Avram|A|;Sachdev|Sarina|S|;Dufresne|Francois|F|",
"chemical_list": "D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.7556/jaoa.2017.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-6151",
"issue": "117(3)",
"journal": "The Journal of the American Osteopathic Association",
"keywords": null,
"medline_ta": "J Am Osteopath Assoc",
"mesh_terms": "D000369:Aged, 80 and over; D000588:Amines; D001707:Biopsy, Needle; D003509:Cyclohexanecarboxylic Acids; D005500:Follow-Up Studies; D000077206:Gabapentin; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010391:Pemphigoid, Bullous; D035583:Rare Diseases; D018570:Risk Assessment; D012640:Seizures; D012720:Severity of Illness Index; D028761:Withholding Treatment; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "7503065",
"other_id": null,
"pages": "191-193",
"pmc": null,
"pmid": "28241331",
"pubdate": "2017-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gabapentin-Induced Bullous Pemphigoid.",
"title_normalized": "gabapentin induced bullous pemphigoid"
} | [
{
"companynumb": "US-DEPOMED, INC.-US-2018DEP001394",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GLIPIZIDE"
},
"drugadditional": null,... |
{
"abstract": "Relapsed/refractory multiple myeloma represents a major challenge in multiple myeloma therapy. For patients with relapsed/refractory multiple myeloma, we developed a treatment schema of metronomically scheduled drug therapy. We identified 186 patients who had been treated with metronomic therapy between March 2004 and January 2012 with a median follow up of 24.2 months. Median age was 61 years (range 36-83). Median number of prior therapies was 14 (range 1-51). Median number of completed metronomic therapy cycles was 1 (range 1-5), while 45 of 186 (25%) received 2 or more cycles. Responses included complete remission in 11 of 186 patients (6%), very good partial remission in 12 of 186 (7%), partial remission in 65 of 179 (36%), and minimal response in 29 of 186 (16%), for an overall response rate of 63% (117 of 186). Median overall survival and progression-free survival were 11.2 and 3.6 months, respectively. Hematologic toxicity grading was problematic as 146 of 186 (78%) of patients presented with at least grade 2 thrombocytopenia within 90 days prior to starting metronomic therapy. Grade 4 leukopenia, anemia, and/or thrombocytopenia following metronomic therapy occurred in 108 of 186 (58%), 12 of 186 (6%), and 147 of 186 (79%) patients, respectively. Incidence of grade 3-4 neutropenic fever was 4 of 186 (2%). Most patients (177 of 186, 95%) were treated in an outpatient unit and secondary admissions due to regimen-related toxicity occurred in 37 of 186 (20%). Treatment-related mortality was evident in 2 of 186 (1%). In conclusion, metronomic therapy is an effective late salvage treatment in relapsed/refractory multiple myeloma, with a high overall response rate and a favorable toxicity profile.",
"affiliations": "Myeloma Institute for Research and Therapy, Little Rock, AR, USA.",
"authors": "Papanikolaou|Xenofon|X|;Szymonifka|Jackie|J|;Rosenthal|Adam|A|;Heuck|Christoph J|CJ|;Mitchell|Alan|A|;Johann|Donald|D|;Keller|Jason|J|;Waheed|Sarah|S|;Usmani|Saad Z|SZ|;Van Rhee|Frits|F|;Bailey|Clyde|C|;Petty|Nathan|N|;Hoering|Antje|A|;Crowley|John|J|;Barlogie|Bart|B|",
"chemical_list": "D013792:Thalidomide; D003907:Dexamethasone; D004317:Doxorubicin; D002945:Cisplatin",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2013.085183",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "98(7)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002945:Cisplatin; D003907:Dexamethasone; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D016879:Salvage Therapy; D015996:Survival Rate; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "1147-53",
"pmc": null,
"pmid": "23716540",
"pubdate": "2013-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "21799510;10955791;20479421;12031911;21356186;7527645;17105813;18338745;16397231;10766175;12039858;20124509;19671111;17068150;10772648;6180819;10772661;1722975;1638024;14534880;21628408;16365178;20026801;17488488;4938153;21292775;10564685;19344415;16705089;15170445",
"title": "Metronomic therapy is an effective salvage treatment for heavily pre-treated relapsed/refractory multiple myeloma.",
"title_normalized": "metronomic therapy is an effective salvage treatment for heavily pre treated relapsed refractory multiple myeloma"
} | [
{
"companynumb": "US-JNJFOC-20130713023",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "Immune-related adverse events (irAEs) should be anticipated with treatment by immune checkpoint inhibitors (ICIs). Although the relationship between irAEs and efficacy of ICI has been reported, it has not yet been clarified whether the benefit from ICI outweighs the low frequency of proceeding to subsequent therapies after discontinuation due to irAEs.\n\n\n\nThe study comprised 61 patients with non-small cell lung cancer who underwent treatment with ICIs (nivolumab or pembrolizumab monotherapy) at the Saga University Medical School Hospital from December 2015 to January 2018. Therapeutic effect and progression-free survival (PFS) were compared between the irAEs discontinuation group (AEg) and the group with discontinuation due to all causes other than irAEs (Non-AEg).\n\n\n\nA total of 30% patients(18/61) had therapy discontinued due to irAEs: 22.5% (9/40) with nivolumab and 42.9% (9/21) with pembrolizumab. The response rate was 50.0% in the AEg and 8.1% in the on-AEg (P = 0.001). The median PFS was significantly longer in the AEg (9.3 months; 95% CI 2.1-12.1) than in the non-AEg (1.9 months; 95% CI 0.9-3.6): HR 0.45 (95%CI 0.20-0.89; log-rank test P = 0.026). The prevalence of drug-induced interstitial lung disease (ILD) was 6.1% (3/49) in cases without interstitial pneumonia (IP) as the underlying disease, whereas it was 50% (6/12) in cases with IP (P = 0.001).\n\n\n\nDiscontinuation of treatment with ICIs due to irAEs predict a good response to ICIs and favorable outcome since their anti-cancer effects continue even after discontinuation. However, the presence of IP as the underlying disease increases the risk of drug-related ILD onset.",
"affiliations": "Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, Saga, Japan.",
"authors": "Komiya|Kazutoshi|K|0000-0002-9026-1137;Nakamura|Tomomi|T|;Abe|Tomonori|T|;Ogusu|Shinsuke|S|;Nakashima|Chiho|C|;Takahashi|Koichiro|K|;Kimura|Shinya|S|;Sueoka-Aragane|Naoko|N|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000077594:Nivolumab; C582435:pembrolizumab",
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.13149",
"fulltext": "\n==== Front\nThorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 10.1111/1759-7714.13149TCA13149Original ArticleOriginal ArticlesDiscontinuation due to immune‐related adverse events is a possible predictive factor for immune checkpoint inhibitors in patients with non‐small cell lung cancer irAE is a predictive factor in NSCLC patientsK. Komiya et al.Komiya Kazutoshi https://orcid.org/0000-0002-9026-1137\n1\nNakamura Tomomi \n1\nAbe Tomonori \n1\nOgusu Shinsuke \n1\nNakashima Chiho \n1\nTakahashi Koichiro \n1\nKimura Shinya \n1\nSueoka‐Aragane Naoko sueokan@cc.saga-u.ac.jp \n1\n\n1 \nDivision of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine\nSaga University\nSaga\nJapan\n* Correspondence\n\nNaoko Sueoka‐Aragane, Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Saga University, 5‐1‐1 Nabeshima, Saga 849‐8501, Japan.\n\nTel: +81 952 34 2369\n\nFax: +81 952 34 20175‐1‐1\n\nEmail: sueokan@cc.saga-u.ac.jp\n22 7 2019 9 2019 10 9 10.1111/tca.v10.91798 1804 18 4 2019 27 6 2019 30 6 2019 © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis 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.Background\nImmune‐related adverse events (irAEs) should be anticipated with treatment by immune checkpoint inhibitors (ICIs). Although the relationship between irAEs and efficacy of ICI has been reported, it has not yet been clarified whether the benefit from ICI outweighs the low frequency of proceeding to subsequent therapies after discontinuation due to irAEs.\n\nMethods\nThe study comprised 61 patients with non‐small cell lung cancer who underwent treatment with ICIs (nivolumab or pembrolizumab monotherapy) at the Saga University Medical School Hospital from December 2015 to January 2018. Therapeutic effect and progression‐free survival (PFS) were compared between the irAEs discontinuation group (AEg) and the group with discontinuation due to all causes other than irAEs (Non‐AEg).\n\nResults\nA total of 30% patients(18/61) had therapy discontinued due to irAEs: 22.5% (9/40) with nivolumab and 42.9% (9/21) with pembrolizumab. The response rate was 50.0% in the AEg and 8.1% in the on‐AEg (P = 0.001). The median PFS was significantly longer in the AEg (9.3 months; 95% CI 2.1–12.1) than in the non‐AEg (1.9 months; 95% CI 0.9–3.6): HR 0.45 (95%CI 0.20–0.89; log‐rank test P = 0.026). The prevalence of drug‐induced interstitial lung disease (ILD) was 6.1% (3/49) in cases without interstitial pneumonia (IP) as the underlying disease, whereas it was 50% (6/12) in cases with IP (P = 0.001).\n\nConclusion\nDiscontinuation of treatment with ICIs due to irAEs predict a good response to ICIs and favorable outcome since their anti‐cancer effects continue even after discontinuation. However, the presence of IP as the underlying disease increases the risk of drug‐related ILD onset.\n\nImmune checkpoint inhibitorimmune‐related adverse eventinterstitial lung diseasenon‐small cell lung cancerpredictive factor source-schema-version-number2.0component-idtca13149cover-dateSeptember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.8 mode:remove_FC converted:02.09.2019\n==== Body\nIntroduction\nIn recent years, immune checkpoint inhibitors (ICIs) have achieved prominence in the treatment of advanced or recurrent non‐small cell lung cancer (NSCLC). Several phase III trials showed prolonged overall survival with ICIs in patients with NSCLC who were previously untreated or treated with alternative therapies.1, 2, 3, 4 Although it was concluded that the safety profile was good in all these trials, there were also serious immune‐related adverse events (irAEs), which is one of the primary reasons for discontinuing ICIs. In the international phase III trials of nivolumab, discontinuation due to treatment‐related AEs occurred in 3% of patients in the CheckMate 017 study and in 5% of patients in the CheckMate 057 study; among the discontinued cases, pneumonitis was the most common treatment‐related AE.1, 2 In KEYNOTE‐024 and KEYNOTE‐021—the international phase III trials of pembrolizumab—4.0–7.1% of patients had therapy discontinued due to treatment‐related AEs.3, 4 In addition, frequency of proceeding to subsequent therapies was lower than with chemotherapy.5\n\n\nAn association between occurrence of irAEs and treatment outcome with immunotherapy has also been previously reported. In a retrospective study, overall response rate (ORR) and median progression‐free survival (PFS) were better in patients with irAEs of grade 3 or higher than in patients with grade less than 3: 25% vs. 6% and 30 weeks vs. 10 weeks, respectively.6 Similar results were seen in a retrospective study from a Japanese institution, in which the efficacy and prognosis were better in the irAE group: ORR was 57% in the irAE group and 12% in the non‐irAE group, PFS was 12.0 months in the irAE group and 3.6 months in the non‐irAE group.7 Other retrospective studies of NSCLC patients who received nivolumab have also reported an association between irAEs and treatment outcome.8, 9 As described above, occurrence of irAEs was deemed to be useful as a predictive and prognostic factor for judging success of immunotherapy. An important clinical question is whether the benefit from ICI overcomes the low frequency of proceeding to subsequent therapies after discontinuation due to irAEs. Therefore, we evaluated detailed clinical courses after discontinuation of ICI due to irAEs, and compared efficacy and prognosis between the group of cases with treatment discontinued due to irAEs and those discontinued for other reasons. In addition, we were able to examine the risk of drug‐related interstitial lung disease (ILD) in patients with a history of ILD, which is cause for exclusion from many clinical trials.\n\nMethods\nPatients\nA total of 61 patients were studied who had NSCLC and received either nivolumab or pembrolizumab at Saga University Medical School Hospital between December 2015 and January 2018. The AE group (AEg) was defined as those whose treatment administration was discontinued due to irAEs, and the non‐AE group (Non‐AEg) was defined as those whose administration was discontinued for all other reasons. We retrospectively examined the efficacy, prognosis, and safety of anti‐programmed death‐1 (PD‐1) antibody therapy. The cutoff for data collection was 30 June 2018. The study protocol was approved by the Saga University Clinical Research Ethics Committee. All patients gave informed consent for the research use of tissue and cytology specimens.\n\nOutcome assessment\nExpression of programmed death‐ligand 1 (PD‐L1) was examined by immunohistochemical staining by using PD‐L1 IHC 22C3 pharmDx. Tumor response was evaluated according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. The severity of irAEs was graded on the basis of the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.\n\nStatistical analysis\nFor testing the difference of clinical background between the AEg and the Non‐AEg, a Chi‐square test or Mann‐Whitney U test was used. The survival rate was calculated according to the Kaplan‐Meier method and the log‐rank test was used for assessing differences. Cox proportional hazards regression analysis, with adjustment for the potentially confounding variables age, smoking index, gender, histology, and the Eastern Cooperative Oncology Group performance status (ECOG PS), was used to calculate the hazard rate (HR) and 95% confidence intervals (CI). P‐values less than 0.05 were regarded as statistically significant. Statistical analyses were conducted using SPSS statistics 19 software (SPSS Japan Inc. Tokyo) and JMP Pro 13 software (SAS Institute Inc., USA).\n\nResults\nPatient characteristics\nAmong the 61 patients undergoing anti‐PD‐1 antibody therapy, 40 were treated with nivolumab and 21 with pembrolizumab (Table 1). Median age at start of treatment was 70 years in the nivolumab group and 69 years in the pembrolizumab group. Most patients were men (89%), were smokers with smoking index greater than 400 (87%), had nonsquamous cell carcinoma (64%), and had ECOG PS 0–1 (82%). Among 52 patients with whom we were able to perform expression analysis of PD‐L1, 23 (44%) were found to express at level 50% or more, 17 (33%) were at levels 1–49%, and 12 (23%) were at levels less than 1%. There were six patients (15%) in the nivolumab group and 6 (29%) in the pembrolizumab group with preexisting ILD.\n\nTable 1 Clinicopathological characteristics of the patients\n\n\tNivolumab (n = 40)\tPembrolizumab (n = 21)\t\nMedian age, years (range)\t70 (44–81)\t69 (48–82)\t\nSex\t\t\t\nMale / Female\t34/6\t20/1\t\nBrinkman index\t\t\t\n≧400/<400\t35/5\t18/3\t\nHistology\t\t\t\nSquamous/Nonsquamous\t16/24\t6/15\t\nStage\t\t\t\nup to III/IV/recurrence\t11/20/9\t7/10/4\t\nECOG PS\t\t\t\n0 / 1 / 2+\t14/18/8\t7/11/3\t\nPD‐L1 expression (%)\t\t\t\n0 / 1–49/50 + / n.d.\t12/14/5/9\t0/3/18/0\t\nTreatment line\t\t\t\n1/2+\t0/40\t14/7\t\nPreexisting IIP or radiation pneumonitis\t\t\t\nY/N\t6/34\t6/15\t\nECOG, Eastern Cooperative Oncology Group; IIP, idiopathic interstitial pneumonia; n.d., not determined; PD‐L1, programmed death‐ligand 1; PS, performance status;\n\nTreatment efficacy and discontinuation rate\nThe therapeutic response rate was 22.5% in the 40 patients who received nivolumab and 42.9% in the 14 patients who received pembrolizumab in the first line therapy, and the disease control rates were 60.0% and 71.5%, respectively (Table 2). Discontinuation due to treatment‐related irAEs occurred in 22.5% of the nivolumab group versus 42.9% of the pembrolizumab group, but the difference was not statistically significant. In the group treated with nivolumab, there were two occurrences of ILD, two of colitis/diarrhea, and one each of ILD/myalgia, fever/malaise/anorexia, diverticulitis, tuberculosis, and skin disorder. In the group treated with pembrolizumab, there were four occurrences of ILD and one each of hemoptysis/hematemesis, ILD/atelectasis, isolated ACTH deficiency, rash/fever/diarrhea/hyperthyroidism, and hypothyroidism. The prevalence of irAEs was 32.4% in the Non‐AEg. The majority of ICI discontinuation in the Non‐AEg was due to disease progression (83.8%); the other reason was general deterioration of physical condition.\n\nTable 2 Response and discontinuation rate by cause\n\n\t\tPembrolizumab (n = 21)\t\t\n\tNivolumab (n = 40)\t1st line (n = 14)\tSecond and subsequent line (n = 7)\t\nP‐value\t\nBest overall response\t\t\t\t\t\nComplete response (CR)\t0 (0%)\t0 (0%)\t0 (0%)\t\t\nPartial response (PR)\t9 (22.5%)\t6 (42.9%)\t1 (14.3%)\t\t\nStable disease (SD)\t15 (37.5%)\t4 (28.6%)\t2 (28.6%)\t\t\nProgressive disease (PD)\t10 (25%)\t3 (21.4%)\t4 (57.1%)\t\t\nNot evaluable (NE)\t6 (15%)\t1 (7.1%)\t0 (0%)\t\t\nOverall response rate (ORR)\t9 (22.5%)\t6 (42.9%)\t1 (14.3%)\t\t\nDisease control rate (DCR)\t24 (60%)\t10 (71.5%)\t3 (42.9%)\t\t\nDiscontinuation due to irAEs\t9 (22.5%)\t9 (42.9%)\t0.140*\n\t\nDiscontinuation due to non‐irAEs\t27 (67.5%)\t10 (47.6%)\t0.171*\n\t\n* Fisher's exact test.\n\nirAE, immune‐related adverse event.\n\nClinical course of irAEs discontinuation group and prognostic analysis\nBetween the AEg and on‐AEg groups, there was no significant difference in age, sex, smoking index, histology, ECOG PS, or treatment duration (Table 3). PD‐L1 expression was slightly higher in the AEg, but the difference was not statistically significant. The response rate in the AEg (50.0%) was higher than that in the Non‐AEg (8.1%; P = 0.001). Similarly, the disease control rate was significantly higher in the AEg (94.4% vs. 37.8%; P < 0.001). The clinical course from the start of administration of anti‐PD‐1 antibody in each case of the AEg is shown in Figure 1. The irAEs and their severity leading to treatment discontinuation are shown in Table S1. Four patients had sustained therapeutic benefit for more than six months after discontinuation due to irAEs (patients N25, N35, P3, and P5). In addition, even if disease progression occurred after discontinuation due to irAEs, follow‐up was possible for more than four months without treatment in five cases (patients N15, N28, N5, N2, and P16). The median period from discontinuation to progression was 117 days (range, 1 to 309).\n\nTable 3 Comparison of clinical background between the AEg and the on‐AEg\n\n\tAEg (n = 18)\tNon‐AEg (n = 37)\t\nP‐value\t\nMedian age (range)\t69 (45–79)\t71 (48–82)\t0.524\t\nSex\t\t\t\t\nMale\t17\t31\t0.406\t\nFemale\t1\t6\t\nBrinkman index, median (range)\t1010 (62–2400)\t1000 (0–2400)\t0.836\t\nHistology\t\t\t\t\nSquamous\t5\t15\t0.391\t\nNonsquamous\t13\t22\t\nECOG PS\t\t\t\t\n0 or 1\t16\t29\t0.470\t\n2\t2\t8\t\nPD‐L1(%)†, median (range)\t65 (0–100)\t20 (0–100)\t0.175\t\nBest overall response\t\t\t\t\nCR/PR (ORR %)\t9 (50.0%)\t3 (8.1%)\t0.001\t\nSD/PD/NE\t9\t34\t\t\nCR/PR/SD (DCR %)\t17 (94.4%)\t14 (37.8%)\t<0.001\t\nPD/NE\t1\t23\t\t\nTreatment duration (days), median (range)\t98 (14–263)\t46 (0–384)\t0.798*\n\t\n* Log‐rank test.\n\n† Evaluable cases only.\n\nCR, complete response; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; NE, not evaluable; ORR, overall response rate; PD‐L1, programmed death‐ligand 1; PD, progressive disease; PR, partial response; PS, performance status; SD, stable disease; Sq.\n\nFigure 1 Clinical course of patients who had therapy discontinued due to irAEs. N represents nivolumab administration; P represents pembrolizumab administration. After discontinuation of ICIs, only two patients were given subsequent treatment.\n\nPFS and overall survival (OS) were analyzed in 43 patients (11 patients in the AEg and 32 in the Non‐AEg) after exclusion of 12 patients who received anti‐PD‐1 antibody in the first line therapy. The median PFS was 9.3 months (95% confidence interval [CI], 2.1 to 12.1) in the AEg and 1.9 months (95% CI, 0.9 to 3.6) in the Non‐AEg: HR, 0.45; 95% CI, 0.20 to 0.89; P = 0.026 (Fig 2(a)). The median OS was not reached in the AEg (lower 95% confidence bound 8.7 months) and was significantly longer than that in the Non‐AEg (8.7 months; 95% CI, 2.4 to 11.3): HR, 0.33; 95% CI, 0.10 to 0.86; P = 0.031 (Fig 2(b)). With multivariable analysis (Table 4), discontinuation due to irAEs was revealed to be a potential prognostic factor for PFS (HR, 0.41; 95% CI, 0.18 to 0.85; P = 0.016) despite adjustment for the other factors.\n\nFigure 2 Kaplan‐Meier curves of progression‐free survival (a) and overall survival (b) in patients in whom ICI was administered as a treatment after the second line therapy.\n\nTable 4 Multivariable Cox regression analysis of the hazard of disease progression\n\nCharacteristics\tHazard ratio (95% CI)\t\nP‐value\t\nAge (≧75 years vs. <75 years)\t0.89 (0.42–1.79)\t0.758\t\nBrinkman index (≧400 vs. <400)\t0.96 (0.32–3.27)\t0.940\t\nSex (male vs. female)\t1.16 (0.32–4.67)\t0.827\t\nHistology (squamous vs. nonsquamous)\t0.65 (0.31–1.30)\t0.225\t\nECOG PS (0/1 vs. 2/3)\t0.77 (0.28–2.38)\t0.631\t\nReason for ICI discontinuation (irAEs vs. non‐irAEs)\t0.41 (0.18–0.85)\t0.016\t\nCI, confidence intervals; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; irAEs, immune‐related adverse events; PS, performance status.\n\nThe period from discontinuation to the time either the next therapy was begun or a decision was made to begin best supportive care was analyzed in those patients. The median period was 5.2 months (95% CI, 4.4 to 5.9) in the AEg and 0.5 months (95% CI, 0.44 to 0.56) in the Non‐AEg: HR, 0.09; 95% CI, 0.02 to 0.27; P < 0.001 (Fig. S1). With multivariable analysis (Table S2), discontinuation due to irAE was revealed to be a potential predictive factor for the period from treatment discontinuation to the next therapy or decision for best supportive care.\n\nHistory of interstitial lung disease is associated with drug‐related ILD\nThere were five cases of idiopathic interstitial pneumonia and seven cases of radiation pneumonitis (12 cases in total) among the 61 patients with a history of ILD. None of the patients was undergoing systemic steroid therapy for preexisting ILD before the start of anti‐PD‐1 antibody therapy. In the nivolumab group, the prevalence of drug‐related ILD in patients without preexisting ILD was 6%, whereas in the patients with preexisting ILD, the prevalence was 17% (Fig 3), but the difference was not statistically significant. In the pembrolizumab group, the prevalence of drug‐related ILD was significantly higher in patients with preexisting ILD than in patients without preexisting ILD: 83% vs. 7%, respectively (P = 0.002). Even among all patients, the prevalence of drug‐related ILD was significantly higher in those with preexisting ILD (50%) than in those without (6%; P = 0.001). Table 5 shows the clinical features of nine patients who developed drug‐related ILD. Seven of them had events of grade 2 or less, and drug‐related ILD rapidly improved with drug withdrawal or oral corticosteroids. Patient P15, with a history of interstitial pneumonia of usual interstitial pneumonia (UIP) pattern, died of respiratory failure without responding to treatment, despite steroid pulse therapy. The response rate of the nine patients who developed ILD was 56%. There were no patients who received ICI rechallenge after the onset of drug‐related ILD.\n\nFigure 3 Prevalence of drug‐induced interstitial lung disease (ILD). Prevalence of drug‐induced ILD is significantly higher in patients with preexisting ILD.\n\nTable 5 Clinical features of patients who developed immune‐related interstitial lung disease (ILD)\n\nPt\tLine\tPeriod until onset (days)\tGrade\tResponse\tPreexisting interstitial lung disease\tRadiological pattern or finding in chest CT\tTreatment (treatment period with corticosteroid, days)\tOutcome\t\nN5\t2\t118\t2\tSD\tNone\tFocal GGO\tOral corticosteroid (139)\tImproved\t\nN15\t4\t259\t1\tPR\tIIP\tOP\tOral corticosteroid (88)\tImproved\t\nN28\t2\t247\t3\tPR\tNone\tOP, fibrosis\tSteroid pulse, NPPV (213)\tNo change\t\nP3\t1\t166\t1\tPR\tRadiation pneumonitis\tFocal GGO\tDrug discontinuation\tImproved\t\nP5\t1\t38\t1\tPR\tIIP\tFocal GGO\tOral corticosteroid (82)\tImproved\t\nP8\t1\t46\t2\tPR\tIIP\tOP\tOral corticosteroid (75)\tImproved\t\nP11\t2\t144\t2\tPD\tRadiation pneumonitis\tOP\tOral corticosteroid (86)\tImproved\t\nP15\t1\t14\t5\tPD\tIIP\tBilateral diffuse GGO\tSteroid pulse (76)\tDeath\t\nP16\t1\t64\t2\tSD\tNone\tOP\tOral corticosteroid (95)\tImproved\t\nCT, computed tomography; GGO, ground‐glass opacity; IIP, idiopathic interstitial pneumonia; N, nivolumab‐treated; NPPV, noninvasive positive pressure ventilation; OP, organizing pneumonia pattern; P, pembrolizumab‐treated; PD, progressive disease; PR, partial response‐; SD, stable disease.\n\nDiscussion\nWe conclude that the patients who developed irAEs leading to discontinuation (AEg) had significantly better outcomes, such as ORR, PFS, and OS, than the patients with discontinuation due to other causes (Non‐AEg), and discontinuation due to irAEs was an independent prognostic factor in that it was associated with prognosis despite adjustment for other factors. Half of the patients who were discontinued due to irAEs showed prolonged progression‐free status or slow progression without further treatment. No patients in the AEg received retreatment by ICI before the cutoff for data collection. Considering retreatment by ICI, it has been reported that benefit may occur in patients who have ICI discontinued due to irAEs before tumor response has been achieved.10\n\n\nILD was most frequently observed among patients with irAEs. With other studies of irAEs, an association between drug‐induced ILD and treatment outcome has been reported.11, 12, 13 In our study, five out of nine patients (56%) who developed drug‐induced ILD had PR, and a high response rate was confirmed. However, association of the computed tomography findings of ILD with efficacy and prognosis has not been clarified. Although ICIs have been applied to treat various malignant tumors, frequency of ILD was higher in patients with lung cancer than in patients with other tumors. A review of clinical trials of patients who received ICI monotherapy reported that pneumonitis occurs more frequently in patients with lung cancer than in patients with malignant melanoma (HR2.3, 95% CI, 1.4 to 3.8), so it is speculated that irAEs are organ specific.14 These data suggest that irAEs affecting the patient's general condition and leading to discontinuation also lead to a strong immune response, which is considered to be related to the therapeutic effect.\n\nPatients with a history of ILD have been excluded from many clinical trials because of a greater risk of drug‐induced ILD. However, patients with preexisting ILD are often encountered in practice, because an appropriate population for treatment with ICIs—such as smokers—contains many patients with preexisting ILD. Therefore, we examined the risk of drug‐induced ILD in patients with preexisting ILD. Our results indicate that the prevalence of drug‐induced ILD is significantly higher among patients with preexisting ILD than among those without ILD, which is similar to the results of Japanese phase II trials.15 According to Kanai et al., the prevalence of drug‐induced ILD with nivolumab is high (31%) in patients with preexisting ILD, but over 50% of patients improve during the course of therapy.13 Also, in a study of nivolumab in patients with radiation pneumonitis, drug‐induced ILD occurred in 26.5% of patients.16 On the other hand, it has been reported that there is no onset of drug‐induced ILD in patients with mild IIP.11 In our study, drug‐induced ILD was seen, even in patients with relatively mild IIP, so care should be taken in the administration of ICIs to such patients. Even though ILD frequently occurred with ICIs among patients with preexisting ILD in our study, all except one of those patients recovered after treatment with corticosteroid (the exception was a patient who died of ILD so that efficacy of ICI could not be observed). Evaluating the image pattern of ILD is therefore important for estimating the therapeutic reactivity to corticosteroid and prognosis.17 Although ILD exhibiting the organizing pneumonia pattern generally responds well to corticosteroid and has a good prognosis, ILD with the diffuse alveolar damage pattern is often accompanied by a poor prognosis.15, 18 Immunological molecular mechanisms are therefore expected to differ among seemingly similar immune‐related adverse events.\n\nIn this study, the prevalence of drug‐induced ILD in first line therapy was higher than that after second line therapy (36% vs. 9%). In a systematic review and meta‐analysis of trials on the incidence of ILD with anti‐PD‐1 antibody and anti‐PD‐L1 antibody, it was reported that treatment‐naïve patients had a significantly higher prevalence of ILD than previously treated patients (4.3% vs. 2.8%, P = 0.03).19 Thus, using ICI in first line therapy for patients with preexisting ILD may result in a high rate of drug‐induced ILD occurrence, so caution should be exercised.\n\nCurrently, PD‐L1 expression is the only predictive marker available in the clinical setting. Regardless of PD‐L1 expression, CheckMate 227, an international phase III trial of nivolumab and ipilimumab, showed benefits of immunotherapy in patients with NSCLC who had a high tumor mutation burden.20 Therefore, it was suggested that we could not select patients effectively by using only PD‐L1 expression. Our study showed that irAEs could be correlated with ICI efficacy and thus could predict outcome. Because ours was a single center retrospective study, the number of patients was not sufficient and discontinuation due to treatment‐related AEs and administration of ICIs to patients with a history of ILD were determined case‐by‐case by a number of different doctors. It is therefore necessary to confirm the association between irAEs and the effect of ICIs in a standardized setting. It has recently been reported that soluble PD‐1 and PD‐L1, and neutrophil‐to‐lymphocyte ratio, are useful as predictive or prognostic markers.21, 22, 23, 24 The combination of these clinical features, including irAEs with PD‐L1 expression, might lead to more precise prediction of ICI efficacy.\n\nIn summary, irAEs are one of the primary causes of discontinuation of ICIs. In our study, the efficacy of ICIs and the prognosis were significantly better in patients with discontinuation due to irAEs than in patients with discontinuation due to other reasons, which suggests that discontinuation due to irAEs might be useful as a prognostic factor. In addition, history of ILD is associated with drug‐induced ILD, so adequate risk assessment is indispensable, especially when considering administration of ICIs in first line therapy.\n\nDisclosure\nThe authors report no conflict of interest in this work.\n\nSupporting information\n\nSupplementary table 1. Severity of immune‐related adverse events (irAEs) leading to treatment discontinuation\n\n\nSupplementary table 2. Multivariable analysis of period from discontinuation to either next therapy or decision for best supportive care\n\nClick here for additional data file.\n\n \nSupplementary figure 1. Kaplan‐Meier curves of period from discontinuation to the next therapy or decision for best supportive care in whom ICI was administered as a treatment after the second line therapy.\n\nClick here for additional data file.\n\n Acknowledgment\nWe express heartfelt thanks to Dr. Haruki Hirakawa, who provided helpful comments and suggestions.\n==== Refs\nReferences\n1 \n\nBrahmer \nJ \n, \nReckamp \nKL \n, \nBaas \nP \n\net al\nNivolumab versus docetaxel in advanced squamous‐cell non‐small‐cell lung cancer . N Engl J Med \n2015 ; 373 : 123 –35 .26028407 \n2 \n\nBorghaei \nH \n, \nPaz‐Ares \nL \n, \nHorn \nL \n\net al\nNivolumab versus docetaxel in advanced nonsquamous non‐small‐cell lung cancer . N Engl J Med \n2015 ; 373 : 1627 –39 .26412456 \n3 \n\nReck \nM \n, \nRodriguez‐Abreu \nD \n, \nRobinson \nAG \n\net al\nPembrolizumab versus chemotherapy for PD‐L1‐positive non‐small‐cell lung cancer . N Engl J Med \n2016 ; 375 : 1823 –33 .27718847 \n4 \n\nHerbst \nRS \n, \nBaas \nP \n, \nKim \nDW \n\net al\nPembrolizumab versus docetaxel for previously treated, PD‐L1‐positive, advanced non‐small‐cell lung cancer (KEYNOTE‐010): A randomised controlled trial . Lancet \n2016 ; 387 : 1540 –50 .26712084 \n5 \n\nSchvartsman \nG \n, \nPeng \nSA \n, \nBis \nG \n\net al\nResponse rates to single‐agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non‐small cell lung cancer . Lung Cancer \n2017 ; 112 : 90 –5 .29191606 \n6 \n\nFujii \nT \n, \nColen \nRR \n, \nBilen \nMA \n\net al\nIncidence of immune‐related adverse events and its association with treatment outcomes: The MD Anderson Cancer Center experience . Invest New Drugs \n2018 ; 36 : 638 –46 .29159766 \n7 \n\nToi \nY \n, \nSugawara \nS \n, \nKawashima \nY \n\net al\nAssociation of Immune‐Related Adverse Events with clinical benefit in patients with advanced non‐small‐cell lung cancer treated with nivolumab . Oncologist \n2018 ; 23 : 1358 –65 .29934411 \n8 \n\nSato \nK \n, \nAkamatsu \nH \n, \nMurakami \nE \n\net al\nCorrelation between immune‐related adverse events and efficacy in non‐small cell lung cancer treated with nivolumab . Lung Cancer \n2018 ; 115 : 71 –4 .29290265 \n9 \n\nHaratani \nK \n, \nHayashi \nH \n, \nChiba \nY \n\net al\nAssociation of Immune‐Related Adverse Events with nivolumab efficacy in non‐small‐cell lung cancer . JAMA Oncol \n2018 ; 4 : 374 –8 .28975219 \n10 \n\nSantini \nFC \n, \nRizvi \nH \n, \nPlodkowski \nAJ \n\net al\nSafety and efficacy of re‐treating with immunotherapy after immune‐related adverse events in patients with NSCLC . Cancer Immunol Res \n2018 ; 6 : 1093 –9 .29991499 \n11 \n\nFujimoto \nD \n, \nYoshioka \nH \n, \nKataoka \nY \n\net al\nEfficacy and safety of nivolumab in previously treated patients with non‐small cell lung cancer: A multicenter retrospective cohort study . Lung Cancer \n2018 ; 119 : 14 –20 .29656747 \n12 \n\nFujimoto \nD \n, \nMorimoto \nT \n, \nIto \nJ \n\net al\nA pilot trial of nivolumab treatment for advanced non‐small cell lung cancer patients with mild idiopathic interstitial pneumonia . Lung Cancer \n2017 ; 111 : 1 –5 .28838377 \n13 \n\nKanai \nO \n, \nKim \nYH \n, \nDemura \nY \n\net al\nEfficacy and safety of nivolumab in non‐small cell lung cancer with preexisting interstitial lung disease . Thorac Med \n2018 ; 9 : 847 –55 .\n14 \n\nKhoja \nL \n, \nDay \nD \n, \nWei‐Wu Chen \nT \n, \nSiu \nLL \n, \nHansen \nAR \n. Tumour‐ and class‐specific patterns of immune‐related adverse events of immune checkpoint inhibitors: A systematic review . Ann Oncol \n2017 ; 28 : 2377 –85 .28945858 \n15 \n\nKato \nT \n, \nMasuda \nN \n, \nNakanishi \nY \n\net al\nNivolumab‐induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non‐small‐cell lung cancer . Lung Cancer \n2017 ; 104 : 111 –8 .28212992 \n16 \n\nTamiya \nA \n, \nTamiya \nM \n, \nNakahama \nK \n\net al\nCorrelation of radiation pneumonitis history before Nivolumab with onset of interstitial lung disease and progression‐free survival of patients with pre‐treated advanced non‐small cell lung cancer . Anticancer Res \n2017 ; 37 : 5199 –205 .28870955 \n17 \n\nRossi \nSE \n, \nErasmus \nJJ \n, \nMcAdams \nHP \n, \nSporn \nTA \n, \nGoodman \nPC \n. Pulmonary drug toxicity: Radiologic and pathologic manifestations . Radiographics \n2000 ; 20 : 1245 –59 .10992015 \n18 \n\nInoue \nA \n, \nSaijo \nY \n, \nMaemondo \nM \n\net al\nSevere acute interstitial pneumonia and gefitinib . Lancet \n2003 ; 361 : 137 –9 .12531582 \n19 \n\nKhunger \nM \n, \nRakshit \nS \n, \nPasupuleti \nV \n\net al\nIncidence of pneumonitis with use of programmed death 1 and programmed death‐ligand 1 inhibitors in non‐small cell lung cancer: A systematic review and meta‐analysis of trials . Chest \n2017 ; 152 : 271 –81 .28499515 \n20 \n\nHellmann \nMD \n, \nCiuleanu \nTE \n, \nPluzanski \nA \n\net al\nNivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden . New Engl J Med \n2018 ; 378 : 2093 –104 .29658845 \n21 \n\nZhu \nX \n, \nLang \nJ \n. Soluble PD‐1 and PD‐L1: Predictive and prognostic significance in cancer . Oncotarget \n2017 ; 8 : 97671 –82 .29228642 \n22 \n\nDiem \nS \n, \nSchmid \nS \n, \nKrapf \nM \n\net al\nNeutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) as prognostic markers in patients with non‐small cell lung cancer (NSCLC) treated with nivolumab . Lung Cancer \n2017 ; 111 : 176 –81 .28838390 \n23 \n\nSuh \nKJ \n, \nKim \nSH \n, \nKim \nYJ \n\net al\nPost‐treatment neutrophil‐to‐lymphocyte ratio at week 6 is prognostic in patients with advanced non‐small cell lung cancers treated with anti‐PD‐1 antibody . Cancer Immunol Immunother \n2018 ; 67 : 459 –70 .29204702 \n24 \n\nFukui \nT \n, \nOkuma \nY \n, \nNakahara \nY \n\net al\nActivity of nivolumab and utility of neutrophil‐to‐lymphocyte ratio as a predictive biomarker for advanced non‐small‐cell lung cancer: A prospective observational study . Clin Lung Cancer \n2019 ; 20 : 208 –14 . 10.1016/j.cllc.2018.04.021 .29803573\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1759-7706",
"issue": "10(9)",
"journal": "Thoracic cancer",
"keywords": "Immune checkpoint inhibitor; immune-related adverse event; interstitial lung disease; non-small cell lung cancer; predictive factor",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D028761:Withholding Treatment",
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "1798-1804",
"pmc": null,
"pmid": "31328416",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": "10992015;12531582;26028407;26412456;26712084;27718847;28212992;28499515;28838377;28838390;28870955;28945858;28975219;29159766;29191606;29204702;29228642;29290265;29656747;29658845;29782069;29803573;29934411;29991499",
"title": "Discontinuation due to immune-related adverse events is a possible predictive factor for immune checkpoint inhibitors in patients with non-small cell lung cancer.",
"title_normalized": "discontinuation due to immune related adverse events is a possible predictive factor for immune checkpoint inhibitors in patients with non small cell lung cancer"
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"abstract": "OBJECTIVE\nFixed drug eruption (FDE) is characterized by a well-defined erythematous patch, plaque, or bullous eruption that recurs at the same site as the result of systemic exposure to a causative drug, and resolves with or without hyperpigmentation. This study was carried out to identify the common causative drugs and clinical features of FDE in Korea.\n\n\nMETHODS\nWe reviewed electronic medical records of all patients diagnosed with FDE from January 2000 to December 2010 at a tertiary hospital in Korea.\n\n\nRESULTS\nA total of 134 cases were diagnosed as FDE. The mean age was 35.9 years (range, 0-82 years) and 69 (51.5%) of the patients were male. The mean duration from the first event to attending hospital was 1.9 years (range, 1-20 years). The mean number of recurrences was 2.6 (1-10), and 72.6% of patients sought medical care after experiencing symptoms twice or more. Four patients (3.1%) needed hospitalization. The most common sites were the upper extremities (47.7%), followed by the lower extremities, face, abdomen, chest, buttocks and perineum. Clear documentation on the causative drugs was available for 38 patients (28.4%), and among these, non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen accounted for 71.1% of cases, and antibiotics accounted for 15.8%. Eighty patients (59.7%) underwent active treatment for FDE, and topical steroids were most frequently prescribed (43.3%), with systemic steroids used in 11.2% of patients.\n\n\nCONCLUSIONS\nNSAIDs and acetaminophen were the main causative agents of FDE, however, the causative agents were not assessed in 25% of patients.",
"affiliations": "Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea. ; Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea. ; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea. ; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea. ; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Jung|Jae-Woo|JW|;Cho|Sang-Heon|SH|;Kim|Kyu-Han|KH|;Min|Kyung-Up|KU|;Kang|Hye-Ryun|HR|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4168/aair.2014.6.5.415",
"fulltext": "\n==== Front\nAllergy Asthma Immunol ResAllergy Asthma Immunol ResAAIRAllergy, Asthma & Immunology Research2092-73552092-7363The Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease 10.4168/aair.2014.6.5.415Original ArticleClinical Features of Fixed Drug Eruption at a Tertiary Hospital in Korea Jung Jae-Woo 12Cho Sang-Heon 13Kim Kyu-Han 4Min Kyung-Up 13Kang Hye-Ryun 131 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.2 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea.3 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.4 Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.Correspondence to: Hye-Ryun Kang, MD, PhD, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. Tel: +82-2-2072-0820; Fax: +82-2-742-3291; helenmed@snu.ac.kr9 2014 26 3 2014 6 5 415 420 03 9 2013 08 10 2013 05 11 2013 Copyright © 2014 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease2014This 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.Purpose\nFixed drug eruption (FDE) is characterized by a well-defined erythematous patch, plaque, or bullous eruption that recurs at the same site as the result of systemic exposure to a causative drug, and resolves with or without hyperpigmentation. This study was carried out to identify the common causative drugs and clinical features of FDE in Korea.\n\nMethods\nWe reviewed electronic medical records of all patients diagnosed with FDE from January 2000 to December 2010 at a tertiary hospital in Korea.\n\nResults\nA total of 134 cases were diagnosed as FDE. The mean age was 35.9 years (range, 0-82 years) and 69 (51.5%) of the patients were male. The mean duration from the first event to attending hospital was 1.9 years (range, 1-20 years). The mean number of recurrences was 2.6 (1-10), and 72.6% of patients sought medical care after experiencing symptoms twice or more. Four patients (3.1%) needed hospitalization. The most common sites were the upper extremities (47.7%), followed by the lower extremities, face, abdomen, chest, buttocks and perineum. Clear documentation on the causative drugs was available for 38 patients (28.4%), and among these, non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen accounted for 71.1% of cases, and antibiotics accounted for 15.8%. Eighty patients (59.7%) underwent active treatment for FDE, and topical steroids were most frequently prescribed (43.3%), with systemic steroids used in 11.2% of patients.\n\nConclusions\nNSAIDs and acetaminophen were the main causative agents of FDE, however, the causative agents were not assessed in 25% of patients.\n\nFixed drug eruptionnon-steroidal anti-inflammatory drugMinistry of Food and Drug Safety\n==== Body\nINTRODUCTION\nDrug eruption refers to an unexpected cutaneous lesion that occurs after a specific drug is administered and is known to be the cause of ~2%-3% of dermatological problems.1 Maculopapular eruption is the most common type of drug eruption, but it is difficult for physicians to diagnose and differentiate between rashes related to infectious conditions. Although fixed drug eruption (FDE) is less common, its diagnosis is usually straightforward.\n\nFDE was first reported in 1889 by Bourns, when he described a lesion that repeatedly developed at the same limited sites after antipyrine was administered.2 In 1894 Brocq named this type of lesion an \"eruptio-erythemato-pigmentee fixe\".3 FDE is currently defined as a cutaneous adverse drug reaction in which a lesion recurs on the same site on the skin or mucous membrane, whenever the causative drug is re-administered. The skin lesion disappears when medication is discontinued, but it can sometimes result in permanent pigmentation.4,5,6 Because of its characteristic features, FDE can be diagnosed with relative ease compared to other drug eruptions.\n\nThe number of diagnosed FDE cases is increasing steadily, due in part to increased awareness by physicians as well as increased requests by patients to identify the precise cause of repeated eruptions and pigmentation.7 Recently, awareness of adverse drug reactions has increased, but no large-scale study has been carried out to provide objective information on the clinical aspects of FDE in Korea.\n\nThis study therefore aimed to analyze cases of FDE at a tertiary medical institution and to identify common causative drugs as well as the clinical patterns of FDE in Korea.\n\nMATERIALS AND METHODS\nSubjects\nPatients diagnosed with FDE at the Seoul National University Hospital between January 2000 and December 2010, were reviewed retrospectively as follows: A) data were obtained from the medical records of patients diagnosed with FDE, B) 2 allergy specialists validated the cases if they satisfied at least one of the following conditions; 1) lesion(s) of the same form occurring twice or more at the same site as a result of a re-administration of a causative drug; 2) confirmation by a challenge test; and 3) the typical morphological features compatible with FDE were alleviated by discontinuation of the causative drug, and the possibility of other diagnoses was low.4 Cases were excluded if biopsy findings suggested other diagnoses. The causal relationship was evaluated using the WHO-UMC causality assessment system and cases with 'certain' or 'probable' causality were included in the analysis.\n\nWe analyzed the age, gender, causative drugs, and morphological features of lesions, onset, treatment, and recurrence of symptoms.\n\nStatistical analysis\nStatistical analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were presented as means and standard deviations (range). Groups were compared by Fischer's exact test, a Chi-squared for trend, and a t-test. Statistical significance was accepted at P<0.05.\n\nRESULTS\nCharacteristics of the subjects\nA total of 184 patients were diagnosed with FDE between 2000 and 2010. Among them, 50 were excluded after clinical history reviews, leaving a total of 134 patients in the study (Table 1). 97 patients (72.6%) experienced recurrent FDE with a causative drug and 9 patients (6.7%) were diagnosed with FDE by a challenge test. Among the study subjects, 69 (51.5%) were male; the mean age was 35.9 years with a range of 0 to 82 years.\n\nThe mean duration from the onset of FDE to the first hospital visit was 1.9 years (0-20 years). Sixty-six patients (49.3%) had typical lesions compatible with FDE at admission, which improved with discontinuation of the causative drug. While typical bullous lesions of active FDE were found in 36.5% of the subjects, 68 (56.7%) had only remnant pigmentation when they saw the physician. Only 27.4% visited the hospital at the onset of lesion development, and 72.6% sought medical care after experiencing repeated symptoms. On average, patients visited the hospital after experiencing FDE 2.6 times.\n\nAlthough there were 2 cases of generalized bullous FDEs, there were no fatalities. One patient had recurrent skin reactions after administration of acetaminophen and another patient experienced a first episode of FDE after taking mefenamic acid. They were diagnosed with generalized bullous FDEs because of the temporal correlation with the drug, the well-demarcated erythematous macules and bullae on the trunk, face and extremities without other systemic symptoms, and the rapid recovery that left residual hyperpigmentation after discontinuation of causality drugs.\n\nMost of the subjects (97%) were treated for FDE in outpatient clinics. Among the 4 hospitalized patients, 2 were admitted for care of generalized bullous FDE and 1 for management of multiple bullous lesions in the mouth, hands and penis, accompanied by severe pain and fever. The fourth patient had skin exfoliation as well as typical bullous lesions of FDE and was admitted for close observation and to determine whether or not the symptoms were due to FDE or Stevens-Johnson syndrome (SJS).\n\nCharacteristics of FDE lesions\nAmong 52 patients with active lesion(s) during their visit to the hospital, bullous lesions were observed in 19 (36.5%). Skin biopsies were carried out in 17 patients (12.7%) to differentiate FDE from other diseases.\n\nThe most common site of FDE was the upper limbs (47.7%) followed by lower limbs (29.9%), face (24.6%), abdomen (17.6%), chest (17.2%), and back (16.4%). FDE lesions were not always localized, and in 41 patients (30.6%) they were widely distributed on the body (Fig. 1A). FDEs frequently developed as multiple lesions but a single solitary lesion was observed in 30.6% of FDE cases (Fig. 1B). Frequently involved sites differed slightly depending on the number of lesions. When FDE appeared at multiple sites, the upper limbs were affected most frequently, followed by the lower limbs, face, abdomen, and chest (Fig. 1C). When FDE developed as a single solitary lesion, the upper limbs were still affected (34.1%), but the lower limbs were less affected (4.9%) (Fig. 1C).\n\nFDE causative drugs\nIn most cases, the link between the causative drug and FDE was determined by a recurrence of symptoms through re-challenge with the drug. In 62 subjects (46.3%), the class or category of causative drug was described in their medical records: cold remedy (26), analgesics (12), antibiotics (10) and others (14). Accurate causative drugs were accessed only in 38 patients (28.4%). Non-steroidal anti-inflammatory drugs (NSAIDs) were the most common drugs (71.1%) causative to FDE. Acetaminophen was a single drug, which was most frequently implicated in FDE (23.7%) (Table 2). A further analysis of areas affected on the body revealed that FDE, resulting from chemotherapeutic agents, was found more frequently in the perineum compared to other drugs (66.7% vs 12.1%, P=0.015). However, the number of lesions was not related to the causative agents. A description of the causative agents was lacking in 34 cases (25.4%) (Fig. 2).\n\nIt was not possible to compare the severity of FDE with specific causative agents. However, most of the patients with NSAIDs-induced FDE (81.5%) sought doctors when they experienced repeated FDE, while patients with FDE induced by other drugs tended to visit the hospital when they experienced FDE for the first time (60%).\n\nTreatment of FDE\nAfter a diagnosis of FDE, 54 patients (40.3%) did not receive any treatment, and 58 patients (43.3%) used a topical steroid (Fig. 3). A local treatment other than topical steroid was prescribed for 26 patients (19.4%) and antihistamines were prescribed for 19 patients (14.2%). A systemic steroid equivalent to prednisolone (26.0±19.2 mg) was prescribed for 15 patients (11.2%) for an average of 11.5±9.7 days. Patients with acute lesions were prescribed systemic steroids in 23.1% cases. Systemic steroid use was not related to any causative drugs or to a multiplicity of FDE lesions.\n\nDISCUSSION\nFDEs develop as round, or oval erythematous plaques with discrete margins, in single or multiple lesions, and can occur as bullae in severe cases. With repeated FDE occurrences, the number and size of lesions tends to increase and they become darker in color. FDE usually develops at 0.5-8 hours after administration of a causative drug, with a mean onset time of 2 hours.4 The FDE lesions usually disappear ~3 weeks after discontinuation of the causative medication, but sometimes cause skin pigmentation.4 In this study, over half of the patients exhibited pigmentation only at their first hospital visit, and this was ~2 years after their initial FDE symptoms.\n\nAcute FDE lesions mainly appear as erythematous or colored spots, with blisters or bullous lesions developing in some instances. Occasionally they appear in the form of erosion or necrosis around an ulcer, and this is frequently observed in perineal lesions.8 In this study, ~43.3% of the patients had acute lesions during their hospital visit; 36.5% of these were bullous lesions. These findings are similar to the results of a previous study.9\n\nGeneralized bullous FDE is a relatively severe reaction that should be differentiated from SJS or toxic epidermal necrolysis (TEN). Generalized bullous FDE usually develops as multiple deep scarlet papules or bullous lesions with discrete margins that are distributed symmetrically on the entire body. The size or number of lesions can increase even after the withdrawal of the causative drugs. Generalized bullous FDE is known to be related to a severe reaction to repeated exposure to causative agents in patients who have already had FDE in the past.10 In this study, generalized bullous FDE was found in 1.5% of the total cases, and none were fatal. FDE (and generalized bullous FDE) seems to be a relatively mild drug eruption in contrast to other bullous drug eruptions, such as SJS or TEN; this finding is consistent with previous studies.10\n\nFDE can develop on any part of the skin or mucous membrane. The most common sites involved are the trunk, limbs, lips, palms, soles, penis, and groin.5 Sharma et al.11 reported that frequently involved sites varied according to the causative drug; tetracycline induced FDE in the mucocutaneous junction of the genital organs, metamizole sodium (analgin®) induced lesions on the trunk and limbs, and phenytoin sodium was significantly associated with generalized FDE. In our study, these associations were not observed; however, we did note that FDE related to chemotherapeutic agents occurred more frequently in the perineal area. As well as the distribution of lesions, some studies reported an association between multiplicity and specific drugs. Tetracycline, trimethoprim-sulfamethoxazole, and butazolidine were reported to be linked with single solitary lesions,11,12 and ibuprofen, trimethoprim-sulfamethoxazole, theophylline, and atenolol, were reported to be linked to multiple lesions.7 These correlations were not observed in this study.\n\nPreviously reported incidences of FDE varied from 2.5%-22% in patients with dermatological problems.4,13 Several factors are known to affect FDE incidences, including geographic location, availability and drug dosage, and the age of the patient.2 Therefore, FDE incidences and causative drug patterns can vary according to the survey area and over time. Antibiotics, antipsychotics, and NSAIDs are known to be major causes of FDE. In studies performed before 2000, the most common causative agent of FDE was trimethoprim-sulfamethoxazole.14,15,16 In the past, FDEs caused by NSAIDs and acetaminophen were known to be rare,18 but in reports after 2000, NSAIDs (16%-35%) were the second most common factor after antibiotics (39%-65%), and followed by anticonvulsant drugs (16%-30%).19,20,21 In Korea, FDE caused by NSAIDs was first reported in 1996,22 and other cases have since been reported.23,24 NSAIDs and acetaminophen were the most common cause of FDE in our study, probably because they can be purchased easily without prescription. In the 1980s, pyrazolone was the most frequently reported causative agent of FDE,25,26,27 and fepraxone in 1993.28 Recently, aspirin use in children has reduced, due to risks associated with inducing Reye's syndrome. In contrast, acetaminophen use has increased in adults and children because it is relatively safer with fewer gastrointestinal side-effects.25,26,27,28,29 In a recent French study on FDE, acetaminophen was the single most common causative drug for FDE.30 Similarly, acetaminophen was found to be the single most common causative drug in this study. Since cross reactions between NSAIDs and acetaminophen were reported in FDE occurrences, patients who have previously experienced FDE after taking these drugs should be careful when choosing analgesics.31\n\nAlthough clinical history is most important in diagnosing FDE, patch tests and drug challenge tests are also helpful and are used frequently for a more objective diagnostic approach. To decrease false negative responses from patch tests, the appropriate location and timing are both critical.32 Moreover, a false negative response can occur if patients are sensitized not only to the drug itself but also to its metabolites. An insufficient dose and inability of the drug to effectively infiltrate into the skin can also result in a false negative response.33 The most accurate diagnostic tool for FDE is a drug challenge test. The challenge test can be performed at varying doses, and usually starts with a very low dose that is increased gradually to a therapeutic dosage.4 A lymphocyte transformation test is a laboratory test approved for delayed drug hypersensitivities such as maculopapular eruption, drug hypersensitivity syndrome and SJS,34 but its usefulness in testing for FDE is still under investigation, even though some studies have reported positive results.18,35 These diagnostic tests are clinically important, not only for diagnosis, but also for identification of the causative drug(s).\n\nThe first step in treating FDE is identification and discontinuation of the causative drug. In many cases, discontinuation of the medication alone can improve symptoms, but antihistamines and topical steroids can be used for more immediate relief of symptoms. In the case of extensive or bullous lesions, administration of a systemic steroid is needed.7 However, it is not clear whether steroid treatment at the acute stage prevents pigmentation. In our study, almost 40.3% of patients were not prescribed any medication because more than half of them visited the hospital after their acute lesions had disappeared. Around 10% of the patients were prescribed a short-term systemic steroid, and most of these patients were at the acute stage with severe symptoms when they visited the hospital.\n\nThe most important method of preventing secondary occurrences of any adverse drug reaction is identification of the causative drug, followed by complete avoidance of repeated exposure to the causative drug. Particularly in skin allergies, repeated exposure increases the risk of recurrence, and in some cases evolves into a more severe form. Thus, it is very important to determine the specific causative drug.5,33 Moreover, a lack of information on the exact causative drug may increase the anxiety of patients about future medication, which, in turn, prevents them from obtaining adequate treatment. In our study, specific causative drugs were clearly recorded in 28.4% of the patients, whereas only the type of drug was described in more than half of the patients. Accordingly, most of the patients did not know the causative drug, and in future more effort should be made to evaluate causative agents for complete prevention of FDE.\n\nThis study was limited due to its retrospective cross-sectional nature; most diagnoses were made on the basis of typical clinical histories without confirmation by a drug challenge. Nevertheless, by examining the clinical characteristics, causative drugs, and treatment of FDE over a long period and in a large number of FDE patients in Korea, this study can serve as a reference point for clinical practice in the diagnosis and treatment of FDE.\n\nIn conclusions, FDE is a relatively common drug hypersensitivity, and over the past 11 years, 130 patients have been diagnosed with FDE at a tertiary medical institution in Korea. NSAIDs and acetaminophen were the most commonly causative drugs. Acetaminophen was the most common single causative agent of FDE in Korea. To prevent recurrence of FDE due to repeated exposure, more effort should be made to identify the causative drugs.\n\nACKNOWLEDGMENTS\nThis research was supported by a grant from Ministry of Food and Drug Safety to operation of the regional pharmacovigilance center in 2013.\n\nThere are no financial or other issues that might lead to conflict of interest.\n\nFig. 1 Involved sites of patients with fixed drug eruption. (A) Most commonly involved sites were the upper extremities, followed by the lower extremities, face, abdomen, chest, buttocks, and perineum. (B) FDE cases developed as multiple lesions in 59.4% and as solitary lesion in 30.6%. (C) Involved sites differed between patients with multiple lesions and those with a solitary lesion.\n\nFig. 2 Causative drugs of fixed drug eruption. Causative drugs were described in broad, ambiguous terms in 46.3% of the study subjects (A) and in specific, accurate terms in 28.4% of the study subjects (B). NSAIDs, Non-steroidal anti-inflammatory drugs.\n\nFig. 3 Treatment for fixed drug eruption. Topical steroids were prescribed most frequently for FDE, followed by other topical agents, oral antihistamines, and systemic steroids.\n\nTable 1 Demographics of patients with fixed drug eruption (n=134)\n\nTable 2 Causative agents of fixed drug eruption in 38 patients whose causative drugs were accurately described in the medical charts\n==== Refs\n1 Arndt KA Jick H Rates of cutaneous reactions to drugs. A report from the Boston Collaborative Drug Surveillance Program JAMA 1976 235 918 923 128641 \n2 Bourns DC Unusual effects of antipyrine Br Med J 1889 2 818 820 \n3 Brocq L Eruption erythémato-pigmentée fixé due à l'antipyrine Ann Dermatol Syphiligr (Paris) 1894 5 308 313 \n4 Sehgal VN Gangwani OP Fixed drug eruption. Current concepts Int J Dermatol 1987 26 67 74 2952612 \n5 Nigen S Knowles SR Shear NH Drug eruptions: approaching the diagnosis of drug-induced skin diseases J Drugs Dermatol 2003 2 278 299 12848112 \n6 Shelley WB Shelley ED Nonpigmenting fixed drug eruption as a distinctive reaction pattern: examples caused by sensitivity to pseudoephedrine hydrochloride and tetrahydrozoline J Am Acad Dermatol 1987 17 403 407 2958519 \n7 Lee AY Fixed drug eruptions. Incidence, recognition, and avoidance Am J Clin Dermatol 2000 1 277 285 11702319 \n8 Sehgal VN Srivastava G Fixed drug eruption (FDE): changing scenario of incriminating drugs Int J Dermatol 2006 45 897 908 16911371 \n9 Bandino JP Wohltmann WE Bray DW Hoover AZ Naproxen-induced generalized bullous fixed drug eruption Dermatol Online J 2009 15 4 19951640 \n10 Roujeau JC Clinical heterogeneity of drug hypersensitivity Toxicology 2005 209 123 129 15767024 \n11 Sharma VK Dhar S Gill AN Drug related involvement of specific sites in fixed eruptions: a statistical evaluation J Dermatol 1996 23 530 534 8854584 \n12 Nnoruka EN Ikeh VO Mbah AU Fixed drug eruption in Nigeria Int J Dermatol 2006 45 1062 1065 16961509 \n13 Browne SG Fixed eruption in deeply pigmented subjects: clinical observations on 350 patients Br Med J 1964 2 1041 1044 14191164 \n14 Sharma VK Dhar S Clinical pattern of cutaneous drug eruption among children and adolescents in north India Pediatr Dermatol 1995 12 178 183 7659648 \n15 Mahboob A Haroon TS Drugs causing fixed eruptions: a study of 450 cases Int J Dermatol 1998 37 833 838 9865869 \n16 Kanwar AJ Bharija SC Singh M Belhaj MS Ninety-eight fixed drug eruptions with provocation tests Dermatologica 1988 177 274 279 2977339 \n17 Alanko K Stubb S Kauppinen K Cutaneous drug reactions: clinical types and causative agents. A five-year survey of in-patients (1981-1985) Acta Derm Venereol 1989 69 223 226 2566225 \n18 Hayashi H Shimizu T Shimizu H Multiple fixed drug eruption caused by acetaminophen Clin Exp Dermatol 2003 28 455 456 12823320 \n19 Gupta R Drugs causing fixed drug eruptions: confirmed by provocation tests Indian J Dermatol Venereol Leprol 2003 69 120 121 17642852 \n20 Pudukadan D Thappa DM Adverse cutaneous drug reactions: clinical pattern and causative agents in a tertiary care center in South India Indian J Dermatol Venereol Leprol 2004 70 20 24 17642552 \n21 Patel RM Marfatia YS Clinical study of cutaneous drug eruptions in 200 patients Indian J Dermatol Venereol Leprol 2008 74 430 18810845 \n22 Nahm DH Suh CH Park HS A case of fixed drug eruption induced by mefenamic acid J Asthma Allergy Clin Immunol 1996 16 346 349 \n23 Min EJ Lim DH Kim JH Choi SW Son BK A case of fixed drug eruption due to acetaminophen J Korean Pediatr Soc 2000 43 1149 1152 \n24 Hong KB Jin YM Kang J Im IJ Roh EJ Son JS Chung EH A case of fixed drug eruption caused by acetaminophen in a child Pediatr Allergy Respir Dis 2007 17 314 319 \n25 Bigby M Stern R Cutaneous reactions to nonsteroidal anti-inflammatory drugs. A review J Am Acad Dermatol 1985 12 866 876 3159761 \n26 Bailin PL Matkaluk RM Cutaneous reactions to rheumatological drugs Clin Rheum Dis 1982 8 493 516 6216041 \n27 Pasricha JS Drugs causing fixed eruptions Br J Dermatol 1979 100 183 185 154920 \n28 Cutaneous reactions to analgesic-antipyretics and nonsteroidal anti-inflammatory drugs. Analysis of reports to the spontaneous reporting system of the Gruppo Italiano Studi Epidemiologici in Dermatologia Dermatology 1993 186 164 169 8453140 \n29 Sehgal VN Paracetamol-induced bilateral symmetric, multiple fixed drug eruption (MFDE) in a child Pediatr Dermatol 1999 16 165 166 10337690 \n30 Brahimi N Routier E Raison-Peyron N Tronquoy AF Pouget-Jasson C Amarger S Machet L Amsler E Claeys A Sassolas B Leroy D Grange A Dupuy A Cordel N Bonnetblanc JM Milpied B Doutre MS Guinnepain MT Barbaud A Chosidow O Roujeau JC Lebrun-Vignes B Descamps V A three-year-analysis of fixed drug eruptions in hospital settings in France Eur J Dermatol 2010 20 461 464 20507840 \n31 Kidon MI Kang LW Chin CW Hoon LS See Y Goh A Lin JT Chay OM Early presentation with angioedema and urticaria in cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs among young, Asian, atopic children Pediatrics 2005 116 e675 e680 16230465 \n32 Barbaud A Gonçalo M Bruynzeel D Bircher A European Society of Contact Dermatitis Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions Contact Dermatitis 2001 45 321 328 11846746 \n33 Shiohara T Fixed drug eruption: pathogenesis and diagnostic tests Curr Opin Allergy Clin Immunol 2009 9 316 321 19474709 \n34 Pichler WJ Tilch J The lymphocyte transformation test in the diagnosis of drug hypersensitivity Allergy 2004 59 809 820 15230812 \n35 Gimenez-Camarasa JM Garcia-Calderon P de Moragas JM Lymphocyte transformation test in fixed drug eruption N Engl J Med 1975 292 819 821 123037\n\n",
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"keywords": "Fixed drug eruption; non-steroidal anti-inflammatory drug",
"medline_ta": "Allergy Asthma Immunol Res",
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"title": "Clinical features of fixed drug eruption at a tertiary hospital in Korea.",
"title_normalized": "clinical features of fixed drug eruption at a tertiary hospital in korea"
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"abstract": "As COVID-19 (coronavirus disease 2019) spreads across the world multiple therapeutic interventions have been tried to reduce morbidity and mortality. We describe a case of collapsing focal sclerosing glomerulosclerosis (FSGS) and acute oxalate nephropathy in a patient treated with high-dose intravenous vitamin C for severe COVID-19 infection. Collapsing FSGS has been described in patients with COVID-19 infection associated with APOL-1; however, this case had collapsing FSGS developing in low-risk heterozygous APOL-1 variant, and we postulate that the intensity of the COVID-19 cytokine storm overwhelmed the protective state of APOL-1 heterozygosity. This case illustrates the importance of assessing the risk and benefit of planned therapeutic interventions on a case-by-case basis especially when there are still so many unknowns in the management of COVID-19 infection. Strong consideration should be given for performing a renal biopsy in patients who develop multifactorial acute kidney injury.",
"affiliations": "Eastern Virginia Medical School, Norfolk, VA, USA.;Eastern Virginia Medical School, Norfolk, VA, USA.;Sentara Norfolk General Hospital, Norfolk, VA, USA.;Eastern Virginia Medical School, Norfolk, VA, USA.",
"authors": "Malhotra|Varun|V|;Magoon|Sandeep|S|;Troyer|Dean A|DA|0000-0002-0337-5890;McCune|Thomas R|TR|",
"chemical_list": "D010070:Oxalates; D014815:Vitamins; D001205:Ascorbic Acid",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620963635\n10.1177_2324709620963635\nCase Report\nCollapsing Focal Segmental Glomerulosclerosis and Acute Oxalate\nNephropathy in a Patient With COVID-19: A Double Whammy\nMalhotra Varun MD1 Magoon Sandeep MD1 https://orcid.org/0000-0002-0337-5890Troyer Dean A. MD2 McCune Thomas R. MD1 1 Eastern Virginia Medical School,\nNorfolk, VA, USA\n2 Sentara Norfolk General Hospital,\nNorfolk, VA, USA\nVarun Malhotra, MD, Department of Internal\nMedicine, Division of Nephrology, Eastern Virginia Medical School, 301 Riverview\nAvenue, Suite 600, Norfolk, VA 23510, USA. Email:\ndocvarun@gmail.com\n5 10 2020 \nJan-Dec 2020 \n8 23247096209636359 8 2020 27 8 2020 4 9 2020 © 2020 American Federation for Medical\nResearch2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).As COVID-19 (coronavirus disease 2019) spreads across the world multiple\ntherapeutic interventions have been tried to reduce morbidity and mortality. We\ndescribe a case of collapsing focal sclerosing glomerulosclerosis (FSGS) and\nacute oxalate nephropathy in a patient treated with high-dose intravenous\nvitamin C for severe COVID-19 infection. Collapsing FSGS has been described in\npatients with COVID-19 infection associated with APOL-1; however, this case had\ncollapsing FSGS developing in low-risk heterozygous APOL-1 variant, and we\npostulate that the intensity of the COVID-19 cytokine storm overwhelmed the\nprotective state of APOL-1 heterozygosity. This case illustrates the importance\nof assessing the risk and benefit of planned therapeutic interventions on a\ncase-by-case basis especially when there are still so many unknowns in the\nmanagement of COVID-19 infection. Strong consideration should be given for\nperforming a renal biopsy in patients who develop multifactorial acute kidney\ninjury.\n\nCOVIDcollapsingglomerulopathyFSGSSARSAKIoxalatecover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nCOVID-19 (coronavirus 2019) has stormed across the globe without a thorough\nunderstanding of its pathogenesis or accepted therapeutic approaches. All around the\nworld multiple therapeutic interventions have been tried to mitigate the disease\nburden associated with COVID-19 infection. One of these treatment strategies\ninvolves high-dose vitamin C (ascorbic acid). This group and others have described\nthe development of collapsing focal sclerosing glomerulosclerosis (FSGS) in patients\nwith COVID-19 infection associated with APOL-1.1,2 We present a case of collapsing\nFSGS and acute oxalate nephropathy in a patient treated with high-dose intravenous\n(IV) vitamin C (ascorbic acid) for severe COVID-19 infection.\n\nCase Report\nA 64-year-old African American male with past medical history of hypertension,\ndiabetes mellitus, chronic kidney disease stage III (without proteinuria), and HIV\ncontrolled on HAART (highly active antiretroviral therapy) presented to the\nemergency department from a nursing home for shortness of breath and fever. There\nwas no past medical history of gastric bypass, bariatric surgery, small bowel\nresection, chronic pancreatitis, malabsorption syndromes, or prior history of\nvitamin C intake. His home medications included lantus, sitagliptin, metoprolol,\namlodipine, HAART regimen, and allopurinol. Initial temperature was 101.9 °F, pulse\nwas 76 beats per minute, respiratory rate was 26 breaths per minute, Blood Pressure\nwas 132/72 mm Hg, and O2 saturation was 96% on 4 L/m oxygen. See Table 1 for laboratory\nresults on presentation. He was started on broad-spectrum antibiotics and COVID-19\nRNA polymerase chain reaction was positive. Chest X-ray revealed airspace opacity in\nthe right upper lobe, peripheral right lower lobe, and left perihilar area. Computed\ntomography angiogram of the chest had no evidence of pulmonary embolism, but\nmultifocal bilateral diffuse ground glass opacities were seen. He had worsening\nrespiratory status and increasing oxygen needs and was eventually placed on\nnon-rebreather oxygen and transferred to the intensive care unit within 24 hours of\nadmission. He was treated with IV solumedrol, zinc, and vitamin C 3 g every 6 hours\nfrom hospital admission day 2 through 9 (total vitamin C dose 84 g). Initial urine\nstudies had new proteinuria and hematuria (Table 1). He had acute kidney injury (AKI)\nwith worsening azotemia, oliguria, and renal ultrasound of kidneys was unremarkable.\nOn day 3, he was initiated on continuous renal replacement therapy (CRRT) due to\nanuric AKI with metabolic acidosis. CRRT with Oxiris filter (Baxter International\nOrixis filter, emergency use authorization by the Food and Drug Association to\nreduce pro-inflammatory cytokine levels in patients with confirmed COVID-19\ninfection) was used for 2 days and then CRRT with standard filter was continued for\nanother 4 days. Worsening respiratory status on the fourth day required intubation\nand mechanical ventilation. He was switched to intermittent hemodialysis on hospital\nadmission day 9. On day 11, he had a renal biopsy due to AKI with proteinuria and\nhematuria.\n\nTable 1. Laboratory Results on Presentation.\n\n\tReference\tOn admission\t\nHemoglobin, g/dL\t12.0-16.0\t11.4\t\nWBC count, K/µL\t4.6-13.2\t7.5\t\nSerum sodium, mmol/L\t136-145\t143\t\nPotassium, mmol/L\t3.5-5.5\t3.9\t\nBUN, mg/dL\t7.0-18\t32\t\nCreatinine, mg/dL\t0.6-1.3\t2.3\t\neGFR, mL/min\t>60\t34\t\nUrinalysis protein\tNegative\t500\t\nUrinalysis blood\tNegative\tModerate\t\nUrine RBC\t0-2/hpf\t20-50\t\nUrine WBC\t0-2/hpf\t5-10\t\nUrinalysis leucocyte esterase\tNegative\tNegative\t\nUrine microscopy\t\t20-50 RBCs, but none were dysmorphic\t\nUrine protein: creatinine ratio\t<0.2\t2.74\t\nHbA1c\t4.8-5.6\t5.7\t\nCD4 count\t404-1308\t291\t\nHIV RNA\t<20 copies\tTarget not detected\t\nAbbreviations: WBC, white blood cell; BUN, blood urea nitrogen; eGFR,\nestimated glomerular filtration rate; RBC, red blood cell; hpf,\nhigh-power field; HbA1c, hemoglobin A1c; HIV RNA, human immunodeficiency\nvirus ribonucleic acid.\n\nRenal biopsy had 6 glomeruli available, 3 were globally sclerosed and 1 of the\nremaining glomeruli showed epithelial hyperplasia, foam cells, and compression of\nglomerular capillaries (Figure\n1A). The remaining glomeruli showed mesangial expansion. There was\nflattening of tubular epithelial cells with debris and cells within tubular lumena\n(Figure 1B). Occasional\ntubules showed neutrophils infiltrating among tubular epithelial cells (Figure 1C). These findings\nsupport the diagnosis of collapsing glomerulopathy.3 There was widely distributed polarizable material within tubular lumens\n(Figure 1D). There was\ninterstitial fibrosis and tubular atrophy involving 25% to 30% of the tissue.\nElectron microscopy was negative for electron dense deposits and there was 80%\neffacement of epithelial cell foot processes. Basement membranes were of normal\nthickness. An instance of an epithelial cell retracted from basement membranes with\ncondensed cytoplasm was seen. Additionally, there was evidence of acute tubular\ninjury with focal pyelonephritis. No viral inclusions were seen.\n\nFigure 1. (A) Periodic acid–Schiff (PAS) stain showing epithelial proliferation and\ncompression of the glomerulus. (B) Hematoxylin and eosin (H&E)-stained\nsection showing dilated tubules with flattened epithelial cells; and cells\nand debris within tubular lumena. (C) H&E-stained section showing\nintraepithelial neutrophils. (D) H&E-stained section photographed with\npolarized light showing crystalline material within tubules.\n\nFollow-up\nCOVID-19 symptoms have fully improved by 30 days after presentation, but the patient\nremains dialysis dependent. Patient’s APOL-1 risk variants were tested on serum\nsample at Labcorp and patient has heterozygous expression of wild type and G1\nvariants, which are considered lower risks for renal failure from collapsing FSGS\ncompared with heterozygous or homozygous expression of higher risk variants.\n\nDiscussion\nThis case demonstrates 2 different renal pathologies in the setting of COVID-19\ninfection. The first is collapsing glomerulopathy due to COVID-19 infection. HIV was\nnot considered as a cause of collapsing FSGS because HIV viral load was undetectable\nand CD4 count was more than 200. The second is oxalate nephropathy because of\nhigh-dose vitamin C use. Although occurring in the same patient these 2 findings are\nunrelated.\n\nCollapsing glomerulopathy in COVID-19 infection is now well reported in patients\nhomozygous for APOL-1.1,2,4 Of the cases\nreported so far, only one had evidence of direct viral infection from SARS-CoV-2\n(severe acute respiratory syndrome coronavirus 2) whereas in the rest direct viral\ntrophism was ruled out as possible etiology for renal injury. Collapsing FSGS in\nthese cases is thought to be due to cytokine storm as a second hit in genetically\npredisposed patients. All reported cases were either homozygous or had 2 high-risk\nheterozygous variants of APOL-1. To our knowledge, this is the first case of\ncollapsing FSGS associated with heterozygous expression of wild type and G1\nvariants, which are considered lower risks for renal failure from collapsing FSGS.\nIt is possible that the intensity of the COVID-19 cytokine storm overwhelmed the\nprotective state of APOL-1 heterozygosity for low-risk variants.\n\nOxalate nephropathy is an uncommon condition resulting in calcium oxalate deposition\nin renal tubules, which results in kidney injury. Primary forms are due to genetic\nmutation but more commonly seen are secondary forms like those related to gastric\nbypass, small bowel resection, Crohn’s disease, and chronic pancreatitis.5 High-dose vitamin C has also been implicated in secondary oxalate\nnephropathy. In 1985, Lawton and colleagues6 reported a case of secondary oxalate nephropathy after a single\nadministration of 45 g of IV ascorbic acid as an adjuvant therapy for primary\namyloidosis with nephrotic syndrome. Clinical presentation can be nonspecific with\nAKI and hematuria. Lumlertgul and colleagues5 reviewed 108 patients with secondary oxalate nephropathy and found that\nproteinuria was the most common urinary finding at 69%, followed by hematuria at\n32%, oxalate crystal deposition was universally found in the tubules and/or the\ninterstitium. High-dose IV vitamin C has shown some benefit in sepsis-related acute\nrespiratory distress syndrome (ARDS). Marik and colleagues7 observed that in patients with sepsis and ARDS, high-dose IV vitamin C,\nhydrocortisone, and thiamine resulted in mortality reduction when compared with\npatients treated with standard procedures (mortality of 8.5% [4 of 47] in the\ntreatment group compared with 40.4% [19 of 47] in the control group\n[P < .001]). In addition, less vasopressor support was\nneeded in the treatment group compared with the control group. In a randomized\ncontrol trial by Fowler and colleagues8 in 167 patients with sepsis-related ARDS, group treated with IV infusion of\nvitamin C (50 mg/kg) every 6 hours for 96 hours had lower mortality 29.8% (25/84)\nthan the placebo group 46.3% (38/82; χ2 = 4.84; P = .03;\nbetween-group difference, 16.58% [95% confidence interval = 2% to 31.1%]).8 Consequently in several centers, vitamin C is part of treatment protocols for\nsevere respiratory illness caused by COVID-19 infection. However, Fontana and colleagues9 just recently reported 2 cases of oxalate nephropathy caused by high-dose\nvitamin C in COVID-19 infection. Our patient developed AKI on chronic kidney disease\ndue to multifactorial causes; factors related to COVID-19 infection, potential renal\nhypoperfusion, and therapeutic intervention, all of which provided milieu for\nsecondary oxalate deposition due to high-dose vitamin C therapy. Serum and urine\noxalate levels were not measured during IV vitamin C therapy to show causative\neffect of vitamin C toxicity on AKI, which is a limitation of our case report.\n\nThe prognosis of secondary forms of oxalate nephropathy is somewhat guarded as\ndescribed in the report by Lumlertgul and colleagues,5 with 55% of patients requiring renal replacement therapy. None of the\npatients had complete recovery and 58% progressed to end-stage renal disease. Some\ncases of oxalate nephropathy have been treated empirically with prednisone with\nvaried results. Our patient received IV solumedrol for 7 days as part of COVID-19\ntreatment protocol, but we did not continue steroids beyond that due to limited\nevidence of its benefit.\n\nThis case highlights 4 important considerations. First, collapsing FSGS may occur\neven in lower risk heterozygous APOL-1 variants when the second hit is as\noverwhelming as seen in severe COVID-19 infection. Second, high-dose IV vitamin C\ntherapy in COVID-19 should be evaluated in prospective randomized studies. Third,\nhigh-dose IV vitamin C therapy in COVID-19 should be used only after assessing for\nrisk factors for oxalate nephropathy and if patient develops renal insufficiency\nvitamin C should be abruptly discontinued and serum oxalate levels measured to\ndetermine if vitamin C toxicity is the possible cause of renal failure. Finally, the\nimportance of renal biopsy to determine the exact etiology of AKI cannot be\noveremphasized in a complex case like this.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized\ninformation to be published in this article.\n\nORCID iD: Dean A. Troyer \nhttps://orcid.org/0000-0002-0337-5890\n==== Refs\nReferences\n1 \nLarsen CP Bourne TD Wilson JD Sagga O Sharshir MA \nCollapsing glomerulopathy in a patient with\ncoronavirus disease 2019 (COVID-19)\n. Kidney Int\nRep .\n2020 ;5 :935 -939\n.32292867 \n2 \nMagoon S Bichu P Malhotra V , et al\nCOVID-19-related\nglomerulopathy: a report of 2 cases of collapsing focal segmental\nglomerulosclerosis\n. Kidney Med .\n2020 ;2 :488 -492\n.\ndoi:10.1016/j.xkme.2020.05.004 32775989 \n3 \nD’Agati VD Alster JM Jennette JC , et al\nAssociation of histologic\nvariants in FSGS clinical trial with presenting features and\noutcomes\n. Clin J Am Soc Nephrol .\n2013 ;8 :399 -406\n.\ndoi:10.2215/CJN.06100612 23220425 \n4 \nPeleg Y Kudose S D’Agati VD , et al\nAcute kidney injury due to\ncollapsing glomerulopathy following COVID-19 infection\n.\nKidney Int Rep .\n2020 ;5 :940 -945\n.\n5 \nLumlertgul N Siribamrungwong M Jaber BL Susantitaphong P \nSecondary oxalate nephropathy: a systematic\nreview\n. Kidney Int Rep .\n2018 ;3 :1363 -1372\n.30450463 \n6 \nLawton JM Conway LT Crosson JT Smith CL Abraham PA \nAcute oxalate nephropathy after massive ascorbic\nacid administration\n. Arch Intern Med .\n1985 ;145 :950 -951\n.3994472 \n7 \nMarik PE Khangoora V Rivera R Hooper MH Catravas J \nHydrocortisone, vitamin C, and thiamine for the\ntreatment of severe sepsis and septic shock: a retrospective before-after\nstudy\n. Chest .\n2017 ;151 :1229 -1238\n.27940189 \n8 \nFowler AA 3rdTruwit JD Hite RD , et al\nEffect of vitamin C infusion\non organ failure and biomarkers of inflammation and vascular injury in\npatients with sepsis and severe acute respiratory failure: the CITRIS-ALI\nrandomized clinical trial\n. JAMA .\n2019 ;322 :1261 -1270\n.31573637 \n9 \nFontana F Cazzato S Giovanella S , et al\nOxalate nephropathy caused\nby excessive vitamin C administration in 2 patients with\nCOVID-19\n. Kidney Int Rep . Published online\nJuly 15, 2020. doi:10.1016/j.ekir.2020.07.008\n\n",
"fulltext_license": "CC BY-NC",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "AKI; COVID; FSGS; SARS; collapsing; glomerulopathy; oxalate",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D001205:Ascorbic Acid; D000073640:Betacoronavirus; D001706:Biopsy; D000086382:COVID-19; D018352:Coronavirus Infections; D018450:Disease Progression; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D006959:Hyperoxaluria; D007275:Injections, Intravenous; D007678:Kidney Glomerulus; D008297:Male; D008875:Middle Aged; D010070:Oxalates; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D014815:Vitamins",
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"pages": "2324709620963635",
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"pmid": "33019829",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Collapsing Focal Segmental Glomerulosclerosis and Acute Oxalate Nephropathy in a Patient With COVID-19: A Double Whammy.",
"title_normalized": "collapsing focal segmental glomerulosclerosis and acute oxalate nephropathy in a patient with covid 19 a double whammy"
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"abstract": "Many health care professions have reacted swiftly to the COVID-19 pandemic. In-person care has been ramped down and telemedicine/telehealth has been thrust to the forefront of clinical care. For people living with chronic pain and often concomitantly dealing with opioid-related issues, this is a time of great stress. With population-wide movements to shelter in place, people living with pain are more isolated, more stressed, and more vulnerable to mental health concerns like depression and anxiety that can increase pain-related suffering. This article presents two case reports of patients struggling with chronic pain and opioid dependence in which a telemedicine-based buprenorphine-naloxone conversion was chosen as a treatment option by two Canadian programs: The Transitional Pain Service at the Toronto General Hospital in Toronto, Ontario, and The Opioid Deprescribing Program in Calgary, Alberta. Both cases presented highlight the use of telemedicine during the COVID-19 pandemic and suggest that there will be substantial need for these services well beyond the apex of the crisis. A buprenorphine-naloxone home induction protocol is presented and we provide insight into important lessons learned regarding the appropriate selection of patients with chronic pain struggling with opioid use disorder for buprenorphine-naloxone conversion. The provision of health care during the COVID-19 pandemic has rapidly forced practitioners to evolve novel health care practices, and these changes will have long-term implications.",
"affiliations": "Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.;Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.;Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.;Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada.;Department of Family Medicine, University of Calgary, Calgary, Alberta, Canada.;Opioid Deprescribing Program, Alberta Health Services, Calgary, Alberta, Canada.",
"authors": "Clarke|Hance|H|;Weinrib|Aliza|A|;Kotteeswaran|Yuvaraj|Y|;Katz|Joel|J|;Yu|Alvis|A|;Tanguay|Robert|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/24740527.2020.1795634",
"fulltext": "\n==== Front\nCan J Pain\nCan J Pain\nCanadian Journal of Pain = Revue canadienne de la douleur\n2474-0527\nTaylor & Francis\n\n10.1080/24740527.2020.1795634\n1795634\nVersion of Record\nCase Report\nRemote buprenorphine-naloxone initiation as an essential service for people with chronic pain and opioid dependence during the COVID-19 pandemic: Case reports, clinical pathways, and implications for the future\nH. CLARKE ET AL.\nCANADIAN JOURNAL OF PAIN\nClarke Hance abc\nWeinrib Aliza bd\nKotteeswaran Yuvaraj ab\nKatz Joel abcd\nYu Alvis ef\nTanguay Robert fgh\na Department of Anesthesiology and Pain Medicine, University of Toronto , Toronto, Ontario, Canada\nb Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network , Toronto, Ontario, Canada\nc University of Toronto Centre for the Study of Pain , Toronto, Ontario, Canada\nd Department of Psychology, York University , Toronto, Ontario, Canada\ne Department of Family Medicine, University of Calgary , Calgary, Alberta, Canada\nf Opioid Deprescribing Program, Alberta Health Services , Calgary, Alberta, Canada\ng Department of Psychiatry and Surgery, University of Calgary , Calgary, Alberta, Canada\nh Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary , Calgary, Alberta, Canada\nCONTACT Hance Clarke hance.clarke@uhn.ca Department of Anesthesia, Pain Research Unit, Toronto General Hospital , Toronto, ON M5G 2C4, Canada.\n15 9 2020\n2020\n4 1 224235\n© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.\n2020\nThe Author(s)\nhttps://creativecommons.org/licenses/by/4.0/ 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 cited.\n\nABSTRACT\n\nMany health care professions have reacted swiftly to the COVID-19 pandemic. In-person care has been ramped down and telemedicine/telehealth has been thrust to the forefront of clinical care. For people living with chronic pain and often concomitantly dealing with opioid-related issues, this is a time of great stress. With population-wide movements to shelter in place, people living with pain are more isolated, more stressed, and more vulnerable to mental health concerns like depression and anxiety that can increase pain-related suffering. This article presents two case reports of patients struggling with chronic pain and opioid dependence in which a telemedicine-based buprenorphine-naloxone conversion was chosen as a treatment option by two Canadian programs: The Transitional Pain Service at the Toronto General Hospital in Toronto, Ontario, and The Opioid Deprescribing Program in Calgary, Alberta. Both cases presented highlight the use of telemedicine during the COVID-19 pandemic and suggest that there will be substantial need for these services well beyond the apex of the crisis. A buprenorphine-naloxone home induction protocol is presented and we provide insight into important lessons learned regarding the appropriate selection of patients with chronic pain struggling with opioid use disorder for buprenorphine-naloxone conversion. The provision of health care during the COVID-19 pandemic has rapidly forced practitioners to evolve novel health care practices, and these changes will have long-term implications.\n\nRÉSUMÉ\n\nDe nombreuses professions de santé ont réagi rapidement à la pandémie de COVID-19. Les soins en personne ont diminué, tandis que la télémédecine et la télésanté ont été propulsées au premier plan des soins cliniques. Pour les personnes vivant avec la douleur chronique, souvent confrontées de manière concomitante à des problèmes liés aux opioïdes, il s’agit d’une période de grand stress. Avec les mouvements de confinemen de la population mis en place, les personnes vivant avec la douleur sont plus isolées, plus stressées et plus vulnérables aux problèmes de santé mentale comme la depression et l’anxiété, qui peuvent augmenter la souffrance liée à la douleur. Cet article présente deux rapports de cas de patients aux prises avec la douleur chronique et la dépendance aux opioides où la conversion à la buprénorphine-naloxone par télémédecine a été choisie comme option de traitement par deux programmes canadiens : Le Service de la douleur transitoire de l’Hôpital général de Toronto, en Ontario, et le Programme de déprescription des opioides à Calgary, Alberta. Les deux cas présentés mettent en évidence l’utilisation de la télémédecine pendant la pandémie de COVID-19 et indiquent qu’il y aura un besoin important pour ces services bien au-delà du sommet de la crise. Un protocole d’induction de la buprénorphine-naloxone à domicile est présenté et nous donnons un aperçu des seignemens tirés quant à la selection appropriée de patients souffrant de douleur chronique et d’un trouble lié à l’usage d’opioïdes pour la conversion à la buprénorphine-naloxone. La prestation de soins de santé durant la pandémie de COVID-19 a rapidement obligé les praticiens à mettre au point de nouvelles pratiques de soins de santé, et ces changements auront des implications à long terme.\n\nKEYWORDS\n\nchronic pain\nsuboxone\nCOVID-19\ntelemedicine\nbuprenorphine-naloxone\ntelepsychology\nUniversity of Toronto 10.13039/501100003579 The authors did not receive any funding for this work. Dr. Clarke is supported in part by a Merit Award from the Department of Anaesthesiology and Pain Medicine at the University of Toronto. Dr. Katz is supported by a Canadian Institutes of Health Research Canada Research Chair in Health Psychology at York University.\n==== Body\nIntroduction\n\nIn response to the COVID-19 pandemic, the health care world has reacted swiftly. Most health care resources have been redirected with the overarching goal of protecting society, while ramping down in-person care in the hopes of “flattening the curve” and stopping the rapid spread of this deadly virus. Consequently, patients are enduring significant delays to their care pathways, having had elective procedures—as well as potentially life-saving procedures, such as cancer surgeries—postponed for weeks and potentially months. The debate over which patient visits/procedures are considered elective vs. essential changes daily. Practice guidelines are urgently needed, and experts have begun to publish treatment recommendations—for example, an expert panel of pain physicians, psychologists, and researchers from Europe and North America recently published chronic pain practice recommendations to guide treatment during COVID-19.1\n\nFor people living with chronic pain and often concomitantly dealing with opioid-related issues,2 this is a time of great stress. With population-wide movements to shelter in place, people living with pain are more isolated, more stressed, and more vulnerable to mental health concerns like depression and anxiety that can increase pain-related suffering. In addition, patients do not have access to in-person services like physiotherapy and some interventional procedures during this time. With ongoing global supply chain issues,3 the fear of running out of medications is significant among patients consuming prescription opioid medications. Long-acting opioid formulations are on back order without a clear indication of when that might be remedied. This shortage can have severe consequences, both physical and psychosocial. Some patients may suffer in isolation as they cope with significant opioid-related withdrawal; others may not be able to tolerate this distress and turn to high-risk illicit opioids in an attempt to mitigate their withdrawal symptoms and distress.4\n\nFor people living with chronic pain who take prescription opioid medications, health care delivery is an essential service. Physicians’ offices cannot simply close and abandon their patients. Interdisciplinary pain treatment must instead be triaged into levels of care with clear indications for in-person and remote/virtual intervention. Services that must be delivered face-to-face (e.g., high-priority interventional procedures) can be prioritized for in-person delivery, and clinical care that can be conducted remotely should be adapted to virtual delivery in order to reduce risk of COVID-19 transmission for patients and providers alike. The risk–benefit analysis for in-person care has been abruptly turned on its head. Accordingly, a key question for clinicians now is how clinical pathways can be effectively adapted for telemedicine and virtual health care. Over the past several years, telemedicine had been slowly progressing as a means of reaching rural clientele5; however, now its role must rapidly expand to reach patients who are practicing physical distancing to prevent the spread of COVID-19.\n\nIn addition to practice-related questions, this rapidly emerging new paradigm raises questions about what technological means should be used by health care providers to communicate remotely with patients, as well as remotely with one another. Health care systems around the world are being thrust into utilizing existing telephone infrastructure and web-based video conferencing platforms, including those developed by public health institutions (e.g., Ontario Telehealth Network) and those developed commercially (e.g., Zoom).\n\nThis article describes care pathways for buprenorphine-naloxone induction when in-person care is not the best option. Two patient case reports will be presented, the first treated by the Transitional Pain Service (TPS) at the Toronto General Hospital. This began with an in-person visit prior to the COVID-19 shut down and rapidly turned into a case needing an interdisciplinary health care model with virtual visits. The second case is an example of a home induction of buprenorphine-naloxone in a person living with chronic pain during the COVID-19 shutdown illustrating an established care pathway developed by the team at the Opioid Deprescribing Program in Calgary. The initials used throughout the article are pseudonyms to protect the patients’ identities. Practice issues and lessons learned will be discussed, with the hope that the home induction protocol we present may continue to be used once the current pandemic has ended. A written informed consent form was signed by each patient who agreed to the publication of the present case report and who also reviewed the article and approved the details of their case.\n\nCase #1: Transition to Buprenorphine-naloxone during the COVID-19 Crisis in the Transitional Pain Service, Toronto General Hospital, Toronto, Ontario\n\nC.D. is a 67-year-old woman who had to reduce her work commitments as of 2014 due to pain-related disability after developing postherpetic neuralgia (PHN) of her face and head. On presentation to the TPS clinic at the start of the COVID-19 pandemic in early March 2020, her pain complaint was mainly on the right side of the head in the cranial nerve V1 distribution of the trigeminal nerve. Her pain was most often in the severe range, with the lowest pain severity score in the moderate range at 6/10 on the 0–10 pain intensity numeric rating scale. Previous visits with neurologists had ruled out migraines or trigeminal neuralgia.\n\nOver the years, C.D. had tried gabapentin to a maximum dose of 3600 mg/day, pregabalin without convincing results, levetiracetam (intolerant due to adverse effects), and carbamazepine 900 mg/day with little benefit. A recent trial of 0.5 g/day of physician-authorized THC-dominant cannabis via vaping worsened her symptoms and caused paranoid hallucinations. CBD oil 20 mg/ml 0.5 ml TID also did not improve her symptoms. A neurosurgeon had suggested the possibility of peripheral neurostimulation; however, because results were often mixed, C.D. decided against it. At the time of the initial assessment, C.D. was taking 60 mg of oxycodone daily, which she would supplement with a carbamazepine tablet (100 mg) on the occasional day when her pain was excruciating. Accordingly, her morphine equivalent dose at TPS intake was 90 mg/day.\n\nC.D. reported that she wished to stop using oxycodone, in part because it was providing only 10% to 20% pain relief and in part because she was concerned about dependence, but she could not taper the oxycodone (even very slowly) because it would induce vomiting. Indeed, at the initial visit to the TPS she kept a container close by in case she needed to vomit, which she did intermittently. It appeared that in addition to severe PHN in the cranial nerve V1 distribution, she had developed an opioid-induced cyclical vomiting syndrome6 in which vomiting is triggered by either opioid tapering or consuming oxycodone tablets. Treatment options were discussed, including rotation to another opioid or conversion to buprenorphine-naloxone. The shared decision was made to initiate the transition to buprenorphine-naloxone. The plan was that once she was stable on a dose of buprenorphine-naloxone, we could target a multimodal plan for her PHN symptoms.\n\nSuboxone Induction\n\nGiven our experience with previous inductions, we selectively chose to start patients on a buprenorphine transdermal patch prior to a buprenorphine-naloxone induction to mitigate some of the anticipated adverse induction withdrawal symptoms, in particular patients consuming less than 90 mg/day. Two 20 μg/h buprenorphine patches (40 μg/h) were placed on her arm 3 days prior to the buprenorphine-naloxone induction. The rationale for this treatment stemmed from H.C.’s experience with a patient who did not need to take an oral buprenorphine-naloxone tablet on the day of the planned induction when converting from low-dose oxycontin/oxycodone (i.e., 60 mg/day) with placement of a transdermal buprenorphine patch. C.D. was advised to stop taking oxycodone at 8 p.m. the night before (12 h prior to the planned induction). On the morning of the induction, C.D. presented to the TPS clinic with a Clinical Opioid Withdrawal Score (COWS)7 of 5. By midday her COWS score was 9 and she displayed increasing restlessness and distress. Y.K. then initiated the first 2 mg dose of sublingual (SL) buprenorphine-naloxone. By 5 p.m. that afternoon (after one of the buprenorphine 20 μg patches had been removed), her COWS score had increased to 14. She was given another 4 mg of buprenorphine-naloxone, discharged home on the remaining 20 μg/h buprenorphine patch, and given instructions to take additional 2 mg tablets of buprenorphine/naloxone as needed overnight to manage her withdrawal symptoms up to a maximum of 16 mg.\n\nThe introduction of the buphrenorphine patch prior to the initiation of oral buprenorphine-naloxone for C.D. is an example of a microdosing technique. Traditional induction of buprenorphine-naloxone requires patients to be in mild to moderate withdrawal from other opioids before administration of buprenorphine-naloxone. This period of opioid withdrawal can be poorly tolerated by patients and may discourage induction, improving retention in people with opioid use disorder. Furthermore, tapering of the full agonist without replacement with partial μ-opioid agonist bears the risk of relapse to illicit opioid use. The Bernese method describes a microdosing induction regimen for buprenorphine that overcomes this opioid withdrawal effect.8 Microdosing can be done either by the sublingual route8 or the transdermal route presented in our case report.9,10 Recently, rapid induction of microdosing by the sublingual route has become more common.11,12 The advantage of the rapid induction microdosing is that it takes 3 to 5 days, in comparison to the Bernese method, which usually takes more than 10 days. The microdosing regimens explained in the above literature tend to occur in classic inpatient settings. However, it has become clear that the microdosing induction technique is manageable and effective in an outpatient setting. A less frequent dosing regimen may be more practical for outpatients.\n\nOur typical clinical care pathway would have been to see C.D. in person, in clinic, the following morning. However, given the rapidly escalating concern over COVID-19, the hospital mandated that all face-to-face patient visits to the clinic be canceled and clinical staff transition to seeing patients using telehealth services.\n\nC.D. was called the following morning to inform her of the unanticipated COVID-19 mandate and to monitor her progress. C.D. reported that the induction had not progressed smoothly and that she was in significant distress. Several hours after leaving the TPS clinic the previous day, she presented to her local emergency department. The emergency physician astutely ascertained that she was dealing with heightened opioid withdrawal, gave her another 2 mg tablet of buprenorphine-naloxone, and discharged her home to continue the induction according to our previous instructions. She had taken another 2 mg buprenorphine-naloxone overnight but during H.C.’s telephone call with her in the morning she continued vomiting throughout the conversation, so it was decided that C.D. would take the entire 12 mg dose that morning. A requisition for a prescription of 12 mg/day SL buprenorphine-naloxone was sent to her pharmacy (1 × 8 mg/2 mg and 2 × 2 mg/0.5 mg tablets). A follow-up call was made that day to C.D. at 12 p.m., by which time she reported that she was starting to feel better. Later that evening as withdrawal symptoms intensified, C.D. took another 2 mg buprenorphine-naloxone. Given the rocky nature of this induction, the hope was that she was over the worst and was heading toward a smooth zone moving forward.\n\nOn the third morning after the start of the buprenorphine-naloxone induction, around 9 a.m., H.C. received a distressed mobile communication from C.D. She explained that she was not able to tolerate the large 8 mg tablet. It caused her to gag when placed under the tongue; hence, she had spit out her morning dose. During the telephone assessment, it was unclear how much of the dose she had absorbed. She stated that she was trembling and alone (her partner was an essential worker who was attending to his public duties), vomiting continually, and unable to leave her bed. At this point, and in the midst of COVID-19, H.C. was struggling to provide the support C.D. required and enlisted the help of the TPS multidisciplinary team (Y.K. and A.W.), who were both in self-isolation, as well as his colleague (R.T.), who resides in Alberta. These colleagues agreed to an impromptu teleconference meeting to discuss the challenges of the current case. Following the meeting, H.C. called C.D. to present a path forward that included a modified pharmacological approach and psychological intervention with A.W.\n\nOn the call to C.D., she reported that the day before, she had left her buprenorphine-naloxone tablets in a downstairs location in her house and was currently unable to navigate the stairs to retrieve them given how weak and unstable she felt. H.C. and C.D. devised a plan for one of C.D.’s neighbors to help by bringing C.D.’s 2 mg tablets from the downstairs location to the upper floor, leaving the medication outside C.D.’s bedroom door. Once her neighbor had departed, C.D. would retrieve the tablets. This plan, for the most part, maintained the physical distancing polices that the provincial government had implemented.\n\nBecause C.D. was not able to take an 8 mg tablet, the team’s plan was to titrate to 16 mg buprenorphine-naloxone, in 2 mg dose escalations, from the 14 mg dose the day before. Given the uncertainty of how much of the 8 mg tablet had been absorbed in the morning, H.C. instructed C.D. to start afresh and take 5 × 2 mg tablets over the next hour with a goal to consume three more 2 mg tablets prior to bedtime for a total daily dose of 16 mg. A telephone call changing her prescriptions from 8 mg to 2 mg tablets of buprenorphine-naloxone was made to the pharmacist who facilitated this change. During the COVID-19 pandemic, Health Canada issued a temporary exemption for patients, practitioners, and pharmacists prescribing and providing controlled substances that enables telephone orders.13\n\nH.C. also informed C.D. that A.W. had agreed to provide her urgent psychological intervention sessions to help her get through this extremely distressing period. That Friday afternoon A.W. reached out to C.D., and by the following morning C.D.’s vomiting had subsided for the first time in weeks. Over the course of the weekend, C.D. reported that she was able to get out of the house (she lives in a rural area of the province), tend to her horses, and walk her dog, significant achievements relative to the pre-induction and immediate postinduction periods.\n\nOne week Postinduction\n\nC.D. was stable on 16 mg buprenorphine-naloxone a day after the oxycodone to buprenorphine-naloxone conversion, and there was complete resolution of her nausea and vomiting symptoms. However, she reported that she was now plagued by an enormous amount of anxiety, with panic attacks four to five times a day. One of the adverse effects associated with buprenorphine-naloxone is significant anxiety, which may be related to an increase in limbic tone. Given her significant emotional distress, a shared decision was again made to reduce the buprenorphine-naloxone dose to 14 mg/day with the goal of getting the dose down to 8 mg, at which point her anxiety might be reduced and the focus would shift to starting neuropathic pain medications for her PHN. Unfortunately, by the following morning, the vomiting cycle had resumed, and it was apparent that C.D. was exquisitely sensitive to changes to her opioid dose. C.D. once again called upon the services of A.W. and we immediately reinstated the 16 mg/day dose.\n\nImplementing Psychological Care Via Telehealth\n\nFor people living with pain and opioid dependence, psychological care during buprenorphine-naloxone induction generally is brief (e.g., two to three sessions). In terms of treatment techniques, sessions are modeled on the focused acceptance and commitment therapy (FACT) protocols developed by Kirk Strosahl and colleagues for use with medical patients.14 In addition, the ACT matrix is used as a visual teaching tool to communicate ACT principles.15 Skills from mindfulness and acceptance-based therapies beyond acceptance and commitment therapy, such as dialectical behavior therapy (DBT),16 are incorporated as appropriate. Finally, in this case, clinical hypnosis was used to treat nausea and vomiting.\n\nA range of techniques are used, but the goal is quite singular: to help patients tolerate the intense withdrawal symptoms so that the transition to buprenorphine-naloxone can be completed and they can move on to a new chapter of their lives, free from the suffering and limitations imposed by opioid dependency. Accordingly, ACT treatment puts personal values first, always emphasizing the kind of life and valued activities (e.g., quality time with family, meaningful work, etc.) the patient is moving toward by taking on this challenging transition. The goal is to dignify the distress and give it purpose and meaning.\n\nOnce the course has been set by clarifying personal values, the next priority is to help the patient identify, remember, and utilize his or her already-present effective strategies for getting through crises, as well as supplement the patient’s skills with helpful behavioral/psychological tools that round out his or her “coping toolbox.” To accomplish this, distress tolerance skills from dialectical behavior therapy are often useful. These skills include distraction, self-soothing, and mindful grounding techniques using sensory awareness (what you can see, what you can hear, what you can touch, etc.) that can help the person to “weather the storm” without making it worse by catastrophizing. C.D. was quite insightful about this, stating that she was keen not to engage in “awfulizing” and instead to engage in meaningful behaviors, such as going for walks, caring for her animals, and spending time with loved ones.\n\nOne of the most psychologically difficult aspects to bear of the transition to buprenorphine-naloxone is increased anxiety. We know that opioid withdrawal increases anxiety, and therefore it is useful to discuss with patients how to respond to this increased anxiety. Within mindfulness and acceptance-based frameworks such as ACT and DBT, we emphasize that the more one tries to suppress anxiety out of fear, the more it rebounds. In other words, fear of fear only leads to a negative cycle that becomes more and more overwhelming. We use metaphors to teach this principle (e.g., like the effort required to hold a beach ball under water). C.D. understood this immediately based on her prior experience living with pain, saying that “if you resist, it persists.” Using the ACT matrix, we highlighted the difference between “away moves” (behaviors driven by avoidance of pain and anxiety; e.g., lying in a dark under the covers, isolating) and “toward moves” (values-based approach behaviors; e.g., spending time with loved ones).\n\nFinally, psychological intervention for C.D. involved clinical hypnosis for nausea and vomiting symptoms. C.D. was already familiar with hypnotherapy for pain relief17; however, she was not aware that it could be used for disorders of gut–brain interaction,18 such as cyclic vomiting syndrome. Indeed, although the published evidence for the Manchester gut-focused hypnotherapy protocol is primarily based on treatment of irritable bowel syndrome,18,19 the protocol also has been used successfully for cases of cyclic vomiting syndrome in Manchester (Pamela Cruikshanks, personal communication, September 2019). Accordingly, A.W. guided C.D. through a hypnotherapy exercise that induces deep relaxation targeted at the gut–brain axis. C.D. reported feeling “very, very calm” afterward. Creating a sense of psychological safety through hypnosis can reduce the likelihood of vomiting, as the brain processes many inputs, including psychological stress, perceived danger, and opioid withdrawal, which converge and summate to trigger the vomiting response. A.W. provided C.D. with a link to audio recordings she had made that could be accessed through the internet by her patients. These recordings included mindfulness and hypnotherapy exercises, which C.D. found useful and used repeatedly to help her to “ride the waves” of pain, nausea, and anxiety during this important transition. Notably, to date, A.W. and C.D. have not met in person, and all psychotherapy, mindfulness, and hypnotherapy sessions were conducted over the Ontario Telehealth Network or (when it failed likely due to a sudden surge in capacity during the initial COVID-19 crisis) by telephone.\n\nThree weeks have elapsed since the day when the in-person induction of buprenorphine-naloxone took place. Currently C.D.’s nausea and vomiting have stabilized, and given her sensitivity to fluctuations in opioid dose, the decision was made to stay on 16 mg of buprenorphine-naloxone for some time. We have started to introduce neuropathic pain medications for the PHN. C.D. has a long road ahead and she will continue to receive the support of the TPS team. She is coming to terms with the fact that there is no “easy” solution or quick fix to her health problem.\n\nPatients living with persistent pain and taking long-term opioids often require ever-increasing doses to maintain pain control due to opioid tolerance, while at the same time experiencing more and more side effects, including opioid-induced hyperalgesia.20 Our experience with buprenorphine-naloxone for complex, chronic, opioid-dependent patients with pain is that it can provide effective pain relief while not feeding into the spiral of escalating opioid requirements typically seen with μ-opioid agonists.21 From a harm reduction perspective (i.e., likelihood of opioid overdose), the safety profile of buprenorphine-naloxone is superior to that of methadone22; hence, we selectively opt for buprenorphine-naloxone preferentially over methadone for patients struggling with opioid escalation/management in the context of a chronic persistent pain.\n\nCase #2: Home Induction Protocol for Buprenorphine-naloxone during the COVID-19 Crisis in the Opioid Deprescribing Program, Calgary, AB\n\nK.S. is a 44-year-old married male currently on disability, who was referred to the Opioid Deprescribing Program secondary to chronic opioid therapy, continued chronic pain, complex medical morbidities, and complex mental health morbidities. He attended an educational lecture on opioid deprescribing and was subsequently offered a consult. He presented for his initial consultation at the beginning of March 2020. He is supported by Assured Income for the Severely Handicapped and lives with his wife, parents, and autistic niece. He has struggled with chronic degenerative myofascial lumbar back pain, along with widespread pain, for which he was prescribed hydromorphone. He also described a right S1 radiculopathy and joint pain reported as 8–10/10 pain intensity daily on a numerical rating scale. He had been seen at the Spine Triage and Assessment Program at Foothills Medical Center where surgery was ruled out. Medical comorbidities included diabetes mellitus type 2, obstructive sleep apnea with CPAP, dyslipidemia, restless leg syndrome, and hypertension. Mental health diagnoses included a history of bipolar disorder. Nonopioid medications included moclobemide, lurasidone, pramipexole, lamotrigine, dextroamphetamine, rosuvastatin, mirabigron, semaglutide injection, diclofenac, ondansetron, gabapentin, and topical lidocaine/gabapentin/diclofenac. He is also prescribed cannabis oil in a 1:1 ratio of THC:CBD. Initial multidisciplinary assessment determined a borderline personality disorder and somatic symptom disorder, with predominant pain along with a high level of pain catastrophizing (scoring in the 85th percentile on the Pain Catastrophizing Scale).\n\nHis chronic opioid therapy included hydromorphone 8 mg q4 h (40 mg daily) and hydromorph contin 3 mg TID, a milligram morphine equivalent dose of 245 mg/day. He often ran out of his medications early, due to uncontrolled pain. There was no history of addiction and no aberrant use of his prescribed opioids, including crushing, snorting, injecting, or purchasing illicit or other prescribed opioids. At the initial visit, buprenorphine-naloxone was discussed as an alternative treatment if he was unable to taper his opioid dose and his pain could not be stabilized. A referral to interventional physiatry was also completed, but due to the COVID-19 pandemic it was put on temporary hold as the program was shut down. It was decided to start with an initial taper of 3 mg/day of his hydromoph contin dose, representing 6% of his total daily milligram morphine equivalent dose.\n\nAt 4 weeks, a telemedicine call was arranged for his next appointment instead of meeting in person. At the beginning of April 2020, the clinic made the decision to eliminate face-to-face appointments to reduce risk of viral transmission. The plan was to taper another 3 mg of hydromorph contin. K.S. reported a recent fall during which he injured a knee. He complained of increased pain and reported a consequent increase in opioid use, which depleted his medication supply early. K.S. admitted that the opioids were causing distress and impairment in his life. He was using more than intended in a day, unable to cut down or stop using them, craving them, especially when he was distressed, and they were affecting his mental health. He met the criteria for opioid use disorder, moderate and was unable to taper off his medication. After education and a discussion of the possible benefits of buprenorphine-naloxone, a first-line treatment for opioid use disorder,23 K.S. decided that it would be best for him. Education was provided on a home induction protocol and a prescription was called into the pharmacy.\n\nOn day 2 of the home induction, K.S. was called and reported feeling better and was stable at 18 mg of buprenorphine-naloxone. His mood had improved, his pain had significantly reduced, and he was thankful for his decision to initiate buprenorphine-naloxone. A follow-up via telephone was done 1 week later when K.S. reported that his pain intensity had dropped to a 2/10 and was not causing him any distress or impairment throughout the day. He did notice some pain at the end of the day, which led to cravings, but these would go away after a couple hours without any further intervention.\n\nHe subsequently met with a therapist via telemedicine within the Opioid Deprescribing Program and they reviewed cravings and triggers for him. DBT skills were reviewed with a focus on distress tolerance and a plan was implemented to continue one-on-one psychological support until he starts a DBT skills group. The goal of DBT in this context is to reduce emotional distress in order to help reduce pain and improve his ability to cope with the pain. Psychological distress and catastrophizing are known to increase pain,24 and an acceptance and values-based approach along with emotion regulation skills, as previously described, is of great importance in developing long-term and meaningful improvement in quality of life.25\n\nHome Induction\n\nThe home induction protocol for prescription opioids was designed to improve patient understanding and reduce patient discomfort and for educational purposes to improve physician prescribing. It is currently part of the continuing medical education for chronic pain offered by the Alberta Pain Society. One barrier to prescribing buprenorphine-naloxone involves a lack of knowledge and skill in the induction phase26; hence, developing a simplified protocol was important. In-office, monitored inductions have been the traditional way to initiate buprenorphine-naloxone treatment, but home inductions have similar efficacy and safety.27–29 In Canada there is a practice of daily witnessed dosing at the clinic or pharmacy for patients prescribed methadone or buprenorphine-naloxone, although this can lead to poorer retention to treatment and higher costs to the health care system with no known benefits30,31 compared to patients who are dispensed weekly/monthly medications. The use of the home induction protocol, which eliminates unnecessary face-to-face visits, is vital to reduce COVID-19 exposure and transmission in the setting of a pandemic.\n\nThe home induction protocol (Figure 1) begins on day 0, the morning before the start of the home induction. The patient stops the long-acting opioid the morning before the start of the home induction and continues taking the short-acting medications until the night before induction. The patient must take the last long-acting opioid dose 24 h before and the short acting dose 12 h before initiation of buprenorphine naloxone. The patient is advised to wait until he or she is in moderate withdrawal (defined by a Subjective Opioid Withdrawal Scale score >17).32 On day 1, a prescription is initiated for buprenorphine-naloxone 2 mg SL q1 h for 8 h (16 mg in total). The patient is advised to “take 2 mg 1 tablet every hour until you start to feel better and the pain improves up to a maximum of 16 mg.” On day 2 (Figure 2) the patient is prescribed two 8 mg tablets (16 mg) for the morning dose then an additional 2 mg q1 h for 4 h for a total daily dose of 24 mg. For patients whose day 1 dose was less than 16 mg, this dose (2–14 mg) becomes the daily total until they are re-assessed. The prescriber then calls the patient on day 2 in the afternoon to confirm the dose and subsequently sends the pharmacy a prescription for 28 days. Over the last 2 years, this protocol has been successfully implemented at the Opioid Deprescribing Program and modified for the Opioid Dependency Program for illicit fentanyl.Figure 1. Suboxone Home Induction Day 1\n\nFigure 2. Suboxone Home Induction Day 2\n\nFor patient K.S. about 30 min was spent discussing the buprenorphine-naloxone home induction. A handout was provided (Figures 1 and 2). On day 1, K.S. completed the maximum dose of 16 mg with no complications. On day 2, K.S. took the total from day 1 (16 mg) in the morning in one dose and then added a second dose of 2 mg 1 h later. He stopped at this dose. He was called by R.T. on day 2 and his dose was confirmed at 18 mg, and he was subsequently provided with a prescription for 28 days, with no witnessed dosing. This was all completed with telephone calls. An example of a prescription in order to complete the Buprenorphine-naloxone home induction is presented in Appendix A.\n\nTechnology and Clinical Care\n\nDuring C.D.’s buprenorphine-naloxone induction, H.C. was, within minutes, able to assemble the entire team via teleconference. This was essential given the lack of face-to-face peer support during this time and essential with respect to sharing ideas and creating a swift plan. This was as helpful in quelling H.C.’s anxieties as it was to further developing the care plan for C.D. A.W.’s telehealth visits were immediately booked by our administrative assistant. C.D. had a home computer and was able to connect via the Ministry of Health and Long Term Care’s telehealth portal.\n\nR.T. was consulted given his experience with buprenorphine-naloxone inductions and the numerous successful home inductions that he and his team have performed. Because C.D.’s rocky induction and cyclic vomiting was indeed novel to him, a larger discussion ensued during our teleconference with respect to home-based buprenorphine-naloxone inductions. R.T.’s team has smoothly transitioned patients from the comfort of their homes over the past years (i.e., case of K.S.). The travel that C.D. endured on the day of the induction (particularly on the way home while experiencing moderate opioid withdrawal) likely contributed to her visit to the emergency department, which could have been avoided.\n\nA recent manuscript highlighted some of the benefits and challenges associated with the rapid introduction of telephone and e-health pain management services33 during COVID-19. Emergency departments are using telemedicine to triage patients with COVID-19 symptoms. In dealing with C.D.’s case, telephone, provincial telemedicine, and social media services were utilized. The Toronto General Hospital TPS clinic has already implemented a mobile health e-platform (Manage My Pain) into clinical care34 and is testing this solution. As e-health technology evolves, platforms that can enable physical examination would be preferable for new consultations. The case of K.S. makes it clear that successful home buprenorphine-naloxone inductions are feasible and likely represent a viable clinical pathway for the future given North America’s current opioid crisis.\n\nThe TPS Psychology Team—Lessons Learned regarding Complex Chronic Pain and Buprenorphine-Naloxone Inductions\n\nPatient education is paramount. Patients routinely receive educational information about the induction process, including a “road map” of the steps involved (see Figures 1 and 2) and frank discussion to manage expectations. The induction protocol is presented and explained to ensure that patients understand the process and their questions are answered satisfactorily. Over time and with experience, we have learned that it is important to screen for several psychological risk factors for complex chronic pain patients if the decision is made to pursue a buprenorphine-naloxone induction. The following are three clinical flags to denote that a patient may need a higher level of clinical support during the induction period, which can be a time of greater distress than baseline. However, patients with a history of other disorders (e.g., major depressive disorder, bipolar disorder, anxiety disorders) also require specialized care and monitoring during buprenorphine-naloxone induction and especially during home induction. History of trauma/current PTSD. In our clinical experience, patients with a history of trauma are more likely to have difficulty with opioid withdrawal and the transition to buprenorphine-naloxone. The increased panic and anxiety during this time requires additional skills training to successfully tolerate and move beyond this transition; however, with support, patients can reach their treatment goals.\n\nHistory of suicidal ideation and behavior. Patients in withdrawal from opioids may experience dysphoria. In patients with a history of suicidal behavior, a suicidal crisis can be triggered. Clinicians should screen in advance for this history (particularly for a history of high-lethality behaviors), monitor closely, and offer additional supports if needed. With psychological support, patients with this history can successfully transition to buprenorphine-suboxone.\n\nDaily anxiolytic use. In our clinical experience, patients who are using both opioids and anxiolytics daily (not intermittent anxiolytic use but daily high-dose use) are more likely to have difficulty with the buprenorphine-naloxone transition. Acceptance and commitment therapy35 or motivational interviewing36 prior to attempting buprenorphine-naloxone induction may be of help in increasing motivation to tolerance distress, as well as skill development in acceptance of aversive sensations and distress tolerance for emotions.21\n\nThe Opioid Deprescribing Team—Lessons Learned regarding Complex Pain and Buprenorphine/Naloxone Home Inductions\n\nAll patients who are enrolled in the program undergo an education session prior to their first appointment. This is important in discussing the role of opioid deprescribing to discontinuation and improvements in pain37 and that enrollment in the program is voluntary. The session reviews evidence and introduces the patients to the interdisciplinary team, including psychology, nursing, nurse practitioners, administration, and physicians. A small section includes the possibility of buprenorphine-naloxone for some patients, specifically those with addiction or suspected opioid-induced hyperalgesia38,39 and/or opioid antinociceptive tolerance.40 About 30% of patients presenting to tertiary chronic pain programs have a comorbidity of borderline personality disorder, leading to higher complexity for both the treatment of their pain and mental health.41 Having skilled therapists with training in DBT has been extremely helpful in improving psychological distress and hence pain outcomes. Often patients with high distress and high anxiety require significant reassurance, validation, and education prior to the buprenorphine-naloxone induction, similar to patients with a history of trauma/PTSD.\n\nEducation is key. Handouts and confirmation of the protocol and possible side effects are key. A video, forthcoming from Alberta Health Services, Addiction and Mental Health, will add extra education as well. The patient should be advised of proper administration of the medication. Phone calls on day 2 are extremely important to determine dose and alleviate anxiety.\n\nOften, a difficulty in tolerating the medication stems from ingestion of the medication orally, instead of letting the medication be absorbed sublingually. This can lead to gastrointestinal upset, nausea, and vomiting. Larger tablets (i.e., an 8 mg SL tab) will take longer to dissolve (up to 10–15 min). If any portion of the tablet is orally ingested, the patient will have a higher chance of experiencing gastrointestingal side effects. When this is suspected, it may also be advised for the patient to rinse his or her mouth after dissolving the medication rather than swallowing the saliva, thereby minimizing oral ingestion.\n\nIt is important to discuss the risk of precipitated withdrawal with the patient, along with proper management of it. Precipitated withdrawal occurs when the patient starts buprenorphine-naloxone before sufficient opioid withdrawal is reached (i.e., there are still opioids in the system). The patient is thus advised to wait for the symptoms of precipitated withdrawal, which often presents as a rapid rise in withdrawal symptoms, to settle and for natural opioid withdrawal to occur, prior to continuing induction. This may take 3 to 4 h. Withdrawal symptoms may be alleviated during the process with the judicial use of medications such as clonidine and gabapentin.\n\nConclusions\n\nC.D. and K.S. both highlight complex chronic pain and opioid use disorder cases that were facilitated via telemedicine during the COVID-19 pandemic. In the case of C.D. it was an abrupt transition that, without the remote capabilities being given to the team to engage patients, may have ended with greater distress. The case of K.S. illustrates that with proper instructions by the team in advance of starting buprenorphine-naloxone, a home buprenorphine induction of a patient on high-dose opioids can be managed safely by the patient in the comfort of his or her own home. Telemedicine has been thrust to the forefront of health care in the past month. Based on our positive interactions with the team and patients and the ability to bring the team together to solve complex situations at the drop of a hat, it is hard to imagine returning to health care without the ability to remotely assess and interact with our patients post-COVID-19.\n\nDisclosure Statement\n\nHance Clarke has not declared any conflicts of interest. Aliza Weinrib has not declared any conflicts of interest. Yuvaraj Kotteeswaran has not declared any conflicts of interest. Joel Katz has not declared any conflicts of interest. Alvis Yu has not declared any conflicts of interest. Robert Tanguay has not declared any conflicts of interest.\n\nAppendix A. Example of a home initiation prescription for buprenorphine-naloxone\n\nName: JOHN DOE\n\nDate of issue: July 1, 2020\n\nDay 1: Buprenorphine-naloxone 2 mg SL q1 h PRN, maximum 16 mg (8 tabs)\n\nDay 2: Buprenorphine-naloxone 16 mg SL QAM (2 × 8 mg tabs) and 2 mg SL q1 h PRN, maximum 8 mg (4 tabs) for maximum total daily dose of 24 mg\n\nDispense 2 × 8 mg tabs and 12 × 2 mg tabs. Dispense all at once. No daily or witnessed dosing.\n\nNote: Discontinue all other opioids. Advise patient to stop Immediate release (IR) opioid doses 12 h prior to first dose and Controlled release/Sustained release (CR/SR) doses 24 h prior to first dose.\n==== Refs\nReferences\n\n1. Shanthanna H, Strand NH, Provenzano DA, Lobo CA, Eldabe S, Bhatia A, Wegener J, Curtis K, Cohen SP, Narouze S. Caring for patients with pain during the COVID-19 pandemic: consensus recommendations from an international expert panel. Anaesthesia. 2020;75 (7 ):935–44. doi:10.1111/anae.15076.32259288\n2. Clarke H, Azargive S, Montbriand J, Nicholls J, Sutherland A, Valeeva L, Boulis S, McMillan K, Ladak SSJ, Ladha K. Opioid weaning and pain management in postsurgical patients at the Toronto General Hospital Transitional Pain Service. Canadian J Pain. 2018;2 (1 ):236–47. doi:10.1080/24740527.2018.1501669.\n3. Volkin S How has COVID-19 impacted supply chains around the world? Johns Hopkins University; Published 2020. https://hub.jhu.edu/2020/04/06/goker-aydin-global-supply-chain/.\n4. Clarke H, Abdool I 4 crucial health-care lessons Canada needs to learn from COVID-19. CBC News; Published 2020 [Accessed 2020 Apr. 5]. https://www.cbc.ca/news/opinion/opinion-canada-health-care-covid-19-1.5510548.\n5. Struminger BB, Arora S. Leveraging telehealth to improve health care access in Rural America: it takes more than bandwidth. Ann Intern Med. 2019;171 (5 ):376–77. doi:10.7326/M19-1200.31108511\n6. Saligram S, Bielefeldt K. The two sides of opioids in cyclical vomiting syndrome. N Am J Med Sci. 2014;6 (3 ):114–18. doi:10.4103/1947-2714.128472.24741549\n7. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003;35 (2 ):253–59. doi:10.1080/02791072.2003.10400007.12924748\n8. Hammig R, Kemter A, Strasser J, Strasser J, von Bardeleben U, Gugger B, Walter M, Dürsteler K. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the “Bernese method”. Subst Abuse Rehabil. 2016;7 :99–105. doi:10.2147/SAR.S109919.27499655\n9. Kornfeld H, Reetz H. Transdermal buprenorphine, opioid rotation to sublingual buprenorphine, and the avoidance of precipitated withdrawal: a review of the literature and demonstration in three chronic pain patients treated with butrans. Am J Ther. 2015;22 (3 ):199–205. doi:10.1097/MJT.0b013e31828bfb6e.23846520\n10. Raheemullah A, Lembke A. Buprenorphine induction without opioid withdrawal: a case series of 15 opioid-dependent inpatients induced on buprenorphine using microdoses of transdermal buprenorphine. Am J Ther. 2019. doi:10.1097/MJT.0000000000001108.\n11. Klaire S, Zivanovic R, Barbic SP, Sandhu R, Mathew N, Azar P. Rapid micro-induction of buprenorphine/naloxone for opioid use disorder in an inpatient setting: a case series. Am J Addict. 2019;28 (4 ):262–65. doi:10.1111/ajad.12869.30901127\n12. Lee DS, Hann JE, Klaire SS, Nikoo M, Negraeff MD, Rezazadeh-Azar P. Rapid induction of buprenorphine/naloxone for chronic pain using a microdosing regimen: a case report. A A Pract. 2020;14 (2 ):44–47. doi:10.1213/XAA.0000000000001138.31770128\n13. Canada H. Subsection 56(1)class exemption for patients, practitioners and pharmacists prescribing and providing controlled substances in Canada during the coronavirus pandemic; Published 2020 [Accessed 2020 Apr.]. https://www.canada.ca/en/health-canada/services/health-concerns/controlled-substances-precursor-chemicals/policy-regulations/policy-documents/section-56-1-class-exemption-patients-pharmacists-practitioners-controlled-substances-covid-19-pandemic.html.\n14. Strosahl KD, Robinson PJ, GUstavsson T. Brief interventions for radical change: principles and practice of focused acceptance and commitment therapy. Oakland (CA): New Harbinger Publications; 2012.\n15. Polk KL, Benjamin S, Webster M, Olaz FO. The essential guide to the ACT Matrix: a step-by-step approach to using the ACT Matrix model in clinical practice. Oakland (CA): New Harbinger Publications; 2016.\n16. Linehan M. DBT skills training manual. 2nd ed. New York (NY): Guilford Press; 2014.\n17. Jensen MP. Hypnosis for chronic pain management: a new hope. Pain. 2009;146 (3 ):235–37. doi:10.1016/j.pain.2009.06.027.19596518\n18. Vasant DH, Whorwell PJ. Gut-focused hypnotherapy for Functional Gastrointestinal Disorders: evidence-base, practical aspects, and the Manchester Protocol. Neurogastroenterol Motil. 2019;31 (8 ):e13573. doi:10.1111/nmo.13573.30815936\n19. Palsson OS. Hypnosis treatment of gastrointestinal disorders: a comprehensive review of the empirical evidence. Am J Clin Hypn. 2015;58 (2 ):134–58. doi:10.1080/00029157.2015.1039114.26264539\n20. Rivat C, Ballantyne J. The dark side of opioids in pain management: basic science explains clinical observation. Pain Rep. 2016;1 (2 ):e570. doi:10.1097/PR9.0000000000000570.29392193\n21. Weinrib AZ, Burns LC, Mu A, Azam MA, Ladak SSJ, McRae K, Katznelson R, Azargive S, Tran C, Katz J. A case report on the treatment of complex chronic pain and opioid dependence by a multidisciplinary transitional pain service using the ACT Matrix and buprenorphine/naloxone. J Pain Res. 2017;10 :747–55. doi:10.2147/JPR.S124566.28392713\n22. Smirnov A, Kemp R. Use and misuse of opioid replacement therapies: a Queensland study. Subst Use Misuse. 2012;47 (1 ):78–85. doi:10.3109/10826084.2011.629017.22216993\n23. Bruneau J, Ahamad K, Goyer ME, Poulin G, Selby P, Fischer B, Wild TC, Wood E. Management of opioid use disorders: a national clinical practice guideline. CMAJ. 2018;190 (9 ):E247–E257. doi:10.1503/cmaj.170958.29507156\n24. Michael ES, Burns JW. Catastrophizing and pain sensitivity among chronic pain patients: moderating effects of sensory and affect focus. Ann Behav Med. 2004;27 (3 ):185–94. doi:10.1207/s15324796abm2703_6.15184094\n25. Vowles KE, McCracken LM, O’Brien JZ. Acceptance and values-based action in chronic pain: a three-year follow-up analysis of treatment effectiveness and process. Behaviour Research and Therapy. 2011;49 (11 ):748–55. doi:10.1016/j.brat.2011.08.002.21885034\n26. Caddy P, Smith K. A quick-reference guide for prescribing buprenorphine/naloxone (Suboxone) in the outpatient setting. BC Med J. 2018;60 :392–97.\n27. Lee JD, Grossman E, DiRocco D, Gourevitch MN. Home buprenorphine/naloxone induction in primary care. J Gen Intern Med. 2009;24 (2 ):226–32. doi:10.1007/s11606-008-0866-8.19089508\n28. Lee JD, Vocci F, Fiellin DA. Unobserved “home” induction onto buprenorphine. J Addict Med. 2014;8 (5 ):299–308. doi:10.1097/ADM.0000000000000059.25254667\n29. Sohler NL, Li X, Kunins HV, Sacajiu G, Giovanniello A, Whitley S, Cunningham CO. Home- versus office-based buprenorphine inductions for opioid-dependent patients. J Subst Abuse Treat. 2010;38 (2 ):153–59. doi:10.1016/j.jsat.2009.08.001.19801178\n30. Amass L, Kamien JB, Mikulich SK. Thrice-weekly supervised dosing with the combination buprenorphine-naloxone tablet is preferred to daily supervised dosing by opioid-dependent humans. Drug Alcohol Depend. 2001;61 (2 ):173–81. doi:10.1016/S0376-8716(00)00141-1.11137282\n31. Bell J, Shanahan M, Mutch C, Rea F, Ryan A, Batey R, Dunlop A, Winstock A. A randomized trial of effectiveness and cost-effectiveness of observed versus unobserved administration of buprenorphine-naloxone for heroin dependence. Addiction. 2007;102 (12 ):1899–907. doi:10.1111/j.1360-0443.2007.01979.x.17784896\n32. Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13 (3 ):293–308. doi:10.3109/00952998709001515.3687892\n33. Eccleston C, Blyth FM, Dear BF, Fisher EA, Keefe FJ, Lynch ME, Palermo TM, Reid MC, Williams ACDC. Managing patients with chronic pain during the Covid-19 outbreak: considerations for the rapid introduction of remotely supported (e-health) pain management services. Pain. 2020;161 (5 ):889–93. doi:10.1097/j.pain.0000000000001885.32251203\n34. Weinrib A, Azam MA, Latman V, Janmohamed T, Clarke H, Katz J. Manage my pain: a patient-driven mobile platform to prevent & manage chronic postsurgical pain. In: El Morr C, editor. Novel applications of virtual communities in healthcare. Hershey (PA): IGI Global. 2017. p. 93–126.\n35. Nicholls JL, Azam MA, Burns LC, Englesakis M, Sutherland AM, Weinrib AZ, Katz J, Clarke H. Psychological treatments for the management of postsurgical pain: a systematic review of randomized controlled trials. Patient Relat Outcome Meas. 2018;9 :49–64. doi:10.2147/PROM.S121251.29403322\n36. Weinrib AZ, Azam MA, Birnie KA, Burns LC, Clarke H, Katz J. The psychology of chronic post-surgical pain: new frontiers in risk factor identification, prevention and management. Br J Pain. 2017;11 (4 ):169–77. doi:10.1177/2049463717720636.29123661\n37. Frank JW, Lovejoy TI, Becker WC, Morasco BJ, Koenig CJ, Hoffecker L, Dischinger HR, Dobscha SK, Krebs EE. Patient outcomes in dose reduction or discontinuation of long-term opioid therapy: a systematic review. Ann Intern Med. 2017;167 (3 ):181–91. doi:10.7326/M17-0598.28715848\n38. Koppert W, Ihmsen H, Korber N, Wehrfritz A, Sittl R, Schmelz M, Schüttler J. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain. 2005;118 (1–2 ):15–22. doi:10.1016/j.pain.2005.06.030.16154698\n39. Weiner M, Sarantopoulos C, Gordon E. Transdermal buprenorphine controls central neuropathic pain. J Opioid Manag. 2012;8 (6 ):414–15. doi:10.5055/jom.2012.0141.23264319\n40. Ossipov MH, Lai J, Vanderah TW, Porreca F. Induction of pain facilitation by sustained opioid exposure: relationship to opioid antinociceptive tolerance. Life Sci. 2003;73 (6 ):783–800. doi:10.1016/S0024-3205(03)00410-7.12801599\n41. Sansone RA, Sansone LA. Chronic pain syndromes and borderline personality. Innov Clin Neurosci. 2012;9 :10–14.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2474-0527",
"issue": "4(1)",
"journal": "Canadian journal of pain = Revue canadienne de la douleur",
"keywords": "COVID-19; buprenorphine-naloxone; chronic pain; suboxone; telemedicine; telepsychology",
"medline_ta": "Can J Pain",
"mesh_terms": null,
"nlm_unique_id": "101720589",
"other_id": null,
"pages": "224-235",
"pmc": null,
"pmid": "33987501",
"pubdate": "2020-09-15",
"publication_types": "D002363:Case Reports",
"references": "21885034;19089508;22216993;11137282;23264319;31833872;30901127;15184094;32259288;28392713;12924748;17784896;22347686;16154698;30815936;29392193;28715848;29403322;26264539;19801178;31770128;24741549;27499655;29123661;19596518;25254667;3687892;32251203;23846520;12801599;29507156;31108511",
"title": "Remote buprenorphine-naloxone initiation as an essential service for people with chronic pain and opioid dependence during the COVID-19 pandemic: Case reports, clinical pathways, and implications for the future.",
"title_normalized": "remote buprenorphine naloxone initiation as an essential service for people with chronic pain and opioid dependence during the covid 19 pandemic case reports clinical pathways and implications for the future"
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"abstract": "Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively novel class of oral medications for the treatment of type 2 diabetes mellitus (T2DM). Their use has increased recently due to their beneficial renal and cardiovascular outcomes, but they come with the rare risk of diabetic ketoacidosis (DKA) at normal or slightly elevated glucose values, termed euglycemic DKA (euDKA). Recently, carbohydrate-deprived, ketogenic diets have gained popularity due to benefits of weight loss and improved control of T2DM. We describe 2 patients with T2DM who developed euDKA caused by SGLT2 inhibitor use while on a ketogenic diet and provide a review of the literature.\nWe describe the hospital course, laboratory data, and treatment of 2 patients and provide a literature review.\nBoth of our patients were found to have normal or mildly elevated serum glucose levels, with an elevated anion gap and ketosis, representative of euDKA. The first patient developed euDKA after only 1 dose of empagliflozin, while the second patient developed euDKA after only 1 week of being on a ketogenic diet while on an SGLT2 inhibitor.\nWhile there have been a few reports of euDKA with SGLT2 inhibitors and ketogenic diets, many physicians prescribing these medications may not be aware of this association. Therefore, they must inform their patients to avoid a ketogenic diet if on an SGLT2 inhibitor. If a patient presents with symptoms of DKA and is eating a carbohydrate-free diet while taking an SGLT2 inhibitor, there should be a low threshold to screen for DKA.",
"affiliations": "Stony Brook Medicine Department of Internal Medicine, Stony Brook University Hospital, Stony Brook, New York.;Stony Brook Medicine Department of Endocrinology, Stony Brook University Hospital, Stony Brook, New York.",
"authors": "Mistry|Serena|S|;Eschler|Deirdre Cocks|DC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.aace.2020.11.009",
"fulltext": "\n==== Front\nAACE Clin Case Rep\nAACE Clin Case Rep\nAACE Clinical Case Reports\n2376-0605\nAmerican Association of Clinical Endocrinology\n\nS2376-0605(20)31010-5\n10.1016/j.aace.2020.11.009\nCase Series\nEuglycemic Diabetic Ketoacidosis Caused by SGLT2 Inhibitors and a Ketogenic Diet: A Case Series and Review of Literature\nMistry Serena MD serena.mistry@stonybrookmedicine.edu\n1∗\nEschler Deirdre Cocks MD 2\n1 Stony Brook Medicine Department of Internal Medicine, Stony Brook University Hospital, Stony Brook, New York\n2 Stony Brook Medicine Department of Endocrinology, Stony Brook University Hospital, Stony Brook, New York\n∗ Address correspondence and reprint requests to Dr Serena Mistry, Stony Brook Medicine Department of Internal Medicine, Stony Brook University Hospital, Department of Internal Medicine, HSC Level 16, 101 Nicolls Road, Stony Brook, NY 11794-8160. serena.mistry@stonybrookmedicine.edu\n28 12 2020\nJan-Feb 2021\n28 12 2020\n7 1 1719\n© 2020 AACE. Published by Elsevier Inc.\n2020\nAACE\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nSodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively novel class of oral medications for the treatment of type 2 diabetes mellitus (T2DM). Their use has increased recently due to their beneficial renal and cardiovascular outcomes, but they come with the rare risk of diabetic ketoacidosis (DKA) at normal or slightly elevated glucose values, termed euglycemic DKA (euDKA). Recently, carbohydrate-deprived, ketogenic diets have gained popularity due to benefits of weight loss and improved control of T2DM. We describe 2 patients with T2DM who developed euDKA caused by SGLT2 inhibitor use while on a ketogenic diet and provide a review of the literature.\n\nMethods\n\nWe describe the hospital course, laboratory data, and treatment of 2 patients and provide a literature review.\n\nResults\n\nBoth of our patients were found to have normal or mildly elevated serum glucose levels, with an elevated anion gap and ketosis, representative of euDKA. The first patient developed euDKA after only 1 dose of empagliflozin, while the second patient developed euDKA after only 1 week of being on a ketogenic diet while on an SGLT2 inhibitor.\n\nConclusion\n\nWhile there have been a few reports of euDKA with SGLT2 inhibitors and ketogenic diets, many physicians prescribing these medications may not be aware of this association. Therefore, they must inform their patients to avoid a ketogenic diet if on an SGLT2 inhibitor. If a patient presents with symptoms of DKA and is eating a carbohydrate-free diet while taking an SGLT2 inhibitor, there should be a low threshold to screen for DKA.\n\nKey words\n\neuglycemic DKA\nSGLT2 inhibitor\nketogenic diet\nAbbreviations\n\nDKA, diabetic ketoacidosis\neuDKA, euglycemic DKA, decarboxylase\nHbA1C, hemoglobin A1C\nSGLT2, sodium-glucose cotransporter-2\nT1DM, type 1 diabetes mellitus\nT2DM, type 2 diabetes mellitus\n==== Body\nIntroduction\n\nDiabetic ketoacidosis (DKA), a metabolic complication commonly seen in patients with type 1 diabetes mellitus (T1DM), also occurs in patients with T2DM. It is caused by an insulin deficiency and an increase in counter-regulatory stress hormones, including glucagon, leading to hyperglycemia, ketosis, and electrolyte abnormalities.1 EuDKA is DKA with normal or mildly elevated serum glucose levels and is defined by the Food and Drug Administration as a serum glucose level of ≤250 mg/dL.2,3 SGLT2 inhibitors were approved in 2013 for the treatment of T2DM.4 These agents cause glycosuria and increase the production of ketones by switching from glucose to lipid utilization. A ketogenic diet, low-carbohydrate, high-fat, or moderate-protein diet can also shift the body toward ketosis because the body begins to break down fats as a source of energy.5 The Food and Drug Administration issued warnings for SGLT2 inhibitors, including an increased risk for ketoacidosis, urinary tract infections, and amputations.3,6 A review of SGLT2 inhibitor-associated ketoacidosis revealed that 71% of the cases were euDKA.2 We present 2 cases of euDKA in patients using SGLT2 inhibitors and on ketogenic diets.\n\nCase 1 Presentation\n\nA 47-year-old woman with a past medical history of T2DM diagnosed 2 months prior to admission, hyperlipidemia, and obesity who presented to the emergency department with acute-onset left-arm numbness and chest pain and a few months history of polyuria and polydipsia. She had been prescribed metformin 500 mg twice daily, empagliflozin 25 mg daily, and linagliptin 5 mg daily. The day prior to admission, she took her first and only dose of empagliflozin, an SGLT2 inhibitor. She had been on a low-carbohydrate diet for 2 months. On presentation, the patient’s plasma glucose level was 187 mg/dL, bicarbonate level was 11 mmol/L, anion gap level was 22 mmol/L, β-hydroxybutyrate level was 6.78 mmol/L, hemoglobin (Hb) A1C level was 13.6% (125 mmol/mol International Federation of Clinical Chemistry units), and her venous blood gas pH was 7.24. Cardiac causes of chest pain were ruled out, with negative troponins, normal electrocardiogram, and chest X-ray. Her laboratory results were consistent with euDKA. The patient was admitted to the intensive care unit and was placed on an insulin drip and dextrose drip per the hospital DKA protocol, requiring the insulin drip for 5 days prior to resolving her acidosis. The patient was discharged on glargine, lispro, and metformin. She was told to discontinue empagliflozin.\n\nCase 2 Presentation\n\nA 34 year-old-man with a past medical history of T2DM diagnosed >5 years prior to presentation, hypertension, hyperlipidemia, and obesity presented to the emergency department with 1 day of chest pain associated with shortness of breath. His home diabetes regimen included canagliflozin 100 mg daily, started 2 months previously, and subcutaneous dulaglutide 0.5 mL every 7 days. He was not on metformin because of a drug allergy. He had started a ketogenic diet a week before presentation. On presentation, her laboratory tests revealed a serum glucose level of 251 mg/dL, bicarbonate level of 12 mmol/L, anion gap level of 24 mmol/L, β-hydroxybutyrate level of 5 mmol/L, HbA1C level of 8.2% (66 mmol/mol International Federation of Clinical Chemistry units), venous blood gas pH of 7.27, D-dimer level of 380 ng/mL, and negative troponins. The electrocardiogram showed sinus tachycardia and a subsequent workup, including an echocardiogram, nuclear stress test, and a computed tomography angiogram, ruled out a cardiac or pulmonary etiology. The patient was admitted to the intensive care unit for euDKA and placed on an insulin drip and dextrose drip. The hospital protocol required the insulin drip for 3 days before resolving the acidosis. The patient was discharged on dulaglutide and glargine and was advised to discontinue canagliflozin.\n\nDiscussion\n\nThe duration of treatment with an SGLT2 inhibitor before the onset of DKA varies in reports from 0.3 to 420 days.7 Interestingly, in both our patients, euDKA took 3 or more days to resolve. Studies have shown that euDKA generally takes twice as long to resolve as classic DKA, 92 hours versus 35 hours, respectively.8 The underlying etiology of this prolonged acidosis is still unclear. SGLT2 inhibitors have gained popularity because of their renal and cardiovascular benefits. These agents reduce the risk of major adverse cardiac outcomes by 11% in patients with a history of atherosclerotic cardiovascular disease, cardiovascular death or hospitalization for heart failure by 23%, and progression of renal disease by 45%.9 Other benefits include weight loss, increased high-density lipoprotein levels, and a small decrease in blood pressure.10 Adverse effects include genital and urinary tract infections, volume depletion, acute kidney injury, bone fractures, Fournier’s gangrene, lower extremity amputations, and DKA.3,6,10,11\n\nSGLT2 inhibitors have been used off-label in patients with T1DM.1 SGLT2 inhibitor-associated DKA in T1DM has a rate of 5% to 12%, compared with <0.1% in T2DM.1 Another study determined that one third of all DKA cases may be attributed to T2DM.12 Precipitating factors leading to SGLT2 inhibitor-associated DKA include insulin reduction, omission, or deficiency along with surgery, alcohol abuse, exercise, and low-carbohydrate diets.1,7 SGLT2 inhibitors inhibit glucose reabsorption by proximal renal tubules and lead to a switch from glucose to lipid utilization, thereby increasing production of ketones in the liver by increasing glucagon and decreasing the insulin-glucagon ratio. This leads to ketogenesis, gluconeogenesis, and glycogenolysis.1,13 SGLT2 inhibitors may cause glucagon secretion by a direct effect on pancreatic α-cells and also reduce renal ketone body clearance.13,14 The near normal blood glucose levels seen in euDKA caused by SGLT2 inhibitors results from a balance between endogenous glucose production and renal glucose clearance.1 The pathophysiology of classic DKA is similar to that of euglycemic DKA, however the latter occurs with near normal or slightly elevated blood glucose levels, which often results in a delay in diagnosis. Similarly, with ketogenic diets there is an inadequate supply of carbohydrates, thus the body begins to burn fats for energy, which are then converted into fatty acids and ketones in the liver. In the 1920s ketogenic diets were used to treat drug-resistant childhood epilepsy. Since then, the diet has been studied in neurodegenerative diseases including Alzheimer's and Parkinson's disease because of its neuroprotective effects.5 Novel benefits of the ketogenic diet include better control of T2DM. In some reports, patients with T2DM experienced a 34% reduction of HbA1C, lower triglyceride levels, increased high-density lipoprotein levels, and weight loss in the first year of a low-carbohydrate diet compared with those on high-carbohydrate diets.15,16 Risks of ketogenic diets include nausea, vomiting, malnutrition, pancreatitis, hypoglycemia, osteopenia, nephrolithiasis, and cardiomyopathy.5\n\nTo date, few cases have been reported of euDKA associated with SGLT2 inhibitor use and ketogenic diets in patients with T2DM. Table compares and contrasts cases reported in literature.17, 18, 19, 20, 21 To our knowledge, our case is the first report of euDKA occurring after just 1 dose of an SGLT2 inhibitor while on a ketogenic diet. Table indicates the number of days a patient received an SGLT2 inhibitor before developing euDKA, which ranged from 1 day (our study) to 365 days. It also shows the number of days a patient was on a low-carbohydrate diet before developing euDKA, which ranged from 7 to 3960 days. Additionally, both our patient cases demonstrate the prolonged need for insulin in such a setting (3 and 5 days). Many previously reported cases do not mention this. Of note, glutamic acid decarboxylase antibodies and islet antigen-2 antibodies were not assayed in either case. It is possible that these patients could have had a missed diagnosis of T1DM or latent autoimmune diabetes. A previous study showed that 22% of patients who presented with DKA were misdiagnosed with T2DM and had T1DM or latent autoimmune diabetes.22 In addition, in patient case 2, the glucose level was 251 mg/dL, which was near the cutoff level for a diagnosis of euDKA, which is a glucose concentration of <250 mg/dL.Table Reported Cases of SGLT2 Inhibitor Use Associated With euDKA and Low-Carbohydrate Diets in Patients With T2DM\n\nPatient age (y)\tGender\tNumber of years patient had T2DM\tNumber of days on a low-carbohydrate diet before developing euDKA\tNumber of days patient took SGLT2 inhibitor before developing euDKA\tPlasma blood glucose (mg/dL) on admission to the hospital for euDKA\tHbA1C at the time of admission for euDKA\tNumber of days patient required insulin drip\tReference\t\n32\tFemale\t22\t∼3960\t13\t191\t9.3% (78 mmol/mol IFCC)\tUnknown\t17\t\n44\tMale\t16\tUnknown\t3-4\t180\t9.3% (78 mmol/mol)\tUnknown\t18\t\n64\tFemale\tUnknown\t60\t365\t∼185.59\t7.5% (58 mmol/mol IFCC)\tUnknown\t19\t\n73\tMale\t10\t7\tUnknown\tUnknown\nPoint-of-care blood glucose: 143\tUnknown\tUnknown\t20\t\n31\tFemale\tUnknown\t14\tUnknown\t139\tUnknown\tUnknown\t21\t\n34a\tMale\t>5\t7\t∼60\t251\tHbA1C 8.2% (66 mmol/mol IFCC)\t3\t\t\n47a\tFemale\t∼0.17\t∼60\t1\t187\tHbA1C 13.6% (125 mmol/mol IFCC)\t5\t\t\nAbbreviations: euDKA = euglycemic diabetic ketoacidosis; HbA1C = hemoglobin A1C; IFCC = International Federation of Clinical Chemistry and Laboratory Medicine; SGLT2 = sodium-glucose cotransporter-2; T2DM = type 2 diabetes mellitus.\n\na Patient case 1 and 2 from our report included for comparison.\n\nPatients should maintain an appropriate carbohydrate-controlled diet while taking an SGLT2 inhibitor, given the increased risk for DKA. To prevent SGLT2 inhibitor-associated DKA, these agents should be withheld in circumstances that may trigger DKA including infection, 3 days prior to surgery, excessive alcohol use, or dehydration.1,3\n\nConclusion\n\nRecently, the increased use of ketogenic diets has been accompanied by reports of patients admitted to the hospital for euDKA in the setting of SGLT2 inhibitor use while on a ketogenic diet. If a patient on an SGLT2 inhibitor and ketogenic diet presents with mildly elevated glucose levels, ketosis, and an elevated anion gap, euDKA should be suspected and included in the differential diagnosis. Patients taking SGLT2 inhibitors should be advised to avoid a ketogenic diet. If a patient develops euDKA in the setting of SGLT2 inhibitor use and a ketogenic diet, the SGLT2 inhibitor should be stopped and avoided in the future.\n\nDisclosure\n\nThe authors have no multiplicity of interest to disclose.\n==== Refs\nReferences\n\n1 Goldenberg R.M. Berard L.D. Cheng A.Y.Y. SGLT2 Inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis Clin Ther 38 12 2016 2654 2664 28003053\n2 Blau J.E. Tella S.H. Taylor S.I. Rother K.I. Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data Diabetes Metab Res Rev 33 8 2017 e2924 10.1002/dmrr.2924\n3 FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections 2015 https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious\n4 Invokana: highlights of prescribing information 2013 [updated 2013] https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf\n5 Wlodarek D. Role of ketogenic diets in neurodegenerative diseases (Alzheimer's disease and Parkinson's disease) Nutrients 11 1 2019 169\n6 FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) 2017 https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-confirms-increased-risk-leg-and-foot-amputations-diabetes-medicine\n7 Bonora B.M. Avogaro A. Fadini G.P. Sodium-glucose co-transporter-2 inhibitors and diabetic ketoacidosis: an updated review of the literature Diabetes Obes Metab 20 1 2018 25 33 28517913\n8 Rafey M.F. Butt A. Coffey B. Prolonged acidosis is a feature of SGLT2i-induced euglycaemic diabetic ketoacidosis Endocrinol Diabetes Metab Case Rep 2019 2019 19-0087\n9 Zelniker T.A. Wiviott S.D. Raz I. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials Lancet 393 10166 2019 31 39 30424892\n10 Desouza C.V. Gupta N. Patel A. Cardiometabolic effects of a new class of antidiabetic agents Clin Ther 37 6 2015 1178 1194 25754876\n11 McGill J.B. Subramanian S. Safety of sodium-glucose co-transporter 2 inhibitors Am J Cardiol 132 10 2019 S49 S57\n12 Wang Z.H. Kihl-Selstam E. Eriksson J.W. Ketoacidosis occurs in both type 1 and type 2 diabetes--a population-based study from northern Sweden Diabet Med 25 7 2008 867 870 18644074\n13 Qiu H. Novikov A. Vallon V. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives Diabetes Metab Res Rev 33 5 2017 e2886\n14 Bonner C. Kerr-Conte J. Gmyr V. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion Nat Med 21 2015 512 517 25894829\n15 van Zuuren E.J. Fedorowicz Z. Kuijpers T. Pijl H. Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments Am J Clin Nutr 108 2 2018 300 331 30007275\n16 Snorgaard O. Poulsen G.M. Andersen H.K. Astrup A. Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes BMJ Open Diabetes Res Care 5 1 2017 354\n17 Hayami T. Kato Y. Kamiya H. Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet J Diabetes Investig 6 5 2015 587 590\n18 Sood M. Simon B. Ryan K.F. Zebrower M. Euglycemic diabetic ketoacidosis with SGLT2 inhibitor use in a patient on the atkins diet: a unique presentation of a known side effect AACE Clin Case Rep 4 2 2018 e104 e107\n19 Sinha S. Gavaghan D. Yew S. Euglycaemic ketoacidosis from an SGLT2 inhibitor exacerbated by a ketogenic diet Med J Aust 212 1 2020 46\n20 Grammatiki M. Rapti E. Dina D. Dapagliflozin and atkins diet in a patient with type 2 diabetes mellitus: a combination that should be avoided Endocrine Abstracts 56 2018 324\n21 Earle M. Ault B. Bonney C. Euglycemic diabetic ketoacidosis in concurrent very low-carbohydrate diet and sodium-glucose transporter-2 inhibitor use: a case report Clin Pract Cases Emerg Med 4 2 2020 185 188 32426668\n22 Hamblin P.S. Wong R. Ekinci E.I. SGLT2 inhibitors increase the risk of diabetic ketoacidosis developing in the community and during hospital admission J Clin Endocrinol Metab 104 8 2019 3077 3087 30835263\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2376-0605",
"issue": "7(1)",
"journal": "AACE clinical case reports",
"keywords": "DKA, diabetic ketoacidosis; HbA1C, hemoglobin A1C; SGLT2 inhibitor; SGLT2, sodium-glucose cotransporter-2; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; euDKA, euglycemic DKA, decarboxylase; euglycemic DKA; ketogenic diet",
"medline_ta": "AACE Clin Case Rep",
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"other_id": null,
"pages": "17-19",
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"pmid": "33851013",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "25754876;31789435;30835263;28003053;28099783;30007275;28736981;30650523;30424892;32426668;25894829;31741440;18644074;28517913;26417418;31600728;28316796",
"title": "Euglycemic Diabetic Ketoacidosis Caused by SGLT2 Inhibitors and a Ketogenic Diet: A Case Series and Review of Literature.",
"title_normalized": "euglycemic diabetic ketoacidosis caused by sglt2 inhibitors and a ketogenic diet a case series and review of literature"
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"abstract": "BACKGROUND\nRecognition of rocuronium-induced anaphylaxis is often challenging, owing to its diverse clinical manifestations. Regarding treatment, several reports have described the efficacy of sugammadex, while conflicting reports have also been published.\n\n\nMETHODS\nA 71-year-old man was scheduled to undergo split-thickness skin grafting surgery on his hip. During the induction of general anesthesia, the patient developed profound circulatory collapse without any cutaneous manifestations, which required 40 min of cardiopulmonary resuscitation. Later, the patient developed circulatory collapse again during the induction of anesthesia for tracheostomy surgery, which apparently coincided with the administration of rocuronium. Rocuronium-induced anaphylactic shock was suspected, and the administration of sugammadex resulted in swift recovery of hemodynamics. The basophil activation test revealed a positive reaction to rocuronium.\n\n\nCONCLUSIONS\nThe possibility of rocuronium-induced anaphylaxis should be considered when the circulatory collapse coincides with rocuronium administration, even though cutaneous manifestation is absent. Sugammadex can be a treatment option in such atypical cases.",
"affiliations": "Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 1608582, Japan.;Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 1608582, Japan. jungo-k@a2.keio.jp.;Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 1608582, Japan.;Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 1608582, Japan.;Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.;Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.;Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.;Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 1608582, Japan.",
"authors": "Takise|Yoshiaki|Y|;Kato|Jungo|J|;Suhara|Tomohiro|T|;Yamada|Takashige|T|;Funakoshi|Takeru|T|;Takahashi|Hayato|H|;Amagai|Masayuki|M|;Morisaki|Hiroshi|H|",
"chemical_list": null,
"country": "Germany",
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"doi": "10.1186/s40981-020-00402-y",
"fulltext": "\n==== Front\nJA Clin Rep\nJA Clin Rep\nJA Clinical Reports\n2363-9024 Springer Berlin Heidelberg Berlin/Heidelberg \n\n402\n10.1186/s40981-020-00402-y\nCase Report\nLife-threatening rocuronium-induced anaphylactic shock without cutaneous manifestations successfully reversed with sugammadex: a case report\nTakise Yoshiaki yotti666@gmail.com 1 Kato Jungo jungo-k@a2.keio.jp 1 Suhara Tomohiro tomohiro_suhara@z5.keio.jp 1 Yamada Takashige yamada.z5@keio.jp 1 Funakoshi Takeru takeruf@a8.keio.jp 2 Takahashi Hayato hayato_takahashi@keio.jp 2 Amagai Masayuki amagai@a7.keio.jp 2 Morisaki Hiroshi morisaki@z8.keio.jp 1 1 grid.26091.3c0000 0004 1936 9959Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 1608582 Japan \n2 grid.26091.3c0000 0004 1936 9959Department of Dermatology, Keio University School of Medicine, Tokyo, Japan \n7 12 2020 \n7 12 2020 \n12 2020 \n6 956 11 2020 26 11 2020 1 12 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Background\nRecognition of rocuronium-induced anaphylaxis is often challenging, owing to its diverse clinical manifestations. Regarding treatment, several reports have described the efficacy of sugammadex, while conflicting reports have also been published.\n\nCase\nA 71-year-old man was scheduled to undergo split-thickness skin grafting surgery on his hip. During the induction of general anesthesia, the patient developed profound circulatory collapse without any cutaneous manifestations, which required 40 min of cardiopulmonary resuscitation. Later, the patient developed circulatory collapse again during the induction of anesthesia for tracheostomy surgery, which apparently coincided with the administration of rocuronium. Rocuronium-induced anaphylactic shock was suspected, and the administration of sugammadex resulted in swift recovery of hemodynamics. The basophil activation test revealed a positive reaction to rocuronium.\n\nConclusion\nThe possibility of rocuronium-induced anaphylaxis should be considered when the circulatory collapse coincides with rocuronium administration, even though cutaneous manifestation is absent. Sugammadex can be a treatment option in such atypical cases.\n\nKeywords\nRocuroniumSugammadexAnaphylaxisBasophil activation testissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAnaphylaxis occurring during general anesthesia is a rare, but sometimes life-threatening event that has been reported to occur in up to 1:20,000 cases [1]. Among the causative agents of perioperative anaphylaxis, the most common are neuromuscular-blocking agents (NMBAs), with the highest incidence reported for rocuronium [1]. However, prompt recognition of rocuronium-induced anaphylaxis can be challenging, potentially causing a significant delay in the diagnosis and treatment, as the patients often fail to exhibit the typical cutaneous manifestations of anaphylaxis, such as pruritus and angioedema. Since the introduction of sugammadex as a reversal agent for rocuronium, numerous reports have documented the efficacy of sugammadex for rocuronium-induced anaphylaxis [2–4], although there are conflicting reports concerning its efficacy [5–7].\n\nHerein, we report a patient who developed profound circulatory collapse on two occasions associated with rocuronium-induced anaphylaxis. Informed consent for the publication of this case report was obtained from the patient.\n\nCase presentation\nA 71-year-old man (174 cm, 70 kg) with no known allergies was scheduled to undergo elective split-thickness skin grafting surgery on his hip. The previous skin surgery performed for skin cancer 6 months earlier under spinal anesthesia and inhalational general anesthesia without the use of NMBA had been uneventful. His medical history was also significant for myocardial infarction 15 months earlier that required a percutaneous coronary intervention to the right coronary artery lesion. The latest follow-up coronary angiography revealed 75% stenoses in the left anterior descending artery and in the left circumflex artery. At the time of the current surgery, he was under treatment with aspirin, perindopril, and rosuvastatin. His preoperative screening tests showed no major abnormalities, except for transthoracic echocardiography showing severe hypokinesia of the inferior wall of the left ventricle. The preanesthetic airway assessment revealed no signs of difficult ventilation/intubation (Mallanpati classification I).\n\nThe standard preanesthetic checkup revealed no significant abnormalities: non-invasive blood pressure, 120/55 mmHg; heart rate, 56 bpm (sinus rhythm); and SpO2, 99% on room air. General anesthesia was induced by intravenous administration of 100 mg propofol, 100 μg fentanyl, and 40 mg rocuronium. Immediately after the induction, however, difficulty in mask ventilation was perceived, with a recorded minimal SpO2 of 85%. Oral intubation was promptly performed, following which he became profoundly hypotensive, with blood pressure becoming unmeasurable with the non-invasive blood pressure monitor. Meanwhile, the electrocardiogram showed tachycardia (114 bpm) followed by significant bradycardia (44 bpm) with ST-segment elevation (maximal 0.34 μV) (Fig. 1). As his carotid pulse became impalpable, cardiac resuscitation was initiated. Return of spontaneous circulation was eventually obtained following intravenous injection of a total of 7.2 mg adrenaline and two extracorporeal defibrillations for ventricular fibrillation, approximately 40 min after the start of resuscitation. Because the hemodynamics remained unstable, extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pumping (IABP) were established (Fig. 2). During this entire period of circulatory collapse, the patient did not exhibit any cutaneous manifestations.\nFig. 1 ECG changes during the first episode of circulatory collapse in our patient. a Baseline ECG waveform (lead II) showing normal morphology of the QRS complexes and ST-segment. b ST-elevation and premature ventricular complexes seen in the early phase of the circulatory collapse\n\nFig. 2 Intractable circulatory collapse following the induction of general anesthesia for skin surgery. a Start of anesthesia, (b) Oral intubation, (c) Emergency call, (d) Recovery of spontaneous circulation, (e) Transfer to hybrid room, (f) Transfer to the intensive care unit. HR, heart rate; BP, blood pressure; SpO2, arterial oxygen saturation; s/dNIBP, systolic/diastolic non-invasively measured blood pressure; s/dABP, systolic/diastolic blood pressure measured through the arterial line; VF, ventricular fibrillation; CPR, cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pumping\n\n\n\nGiven his past medical history, the circulatory collapse was initially suspected as caused by acute coronary syndrome. However, a coronary angiography performed immediately after the event did not reveal any new positive findings. The skin surgery was canceled, and the patient was transferred to the intensive care unit. He was successfully weaned from ECMO and IABP on post-operative days (POD) 1 and 2, respectively. On the other hand, as his mechanical ventilatory support was expected to be prolonged due to concomitant aspiration pneumonia, a tracheostomy was scheduled on POD 9.\n\nAt arrival in the operating room on the scheduled day for tracheostomy, the baseline vital parameters were as follows: arterial blood pressure, 122/48 mmHg; HR, 56 bpm (sinus rhythm); and SpO2, 99% under an FiO2 of 40%. General anesthesia was induced by the administration of sevoflurane via the endotracheal tube. Then, following the administration of 50 mg rocuronium, the invasive arterial blood pressure monitor showed a sudden precipitous decrease up to 30/18 mmHg, which proved refractory to repeated intravenous injections of ephedrine (up to a total of 8 mg) and phenylephrine (up to a total of 0.8 mg). Although the patient still did not exhibit any cutaneous manifestations, rocuronium-induced anaphylaxis was suspected, as the onset of circulatory collapse appeared to be associated with rocuronium administration on both occasions. Consequently, 6 min after the rocuronium administration, 200 mg sugammadex was administered by intravenous injection. Apparently, coincidentally with the intravenous administration of sugammadex, the patient’s hemodynamics began to show sudden dramatic improvement, to the extent that further vasopressor administration was no longer needed (Fig. 3). The tracheostomy was performed successfully, as planned.\nFig. 3 Circulatory collapse following the administration of rocuronium for tracheostomy surgery, which was reversed by sugammadex. The systolic blood pressure decreased to 30 mmHg after the administration of rocuronium 50 mg, which recovered promptly by sugammadex 200 mg. a Start of anesthesia, (b) Restart of anesthesia. HR, heart rate; BP, blood pressure; SpO2, arterial oxygen saturation; s/dABP, systolic/diastolic blood pressure measured through the arterial line\n\n\n\nLaboratory examination revealed a marked elevation of the serum tryptase level to 7.7 μg/dL at 14 h after the tracheostomy. In addition, the basophil activation test (BAT) revealed a strong positive reaction to rocuronium, indicating that the repetitive episodes of circulatory collapses were attributable to rocuronium-induced anaphylaxis. Skin testing was avoided due to the potential risk of a fatal allergic reaction. The post-operative course was uneventful, and the patient was discharged home on POD 40 with no discernible sequelae.\n\nDiscussion\nIn the current case, we encountered abrupt life-threatening circulatory collapse immediately following the induction of general anesthesia on two occasions, which were eventually found to be attributable to rocuronium-induced anaphylaxis.\n\nThe absence of the typical cutaneous manifestations of anaphylaxis significantly delayed our recognition of anaphylaxis. While cutaneous manifestations, such as pruritus and angioedema, are commonly observed in patients with anaphylaxis, the current guidelines warn that approximately 10% of patients with anaphylaxis may not exhibit the typical cutaneous symptoms/signs, especially when the peripheral circulation is severely compromised [8]. Moreover, a recent survey demonstrated that only 20% of patients with rocuronium-induced anaphylaxis exhibited skin manifestations [1]. Therefore, it is crucial for the anesthesiologist to bear a high index of suspicion for rocuronium-induced anaphylaxis, in a patient developing circulatory collapse coincidentally with rocuronium administration, even in the apparent absence of cutaneous manifestations.\n\nClassically, IgE/Fcε receptor-mediated activation of mast cells/basophils has been proposed to be the main mechanism underlying rocuronium-induced anaphylaxis [9]. The quaternary ammonium structure of rocuronium is considered to be the major epitope in the IgE-mediated reactions [10]. Indeed, the elevated serum tryptase level and the positive result of the BAT support the involvement of mast cell/basophil activation in the present case. On the other hand, IgE-independent mechanisms, including direct activation of mast cells/basophils via Mas-related G-protein-coupled receptor X2 (MRGPRX2) and rocuronium-specific IgG-mediated neutrophil activation, have also been implicated [11]. Given the lack of the typical cutaneous manifestations, such non-canonical pathways were probably involved in the current case.\n\nAnother possible mechanism for profound circulatory collapse could be anaphylaxis-related coronary arterial vasospasm, which is designated as Kounis syndrome [12]. A previous report described the occurrence of rocuronium-induced Kounis syndrome [13]. Despite the negative findings of coronary angiography, the development of Kounis syndrome could also have contributed to the profound circulatory collapse in the present case, given the previous history of coronary artery disease and the ST-segment elevation observed during the circulatory collapse (Fig. 1).\n\nIn sharp contrast to the first episode, the swift recovery of the hemodynamics following sugammadex administration after the second episode of circulatory collapse strongly suggests the therapeutic potential of sugammadex for rocuronium-induced anaphylaxis. Numerous reports have documented successful reversal of rocuronium-induced anaphylaxis following sugammadex administration [3, 4]. The dramatic response in our case indicates that sugammadex may also be effective in cases of atypical anaphylaxis that fail to show cutaneous manifestations. An in vitro study suggests that pre-incubation with sugammadex is effective for preventing the rocuronium-induced anaphylactic processes [5]. Conversely, other reports have suggested that sugammadex administration failed to reverse already-activated basophils or cutaneous manifestations in rocuronium-allergic patients [6, 7]. Considering the findings collectively, we also doubt that sugammadex can halt the reaction of already-activated mast cells/basophils. Rather, when it is given shortly after the rocuronium administration, the encapsulation of unbound rocuronium may have been responsible for preventing further activation of the anaphylactic cascade, thereby making vasopressor treatment more effective. In addition, its effects on alternative mechanisms, such as IgG-mediated pathway or MRGPRX2-mediated direct activation, remain entirely unknown.\n\nMoreover, the dose of sugammadex for rocuronium-induced anaphylaxis remains open to question. The effective doses on rocuronium-induced anaphylaxis range from 4 to 18 mg/kg in previous case reports [14]. Assuming that sugammadex (2178 Da) encapsulates rocuronium (610 Da) at a molar ratio of 1:1, theoretically, 3.57 mg of sugammadex would be needed per milligram of rocuronium. In the present case, the administration of 200 mg sugammadex 6 min after the administration of 50 mg of rocuronium was sufficient to halt the rocuronium-induced circulatory collapse. Because of the linear, dose-dependent pharmacokinetics of sugammadex [15], we believe a higher dose (e.g., 16 mg/kg) might have been more efficient, with faster and more definite action. In addition, the timing of sugammadex administration may also be important, as profound circulatory failure may delay the distribution of sugammadex, thereby slowing its therapeutic effect.\n\nTaken together, our case illustrates major challenges associated with rocuronium-induced anaphylaxis developing during induction of general anesthesia, particularly when cutaneous manifestations are absent. Our experience suggests that sugammadex can be an effective treatment option for rocuronium-induced anaphylaxis in selected cases. Nevertheless, further accumulation of evidence is necessary to determine the patient selection and the optimal dose and timing of administration of sugammadex for rocuronium-induced anaphylaxis.\n\nAbbreviations\nNMBANeuromuscular-blocking agent\n\nECMOExtracorporeal membrane oxygenation\n\nIABPIntra-aortic balloon pumping\n\nPODPost-operative day\n\nBATBasophil activation test\n\nMRGPRX2Mas-related G-protein-coupled receptor X2\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nYT and JK designed this case report, wrote the manuscript, and prepared the images and figures. TS, TY, and HM helped confirm the accuracy and integrity of the manuscript. TF, HT, and MA performed the allergic tests and contributed to the conception and design of the current work. The authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe data in this case report are available from the corresponding author on reasonable requests.\n\nEthics approval and consent to participate\nIn our institution, the publication of case reports is exempted from ethics committee approval.\n\nConsent for publication\nThe written informed consent was obtained from the patient for the publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare no competing interests regarding this publication.\n==== Refs\nReferences\n1. Harper NJN Cook TM Garcez T Farmer L Floss K Marinho S Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6) Br J Anaesth 2018 121 1 159 171 10.1016/j.bja.2018.04.014 29935567 \n2. Badaoui R Popov I Dupont H A case of rocuronium-induced anaphylactic shock, improved by sugammadex Can J Anaesth 2012 59 9 909 910 10.1007/s12630-012-9740-6 22653841 \n3. Barbosa FT da Cunha RM Case of anaphylaxis induced by rocuronium treated with sugammadex Rev Bras Anestesiol 2012 62 4 538 542 10.1016/S0034-7094(12)70152-6 22793969 \n4. De La Cruz I Errando C Calaforra S Treatment of anaphylaxis to rocuronium with sugammadex: a case report with bronchospasm as the only symptom Turk J Anaesthesiol Reanim 2019 47 1 69 72 10.5152/TJAR.2019.21298 31276114 \n5. Leysen J Bridts CH De Clerck LS Ebo DG Rocuronium-induced anaphylaxis is probably not mitigated by sugammadex: evidence from an in vitro experiment Anaesthesia. 2011 66 6 526 527 10.1111/j.1365-2044.2011.06729.x 21568994 \n6. Binczak M Fischler M Le Guen M Efficacy of sugammadex in preventing skin test reaction in a patient with confirmed rocuronium anaphylaxis: a case report A A Pract 2019 13 1 17 19 10.1213/XAA.0000000000000973 30720535 \n7. Clarke RC Sadleir PH Platt PR The role of sugammadex in the development and modification of an allergic response to rocuronium: evidence from a cutaneous model Anaesthesia. 2012 67 3 266 273 10.1111/j.1365-2044.2011.06995.x 22321083 \n8. Muraro A Roberts G Worm M Bilò MB Brockow K Fernández Rivas M Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology Allergy. 2014 69 8 1026 1045 10.1111/all.12437 24909803 \n9. Reber LL Hernandez JD Galli SJ The pathophysiology of anaphylaxis J Allergy Clin Immunol 2017 140 2 335 348 10.1016/j.jaci.2017.06.003 28780941 \n10. Baldo BA Fisher MM Substituted ammonium ions as allergenic determinants in drug allergy Nature. 1983 306 5940 262 264 10.1038/306262a0 6196640 \n11. Spoerl D D’Incau S Roux-Lombard P Harr T Czarnetzki C Non-IgE-dependent hypersensitivity to rocuronium reversed by sugammadex: report of three cases and hypothesis on the underlying mechanism Int Arch Allergy Immunol 2016 169 4 256 262 10.1159/000446182 27240836 \n12. Kounis NG Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management Clin Chem Lab Med 2016 54 10 1545 1559 10.1515/cclm-2016-0010 26966931 \n13. Del Val VB Telletxea Benguria S Gonzalez-Larrabe I Suarez Romay JM Kounys syndrome after rocuronium administration Rev Esp Anestesiol Reanim 2018 65 6 343 346 10.1016/j.redar.2017.12.009 29361310 \n14. Plaud B A new option for the treatment of anaphylaxis linked to steroidal neuromuscular blockers: how much value should we grant to case reports? Can J Anaesth 2014 61 6 511 518 10.1007/s12630-014-0150-9 24818711 \n15. Akha AS Rosa J 3rd Jahr JS Li A Kiai K Sugammadex: cyclodextrins, development of selective binding agents, pharmacology, clinical development, and future directions Anesthesiol Clin 2010 28 4 691 708 10.1016/j.anclin.2010.08.014 21074746\n\n",
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"title": "Life-threatening rocuronium-induced anaphylactic shock without cutaneous manifestations successfully reversed with sugammadex: a case report.",
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"abstract": "To assess pregnancy outcomes in an unselected Takayasu arteritis (TAK) cohort, and identify pregnancy-related concerns.\n\n\n\nConsenting female patients with TAK were predominantly recruited from a population-based southeast Norway TAK cohort. Additional cases (n = 8) were recruited at Oslo University Hospital. Data on the number of pregnancies, births, and pregnancy outcomes before and after disease onset were retrieved from medical charts, patient questionnaires, and the Medical Birth Registry of Norway (MBRN). Data on pregnancy-related concerns were gathered from patient questionnaires.\n\n\n\nAltogether, the 58 women in the TAK study cohort had been through 110 pregnancies, 73 (in 33 patients) before disease onset and 37 (in 23 patients) after onset. The frequencies of miscarriages, induced abortions, and maternal complications did not differ between pregnancies occurring before and after TAK onset. Pregnancy-related hypertension was seen in 4.2% of the patients, compared to 1.5% (P = 0.37) in the reference cohort from MBRN, and preeclampsia/eclampsia in 4.5% compared to 3% (P = 0.2). The mean gestational age at delivery in pregnancies after TAK onset was 37.5 weeks, compared to 39.5 weeks in the MBRN references (P < 0.001). Cesarean sections were more frequent in deliveries after TAK onset (42%) than in MRBN controls (11%) (P < 0.001). Pregnancy-related concerns were recorded in 80% of the TAK cohort, with 60% expressing concerns about passing the disease to offspring.\n\n\n\nIn this population-based TAK cohort, the maternal and fetal outcomes were favorable. This study reveals a high prevalence of pregnancy-related concerns in TAK patients.",
"affiliations": "Institute of Clinical Medicine, University of Oslo, Oslo, Norway.;Trondheim University Hospital and NTNU Norwegian University of Science and Technology, Trondheim, Norway.;Oslo University Hospital, Oslo, Norway.;Oslo University Hospital, Rikshospitalet, Oslo, Norway.;Institute of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.;Oslo University Hospital, Oslo, Norway.",
"authors": "Gudbrandsson|Birgir|B|;Wallenius|Marianne|M|;Garen|Torhild|T|;Henriksen|Tore|T|;Molberg|Øyvind|Ø|;Palm|Øyvind|Ø|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002585:Cesarean Section; D002648:Child; D036861:Delivery, Obstetric; D005260:Female; D005865:Gestational Age; D006801:Humans; D046110:Hypertension, Pregnancy-Induced; D007231:Infant, Newborn; D008875:Middle Aged; D009664:Norway; D011225:Pre-Eclampsia; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D015995:Prevalence; D012042:Registries; D011795:Surveys and Questionnaires; D013625:Takayasu Arteritis; D055815:Young Adult",
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"title": "Takayasu Arteritis and Pregnancy: A Population-Based Study on Outcomes and Mother/Child-Related Concerns.",
"title_normalized": "takayasu arteritis and pregnancy a population based study on outcomes and mother child related concerns"
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"abstract": "BACKGROUND\nLocoregional anesthesia techniques are increasingly used for cataract surgery. From these techniques, peribulbar anesthesia has been very successful over the retrobulbar anesthesia seen its effectiveness and safety. However, peribulbar anesthesia is not without risk.\n\n\nMETHODS\nA 70-year-old African man was scheduled for cataract surgery and lens implant for his right eye. His medical history included hypertension, diabetes mellitus and gall bladder surgery. There were no personal or family antecedents of allergy, epilepsy or taking food or toxic drug. No abnormalities were detected in his preoperative evaluation. In the operating room, standard monitoring was installed and a peripheral venous catheter 18g was inserted. Peribulbar anesthesia was realized with two injections in primary gaze position. The anesthetic mixture contained lidocaine 2% and bupivacaine 0.5%. The needle used was 25GA, 19mm, ¾ inch. The first injection was performed in his lower temporal peribulbar space with 5mL of mixture; the second injection was performed with 3mL of mixture in his upper nasal peribulbar space. These injections were performed after a negative aspiration test and followed by manual compression of his globe for 5 minutes. Five minutes after peribulbar anesthesia, his blood pressure increased to 209/115mmHg requiring three bolus of nicardipine (3.0mg) to reduce his blood pressure to 134/56mmHg. One minute after, he had generalized tonic-clonic seizures. Tracheal intubation was performed. His capillary blood glucose was 170mg/dL, axillary temperature was 36.5°C, and his serum electrolytes were normal. He recovered spontaneous ventilation 1.5 hours later. A neurological examination noted no deficit. Extubation was performed 15 minutes later without incident. A brain computed tomography and electroencephalogram were unremarkable. He was discharged on the second day and operated on 1 month later under general anesthesia.\n\n\nCONCLUSIONS\nVarious serious complications can occur during locoregional anesthesia techniques in ophthalmic surgery. The mastering and perfecting of these techniques by practitioners and compliance with safety standards in anesthesia are the only way to guarantee the prevention of such complications.",
"affiliations": "Department of Anesthesiology Military Hospital Mohammed V Rabat, University of Mohammed V Souissi, Rabat, Morocco. mustaphabens_15rea@hotmail.com.",
"authors": "Bensghir|Mustapha|M|;Badou|Najlae|N|;Houba|Abdelhafid|A|;Balkhi|Hicham|H|;Haimeur|Charki|C|;Azendour|Hicham|H|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-2182495765910.1186/1752-1947-8-218Case ReportConvulsions during cataract surgery under peribulbar anesthesia: a case report Bensghir Mustapha 1mustaphabens_15rea@hotmail.comBadou Najlae 1najlaebadou@hotmail.comHouba Abdelhafid 1abdelhafidhouba@hotmail.comBalkhi Hicham 1hbalkhi@hotmail.comHaimeur Charki 1chaimeur@hotmail.comAzendour Hicham 1Hazendour@gmail.com1 Department of Anesthesiology Military Hospital Mohammed V Rabat, University of Mohammed V Souissi, Rabat, Morocco2014 23 6 2014 8 218 218 25 11 2013 28 4 2014 Copyright © 2014 Bensghir et al.; licensee BioMed Central Ltd.2014Bensghir 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/2.0), 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.Introduction\nLocoregional anesthesia techniques are increasingly used for cataract surgery. From these techniques, peribulbar anesthesia has been very successful over the retrobulbar anesthesia seen its effectiveness and safety. However, peribulbar anesthesia is not without risk.\n\nCase presentation\nA 70-year-old African man was scheduled for cataract surgery and lens implant for his right eye. His medical history included hypertension, diabetes mellitus and gall bladder surgery. There were no personal or family antecedents of allergy, epilepsy or taking food or toxic drug. No abnormalities were detected in his preoperative evaluation. In the operating room, standard monitoring was installed and a peripheral venous catheter 18g was inserted. Peribulbar anesthesia was realized with two injections in primary gaze position. The anesthetic mixture contained lidocaine 2% and bupivacaine 0.5%. The needle used was 25GA, 19mm, ¾ inch. The first injection was performed in his lower temporal peribulbar space with 5mL of mixture; the second injection was performed with 3mL of mixture in his upper nasal peribulbar space. These injections were performed after a negative aspiration test and followed by manual compression of his globe for 5 minutes. Five minutes after peribulbar anesthesia, his blood pressure increased to 209/115mmHg requiring three bolus of nicardipine (3.0mg) to reduce his blood pressure to 134/56mmHg. One minute after, he had generalized tonic–clonic seizures. Tracheal intubation was performed. His capillary blood glucose was 170mg/dL, axillary temperature was 36.5°C, and his serum electrolytes were normal. He recovered spontaneous ventilation 1.5 hours later. A neurological examination noted no deficit. Extubation was performed 15 minutes later without incident. A brain computed tomography and electroencephalogram were unremarkable. He was discharged on the second day and operated on 1 month later under general anesthesia.\n\nConclusions\nVarious serious complications can occur during locoregional anesthesia techniques in ophthalmic surgery. The mastering and perfecting of these techniques by practitioners and compliance with safety standards in anesthesia are the only way to guarantee the prevention of such complications.\n\nBrainstem anesthesiaCataract surgeryConvulsionsPeribulbar anesthesia\n==== Body\nIntroduction\nIn ophthalmic surgery several anesthetic techniques are possible [1-3]. The use of locoregional anesthesia (LRA) is more practiced at the expense of general anesthesia. These techniques have had major developments in recent years [4-6].\n\nFrom these techniques, peribulbar anesthesia (PBA) has been very successful over the retrobulbar anesthesia seen its effectiveness and safety [7,8]. Despite this success, varying complications during PBA have been described [9-11]. Of these, convulsions are a serious complication [12-14].\n\nThrough a clinical case of a convulsion during PBA and a literature review, we discuss the mechanisms involved in this complication and possible means of prevention.\n\nCase presentation\nA 70-year-old, 83kg African man was scheduled for cataract surgery and lens implant for his right eye. His medical history included hypertension, diabetes mellitus and gall bladder surgery under general anesthesia. There was no surgery on his contralateral eye. His medications included amlodipine, insulin, antiplatelets and statins. There were no personal or family antecedents of allergy, epilepsy or taking food or toxic drug.\n\nA routine preoperative evaluation noted a blood pressure (BP) of 149/78mmHg, a heart rate (HR) of 81 beats/minute and arterial oxygen saturation (SpO2) of 99%.\n\nA clinical examination did not show dyspnea or angina. No abnormalities were detected on an electrocardiogram and a chest X-ray. In laboratory tests, his blood glucose was 158mg/dL, urea plasma was 0.49g/L and creatinine was 13mg/L. In the anesthetic consultation, it was decided to continue all treatments and to stop insulin on the morning of surgery. After a preoperative fasting of 6 hours, premedication by hydroxyzine (75mg), and oral administration of prophylactic antibiotic (ciprofloxacin 1g), the patient was admitted to the operating room where monitoring including BP, HR and SpO2 was installed (Zeus Infinity Empowered Dräger Medical AG & Co. KG. Lübeck, Germany). A peripheral venous catheter 18g was inserted in his right hand and powered by an infusion of saline serum (0.9%).\n\nAfter swabbing and explanation of the technique to the patient, we proceeded to PBA with two injections in primary gaze position. The anesthetic mixture contained lidocaine 2% and bupivacaine 0.5%. The needle used was 25GA, 19mm, ¾ inch (Alcon® Surgical Malmaison Cedex, France). The first injection was performed in his lower temporal peribulbar space with 5mL of mixture; the second injection was performed with 3mL of mixture in his upper nasal peribulbar space. These injections were performed after a negative aspiration test and followed by manual compression of his globe for 5 minutes. During injections no change in BP, HR or SpO2 was noted. Five minutes after PBA, his BP increased to 209/115mmHg but his HR did not change (85 beats/minute) neither did his SpO2 (99%). This hypertension lasted 3 minutes; three bolus of nicardipine (3.0mg) were required to reduce his BP to 134/56mmHg. One minute after, he had generalized tonic–clonic seizures. He was placed in a lateral position and 3mg of midazolam was administered. Tracheal intubation was performed successfully after a bolus of propofol (150mg) and fentanyl (150μg) without muscle relaxants. The controlled ventilation was made with sedation by isoflurane 1%. His capillary blood glucose was 170mg/dL, axillary temperature was 36.5°C, and his serum electrolytes were normal. He recovered spontaneous ventilation 1.5 hours later. A neurological examination noted no deficit. Extubation was performed 15 minutes later without incident. A brain computed tomography and electroencephalogram were unremarkable. He was discharged on the second day and operated on 1 month later under general anesthesia.\n\nDiscussion\nThere has been much development in LRA in recent years from a technical standpoint and in equipment. In ophthalmic surgery, PBA has been very successful over the retrobulbar anesthesia seen its effectiveness and safety [7,8]. Despite this success, varying complications during PBA have been described. Of these, convulsions represent a serious complication [12-14].\n\nDuring surgery under LRA, convulsions may have several causes such as hypoglycemia, medication errors, stroke, severe hypoxia caused by deep sedation or following a cardiac arrest complicating cardiac ocular reflex and central nervous system intoxication by spread of local anesthetic agent (LAA) (Table 1). Several mechanisms may explain the spread of LAA used in PBA to brain structures causing various neurological signs.\n\nTable 1 Perioperative causes of convulsions and their management and prevention\n\nCauses\tSymptoms\tManagement\tPrevention\t\nOculocardiac reflex\tBradycardia/cardiac arrest\tRelease of muscle tension\tGentle muscle tractions\t\nInjection of atropine\tInjection of atropine\t\nDrug errors\tTachycardia/bradycardia/convulsions… (depends on type of drugs injected)\tSymptomatic treatment\tLabeling of syringes\t\nVerification of syringes before injection\t\nHypoglycemia\tSweating, drowsiness, confusion, abnormal behavior … convulsions\tAdministration of serum glucose (10%)\tNo taking of hypoglycemic medications the morning of surgery\t\nPerioperative monitoring of blood glucose\t\nHypoxia\tDesaturation, consciousness disorders … convulsions.\tOxygen therapy, liberation of superior airways, intubation\tMonitoring of oxygen saturation\t\nSystematic supplemental oxygen during sedation\t\nMonitoring of sedation\t\nStroke\tConsciousness disorders, respiratory distress, hemodynamic instability, convulsions\tControl of airway, control of hemodynamics parameters\tManagement of cardiovascular drugs\t\nNeurological monitoring\t\nMaintaining a stable hemodynamic and normal oxygenation\t\nToxicity of local anesthetics\tSomnolence, diplopia, shivering,\tOxygen therapy\tAspiration before injection\t\nDifficulty speaking, arrhythmias\tAirway liberation\tReduction of local anesthetic doses\t\nConvulsions, coma\tAnticonvulsants,\tUse of ultrasound\t\nFat emulsion\t\nThe first mechanism is an inadvertent intra-arterial injection in the ophthalmic artery or its branches. The injection pressure can reverse the direction of blood flow in the artery and the anesthetic solution flows back into the internal carotid artery and is delivered to the thalamus and other midbrain structures [14-16].\n\nIndeed the ophthalmic artery is in an abnormal position inferior to the optic nerve in 15% of cases, this exposes inadvertent intra-arterial injection during a PBA [16]. In this case, the direct exposure of brain structures to a low volume of LAA is similar to intoxication after inadvertent peripheral intra-arterial injection of a large volume of LAA, thereby clinical presentation is similar. Clinical signs have rapid onset and can range from loss of consciousness to cardiac arrest. Convulsions may be present or replaced by an electric silence [17].\n\nThe second mechanism is inadvertent brainstem anesthesia [18-21]. The optic nerve is surrounded by three envelopes, which are an extension of the cerebral meninges. Studies have shown that there is communication between the central cerebral structures and the optic nerve [22,23]. Thereby an accidental injection through these envelopes causing a diffusion of LAA under arachnoid or subdural space to brain structures can cause a direct intoxication of brain structures. The main risk factors for this iatrogenic injection are the size of the needle used and the position of the eye at the time of realization of the PBA.\n\nDuring PBA, with the globe in superonasal gaze, the optic nerve is in close proximity to the introduced needle [10]. In this superonasal gaze position, the risk of puncture of the envelope of the optic nerve is important with a diffusion of LAA into the brain structures. However, in a primary gaze position, the risk of accidental puncture of the optic nerve is low.\n\nAlthough the distance between the temporal region and lower optical foramen is between 42mm and 54mm, the use of shorter needles between 16mm and 25mm and a higher volume of LAA allows, after a period of time, complete anesthesia. The onset of action is explained by the diffusion of LAA at the site of action. With these needles the risk of puncture of the optic nerve is low in comparison with the use of long needles of 31mm or more, which provide an immediate anesthesia with a low volume of LAA, but increase the risk of puncture of the optic nerve [24,25]. Another mechanism that can be evoked is the absorption of LAA by the arachnoid villi and spread to cerebral structures [26]. This absorption is favored by manual compression and the use of hyaluronidase.\n\nIn our patient, there was no hypoglycemia (capillary blood glucose was 170mg/dL), no medication error in the verification of injected drugs, and no metabolic disorders in laboratory analysis. There was no neurological deficit after awakening and his postoperative brain computed tomography was normal eliminating a cerebral stroke. Thus, the convulsions were very probably related to PBA technique.\n\nThe delayed onset of convulsions after PBA and recovery of spontaneous ventilation after 1 hour are in favor of the second mechanism (inadvertent brainstem anesthesia). Using a 19mm needle in our case, we cannot exclude the possibility of this mechanism. Two elements are against the first mechanism of intra-arterial injection: negativity of needle aspiration test and delayed onset of symptoms. Whatever the mechanism involved in this complication, prevention is necessary to avoid the occurrence of such complications.\n\nDuring these last years, surgeons increasingly perform LRA in ophthalmic surgery [27]; this raises the question of the necessity of the presence of anesthetists in the operative room. This presence of anesthetists always remains required during the LRA for the management of complications.\n\nThe respect of standards in anesthetic safety in ophthalmic surgery is mandatory [28,29]. The type of monitoring used during ophthalmic local anesthesia should be similar to that used during general anesthesia and all technical and human resources must be available, in the operative room, to deal with the occurrence of any complications [30]. The other elements of prevention are: the systematic practice of needle test aspiration before each injection, maintaining the position of the globe in a neutral position at the completion of the PBA, and the use of needles no longer than 25mm.\n\nThe use of ultrasound in LRA in ophthalmic surgery could help guide the direction of the needle, see the injection sites, reduce the volume of injected LAA and reduce the complication rate and improve the safety and performance of these techniques. These benefits have already been demonstrated in LRA for other surgeries; in ophthalmic surgery, the use of ultrasound for the realization of LRA is in full development [31-33].\n\nConclusions\nLRA techniques in ophthalmic surgery should not be trivialized. Various serious complications can occur during LRA techniques in ophthalmic surgery.\n\nThe mastering and perfecting of these techniques by practitioners and compliance with safety standards in anesthesia are the only way to guarantee the prevention of such complications.\n\nConsent\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\nAbbreviations\nBP: Blood pressure; HR: Heart rate; LAA: Local anesthetic agent; LRA: Locoregional anesthesia; PBA: Peribulbar anesthesia; SpO2: Arterial oxygen saturation.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nMB, NB and AH analyzed and interpreted the patient data. MB and NB were major contributors in writing the manuscript. HB, CH and HA made the final corrections. All authors read and approved the final manuscript.\n==== Refs\nHaberer JP Obstler C Anesthésie en Ophtalmologie EMC Anesthésie-Réanimation 2008 Paris: Elsevier Masson SAS 1 24 36-620-E-30 \nMcGoldrick KE Foldes PJ General anesthesia for ophthalmic surgery Ophthalmol Clin North Am 2006 19 179 191 16701155 \nRipart J Nouvellon E Chaumeron A Regional anesthesia for eye surgery Reg Anesth Pain Med 2005 30 72 82 15690272 \nNouvellon E Cuvillon P Ripart J Regional anesthesia and eye surgery Anesthesiology 2010 113 1236 1242 10.1097/ALN.0b013e3181f7a78e 20938330 \nAqil M Local anesthesia for the ophthalmic surgery. Select the best technique for your patient Saudi Med J 2010 31 605 614 20563356 \nKumar C Dowd T Ophthalmic regional anaesthesia Curr Opin Anaesthesiol 2008 21 632 637 10.1097/ACO.0b013e32830abc09 18784491 \nWeiss JL Deichman CB A comparison of retrobulbar and periocular anesthesia for cataract surgery Arch Ophthalmol 1989 107 96 98 10.1001/archopht.1989.01070010098035 2910293 \nAlhassan MB Kyari F Ejere HO Peribulbar versus retrobulbar anaesthesia for cataract surgery Cochrane Database Syst Rev 2008 16 3 CD004083. doi:10.1002/14651858.CD004083.pub2 \nDavis DB Mandel MR Peribulbar anesthesia. A review of technique and complications Ophthalmol Clin North Am 1990 3 101 110 \nRouxel JM Zahwa A Obstler C Haberer JP Complications de l’anesthésie rétrobulbaire et péribulbaire Cah Anesthesiol 1997 45 193 205 \nDavis DB 2ndMandel MR Efficacy and complication rate of 16,224 consecutive peribulbar blocks. A prospective multicenter study J Cataract Refract Surg 1994 20 327 337 10.1016/S0886-3350(13)80586-X 8064611 \nBoret H Petit D Ledantec P Bénéfice S Brainstem anesthesia after peribulbar anesthesia Ann Fr Anesth Reanim 2002 21 725 727 10.1016/S0750-7658(02)00782-7 12494806 \nRozentsveig V Yagev R Wecksler N Gurman G Lifshitz T Respiratory arrest and convulsions after peribulbar anesthesia J Cataract Refract Surg 2001 27 960 962 10.1016/S0886-3350(00)00815-4 11408148 \nGomez R Andrade L Rezende Costa JR Brainstem anaesthesia after peribulbar anesthesia Can J Anaesth 1997 44 732 734 10.1007/BF03013387 9232303 \nAldrete JA Romo-Salas F Arora S Wilson R Rutherford R Reverse arterial blood flow as a pathway for central nervous system toxic responses following injection of local anesthetics Anesth Analg 1978 57 428 433 101097 \nMeyers EF Ramirez RC Boniuk I Grand mal seizures after retrobulbar block Arch Ophthalmol 1978 96 847 10.1001/archopht.1978.03910050453011 418755 \nRosenblatt RM May DR Barsoumian K Cardiopulmonary arrest after retrobulbar block Am J Ophthalmol 1980 90 425 427 7425062 \nHamilton RC Brain-stem anesthesia as a complication of regional anesthesia for ophthalmic surgery Can J Ophthalmol 1992 27 323 325 1490240 \nRenato S Gomez MSC Andrade LOF Rezende Costa JR Brainstem anaesthesia after peribulbar anaesthesia Can J Anaesth 1997 44 732 734 10.1007/BF03013387 9232303 \nEdge KR Davis A Brainstem anaesthesia following a peribulbar block for eye surgery Anaesth Intensive Care 1995 23 219 221 7793600 \nSinger SB Preston RG Hodge W Respiratory arrest following anesthesia for cataract surgery: case report and review of the literature Can J Ophthalmol 1997 32 450 454 9435979 \nKobet KA Cerebral spinal fluid recovery of lidocaine and bupivacaine following respiratory arrest subsequent to retrobulbar block Ophtalmic Surg 1987 1 11 13 \nRed JW Mac Millan AS Lazenby GW Transient neurologic complication of positive contrast orbitography Arch Ophtalmol 1969 81 508 511 10.1001/archopht.1969.00990010510008 \nKatsev DA Drews RC Rose BT An anatomic study of retrobulbar needle path length Ophthalmology 1989 96 1221 1224 10.1016/S0161-6420(89)32748-5 2797726 \nOrtiz M Valls R Vallès J Blanco D Vidal F Topography of peribulbar anesthesia Reg Anesth 1995 20 337 342 7577783 \nShantha TR The relationship of retrobulbar local anaesthetic spread to the neural membranes of the eyeball, optic nerve, and arachnoid villi in the optic nerve Anesthesiology 1990 72 3A A849 \nChandradeva K Nangalia V Hugkulstone CE Role of the anaesthetist during cataract surgery under local anaesthesia in the UK: a national survey Br J Anaesth 2010 104 577 581 10.1093/bja/aeq056 20338956 \nMerry AF Cooper JB Soyannwo O Wilson IH Eichhorn JH International standards for a safe practice of anesthesia 2010 Can J Anaesth 2010 57 1027 1034 10.1007/s12630-010-9381-6 20857254 \nMellin-Olsen J Staender S Whitaker DK Smith AF The Helsinki declaration on patient safety in anaesthesiology Eur J Anaesthesiol 2010 27 592 597 10.1097/EJA.0b013e32833b1adf 20520556 \nKumar CM Eke T Dodds C Deane JS El-Hindy N Johnston RL Kong KL McLure HA Shah P Tighe SQ Vohra SB Local anaesthesia for ophthalmic surgery – new guidelines from the Royal College of Anaesthetists and the Royal College of Ophthalmologists Eye (Lond) 2012 26 897 898 10.1038/eye.2012.82 22538216 \nLuyet C Eichenberger U Moriggl B Remonda L Greif R Real-time visualization of ultrasound-guided retrobulbar blockade: an imaging study Br J Anaesth 2008 101 855 859 10.1093/bja/aen293 18948389 \nChang WM Stetten GD Lobes LA JrShelton DM Tamburo RJ Guidance of retrobulbar injection with real-time tomographic reflection J Ultrasound Med 2002 21 1131 1135 12369668 \nLuyet C Eng KT Kertes PJ Avila A Muni RH McHardy P Real-time evaluation of diffusion of the local anesthetic solution during peribulbar block using ultrasound imaging and clinical correlates of diffusion Reg Anesth Pain Med 2012 37 455 459 10.1097/AAP.0b013e31825541e8 22609643\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "8()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D000772:Anesthesia, Local; D000779:Anesthetics, Local; D002045:Bupivacaine; D002387:Cataract Extraction; D006801:Humans; D007267:Injections; D008012:Lidocaine; D008297:Male; D009915:Orbit; D012640:Seizures",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "218",
"pmc": null,
"pmid": "24957659",
"pubdate": "2014-06-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18948389;9435979;4305061;15690272;101097;7425062;2797726;7577783;8064611;20338956;18646099;22538216;18784491;3561931;9232303;12369668;1490240;12494806;20938330;2910293;11408148;418755;20520556;20563356;20857254;22609643;7793600;16701155",
"title": "Convulsions during cataract surgery under peribulbar anesthesia: a case report.",
"title_normalized": "convulsions during cataract surgery under peribulbar anesthesia a case report"
} | [
{
"companynumb": "MA-WATSON-2015-08848",
"fulfillexpeditecriteria": "1",
"occurcountry": "MA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": nul... |
{
"abstract": "Mycophenolate mofetil is a commonly used immunosuppressive medication in the postliver transplant setting where gastrointestinal side effects tend to predominate. However, in more recent times, emerging and rare side effects are being reported in the literature. We present a case of a patient who had a significant inflammatory response and associated marked weight loss with the uptitration in dose of mycophenolate mofetil. Extensive investigations were performed to exclude other infective, inflammatory or malignant aetiologies for these symptoms, however no other cause was identified. The patient had the medication ceased and subsequently had a dramatic improvement in his inflammatory markers and regained the weight lost while on the medication.",
"affiliations": "Liver Transplant Unit Victoria, Austin Health, Australia.;Liver Transplant Unit Victoria, Austin Health, Australia.",
"authors": "Smith|Rebecca|R|;Testro|Adam|A|",
"chemical_list": "D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D002097:C-Reactive Protein; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223767",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "gastrointestinal system; transplantation",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D002097:C-Reactive Protein; D003937:Diagnosis, Differential; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D009173:Mycophenolic Acid; D018746:Systemic Inflammatory Response Syndrome; D015431:Weight Loss",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29592993",
"pubdate": "2018-03-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17524943;15630748;11120003;21466650;9028422;15973716;12777873;11522119;19441125",
"title": "Systemic inflammatory response in a liver transplant recipient: a potential side effect of mycophenolate mofetil.",
"title_normalized": "systemic inflammatory response in a liver transplant recipient a potential side effect of mycophenolate mofetil"
} | [
{
"companynumb": "PHHY2018AU067994",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Untangling catatonia and delirium can be challenging. Furthermore, treatment of one syndrome can potentially worsen another.\n\n\n\nWe present the case of a 71-year-old patient with a history of schizoaffective disorder, bipolar subtype, who developed catatonia and delirium with prominent psychotic symptoms, during a single hospitalization. Treatment of this patient's catatonia with benzodiazepines exacerbated delirium, while treatment of psychotic symptoms precipitated by delirium with antipsychotics led to catatonia. Catatonia and psychotic symptoms were eventually successfully managed with electroconvulsive therapy (ECT).\n\n\n\nThis case report highlights some of the treatment challenges faced when delirium and catatonia overlap in a medically ill patient. The use of benzodiazepines, valproic acid, antipsychotics, ECT and alternate medications to treat catatonia are also discussed.",
"affiliations": "Harvard South Shore Psychiatry Residency Program, United States. Electronic address: Rachel.Meyen@va.gov.;Boston University Medical Center Psychiatry Residency Program, United States.;Boston Veterans Affairs Healthcare System, Harvard Medical School, Boston MA, United States.",
"authors": "Meyen|Rachel|R|;Acevedo-Diaz|Elia E|EE|;Reddy|Sparsha S|SS|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.schres.2018.02.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-9964",
"issue": "197()",
"journal": "Schizophrenia research",
"keywords": "Benzodiazepines; Catatonia; Delirium; Electroconvulsive therapy; Schizoaffective disorder",
"medline_ta": "Schizophr Res",
"mesh_terms": "D000368:Aged; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D002389:Catatonia; D003693:Delirium; D004565:Electroconvulsive Therapy; D006801:Humans; D008297:Male; D011618:Psychotic Disorders",
"nlm_unique_id": "8804207",
"other_id": null,
"pages": "557-561",
"pmc": null,
"pmid": "29510926",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Challenges of managing delirium and catatonia in a medically ill patient.",
"title_normalized": "challenges of managing delirium and catatonia in a medically ill patient"
} | [
{
"companynumb": "US-APOTEX-2018AP009357",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "A previously healthy 5-week-old female was admitted for sepsis secondary to methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. After several days of hospitalization, she experienced acute decompensation in mental status despite having received targeted antibiotic therapy. Imaging revealed left peritonsillar/parapharyngeal space abscess, left venous thrombophlebitis of the internal jugular vein, and septic emboli of the lungs and brain consistent with Lemierre syndrome. Bedside needle aspiration of the parapharyngeal abscess confirmed MRSA involvement. Unfortunately, the patient continued to deteriorate over the next several days and life support was withdrawn on hospital day 16. We present the youngest reported case of Lemierre syndrome and review the literature.",
"affiliations": "1 Tulane University Medical Center, New Orleans, LA, USA.;1 Tulane University Medical Center, New Orleans, LA, USA.;2 Ochsner Health System of New Orleans, New Orleans, LA, USA.;1 Tulane University Medical Center, New Orleans, LA, USA.",
"authors": "Raggio|Blake S|BS|;Grant|Maria C|MC|;Rodriguez|Kimsey|K|;Cripe|Patrick J|PJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0009922817721156",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9228",
"issue": "57(3)",
"journal": "Clinical pediatrics",
"keywords": "Fusobacterium; Lemierre syndrome; jugular vein; septic thrombosis; thrombophlebitis",
"medline_ta": "Clin Pediatr (Phila)",
"mesh_terms": "D016470:Bacteremia; D018450:Disease Progression; D004636:Emergency Service, Hospital; D017809:Fatal Outcome; D005260:Female; D005674:Fusobacterium Infections; D006801:Humans; D007231:Infant, Newborn; D057831:Lemierre Syndrome; D008279:Magnetic Resonance Imaging; D055624:Methicillin-Resistant Staphylococcus aureus; D035583:Rare Diseases; D018570:Risk Assessment; D013203:Staphylococcal Infections; D015163:Superinfection; D013924:Thrombophlebitis",
"nlm_unique_id": "0372606",
"other_id": null,
"pages": "294-299",
"pmc": null,
"pmid": "28719983",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Neonatal Lemierre Syndrome: Youngest Reported Case and Literature Review.",
"title_normalized": "neonatal lemierre syndrome youngest reported case and literature review"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-01418",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugad... |
{
"abstract": "BACKGROUND\nAsians with atrial fibrillation carry a higher risk of ischemic stroke than non-Asians even under treatment of nonvitamin K antagonist oral anticoagulants. The purpose of the study was to observe the feasibility of intravenous thrombolytic therapy after administering a reversal agent, idarucizumab, in dabigatran-treated patients with acute ischemic stroke in Taiwan.\n\n\nMETHODS\nDabigatran-treated patients with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (rt-PA) after idarucizumab reversal were enrolled in the retrospective nationwide study. The clinical data, treatment course, and outcomes were recorded. Stroke severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) score. Any intracerebral hemorrhage (ICH) after rt-PA was detected by neuroimaging studies.\n\n\nRESULTS\nTen dabigatran-treated patients (6 men, mean age 71.10 ± 7.96 years) with acute ischemic stroke were included. Before stroke, the mean CHA2DS2-VASc score was 4.50 ± 1.57 and 8 patients (80%) received dabigatran 110 mg twice daily. All patients were treated with 5 g idarucizumab, following which the activated partial thromboplastin time normalized. Intravenous rt-PA (mean dose .78 mg/kg) was initiated a mean time of 11.11 minutes after idarucizumab infusion. The NIHSS score improved significantly after thrombolysis (16.0 ± 6.67 at admission to 9.38 ± 4.75 at discharge, P = .016). ICH developed in 3 patients (30%). Two of them were asymptomatic and 1 patient suffered from symptomatic ICH leading to mortality.\n\n\nCONCLUSIONS\nOur data reconfirmed the feasibility of intravenous rt-PA for Asian stroke patients after reversal of dabigatran effect with idarucizumab.",
"affiliations": "Department of Neurology, National Taiwan University Hospital, Yunlin Branch, Yunlin, Taiwan.;Department of Neurology, National Taiwan University Hospital, Yunlin Branch, Yunlin, Taiwan.;Department of Neurology, National Taiwan University Hospital, Hsinchu Branch, Hsinchu, Taiwan.;Department of Neurology, Ton Yen General Hospital, Hsinchu, Taiwan.;Department of Neurology, Feng Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan.;Department of Cardiology, Feng Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan.;Department of Neurology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan.;Stroke Center and Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.;Department of Neurology, Yunlin Christian Hospital, Yunlin, Taiwan.;Department of Neurology, Tainan Sin Lau Hospital, Tainan, Taiwan.;Department of Neurology, Mackay Memorial Hospital, Taipei, Taiwan.;Stroke Center, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan.;Medical Department, Boehringer Ingelheim Taiwan Limited, Taipei, Taiwan.;Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: heng@mail.ncku.edu.tw.",
"authors": "Fang|Chen-Wen|CW|;Tsai|Yi-Te|YT|;Chou|Ping-Chen|PC|;Chen|Hsi-Ming|HM|;Lu|Chien-Ming|CM|;Tsao|Chen-Rong|CR|;Chen|Chih-Lin|CL|;Sun|Mu-Chien|MC|;Shih|Yu-Song|YS|;Hsieh|Cheng-Yang|CY|;Chen|Lu-An|LA|;Chen|Po-Lin|PL|;Yeh|Jung-Tze|JT|;Li|Yi-Heng|YH|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000991:Antithrombins; D005343:Fibrinolytic Agents; C000594745:idarucizumab; D010959:Tissue Plasminogen Activator; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.11.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "28(3)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Ischemic stroke; atrial fibrillation; dabigatran; idarucizumab",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000991:Antithrombins; D001281:Atrial Fibrillation; D001777:Blood Coagulation; D002543:Cerebral Hemorrhage; D000069604:Dabigatran; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke; D013624:Taiwan; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "815-820",
"pmc": null,
"pmid": "30573284",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intravenous Thrombolysis in Acute Ischemic Stroke After Idarucizumab Reversal of Dabigatran Effect: Analysis of the Cases From Taiwan.",
"title_normalized": "intravenous thrombolysis in acute ischemic stroke after idarucizumab reversal of dabigatran effect analysis of the cases from taiwan"
} | [
{
"companynumb": "TW-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-062205",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nPrimary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (ASC) are often associated with ulcerative colitis (UC). The impact on the course of UC remains unclear, and up-to-date evidence in pediatric populations is scarce. The aim of the study was to analyze the course of UC in pediatric patients transplanted owing to PSC or ASC.\n\n\nMETHODS\nWe retrospectively reviewed data from children with PSC/ASC and UC who underwent orthotopic liver transplantation (OLT). In all patients UC diagnosis was based on clinical presentation, endoscopy, and histology.\n\n\nRESULTS\nSeventeen patients (9 female) with PSC or ASC underwent OLT from deceased donors at a median age of 16.8 years (range = 11.5-18.2 years). In 15 patients, UC was diagnosed before OLT (median age of diagnosis = 10.6 years; range = 6.6-18.0 years), and 2 patients developed UC after OLT. Ten patients (59%) presented with pancolitis on initial endoscopy. Disease activity was severe in 9 patients (53%) and most patients improved after initial treatment with steroids. Before OLT only 2 patients (13%) had severe disease activity. After OLT, 4 patients developed flares of the disease. These patients were successfully treated and remained in remission at the end of the posttransplant follow-up period (median = 3.76 years; range = 0.4-15.5 years). None of the patients developed colorectal cancer or underwent colectomy during 3.7 years of post-OLT follow-up.\n\n\nCONCLUSIONS\nIn our experience, the course of UC was not aggravated by OLT for PSC, and UC did not adversely affect patient or graft survival.",
"affiliations": "Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland. Electronic address: marcin.osiek@wp.pl.;Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Paediatric Surgery and Organ Transplantation, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland.",
"authors": "Osiecki|Marcin|M|;Kierkuś|Jarosław|J|;Pawłowska|Joanna|J|;Woźniak|Małgorzata|M|;Jankowska|Irena|I|;Teisseyre|Mikołaj|M|;Dądalski|Maciej|M|;Jarzębicka|Dorota|D|;Stefanowicz|Marek|M|;Czubkowski|Piotr|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.09.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000293:Adolescent; D002648:Child; D015209:Cholangitis, Sclerosing; D003093:Colitis, Ulcerative; D005260:Female; D006085:Graft Survival; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "244-249",
"pmc": null,
"pmid": "33162100",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Course of Ulcerative Colitis After Pediatric Liver Transplantation for Sclerosing Cholangitis.",
"title_normalized": "the course of ulcerative colitis after pediatric liver transplantation for sclerosing cholangitis"
} | [
{
"companynumb": "PL-ASTELLAS-2021US006558",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
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"activesubstancename": "TACROLIMUS"
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... |
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"abstract": "This article provides a concise overview of local anesthetic systemic toxicity, its history, mechanisms, risk factors, prevention, clinical presentation, and treatment, with a special emphasis on issues specific to the geriatric population. The authors used MEDLINE, Scopus, and Google Scholar to search for original research articles (human and animal studies), registries data, case reports, review articles, and pertinent online publications using the combinations of the following search terms: local anesthetics, local anesthetic systemic toxicity, intralipid, lipid emulsion, Exparel, ultrasound-guidance, regional anesthesia, lidocaine, bupivacaine, ropivacaine, cocaine, procaine, tetracaine, levobupivacaine, liposomal bupivacaine, lignocaine. Local anesthetic systemic toxicity continues to occur despite the use of putatively less cardiotoxic formulations of local anesthetics and more common use of ultrasound guidance. The elderly appear to be at a disproportionately increased risk for toxicity owing to the presence of relevant comorbidities and decreased muscle mass. Examination of recent case reports involving patients over the age of 65 years demonstrates that inadvertent overdosing is responsible for some cases of local anesthetic systemic toxicity. Elderly patients are at increased risk of local anesthetic systemic toxicity. When considering use of local anesthetics in older patients, special attention should be paid to the presence of systemic disease and muscle wasting. The safety of regional anesthesia and multi-modal analgesia among these at-risk patients will be improved by educating physicians and staff to recognize and manage local anesthetic systemic toxicity.",
"affiliations": "Department of Anesthesiology, University of Illinois Hospital, 1740 W. Taylor St, Suite 3200W, Chicago, IL, 606012, USA.;Department of Anesthesiology, University of Illinois Hospital, 1740 W. Taylor St, Suite 3200W, Chicago, IL, 606012, USA.;Department of Anesthesiology, University of Illinois Hospital, 1740 W. Taylor St, Suite 3200W, Chicago, IL, 606012, USA. gitman@uic.edu.",
"authors": "Waldinger|Rachel|R|;Weinberg|Guy|G|;Gitman|Marina|M|0000-0001-6134-7831",
"chemical_list": "D000779:Anesthetics, Local",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40266-019-00718-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1170-229X",
"issue": "37(1)",
"journal": "Drugs & aging",
"keywords": null,
"medline_ta": "Drugs Aging",
"mesh_terms": "D000368:Aged; D000698:Analgesia; D000765:Anesthesia, Conduction; D000779:Anesthetics, Local; D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D059408:Pain Management; D010353:Patient Education as Topic",
"nlm_unique_id": "9102074",
"other_id": null,
"pages": "1-9",
"pmc": null,
"pmid": "31598909",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "25729664;30301317;29525187;23927841;25098145;22156330;18420880;5406391;20216034;28538107;26596229;27199310;26378712;28816893;30004951;15635516;28079735;12766665;25867875;30074492;19224770;29356773;29356774;17923598;26469367;20301824;29280923;17643405;27302637;26695877;30386028;30417244;21841477;31461049;11895133;24694849;24747324;29295799;26895001;29757886;29303925;23788067;29885261;26650424;385208",
"title": "Local Anesthetic Toxicity in the Geriatric Population.",
"title_normalized": "local anesthetic toxicity in the geriatric population"
} | [
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-09280",
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"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
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"drugad... |
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"abstract": "Transplantation of insulin-secreting tissues is currently being evaluated as a possible method of treating diabetic patients. Isolation of islets of Langerhans from the rat pancreas is now routinely accomplished, and methods for islet isolation from the human pancreas are being explored. Transplantation of isolated islets into isologous rats is capable of reversing streptozotocin-induced diabetes. Unfortunately, isolated islets are not immunologically privileged and various immunosuppression regimens have not effectively obviated the rejection phenomena seen in rat allograft experiments.",
"affiliations": null,
"authors": "Karl|R C|RC|",
"chemical_list": "D013311:Streptozocin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-0153",
"issue": "99(8)",
"journal": "Archives of pathology",
"keywords": null,
"medline_ta": "Arch Pathol",
"mesh_terms": "D000818:Animals; D003920:Diabetes Mellitus; D004195:Disease Models, Animal; D006084:Graft Rejection; D006801:Humans; D016381:Islets of Langerhans Transplantation; D051381:Rats; D013311:Streptozocin; D014184:Transplantation, Homologous",
"nlm_unique_id": "7605251",
"other_id": null,
"pages": "401-2",
"pmc": null,
"pmid": "125078",
"pubdate": "1975-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Transplantation of islets of Langerhans.",
"title_normalized": "transplantation of islets of langerhans"
} | [
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"companynumb": "NL-MYLANLABS-2018M1034096",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"drugadditional": n... |
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"abstract": "BACKGROUND\nWe report a case of a factitious disorder presenting with recurrent episodes of supraventricular tachycardia (SVT).\n\n\nMETHODS\nA 26-year-old woman presented with recurrent episodes of SVT. Medical history included SVT, asthma, anxiety, depression, type 2 diabetes, and migraine headaches. The patient had frequent emergency department (ED) visits with complaints of chest pain, palpitations, and heart rates typically between 130 and 150 beats/min. Electrocardiograms revealed sinus tachycardia; laboratory studies were consistently normal except for periodic episodes of hypokalemia. Over the 3 years, the patient had more than 50 visits for health care and underwent multiple diagnostic evaluations, including comprehensive laboratory testing, echocardiography, Holter monitoring, and event monitoring. Given the constellation of clinical features, a plasma albuterol concentration was obtained during an ED visit for SVT, which was 17 ng/mL (reference range for peak plasma concentration after 0.04-0.1-mg inhaler dose = 0.6-1.4 ng/mL). A subsequent ED visit with a similar presentation revealed a plasma albuterol level of 11 ng/mL. The patient adamantly denied using this medication. Due to concerns about a factitious disorder, a multidisciplinary hospital discussion was planned for subsequent interventions; however, the patient was lost to follow-up. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This is a compelling case report of a factitious disorder and occult albuterol abuse resulting in recalcitrant SVT with numerous ED visits and interventions. Patients with factitious disorders can have multiple visits for emergency care and are challenging to evaluate and treat. Albuterol toxicity can present with pronounced sinus tachycardia, fine tremor, and often with transient hypokalemia.",
"affiliations": "Department of Emergency Medicine, VCU Medical Center, Richmond, Virginia; Virginia Poison Center, Richmond, Virginia.;Department of Emergency Medicine, VCU Medical Center, Richmond, Virginia.;Department of Emergency Medicine, VCU Medical Center, Richmond, Virginia.;Madigan Army Medical Center, Tacoma, Washington.;Madigan Army Medical Center, Tacoma, Washington.",
"authors": "Wills|Brandon K|BK|;Kwan|Constance|C|;Bailey|Michael|M|;Johnson|Leigh|L|;Allan|Nicholas|N|",
"chemical_list": "D001993:Bronchodilator Agents; D000420:Albuterol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "49(4)",
"journal": "The Journal of emergency medicine",
"keywords": "albuterol; factitious disorder; toxicity",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000328:Adult; D000420:Albuterol; D001993:Bronchodilator Agents; D005162:Factitious Disorders; D005260:Female; D006801:Humans; D063487:Prescription Drug Misuse; D013617:Tachycardia, Supraventricular",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "436-8",
"pmc": null,
"pmid": "26162766",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recalcitrant Supraventricular Tachycardia: Occult Albuterol Toxicity Due to a Factitious Disorder.",
"title_normalized": "recalcitrant supraventricular tachycardia occult albuterol toxicity due to a factitious disorder"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-100927",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALBUTEROL"
},
"druga... |
{
"abstract": "OBJECTIVE\nTo evaluate the effects of diet control and Metformin on placental morphology in gestational diabetes mellitus (GDM).\n\n\nMETHODS\nAfter written informed consent 62 GDMs were enrolled. According to WHO criteria, 30 cases of GDMs with blood sugar level <130 mg/dl, were assigned Group B (2000-2500Kcal/day and 30 minute walk thrice weekly were kept on diet control and 32 cases of GDM with blood sugar level >130 mg/dl, assigned Group C were kept on diet with tablet Metformin,(500mg TDS) Finally 25 normal pregnant females were kept in Group A as control. After delivery placentae were preserved and evaluated for morphology.\n\n\nRESULTS\nHeavy placentae with abundant villous immaturity, chorangiosis and syncytial knots in group B and fibrinoid necrosis and calcification in group C were seen. In group B versus A placental and cord width while in Group C versus A only cord width in gross morphology showed significant results. In group B versus A villous immaturity, chorangiosis, infarction and syncytial knots in light microscopy were present; similarly in B versus C placental width, chorangiosis and syncytial knots showed significant results, while in C versus A results were non-significant.\n\n\nCONCLUSIONS\nMetformin produced beneficial effects on placental morphology being comparable to normal control in contrast to diet group.",
"affiliations": "Dr. Rabia Arshad, MBBS, M. Phil. Assistant Professor and Head of Pharmacology Department, Altamash Institute of Dental Medicine, 2-R Sunset Boulevard, DHA, Karachi, Pakistan.;Dr. Muhammad Adnan Kanpurwala, MBBS, M. Phil. Associate Professor, Physiology Department, Karachi Institute of Medical Sciences, Karachi, Pakistan.;Dr. Nasim Karim, MBBS, M. Phil, Ph D, Post Doc. Professor and Head of Pharmacology Department, Bahria University Medical and Dental College, Karachi, Pakistan.;Dr. Jahan Ara Hasan, MBBS, FCPS, MCPS. Associate Professor, Gynecology and Obstetrics Department, Dow University of Health Sciences, Karachi, Pakistan.",
"authors": "Arshad|Rabia|R|;Kanpurwala|Muhammad Adnan|MA|;Karim|Nasim|N|;Hassan|Jahan Ara|JA|",
"chemical_list": null,
"country": "Pakistan",
"delete": false,
"doi": "10.12669/pjms.326.10872",
"fulltext": "\n==== Front\nPak J Med SciPak J Med SciPakistan Journal of Medical Sciences1682-024X1681-715XProfessional Medical Publications Pakistan PJMS-32-152210.12669/pjms.326.10872Original ArticleEffects of Diet and Metformin on placental morphology in Gestational Diabetes Mellitus Arshad Rabia 1Kanpurwala Muhammad Adnan 2Karim Nasim 3Hassan Jahan Ara 41 Dr. Rabia Arshad, MBBS, M. Phil. Assistant Professor and Head of Pharmacology Department, Altamash Institute of Dental Medicine, 2-R Sunset Boulevard, DHA, Karachi, Pakistan2 Dr. Muhammad Adnan Kanpurwala, MBBS, M. Phil. Associate Professor, Physiology Department, Karachi Institute of Medical Sciences, Karachi, Pakistan3 Dr. Nasim Karim, MBBS, M. Phil, Ph D, Post Doc. Professor and Head of Pharmacology Department, Bahria University Medical and Dental College, Karachi, Pakistan4 Dr. Jahan Ara Hasan, MBBS, FCPS, MCPS. Associate Professor, Gynecology and Obstetrics Department, Dow University of Health Sciences, Karachi, Pakistan\nCorrespondence: Dr. Rabia Arshad, House No. D-184, Navy Housing Scheme, Zamzama, Clifton, Karachi, Pakistan. E-mail: rabs78@gmail.comNov-Dec 2016 32 6 1522 1527 23 6 2016 25 7 2016 02 12 2016 05 12 2016 Copyright: © Pakistan Journal of Medical Sciences2016This 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.Objective:\nTo evaluate the effects of diet control and Metformin on placental morphology in gestational diabetes mellitus (GDM).\n\nMethods:\nAfter written informed consent 62 GDMs were enrolled. According to WHO criteria, 30 cases of GDMs with blood sugar level <130 mg/dl, were assigned Group B (2000-2500Kcal/day and 30 minute walk thrice weekly were kept on diet control and 32 cases of GDM with blood sugar level >130 mg/dl, assigned Group C were kept on diet with tablet Metformin,(500mg TDS) Finally 25 normal pregnant females were kept in Group A as control. After delivery placentae were preserved and evaluated for morphology.\n\nResults:\nHeavy placentae with abundant villous immaturity, chorangiosis and syncytial knots in group B and fibrinoid necrosis and calcification in group C were seen. In group B versus A placental and cord width while in Group C versus A only cord width in gross morphology showed significant results. In group B versus A villous immaturity, chorangiosis, infarction and syncytial knots in light microscopy were present; similarly in B versus C placental width, chorangiosis and syncytial knots showed significant results, while in C versus A results were non-significant.\n\nConclusion:\nMetformin produced beneficial effects on placental morphology being comparable to normal control in contrast to diet group.\n\nKEY WORDS\nGestational diabetesDietExerciseMetforminPlacentaGross morphologyMicroscopic morphology\n==== Body\nINTRODUCTION\nGestational diabetes is glucose intolerance identified in the second trimester of pregnancy. This occurs mainly due to the diabetogenic effects of placental hormones and is associated with certain critical fetal and maternal consequences.1 The worldwide prevalence of GDM is 3-9% whereas in our population prevalence is 3-3.45% but the outcomes are much worse due to lack of knowledge and medical care facilities.2\n\nPlacenta is involved in the nutritional supply of the maturing fetus. It is a discoid shaped structure covered with membranes and microscopically composed of multiple villi containing minute blood vessels and mesenchymal supportive tissue. Change in the maternal atmosphere influences the physiology and structure of this central organ.3 The placenta exhibits multiple gross and microscopic alterations in gestational diabetes mellitus such as increase in the proliferative rate of trophoblasts, stromal cells and villous capillaries of placental tissue. This mainly happens due to enhanced effects of endogenous fetal insulin. Other main feature is hypoxia, which occurs in the placental tissue due to increase in fetal size (macrosomia) and demands. This subsequently leads to increase in the weight, diameter and thickness of placenta.4 Excessive amount of glucose in maternal blood also gets stored in the placental tissue.5 Patho-physiology can be linked to altered levels of placental vascular endothelial growth factor, insulin and other related growth factors (IGF1, IGF2 and IGF binding proteins) which regulate the placental development and growth.6 This results ultimately in increase in size and weight of the placenta. Furthermore on microscopic evaluation, all hypoxic parameters are notably increased in placentae of GDM patients.7\n\nDiet and exercise is the necessary management but patients with higher glucose level also need pharmacological management. Insulin is a gold standard therapy but it was seen that even with insulin therapy there were chances of maternal weight gain, macrosomic babies and unexplained term deaths of fetus and still births. There are well documented hypoxic changes in placenta due to use of insulin.8 In contradiction to the past when oral anti-diabetic drugs were thought to be teratogenic,8 in the recent years, Metformin is said to be the safest as classified category B drug. It produces euglycemia, by improving insulin resistance, enhances glucose uptake and also decreases intracellular glucose production. Furthermore, it improves capillary functions, reduces hyperglycemia, and decreases the onset and severity of micro and macro vascular complications in type 2 diabetes.9 Therapeutic trials have also confirmed that during pregnancy Metformin has good patient compliance, with no significant side effects.10 On account of paucity of data regarding effects of metformin on placental morphology, present study was designed to compare the effect of diet control with Metformin on placental morphology in gestational diabetes mellitus (GDM).\n\nMETHODS\nThis study was conducted at Lyari General Hospital, Civil Hospital and Mamji Hospital Karachi from June 2010- June 2011. For this clinical trial study, fasting and random blood sugar level of the patients attending antenatal clinic were checked. Diagnosis of GDM according to WHO criteria (FBS > 100mg/dl and RBS > 126mg/dl) was made using glucometer and rechecked with lab reports. In high risk patients such as with previous GDM or bad obstetrical history, diagnosis was made by 50 G oral glucose challenge test (value RBS ≥140mg/dl), confirmation being done by OGTT.11 Non-probability purposive sampling was done and after written informed consent, 25 healthy females with no co-morbidity as control (Group A) and 62 GDM females were enrolled in study. Thirty of these GDM patients, with blood sugar levels less than 130 mg/dl were advised life style modification, including exercise and diet control, were kept in Group B. They were advised to take only 2500 calories per day with provision of suitable diet charts and 30 minutes of walk thrice weekly. Thirty-two GDM patients in Group C were with RBS more than 130 mg/dl received tablet Metformin 500mg along with strict diet control therapy (<2500 calories/ day and 30 minutes of walk thrice weekly). Metformin was started with 500 mg then was increased up to 1500 mg according to the tolerance and glycemic values of the patient. These patients were followed regularly in the antenatal clinics till term. On every visit their treatment, any side effects and blood sugar level were assessed and proper management was reassured. Patients (5 in group B, 7 in group C) were excluded from the study as they delivered elsewhere or were added insulin for the treatment with Metformin. Placentae were collected within 30-40 minutes of delivery from these patients and were preserved in 10% formalin in labeled containers. Gross morphological evaluation of placenta was done (Table-I & II), following the dissection and tissues were taken from 6 o’clock, 12o’clock and central areas for slide preparation. The sections were treated with alcohol and xylene and then blocks were prepared using paraffin wax. For slide preparation, sections were sliced into 4mm thin films with manual microtome and slides were prepared. These slides were finally stained with hematoxyline and eosin, PAS and trichome stains and after drying, visualized under light microscope. Microscopically placental hypoxic parameters were observed. (Table-III).12\n\nTable-I Gross Morphology within and between groups N=75 (n=25).\n\nS. No\tGroups\tCharacteristics\t\n\t\nPlacental size1(cm)\tPlacental size2 (cm)\tPlacental width (cm)\tPlacental weight (gm)\tCord length (cm)\tCord width (cm)\tCord vessels (n)\t\n1\tGroup A\t16.32±2.34\t14.00±1.91\t2.12±0.58\t567.6±138.9\t41.98±7.88\t1.34±0.45\t3±0\t\n2\tGroup B\t15.06±2.41\t12.88±2.92\t2.84±0.62\t590±147.9\t42.96±7.4\t1.84±0.34\t3±0\t\n3\tGroup C\t15.88±2.58\t13.92±2.72\t2.20±0.5\t626.4±122.6\t45.54±7.37\t1.68±0.45\t3±0\t\n\t\nP-value\t\n\t\n1\tGroup B v/s A\t0.06\t0.12\t0.00*\t0.58\t0.65\t0.00*\tNA\t\n2\tGroup C v/s A\t0.5\t0.9\t0.6\t0.119\t0.1\t0.01*\tNA\t\n3\tGroup B v/s C\t0.25\t0.12\t0.001*\t0.34\t0.22\t0.16\tNA\t\nKey:Group A: Normal control group, Group B: GDM females on diet control, Group C: Metformin treated group,\n\n* Statistically significant, NA: Independent t test not applicable.\n\nTable-II Gross morphology within and between groups N=75(n=25).\n\nS.No\tGroups\tCharacteristics\t\n\t\tPlacental consistency\tPlacental shape\tColor of membrane\tCord insertion\tCord knots\tCord strictures\tCord hematoma\t\n\t\tSoft\tHard\tDiscoid\tOther\tBlue\tPale\tCentral\tPeripheral\tP\tA\tP\tA\tP\tA\t\n1\tGroup A\t17(68%)\t8(32%)\t19(76%)\t6(24%)\t8(32%)\t17(68%)\t7(28%)\t18(72%)\t2(8%)\t23(92%)\t1(4%)\t24(96%)\t9(36%)\t16(64%)\t\n2\tGroup B\t16(64%)\t9(36%)\t19(76%)\t6(24%)\t11(44%)\t14(56%)\t8(32%)\t17(68%)\t6(24%)\t19(76%)\t6(24%)\t19(76%)\t5(20%)\t20(80%)\t\n3\tGroup C\t16(64%)\t9(36%)\t17(68%)\t8(32%)\t11(44%)\t14(56%)\t10(40%)\t15(60%)\t3(12%)\t22(88%)\t6(24%)\t19(76%)\t10(40%)\t15(16%)\t\nP-value\t\n4\tGroup B v/s A\t0.76\t>0.99\t0.38\t0.75\t0.24\t0.09^\t0.2\t\n5\tGroup C v/s A\t0.76\t0.52\t0.38\t0.37\t>0.99\t0.09^\t0.77\t\n6\tGroup B v/s C\t>0.99\t0.52\t>0.99\t0.5\t0.46\t>0.99\t0.12\t\nTable-III Microscopic morphology within and between groups N=75 (n=25).\n\nS. No\tGroups\tCharacteristics\t\n\t\nVillous immaturity\tChorangiosis\tInfarction\tVillous fibroid necrosis\tCalcification\tSyncytial Knots\t\n\t\nP\tA\tP\tA\tP\tA\tP\tA\tP\tA\tP\tA\t\n1\tGroup A\t4(16%)\t21(64%)\t6(24%)\t19(76%)\t7(28%)\t18(72%)\t18(72%)\t7(28%)\t11(44%)\t14(56%)\t4(16%)\t21(84%)\t\n2\tGroup B\t10(40%)\t15(60%)\t13(52%)\t12(48%)\t14(56%)\t11(44%)\t19(76%)\t6(24%)\t10(40%)\t15(60%)\t14(56%)\t11(44%)\t\n3\tGroup C\t5(20%)\t20(805)\t5(20%)\t20(80%)\t9(36%)\t16(64%)\t22(88%)\t3(12%)\t15(60%)\t10(40%)\t7(28%)\t18(72%)\t\n\t\nP-value\t\n\t\n4\tGroup B v/s A\t0.05*\t0.04*\t0.04*\t0.74\t0.77\t0.003*\t\n5\tGroup C v/s A\t>0.9^\t0.73\t0.54\t0.15\t0.25\t0.3\t\n6\tGroup B v/s C\t0.12\t0.01*\t0.15\t0.24^\t0.15\t0.04*\t\nKey:Group A: Normal control group, Group B: GDM females on diet control, Group C: Metformin treated group,\n\n* Statistically significant, P: Present, A: Absent,\n\n^ fisher exact test applied due to decrease cell count.\n\nData was tabulated and analyzed by SPSS version 16. P value of 0.05 or less was considered statistically significant for the results. For the numerical variables mean with Independent t test and for categorical variables percentages with chi square tests were applied for evaluation. Fisher exact test was used where chi square test was not applicable due to decreased cell counts.\n\nRESULTS\nSignificant differences were observed in FBS, RBS, HbAIC as they were diabetics and non-diabetics. HbAIC evaluated at 36 weeks of pregnancy has shown significant decrease in group C as compared to group B. (Table-IV)\n\nTable-IV Maternal characteristics group (B v/s A) (C v/s A) & (B v/s C) N=75.\n\nS. No.\tMaternal Characteristics\tAGE (years)\tWEIGHT (kg)\tFBS (mg/dl)\tRBS (mg/dl)\tHbAIC 1\tHbAIC 2\t\n\t\n\tMean ± S.D\tMean ± S.D\tMean ± S.D\tMean ± S.D\t%\t%\t\n1\tGroup A\t29.0±4.37\t73.84±9.97\t72.24±9.34\t126.8±35.8\t4.84\t4.97\t\n2\tGroup B\t30.08±3.16\t78.54±6.93\t90.9±16.8\t148.72±38.9\t5.34\t5.74\t\n3\tGroup C\t29.76±3.41\t77.9±7.6\t104.4±13.12\t171±37.44\t5.28\t5.42\t\n\t\nP-value\t\n\t\n1\tGroup B v/s A\t0.32\t0.059\t0.00*\t0.03*\t0.00*\t0.00*\t\n2\tGroup C v/s A\t0.49\t0.11\t0.00*\t0.00*\t0.001*\t0.00*\t\n3\tGroup B v/s C\t0.75\t0.75\t0.00*\t0.04*\t0.693\t0.01*\t\nGroup A: Normal control group, Group B: GDM females on diet control, Group C: Metformin treated group,\n\n* Statistically significant, FBS: fasting blood sugar at the time of enrollment;RBS: Random blood sugar at the time of enrollment,\n\nHbAIC 1: at the time of patient enrollment, HbAIC 2: at 36 weeks of gestation.\n\nResults were statistically significant between group B and A for placental width and cord width (p value of 0.00). Comparison of group C and A showed only significant results for cord width (p=0.01), while other parameters were similar. The results were statistically significant for placental width when group B and C were compared (p= 0.001) and all remaining parameters were non-significant, showing that diet controlled GDM placentae were thicker than Metformin treated GDM placentae. (Table-I)\n\nThe results between all the three groups (normal control, GDM on diet therapy, GDM on metformin therapy) were statistically non-significant. (Table-II)\n\nOn light microscopy hypoxic placental features between group B and A were statistically significant for villous immaturity, chorangiosis, infarction and syncytial knots (p=0.05, 0.04, 0.04 and 0.03 respectively). (Fig.1). For group C and A, all the microscopic parameters were statistically non-significant, showing that metformin treated placentae were similar to normal controlled placentae. (Fig.1). For group B and C for microscopic parameters, results were significant for chorangiosis and syncytial knots formation (p= 0.01 & 0.04 respectively) showing that the diet controlled placentae had chorangiosis and syncytial knots when compared to Metformin treated placentae. (Table-III)\n\nFig.1A Histology of normal healthy placenta.\n\nFig.1B Diet control placenta.\n\nFig.1C Metformin treated placentae.\n\nDISCUSSION\nGDM is associated with structural and functional alterations in placenta leading to fetal hypoxia, fetal morbidity and still birth13. These can be envisioned by gross and microscopic changes in the morphology of placentae, the main communicating tissue between mother and the growing fetus.\n\nChanges in placental morphology due to hypoxia in GDM include immaturity of villi, ischemia, villious fibrotic and necrotic patches. Chorangiosis (presence of more than 5 vessels per villi), calcification, syncytial knots formation (excessive amounts and formation of trophoblastic nuclear out pouching) are also important signs of altered placental texture.14 These increased hypoxic parameters in placental tissues are associated with increased in fetal and maternal mortality and morbidity. Proper diagnosis and management significantly reduces the risks for complications.15 In this study two groups of GDM, one on diet therapy and other on Metformin treatment were compared with each other and with the normal control.\n\nIt was expected that placentae of diet controlled patients would not differ much from normal morphology because the glucose levels were strictly kept near to normal, but significant change in placental gross morphology of GDM patients were observed despite strict diet control. Leo et al. 1977; documented that the placentae of diet controlled patients are slightly heavier in weight than normal placentae16 and was similar to our findings (590±147.9gms vs 567.6±138.9gms). Kucuk et al. also indicated that GDM patients kept on diet only has increased placental weight as compared to normal. (694.8±152.1 gms v/s 610.2±116.6gms).17 Our study also indicated that the placental width and cord width were significantly more in these diet treated GDM patients. The reason could be that diet alone is unable to oppose the altered levels of placental vascular endothelial growth factor, insulin and other growth factors (IGF1, IGF2 and IGF binding proteins) which regulate the placental development and are altered in GDM leading to thickened placenta and its cord.18\n\nDiet controlled placentae were significantly different from normal placentae as they showed villous immaturity, infarction, chorangiosis and syncytial knots formation when compared to normal control. Verma et al. 2010 has documented that in GDM treated with diet only, placentae showed fibrosis and ischemic changes, more syncytial knots, mild edema and fibrinoid necrosis, which is similar to our results.19 Placentae treated with Metformin revealed non-significant results when compared to normal control in gross placental morphology except for cord width. All remaining gross and microscopic hypoxic parameters were non-significant between the groups, making it near to control. Metformin treated placenta had significantly less thickness, chorangiosis and syncytial knot formation as compared to diet controlled placentae when light microscopic results were evaluated. Remaining microscopic hypoxic parameters were also numerically lowered in metformin group than diet control group.\n\nUsing multiple related key words and utilizing search such as engines google.com, Google scholar, PubMed, Science direct, Wiley.com from 1980 till Dec 2015, no documentation was found on the details of placental morphology with Metformin in GDM. Except a single case documented by Campbell in 2009 in which a GDM patient with preeclampsia on Metformin had intrauterine death and the placental morphology showed pronounced changes such as villous dysmaturity, chorioamniotis, villi fibrosis.20 However it was not clarified that the placental changes were purely because of gestational diabetes or the combination of GDM with hypertension had produced them.\n\nMost of the in-vivo and in-vitro studies have shown that Metformin produces its anti-diabetic effect by decreasing the gluconeogenesis primarily through the inhibition of lactate uptake in adipocytes. Other main mechanism reported is decrease in ATP concentration in hepatocytes, leading to decrease in glucose production from glycogen in hepatocytes. At cellular level it also disrupts the respiratory chain oxidation in mitochondria of the liver cell.21 Also, Metformin significantly lower down the HbAIC which could add on in its beneficial effects in GDM patients. These multiple actions of Metformin in diabetic cells could be the reason of its beneficial effects on the placenta as compared to diet control only.\n\nIn conclusion, when we compared the placental morphology of diet controlled and Metformin treated placentae to the normal control placentae, Metformin treated placentae had morphology near to normal placentae whereas diet control had shown significant gross and histological changes. Large sample sized studies of Metformin treated placenta, based on electron microscopy and immuno-histochemistry testing would be an open avenue for the new researchers.\n\nCONCLUSION\nIn GDM patients, Metformin and diet control produced beneficial effects on placental morphology being comparable to normal control and in contrast to diet plus exercise groups.\n\nSource of funding: Self and DUHS.\n\n\nAuthors’ Contributions\nRA: Principal, researcher collected the data and Preparation of manuscript.\n\nMAK: Helped in data collection, write up, analysis and proof reading of manuscript.\n\nNK: Research supervisor of the study, designed the study, helped in write up and critically reviewed the manuscript.\n\nJAH: Clinical supervisor of the study, guided and evaluated clinical aspects of the research.\n==== Refs\nREFERENCES\n1 Territi K Ekbald U Vehlberg T Ronnemaa T Comparison of metformin and insulin in the treatment of gestational diabetes: A retrospective;case control study Rev Diabet Stud 2008 5 2 95 101 18795211 \n2 Ben Haroush A Yogev V Hod M Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes Diabetic Med 2003 21 103 113 \n3 Hiden U Glitzner E Hartmann M Desove G Insulin and IGF system in human placenta of normal and diabetic pregnancies J Anat 2009 215 1 60 68 19467150 \n4 Cowet RM The infant of diabetic mother Neo Rev 2002 3 9 173 189 \n5 Janson T Certin I Powell TL Desoye G Radaelli T Ericsson A Placental transport and metabolism in fetal overgrowth, a workshop report Placenta 2006 27 109 113 doi:10.1016/j.placenta.2006.10.017 16338456 \n6 Akhter F Anjuman Bano ML Ferdaus R Effects of gestational diabetes mellitus on gross morphological structure of preterm placenta Bangladesh J Anat 2010 8 1 34 38 \n7 Tewari V Tewari A Bhardwaj N Histological and histo-chemical changes in placenta of diabetic pregnant females and its comparison with normal placenta Asian Pacific J Tropical Dis 2011 1 1 4 \n8 Gutzin SJ Kozer E Magee LA Feig DS Koren G The safety of oral hypoglycemic agents in first trimester of pregnancy: A meta-analysis Can J Clini Pharm 2003 10 4 179 183 \n9 Singh AK Singh R Metformin in gestational diabetes: An emerging contender, Indian J Endocr Metab 2015 19 2 236 244 \n10 Gandhi P Bustani R Madhuvrata P Farrell T Introduction of metformin for Gestational diabetes mellitus in clinical practice: Has it had an impact Euro J Obstet Gynae Rep Bio 2012 160 2 147 150 \n11 Perkins JM Dunn JP Jagasia SM Perspectives in Gestational Diabetes Mellitus;A review of screening, Diagnosis and Treatment Clin Diabetics 2007 25 2 57 62 \n12 Benirschke K Lewis SH Stacey E Placenta Histology of pathologists New York Lippincott and Williams Inc 1096 1099 \n13 Madazal R Tuten A Calary Z Uzun H Uludag S Ocak V Incidence of placental abnormalities, maternal and cord plasma malondialdehyde and vascular endothelial growth factors levels in women with gestational diabetes mellitus and non-diabetic controls Gynecol Obstet Invest 2008 65 4 227 232 18196904 \n14 Ghidin A Salafia CM Histological placental lesions in women with recurrent preterm delivery Acta Obstet Gynacol Scand 2005 84 6 547 540 \n15 Spaight C Gross J Horch A Pudder JJ Gestational Diabetes Mellitus Endocr Dev 2016 31 163 178 doi:10.1159/000434913 26824237 \n16 Leo TT Lee CP Wong WM Placental weight to birth weight ratio is increased in mild gestational glucose intolerance Placenta 1997 18 227 230 9089786 \n17 Kuck M Doymaz F Placental weight and placental weight-to-birth weight ratio are increased in diet- and exercise-treated gestational diabetes mellitus subjects but not in subjects with one abnormal value on 100-g oral glucose tolerance test, Journal of Diabetes and its Complications J Diabetes Complications 2009 23 1 25 31 18413216 \n18 Hiden U Glitzner E Hartmann M Desove G Insulin and IGF system in human placenta of normal and diabetic pregnancies J Anat 2009 215 1 60 68 19467150 \n19 Verma R Mishra S Kaul JM Cellular changes in the placenta in pregnancies complicated with diabetes Int J Morphol 2010 28 1 259 264 \n20 Cambell IW Duncan C Urquhart R Evans M Placental dysfunction and still birth in gestational diabetes mellitus Br J Diabetes Vascular Dis 2009 9 1 38 40 \n21 Kirpichnikov D Macferlarne SL Sowers JR Metformin: An update Ann Intern Med 2002 137 25 33 12093242\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1681-715X",
"issue": "32(6)",
"journal": "Pakistan journal of medical sciences",
"keywords": "Diet; Exercise; Gestational diabetes; Gross morphology; Metformin; Microscopic morphology; Placenta",
"medline_ta": "Pak J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "100913117",
"other_id": null,
"pages": "1522-1527",
"pmc": null,
"pmid": "28083057",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "18795211;22137984;15901265;14984444;25729685;18413216;14712322;12093242;19467150;26824237;18196904;16542722;9089786",
"title": "Effects of Diet and Metformin on placental morphology in Gestational Diabetes Mellitus.",
"title_normalized": "effects of diet and metformin on placental morphology in gestational diabetes mellitus"
} | [
{
"companynumb": "PK-ALKEM LABORATORIES LIMITED-PK-ALKEM-2021-06164",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Central nervous system bleeding, which can be a life-threatening complication, is seen in 2.7% of patients with haemophilia. Spinal epidural haematomas represent about one-tenth of such cases. Here, we report on a 10-month-old boy with severe haemophilia A, who presented with torticollis. Although administration of factor VIII at a dose of 50 U/kg, the patient developed flaccid paralysis of the upper extremities. Factor VIII inhibitor screen was positive. Magnetic resonance imaging of the spine revealed spinal epidural haematomas, extending from C-1 to the cauda equina. Treatment was continued with recombinant activated factor VIIa without surgery. After 1 month, complete neurological recovery was achieved and fully resolved haematomas were detected on spinal MRI. A prompt radiological evaluation of the cervical spine with MRI should be made in patients with haemophilia presenting with torticollis. In addition, in the case of life-threatening bleeding in patients with haemophilia, the possibility of an inhibitor should be kept in mind.",
"affiliations": "aClinic of Hematology bDivision of Neurosurgery, Dr Behcet Uz Children's Hospital, Konak cAlsancak MR, Radiology Alsancak, Izmir, Turkey.",
"authors": "Oymak|Yesim|Y|;Muminoglu|Neryal|N|;Ay|Yilmaz|Y|;Karapinar|Tuba H|TH|;Köker|Sultan A|SA|;Töret|Ersin|E|;Ylmaz|Aşiyan K|AK|;Gürçnar|Müge|M|;Vergin|Canan|C|",
"chemical_list": "D011994:Recombinant Proteins; D005169:Factor VIII; C103587:recombinant FVIIa; D015942:Factor VIIa",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000465",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "27(5)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D005169:Factor VIII; D015942:Factor VIIa; D046748:Hematoma, Epidural, Spinal; D006467:Hemophilia A; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D011994:Recombinant Proteins; D014103:Torticollis; D016896:Treatment Outcome",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "576-9",
"pmc": null,
"pmid": "26650462",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Torticollis in a haemophilic infant with inhibitor: a case of spinal epidural haematoma.",
"title_normalized": "torticollis in a haemophilic infant with inhibitor a case of spinal epidural haematoma"
} | [
{
"companynumb": "TR-BAYER-2016-147726",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT"
},
"dru... |
{
"abstract": "OBJECTIVE\nWe aim to compare 20 noninvasive fibrosis scores (NIFS), derived from routine blood tests, for predicting significant liver-related adverse events (SLRE) in patients with chronic hepatitis C (CHC) after anti-viral treatment (AVT) with the goal to identify independent predictors for these outcomes.\n\n\nMETHODS\nFrom 1605 patients who received AVT (pegylated interferon and ribavirin) from January 2002 to June 2014, 20 NIFS were calculated from routine blood tests prior to AVT. Areas under the receiver-operating characteristic curve (AUROC) were calculated for each of these NIFS for predicting non-response to AVT and development of SLRE on follow-up.\n\n\nRESULTS\nMean age was 41.9 ± 9.7 years, and patients were predominantly genotype 4 (65%). After AVT, there were 1089 (67.8%) responders, 482 (30%) non-responders and 34 (2.1%) relapsers. After median follow-up of 6580.5 patient-years, 60 (3.8%) had SLRE, 52 (3.2%) had decompensation, and 11 (0.7%) had hepatocellular carcinoma (HCC). The predictive accuracy of NIFS and liver biopsy (LB) for non-response to AVT was low. FIB-4, FibroQ and King score showed high accuracy for predicting adverse events. For predicting decompensation, HCC and SLRE, FibroQ (0.881), King score (0.905) and FibroQ (0.877) had the highest AUROC, respectively. On multivariate analysis, independent predictors for treatment non-response (age, ALT, GGT, platelet count), HCC (albumin, GGT) and SLRE (albumin, GGT, platelet count) were identified.\n\n\nCONCLUSIONS\nSome simple pretreatment blood parameters and NIFS showed high accuracy for predicting development of SLRE post treatment. Application of these simple scores can improve assessment of long-term liver prognosis for CHC.",
"affiliations": "Division of Gastroenterology, Department of Medicine, Hamad General Hospital, Doha, Qatar. doc.ragesh@gmail.com.;Division of Gastroenterology, Department of Medicine, Hamad General Hospital, Doha, Qatar.;Department of Laboratory Medicine and Pathology, Hamad General Hospital, Doha, Qatar.;Department of Gastroenterology, University of Arkansas Medical Center, Little Rock, AR, USA.;Department of Biostatistics, Hamad General Hospital, Doha, Qatar.",
"authors": "Thandassery|Ragesh Babu|RB|;Kaabi|Saad Al|SA|;Soofi|Madiha E|ME|;Tharian|Benjamin|B|;Singh|Rajvir|R|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D012254:Ribavirin",
"country": "United States",
"delete": false,
"doi": "10.1007/s12072-017-9800-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1936-0533",
"issue": "11(4)",
"journal": "Hepatology international",
"keywords": "Antiviral treatment; Chronic hepatitis C; Decompensation; Noninvasive fibrosis scores; Significant liver-related events",
"medline_ta": "Hepatol Int",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D019540:Area Under Curve; D006528:Carcinoma, Hepatocellular; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012254:Ribavirin",
"nlm_unique_id": "101304009",
"other_id": null,
"pages": "401-408",
"pmc": null,
"pmid": "28634687",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "25078309;20675691;26945918;16931569;24428467;26904396;20179698;22298979;8279675;16842444;24889599;21376047;23687416;19053048;20564351;23504622;26275082;26933896;1808228;18846542;26946190;17439504;20675693;23954643;17164553;27110127;24034439;15368524;23849588;17058238;25164152;26974762",
"title": "Noninvasive serum models to predict significant liver related events in chronic hepatitis C.",
"title_normalized": "noninvasive serum models to predict significant liver related events in chronic hepatitis c"
} | [
{
"companynumb": "QA-009507513-1707QAT007108",
"fulfillexpeditecriteria": "1",
"occurcountry": "QA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2B"
},
"drugadditional": ... |
{
"abstract": "Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure.\n\n\n\nCases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period.\n\n\n\nIn the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2).\n\n\n\nThis study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease.",
"affiliations": "CHU de Bordeaux, Pôle de Santé Publique, Service de pharmacologie médicale, Centre Régional de pharmacovigilance de Bordeaux, Bordeaux, France.;CHU de Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire Bordeaux, France.;CHU d'Amiens, Pôle Cœur-Thorax-Vaisseaux, Département de Cardiologie, Amiens Cedex, France.;Pharmacie à Usage Intérieur, CHU de Bordeaux, Pessac, France.;Pharmacie à Usage Intérieur, CHU de Bordeaux, Pessac, France.;Service des soins intensifs cardiologiques Haut-Lévêque (intensive care unit), Pessac, France.;Service d'Hematologie Seniors, Hôpital Saint Louis, Ass Pub Hôp Paris and Paris 7 Université Paris, France.;Service d'Hematologie, Centre Hospitalier du Mans, Le Mans, France.;Service d'Hematologie, Institut Paoli Calmettes, Marseille, France.;Service d'Hematologie, Institut Paoli Calmettes, Marseille, France.;CHU de Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire Bordeaux, France.;Univ. Bordeaux, Inserm, Bordeaux Population Health Research Centre, team Pharmacoepidemiology, Bordeaux, France.;CHU de Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire Bordeaux, France.;CHU de Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire Bordeaux, France.;CHU de Bordeaux, Pôle de Santé Publique, Service de pharmacologie médicale, Centre Régional de pharmacovigilance de Bordeaux, Bordeaux, France.;CHU de Bordeaux, Pôle de Santé Publique, Service de pharmacologie médicale, Centre Régional de pharmacovigilance de Bordeaux, Bordeaux, France.;CHU de Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire Bordeaux, France.",
"authors": "Perino|Justine|J|0000-0003-0039-0734;Mottal|Nathan|N|;Bohbot|Yohann|Y|;Servant|Vincent|V|;Berroneau|Aude|A|;Poustis|Pierre|P|;Fenaux|Pierre|P|;Laribi|Kamel|K|;Charbonnier|Aude|A|;Bilion|Emilien|E|;Calmettes|Claire|C|;Bégaud|Bernard|B|;Pigneux|Arnaud|A|;Milpied|Noël|N|;Miremont-Salamé|Ghada|G|;Théophile|Hélène|H|;Dimicoli-Salazar|Sophie|S|",
"chemical_list": "D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D001374:Azacitidine",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.14211",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "86(5)",
"journal": "British journal of clinical pharmacology",
"keywords": "anticancer drugs; drug safety; heart failure",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001374:Azacitidine; D016208:Databases, Factual; D005260:Female; D006333:Heart Failure; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D060735:Pharmacovigilance; D012189:Retrospective Studies; D013318:Stroke Volume; D014182:Transplantation, Autologous; D016277:Ventricular Function, Left",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "991-998",
"pmc": null,
"pmid": "31912911",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21357777;23300745;23585522;18720364;22915641;31089280;31912911;20354132;18248442;29933727;19230772;29336052;28345491;25090621;26940554;27420897;20136825;28098949;9179072;20567826;17670726;21515844;19255328;30363961;9058730;31469910",
"title": "Cardiac failure in patients treated with azacitidine, a pyrimidine analogue: Case reports and disproportionality analyses in Vigibase.",
"title_normalized": "cardiac failure in patients treated with azacitidine a pyrimidine analogue case reports and disproportionality analyses in vigibase"
} | [
{
"companynumb": "FR-CELGENEUS-FRA-20200106864",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Anticoagulation-related nephropathy (ARN) is a rare form of acute kidney injury where the use of anticoagulation causes hemorrhage in various compartments of nephron including glomerulus, renal tubules, and interstitial compartment. Also, warfarin-induced vasculitis is an extremely rare condition characterized by the appearance of purpuric lesions on the skin which on biopsy are suggestive of leukocytoclastic vasculitis (LV). We hereby report a case presenting with coexistent warfarin-induced nephropathy and cutaneous vasculitis. A 64-year-old male, on warfarin for 10 years, presented with complaints of palpable purpuric rashes over lower limbs, hematuria, and decrease urine output. INR was in the supratherapeutic range (INR-6.3). Skin biopsy of the lesion was suggestive of LV and kidney biopsy showed RBCs in Bowman's capsule, RBCs and RBC casts in tubules suggestive of ARN. All vasculitic markers were negative. Thus, a diagnosis of warfarin-induced nephropathy and cutaneous vasculitis was made. Warfarin was discontinued and oral steroids were started. Gradually, his skin lesions improved, and he became dialysis independent. He was then discharged on apixaban. On follow-up after 3 months, his skin lesions had disappeared with partial recovery of kidney function (cr-5.49).",
"affiliations": "Department of Nephrology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, 110060, India.;Department of Nephrology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, 110060, India. drvt87@gmail.com.;Department of Nephrology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, 110060, India.;Department of Pathology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, 110060, India.;Department of Nephrology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, 110060, India.;Department of Nephrology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, 110060, India.;Department of Nephrology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, 110060, India.;Department of Nephrology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, 110060, India.",
"authors": "Bhandari|Gaurav|G|;Tiwari|Vaibhav|V|http://orcid.org/0000-0003-0128-0959;Gupta|Anurag|A|;Gupta|Pallav|P|;Bhargava|Vinant|V|;Malik|Manish|M|;Gupta|Ashwani|A|;Bhalla|Anil Kumar|AK|;Rana|D S|DS|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-021-00642-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": null,
"journal": "CEN case reports",
"keywords": "AKI; Anticoagulant-related nephropathy; Leukocytoclastic vasculitis; Warfarin",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34533696",
"pubdate": "2021-09-17",
"publication_types": "D016428:Journal Article",
"references": "16047871",
"title": "Double whammy: anticoagulant-related nephropathy with leukocytoclastic vasculitis due to warfarin.",
"title_normalized": "double whammy anticoagulant related nephropathy with leukocytoclastic vasculitis due to warfarin"
} | [
{
"companynumb": "IN-CIPLA LTD.-2021IN06562",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo describe three patients with human immunodeficiency virus (HIV) who were successfully managed with unboosted darunavir (uDRV).\n\n\nMETHODS\nThe three cases included one woman and two men aged 58, 54, and 51 years, respectively. All patients were HIV positive and unable to tolerate ritonavir-boosted protease inhibitors secondary to significant gastrointestinal intolerance. Unboosted darunavir was tolerated without any further issues when prescribed with an optimized antiretroviral (ARV) background regimen. Despite low darunavir (DRV) concentrations, all three patients achieved a virologic response.\n\n\nCONCLUSIONS\nDarunavir is a relatively well-tolerated ARV, but concurrent ritonavir administration has several disadvantages (e.g., dose-related hyperlipidemia, gastrointestinal intolerance, drug-drug interactions) which may decrease patient adherence. The use of uDRV may be particularly useful in patients with limited therapy options who are unable to tolerate ritonavir-boosted protease inhibitors. Therapeutic drug monitoring (TDM) was performed as unboosted DRV has a bioavailability of 37% and the virologic and immunologic response has only been demonstrated with ritonavirboosted DRV.\n\n\nCONCLUSIONS\nSuccessful use of uDRV may be an acceptable ARV option in carefully selected patients with limited treatment options, particularly when an optimized background regimen is included. Darunavir TDM should be strongly considered if uDRV is initiated.",
"affiliations": null,
"authors": "Smith|Katelyn|K|;Gomes|Denese|D|;Nixon|Daniel|D|;Fulco|Patricia Pecora|PP|",
"chemical_list": "D017320:HIV Protease Inhibitors; D019438:Ritonavir; D000069454:Darunavir",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP202476",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "54(1)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000069454:Darunavir; D016903:Drug Monitoring; D005260:Female; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D019438:Ritonavir",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "52-7",
"pmc": null,
"pmid": "26636419",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The use of unboosted darunavir in the setting of ritonavir intolerance: three case reports.",
"title_normalized": "the use of unboosted darunavir in the setting of ritonavir intolerance three case reports"
} | [
{
"companynumb": "US-JNJFOC-20160115817",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ABACAVIR\\LAMIVUDINE"
},
"drugadditional": null,... |
{
"abstract": "The standard treatment of thrombotic antiphospholipid syndrome (APS) is lifelong oral anticoagulation with a vitamin K antagonist (VKA), generally warfarin. A minority of patients with APS rethrombose despite seemingly adequate anticoagulation. These patients are deemed anticoagulant refractory. The management of anticoagulant-refractory APS is largely empirical and extrapolated from other clinically similar situations. Further options include increased VKA anticoagulation intensity or alternative antithrombotic strategies, including low-molecular-weight heparin, fondaparinux, the addition of antiplatelet therapy, and consideration of vascular options. Patients with anticoagulant-refractory thrombotic APS may have APS-associated thrombocytopenia, which necessitates balancing the risk of recurrent thrombosis vs bleeding to achieve adequate anticoagulation. The multiple mechanisms involved in the generation of the thrombotic phenotype in APS suggest that anticoagulation alone may not control thrombosis. Thus, other modalities, including adjunctive treatment (hydroxychloroquine, statins, and vitamin D) for APS-related thrombosis, merit consideration, as do immunomodulatory therapy and complement inhibition. Patients with APS may have coexistent systemic lupus erythematosus, which adds to the complexity of managing their thromboembolic disease. However, with attention to detail and judicious application of the limited data, it is possible to minimize the morbidity resulting from anticoagulant-refractory thrombotic APS. Multicenter studies are required to guide the sequence of interventions and their comparative efficacy in patients with anticoagulant-refractory thrombotic APS.",
"affiliations": "Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, United Kingdom; and.",
"authors": "Cohen|Hannah|H|;Isenberg|David A|DA|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2020004942",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "137(3)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000925:Anticoagulants; D016736:Antiphospholipid Syndrome; D005260:Female; D006470:Hemorrhage; D006801:Humans; D007511:Ischemia; D008180:Lupus Erythematosus, Systemic; D013921:Thrombocytopenia; D013927:Thrombosis",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "299-309",
"pmc": null,
"pmid": "32898856",
"pubdate": "2021-01-21",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "How I treat anticoagulant-refractory thrombotic antiphospholipid syndrome.",
"title_normalized": "how i treat anticoagulant refractory thrombotic antiphospholipid syndrome"
} | [
{
"companynumb": "GB-MYLANLABS-2021M1046936",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
... |
{
"abstract": "Planning pregnancy in patients with active multiple sclerosis (MS) is highly challenging because treatment withdrawn may be associated with dramatic disease reactivation.\n\n\n\nTo compare two strategies for women with active MS who were planning pregnancy: stopping natalizumab (1) at the end of the first trimester and (2) at conception.\n\n\n\nStandardized strategy for women with active MS was initiated in our department. Maintenance of natalizumab until the end of first trimester was recommended (\"secured first trimester\" (SFT)). When patients refused, they were advised to continue until conception (\"secured conception\" (SC)). Predictors of disease activity during pregnancy were assessed.\n\n\n\nForty-six pregnancies were prospectively followed (30 with SFT and 16 with SC). One congenital anomaly occurred in the SC group. The proportions of patients with relapse and disability progression during pregnancy were lower in the SFT than in the SC group (3.6% vs 38.5%, p < 0.005 and 3.6% vs 30.8%, p < 0.05, respectively). Predictors of relapse and disability progression during pregnancy were the time when natalizumab was stopped (conception vs end of first trimester) and the number of relapses during the year before natalizumab.\n\n\n\nMaintaining natalizumab during the first trimester may reduce the risk of disease reactivation during pregnancy in patients with active MS.",
"affiliations": "Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France.;Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France.;Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France.;Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France.;Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France.;Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Aix-Marseille University, Marseille, France.",
"authors": "Demortiere|Sarah|S|;Rico|Audrey|A|;Maarouf|Adil|A|;Boutiere|Clémence|C|;Pelletier|Jean|J|;Audoin|Bertrand|B|0000-0002-9860-7657",
"chemical_list": "D007155:Immunologic Factors; D000069442:Natalizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1352458520912637",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "27(5)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Active multiple sclerosis; natalizumab; pregnancy",
"medline_ta": "Mult Scler",
"mesh_terms": "D005260:Female; D006801:Humans; D007155:Immunologic Factors; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "712-718",
"pmc": null,
"pmid": "32202216",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Maintenance of natalizumab during the first trimester of pregnancy in active multiple sclerosis.",
"title_normalized": "maintenance of natalizumab during the first trimester of pregnancy in active multiple sclerosis"
} | [
{
"companynumb": "FR-BIOGEN-2019BI00788244",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWe report a case of post-partum hemophagocytic lymphohistiocytosis with marked macrovesicular hepatic steatosis.\n\n\nMETHODS\nA 39-year-old woman was admitted for hemophagocytic lymphohistiocytosis with a serum ferritin level of 103,380 μg/L. Thoracic abdominal and pelvic CT-scan showed hepatomegaly with marked steatosis. Liver biopsy confirmed macrovesicular steatosis. The diagnosis was a primary hemophagocytic lymphohistiocytosis. After treatment failure including corticosteroids, intravenous immunoglobulin, tetracycline, acyclovir, antituberculosis drugs, and anti-IL1R therapy, clinical improvement was obtained with intravenous cyclosporine. At 4-year follow-up, the patient remained asymptomatic.\n\n\nCONCLUSIONS\nSeveral aspects of this report of primary hemophagocytic lymphohistiocytosis are remarkable and include the association with post-partum, the severe radiologic and histologic macrovesicular steatosis, and the dramatic efficacy of cyclosporine.",
"affiliations": "Service de médecine interne, CHU Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes cedex 1, France.;Service de médecine interne, CHU Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes cedex 1, France.;Service de médecine interne, CHU Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes cedex 1, France.;Laboratoire d'anatomopathologie, CHU Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes cedex 1, France.;Service de médecine interne, CHU Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes cedex 1, France.;Service de médecine interne, centre hospitalier de Guingamp, 17, rue de l'Armor, BP 10548, 22205 Guingamp, France.;Service de médecine interne, CHU Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes cedex 1, France. Electronic address: mohamed.hamidou@chu-nantes.fr.",
"authors": "Wahbi|A|A|;Graveleau|J|J|;Néel|A|A|;Joubert|M|M|;Masseau|A|A|;Joly|G Magadur|GM|;Hamidou|M|M|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "36(8)",
"journal": "La Revue de medecine interne",
"keywords": "Fatty liver; Grossesse; Hemophagocytic lymphohistiocytis; Hemophagocytic syndrome; Postpartum; Pregnancy; Stéatose hépatique; Syndrome d’activation lymphohistiocytaire; Syndrome d’activation macrophagique",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000328:Adult; D005234:Fatty Liver; D005260:Female; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D011247:Pregnancy; D011644:Puerperal Disorders",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "555-7",
"pmc": null,
"pmid": "25304169",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Macrovesicular hepatic steatosis revealing pregnancy hemophagocytic lymphohistiocytosis.",
"title_normalized": "macrovesicular hepatic steatosis revealing pregnancy hemophagocytic lymphohistiocytosis"
} | [
{
"companynumb": "FR-MYLANLABS-2015M1028991",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "To report a case of profound bilateral sensorineural hearing and vestibular loss from relapsing polychondritis and hearing outcomes after cochlear implantation.\nCase report and literature review.\nA 43 year-old woman developed sudden loss of hearing and balance that progressed over several weeks to bilateral, profound hearing and vestibular loss. Steroid treatments were ineffective. She underwent vestibular physical therapy and left cochlear implantation. About 10 months after her initial presentation, she developed erythema, warmth, swelling, and pain of the left auricle sparing the lobule, flattening of the bridge of her nose, and right ankle swelling, warmth, and skin erythema. A biopsy of the left auricle revealed histopathologic findings consistent with relapsing polychondritis. She was treated with high dose prednisolone. The ear inflammation resolved, however, despite excellent auditory response to pure tone thresholds, the patient reported no improvement in speech perception after cochlear implantation.\nRelapsing polychondritis can present with rapidly progressive, profound loss of hearing and vestibular function. Hearing outcomes after cochlear implantation can include poor speech discrimination despite good pure tone detection thresholds.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA.;Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA.;Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.;Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA.;Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA.",
"authors": "Akdoğan|Özge|Ö|;Exilus|Smirnov|S|https://orcid.org/0000-0003-4607-1157;Ward|Bryan K|BK|https://orcid.org/0000-0001-5201-6117;McArthur|Justin C|JC|;Della Santina|Charles C|CC|;Carey|John P|JP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/00034894211005979",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4894",
"issue": "130(12)",
"journal": "The Annals of otology, rhinology, and laryngology",
"keywords": "bilateral vestibulopathy; cochlear implant; relapsing polychondritis; sensorineural hearing loss",
"medline_ta": "Ann Otol Rhinol Laryngol",
"mesh_terms": "D000328:Adult; D001301:Audiometry, Pure-Tone; D003054:Cochlear Implants; D005260:Female; D006309:Hearing; D006319:Hearing Loss, Sensorineural; D003639:Hearing Loss, Sudden; D006801:Humans; D008279:Magnetic Resonance Imaging; D011081:Polychondritis, Relapsing; D013067:Speech Perception; D014722:Vestibule, Labyrinth",
"nlm_unique_id": "0407300",
"other_id": null,
"pages": "1412-1416",
"pmc": null,
"pmid": "33813869",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sudden Sensorineural Hearing and Vestibular Loss in a Case of Relapsing Polychondritis.",
"title_normalized": "sudden sensorineural hearing and vestibular loss in a case of relapsing polychondritis"
} | [
{
"companynumb": "US-AMERICAN REGENT INC-2022000571",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE SODIUM PHOSPHATE"
},
"d... |
{
"abstract": "BACKGROUND\nGastrointestinal disorders in solid organ recipients may have various origins including cryptosporidiosis and microsporidiosis. The prevalence of these infections is poorly known in solid organ transplant (SOT) patients in industrialized countries.\n\n\nMETHODS\nWe prospectively assessed the infectious causes of diarrhea in SOT patients. Secondary objectives were to gain further insight into the main characteristics of cryptosporidiosis, and to assess risk factors for this infection. All adult kidney and/or pancreas recipients presenting with diarrhea and admitted to our facility between May 1, 2014 and June 30, 2015 were enrolled. A stool sample was analyzed using a standardized protocol including bacteriological, virological, and parasitological investigations. Data related to clinical symptoms, immunosuppression, and environmental potential risk factors were collected through a self-administered questionnaire and computerized medical records.\n\n\nRESULTS\nOut of 73 enrolled patients, 36 had infectious diarrhea (49.3%). Viruses ranked first (17/36), followed by parasites and fungi (11/17). Cryptosporidiosis was the most common parasitic disease (n=6 patients). We observed four microsporidiosis cases. The estimated prevalence of cryptosporidiosis and microsporidiosis in this cohort was 3.7 and 2.40/00, respectively. No significant risk factor for cryptosporidiosis or microsporidiosis, neither environmental nor immunological, could be evidenced.\n\n\nCONCLUSIONS\nBoth cryptosporidiosis and microsporidiosis represent a significant cause of diarrhea in kidney transplant recipients.",
"affiliations": "Institute for Transplantation, Urology and Nephrology (ITUN) Nantes University Hospital, 44000 Nantes, France. Electronic address: clement.deltombe@chu-nantes.fr.;Infectious Diseases Department and CIC 1413, Inserm, Nantes University Hospital, 44000 Nantes, France.;Parasitology and Medical Mycology Laboratory, Nantes University Hospital, 44000 Nantes, France.;Infectious Diseases Department and CIC 1413, Inserm, Nantes University Hospital, 44000 Nantes, France.;Virology Department, Nantes University Hospital, 4000 Nantes, France.;Parasitology and Medical Mycology Laboratory, Nantes University Hospital, 44000 Nantes, France.;Infectious Diseases Department and CIC 1413, Inserm, Nantes University Hospital, 44000 Nantes, France.;Institute for Transplantation, Urology and Nephrology (ITUN) Nantes University Hospital, 44000 Nantes, France.",
"authors": "Deltombe|C|C|;Lefebvre|M|M|;Morio|F|F|;Boutoille|D|D|;Imbert|B M|BM|;Le Pape|P|P|;Raffi|F|F|;Hourmant|M|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.medmal.2019.07.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0399-077X",
"issue": "50(5)",
"journal": "Medecine et maladies infectieuses",
"keywords": "Cryptosporidiose; Cryptosporidiosis; Diarrhea; Diarrhée; Microsporidiose; Microsporidiosis; Solid organ transplantation; Transplantation d’organe solide",
"medline_ta": "Med Mal Infect",
"mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003457:Cryptosporidiosis; D003967:Diarrhea; D005260:Female; D005602:France; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D016881:Microsporidiosis; D008875:Middle Aged; D016377:Organ Transplantation; D016035:Pancreas Transplantation; D066027:Transplant Recipients",
"nlm_unique_id": "0311416",
"other_id": null,
"pages": "407-413",
"pmc": null,
"pmid": "31472993",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cryptosporidiosis and microsporidiosis as causes of diarrhea in kidney and/or pancreas transplant recipients.",
"title_normalized": "cryptosporidiosis and microsporidiosis as causes of diarrhea in kidney and or pancreas transplant recipients"
} | [
{
"companynumb": "FR-STRIDES ARCOLAB LIMITED-2021SP026633",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drug... |
{
"abstract": "OBJECTIVE\nAdding nitroglycerin to the combination of vinorelbine plus cisplatin has been reported to improve the overall survival (OS) of Asian patients with stage IIIB/IV non-small cell lung cancer (NSCLC) probably due to better drug delivery based on changed vascular tonus. The main objective of our study was to evaluate the effect of adding nitroglycerin to vinorelbine and cisplatin in a Caucasian population.\n\n\nMETHODS\n66 chemonaïve patients with stage IIIB/IV NSCLC received oral vinorelbine (first cycle 60 mg/m(2), subsequent cycles: 80 mg/m(2) in the absence of any hematological toxicity ≥ grade 3 in cycle 1) once daily on days 1 and 8 of each cycle and cisplatin (80 mg/m(2) i.v.) on day 1 of each cycle (q3w). Nitroglycerin (arm A, n=34) or placebo patches (arm B, n=32) were administered once daily from day -3 to day 2 of each cycle and were removed about 12h after administration. One nitroglycerin patch contained 25mg nitroglycerin.\n\n\nRESULTS\nMedian age was 62.5 (33-82) years. In the overall population (n=66), the objective response rate (ORR) was 27.3% (all PR; 95%CI: 17.0-39.6), with a disease control rate (DCR) of 57.6% (95%CI: 44.8-69.7), a median time to progression (TTP) of 4.8 months (n=58; 95%CI: 3.4-5.9) and a median overall survival (OS) of 11.5 months (95%CI: 7.9-13.6). ORR and DCR were numerically higher in arm A than in arm B (35.3% vs. 18.8% and 61.8% vs. 53.1%, respectively), whereas TTP and OS were comparable. The main hematological and non-hematological toxicities grade ≥ 3 were moderate with no significant differences between the two treatment arms.\n\n\nCONCLUSIONS\nOverall, oral vinorelbine plus cisplatin showed a high level of efficacy and adequate tolerability in first line treatment of NSCLC. Despite the low sample size per group the results seem to confirm the previous results reported in Asian patients.",
"affiliations": "LungenClinic Grosshansdorf, Department of Thoracic Oncology, member of the German Center for Lung Research, Grosshansdorf, Germany.;Kliniken Maria Hilf, Pneumology, Moenchengladbach, Germany.;Malteser Krankenhaus St. Franziskus, Internal Medicine, Flensburg, Germany.;Universitaetsklinikum, Internal Medicine, Greifswald, Germany.;Sana Kliniken Ostholstein, Internal Medicine, Oldenburg, Germany.;Helios Kliniken, Pneumology, Schwerin, Germany.;Universitaetsklinikum, Pneumology, Rostock, Germany.;Hanse-Klinikum, Oncology, Stralsund, Germany.;Gesellschaft für medizinische Innovation Hämatologie und Onkologie mbH, Berlin, Germany.;LungenClinic Grosshansdorf, Department of Thoracic Oncology, member of the German Center for Lung Research, Grosshansdorf, Germany. Electronic address: dr.martin.reck@web.de.",
"authors": "Reinmuth|N|N|;Meyer|A|A|;Hartwigsen|D|D|;Schaeper|C|C|;Huebner|G|G|;Skock-Lober|R|R|;Bier|A|A|;Gerecke|U|U|;Held|C-P|CP|;Reck|M|M|",
"chemical_list": "D014747:Vinblastine; D005996:Nitroglycerin; D002945:Cisplatin; D000077235:Vinorelbine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "83(3)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Chemotherapy; Cisplatin; First-line therapy; Nitroglycerin; Non-small cell lung cancer; Oral vinorelbine",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D005996:Nitroglycerin; D016019:Survival Analysis; D014747:Vinblastine; D000077235:Vinorelbine; D044465:Whites",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "363-8",
"pmc": null,
"pmid": "24462464",
"pubdate": "2014-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized, double-blind phase II study to compare nitroglycerin plus oral vinorelbine plus cisplatin with oral vinorelbine plus cisplatin alone in patients with stage IIIB/IV non-small cell lung cancer (NSCLC).",
"title_normalized": "randomized double blind phase ii study to compare nitroglycerin plus oral vinorelbine plus cisplatin with oral vinorelbine plus cisplatin alone in patients with stage iiib iv non small cell lung cancer nsclc"
} | [
{
"companynumb": "DE-WEST-WARD PHARMACEUTICALS CORP.-DE-H14001-18-00491",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE"
... |
{
"abstract": "Cytomegalovirus (CMV) retinitis (CMVR) has been reported rarely in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In addition, little is known about strategies for ophthalmic surveillance and adequate antiviral treatment of CMVR. A case of CMVR in an allogeneic HSCT recipient is described, including clinical signs and therapy. An adult patient received HSCT from a matched unrelated donor for treatment of a Burkitt lymphoma. Donor and recipients were both CMV positive. Starting on day +40, the patient presented multiple CMV reactivation, treated with valganciclovir, foscarnet and a combination of both. On day +160, the patient started complaining of conjunctival hyperaemia and a decrease in visual acuity. Fundoscopy revealed retinal lesions consistent with CMVR, although whole blood CMV DNAemia was negative. Aqueous humor biopsy showed the presence of CMV infection (CMV DNA 230400 UI/ml). CMVR was treated with foscarnet (180 mg i.v. and 1.2 mg intravitreal injection) combined with anti CMV immunoglobulin at 0.5 ml/kg every 2 weeks. After 4 weeks of systemic therapy, 20 weekly doses of intravitreal foscarnet and six cycles of immunoglobulins, a significant improvement of visual acuity was observed. The treatment was well tolerated with no side effect. In conclusion, our case suggests that systemic and local antiviral treatment combined with CMV-specific-IVIG, may reduce CMV load in the eye of patients with CMVR, leading to a consistent improvement of visual acuity. Systematic ophthalmologic examination should be recommended in HSCT recipients with multiple CMV reactivations and high peak CMV DNA levels.",
"affiliations": "Department of Oncology and Hematology, AOU Citta' della Salute e della Scienza, Turin, Italy.;Eye Clinic Section, Department of Surgical Sciences, University of Turin, Italy.;Eye Clinic Section, Department of Surgical Sciences, University of Turin, Italy.;Stem Cell Transplant Center, AOU Citta' della Salute e della Scienza, Turin, Italy.;Stem Cell Transplant Center, AOU Citta' della Salute e della Scienza, Turin, Italy.;Department of Medical Sciences, University of Turin, Italy.;SC Microbiology and Virology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.;Department of Oncology and Hematology, AOU Citta' della Salute e della Scienza, Turin, Italy.;Stem Cell Transplant Center, AOU Citta' della Salute e della Scienza, Turin, Italy.;Stem Cell Transplant Center, AOU Citta' della Salute e della Scienza, Turin, Italy.;Stem Cell Transplant Center, AOU Citta' della Salute e della Scienza, Corso Bramante 88, Turin, 10126, Italy.",
"authors": "Vassallo|Francesco|F|;Nuzzi|Raffaele|R|;Cattani|Ilaria|I|;Dellacasa|Chiara|C|;Giaccone|Luisa|L|;De Rosa|Francesco Giuseppe|FG|;Cavallo|Rossana|R|;Iovino|Giorgia|G|;Brunello|Lucia|L|;Bruno|Benedetto|B|;Busca|Alessandro|A|https://orcid.org/0000-0001-5361-5613",
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"doi": "10.1177/2040620720975651",
"fulltext": "\n==== Front\nTher Adv Hematol\nTher Adv Hematol\nTAH\nsptah\nTherapeutic Advances in Hematology\n2040-6207 2040-6215 SAGE Publications Sage UK: London, England \n\n10.1177/2040620720975651\n10.1177_2040620720975651\nCase Report\nCMV retinitis in a stem cell transplant recipient treated with foscarnet intravitreal injection and CMV specific immunoglobulins\nVassallo Francesco Department of Oncology and Hematology, AOU Citta’ della Salute e della Scienza, Turin, Italy\n Nuzzi Raffaele Eye Clinic Section, Department of Surgical Sciences, University of Turin, Italy\n Cattani Ilaria Eye Clinic Section, Department of Surgical Sciences, University of Turin, Italy\n Dellacasa Chiara Stem Cell Transplant Center, AOU Citta’ della Salute e della Scienza, Turin, Italy\n Giaccone Luisa Stem Cell Transplant Center, AOU Citta’ della Salute e della Scienza, Turin, Italy\n De Rosa Francesco Giuseppe Department of Medical Sciences, University of Turin, Italy\n Cavallo Rossana SC Microbiology and Virology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy\nDepartment of Public Health and Pediatrics, University of Torino, Torino, Italy\n Iovino Giorgia Department of Oncology and Hematology, AOU Citta’ della Salute e della Scienza, Turin, Italy\n Brunello Lucia Stem Cell Transplant Center, AOU Citta’ della Salute e della Scienza, Turin, Italy\n Bruno Benedetto Stem Cell Transplant Center, AOU Citta’ della Salute e della Scienza, Turin, Italy\n https://orcid.org/0000-0001-5361-5613Busca Alessandro Stem Cell Transplant Center, AOU Citta’ della Salute e della Scienza, Corso Bramante 88, Turin, 10126, Italy\n abusca@cittadellasalute.to.it\n10 12 2020 \n2020 \n11 204062072097565130 6 2020 23 10 2020 © The Author(s), 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Cytomegalovirus (CMV) retinitis (CMVR) has been reported rarely in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In addition, little is known about strategies for ophthalmic surveillance and adequate antiviral treatment of CMVR. A case of CMVR in an allogeneic HSCT recipient is described, including clinical signs and therapy. An adult patient received HSCT from a matched unrelated donor for treatment of a Burkitt lymphoma. Donor and recipients were both CMV positive. Starting on day +40, the patient presented multiple CMV reactivation, treated with valganciclovir, foscarnet and a combination of both. On day +160, the patient started complaining of conjunctival hyperaemia and a decrease in visual acuity. Fundoscopy revealed retinal lesions consistent with CMVR, although whole blood CMV DNAemia was negative. Aqueous humor biopsy showed the presence of CMV infection (CMV DNA 230400 UI/ml). CMVR was treated with foscarnet (180 mg i.v. and 1.2 mg intravitreal injection) combined with anti CMV immunoglobulin at 0.5 ml/kg every 2 weeks. After 4 weeks of systemic therapy, 20 weekly doses of intravitreal foscarnet and six cycles of immunoglobulins, a significant improvement of visual acuity was observed. The treatment was well tolerated with no side effect. In conclusion, our case suggests that systemic and local antiviral treatment combined with CMV-specific-IVIG, may reduce CMV load in the eye of patients with CMVR, leading to a consistent improvement of visual acuity. Systematic ophthalmologic examination should be recommended in HSCT recipients with multiple CMV reactivations and high peak CMV DNA levels.\n\nCMVfoscarnetretinitiscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nImpaired cellular immunity after allogeneic hematopoietic stem cell transplantation (HSCT) may lead to cytomegalovirus (CMV) reactivation, which is associated with increased risk of CMV disease and ultimately to higher morbidity and mortality of HSCT recipients.1 Clinical manifestations of CMV disease usually include colitis, hepatitis and pneumonitis, while CMV retinitis (CMVR) is reported by far more occasionally in hematopoietic stem cell transplantation (HSCT) recipients than in acquired immunodeficiency syndrome (AIDS) patients.2 CMVR, if underestimated or misdiagnosed, frequently leads to visual impairment or blindness,3,4 and therefore needs timely treatment usually combining systemic and intraocular administration.5,6 Ganciclovir represents the treatment of choice for patients with CMVR, although toxicity, in particular myelosuppression, limits its use in a consistent number of cases.2,7–10 Foscarnet is an alternative approach, although clinical experience in this setting is rather limited.7,10,11 Here, we present the case of an HSCT recipient who developed CMVR that was treated successfully by combining systemic and intravitreal administration of foscarnet.\n\nCase presentation\nA 32-year-old man was diagnosed with diffuse large B cell lymphoma infiltrating the thorax wall with involvement of costal cartilages in August 2017. He was first treated with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) followed by four cycles of R-DHAP (rituximab, prednisone, cisplatin and cytarabine) without achieving remission. Surprisingly, disease restaging showed Burkitt lymphoma on chest biopsy, for which the patient was treated with an R Magrath regimen (R-IVAC: rituximab, ifosfamide, etoposide and cytarabine alternated with R-CODOX-M: cyclophosphamide, vincristine, doxorubicin and methotrexate) attaining complete remission. In September 2018, the patient underwent a stem cell transplant from a 10/10 human leukocyte antigen (HLA)-matched unrelated donor (MUD). Donor and recipient were both CMV immunoglobulin G (IgG) positive. The conditioning regimen consisted of thiotepa, busulfan and fludarabine. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine, short course methotrexate and anti thymocyte globulin (2.5 mg/kg for 2 consecutive days). Fluconazole and acyclovir were given as antimicrobial prophylaxis. Neutrophil engraftment occurred on day +27 after transplant. During the first month after transplant, CMV DNAemia, tested two times per week, was around 1300–2000, below the threshold used to start therapy (3000 copies). On day +40, whole blood CMV DNA reached 37,000 UI/ml, and the patient was started on valganciclovir (VGCV) at 900 mg bid. However, after 9 days of therapy, DNAemia increased up to 1,46,800 UI/ml. Second line treatment with foscarnet 120 mg/kg was started promptly, leading to a slow decrease of viral load up to 25,800 UI/ml after 2 weeks of treatment (Figure 1). Following administration of steroids for the treatment of possible gut GVHD, a new flare of CMV DNAemia occurred on day +95. Genotypic resistance testing for the UL54 and UL97 genes was negative. The patient was treated with a combination of foscarnet 120mg/kg and VGCV 450 mg bid, resulting in the clearance of CMV DNAemia after 2 weeks of treatment (Figure 1). On day +160, the patient started complaining of conjunctival hyperaemia and a moderate decrease in visual acuity. Fundoscopy revealed papillary hyperaemia, retinal necrosis, haemorrhage and vasculitis consistent with CMVR (Figure 2), although whole blood CMV DNAemia was negative. Lymphocyte recovery was impaired significantly, with 69 CD4+ cells/μl, 221 CD8+ cells/μl and 82 CD19+ cells/μl. Aqueous humor biopsy showed presence of CMV infection (CMV DNA 230,400 UI/ml) while the presence of other viruses (herpes simplex virus, virus varicella zoster or Epstein Barr virus) was excluded; at the same time CMV serum DNAemia was negative. CMVR, once written informed consent had been obtained, was treated with foscarnet (180 mg i.v. and 1.2 mg intravitreal injection) combined with anti CMV immunoglobulin (cytomegatect) at 0.5 ml/kg every 2 weeks. After 4 weeks of systemic therapy, 20 weekly doses of intravitreal foscarnet and six cycles of immunoglobulins, a significant improvement in visual acuity was observed. The treatment was well tolerated with no side effects. Cyclosporine was tapered and then stopped on day + 315 (Figure 1). At 3 months after discontinuation of treatment, the patient started complaining of blurry vision. Diffuse atrophic chorioretinitis and posterior haemorrhage were observed. Retinal fluoroscopy demonstrated diffuse retinal vasculitis with loss of capillary, bilateral macular oedema, diffuse damage, vitreitis and steadily atrophic CMV lesions consistent with vasculitis requiring the administration of steroids at 1 mg/kg daily. Fundoscopic evaluation 2 weeks later was suggestive of reactivation of the viral infection given the presence of periangioitis and hyalinosis of the temporal area of the right retina. However, whole blood and humor aqueous CMV DNA were both negative. Maintenance therapy with VGCV at 450 mg bid was started during steroid treatment. After 4–6 weeks, visual acuity showed a moderate improvement, allowing a slow steroid taper. At 7 months after the diagnosis of CMV retinitis, the patient is in good general conditions and in continuous haematological remission (Figure 3).\n\nFigure 1. Clinical course of patient with CMV retinitis following allogeneic HSCT. Day 0 indicates the day of transplantation. The solid line indicates the CMV viral load in whole blood.\n\nCMV, cytomegalovirus; CMVR, CMV retinitis; HSCT, hematopoietic stem cell transplantation; VGCV, valgancyclovir.\n\nFigure 2. Fundoscopic finding at the time of initial diagnosis (day+160 after transplantation). Evolutionary CMVR with initial vitreitis, optic papilla hyperaemia, peripheral/equatorial retinal necrosis, retinal haemorrhages, retinal oedema, retinal vasculitis.\n\nCMV, cytomegalovirus; CMVR, CMV retinitis.\n\nFigure 3. (A) OCT 3 months after the end of systemic and local antiviral treatment. Regression of CMVR with persistence only of increased central retinal thickness. (B) Retinal fluoroscopy 3 months after the end of systemic and local antiviral treatment.\n\nCMV, cytomegalovirus; CMVR, CMV retinitis; LE, left eye; OCT, optical coherence tomography; RE, right eye.\n\nDiscussion\nThis paper describes a patient who presented with severe CMV retinitis after allogeneic HSCT and highlights the aggressive nature of this complication. CMVR is reported infrequently in adult patients undergoing allogeneic HSCT, with rates ranging between 0.19 and 5.6%, while it appears more frequent in children.2,7,8,12–14 CMVR diagnosis is challenging. Our patient showed characteristics lesions in the fundus and both fluorescein angiography and CMV DNA load in the aqueous humor were consistent with CMVR. Nevertheless, a few cases of asymptomatic CMVR have been described,9,15 underlining the importance of ruling out retinal involvement in immunocompromised hosts with CMV infection. Thus, it is important to stress that CMVR management requires the close cooperation of haematologists with ophthalmologists.\n\nAs reported elsewhere, it is not surprising that, in our patient, CMV DNA was not detectable in whole blood at the time of CMVR diagnosis.8,13,16 In fact, it is possible to speculate that the eyes may represent a sanctuary site where immunocompetent cells as well as antiviral therapies penetrate with extreme difficulty.17 According to these observations, our therapeutic approach included the association of both intravenous and intravitreal injections of foscarnet. This antiviral agent was chosen in the light of the poor response to the initial treatment with VGCV and, more importantly, of the presence of a significant peripheral cytopenia, potentially related, at least partly, to VGCV toxicity. Indeed, foscarnet showed efficacy in clearing the virus and clinically resolving CMVR, without any side effect associated with both systemic and local injections. Overall, GCV or Foscarnet represent the most widely used systemic therapies for CMVR.2,7–10,12,18 Only a few patients have been treated with intravitreal injection of GCV (Table 1). Larsson et al. described two patients who received combined systemic and local treatment with intravitreal injections of GCV,12 while Zhang et al. described 12 patients who received combined systemic and intravitreal injection16; 11 eyes showed improvements or stabilization whereas 8 eyes deteriorated. Transplant from a HLA-mismatched donor and CMV DNA copies higher than 1 × 104 were adverse factors for visual outcomes. Miao et al. reported the largest experience on 14 haematological patients with CMVR who were treated with four intravitreal injections of GCV.19 The procedure was well-tolerated and was capable of reducing the level of CMV DNA in the eye. Our patient required a total of 20 intravitreal injections, suggesting that this procedure may be considered rather safe and effective. Moreover, to our knowledge, this is the first case of a patient with CMVR where CMV-specific-IVIG were combined with antiviral treatment. Studies evaluating the efficacy of IVIG in HSCT recipients with CMV infection are lacking.20–22 Since foscarnet is virostatic,23 we can speculate that IVIG might have contributed to control viral replication once systemic treatment with foscarnet has been discontinued.\n\nTable 1. Summary of published cases of adult patients with CMVR following allogeneic HSCT treated with local antiviral therapy.\n\nReference\tNo. patients\tHSCT\tMedian onset of CMVR (days from HSCT)\tSystemic antiviral therapy\tLocal antiviral therapy\tOutcome\t\nZhang et al.16\t12\tMUD (7)\nMMUD(5)\t126\tNo\tGCV, 4 injections\t4 improvement\n4 stabilization\n4 deterioration\t\nMiao et al.19\t14\t\t156\tNo\tGCV 4 injections\timprovement\t\nJeon and Lee13\t10\tMUD (4)\nMMUD (6)\t\t3 GCV\n3GCV + FOS\n4 other\tGCV 4 injections\t4 improvement\n5 stabilization\t\nZöllner et al.2\t11\tMUD (2)\nMMUD(3)\t147\t2 GCV\tGCV 4 injections\t2 improvement\n1 deterioration\t\nCMV, cytomegalovirus; CMVR, CMV retinitis; FOS, foscarnet; GCV, ganciclovir; HSCT, hematopoietic stem cell transplantation; MMUD, mismatched unrelated donor; MUD, matched unrelated donor.\n\nSeveral risk factors for CMVR have been reported in different studies. Jeon et al. found that HSCT from MUD or mismatched donors, delayed engraftment, peak CMV levels and duration of viremia were factors associated with the development of CMVR in univariate analysis, although only CMV DNA level remained statistically significant in multivariate analysis.13 A study from the Seattle group showed that CMV seropositive recipients, CMV reactivation before day 100, delayed post-transplant lymphocyte recovery and presence of chronic GVHD were factors potentially associated with CMVR.7 All these risk factors were observed in our patient with the exception of GVHD, although a short course of steroids was administered for suspected diagnosis GVHD-related diarrhoea, promptly discontinued after a gut biopsy ruled out histological signs of GVHD. Even in the absence of clinically evident GVHD, our patient showed a remarkably slow lymphocyte recovery, with 69/μl CD4+ T cells at day +160. We can hypothesize that GVHD prophylaxis including antithymocyte globulin (ATG) and the prolonged administration of VGCV (total duration 38 days) may have negatively influenced the immune recovery. Regarding the prolonged use of antiviral drugs, those currently available are toxic and poorly tolerated and must be used wisely. The availability of less toxic compounds might potentially change the paradigm of CMV treatment with long-lasting treatment in selected patients.\n\nIn conclusion, our case suggests that systemic and local antiviral treatments with foscarnet, combined with CMV-specific-IVIG, may significantly and safely reduce CMV load in the eye of patients with CMVR, eventually leading to a consistent improvement of visual acuity. Routine ophthalmologic examination should be recommended in HSCT recipients with multiple CMV reactivations and high peak CMV DNA every 2 months until negative viral load, irrespective of visual symptoms or the presence of GVHD.\n\nAuthors’ Note: Lucia Brunello is now affiliated with Hematology, AO SS Antonio e Biagio e Cesare Arrigo Alessandria, Italy.\n\nAuthor contributions: FV: concept/design, drafting manuscript, critical revision of article; AB: concept/design, drafting manuscript, critical revision of article; RN: critical revision of article; IC: critical revision of article; CDC: concept/design, drafting manuscript, critical revision of article; LG: concept/design, drafting manuscript, critical revision of article; FGDR: critical revision of article; GI: concept/design, drafting manuscript, critical revision of article; RC: critical revision of article; LB: concept/design, drafting manuscript, critical revision of article; BB: concept/design, drafting manuscript, critical revision of article.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthical approval: Our study did not require an ethical board approval because the drugs used were in label.\n\nORCID iD: Alessandro Busca \nhttps://orcid.org/0000-0001-5361-5613\n==== Refs\nReferences\n1. \nBoeckh M Nichols WG Papanicolaou G , et al\nCytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies\n. Biol Blood Marrow Transplant \n2003 ; 9 : 543 –558\n.14506657 \n2. \nZöllner SK Herbrüggen H Kolve H , et al\nCytomegalovirus retinitis in children and adolescents with acute leukemia following allogeneic hematopoietic stem cell transplantation\n. Transpl Infect Dis \n2019 ; 21 : e13089 .30972869 \n3. \nLewis RA Clogston P Fainstein V , et al\nStudies of ocular complications of AIDS Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial: 1. Rationale, design, and methods\n. Control Clin Trials \n1992 ; 13 : 22 –39\n.1315661 \n4. \nThorne JE Jabs DA Kempen JH , et al\nCauses of visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy\n. Ophthalmology \n2006 ; 113 : 1441 –1445\n.16781775 \n5. \nJabs DA Ahuja A Van Natta M , et al\nComparison of treatment regimens for cytomegalovirus retinitis in patients with AIDS in the era of highly active antiretroviral therapy\n. Ophthalmology \n2013 ; 120 : 1262 –1270\n.23419804 \n6. \nPort AD Orlin A Kiss S , et al\nCytomegalovirus retinitis: a review\n. J Ocul Pharmacol Ther \n2017 ; 33 : 224 –234\n.28355091 \n7. \nCrippa F Corey L Chuang EL , et al\nVirological, clinical, and ophthalmologic features of cytomegalovirus retinitis after hematopoietic stem cell transplantation\n. Clin Infect Dis \n2001 ; 32 : 214 –219\n.11170910 \n8. \nXhaard A Robin M Scieux C , et al\nIncreased incidence of cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation\n. Transplantation \n2007 ; 83 : 80 –83\n.17220797 \n9. \nEid AJ Bakri SJ Kijpittayarit S , et al\nClinical features and outcomes of cytomegalovirus retinitis after transplantation\n. Transpl Infect Dis \n2008 ; 10 : 13 –18\n.17511815 \n10. \nOhta H Matsuda Y Tokimasa S , et al\nFoscarnet therapy for ganciclovir-resistant cytomegalovirus retinitis after stem cell transplantation: effective monitoring of CMV infection by quantitative analysis of CMV mRNA\n. Bone Marrow Transplant \n2001 ; 27 : 1141 –1145\n.11551024 \n11. \nGanly PS Arthur C Goldman JM , et al\nFoscarnet as treatment for cytomegalovirus retinitis following bone marrow transplantation\n. Postgrad Med J \n1988 ; 64 : 389 –391\n.2849092 \n12. \nLarsson K Lönnqvist B Ringdén O , et al\nCMV retinitis is after allogeneic bone marrow transplantation: a report of five cases\n. Transpl Infect Dis \n2002 ; 4 : 75 –79\n.12220243 \n13. \nJeon S Lee WK. \nCytomegalovirus retinitis in a human immunodeficiency virus-negative cohort: long-term management and complications\n. Ocul Immunol Inflamm \n2015 ; 23 : 392 –399\n.25760914 \n14. \nTan PL Lim LM Khanlian C , et al\nA single-center experience of cytomegalovirus infections in asian pediatric patients undergoing allogeneic hematopoietic stem cell transplant for leukemia in Singapore\n. Transpl Infect Dis \n2014 ; 16 : 556 –560\n.24862456 \n15. \nFriedberg DN. \nCytomegalovirus retinitis: diagnosis and status of systemic therapy\n. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology \n1997 ; 14 : S1 –S6\n.\n16. \nZhang Y Ruan X Yang W , et al\nHigh ocular CMV copies and mismatched receipts may predict poor visual prognosis in CMV retinitis patients following allogeneic haematopoietic stem cell transplantation\n. BMC Ophthalmol \n2017 ; 17 : 224 .29187167 \n17. \nArevalo JF , et al\nIntravitreous and plasma concentrations of ganciclovir and foscarnet after intravenous therapy in patients with aids and cytomegalovirus retinitis\n. J Infect Dis \n1995 ; 172 : 951 –956\n.7561215 \n18. \nZhao N Liu L Xu J. \nCytomegalovirus retinitis in a patient with secondary acute lymphosarcoma leukemia undergoing allogeneic hematopoietic stem-cell transplantation\n. Med \n2017 ; 96 : 1 –3\n.\n19. \nMiao H Tao Y Jiang YR , et al\nMultiple intravitreal injections of ganciclovir for cytomegalovirus retinitis after stem-cell transplantation\n. Graefe’s Arch Clin Exp Ophthalmol \n2013 ; 251 : 1829 –1833\n.23665863 \n20. \nLjungman P Cordonnier C Einsele H , et al\nUse of intravenous immune globulin in addition to antiviral therapy in the treatment of CMV gastrointestinal disease in allogeneic bone marrow transplant patients: a report from the European Group for Blood and Marrow Transplantation (EBMT)\n. Bone Marrow Transplant \n1998 ; 21 : 473 –476\n.9535039 \n21. \nVigil KJ Adachi JA Chemaly RF. \nAnalytic review: viral pneumonias in immunocompromised adult hosts\n. J Intensive Care Med \n2010 ; 25 : 307 –326\n.20837633 \n22. \nMalagola M Greco R Santarone S , et al\nCMV management with specific immunoglobulins: a multicentric retrospective analysis on 92 allotransplanted patients\n. Mediterr J Hematol Infect Dis \n2019 ; 11 : 1 –8\n.\n23. \nAschan J Ringdén O Ljungman P , et al\nFoscarnet for treatment of cytomegalovirus infections in bone marrow transplant recipients\n. Scand J Infect Dis \n1992 ; 24 : 143 –150\n.1322557\n\n",
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"title": "CMV retinitis in a stem cell transplant recipient treated with foscarnet intravitreal injection and CMV specific immunoglobulins.",
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"title": "Toxic epidermal necrolysis in a child successfully treated with infliximab.",
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"abstract": "Tuberous sclerosis complex (TSC) is a genetic disorder characterized by abnormal cell proliferation and tumor growth in a number of organ systems, primarily the brain, kidneys, eyes and heart. Clinical symptoms vary according to the location of the tumor. The most common disorders are seizures, neurodevelopmental disorders, renal failure and arrhythmias. TSC was found to be influenced by inhibitors of the protein kinase mammalian target of rapamycin (mTOR), which regulates abnormal cellular proliferation. mTOR inhibitors have been studied effectively in patients with subependymal giant-cell astrocytomas and renal angiolipomas in the context of TSC. We describe a prenatally diagnosed case of giant rhabdomyoma, due to right ventricular outflow tract obstruction, which presented as a duct-dependent lesion. Postnatal treatment with the mTOR inhibitor everolimus initiated significant regression of the cardiac tumor. This finding suggests that mTOR inhibitor therapy is an option for giant rhabdomyomas that develop in the neonatal period.",
"affiliations": "Pediatric Heart Center, Department of Pediatrics and Adolescent Medicine, Division for Pediatric Cardiology, Medical University of Vienna, Vienna, Austria.",
"authors": "Mlczoch|E|E|;Hanslik|A|A|;Luckner|D|D|;Kitzmüller|E|E|;Prayer|D|D|;Michel-Behnke|I|I|",
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"keywords": "brain cortical tumor; mTOR inhibitor; magnetic resonance imaging; right ventricular outflow obstruction",
"medline_ta": "Ultrasound Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D004305:Dose-Response Relationship, Drug; D015150:Echocardiography, Doppler; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006338:Heart Neoplasms; D006801:Humans; D007231:Infant, Newborn; D056687:Off-Label Use; D011247:Pregnancy; D011296:Prenatal Diagnosis; D012207:Rhabdomyoma; D016896:Treatment Outcome; D014402:Tuberous Sclerosis; D047368:Tumor Burden",
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"title": "Prenatal diagnosis of giant cardiac rhabdomyoma in tuberous sclerosis complex: a new therapeutic option with everolimus.",
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"abstract": "Oxaliplatin is a common chemotherapy drug, used mainly for colon and gastric cancer. Most common side effects are peripheral sensory neuropathy, hematological toxicity, and allergic reactions. A less common side effect is pulmonary toxicity, characterized mainly by interstitial pneumonitis. The incidence of this side effect is unknown, but the toxicity can be fatal. Twenty-six cases of pulmonary toxicity have been described in the literature, seven in the setting of adjuvant treatment. We describe two fatal cases of pulmonary injury related to oxaliplatin and a review of the literature.",
"affiliations": "Division of Oncology, Rambam Health Care Campus, 3109601 Haifa, Israel.;Division of Oncology, Rambam Health Care Campus, 3109601 Haifa, Israel.;Division of Oncology, Rambam Health Care Campus, 3109601 Haifa, Israel.",
"authors": "Moskovitz|Mor|M|;Wollner|Mira|M|;Haim|Nissim|N|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2015/341064Case ReportOxaliplatin-Induced Pulmonary Toxicity in Gastrointestinal Malignancies: Two Case Reports and Review of the Literature Moskovitz Mor \n*\nWollner Mira Haim Nissim Division of Oncology, Rambam Health Care Campus, 3109601 Haifa, Israel*Mor Moskovitz: m_moskovitz@rambam.health.gov.ilAcademic Editor: David Lindquist\n\n2015 10 5 2015 2015 34106412 1 2015 12 4 2015 15 4 2015 Copyright © 2015 Mor Moskovitz et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Oxaliplatin is a common chemotherapy drug, used mainly for colon and gastric cancer. Most common side effects are peripheral sensory neuropathy, hematological toxicity, and allergic reactions. A less common side effect is pulmonary toxicity, characterized mainly by interstitial pneumonitis. The incidence of this side effect is unknown, but the toxicity can be fatal. Twenty-six cases of pulmonary toxicity have been described in the literature, seven in the setting of adjuvant treatment. We describe two fatal cases of pulmonary injury related to oxaliplatin and a review of the literature.\n==== Body\n1. Introduction\nOxaliplatin is a common chemotherapy drug of the platinum salts class and is used for the treatment of colon cancer and other gastrointestinal malignancies, usually in combination with 5-fluorouracil [1, 2]. The main dose-limiting toxicities of oxaliplatin are peripheral sensory neuropathy and hematological toxicity [3]. A less common side effect is pulmonary toxicity, characterized mainly by interstitial pneumonitis. The incidence of this side effect is unknown, as well as the risk factors, but the pulmonary toxicity can be fatal. Hereby we present two fatal cases of pulmonary injury related to oxaliplatin and a review of the literature.\n\n2. Case 1\nA 65-year-old female, never smoker, with a history of hypertension, was diagnosed with colon cancer metastatic to the liver in June 2007. The patient commenced chemotherapy treatment according to the FOLFIRI protocol (bevacizumab/5-fluorouracil/irinotecan). From July 2007 to July 2009, she received 19 cycles of therapy with good response. Then she underwent liver metastasectomy and, in October 2009, she started chemotherapy according to the FOLFOX protocol (bevacizumab/5-fluorouracil/oxaliplatin) [1, 2]. No treatment related side effects were noted and the patient was in very good performance status (WHO 1) until the 6th cycle of chemotherapy. On day 15 of the 6th cycle, she developed dyspnea and fever immediately after the treatment with oxaliplatin. She was treated with intravenous corticosteroids and promethazine with symptomatic improvement of the dyspnea. The following day her dyspnea worsened, with several episodes of near-syncope. Her saturation without oxygen was measured as low as 73%, and blood pressure was as low as 100/50 mm/Hg, but no tachycardia was observed. On physical examination, the patient was dyspneic, rales were heard on auscultation to the lungs, and mild pitting edema was noticed on the lower limbs. Initial blood tests revealed respiratory alkalosis, moderate acute-on-chronic renal failure, and hyponatremia of 122 mEq/L. Troponin and brain natriuretic peptide levels, as well as echocardiography, did not show cardiac failure or ischemia. Chest X-ray showed no pulmonary congestion (following treatment with loop diuretics) or infection. Chest CT scan showed diffused bilateral ground glass infiltrates and no pulmonary emboli (Figure 1). After ruling out cardiac and thromboembolic etiology of the dyspnea, diagnostic bronchoscopy was performed. Bronchoalveolar lavage analysis, along with blood cultures, revealed no sign of bacterial, viral, or Pneumocystis carinii infection, and no eosinophilia. Candida infection was present in fungal cultures. Pulmonary biopsy showed organizing diffuse alveolar damage. A diagnosis of interstitial pneumonitis was concluded, most probably drug-induced. The patient was treated with high-dose corticosteroids and wide ranging antibiotics, until the diagnosis of bacterial infection was ruled out, antifungal drugs, and loop diuretics. She received respiratory support with oxygen and continuous positive airway pressure. The patient's respiratory failure did not improve with treatment and she died 15 days following initial presentation.\n\n3. Case 2\nAn 80-year-old male, never smoker, with a history of hypertension was diagnosed in September 2005 with adenocarcinoma of the rectum, stage IIIB. He received standard neoadjuvant treatment of a combination of radiation therapy and 5-fluorouracil and then underwent total mesorectal excision. In July 2006, the patient had local recurrence of the rectal cancer confirmed by rectoscopy, and biopsy from the rectum and inguinal lymph node revealed well-differentiated adenocarcinoma of the rectum, with bilateral inguinal lymph node involvement, a nonresectable disease. CT scan of the chest, abdomen, and pelvis was normal except for the rectal mass and enlarged inguinal lymph nodes. The patient started treatment with chemotherapy for metastatic disease, the FOLFIRI protocol (bevacizumab/5-fluorouracil/irinotecan) for two cycles. Due to the severe side effects of diarrhea, the treatment was changed to FOLFOX protocol (bevacizumab/5-fluorouracil/oxaliplatin). The patient was treated with this protocol for nine months with no side effects reported. Following the 17th treatment cycle, he was hospitalized due to fever, cough, and dyspnea. Physical examination revealed mild dyspnea, and blood tests showed mild respiratory acidosis and acute-on-chronic renal failure. Chest X-ray showed diffuse bilateral interstitial infiltrates. CT scan showed a picture consistent with diffuse alveolar damage without pulmonary fibrosis, with a differential diagnosis of atypical infection or drug-induced pneumonitis (Figure 2). These findings did not appear on the previous CT scan taken three months earlier. Blood and urine cultures were negative. Bronchoscopy including bronchoalveolar lavage was performed. Bronchoalveolar lavage analysis as well as blood cultures revealed no sign of bacterial, viral, or Pneumocystis carinii, Legionella, and Aspergillus infection and no eosinophilia. Candida infection was present on lavage analysis. There was no sign of malignancy on bronchial cytology. The patient was treated with wide spectrum empiric antibiotics, glucocorticosteroids, and oxygen, with continuous clinical deterioration and respiratory failure. He died 27 days following his initial presentation.\n\n4. Discussion\nOxaliplatin (third generation platin, like trans-L-1,2 diaminocyclohexane, Eloxatin) was first introduced in the year 2000 as part of the treatment in metastatic colorectal carcinoma and demonstrated efficacy both in the metastatic and adjuvant settings [1, 2]. Oxaliplatin demonstrated efficacy in other gastrointestinal malignancies as well, such as gastric and pancreatic cancer. Most common side effects reported in Phase 3 randomized controlled trials were peripheral sensory neuropathy, hematological toxicity, and allergic reactions, including acute laryngeal spasm, mostly at the beginning of therapy, gastrointestinal toxicity, increase in transaminase and alkaline phosphatase levels, and fatigue [3]. Pulmonary fibrosis and grade IV pulmonary toxicity were reported in less than 1% of patients treated in trials that included oxaliplatin, and one patient died of eosinophilic pneumonia [3]. The oxaliplatin prescribing information indicates discontinuation of the drug in any case of unexplained respiratory symptoms, such as nonproductive cough, dyspnea, crackles, or radiological pulmonary infiltrates, until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis. Data collected in Phase 4 trials revealed more cases with pulmonary interstitial lung disease. Twenty-six cases of oxaliplatin-related pulmonary toxicity have been described in the English literature [4–21] and are presented in Table 1. Sixteen of these cases (61.5%) were fatal. The real incidence is probably higher and, very likely, only selected cases were described in the literature. Most patients were males (20/26, 77%), were older than 60 years (24/26, 92.3%), with a diagnosis of metastatic colorectal carcinoma (16/26, 61.5%), and were treated with oxaliplatin for less than six months (20/26, 76%). As shown in Table 1, seven of these 26 (27%) patients had previous lung disease, two (8%) were smokers, and 4 (15%) were hypertensive. In the current report, both our patients were hypertensive but none had previous lung disease or smoking history. It was suggested that previous lung disease can be a risk factor for oxaliplatin-induced pulmonary toxicity [15]. However, due to the small number of reported patients, it is difficult to draw firm conclusions regarding such correlation. Of the 26 patients described above, 10 received oxaliplatin as part of adjuvant therapy, and seven died as a result of pulmonary toxicity.\n\nDrug-induced pneumonitis is a diagnosis of exclusion. All the patients described above, including the two patients in this report, underwent extensive workup to exclude the more common causes for pneumonitis: infections, pulmonary emboli, pulmonary bleeding, lymphangitic carcinomatosis, and heart failure. All underwent CT scan and most, including the first patient in this report, underwent bronchoscopy with a lung biopsy that confirmed the less common diagnosis of drug-induced interstitial pneumonitis. Fifteen of the 26 patients were treated according to the FOLFOX protocol (oxaliplatin/5-fluorouracil/leucovorin), and five of the 26 patients were treated with the FOLFOX protocol with the addition of bevacizumab, a vascular endothelial growth factor inhibitor monoclonal antibody. Few incidents of acute lung fibrosis have been reported in patients treated with 5-FU and cisplatin, although 5-fluorouracil is a widely used agent. In two cases of interstitial lung disease that improved with therapy, 5-fluorouracil was reintroduced without additional pulmonary toxicity. This implies that the most likely agent to cause the pulmonary toxicity is oxaliplatin [5, 14].\n\nThe mechanism for this pulmonary injury is not yet determined. One study that examined liver specimens of patients with colorectal carcinoma who underwent neoadjuvant chemotherapy and metastasectomy of liver lesions suggested that oxaliplatin may cause sinusoidal injury complicated by fibrosis and veno-occlusive lesions [22]. This injury may be related to oxidative damage and glutathione depletion caused by oxaliplatin. It is possible that this kind of damage may be the pathological base of the pulmonary injury of oxaliplatin.\n\nSome chemotherapy agents are known to cause pulmonary toxicity (bleomycin, busulfan) and have well-established guidelines for follow-up and treatment of this side effect of the drug [23]. There are few case reports on the pulmonary toxicity of oxaliplatin, but this side effect is less recognized. In addition, oxaliplatin is usually given in a multidrug regimen, usually 5-fluorouracil, leucovorin, bevacizumab, or cetuximab; thus the offending agent is not clear. Since this drug is widely administered as the treatment for metastatic colorectal cancer, as well as adjuvant therapy for stage 3 resectable disease and other malignancies, it is important to be aware of this rare but potentially fatal side effect of the drug. It is important to take action for early detection and treatment of this complication.\n\nOur recommendations to reduce the risk of death from pulmonary toxicity of oxaliplatin are as follows:awareness of the potential of pulmonary toxicity of oxaliplatin, which is probably underestimated;\n\ndiscontinuation of the drug in any case of respiratory symptoms associated with radiology findings consistent with interstitial lung injury and considering early treatment with corticosteroids.\n\nIn summary, treatment with oxaliplatin for early or metastatic colorectal carcinoma can cause pulmonary toxicity, often fatal, as a rare side effect of the drug. Of the 26 cases reported in the English literature, most patients were males, were older than 60 years, had metastatic disease, and had no previous lung disease. Sixteen patients died of pulmonary toxicity related to oxaliplatin, 10 in the course of adjuvant therapy for resected colon cancer.\n\nConflict of Interests\nThe authors have declared that there is no conflict of interests.\n\nFigure 1 (a) Chest CT scan of patient 1, three months prior to symptoms of pneumonitis. (b) Chest CT scan of patient 1, at the beginning of respiratory symptoms: diffuse interstitial infiltrates and ground glass opacities shown in both lung fields.\n\nFigure 2 (a) Chest CT scan of patient 2, three months prior to development of respiratory symptoms. (b) Chest CT scan of patient 2, at the beginning of respiratory symptoms: diffuse interstitial infiltrates shown in both lungs.\n\nTable 1 Reported cases of pulmonary toxicity related to oxaliplatin∗.\n\nReferences number\tPatient age/gender\tAim of treatment∗\n\tCumulative dose of oxaliplatin (mg/m2)\tNumber of cycles\tRegimen∗∗\n\tPrevious lung disease\tOutcome\t\n[4]\t60/M\tMetastatic disease\t910\t7\tFOLFOX\tNone\tResolved\t\n\n\n\t\n[5]\t60/F\tMetastatic disease\tNA\tNA\tFOLFOX\tNone\tResolved \t\n\n\n\t\n[6]\t68/F\tAdjuvant\t510\t6\tFOLFOX/single agent oxaliplatin\tNone\tDeath \t\n\n\n\t\n\n[7]\t64/M\tMetastatic disease (gastric ca)\t200\t2\tFOLFOX\tNone\tResolved\t\n75/M\tMetastatic disease (gastric ca)\t100\t1\tFOLFOX\tNone\tResolved\t\n\n\n\t\n[8]\t74/M\tAdjuvant\t510\t6\tFOLFOX\tNone\tDeath\t\n\n\n\t\n[9]\t67/M\tMetastatic disease (HCC)\t1100\t11\tFOLFOX\tPulmonary artery stenosis, lung metastases\tResolved\t\n\n\n\t\n\n[10]\t62/M\tAdjuvant\t595\t7\tFOLFOX\tNone\tDeath\t\n77/M\tMetastatic disease\t595\t7\tFOLFOX\tNone\tResolved\t\n\n\n\t\n[11]\t30/F\tAdjuvant\t510\t6\tFOLFOX\tNone\tResolved\t\n\n\n\t\n[12]\t66/M\tMetastatic disease\t1020\t12\tFOLFOX\tNone\tDeath\t\n\n\n\t\n\n[13]\t73/F\tMetastatic disease\t340\t4\tFOLFOX\tLung metastases\tDeath\t\n71/M\tAdjuvant\t340\t4\tFOLFOX\tWegener's granulomatosis, mild COPD\tDeath\t\n\n\n\t\n[14]\t82/M\tMetastatic disease\t850\t10\tFOLFOX\tNone\tResolved \t\n\n\n\t\n\n[15]\t71/M\tAdjuvant\t510\t6\tFOLFOX\tMild interstitial lung disease\tDeath \t\n77/F\tAdjuvant\t1020\t12\tFOLFOX\tAsymptomatic ground glass opacities at right lung base\tResolved\t\n69/M\tAdjuvant\tNA\t6\tFOLFOX\tAsymptomatic subpleural infiltrate\tResolved partially\t\n\n\n\t\n[16]\t76/M\tMetastatic disease\t260\t2\tXELOX\tNone\tDeath\t\n\n\n\t\n[17]\t47/M\tMetastatic disease\tNA\tNA\tXELOX + bevacizumab\tLung metastases\tResolved\t\n\n\n\t\n\n[18]\t55/M\tMetastatic disease\t1105\t13\tFOLFOX\tNone\tDeath \t\n73/M\tAdjuvant\t765\t9\tFOLFOX\tEmphysematous lungs\tDeath\t\n\n\n\t\n[19]\t69/F\tMetastatic disease\t595\t7\tFOLFOX + cetuximab\tMalignant pleural effusion \tDeath\t\n\n\n\t\n\n[20]\t73/F\tMetastatic disease\t1785\t11\tFOLFOX + bevacizumab\tSmoking, suspected lung metastases\tDeath \t\n75/M\tMetastatic disease (gastric ca)\t765\t9\tFOLFOX\tLung metastases\tDeath \t\n64/M\tAdjuvant\t1020\t12\tFOLFOX\tSmoking\tDeath \t\n\n\n\t\n[21]\t57/M\tMetastatic disease\t765\t9\tNA\tNone \tResolved\t\n\n\n\t\n\nCurrent paper\t65/F\tMetastatic disease\t1020\t12\tFOLFOX + bevacizumab\tNone\tDeath\t\n80/M\tAdvanced locoregional disease\t1445\t17\tFOLFOX + bevacizumab\tNone\tDeath\t\n\nNote. ∗If not stated otherwise, the patient was treated for colon cancer.\n\n\n∗∗FOLFOX-oxaliplatin/5-fluorouracil/leucovorin, XELOX-oxaliplatin/capecitabine.\n\nca: cancer.\n==== Refs\n1 De Gramont A. Figer A. Seymour M. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer Journal of Clinical Oncology 2000 18 16 2938 2947 2-s2.0-0033874892 10944126 \n2 André T. Boni C. Mounedji-Boudiaf L. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer The New England Journal of Medicine 2004 350 23 2343 2351 10.1056/nejmoa032709 2-s2.0-2542615200 15175436 \n3 Ramanathan R. K. Clark J. W. Kemeny N. E. Safety and toxicity analysis of Oxaliplatin combined with fluorouracil or as a single agent in patients with previously treated advanced colorectal cancer Journal of Clinical Oncology 2003 21 15 2904 2911 10.1200/jco.2003.11.045 2-s2.0-0042386685 12885808 \n4 Trisolini R. Lazzari Agli L. Tassinari D. Acute lung injury associated with 5-fluorouracil and oxaliplatinum combined chemotherapy European Respiratory Journal 2001 18 1 243 245 2-s2.0-0034895685 11510798 \n5 Gagnadoux F. Roiron C. Carrie E. Monnier-Cholley L. Lebeau B. Eosinophilic lung disease under chemotherapy with oxaliplatin for colorectal cancer American Journal of Clinical Oncology 2002 25 4 388 390 10.1097/00000421-200208000-00014 2-s2.0-0036338002 12151971 \n6 Yagüe X. H. Soy E. Merino B. Q. Puig J. Fabregat M. B. Colomer R. Interstitial pneumonitis after oxaliplatin treatment in colorectal cancer. Clinical & Translational Oncology 2005 7 11 515 517 2-s2.0-33645251338 16373064 \n7 Jung K. H. Kil S. Y. Choi I. K. Interstitial lung diseases in patients treated with oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) International Journal of Tuberculosis and Lung Disease 2006 10 10 1181 1182 2-s2.0-33749468366 17044215 \n8 Pasetto L. M. Monfardini S. Is acute dyspnea related to oxaliplatin administration? World Journal of Gastroenterology 2006 12 36 5907 5908 2-s2.0-33750136061 17007064 \n9 Ruiz-Casado A. García M. D. Racionero M. A. Pulmonary toxicity of 5-fluoracil and oxaliplatin Clinical and Translational Oncology 2006 8 8 p. 624 10.1007/s12094-006-0072-2 2-s2.0-33749070346 \n10 Pena Álvarez C. Suh Oh H. J. Sáenz de Miera Rodríguez A. Interstitial lung disease associated with oxaliplatin: description of two cases Clinical and Translational Oncology 2009 11 5 332 333 10.1007/s12094-009-0364-4 2-s2.0-68849130657 19451069 \n11 Garrido M. O'Brien A. González S. Clavero J. M. Orellana E. Cryptogenic organizing pneumonitis during oxaliplatin chemotherapy for colorectal cancer: case report Chest 2007 132 6 1997 1999 10.1378/chest.07-0536 2-s2.0-37549063394 18079234 \n12 Mundt P. Mochmann H.-C. Ebhardt H. Zeitz M. Duchmann R. Pauschinger M. Pulmonary fibrosis after chemotherapy with oxaliplatin and 5-fluorouracil for colorectal cancer Oncology 2008 73 3-4 270 272 10.1159/000127425 2-s2.0-43049086345 18424892 \n13 Lobera S. A. Mariñelarena N. S. Echeberría I. E. Fatal pneumonitis induced by oxaliplatin Clinical and Translational Oncology 2008 10 11 764 767 10.1007/s12094-008-0285-7 2-s2.0-59249088649 19015075 \n14 Muneoka K. Shirai Y. Sasaki M. Wakai T. Sakata J. Hatakeyama K. Interstitial pneumonia arising in a patient treated with oxaliplatin, 5-fluorouracil, and, leucovorin (FOLFOX) International Journal of Clinical Oncology 2009 14 5 457 459 10.1007/s10147-008-0863-2 2-s2.0-70350475920 19856057 \n15 Wilcox B. E. Ryu J. H. Kalra S. Exacerbation of pre-existing interstitial lung disease after oxaliplatin therapy: a report of three cases Respiratory Medicine 2008 102 2 273 279 10.1016/j.rmed.2007.09.001 2-s2.0-37349125978 17945475 \n16 Shah A. Udwadia Z. F. Almel S. Oxaliplatin-induced lung fibrosis Indian Journal of Medical and Paediatric Oncology 2009 30 3 116 118 10.4103/0971-5851.64259 20838550 \n17 Fekrazad M. H. Eberhardt S. Jones D. Lee F.-C. Development of bronchiolitis obliterans organizing pneumonia with platinum-based chemotherapy for metastatic rectal cancer Clinical Colorectal Cancer 2010 9 3 177 178 10.3816/ccc.2010.n.024 2-s2.0-77954912728 20643623 \n18 Ryu C.-G. Jung E.-J. Kim G. Kim S. R. Hwang D.-Y. Oxaliplatin-induced pulmonary fibrosis: two case reports Journal of the Korean Society of Coloproctology 2011 27 5 266 269 10.3393/jksc.2011.27.5.266 2-s2.0-82555161674 22102978 \n19 Lai J.-I. Wang W.-S. Lai Y.-C. Lin P.-C. Chang S.-C. Acute interstitial pneumonitis in a patient receiving a FOLFOX-4 regimen plus cetuximab treated with pulse therapy International Journal of Clinical Pharmacology and Therapeutics 2010 48 7 425 428 10.5414/cpp48425 2-s2.0-77954925598 20557834 \n20 Pontes L. B. Armentano D. P. D. Soares A. Gansl R. C. Fatal pneumonitis induced by oxaliplatin: description of three cases Case Reports in Oncology 2012 5 1 104 109 10.1159/000337030 2-s2.0-84860778884 22539922 \n21 Lee E. J. Lee S. Y. In K. H. Kim C. H. Park S. Organizing pneumonia associated with oxaliplatin-combined chemotherapy: a case report Medical Principles and Practice 2012 21 1 89 92 10.1159/000331898 2-s2.0-82955162733 22025010 \n22 Rubbia-Brandt L. Audard V. Sartoretti P. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer Annals of Oncology 2004 15 3 460 466 10.1093/annonc/mdh095 2-s2.0-11144354740 14998849 \n23 Meadors M. Floyd J. Perry M. C. Pulmonary toxicity of chemotherapy Seminars in Oncology 2006 33 1 98 105 10.1053/j.seminoncol.2005.11.005 2-s2.0-32244438528 16473648\n\n",
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"title": "Oxaliplatin-Induced Pulmonary Toxicity in Gastrointestinal Malignancies: Two Case Reports and Review of the Literature.",
"title_normalized": "oxaliplatin induced pulmonary toxicity in gastrointestinal malignancies two case reports and review of the literature"
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"abstract": "The influence of hepatitis C virus (HCV) infection on the outcome of patients with diffuse large B cell lymphoma (DLBCL) treated with rituximab-based chemotherapy is controversial. We retrospectively analyzed the characteristics and clinical outcomes of 168 patients with DLBCL diagnosed between January 2005 and December 2011. Twenty-nine patients who were HCV-positive before lymphoma treatment were compared with 139 patients who did not have HCV infection. The median follow-up duration was 3.0 (0.07-8.02) years. HCV infection resulted in more hepatic toxicity in both univariate (p=0.001) and multivariate (p=0.003) analyses. In addition, HCV-positive DLBCL patients were more likely to have treatment delay (20.1% vs. 0.7%, p<0.001). For patients who developed hepatic toxicity during immunochemotherapy, HCV-positive patients had significantly higher folds of aspartate aminotransferase elevation (p=0.042) and total bilirubin elevation (p=0.012) compared with those who were HCV negative. However, HCV did not influence the 5-year progression-free survival rate (p=0.412) or 5-year overall survival rate (p=0.410). In conclusion, HCV infection is associated with increased hepatic toxicity and delayed chemotherapy without compromised survival in DLBCL patients treated with rituximab-based chemotherapy.",
"affiliations": "Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan.;Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan; Cancer Center, China Medical University Hospital, Taichung 40402, Taiwan; College of Medicine, School of Medicine, China Medical University, Taichung 40402, Taiwan.;Molecular and Genomic Epidemiology Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan; Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan.;Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan.;Charles River Laboratories, Preclinical Services, Spencerville, OH 45887, USA.;Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan; College of Medicine, School of Medicine, China Medical University, Taichung 40402, Taiwan.;Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan.;Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan; College of Medicine, School of Medicine, China Medical University, Taichung 40402, Taiwan. Electronic address: lybai6@gmail.com.",
"authors": "Chen|Tzu-Ting|TT|;Chiu|Chang-Fang|CF|;Yang|Tse-Yen|TY|;Lin|Ching-Chan|CC|;Sargeant|Aaron M|AM|;Yeh|Su-Peng|SP|;Liao|Yu-Min|YM|;Bai|Li-Yuan|LY|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "0145-2126",
"issue": "39(2)",
"journal": "Leukemia research",
"keywords": "Chemotherapy; Diffuse large B cell lymphoma; Hepatitis C virus; Prognosis; Rituximab",
"medline_ta": "Leuk Res",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D018572:Disease-Free Survival; D005260:Female; D006526:Hepatitis C; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D015996:Survival Rate",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "151-6",
"pmc": null,
"pmid": "25524176",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hepatitis C infection is associated with hepatic toxicity but does not compromise the survival of patients with diffuse large B cell lymphoma treated with rituximab-based chemotherapy.",
"title_normalized": "hepatitis c infection is associated with hepatic toxicity but does not compromise the survival of patients with diffuse large b cell lymphoma treated with rituximab based chemotherapy"
} | [
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"companynumb": "TW-ROCHE-1530619",
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"abstract": "Insufficient control of chronic breathlessness may induce excessive use of fentanyl nasal spray in COPD patients. Prescription of fentanyl nasal spray for breathlessness should only be done as part of palliative treatment and requires close follow-up. http://bit.ly/2YdOjJ1.",
"affiliations": "CIRO, Horn, The Netherlands.;Centre of Expertise for Palliative Care, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.;Dept of Health Services Research, Maastricht University, Maastricht, The Netherlands.;Dept of Respiratory Medicine, Catharina Hospital, Eindhoven, The Netherlands.;CIRO, Horn, The Netherlands.",
"authors": "Janssen|Daisy J A|DJA|;van den Beuken-van Everdingen|Marieke H J|MHJ|;Verberkt|Cornelia A|CA|https://orcid.org/0000-0002-5693-1256;Creemers|Jacques P H M|JPHM|;Wouters|Emiel F M|EFM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1183/20734735.0183-2019",
"fulltext": "\n==== Front\nBreathe (Sheff)Breathe (Sheff)BREATHEbreatheBreathe1810-68382073-4735European Respiratory Society 3177757510.1183/20734735.0183-2019EDU-0183-2019Expert OpinionCase Report118Fentanyl nasal spray in a patient with end-stage COPD and severe chronic breathlessness Fentanyl nasal spray in a patient with end-stage COPDJanssen Daisy J.A. 12van den Beuken-van Everdingen Marieke H.J. 2https://orcid.org/0000-0002-5693-1256Verberkt Cornelia A. 3Creemers Jacques P.H.M. 4Wouters Emiel F.M. 151 CIRO, Horn, The Netherlands2 Centre of Expertise for Palliative Care, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands3 Dept of Health Services Research, Maastricht University, Maastricht, The Netherlands4 Dept of Respiratory Medicine, Catharina Hospital, Eindhoven, The Netherlands5 Dept of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, The NetherlandsEmail: daisyjanssen@ciro-horn.nl9 2019 15 3 e122 e125 Copyright ©ERS 20192019http://creativecommons.org/licenses/by-nc/4.0/Breathe articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.Chronic breathlessness syndrome, defined as breathlessness that persists despite optimal treatment of the underlying pathophysiology, resulting in disability, is a major problem for patients with advanced chronic lung disease, and can be difficult to manage [1, 2]. Opioids should be considered for treatment of these patients [3]. Episodic breathlessness is severe worsening of breathlessness intensity, which can be predictable or unpredictable [4]. Episodic breathlessness can have a major impact on activities of daily life, but ∼90% of episodes last for 20 min or less [5]. Therefore, the selection of appropriate palliative pharmacological therapy is a complex issue. Indeed, the onset of action of short-acting oral opioids is between 15 and 30 min [6]. The rapid onset of action (between 1 and 4 min [7]) is the major advantage of fentanyl nasal spray. This case report relates the experience and insight gained when fentanyl nasal spray was prescribed to a patient with end-stage chronic obstructive pulmonary disease (COPD) and the lessons we have learned. Written informed consent for publication of the clinical details was obtained from the deceased patient's spouse.\n\nInsufficient control of chronic breathlessness may induce excessive use of fentanyl nasal spray in COPD patients. Prescription of fentanyl nasal spray for breathlessness should only be done as part of palliative treatment and requires close follow-up.\nhttp://bit.ly/2YdOjJ1\n==== Body\nChronic breathlessness syndrome, defined as breathlessness that persists despite optimal treatment of the underlying pathophysiology, resulting in disability, is a major problem for patients with advanced chronic lung disease, and can be difficult to manage [1, 2]. Opioids should be considered for treatment of these patients [3]. Episodic breathlessness is severe worsening of breathlessness intensity, which can be predictable or unpredictable [4]. Episodic breathlessness can have a major impact on activities of daily life, but ∼90% of episodes last for 20 min or less [5]. Therefore, the selection of appropriate palliative pharmacological therapy is a complex issue. Indeed, the onset of action of short-acting oral opioids is between 15 and 30 min [6]. The rapid onset of action (between 1 and 4 min [7]) is the major advantage of fentanyl nasal spray. This case report relates the experience and insight gained when fentanyl nasal spray was prescribed to a patient with end-stage chronic obstructive pulmonary disease (COPD) and the lessons we have learned. Written informed consent for publication of the clinical details was obtained from the deceased patient's spouse.\n\nCase report\nA 59-year-old woman was admitted to the palliative and supportive care unit for patients with end-stage chronic lung disease for end-stage COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 4D). Before transfer to our unit, she was admitted to the hospital for exacerbation of COPD.\n\nShe had completed an in-patient pulmonary rehabilitation programme, 3 years prior to admission. She experienced severe breathlessness even then, mainly due to very severe hyperinflation. During this pulmonary rehabilitation programme, she was prescribed morphine sustained release (SR) 10 mg tablets, twice daily. She was prescribed fentanyl 50 μg nasal spray, for episodes of acute breathlessness, as needed, with a maximum of four doses per day. She had been prescribed morphine immediate release (IR) 5 mg oral solution for acute breathlessness earlier. However, this did not control the episodes of acute breathlessness fast enough. She was discharged after the programme. She continued to receive prescriptions from both her chest physician and her general practitioner.\n\nTask 1\nWhat is the evidence for using fentanyl nasal spray for breathlessness?\n\nAnswer 1\nIn 2013, Simon\net al. [8] published a systematic review concerning fentanyl for the relief of refractory breathlessness. They found two before–after studies, nine case studies and two randomised controlled trials (RCTs) (one including two patients). All descriptive studies reported relief of breathlessness after the use of fentanyl, but the pilot RCT (n=12) didn't find a statistically significant improvement in breathlessness compared with placebo. In total, five patients were described using intranasal fentanyl, while the other studies concerned nebulised fentanyl (n=70), oral transmucosal fentanyl (n=9), transdermal fentanyl (n=3) and intravenous remifentanil (n=1) [8]. Since then, a few other studies have been published using intranasal fentanyl for breathlessness. Harlos\net al. [9] reported the use of intranasal fentanyl in 11 dying newborns and infants, and reported that in eight cases a decrease in laboured breathing and restlessness was observed. A more recent case series (n=16) described successful use in children with life-limiting conditions and acute respiratory distress (after the first dosage laboured breathing improved in 89%; tachypnoea improved in 73% and, if reported, dyspnoea improved in 59%) [10]. A pilot RCT in 23 patients with cancer did not show a difference in exercise-induced dyspnoea between the nasal fentanyl and control group, although the study was not powered to detect between-group differences [11]. Finally, a pilot RCT in six patients with chronic heart failure suggested lower breathlessness scores after a 6-min walk test with than without intranasal fentanyl (p=0.048), but did not include a placebo arm [12]. To conclude, several case series show the benefits of fentanyl nasal spray for treatment of breathlessness, but scientific evidence is scarce.\n\nAt the time of the current admission, the hospital discharge letter of our patient, mentioned the prescription of fentanyl 50 μg nasal spray. She told us that she used one bottle with 10 doses, every day, for chronic breathlessness. She did not have the nasal spray with her at the time of admission. Fentanyl nasal spray was ordered and delivered to our unit the next day. She did not use other opioids. On the day of admission, we decided to administer a fentanyl 12 μg·h−1 patch, one patch to be administered every 72 h. We also prescribed 5 mg morphine IR oral solution, as needed, with a maximum of six doses per day, for episodic breathlessness. She tried morphine IR 5 mg oral solution once, after which she felt drowsy and uncomfortable for several hours. The next day, she took 10 doses of fentanyl nasal spray within a few hours. She continuously asked for more fentanyl nasal spray. She experienced anxiety, restlessness, sweating and shaking. At this point, she told us that before admission she had used at least 40 doses of fentanyl nasal spray, every day, instead of 10. Only then did we realise the overdose of fentanyl nasal spray, due to uncontrolled chronic breathlessness.\n\nTask 2\nHow often does fentanyl dependence occur in patients taking rapid-onset fentanyl for nonmalignant diseases?\n\nAnswer 2\nData concerning fentanyl dependence in patients with nonmalignant diseases taking rapid-onset fentanyl are scarce. A study in 105 patients using oral transmucosal fentanyl for nonmalignant pain did not show a difference in the Leeds Dependence Questionnaire between baseline and the end of the study (follow-up was limited to 30 days) [13]. Fine\net al. [14] reported <1% dependency in an 18-month study exploring long-term safety and tolerability of oral transmucosal fentanyl in 646 patients with chronic nonmalignant pain. Sitte and Bausewein [7] reported no evidence of excess use in over 200 patients self-administrating their dosages of intranasal fentanyl for episodic breathlessness.\n\nWe discussed the excessive use of fentanyl with the patient and her husband. Together, we decided to discontinue fentanyl nasal spray. Instead, we increased the fentanyl patch dose to 50 μg·h−1, one patch every 72 h. Until the fentanyl patch achieved the optimal effect, 2.5 mg morphine was administered subcutaneously, six times daily, at fixed times, to treat chronic breathlessness, to prevent breathlessness episodes and to decrease her withdrawal symptoms. Meanwhile, our psychosocial team started treating her for anxiety. They also advised the interdisciplinary team on the management of her complex behaviour. The interdisciplinary team started the treatment programme, with a focus on breathlessness management. A few days later (1 week after admission), the withdrawal symptoms disappeared. Both her chronic breathlessness as well as acute episodes of breathlessness and anxiety were within control. We found a highly motivated patient, who participated in all treatment activities. Every week we decreased the dosage of the fentanyl patch, step-wise from 50 μg·h−1 to 37 μg·h−1, then 25 μg·h−1, and 12 μg·h−1, until it could be discontinued. We discussed alternatives to the morphine injections, such as morphine SR tablets, but she strongly preferred morphine injections, with a butterfly cannula. She continued with 2.5 mg subcutaneous morphine administration, five to six times daily, until she was admitted to the hospital 10 months later. She died after a few weeks in the hospital.\n\nLessons learned\nWe have learned several important lessons from this case. First, previous authors found no evidence of excessive use of fentanyl nasal spray for episodic breathlessness [7]. However, we discovered excessive use of fentanyl nasal spray in a patient with advanced lung disease and chronic severe breathlessness. Secondly, treatment of chronic severe breathlessness is complex, and close follow-up of opioid treatment is needed. There was no follow-up for this case after discharge from the pulmonary rehabilitation centre in 2014. Her chronic breathlessness was very severe and uncontrolled. She stopped using morphine SR tablets when she experienced discomfort with the medication and tried to control her severe chronic breathlessness with the medication prescribed for episodic breathlessness. The frequent use of fentanyl spray by patients to relieve uncontrolled chronic breathlessness is explained by the short duration of action of fentanyl nasal spray [15]. Thus, the prescription of fentanyl nasal spray for acute episodes of breathlessness needs to be part of a comprehensive palliative breathlessness treatment programme, for both chronic breathlessness as well as acute episodes of breathlessness. In this case, we chose morphine subcutaneous injections, with a butterfly cannula, to treat breathlessness. This was not our first choice, obviously. We preferred to prescribe morphine SR tablets, with a maximum dose of 30 mg per day. Indeed, most patients respond to a relatively low dose of morphine SR tablets [16], and oral morphine ≤30 mg a day is not associated with increased hospital admission or mortality in patients with COPD [17]. Nevertheless, our patient, who had a poor prognosis of survival, had a strong preference for morphine injections, because she had previously experienced discomfort with morphine SR tablets. It is not known if short-acting injections have a higher risk for overdose than SR tablets in patients with end-stage lung disease and breathlessness. In fact, a study on long-term use of opioids showed that patients with initiation with long-acting opioids were more likely to become long-term users than those initiated with short-acting drugs [18]. While she stayed in our specialised unit, we were able to closely monitor and control the use of morphine injections. Thirdly, continuity of care for these patients with very severe breathlessness is of paramount importance. At admission, the excessive use of fentanyl nasal spray was not communicated to our team. Hence, we were unaware of the doses used by the patient and were unprepared for the challenges faced. It took us several days to discover the actual dose of fentanyl taken by the patient, and to start a fentanyl patch with an appropriate dosage to treat the withdrawal symptoms. Finally, excessive use of fentanyl nasal spray in a patient with severe breathlessness can be managed by providing an interdisciplinary palliative treatment programme, including pharmacological and non-pharmacological treatment of breathlessness. This improved the quality of life of our patient in the last year of her life.\n\nConflict of interest: D.J.A. Janssen reports personal fees for lectures from Boehringer Ingelheim, Novartis, AstraZeneca and GlaxoSmithKline, outside the submitted work.\n\nConflict of interest: M.H.J. van den Beuken-van Everdingen reports personal fees for lectures from Takeda and Mundipharma, outside the submitted work.\n\nConflict of interest: C.A. Verberkt has nothing to disclose.\n\nConflict of interest: J.P.H.M. Creemers has nothing to disclose.\n\nConflict of interest: E.F.M. Wouters reports personal fees for board membership from Nycomed and Boehringer Ingelheim, personal fees for lectures from AstraZeneca, GlaxoSmithKline, Novartis and Chiesi, and grants from AstraZeneca and GlaxoSmithKline, outside the submitted work.\n==== Refs\nReferences\n1 Janssen DJ , Wouters EF , Spruit MA \nPsychosocial consequences of living with breathlessness due to advanced disease . Curr Opin Support Palliat Care \n2015 ; 9 : 232 –237 .26125305 \n2 Johnson MJ , Yorke J , Hansen-Flaschen J , et al. \nTowards an expert consensus to delineate a clinical syndrome of chronic breathlessness . Eur Respir J \n2017 ; 49 : 1602277 .28546269 \n3 Ekstrom M , Nilsson F , Abernethy AA , et al. \nEffects of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease. A systematic review . Ann Am Thorac Soc \n2015 ; 12 : 1079 –1092 .25803110 \n4 Simon ST , Weingartner V , Higginson IJ , et al. \nDefinition, categorization, and terminology of episodic breathlessness: consensus by an international Delphi survey . J Pain Symptom Manage \n2014 ; 47 : 828 –838 .24095285 \n5 Weingartner V , Bausewein C , Higginson IJ , et al. \nCharacterizing episodic breathlessness in patients with advanced disease . J Palliat Med \n2013 ; 16 : 1275 –1279 .24053592 \n6 Bausewein C , Simon ST \nInhaled nebulized and intranasal opioids for the relief of breathlessness . Curr Opin Support Palliat Care \n2014 ; 8 : 208 –212 .25004175 \n7 Sitte T , Bausewein C \nIntranasal fentanyl for episodic breathlessness . J Pain Symptom Manage \n2008 ; 36 : e3 –e6 .\n8 Simon ST , Koskeroglu P , Gaertner J , et al. \nFentanyl for the relief of refractory breathlessness: a systematic review . J Pain Symptom Manage \n2013 ; 46 : 874 –886 .23742735 \n9 Harlos MS , Stenekes S , Lambert D , et al. \nIntranasal fentanyl in the palliative care of newborns and infants . J Pain Symptom Manage \n2013 ; 46 : 265 –274 .23017621 \n10 Pieper L , Wager J , Zernikow B \nIntranasal fentanyl for respiratory distress in children and adolescents with life-limiting conditions . BMC Palliat Care \n2018 ; 17 : 106 .30200942 \n11 Hui D , Kilgore K , Park M , et al. \nImpact of prophylactic fentanyl pectin nasal spray on exercise-induced episodic dyspnea in cancer patients: a double-blind, randomized controlled trial . J Pain Symptom Manage \n2016 ; 52 : 459 –468 .27401508 \n12 Pilkey J , Pedersen A , Tam JW , et al. \nThe use of intranasal fentanyl for the palliation of incident dyspnea in advanced congestive heart failure: a pilot study . J Palliat Care \n2019 ; 34 : 96 –102 .29848173 \n13 Canovas-Martinez L , Carceller-Ruiz JJ , Diaz-Parada P , et al. \nEfficacy and safety of sublingual fentanyl tablets for the management of breakthrough pain in patients with chronic musculoskeletal pain with neuropathic component: multicenter prospective study . Clin Drug Investig \n2015 ; 35 : 169 –177 .\n14 Fine PG , Messina J , Xie F , et al. \nLong-term safety and tolerability of fentanyl buccal tablet for the treatment of breakthrough pain in opioid-tolerant patients with chronic pain: an 18-month study . J Pain Symptom Manage \n2010 ; 40 : 747 –760 .20594801 \n15 Chang A , Roeland EJ , Atayee RS , et al. \nTransmucosal immediate-release fentanyl for breakthrough cancer pain: opportunities and challenges for use in palliative care . J Pain Palliat Care Pharmacother \n2015 ; 29 : 247 –260 .26368648 \n16 Currow DC , McDonald C , Oaten S , et al. \nOnce-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study . J Pain Symptom Manage \n2011 ; 42 : 388 –399 .21458217 \n17 Ekstrom MP , Bornefalk-Hermansson A , Abernethy AP , et al. \nSafety of benzodiazepines and opioids in very severe respiratory disease: national prospective study . BMJ \n2014 ; 348 : g445 .24482539 \n18 Deyo RA , Hallvik SE , Hildebran C , et al. \nAssociation between initial opioid prescribing patterns and subsequent long-term use among opioid-naive patients: a statewide retrospective cohort study . J Gen Intern Med \n2017 ; 32 : 21 –27 .27484682\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1810-6838",
"issue": "15(3)",
"journal": "Breathe (Sheffield, England)",
"keywords": null,
"medline_ta": "Breathe (Sheff)",
"mesh_terms": null,
"nlm_unique_id": "101231007",
"other_id": null,
"pages": "e122-e125",
"pmc": null,
"pmid": "31777575",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": "24053592;24482539;25004175;23742735;27484682;25655006;29848173;25803110;20594801;26368648;18954962;26125305;21458217;28546269;24095285;27401508;30200942;23017621",
"title": "Fentanyl nasal spray in a patient with end-stage COPD and severe chronic breathlessness.",
"title_normalized": "fentanyl nasal spray in a patient with end stage copd and severe chronic breathlessness"
} | [
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"companynumb": "NL-MYLANLABS-2020M1010849",
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{
"abstract": "BACKGROUND\nPatients with recurrent hepatitis C (HCV) infection post-liver transplant can be difficult to treat safely and effectively. A prior (COSMOS) study in patients with non-transplant HCV, using sofosbuvir plus simeprevir, had high efficacy and tolerability in treating patients with HCV genotype 1, even prior non-responders to interferon therapy and those with cirrhosis. Our aim was to evaluate the efficacy of sofosbuvir and simeprevir in patients with genotype 1 HCV post-liver transplant.\n\n\nMETHODS\nIn this prospective, observational study, patients received sofosbuvir 400 mg plus simeprevir 150 mg daily for 12 wk without ribavirin. The primary end point was a sustained virologic response 12 wk after the end of therapy.\n\n\nRESULTS\nForty-two patients completed the treatment. Twenty-six percent started the treatment ≤ 6 months post-liver transplant. Nineteen percent of the included patients had cirrhosis, 14% with decompensation. At week 4 on the treatment, 21% of patients had detectable virus but at the end of the treatment, 100% were undetectable. Twelve weeks after the end of the treatment, 95% of the patients had undetectable hepatitis C. The regimen was generally well tolerated.\n\n\nCONCLUSIONS\nThe oral regimen of sofosbuvir plus simeprevir without ribavirin is efficacious and well tolerated in the treatment of patients with genotype 1 hepatitis C post-liver transplant.",
"affiliations": "Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA, USA.;Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA, USA.;Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA, USA.;Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA, USA.;Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA, USA.;Division of Transplant Surgery, Department of Surgery, University of Massachusetts Medical Center, Worcester, MA, USA.;Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical Center, Worcester, MA, USA.",
"authors": "Punzalan|Carmi Santos|CS|;Barry|Curtis|C|;Zacharias|Isabel|I|;Rodrigues|Julie|J|;Mehta|Savant|S|;Bozorgzadeh|Adel|A|;Barnard|Graham F|GF|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.12634",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "29(12)",
"journal": "Clinical transplantation",
"keywords": "direct acting antiviral agents; hepatitis C; liver transplant; simeprevir; sofosbuvir",
"medline_ta": "Clin Transplant",
"mesh_terms": "D064591:Allografts; D000998:Antiviral Agents; D004279:DNA, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D000069616:Simeprevir; D000069474:Sofosbuvir",
"nlm_unique_id": "8710240",
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"pages": "1105-11",
"pmc": null,
"pmid": "26358816",
"pubdate": "2015-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Sofosbuvir plus simeprevir treatment of recurrent genotype 1 hepatitis C after liver transplant.",
"title_normalized": "sofosbuvir plus simeprevir treatment of recurrent genotype 1 hepatitis c after liver transplant"
} | [
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"companynumb": "US-JNJFOC-20160116800",
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{
"abstract": "BACKGROUND\nThe uniqueness of adolescent and young adult (AYA) non-Hodgkin lymphomas (NHL) with respect to biology and treatment have largely remained unanswered due to marked heterogeneity in treatment, paucity of prospective, or retrospective studies and poor representation of AYA in clinical trials. This audit attempts to put forward the clinicopathological attributes and treatment outcomes of AYA NHL treated with both pediatric and adult protocols from a single centre in a developing country.\n\n\nMETHODS\nHospital records of all consecutive NHL patients registered in lymphoma clinic from January 2007 to May 2010 were reviewed for information on demography, clinical features, histology subtype, staging, treatment regimen, response rates, toxicities, and follow up. Two-year progression-free (PFS) and overall survival (OS) were calculated with Kaplan-Meier method.\n\n\nRESULTS\nAYA NHL constituted 4% of all lymphomas. Diffuse large B-cell (DLBL) was the most frequent subtype. Following were the 2-year PFS and OS - DLBL 64%, 76.9%, Burkitt's lymphoma: 56%, 56%, lymphoblastic lymphoma: 33.2%, 44%. Our results did not show any improvement in outcome of DLBL with the use of Burkitt's lymphoma like regimen.\n\n\nCONCLUSIONS\nThis study highlights some of the key features of AYA NHL occurring in developing world.",
"affiliations": "Department of Medical Oncology, Adult Hematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, India.",
"authors": "Sengar|Manju|M|;Akhade|A|A|;Nair|R|R|;Menon|H|H|;Shet|T|T|;Gujral|S|S|;Sridhar|E|E|;Laskar|S|S|;Muckaden|M|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.4103/0971-5851.95140",
"fulltext": "\n==== Front\nIndian J Med Paediatr OncolIndian J Med Paediatr OncolIJMPOIndian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology0971-58510975-2129Medknow Publications & Media Pvt Ltd India IJMPO-32-19710.4103/0971-5851.95140Original ArticleA retrospective audit of clinicopathological attributes and treatment outcomes of adolescent and young adult non-Hodgkin lymphomas from a tertiary care center Sengar Manju Akhade A. Nair R. Menon H. Shet T. 1Gujral S. 1Sridhar E. 1Laskar S. 2Muckaden M. 2Department of Medical Oncology, Adult Hematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, India1 Department of Pathology, Adult Hematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, India2 Department of Radiation Oncology, Adult Hematolymphoid Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra, IndiaAddress for correspondence: Dr. Manju Sengar, Adult Hematolymphoid Disease Management Group, Room No-16, Department of Medical Oncology, Tata Memorial Centre, E. Borges Road, Parel, Mumbai - 400 012, India. E-mail: manju.sengar@gmail.comOct-Dec 2011 32 4 197 203 Copyright: © Indian Journal of Medical and Paediatric Oncology2011This 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.Background:\nThe uniqueness of adolescent and young adult (AYA) non-Hodgkin lymphomas (NHL) with respect to biology and treatment have largely remained unanswered due to marked heterogeneity in treatment, paucity of prospective, or retrospective studies and poor representation of AYA in clinical trials. This audit attempts to put forward the clinicopathological attributes and treatment outcomes of AYA NHL treated with both pediatric and adult protocols from a single centre in a developing country.\n\nPatients and Methods:\nHospital records of all consecutive NHL patients registered in lymphoma clinic from January 2007 to May 2010 were reviewed for information on demography, clinical features, histology subtype, staging, treatment regimen, response rates, toxicities, and follow up. Two-year progression-free (PFS) and overall survival (OS) were calculated with Kaplan-Meier method.\n\nResults:\nAYA NHL constituted 4% of all lymphomas. Diffuse large B-cell (DLBL) was the most frequent subtype. Following were the 2-year PFS and OS - DLBL 64%, 76.9%, Burkitt's lymphoma: 56%, 56%, lymphoblastic lymphoma: 33.2%, 44%. Our results did not show any improvement in outcome of DLBL with the use of Burkitt's lymphoma like regimen.\n\nConclusions:\nThis study highlights some of the key features of AYA NHL occurring in developing world.\n\nAdolescent and young adultsadolescent and young adults malignanciesnon-Hodgkin lymphoma\n==== Body\nINTRODUCTION\nIssues pertaining to biology and therapy of malignancies occurring amongst adolescent and young adults (AYA) have largely remained neglected till last few years when data emerging from epidemiology and outcome registries suggested the need for active research in this field. Over the years, improvements in the understanding of biology and survival rates in this age group have lagged behind than those in pediatric and adult malignancies. The same story holds true for lymphomas which constitute 13% of all cancer diagnoses in AYA.[12] AYA non-Hodgkin lymphomas (NHL) have become a reason of concern among oncologists due to their rising incidence without a commensurate improvements in survival. The major reasons for the above observation are remarkable heterogeneity in the management of AYA NHL and lack of prospective trial for this subset of patients.[3] Diagnosis, staging, risk stratification and treatment protocols are largely dependent on whether the patient is referred to a pediatric or adult medical oncologist. These diversities in management make it difficult to compare the results from different protocols and identify the optimal therapy for this subgroup. Several retrospective analyses have suggested that pediatric protocol based treatment improves the event free and overall survival of AYA acute lymphoblastic leukemia. However, similar data is lacking for AYA NHLs. Considering AYA patients as older children and treating them with pediatric protocols might not be helpful in improving outcomes due to differences in toxicity patterns, drug pharmacokinetics, and disease biology. To compound this further, AYA NHLs neither features prominently in the clinical trials done in pediatric or adult NHLs nor any specific trials have been done for this age group.\n\nThese pertinent issues can only be resolved by the retrospective analysis of existing data from various centers and then designing appropriate prospective studies. Unfortunately, due to lack of data, most of the studies in oncology fail to incorporate the perspective of developing world in terms of disease nature and treatment outcomes.\n\nThe present retrospective analysis provides information on clinical presentation, histology patterns, and outcome results of AYA NHL treated with both adult and pediatric protocols at a tertiary cancer in India.\n\nPATIENTS AND METHODS\nPatients\nRecords of all consecutive patients with confirmed diagnosis of de-novo non-Hodgkin lymphoma (NHL) registered in lymphoma joint clinic at our hospital from January 2007 to July 2010 were reviewed in this audit. For this audit, we considered any patient between 15-25 years of age as AYA. Electronic medical records and hospital records were retrospectively reviewed and demographic details, duration of symptoms, presence or absence of B symptoms at diagnosis, clinical features, treatment regimen, and follow up information were collected. Evaluated parameters and initial staging procedures included physical examination, performance status as per Eastern Cooperative Oncology Group (ECOG) scale, complete blood count with differential, serum chemistry panel, LDH levels, chest radiography, CT scan of the thorax, abdomen and pelvis or PET-CT and bone marrow biopsy. Patients were staged according to the Ann Arbor system. Patients were assigned to one of four prognostic scores according to the International Prognostic Index (IPI) that takes into account the presence or absence of prognostic factors (serum LDH level, age, stage, performance status, and number of extranodal sites).\n\nPathology\nHistopathological diagnosis in all cases was reviewed and reported by the expert hematopathologists as per WHO 2008 classification for hematolymphoid neoplasms.[4] Only patients with aggressive NHL like Burkitt's lymphoma (BL), lymphomas intermediated between Burkitt's and Diffuse large B-cell (Burkitt's-like), diffuse large B-cell lymphoma (DLBL), T-cell rich B-cell lymphoma, lymphoblastic lymphoma (LL), anaplastic large-cell lymphoma (ALCL) (alk-positive and alk-negative) and other aggressive T-cell lymphomas were included in the analysis.\n\nTreatment, response assessment, and follow up\nTreatment was done according to the lymphoma joint clinic decision. Various chemotherapy protocol used were- CHOP with or without rituximab, BFM-90, MCP-842, and MCP-841. MCP-842 protocol[5] is used at our centre for treatment of pediatric large-cell lymphomas and Burkitt's lymphomas. It is a short course, intensive, alternating cycle multiagent chemotherapy regimen based on cyclophosphamide, cytarabine, adriamycin, vincristine, etoposide, ifosfamide, and methotrexate. MCP-841 regimen was used for the treatment of acute lymphoblastic leukemia and lymphoblastic lymphomas.[6] Information regarding chemotherapy type and number of cycles received was recorded.\n\nResponse assessment was done as per the standards at our centre and it included clinical and radiological evaluation. Responses were classified into complete response, partial response, stable or progressive disease. Bone marrow biopsies were done at the end of therapy if it was involved at the baseline.\n\nIncidence and severity of toxicities were recorded in form of number of episodes of febrile neutropenia, duration of hospitalization for management of febrile neutropenia, use of antifungals, use of inotropes, and intensive care support and organ toxicities.\n\nFollow-up was done with clinical evaluation every 3 months for first 2 years and then every 6 months for the following 2 years. Relapses or progression were confirmed with radiological imaging and appropriate biopsies. Dates of relapse, progression, death and last follow up were recorded. Disease status at last follow up was noted down from the records.\n\nStatistical analysis\nDescriptive statistical analysis was done for demographic variables, clinical features, serum LDH levels, serum albumin, stage, IPI score, histopathologic subtype, type of chemotherapy received, response rates, relapse, progression, and toxicities.\n\nOverall survival was calculated from date of registration to the date of death due to disease or any other cause or last date of follow up. Progression-free survival was calculated from the date of registration to the time of relapse, disease progression, death due to disease or treatment related complications or last follow up. Kaplan–Meier curves were generated for the overall and progression-free survival. SPSS version 16 was used for all analyses.\n\nRESULTS\nA total of 2745 patients with confirmed diagnosis of NHL were registered in lymphoma joint clinic at our centre from January 2007 to July 2010. One hundred and fourteen patients were between 15–25 years of age and had aggressive NHL. Complete information regarding treatment and response was available in 100 AYA patients. The demography, clinical features, distribution of histopathologic subtypes, stage at diagnosis and IPI scores in the group with complete information were similar to the whole group of 114 patients. The remaining patients did not complete staging work up (ten patients) or were not treated at our centre subsequently (four patients). The median age at diagnosis was 20.5 years. Male to female ratio was 4.9:1. A significant proportion of patients had B symptoms (53%) and bulky disease (58%) at presentation. Approximately two-third of patients had good performance status at presentation. Sixty percent of patients had stage III/IV disease at presentation. Extranodal disease involving bones, gastrointestinal tract, paranasal sinuses and ovaries was seen in 43% of patients. Seventy-eight percent patients had raised serum LDH levels. Low serum albumin (<3.5 g/ dL) level was found in 32% patients [Table 1].\n\nTable 1 Baseline characteristics of AYA NHL\n\nDistribution of histopathologic subtypes in order of their frequency was as follows. Diffuse large B-cell: 42%, T-lymphoblastic lymphomas: 18%, Burkitt's lymphoma: 11%, anaplastic large-cell lymphomas-alk-positive: 9%, lymphomas intermediate between DLBL and Burkitt's: 8%, anaplastic large-cell lymphoma-alk- negative: 6%, others (mantle cell lymphoma, peripheral T-cell lymphoma- NOS, T/NK cell lymphoma, hepatosplenic gamma- delta T-cell lymphoma) 6%.\n\nDescription of chemotherapy protocols as per histopathological subtypes is given in Table 2. Patients with DLBL (40 patients) and lymphoma intermediate between DLBL and Burkitt's were treated with CHOP, R-CHOP or MCP-842 protocol as per the decision in lymphoma clinic. Two patients in DLBL category had primary CNS lymphoma and received treatment as per De-Angelis regimen. All patients with Burkitt's lymphoma received treatment with MCP-842 regimen. Patients with ALCL were treated predominantly with MCP-842 regimen. Chemotherapy regimens used for lymphoblastic lymphoma were very variable (BFM-90, MCP-841, Continuous CHOP, and LSA2L2) and were decided based on the socioeconomic status of the patients.\n\nTable 2 Distribution of chemotherapy regimen among various histopathological subtypes\n\nComplete response rates at the completion of treatment amongst different histological subtypes (irrespective of the chemotherapy used) were DLBL: 67.5%, BL: 63%, lymphoma intermediate between DLBL and Burkitt's: 100%, ALCL-alk positive: 100%, ALCL- alk negative: 100%, LL- 44% [Table 3]. Two patients with primary CNS DLBL were in complete remission at the end of treatment.\n\nTable 3 Responses to various chemotherapeutic regimens in individual histopathological subtype\n\nAmong patients with systemic DLBL complete remission was seen in 61.5%, 63%, and 87.5% patients treated with MCP-842, CHOP, and R-CHOP regimen, respectively. One patient each in MCP-842 regimen and CHOP was on therapy at the time of this analysis thus nonevaluable for the response.\n\nTherapy was well tolerated in majority of patients. Forty-five percent of patients developed febrile neutropenia requiring hospitalization. Twenty-five percent of patients developed ≥2 episodes of febrile neutropenia. Median duration of hospitalization was 3 days (range 0-52 days). Among patients requiring hospitalization 45% remained in-patients for ≥5 days. Requirement of inotropic support, care at intensive care unit, and antifungal therapy was seen in 2%, 4%, and 7%, respectively. There were two treatment related deaths. Table 4 describes the details of toxicity differences among different chemotherapeutic regimen in DLBL patients. There was one treatment related death in MCP-842 regimen due to bleeding secondary to grade-4 thrombocytopenia.\n\nTable 4 Details of toxicities in patients with diffuse large B-cell lymphoma treated with different chemotherapy regimen\n\nThe 2-year progression-free survival (PFS) for various histopathologic subtypes was as follows DLBL: 64%, BL: 56%, lymphoma intermediate between DLBL and Burkitt's: 70%, ALCL-alk positive: 85.7%, ALCL-alk negative: 66.7%, and LL: 33.2% [Figure 1].\n\nFigure 1 Progression free survival for different subtypes of non-Hodgkin lymphoma\n\nTwo-year overall survival (OS) rates were DLBL: 76.9%, Burkitt's lymphoma: 56%, lymphoma intermediate between DLBL and Burkitt's: 80%, ALCL- alk positive and alk-negative: 100%, and LL: 44% [Figure 2].\n\nFigure 2 Overall survival for different subtypes of non-Hodgkin lymphoma\n\nAmong 42 patients of DLBL subgroup the 2-year PFS and OS according to different chemotherapy regimens were following. MCP-842 51% and 69.2%, CHOP: 65% and 80%, R-CHOP: 83.3%, and 88.7% [Figures 3 and 4].\n\nFigure 3 Progression free survival for diffuse large B-cell lymphoma according to type of chemotherapy\n\nFigure 4 Overall survival for diffuse large B-cell lymphoma according to type of chemotherapy\n\nDISCUSSION\nThis single centre retrospective analysis highlights few relevant features of AYA NHLs in our country. In this study, AYA aggressive NHL constituted 4% of all lymphoma cases registered during the study period. Increased propensity of males to develop NHL as reported in SEER data could not reasonably explain the striking disproportionate male to female ratio of 4.9:1. Gender bias in seeking medical care is a more likely reason as seen for other diseases in our country. Clinical features associated with adverse outcomes like B symptoms, bulky disease, raised LDH, and advanced stage at presentation figured prominently in our patient population. This observation differs from literature where in more than 50% of adult patients are reported to have stage I or II disease at diagnosis. Delay in seeking medical care cannot be the sole reason for the high frequency of poor prognostic clinical correlates as the median duration of symptoms were only 2 months. It would be pertinent to study the underlying biology to answer these clinical differences.\n\nThe distribution of histological subtypes has few similarities and differences in comparison to the reported literature.[7] DLBL was the most frequent subtype in our study followed by lymphoblastic lymphomas-T cell. There is a conspicuous lack of data on frequency distribution of Lymphomas intermediate between Burkitt's and DLBL and alk-negative anaplastic large cell lymphomas in literature that constituted approximately 9% of AYA NHL in our analysis.\n\nThe choice of therapy for DLBL in AYA population remains difficult and controversial. Based on the referral, these patients are treated with chemotherapy regimens used in either adults or pediatric patients. Treatment of adult patients with CHOP based regimen has resulted in 5-year OS of only 30-40%.[8] Subsequent studies demonstrated that addition of rituximab lead to significant improvement in 2-year event-free survival (EFS) to 57% from 38% and 2 year OS to 70% from 57%. In contrast to adults, children with DLBL are treated with Burkitt's lymphoma like regimen with 5-year event-free survival of 89–97%.[9] The impressive survival rates in pediatric DLBL population with Burkitt's lymphoma like regimen makes the oncologist feel that AYA NHL should be treated with intensive regimens as they are older children. However, due to lack of retrospective or prospective comparisons it remains unclear whether increase toxicities and toxic deaths on intensive regimens can offset the benefit. Our analysis failed to show any remarkable difference in outcomes with the use of Burkitt's lymphoma like regimen in patients DLBL. Potential explanations for this lack of benefit are smaller number of patients, inclination to use intensive regimens in patients with poor risk disease, higher toxicity leading to treatment delays. The best results in our patients were obtained with R-CHOP (2-year PFS: 83.3%, 2 year OS: 85.7%); however, the number of patients in this subgroup were few.\n\nThere has not been much literature on the incidence and optimal management of lymphomas intermediate between DLBL and Burkitt's as it has come in to existence after WHO 2008 classification. The limited information available on its therapy suggests the use of Burkitt's lymphoma like regimens. At our centre, we have treated these patients with both MCP-842 regimen and CHOP chemotherapy with 2-year PFS and OS of 70% and 80%, respectively.\n\nThe treatment of Burkitt's lymphomas has seen great advances since its first recognition. Currently practiced regimen in pediatric population like LMB- 96 and BFM-90 protocols achieve 4-year EFS of 92%.[9] Two-year EFS of 92% have been obtained in adult patients too with protocols like CODOX-M/IVAC and Hyper-CVAD.[10–12] In this analysis, patients with Burkitt's lymphoma have shown relatively inferior results (complete response rate of 63% with 2-year PFS of 56%) as compared to the results reported in the literature for pediatric and adult population (complete remission rates of 97% and EFS of 92% at 2 years). This may be due to poor tolerance of therapy, poor risk features like advanced stage at presentation and delay in starting therapy due to financial constraints.\n\nThe outcome of lymphoblastic lymphoma is inferior in this analysis with 2-year PFS and OS rates of 33.2% and 44%, respectively. The treatment outcomes with various regimens have been in excess of 70% for patients in age group of 15-50 years.[1314] Use of multiple regimens, advanced stage of disease was the potential reasons for this inferior outcome.\n\nAlk-negative ALCL is seen more frequently in older adults and Alk-positive ALCL is the predominantly the disease of children and young adults. In our study, the frequency of both subtypes of ALCL was similar.\n\nIn pediatric population strategy of intensive therapy is efficacious and it results in overall survival of 65% at 5 years for patients with Alk+ ALCL.[15–17]\n\n Alk-negative ALCL has relatively poor outcome with 5 year OS of 49%.[18] Several attempts to improve its outcome in adult patients have met with failures. Most of the patients are treated with CHOP like regimens. In this retrospective analysis, patients with both alk-negative and positive ALCL received treatment with MCP-842 regimen predominantly. The 2-year PFS rates in alk-negative and alk-positive groups were 66.7% and 85.7%, respectively.\n\nThis study is the only study reporting the disease patterns and treatment outcome results for AYA NHL from the developing country. As for developed world, differences in biology and uniqueness of this disease will hold true in developing countries too. However, there are several other important issues relevant to the developing world which needs to be addressed for improving the treatment results. These include poor compliance, lack of financial help for treatment and higher toxicities due to poor nutritional status of the host.\n\nCONCLUSIONS\nThis is a very small and retrospective study of AYA NHL and thus it has several limitations in terms of applicability of the results. However, it does give an insight on the various aspects of clinical presentation and treatment outcome in this subgroup.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Jemal A Siegel R Ward E Hao Y Xu J Thun MJ Cancer Statistics 2009 CA Cancer J Clin 2009 59 225 49 19474385 \n2 O’Leary M Sheaffer J Keller F Shu XO Cheson B Bleyer A O’Leary M Barr R Ries LA Lymphomas and reticuloendothelial neoplasms Cancer epidemiology in older adolescents and young adults 15 to 29 years of age, including SEER incidence and survival: 1975-2000 2006 Bethesda, MD National Cancer Institute NIH Pub. No. 06-5767 \n3 Bleyer A The adolescent and young adult gap in cancer care and outcome Curr Probl Pediatr Adolesc Health Care 2005 35 182 217 15841070 \n4 Harris NL Swerdlow SH Jaffe ES WHO classification of tumors of hematopoietic and lymphoid tissues 2008 4 Lyon International Agency for Research on Cancer \n5 Advani S Pai S Adde M Vaidya S Vats T Naresh K Preliminary report of an intensified, short duration chemotherapy protocol for the treatment of pediatric non-Hodgkin's lymphoma in India Ann Oncol 1997 8 893 7 9358941 \n6 Raje SN Vaidya SJ Kapoor G Pai SK Nair CN Kurkure PA Low incidence of CNS relapse with cranial radiotherapy and intrathecal methotrexate in acute lymphoblastic leukemia Indian Pediatr 1996 33 556 60 8979564 \n7 Jaglowski SM Linden E Termuhlen AM Flynn JM Lymphoma in adolescents and young adults Semin Oncol 2009 36 381 418 19835736 \n8 Fisher RI Gaynor ER Dahlberg S Oken MM Grogan TM Mize EM Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma N Engl J Med 1993 328 1002 6 7680764 \n9 Reiter A Schrappe M Tiemann M Ludwig WD Yakisan E Zimmermann M Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Munster group trial NHL-BFM - 90 Blood 1999 94 3294 306 10552938 \n10 Moleti ML Testi Am Giona F Malandruccolo L Pescarmona E Martino P CODOX-M/IVAC (NCI 89-C-41) in children and adolescents with Burkitts Leukemia/Lymphoma amd large B-cell lymphomas: A 15-year monocentric experience Leuk Lymph 2007 48 551 9 \n11 Blum KA Lozanski G Byrd JC Adult Burkitt leukemia and lymphoma Blood 2004 104 3009 20 15265787 \n12 Thomas DA Cortes J O’Brien S Pierce S Faderl S Albitar M Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia J Clin Oncol 1999 17 2461 70 10561310 \n13 Reiter A Schrappe M Ludwig WD Tiemann M Parwaresch R Zimmermann M Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-Cell lymphoblastic lymphoma: A BFM group report Blood 2000 95 416 21 10627444 \n14 Hoelzer D Gokbuget N Diget W Faak T Kneba M Reutzel R Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia Blood 2002 99 4379 85 12036865 \n15 Williams DM Hobson R Imeson J Gerrard M McCarthy K Pinkerton CR Anaplastic large cell lymphoma in childhood: Analysis of 72 patients treated on the United Kingdom Children's Cancer Study Group chemotherapy regimens Br J Haematol 2002 117 812 20 12060115 \n16 Seidemann K Tiemann M Schrappe M Yakisan E Simonitsch I Janka-Schaub G Short-pulse B-non-Hodgkins lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: A report of the Berlin-Frankfurt-Munster group trial NHL-BFM-90 Blood 2001 97 3699 706 11389005 \n17 Lowe EJ Sposto R Perkins SL Gross TG Finlay J Zwick D Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: Final results of Children's Cancer Group study 5941 Pediatr Blood Cancer 2009 52 335 9 18985718 \n18 Fanin R Sperotto A Silvestri F Cerno M Geromin A Stocchi R The therapy of primary adult systemic CD30-positive anaplastic large cell lymphoma: Results of 40 cases treated in a single center Leuk Lymph 1999 35 159 69\n\n",
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"keywords": "Adolescent and young adults; adolescent and young adults malignancies; non-Hodgkin lymphoma",
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"title": "A retrospective audit of clinicopathological attributes and treatment outcomes of adolescent and young adult non-Hodgkin lymphomas from a tertiary care center.",
"title_normalized": "a retrospective audit of clinicopathological attributes and treatment outcomes of adolescent and young adult non hodgkin lymphomas from a tertiary care center"
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"abstract": "The use of next-generation sequencing for fusion identification is being increasingly applied and aids our understanding of tumor biology. Some fusions are responsive to approved targeted agents, while others have future potential for therapeutic targeting. Although some pediatric central nervous system tumors may be cured with surgery alone, many require adjuvant therapy associated with acute and long-term toxicities. Identification of targetable fusions can shift the treatment paradigm toward earlier integration of molecularly targeted agents.\n\n\n\nPatients diagnosed with glial, glioneuronal, and ependymal tumors between 2002 and 2019 were retrospectively reviewed for fusion testing. Testing was done primarily using the ArcherDx FusionPlex Solid Tumor panel, which assesses fusions in 53 genes. In contrast to many previously published series chronicling fusions in pediatric patients, we compared histological features and the tumor classification subtype with the specific fusion identified.\n\n\n\nWe report 24 cases of glial, glioneuronal, or ependymal tumors from pediatric patients with identified fusions. With the exception of BRAF:KIAA1549 and pilocytic/pilomyxoid astrocytoma morphology, and possibly QKI-MYB and angiocentric glioma, there was not a strong correlation between histological features/tumor subtype and the specific fusion. We report the unusual fusions of PPP1CB-ALK, CIC-LEUTX, FGFR2-KIAA159, and MN1-CXXC5 and detail their morphological features.\n\n\n\nFusion testing proved to be informative in a high percentage of cases. A large majority of fusion events in pediatric glial, glioneuronal, and ependymal tumors can be identified by relatively small gene panels.",
"affiliations": "Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;Department of Neurosurgery, University of Colorado, Aurora, Colorado.;Department of Pathology, University of Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;Department of Pathology, University of Colorado, Aurora, Colorado.;Departments of Pathology, Neurology, Neurosurgery, University of Colorado, Aurora, Colorado.;The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado.;Department of Pathology, Children's Hospital Colorado, University of Colorado, Aurora, Colorado.",
"authors": "Lake|Jessica A|JA|0000-0001-7739-0850;Donson|Andrew M|AM|;Prince|Eric|E|;Davies|Kurtis D|KD|;Nellan|Anandani|A|;Green|Adam L|AL|0000-0002-4469-2358;Mulcahy Levy|Jean|J|;Dorris|Kathleen|K|;Vibhakar|Rajeev|R|;Hankinson|Todd C|TC|;Foreman|Nicholas K|NK|;Ewalt|Mark D|MD|;Kleinschmidt-DeMasters|Bette K|BK|0000-0002-4471-1678;Hoffman|Lindsey M|LM|;Gilani|Ahmed|A|",
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"keywords": "CNS tumors; ependymoma; glioma; glioneuronal; molecular fusion; pediatric",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D014408:Biomarkers, Tumor; D001932:Brain Neoplasms; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D004806:Ependymoma; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma; D006801:Humans; D007223:Infant; D008297:Male; D018302:Neoplasms, Neuroepithelial; D015514:Oncogene Proteins, Fusion; D011379:Prognosis; D012189:Retrospective Studies",
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"title": "Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors.",
"title_normalized": "targeted fusion analysis can aid in the classification and treatment of pediatric glioma ependymoma and glioneuronal tumors"
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"abstract": "Weeksella virosa is one of the two species of the genus Weeksella. Clinical disease due to this bacterium in humans is rare, for which only nine cases have been reported in the literature.\n\n\n\nA 4-year-old male patient was diagnosed with a left orbit rhabdomyosarcoma Stage III and was admitted to a northeast third level referral center in Mexico. Aerobic, non-pigmented, Gram-negative rod was isolated from a blood culture. W. virosa was identified by Sensititre™ ARIS. This organism has been described in cases of spontaneous bacterial peritonitis, sepsis, pneumonia, ventriculitis, and urinary tract infection.\n\n\n\nClinicians should consider the diagnosis of W. virosa bacteremia in cases involving immunocompromised patients with oral lesions, although it is infrequent. To the best of our knowledge, this is the first clinical report of W. virosa bacteremia described in an immunocompromised pediatric patient.",
"affiliations": "Servicio de Enfermedades Infecciosas, Departmento de Pediatría, Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, Mexico.;Servicio de Enfermedades Infecciosas, Departmento de Pediatría, Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, Mexico.;Departmento de Patología Clínica, Departmento de Microbiología Clínica, Hospital Universitario Dr. José Eleuterio González, Monterrey, Mexico.;Servicio de Enfermedades Infecciosas, Departmento de Pediatría, Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, Mexico.;Departmento de Patología Clínica, Departmento de Microbiología Clínica, Hospital Universitario Dr. José Eleuterio González, Monterrey, Mexico.;Departmento de Microbiología, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí. Mexico.;Servicio de Enfermedades Infecciosas, Departmento de Pediatría, Hospital Universitario Dr. José Eleuterio González, Monterrey, Nuevo León, Mexico.",
"authors": "Vaquera-Aparicio|Denisse N|DN|;Mascareñas-De Los Santos|Abiel H|AH|;Casillas-Vega|Néstor|N|;Riojas-Hernández|Patricia|P|;Llaca-Díaz|Jorge|J|;Herrera-Benavente|Ismael|I|;Castillo-Bejarano|José I|JI|",
"chemical_list": null,
"country": "Mexico",
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"doi": "10.24875/BMHIM.19000205",
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"issn_linking": "0539-6115",
"issue": "77(3)",
"journal": "Boletin medico del Hospital Infantil de Mexico",
"keywords": "Bacteremia; Bacteriemia; Mucositis; Neutropenia",
"medline_ta": "Bol Med Hosp Infant Mex",
"mesh_terms": "D016470:Bacteremia; D002648:Child; D002675:Child, Preschool; D041965:Flavobacteriaceae; D006801:Humans; D008297:Male; D018233:Rhabdomyosarcoma, Embryonal; D018805:Sepsis",
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"pages": "149-152",
"pmc": null,
"pmid": "32496471",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bacteremia due to Weeksella virosa in a pediatric patient with embryonal rhabdomyosarcoma.",
"title_normalized": "bacteremia due to weeksella virosa in a pediatric patient with embryonal rhabdomyosarcoma"
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"abstract": "Radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is a rare form of DTC which poses a therapeutic challenge due to the scarcity of effective treatment options. In recent years several tyrosine kinase inhibitors targeting specific molecular pathways involved in its pathogenesis have been investigated, such as sorafenib, lenvatinib, and sunitinib. These appear to be associated with improved progression-free survival (PFS).\nWe aim to describe our experience with sorafenib and sunitinib in the treatment of RAI-refractory metastatic DTC and to evaluate and compare their efficacy and adverse effect profiles.\nA total of 28 patients with RAI-refractory metastatic DTC were included - 26 had first-line treatment with sorafenib (8 subsequently switched to sunitinib, most due to disease progression) and 2 with sunitinib. We evaluated PFS and best radiological response achieved with each agent as primary endpoints. The secondary objective was to describe adverse effects and safety profile.\nMean PFS was 10.8 months with sorafenib and 6 months with sunitinib as a second-line treatment. Best overall response was partial remission (PR) with either agent - PR rate of 30.7% with sorafenib and 37.5% with second-line sunitinib. All treatment courses had registered adverse effects and 13.9% justified definitive treatment cessation.\nSorafenib and sunitinib appear to be effective treatment options in delaying disease progression of patients with RAI-refractory metastatic DTC, with an acceptable safety profile. Interestingly, sunitinib appears to show some efficacy even in patients who experience disease progression on sorafenib.",
"affiliations": "Endocrinology Department, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.;Endocrinology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.;Endocrinology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.",
"authors": "Sousa Santos|Francisco|F|;Joana Santos|Rita|R|;Leite|Valeriano|V|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000501680",
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"issn_linking": "2235-0640",
"issue": "8(5)",
"journal": "European thyroid journal",
"keywords": "Sorafenib; Sunitinib; Thyroid cancer; Tyrosine kinase inhibitors",
"medline_ta": "Eur Thyroid J",
"mesh_terms": null,
"nlm_unique_id": "101604579",
"other_id": null,
"pages": "262-267",
"pmc": null,
"pmid": "31768337",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "19097774;18657022;20847059;29313949;24424318;30539828;20392874;28911730;27666535;27189322;28301826;24768112;23575762;26105190;29275532;26462967;28225999;26671977;21890651",
"title": "Sorafenib and Sunitinib for the Treatment of Metastatic Thyroid Cancer of Follicular Origin: A 7-Year Single-Centre Experience.",
"title_normalized": "sorafenib and sunitinib for the treatment of metastatic thyroid cancer of follicular origin a 7 year single centre experience"
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"activesubstancename": "SUNITINIB MALATE"
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"abstract": "Chronic subdural hematomas mainly occur amongst elderly people and usually develop after minor head injuries. In younger patients, subdural collections may be related to hypertension, coagulopathies, vascular abnormalities, and substance abuse. Different techniques can be used for the surgical treatment of symptomatic chronic subdural hematomas : single or double burr-hole evacuation, with or without subdural drainage, twist-drill craniostomies and classical craniotomies. Failure of the brain to re-expand, pneumocephalus, incomplete evacuation, and recurrence of the fluid collection are common complications following these procedures. Acute subdural hematomas may also occur. Rarely reported hemorrhagic complications include subarachnoid, intracerebral, intraventricular, and remote cerebellar hemorrhages. The causes of such uncommon complications are difficult to explain and remain poorly understood. Overdrainage and intracranial hypotension, rapid brain decompression and shift of the intracranial contents, cerebrospinal fluid loss, vascular dysregulation and impairment of venous outflow are the main mechanisms discussed in the literature. In this article we report three cases of different post-operative intracranial bleeding and review the related literature.",
"affiliations": "Department of Life Sciences, University of Insubria, Varese, Italy.;Neurosurgical Unit, Ospedale di Circolo, Varese, Italy.;Department of Life Sciences, University of Insubria, Varese, Italy.;Department of Life Sciences, University of Insubria, Varese, Italy.",
"authors": "Rusconi|Angelo|A|;Sangiorgi|Simone|S|;Bifone|Lidia|L|;Balbi|Sergio|S|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3340/jkns.2015.57.5.379",
"fulltext": "\n==== Front\nJ Korean Neurosurg SocJ Korean Neurosurg SocJKNSJournal of Korean Neurosurgical Society2005-37111598-7876The Korean Neurosurgical Society 10.3340/jkns.2015.57.5.379Case ReportInfrequent Hemorrhagic Complications Following Surgical Drainage of Chronic Subdural Hematomas Rusconi Angelo M.D.1Sangiorgi Simone M.D.Ph.D.2Bifone Lidia M.D.1Balbi Sergio M.D.11 Department of Life Sciences, University of Insubria, Varese, Italy.2 Neurosurgical Unit, Ospedale di Circolo, Varese, Italy.Address for reprints: Angelo Rusconi, M.D. Department of Life Sciences-University of Insubria-Varese, Italy Via Sopranzi 20, 21049 Tradate-Va, Italy. Tel: +39-32854-17119, Fax: +39-03322-278945, angelo.rusconi@hotmail.com5 2015 31 5 2015 57 5 379 385 02 4 2014 18 12 2014 23 12 2014 Copyright © 2015 The Korean Neurosurgical Society2015This 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.Chronic subdural hematomas mainly occur amongst elderly people and usually develop after minor head injuries. In younger patients, subdural collections may be related to hypertension, coagulopathies, vascular abnormalities, and substance abuse. Different techniques can be used for the surgical treatment of symptomatic chronic subdural hematomas : single or double burr-hole evacuation, with or without subdural drainage, twist-drill craniostomies and classical craniotomies. Failure of the brain to re-expand, pneumocephalus, incomplete evacuation, and recurrence of the fluid collection are common complications following these procedures. Acute subdural hematomas may also occur. Rarely reported hemorrhagic complications include subarachnoid, intracerebral, intraventricular, and remote cerebellar hemorrhages. The causes of such uncommon complications are difficult to explain and remain poorly understood. Overdrainage and intracranial hypotension, rapid brain decompression and shift of the intracranial contents, cerebrospinal fluid loss, vascular dysregulation and impairment of venous outflow are the main mechanisms discussed in the literature. In this article we report three cases of different post-operative intracranial bleeding and review the related literature.\n\nChronic subdural hematomaSubarachnoid hemorrhageRemote cerebellar hemorrhageHead trauma\n==== Body\nINTRODUCTION\nChronic subdural hematomas (CSH) are frequently encountered in neurosurgical practice. Risk factors include head trauma, advanced-age, frequent falls, coagulopathies, and therapeutic anticoagulation1012). Cerebrospinal fluid (CSF) shunts and overshunting conditions, and the age-related increase of subdural space and subarachnoid cisterns may also promote CSH formation1124). Furthermore, the cause of CSH is unknown in 29-38% of cases1224). Spontaneous subdural hematomas occurring in younger patients1) are supposed to be due to severe arterial hypertension, intracranial hypotension7), CSF leaks, repeated Valsalva maneuvers13), vascular abnormalities-like arteriovenous malformations (AVM) and aneurysms20)-dural sinus thrombosis21), neoplasms, infections, coagulopathies and alcohol or cocaine abuse18).\n\nSeveral techniques are used for the surgical treatment of symptomatic subdural hematomas12) : single burr-hole craniectomy under local anesthesia, with or without positioning a subdural drainage system, double burr-hole evacuation technique, twist-drill craniostomy and formal craniotomy. Neuroendoscopic techniques have also been proposed for multiloculated or septated haematomas14), but are rarely recommended. Although craniotomy has been widely used in combination with inner membranectomy27), a higher mortality rate was demonstrated. For this reason, less invasive procedures such as subdural evacuating port systems, are currently spreading over28).\n\nMori and Maeda24) reported in 2001 that post-operative acute subdural hematoma (2.6%) and tension pneumocephalus (0.8%) were the most common complications in CSH surgery. In this series, acute subdural hematoma is attributed to fresh bleeding from the scalp wound. Residual subdural fluid collections and failure of the brain to re-expand may also occur after these surgical procedures. Other post-operative complications include CSH recurrence, seizures and subdural empyema2730).\n\nCortical hyperemia beneath the hematoma, subarachnoid hemorrhage (SAH), supratentorial intracerebral, intraventricular, and remote cerebellar hemorrhages (RCHs) are rarely observed. In a large series of 1000 CSH12), 4 cases of post-operative intracranial bleeding were described (0.4%). Other authors report an incidence range between 0.2 and 4%824). In our case series, 385 CSH were operated in the Neurosurgery Unit of the University Hospital of Varese, from January 2006 to December 2013. Unusual post-operative hemorrhagic events occurred in 3 patients, with an incidence of 0.78%. The causes of these uncommon complications remain unexplained. Overdrainage, rapid brain decompression and shift of the intracranial contents, massive CSF loss, venous outflow impairment and vascular dysregulation with blood flow increase, are the mechanisms currently debated.\n\nCASE REPORT\nCase 1\nIn case 1 we report the clinical findings regarding a 62-years-old man. He presented with a fortnight history of headache and progressive weakness of the left limbs. He did not suffer from any previous pathology and he did not refer substance abuse. No history of trauma was detected. The neurologic examination demonstrated a slight left hemiparesis. Computed tomography (CT) revealed a right chronic subdural hematoma with mass effect on brain parenchyma and mild shift of the midline structures (Fig. 1). Consequently, we proceeded with the surgical evacuation of the right subdural hematoma via a single parietal burr-hole craniectomy. At the end of the operation, a subdural drainage tube was positioned, open to gravity. A few hours after the procedure the patient developed intense headache and mental confusion, without neurological focal deficits. Arterial blood pressure was 150/90 mm Hg. A large amount of recent reddish blood was found in the drainage system, which contained 650 mL of fluid. We decided to immediately close the drainage and perform a CT scan. This revealed a diffuse SAH localized in the basal cisterns, bilaterally in the sylvian fissures, and over the cerebral surface (Fig. 2). No residual fluid collection, acute bleeding or severe pneumocephalus were found in the cavity of the hematoma. CT-angiography and cerebral angiography excluded the presence of cerebral aneurysms and AVM. The drainage system was kept closed for the next two days. The patient was left in supine position and the fluid intake was increased to 1.5 L per day. Headache was successfully treated with analgesics. After two days, a CT scan showed normal brain expansion and the re-absorption of subarachnoid blood without further complications. Therefore the drainage tube was removed. The patient's conditions gradually improved, the headache decreased and after five days he was discharged without neurological deficits. The one-month follow-up showed that the patient was in good conditions. Accordingly, he returned to his work and leisure activities. Head CT was normal.\n\nCase 2\nIn case 2 we report the findings regarding an 85-years-old man with a history of hypertension, ischemic heart disease, cardiac arrhythmia and chronic obstructive pulmonary disease (COPD). He was admitted to our department due to mental confusion, disorientation and dizziness which had occurred ten days back. Previous mild head trauma due to an accidental fall was reported. Neurological evaluation confirmed mental confusion, spatial disorientation and gait imbalance, without focal deficits. The CT scan revealed a sizeable right chronic-subacute subdural hematoma with mass effect and midline shift (Fig. 3). Blood thinners (clopidogrel 75 mg per day) were discontinued 7 days before surgery. The patient underwent a single parietal burr-hole craniectomy and the right CSH was uneventfully evacuated. A subdural drainage apparatus was positioned, open to gravity. The day after the patient suddenly developed arterial hypertension (200/110 mm Hg), intense headache and vomit. We found a large amount of fluid (500 mL) in the drainage bag. The device was closed and a CT scan was performed. This revealed the presence of SAH in the right sylvian fissure, and a small contralateral occipital intraparenchymal hemorrhage (Fig. 4). The patient was kept in recumbent position for two days and the fluid intake was increased to 1.5 L per day. Normal arterial pressure values were restored with medical therapy and the headache gradually decreased. Two days after, a CT scan did not show other complications. The drainage system was then removed and after five days the patient was discharged without neurological deficits. The one-month follow-up showed the patient was in good conditions. The CT scan of the head revealed complete resolution of the previous hemorrhagic findings.\n\nCase 3\nIn case 3 we report the findings regarding an 80-years-old man with a history of alcohol abuse, arterial hypertension and ischemic heart disease. He was admitted to our hospital due to headache and dizziness. He reported frequent falls in the previous month and a minor head trauma. The CT scan showed a right CSH with mass effect and a thin liquid collection on the left side (Fig. 5). The neurologic evaluation revealed mental confusion and weakness of the left limbs. Antiplatelet therapy (aspirin 100 mg per day) was discontinued 5 days before surgery. The evacuation of the subdural hematoma was performed with a single parietal burr-hole craniectomy on the right side. A subdural drainage catheter was positioned, open to gravity, without evidence of complications. The following day we observed a worsening of the neurologic conditions with mental confusion and lethargy. A large amount of fluid (600 mL) was encountered in the drainage system. Arterial pressure was 170/100 mm Hg. The post-operative CT scan (Fig. 6) showed frontal bilateral pneumocephalus and a small left temporal intracerebral hemorrhage. No acute bleedings or increase in the left hemispheric hygroma were found. Additionally, thin blood layers along the tentorium and within the cerebellar folia were demonstrated. The drainage tube was removed, the patient was left in recumbent position and the fluid intake was increased to 1.5 L per day. The CT findings gradually resolved and did not require surgical exploration. The neurologic evaluation revealed a slight postural instability and for this reason the patient was addressed to physical therapy. At two-month follow-up, the patient was able to walk unaided and the control CT scan was normal.\n\nDISCUSSION\nThree different bleeding patterns occurred after CSH evacuation are described in our report. The characteristics of patients are summarized in Table 1. The first case is a diffuse bilateral SAH localized in the basal and sylvian cisterns and over the cerebral convexity. The patient was a healthy 62 years old man, without history of trauma, coagulation disorders or substance abuse. He developed a slight post-operative hypertension with headache. No aneurysms or AVM were detected by the cerebral angiography. Further causes of SAH include angiographically occult vascular malformations, coagulation disorders, pituitary apoplexy, sickle cell anemia, drug consumption, cerebral artery dissection and vasculitides, but none of these was demonstrated. Spontaneous, \"sine materia\" subarachnoid hemorrages517) have also been described and even this unlikely and quite benign condition has to be considered.\n\nMiyazaki et al.22) reported in 2004 the only case of post-operative SAH of unknown origin after CSH drainage. The patient was a 52-years-old man with a history of cerebral infarctions being treated with anticoagulants, complaining of headache without evidence of head trauma. The authors mainly related this hemorrhagic complication to peri-operative hypertension and anticoagulant therapy. Other discussed mechanisms are the rapid shift of the cerebral hemisphere after hematoma evacuation, overdrainage of the subdural space and the hyperperfusion syndrome. This condition was described in the elderly by Ogasawara et al.25). According to this study vascular autoregulation is impaired due to long-term brain compression by CSH, and a rapid decrease of intracranial pressure occurs after the drainage of the hematoma. The consequent hemodynamic changes can lead to hyperperfusion and cortical hyperemia, resulting in the rupture of a weak subarachnoid vessel. Moreover, peri-operative mean arterial pressure was significantly higher in patients exhibiting this syndrome.\n\nStandard bore (19 Fr), open to gravity drainage systems are routinely utilized in our unit, without suction bulb. Catheters are inserted in the subdural space and usually removed 48-72 hours after surgery. We usually perform a CT scan on first post-operative day. Patients are kept in supine position until the drainage is removed. In case 1, a large amount of fluid was found in the patient's drainage bag soon after surgery, and fresh blood traces were remarkable. We suppose that the combination of rapid parenchymal shift and diffuse cortical hyperemia were responsible for developing of SAH in our patient. The former may be related to the prompt expansion of a \"healthy\" brain after sudden decompression, whereas the latter has probably been promoted by hypertension and hyperperfusion.\n\nThe second case is an 85-years-old man with a history of hypertension, ischemic heart disease, cardiac arrhythmia, and COPD. He developed an important hypertensive condition with headache and vomit the day after burr-hole trephination. Head CT revealed a right sylvian SAH and a contralateral occipital hematoma.\n\nSeveral cases of intracerebral hemorrhages following CSH evacuation have been reported, but the pathogenesis of this dangerous complication remains unclear. Modesti et al.23) reported a 5% incidence of post-operative intracerebral hematomas and many of these patients did not survive or were left with severe disability. Hemorrhage into previously undetected contusions, sudden increase in cerebral blood flow and arterial hypertension, combined with faulty local autoregulation, were accounted as pathogenic mechanisms. The authors concluded that these factors led to vascular damage and the consequent bleeding.\n\nKim et al.19) reported in 2013 the case of a massive and fatal intracerebral hemorrhage after CSH drainage. In their case the patient was a young man previously treated with a low dose of aspirin. The patient developed post-operative disseminated intravascular coagulation. Parenchymal bleeding was ascribed to overdrainage of the subdural space with rapid parenchymal shift and to the coagulation disorder. The authors state that the loss of equilibrium among the tightly regulated coagulation factors can lead either to hypercoagulable states, with microthrombosis and ischemia, or to hypocoagulable states with possible onset or progression of hemorrhagic lesions. In addition, Spetzler et al.29) obtained experimental evidence of the loss of CO2 reactivity and autoregulation in the ischemic hemisphere of animals. The loss of vascular autoregulation might be also related to the gap between pre-operative cerebral blood flow (reduced by long term compression due to impeded venous drainage) and sudden hyperemia after surgery.\n\nIntracerebral hematomas reported in the literature are usually ipsilateral to CSH, while our patient developed a remote contralateral occipital bleeding. To our knowledge, remote bleeding after CSH evacuation has been reported in just two other cases68). In a recent paper, Cohen-Gadol6) described a contralateral intraparenchymal hemorrhage associated with intraventricular blood and SAH. The author believes that overdrainage of subdural fluid and CSF was most likely to be the cause of bleeding, since the patient's neurologic conditions improved expeditiously after discontinuation of subdural drainage. It is likely that CSF overdrainage may have led to acute intracranial hypotension and this process placed the contralateral bridging veins under tension, thus causing their collapse and ultimately resulting in venous insufficiency and hemorrhagic infarction.\n\nDinc et al.8) reported in 2008 the case of a contralateral hematoma after CSH drainage. The authors recommended slow decompression, by twist-drill craniostomy, in order to prevent rapid dynamic intracranial changes.\n\nOur patient developed headache and acute post-operative hypertension and this, in association with CSF drainage and shift of intracranial structures, may have caused the formation of SAH and parenchymal hematoma.\n\nThe third patient is an 80-years-old man with a history of hypertension, ischemic heart disease and alcohol abuse. In the post-operative period there was a worsening of neurologic conditions and the head CT showed a contralateral temporal hemorrhage. Unexpectedly, subdural blood along the tentorium and cerebellar hemorrhage within the cerebellar folia were revealed.\n\nThe possible pathogenic mechanisms have been illustrated for supratentorial hemorrhages, whereas explanations of remote cerebellar hemorrhage are still tentative. RCH is an infrequent but potentially life-threatening complication that rarely occurs after supratentorial craniotomies and spinal surgery (<5%)2). The incidence of post-operative RCH increased in the CT era. The classic findings comprise subarachnoid blood in the sulci of tentorial surfaces of cerebellar hemispheres and vermis, and additional intracerebellar hemorrhage. In these cases bleeding is characterized by alternating hyperdense (blood), and hypodense (cerebellum) curvilinear and irregular stripes in one or both cerebellar hemispheres. The pattern imitates that of the fur of a zebra, and is thus called zebra sign3). Other depicted CT and magnetic resonance findings are punctuate hemosiderin spots at the superior cerebellar folia, SAH, diffuse hemorrhage in the cerebellar tonsils, vermis and within the fourth ventricle9).\n\nProlonged awakening from anesthesia, cerebellar symptoms, motor deficits and gait ataxia, diminished consciousness and headache may be signs of RCH. However, RCH may often manifest itself as an asymptomatic incidental finding on post-operative head CT. More severe presentations are related to mass effect upon the fourth ventricle, brainstem compression and development of obstructive hydrocephalus.\n\nThe underlying mechanisms of RCH have been extensively discussed in the literature. Currently, most authors agree on multifactorial etiology of RCH2) : CSF overdrainage during or after surgery, episodes of arterial hypertension, impaired venous drainage due to intraoperative head rotation with obstruction of one jugular vein, and coagulation abnormalities have been proposed. In addition, Huang et al.15) recently observed that RCH incidence after supratentorial craniotomy is related with history of cerebrovascular accident with cerebral atrophy. No consensus regarding the exact pathomechanism has been reached. In a wide review and retrospective analysis of 154 cases of RCH, Park et al.26) observed in 2009 the following common features : 1) hemorrhage occurred mostly in the tentorial cerebellar surface, which differed clearly from hypertensive cerebellar hemorrhage, in which dentate nuclei are commonly involved; 2) most cases had SAH with typical streaky bleeding pattern (zebra sign); 3) presentation was incidental in many cases, and in cases with symptomatic deterioration the timing of onset was delayed; 4) drainage systems were used with negative pressure in most cases. On the back of these common features, most authors agree on two facts : 1) RCH is venous in origin, and most likely the superior vermian vein is affected; 2) RCH is likely to be the result of intraoperative and, even more likely, post-operative loss of CSF.\n\nThe role of intracranial hypotension has been debated in relation to several post-craniotomy complications31), such as delayed awakening, bradycardia34), brain swelling and RCH. Van Roost et al.32) attributed intracranial hypotension to suction drains. The authors' \"mechanistic\" negative-pressure theory asserts that the volume removal that occurs when drainage is applied after intracranial surgery may transmit a massive, nonphysiological negative pressure to the brain. This, together with the caudal displacement of the cerebellum due to CSF loss, may induce stretching of cortical veins and venous transmural pressure increase, finally leading to rupture of a small vessel.\n\nWhile most of RCHs develop after supratentorial craniotomy, only a few cases are reported following burr-hole evacuation of CSH41633). Our patient had arterial hypertension, a history of alcohol consumption, and was assuming antiplatelet therapy prior to surgery. We suppose that rapid brain decompression, in association with an excessive amount of fluid drainage and intracranial hypotension, led to parenchymal shift and consequent vascular damage. This finally resulted in remote hemorrhage in the contralateral temporal lobe and cerebellar hemispheres.\n\nCONCLUSION\nWe reported three cases of uncommon hemorrhagic complications after burr-hole craniectomy for CSH. The pathomechanisms are not completely understood. They are probably related to coagulation disorders, arterial and venous pressure imbalance, shift of intracranial contents during surgery, uncontrolled fluid drainage and intracranial hypotension.\n\nAlthough CSH drainage is considered as a minor procedure, neurosurgeons must be aware of these rare but known adverse events. Correction of coagulopathies, control of blood pressure and management of related medications are essential in order to prevent such complications.\n\nAt the time of surgery, careful and gentle evacuation of the subdural hematoma without excessive head rotation is suggested, since delicate irrigation of the cavity of the hematoma is less likely to induce rapid shift of intracranial contents. The use of drains without vacuum bulb is recommended at the end of the operation. Furthermore, tight post-operative monitoring of drainage amounts and characteristics, repeated evaluation of neurologic conditions and prompt radiological assessment are mandatory.\n\nFig. 1 Head CT showing a large right CSH with midline shift. CSH : chronic subdural hematoma.\nFig. 2 Post-operative head CT showing diffuse SAH in the basal cisterns (A) and over cerebral convexity (B). SAH : subarachnoid hemorrhage.\nFig. 3 CT scan showing a large right CSH with recent blood. CSH : chronic subdural hematoma.\nFig. 4 Right sylvian SAH (A) and contralateral occipital hematoma (B) on a post-operative head CT. SAH : subarachnoid hemorrhage.\nFig. 5 Pre-operative head CT showing a right CSH and a contralateral hemispheric hygroma. CSH : chronic subdural hematoma.\nFig. 6 Post-operative head CT showing a small left temporal hematoma and subdural blood along the tentorium (A) and a cerebellar hemorrhage (B).\nTable 1 Characteristics of patients\nCSH : chronic subdural hematoma, ICH : intracerebral hematoma, RCH : remote cerebellar hemorrhage, SAH : subarachnoid hemorrhage, M : male, R : right, BP : blood pressure\n==== Refs\n1 Arpino L Gravina M Basile D Franco A Spontaneous chronic subdural hematoma in a young adult J Neurosurg Sci 2009 53 55 57 19546844 \n2 Brockmann MA Groden C Remote cerebellar hemorrhage : a review Cerebellum 2006 5 64 68 16527766 \n3 Brockmann MA Nowak G Reusche E Russlies M Petersen D Zebra sign : cerebellar bleeding pattern characteristic of cerebrospinal fluid loss. Case report J Neurosurg 2005 102 1159 1162 16028781 \n4 Chang SH Yang SH Son BC Lee SW Cerebellar hemorrhage after burr hole drainage of supratentorial chronic subdural hematoma J Korean Neurosurg Soc 2009 46 592 595 20062580 \n5 Cioffi F Pasqualin A Cavazzani P Da Pian R Subarachnoid haemorrhage of unknown origin : clinical and tomographical aspects Acta Neurochir (Wien) 1989 97 31 39 2718794 \n6 Cohen-Gadol AA Remote contralateral intraparenchymal hemorrhage after overdrainage of a chronic subdural hematoma Int J Surg Case Rep 2013 4 834 836 23959412 \n7 de Noronha RJ Sharrack B Hadjivassiliou M Romanowski CA Subdural haematoma : a potentially serious consequence of spontaneous intracranial hypotension J Neurol Neurosurg Psychiatry 2003 74 752 755 12754345 \n8 Dinc C Iplikcioglu AC Bikmaz K Navruz Y Intracerebral haemorrhage occurring at remote site following evacuation of chronic subdural haematoma Acta Neurochir (Wien) 2008 150 497 499 discussion 499 18305890 \n9 Dincer A Özcan Ü Kaya D Usseli MI Erzen C Pamir MN Asymptomatic remote cerebellar hemorrhage : CT and MRI findings Cerebellum 2012 11 880 886 22249914 \n10 Drapkin AJ Chronic subdural hematoma : pathophysiological basis for treatment Br J Neurosurg 1991 5 467 473 1764228 \n11 Fogelholm R Heiskanen O Waltimo O Chronic subdural hematoma in adults. Influence of patient's age on symptoms, signs, and thickness of hematoma J Neurosurg 1975 42 43 46 1167376 \n12 Gelabert-González M Iglesias-Pais M García-Allut A Martínez-Rumbo R Chronic subdural haematoma : surgical treatment and outcome in 1000 cases Clin Neurol Neurosurg 2005 107 223 229 15823679 \n13 Haykowsky MJ Eves ND R Warburton DE Findlay MJ Resistance exercise, the Valsalva maneuver, and cerebrovascular transmural pressure Med Sci Sports Exerc 2003 35 65 68 12544637 \n14 Hellwig D Kuhn TJ Bauer BL List-Hellwig E Endoscopic treatment of septated chronic subdural hematoma Surg Neurol 1996 45 272 277 8638225 \n15 Huang CY Lee PH Lin SH Chuang MT Sun YT Hung YC Remote cerebellar hemorrhage following supratentorial craniotomy Neurol Res 2012 34 422 429 22664148 \n16 Hyam JA Turner J Peterson D Cerebellar haemorrhage after repeated burr hole evacuation for chronic subdural haematoma J Clin Neurosci 2007 14 83 86 17071089 \n17 Infuso L [Subarachnoid hemorrhage of unknown origin] Minerva Anestesiol 1998 64 149 153 9773644 \n18 Keller TM Chappell ET Spontaneous acute subdural hematoma precipitated by cocaine abuse: case report Surg Neurol 1997 47 12 14 discussion 14-15 8986158 \n19 Kim JK Kim SW Kim SH Intracerebral hemorrhage following evacuation of a chronic subdural hematoma J Korean Neurosurg Soc 2013 53 108 111 23560175 \n20 Korosue K Kondoh T Ishikawa Y Nagao T Tamaki N Matsumoto S Acute subdural hematoma associated with nontraumatic middle meningeal artery aneurysm : case report Neurosurgery 1988 22 411 413 3352892 \n21 Missori P Domenicucci M Sassun TE Tarantino R Peschillo S Alterations in the intracranial venous sinuses in spontaneous nontraumatic chronic subdural hematomas J Clin Neurosci 2013 20 389 393 23219821 \n22 Miyazaki T Matsumoto Y Ohta F Daisu M Moritake K A case of unknown origin subarachnoid hemorrhage immediately following drainage for chronic subdural hematoma Kurume Med J 2004 51 163 167 15373234 \n23 Modesti LM Hodge CJ Barnwell ML Intracerebral hematoma after evacuation of chronic extracerebral fluid collections Neurosurgery 1982 10 6 Pt 1 689 693 7110541 \n24 Mori K Maeda M Surgical treatment of chronic subdural hematoma in 500 consecutive cases : clinical characteristics, surgical outcome, complications, and recurrence rate Neurol Med Chir (Tokyo) 2001 41 371 381 11561347 \n25 Ogasawara K Ogawa A Okuguchi T Kobayashi M Suzuki M Yoshimoto T Postoperative hyperperfusion syndrome in elderly patients with chronic subdural hematoma Surg Neurol 2000 54 155 159 11077097 \n26 Park JS Hwang JH Park J Hamm IS Park YM Remote cerebellar hemorrhage complicated after supratentorial surgery : retrospective study with review of articles J Korean Neurosurg Soc 2009 46 136 143 19763216 \n27 Sambasivan M An overview of chronic subdural hematoma : experience with 2300 cases Surg Neurol 1997 47 418 422 9131021 \n28 Singla A Jacobsen WP Yusupov IR Carter DA Subdural evacuating port system (SEPS)--minimally invasive approach to the management of chronic/subacute subdural hematomas Clin Neurol Neurosurg 2013 115 425 431 22763191 \n29 Spetzler RF Wilson CB Weinstein P Mehdorn M Townsend J Telles D Normal perfusion pressure breakthrough theory Clin Neurosurg 1978 25 651 672 710017 \n30 Tindall GT Payne NS 2nd O'Brien MS Complications of surgery for subdural hematoma Clin Neurosurg 1976 23 465 482 975697 \n31 Toledo E Eynan N Shalit M Intracranial hypotension--an iatrogenic complication of vacuum drainage systems Acta Neurochir (Wien) 1980 52 55 59 7376946 \n32 Van Roost D Thees C Brenke C Oppel F Winkler PA Schramm J Pseudohypoxic brain swelling : a newly defined complication after uneventful brain surgery, probably related to suction drainage Neurosurgery 2003 53 1315 1326 discussion 1326-1327 14633298 \n33 Vogels RL Verstegen MJ van Furth WR Cerebellar haemorrhage after non-traumatic evacuation of supratentorial chronic subdural haematoma : report of two cases Acta Neurochir (Wien) 2006 148 Wien 993 996 16804644 \n34 Wasnick JD Lien CA Rubin LA Fraser RA Unexplained bradycardia during craniotomy closure : the role of intracranial hypotension Anesth Analg 1993 76 432 433 7818607\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1225-8245",
"issue": "57(5)",
"journal": "Journal of Korean Neurosurgical Society",
"keywords": "Chronic subdural hematoma; Head trauma; Remote cerebellar hemorrhage; Subarachnoid hemorrhage",
"medline_ta": "J Korean Neurosurg Soc",
"mesh_terms": null,
"nlm_unique_id": "101467054",
"other_id": null,
"pages": "379-85",
"pmc": null,
"pmid": "26113968",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports",
"references": "16028781;8638225;17071089;22763191;710017;7818607;20062580;23959412;14633298;23560175;18305890;8986158;19763216;7110541;3352892;16804644;15373234;23219821;2718794;1764228;11561347;16527766;12754345;19546844;7376946;12544637;9773644;11077097;15823679;22664148;975697;22249914;9131021;1167376",
"title": "Infrequent Hemorrhagic Complications Following Surgical Drainage of Chronic Subdural Hematomas.",
"title_normalized": "infrequent hemorrhagic complications following surgical drainage of chronic subdural hematomas"
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"abstract": "Primary carcinoma of the fallopian tube is a rare disease and has traditionally been managed in the same manner as epithelial ovarian cancer. However, unlike ovarian cancer, fallopian tube cancer is not routinely suspected and treatment may be delayed. The clinical presentations of seven cases of fallopian tube cancer emphasize the need for accurate assessment of symptoms to ensure early diagnosis and treatment of this disease.",
"affiliations": "David Grant USAF Medical Center, Travis Air Force Base, California.",
"authors": "Kimmel|K D|KD|;Chamberlain|D H|DH|;Bostrom|S G|SG|;Christman|J E|JE|",
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D002277:Carcinoma; D002291:Carcinoma, Papillary; D002296:Carcinosarcoma; D003131:Combined Modality Therapy; D005185:Fallopian Tube Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fallopian tube cancer.",
"title_normalized": "fallopian tube cancer"
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"abstract": "Immune-related adverse events (irAEs) is a term used to describe the various toxicities associated with immune checkpoint inhibitor (ICI) use. As this class of cancer immunotherapy grows, the diversity of documented irAEs also continues to expand. Ocular toxicities secondary to ICI use are relatively rare, with dry eye and uveitis as the most frequently reported ocular side effects. This article specifically investigates the relationship between ocular surface disease and ICI therapy through a review of the existing literature. Dry eye disease (DED), conjunctivitis, and keratitis were the most commonly reported irAEs affecting the ocular surface across the 29 studies reviewed. Keratoplasty graft rejection was also described in two case reports. Our review of eight clinical trials found the incidence of DED, the most common ocular surface irAE, to range from 1 to 4%. Nearly all cases of ocular surface irAEs were graded as mild or moderate in severity and were often self-limited or controlled with conservative treatment. Duration of checkpoint inhibitor use prior to onset of ocular surface side effects varied widely, ranging from days to months. Ocular surface toxicities associated with checkpoint immunotherapy appear to be under-reported and under-investigated. Further work remains to be done to investigate the full breadth of ocular surface pathologies and the molecular mechanisms by which these toxicities occur.",
"affiliations": "State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY, 11203, USA.;Department of Ophthalmology & Visual Sciences, University of Illinois at Chicago, 1855 W. Taylor St. M/C 648, Chicago, IL, 60612, USA.;State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY, 11203, USA.;Department of Ophthalmology, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY, 11203, USA. Electronic address: Jennifer.Park@downstate.edu.",
"authors": "Park|Royce B|RB|;Jain|Sandeep|S|;Han|Hui|H|;Park|Jennifer|J|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
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"doi": "10.1016/j.jtos.2021.02.004",
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"journal": "The ocular surface",
"keywords": "Conjunctivitis; Dry eye disease; Immune checkpoint inhibitor; Immune related adverse event; Keratitis; Ocular rosacea; Ocular surface disease; T cell",
"medline_ta": "Ocul Surf",
"mesh_terms": "D064420:Drug-Related Side Effects and Adverse Reactions; D005123:Eye; D005128:Eye Diseases; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy",
"nlm_unique_id": "101156063",
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"pubdate": "2021-04",
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"references": null,
"title": "Ocular surface disease associated with immune checkpoint inhibitor therapy.",
"title_normalized": "ocular surface disease associated with immune checkpoint inhibitor therapy"
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"abstract": "Pneumatosis intestinalis (PI) occurs when gas is discovered in the intestinal wall and is categorized into two types: primary PI which is idiopathic and mainly occurs in the colon, and secondary PI which occurs more often in the small bowel but has variable presentation and etiology. We report a case of a patient status post-orthotopic deceased liver transplantation complicated by a portal vein thrombus on chronic lactulose for portosystemic encephalopathy who presented due to pyelonephritis and persistent diarrhea. The patient underwent colonoscopy with random biopsies and subsequently developed acute sepsis with Escherichia coli bacteremia. The findings of PI were noted on computed tomography imaging obtained 5 days post-colonoscopy, due to persistent post-procedure abdominal pain. The patient was treated with discontinuation of lactulose, supportive care, and antibiotics for her bacteremia with resolution of her PI 3 days later. This suggests that a combination of factors may lead to the development of PI, and while some cases require emergent intervention including surgery, others may be treated conservatively. Awareness of risk factors that may precipitate PI and specific clinical predictors may help to both mitigate and manage PI appropriately.",
"affiliations": "Department of Internal Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA. jroy8806@gmail.com.;Division of Gastroenterology and Hepatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Gastroenterology and Hepatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Gastroenterology and Hepatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Gastroenterology and Hepatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.",
"authors": "Roy|Justin|J|http://orcid.org/0000-0002-9584-5027;Kang|Mitchell|M|;Stern|Benjamin|B|;Riley|Thomas|T|;Schreibman|Ian|I|",
"chemical_list": "D007792:Lactulose",
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"doi": "10.1007/s12328-021-01392-9",
"fulltext": null,
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"issn_linking": "1865-7265",
"issue": "14(4)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Colonoscopy; Intestinal emphysema; Lactulose; Pneumatosis cystoides intestinalis",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D001706:Biopsy; D003113:Colonoscopy; D005260:Female; D006801:Humans; D007792:Lactulose; D011006:Pneumatosis Cystoides Intestinalis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1152-1156",
"pmc": null,
"pmid": "33772734",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9530294;4929274;9250851;7572888;11713968;8943984;14923068;2375647;2013193;3516602;2671335;13580754;4938483;13345634;2311891;14031571;4365449;13752845;2192457;19918292;18925310;18657272;27106233;2714610;26190327;23198249;10587121;17885285;31692099;8425681;24797647;28917259;25531306;31694581;20871638",
"title": "Lactulose-induced pneumatosis intestinalis following colonoscopy: a case report.",
"title_normalized": "lactulose induced pneumatosis intestinalis following colonoscopy a case report"
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"abstract": "Tuberculosis is one of the top 10 causes of death worldwide according to the World Health Organization. Central nervous system involvement is usually the least common presentation of tuberculosis occurring in about 1% of all cases but yet can have very devastating outcomes. Lupus nephritis is one of the most common complications of systemic lupus erythematosus with up to two thirds of patients presenting with some degree of renal dysfunction. The mainstay of treatment is glucocorticoids; however, to sustain remission, steroid sparing agents such as cyclophosphamide, azathioprine and mycophenolate mofetil are used. Such patients, in addition to their baseline dysfunctional immune system, have a heightened risk of infections due to these drugs. In this article, we present a young woman who had recently been started on mycophenolate mofetil for control of class V lupus nephritis who presented with headaches, sinus pressure, and fevers. She had a protracted course of hospitalization as she failed to improve clinically and to respond to conventional therapy for acute bacterial sinusitis and meningitis. She was empirically started on antitubercular therapy 9 days after hospitalization. The diagnosis was not confirmed until day 18, the day results of cerebrospinal fluid acid-fast bacillus culture was reported. This case is reported to highlight the challenges in diagnosing Mycobacterium tuberculosis infection in an immunocompromised state and to demonstrate that its presentation can mimic numerous other conditions. Clinicians must maintain a high index of suspicion of Mycobacterium tuberculosis infection in such patients who present with nonspecific or unexplainable symptoms.",
"affiliations": "Maimonides Medical Center, Brooklyn, NY, USA.;Yeshiva University Albert Einstein College of Medicine, Bronx, NY, USA.;Yeshiva University Albert Einstein College of Medicine, Bronx, NY, USA.;Maimonides Medical Center, Brooklyn, NY, USA.;Maimonides Medical Center, Brooklyn, NY, USA.;Maimonides Medical Center, Brooklyn, NY, USA.;Maimonides Medical Center, Brooklyn, NY, USA.",
"authors": "Macauley|Precious|P|;Rapp|Mark|M|;Park|Sarah|S|;Lamikanra|Olaoluwatomi|O|;Sharma|Pratibha|P|;Marcelin|Michael|M|;Sharma|Kavita|K|",
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"doi": "10.1177/2324709618770226",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961877022610.1177_2324709618770226Case ReportMiliary Tuberculosis Presenting With Meningitis in a Patient Treated With Mycophenolate for Lupus Nephritis: Challenges in Diagnosis and Review of the Literature Macauley Precious MD1Rapp Mark BSc2Park Sarah BSc2Lamikanra Olaoluwatomi MBBS1Sharma Pratibha MBBS1Marcelin Michael MD1Sharma Kavita MBBS11 Maimonides Medical Center, Brooklyn, NY, USA2 Yeshiva University Albert Einstein College of Medicine, Bronx, NY, USAPrecious Macauley, Department of Internal Medicine, Maimonides Medical Center, 4802 10th Avenue, Brooklyn, NY 11219, USA. Email: preciousmacauley@yahoo.co.uk18 4 2018 Jan-Dec 2018 6 23247096187702269 11 2017 6 3 2018 18 3 2018 © 2018 American Federation for Medical Research2018American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Tuberculosis is one of the top 10 causes of death worldwide according to the World Health Organization. Central nervous system involvement is usually the least common presentation of tuberculosis occurring in about 1% of all cases but yet can have very devastating outcomes. Lupus nephritis is one of the most common complications of systemic lupus erythematosus with up to two thirds of patients presenting with some degree of renal dysfunction. The mainstay of treatment is glucocorticoids; however, to sustain remission, steroid sparing agents such as cyclophosphamide, azathioprine and mycophenolate mofetil are used. Such patients, in addition to their baseline dysfunctional immune system, have a heightened risk of infections due to these drugs. In this article, we present a young woman who had recently been started on mycophenolate mofetil for control of class V lupus nephritis who presented with headaches, sinus pressure, and fevers. She had a protracted course of hospitalization as she failed to improve clinically and to respond to conventional therapy for acute bacterial sinusitis and meningitis. She was empirically started on antitubercular therapy 9 days after hospitalization. The diagnosis was not confirmed until day 18, the day results of cerebrospinal fluid acid-fast bacillus culture was reported. This case is reported to highlight the challenges in diagnosing Mycobacterium tuberculosis infection in an immunocompromised state and to demonstrate that its presentation can mimic numerous other conditions. Clinicians must maintain a high index of suspicion of Mycobacterium tuberculosis infection in such patients who present with nonspecific or unexplainable symptoms.\n\nMycobacterium tuberculosislupus nephritisimmunosuppressionmycophenolate mofetilmiliary tuberculosiscover-dateJanuary-December 2018\n==== Body\nIntroduction\nTuberculosis (TB) is one of the top 10 causes of death worldwide according to the World Health Organization. In 2015, 10.4 million people became ill with a subsequent death toll of 1.8 million. Sixty-one percent of TB cases occur in Asia and 26% in occur in Africa.1 TB risk factors include advanced age, HIV infection, malnutrition, alcoholism, and other immunocompromised states.2,3 It is well known that patients with systemic lupus erythematosus (SLE) have a dysfunction of both innate and adaptive immune systems, which increases their risk of infections. This risk is further elevated by treatment with immunosuppressive agents.3 Evidence suggests that TB may be more prevalent among patients with SLE than within the general population. This increased prevalence is particularly apparent in areas where TB is endemic: with extrapulmonary TB being more common than pulmonary TB, this creates a challenge and delays diagnosis.3-5 The least common presentation of TB, occurring in approximately 1% of all cases, is central nervous system (CNS) involvement. Although it is rare, this presentation can have devastating outcomes.2\n\nLupus nephritis (LN) is one of the most common complications of SLE, with up to two thirds of patients presenting with some degree of renal dysfunction.6,7 Corticosteroids remain the mainstay of treatment of SLE and LN; however, while they are effective in controlling flares, the effect of corticosteroids on the long-term outcome of patients has not been proven. Maintenance of LN remission is achieved by one or a combination of the following agents: cyclophosphamide, azathioprine, mycophenolate mofetil (MMF), calcineurin inhibitors, and biologic agents.6,7 We present the case of a patient with LN, being treated with MMF who develops miliary TB.\n\nCase Presentation\nA 40-year-old Nepali female with a history of class V LN presented with 4 days of fevers, sinus pressure, chills, rigors, and an occipital headache. She had no cough, weight loss, night sweats, or sick contacts nor had she recently travelled. The patient’s medications included prednisone (20 mg daily for many years) and MMF 500 mg 3 times daily, which was started approximately 2 months prior to presentation. On presentation she was febrile to 103°F; complete blood count revealed no elevation in white blood cell counts but demonstrated neutrophilia at 87%. Computed tomography (CT) showed paranasal sinus inflammatory changes with partial opacification of the right ethmoid sinus and mucosal thickening of the bilateral ethmoid and right sphenoid sinuses. The patient was admitted for acute bacterial sinusitis and treated initially with ampicillin followed by the addition of doxycycline for community-acquired methicillin-resistant Staphylococcus aureus coverage. On the third day, sinus pressure had abated; however, the patient had persistent spiking fevers with occipital headache. Infectious Disease service was consulted on day 4 for evaluation and recommendations regarding persistent fever spikes in an immunocompromised patient. At this point, the patient had no sinus tenderness, neck stiffness, or nuchal rigidity. A lumbar puncture was performed and results suggested a partially treated bacterial meningitis (see Table 1). A lupus flare was ruled out as dsDNA and complement levels were within normal limits (see Table 2). On the same day (day 4), the patient was started on a 5-day course of vancomycin, cefepime, ampicillin, and acyclovir pending complete results of the cerebrospinal fluid (CSF) analysis. Magnetic resonance imaging (MRI) of the brain obtained due to persistent headaches revealed leptomeningeal enhancement in the folia of the cerebellum (Figure 1). The clinical picture of spiking fevers in an immunosuppressed patient, together with the CSF and imaging findings, raised suspicion of CNS TB or an opportunistic fungal infection.\n\nTable 1. CSF Results.\n\n\tAppearance\tGlucose\tProtein\tWBCs\tRBCs\t\nFirst CSF, day 4 of admission\tColorless/clear\t<10\t137\t426 (50% N, 46% L, 5% M)\t200\t\nSecond CSF, day 9 of admission\tColorless/clear\t<10\t169\t218 (differential not given but many lymphocytes)\t138\t\nAbbreviations: CSF, cerebrospinal fluid; WBCs, white blood cells; RBCs, red blood cells; N, neutrophils; L, lymphocytes; M, monocytes.\n\nTable 2. Inpatient Workup.\n\nInfectious\tCSF meningitis/encephalitis panel: no detection\t\n\t• Panel tests for Escherichia coli; Haemophilus influenza, Listeria monocytogenes, Neisseria meningitides, Streptococcus agalactiae, Streptococcus pneumoniae, cytomegalovirus, enterovirus; HSV-1, HSV-2, human herpesvirus 6, parechovirus; varicella zoster virus, and Cryptococcus neoformans\t\n\tBacterial:\t\n\t• Serum Quantiferon-TB Gold Test: negative\t\n\t• Procalcitonin: <0.05 ng/mL (0.00-0.04 ng/mL)\t\n\t• CSF: VRDL negative\t\n\t ○ Lyme borderline\t\n\t ○ CSF AFB smear—positive after 18 days\t\n\t ○ CSF cultures: (CSF 1) AFB detected in broth on day 18\t\n\t ○ Adenosine deaminase: 1.8 U/L (normal <7 U/L)\t\n\t• Sputum AFB smear: negative until post discharge\t\n\t• Bronchial lavage AFB smear: positive post discharge\t\n\t• Urine cultures ×4—no growth\t\n\t• Blood cultures ×10—no growth\t\n\t• Echocardiogram: no vegetations\t\n\tFungal:\t\n\t• CSF: Cryptococcus antigen A and B negative\t\n\t• CSF fungal cultures ×2—negative\t\n\t• Serum 1,3-B-D-glucan assay—negative\t\n\t• Bronchial lavage fungal—no growth\t\n\t• Histoplasma capsulatum and Coccidiodes immitis antibody negative, Aspergillus assay negative\t\n\tViral:\t\n\t• CSF: parvovirus antibody B19 IgM and IgG negative\t\n\t• HSV negative; JCV antibody positive\t\n\t• EBV IgG: positive, IgM negative\t\n\t• HIV1/2: negative by enzyme immunoassay\t\nNeoplastic\tCSF cytology negative for malignant cells\t\nRheumatologic\tComplement C3, CH50 and dsDNA—normal\t\nImaging\tDay 0: CT without contrast of head—suggestive of sinusitis and mucositis\nDay 8: MRI brain—small areas of leptomeningeal enhancement\nDay 10: CT chest, abdomen, and pelvis: no intraabdominal abscess, multiple tiny nodules scattered in bilateral lungs\nDay 22: MRI brain—stable mild leptomeningeal enhancement\t\nAbbreviation: CSF, cerebrospinal fluid; HSV, herpes simplex virus; AFB, acid-fast bacilli; IgM, immunoglobulin M; IgG, immunoglobulin G; EBV, Epstein-Barr virus; CT, computed tomography; MRI, magnetic resonance imaging.\n\nFigure 1. (Left) Axial contrast enhanced flair showing leptomeningeal enhancement in folia of the cerebellum (white arrow). (Right) Coronal contrast enhanced flair showing 0.5 cm nodule in the right inferior cerebellum (black arrow).\n\nOn day 9, a second lumbar puncture was performed and sent for analysis. The patient was started on empiric antitubercular therapy with rifampin, isoniazid, pyrazinamide, and ethambutol despite a negative QuantiFERON-TB Gold test (QTF-G), chest radiography showing no evidence of pulmonary involvement, and initially negative sputum acid-fast bacilli (AFB) smears. A CT angiography of the patient’s chest, abdomen, and pelvis revealed multiple tiny nodules scattered in bilateral lung fields (Figure 2), not observed in a CT chest scan performed 4 months earlier (Figure 3).\n\nFigure 2. Computed tomography angiography at current presentation. Black arrows indicate bilateral scattered nodules consistent with miliary tuberculosis.\n\nFigure 3. Computed tomography angiography 4 months prior to current presentation. Black arrow showing trace pleural effusion.\n\nOver the next few days the patient remained febrile with headaches; CSF and sputum cultures revealed no organism growth and malignant cells were absent in CSF cytology. Broad-spectrum antibiotics to cover bacterial and fungal meningitis were continued. On day 16, bronchoscopy with bronchoalveolar lavage was performed and samples sent for AFB smear, herpes simplex virus polymerase chain reaction and cryptococcal antigen.\n\nThe patient slowly became afebrile, with a decrease in the intensity of headaches and restoration of appetite, and on day 18, results from the first sample of CSF was positive for AFB, identified as Mycobacterium tuberculosis (MTB). The patient was discharged on day 25 after admission to follow-up with the Department of Health. After the patient’s discharge, sputum, CSF, and bronchial cultures were reported positive for MTB.\n\nDiscussion\nSLE patients have an increased risk of infections; TB in particular occurs in SLE patients at a rate of 3.6% to 5%, which is higher than in the general population.3,8 Glucocorticoids, the cornerstone of the management of SLE and numerous other autoimmune diseases, exert their effect through suppression of T-lymphocyte-mediated immunity, which takes approximately 21 days to become long lasting.8 Studies have shown that glucocorticoid doses below 5 mg per day do not confer an increased risk of developing infections.8 In one case series by Vargas et al of 23 SLE patients with CNS infections, 30.4% were diagnosed with MTB and their average daily dose was 28.9 mg of prednisone.9 This finding can be corroborated by the retrospective study conducted by Hou et al,5 who discovered that of the 19 patients who developed clinical TB only 6 (31.6%) were taking less than 20 mg of prednisone per day, and the average cumulative daily dose of prednisone was 37.7 mg.\n\nThe general consensus among major societies is that for class III and class IV LN (the 2 classes with active proliferative glomerulonephritis), therapy consists of steroids in addition to cyclophosphamide or MMF. However, the latter has increasingly been used as first-line therapy for LN due to its better safety profile and lower rates of relapse when compared with cyclophosphamide.6,10\n\nMMF is converted in vivo to mycophenolic acid, the active immunosuppressive agent that inhibits the synthesis of guanosine nucleotides, thereby depleting both T- and B-cell population. It is therefore no surprise that infections are a common complication as both humoral and cellular immunity are profoundly suppressed.11,12 However, when compared with the older agent cyclophosphamide, MMF causes less bone marrow suppression and hence is associated with less infectious complications.7,10 When compared with azathioprine, the other first-line agent in the treatment of LN, studies have not shown a difference in rates of infection.7,13 The exact increase in the risk of developing TB in SLE patients being treated with MMF has not yet been clearly investigated, although one case series by Bhattacharya et al showed 2 out of the 5 patients who developed TB were being treated with MMF. One of the patients was diagnosed with pulmonary TB and the other with brain tuberculomas.4 Several case reports looking at renal transplant recipients showed reactivation of latent TB once azathioprine was switched to MMF.11,14,15 In our patient, we have no tuberculin skin test (TST) to show prior status; however; the CT scan performed 4 months prior to this presentation showed no cavitary lesions, nodules, or opacifications. The pleural effusions were most likely due to the patient’s fluid overload at the time of the CT scan (Figure 3).\n\nThe challenges in diagnosing TB stem from the nonspecificity and extrapulmonary manifestations such as joint swelling, arthralgia, unexplained pulmonary infiltrates, dyspnea, fever, and cough. The differential diagnosis can include pleurisy, inflammatory arthritis, and cellulitis.4,5,16 The retrospective analysis by Balakrishnan et al17 in Mumbai found the average time to diagnosis to be 22.5 days, whereas it took over 60 days to reach a diagnosis according to Hou et al in Taiwan.5 In our patient, definitive diagnosis was made 18 days after presentation, although an empiric anti-TB regimen was started on day 8 as clinical suspicion was high.\n\nThe TST, which was originally the gold standard in the diagnosis of latent TB, has limitations, which include false positivity in individuals who received the Bacillus Calmette-Guerin (BCG) vaccine and false negativity in those who are chronically immunosuppressed.18 Our patient had received the BCG vaccine as a child in Nepal. QTF-G has been used to aid the diagnosis of latent tuberculosis infection as it possesses higher sensitivity than TST and better specificity in the BCG-vaccinated population.18,19 The QTF-G test assesses the response to synthetic overlapping peptides such as early secretory antigenic target-6 and culture filtrate protein-10 that are usually present in all MTB strains. These proteins which act as antigens are incubated with whole blood and stimulate the release of interferon-γ, which is measured by enzyme-linked immunosorbent assay.18,19 This test is not without its drawbacks; several studies have shown that a large proportion of SLE individuals show an indeterminate result when the QTF-G test is performed. One study by Takeda et al19 showed that 32.4% of SLE patients fell in this category. Factors that were associated with indeterminate results included lymphocytopenia and a high SLE disease activity index. Other proposed contributing factors are old age, hypoalbuminemia, and use of immunosuppressive agents. Our patient demonstrated nearly all of these traits, she had low serum albumin (between 1.8 and 2.8 g/dL), lymphocytopenia (percentages of as low as 7.2%), and was on long-term immunosuppressive agents. It is therefore safe to state that neither latent tuberculosis infection nor active TB in SLE patients can be diagnosed using the TST or the QTF-G assay.\n\nAnother emerging diagnostic tool is the adenosine deaminase (ADA) activity in CSF. ADA is an enzyme that converts the purine adenosine and deoxyadenosine to inosine and deoxyinosine, which are essential to the differentiation and proliferation of lymphocytes in cell-mediated immunity particularly in T lymphocytes.20 This test is mainly used when analyzing pleural fluid when there is a moderate to high suspicion of a tuberculous effusion; however, several studies have begun to utilize this test in the analysis of CSF in similar cases. There have been discrepancies in the cutoff values among these studies; for example, Agarwal et al20 found that a cutoff value of 10 IU/L yielded a sensitivity and specificity of 87.5% and 83.3%, respectively, whereas, the study by Raviraj et al21 proposed a lower cut-off of 6.65 IU/L with sensitivity and specificity of 85.3 and 84.3%, respectively. Ekermans et al22 used an even lower cutoff value of 2 IU/L and yielded sensitivity and specificity values of 85.9% and 77.7%, respectively. They also found that 13 out of 92 TB meningitis cases were missed initially. Our patient had a CSF ADA level of 1.8 IU/L, and our facility had a cutoff value of 7 IU/L, and using this value gives a false negative result and was not useful in ruling out the TB diagnosis.\n\nIt is extremely important to make a TB diagnosis in order to prevent the devastating outcomes that could arise as a consequence of the complications of disseminated TB infection particularly when the CNS is involved. TB in the CNS can manifest in 3 categories: subacute, chronic, or intracranial tuberculomas.23 The classic presentation is a prodrome of anorexia, low-grade fevers, fatigue, and headaches; not all individuals demonstrate signs of meningeal irritation. Our patient had nonspecific symptoms of headache and facial pain and had no neck stiffness or focal neurological deficits. The complications of CNS TB include cranial nerve palsies, hemiparesis, hemiplegia, and cerebrovascular accidents. A small subset of patients may demonstrate a syndrome of slowly progressive dementia, personality changes, and social withdrawal.3,23\n\nConclusion\nTaken together, the nonspecificity of symptoms, lack of classic radiologic evidence, and indeterminate serologic and laboratory test results that can be encountered in an SLE patient with TB should cause clinicians to maintain a high index of suspicion when a patient presents with nonspecific symptoms of fevers, chills, headache, and myalgias, especially once a lupus flare has been ruled out through the demonstration of low titers of dsDNA and normal levels of complement.\n\nThe authors would to thank Dr Evan Stein for the interpretation of the MRI findings and Dr Isaac Boyack for editing the figures.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n==== Refs\nReferences\n1 \nWorld Health Organization . Global tuberculosis report—2016 . http://apps.who.int/medicinedocs/documents/s23098en/s23098en.pdf. Accessed March 29, 2016 .\n2 \nCherian A Thomas SV. \nCentral nervous system tuberculosis . Afr Health Sci . 2011 ;11 :116 -127 .21572867 \n3 \nDoaty S Agrawal H Bauer E Furst DE. \nInfection and lupus: Which causes which? \nCurr Rheumatol Rep . 2016 ;18 :13 .26951251 \n4 \nBhattacharya PK Jamil M Roy A Talukdar KK. \nSLE and tuberculosis: a case series and review of literature . J Clin Diagn Res . 2017 ;11 :OR01 -OR03 .\n5 \nHou CL Tsai YC Chen LC Huang JL. \nTuberculosis infection in patients with systemic lupus erythematosus: pulmonary and extra-pulmonary infection compared . Clin Rheumatol . 2008 ;27 :557 -563 .17940720 \n6 \nJaryal A Vikrant S. \nCurrent status of lupus nephritis . Indian J Med Res . 2017 ;145 :167 -178 .28639592 \n7 \nKaballo BG Ahmed AE Nur MM Khalid IO Abu-Aisha H. \nMycophenolate mofetil versus azathioprine for maintenance treatment of lupus nephritis . Saudi J Kidney Dis Transpl . 2016 ;27 :717 -725 .27424688 \n8 \nYun JE Lee SW Kim TH et al \nThe incidence and clinical characteristics of Mycobacterium tuberculosis infection among systemic lupus erythematosus and rheumatoid arthritis patients in Korea . Clin Exp Rheumatol . 2002 ;20 :127 -132 .12051389 \n9 \nVargas PJ King G Navarra SV. \nCentral nervous system infections in Filipino patients with systemic lupus erythematosus . Int J Rheum Dis . 2009 ;12 :234 -238 .20374352 \n10 \nMok CC. \nMycophenolate mofetil for lupus nephritis: an update . Expert Rev Clin Immunol . 2015 ;11 :1353 -1364 .26364748 \n11 \nSkhiri H Guedri Y Souani Y et al \nPrimary tuberculosis 1 year after conversion from azathioprine to mycophenolate in recipient kidney transplantation: a case report . Transplant Proc . 2003 ;35 :2678 -2679 .14612069 \n12 \nRezaieyazdi Z Tavakoli T Khajehdaluee M Honarmand S. \nEfficacy of long-term maintenance therapy with mycophenolate mofetil in lupus nephritis . Springerplus . 2014 ;3 :638 .25392806 \n13 \nProkopenko E Scherbakova E Vatazin A Pasov S Budnikova N Agafonova S. \nDoes mycophenolate mofetil increase the incidence of infections in renal transplant recipients? \nDrugs Exp Clin Res . 2005 ;31 :199 -205 .16425976 \n14 \nMercadal L Foltz V Isnard-Bagnis C et al \nTuberculosis after conversion from azathioprine to mycophenolate mofetil in a long-term renal transplant recipient . Transplant Proc . 2005 ;37 :4241 -4243 .16387088 \n15 \nWaiser J Schötschel R Budde K Neumayer HH. \nReactivation of tuberculosis after conversion from azathioprine to mycophenolate mofetil 16 years after renal transplantation . Am J Kidney Dis . 2000 ;35 :E12 .10692297 \n16 \nTam LS Li EK Wong SM Szeto CC. \nRisk factors and clinical features for tuberculosis among patients with systemic lupus erythematosus in Hong Kong . Scand J Rheumatol . 2002 ;31 :296 -300 .12455821 \n17 \nBalakrishnan C Mangat G Mittal G Joshi VR. \nTuberculosis in patients with systemic lupus erythematosus . J Assoc Physicians India . 1998 ;46 :682 -683 .11229272 \n18 \nYilmaz N Zehra Aydin S Inanc N Karakurt S Direskeneli H Yavuz S. \nComparison of QuantiFERON-TB Gold test and tuberculin skin test for the identification of latent Mycobacterium tuberculosis infection in lupus patients . Lupus . 2012 ;21 :491 -495 .22140142 \n19 \nTakeda N Nojima T Terao C et al \nInterferon-gamma release assay for diagnosing Mycobacterium tuberculosis infections in patients with systemic lupus erythematous . Lupus . 2011 ;20 :792 -800 .21562022 \n20 \nAgarwal AK Bansal S Nand V. \nA hospital based study on estimation of adenosine deaminase activity (ADA) in cerebrospinal fluid (CSF) in various types of meningitis . J Clin Diagn Res . 2014 ;8 :73 -76 .\n21 \nRaviraj Henry RA Rao GG. \nDetermination and validation of a lower cut off value of cerebrospinal fluid adenosine deaminase (CSF-ADA) activity in diagnosis of tuberculous meningitis . J Clin Diagn Res . 2017 ;11 :OC22 -OC24 .\n22 \nEkermans P Dusé A George J. \nThe dubious value of cerebrospinal fluid adenosine deaminase measurement for the diagnosis of tuberculous meningitis . BMC Infect Dis . 2017 ;17 :104 .28143441 \n23 \nLeonard JM. \nCentral nervous system tuberculosis . Microbiol Spectr . 2017 ;5 . doi:10.1128/microbiolspec.TNMI7-0044-2017.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "6()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "Mycobacterium tuberculosis; immunosuppression; lupus nephritis; miliary tuberculosis; mycophenolate mofetil",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709618770226",
"pmc": null,
"pmid": "29707591",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "10692297;12051389;28281443;25392806;16425976;28384925;12455821;14612069;16387088;17940720;11229272;22140142;20374352;28639592;28143441;26364748;28571185;21562022;21572867;26951251;27424688;24701487",
"title": "Miliary Tuberculosis Presenting With Meningitis in a Patient Treated With Mycophenolate for Lupus Nephritis: Challenges in Diagnosis and Review of the Literature.",
"title_normalized": "miliary tuberculosis presenting with meningitis in a patient treated with mycophenolate for lupus nephritis challenges in diagnosis and review of the literature"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-04082",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"druga... |
{
"abstract": "Methaemoglobin is the oxidised form of haemoglobin containing iron in ferric state (Fe3+) that impairs oxygenation and produces metabolic acidosis. It may be hereditary or acquired (contact with external oxidising agents). Cyanosis, is the main symptom and itr does not respond to the external administration of oxygen. Co-oximetry helps in the final diagnosis. Methylene blue is the treatment of choice. We present the case of a 21 year old female with methaemoglobinemia after using topical lidocaine and prilocaine anaesthetic cream for laser depilation.",
"affiliations": "Servicio de Anestesiología y Reanimación, Hospital Universitario San Cecilio, Granada, España. plugona@hotmail.com",
"authors": "García-Saura|P L|PL|;Serrano Álvarez|C|C|",
"chemical_list": "D000779:Anesthetics, Local; D004364:Pharmaceutical Preparations",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-9356",
"issue": "60(5)",
"journal": "Revista espanola de anestesiologia y reanimacion",
"keywords": null,
"medline_ta": "Rev Esp Anestesiol Reanim",
"mesh_terms": "D000779:Anesthetics, Local; D005260:Female; D006204:Hair Removal; D006801:Humans; D007834:Lasers; D008708:Methemoglobinemia; D004364:Pharmaceutical Preparations; D055815:Young Adult",
"nlm_unique_id": "0134516",
"other_id": null,
"pages": "284-7",
"pmc": null,
"pmid": "22698859",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Methaemoglobinaemia in a healthy patient after using topical anaesthetic cream, for laser depilation.",
"title_normalized": "methaemoglobinaemia in a healthy patient after using topical anaesthetic cream for laser depilation"
} | [
{
"companynumb": "PHHY2015ES085334",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE\\PRILOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nB-type natriuretic peptide (BNP, nesiritide) has anti-fibrotic, anti-hypertrophic, anti-inflammatory, vasodilating, lusitropic and aldosterone-inhibiting properties but conventional doses of BNP cause hypotension, limiting its use in heart failure.\n\n\nOBJECTIVE\nTo determine whether infusion of low-dose BNP within 24 h of successful reperfusion for anterior acute myocardial infarction (AMI) would prevent adverse left ventricular (LV) remodelling and suppress aldosterone.\n\n\nMETHODS\nA translational proof-of-concept study was carried out to determine tolerability and biological activity of intravenous BNP at 0.003 and 0.006 microg/kg/min, without bolus started within 24 h of successful reperfusion for anterior AMI. 24 patients with first anterior wall ST elevation AMI and successful revascularisation were randomly assigned to receive 0.003 (n = 12) or 0.006 (n = 12) microg/kg/min of IV BNP for 72 h in addition to standard care during hospitalisation for anterior AMI.\n\n\nRESULTS\nBaseline characteristics, drugs and peak cardiac biomarkers for myocardial damage were similar between both groups. Infusion of BNP at 0.006 microg/kg/min resulted in greater biological activity than infusion at 0.003 microg/kg/min as measured by higher mean (SEM) plasma cGMP levels (8.6 (1) vs 5.5 (1) pmol/ml, p<0.05) and suppression of plasma aldosterone (8.0 (2) to 4.6 (1) ng/dl, p<0.05), which was not seen in the 0.003 microg/kg/min group. LV ejection fraction (LVEF) improved significantly from baseline to 1 month (40 (4)% to 54 (5)%, p<0.05) in the 0.006 group but not in the 0.003 group. Infusion of BNP at 0.006 microg/kg/min was associated with a decrease of LV end-systolic volume index (61 (9) to 43 (8) ml/m(2), p<0.05) at 1 month, which was not seen in the 0.003 group. No drug-related serious adverse events occurred in either group.\n\n\nCONCLUSIONS\n72 h infusion of low BNP at the time of anterior AMI is well tolerated and biologically active. Patients treated with low-dose BNP had improved LVEF and smaller LV end-systolic volume at 1 month.",
"affiliations": "Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN 55904, USA. chen.horng@mayo.edu",
"authors": "Chen|H H|HH|;Martin|F L|FL|;Gibbons|R J|RJ|;Schirger|J A|JA|;Wright|R S|RS|;Schears|R M|RM|;Redfield|M M|MM|;Simari|R D|RD|;Lerman|A|A|;Cataliotti|A|A|;Burnett|J C|JC|",
"chemical_list": "D000451:Mineralocorticoid Receptor Antagonists; D045283:Natriuretic Agents; D011994:Recombinant Proteins; D014665:Vasodilator Agents; D020097:Natriuretic Peptide, Brain",
"country": "England",
"delete": false,
"doi": "10.1136/hrt.2008.153916",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-6037",
"issue": "95(16)",
"journal": "Heart (British Cardiac Society)",
"keywords": null,
"medline_ta": "Heart",
"mesh_terms": "D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists; D009203:Myocardial Infarction; D045283:Natriuretic Agents; D020097:Natriuretic Peptide, Brain; D011994:Recombinant Proteins; D013318:Stroke Volume; D014665:Vasodilator Agents; D020257:Ventricular Remodeling",
"nlm_unique_id": "9602087",
"other_id": null,
"pages": "1315-9",
"pmc": null,
"pmid": "19447837",
"pubdate": "2009-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "17639095;12668699;14726474;12473544;16200208;6796783;12480813;15023890;15289388;12742984;17291931;17846293;11401117;12521930;17964349;16750705;10644581;11356434;12727932;11300426;15452027;12621153",
"title": "Low-dose nesiritide in human anterior myocardial infarction suppresses aldosterone and preserves ventricular function and structure: a proof of concept study.",
"title_normalized": "low dose nesiritide in human anterior myocardial infarction suppresses aldosterone and preserves ventricular function and structure a proof of concept study"
} | [
{
"companynumb": "US-JNJFOC-20131004674",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": null,
... |
{
"abstract": "Paradoxical reactions, including immune reconstitution inflammatory syndrome (IRIS), are common in patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB). Paradoxical reactions may confer substantial morbidity and mortality, especially in cases of central nervous system (CNS) TB, or through protracted usage of corticosteroids. No high-quality evidence is available to guide management in this scenario. Interleukin-1-mediated inflammation has been implicated in the pathophysiology of TB-IRIS. We describe two cases where anakinra (human recombinant interleukin-1 receptor antagonist) was used as steroid-sparing therapy for life-threatening protracted paradoxical inflammation in HIV-associated TB. In the first case of disseminated TB with lymphadenitis, protracted TB-IRIS led to amyloid A amyloidosis and nephrotic syndrome. In the second case of disseminated TB with cerebral tuberculomata, paradoxical inflammation caused unstable tuberculomata leading to profound neuro-disability. In both cases, paradoxical inflammation persisted for over a year. Protracted high-dose corticosteroid use led to adverse events yet failed to control inflammatory pathology. In both patients, anakinra successfully controlled paradoxical inflammation and facilitated withdrawal of corticosteroid therapy. Following anakinra therapy, nephrotic syndrome and neuro-disability resolved, respectively. Anakinra therapy for protracted paradoxical inflammation in HIV-associated TB may be a viable therapeutic option and warrants further research.",
"affiliations": "Department of Infection, Immunity and Cardiovascular Disease and Florey Institute, University of Sheffield, Sheffield, UK.;Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Infection, Immunity and Cardiovascular Disease and Florey Institute, University of Sheffield, Sheffield, UK.;Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.;Department of Rheumatology, Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.",
"authors": "Keeley|Alexander J|AJ|0000-0001-9386-1157;Parkash|Vivak|V|;Tunbridge|Anne|A|;Greig|Julia|J|;Collini|Paul|P|0000-0001-6696-6826;McKane|William|W|;Tattersall|Rachel S|RS|",
"chemical_list": "D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D053590:Interleukin 1 Receptor Antagonist Protein",
"country": "England",
"delete": false,
"doi": "10.1177/0956462420915394",
"fulltext": "\n==== Front\nInt J STD AIDS\nInt J STD AIDS\nSTD\nspstd\nInternational Journal of STD & AIDS\n0956-4624 1758-1052 SAGE Publications Sage UK: London, England \n\n10.1177/0956462420915394\n10.1177_0956462420915394\nCase Report\nAnakinra in the treatment of protracted paradoxical inflammatory reactions in HIV-associated tuberculosis in the United Kingdom: a report of two cases\nhttps://orcid.org/0000-0001-9386-1157Keeley Alexander J 1 Parkash Vivak 2 Tunbridge Anne 2 Greig Julia 2 https://orcid.org/0000-0001-6696-6826Collini Paul 1 McKane William 3 Tattersall Rachel S 4 \n1 Department of Infection, Immunity and Cardiovascular Disease and Florey Institute, University of Sheffield, Sheffield, UK\n\n2 Department of Infection and Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK\n\n3 Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK\n\n4 Department of Rheumatology, Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, UK\nAlexander J Keeley, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. Email: a.keeley@sheffield.ac.uk\n6 7 2020 \n7 2020 \n31 8 808 812\n19 11 2019 25 2 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Paradoxical reactions, including immune reconstitution inflammatory syndrome (IRIS), are common in patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB). Paradoxical reactions may confer substantial morbidity and mortality, especially in cases of central nervous system (CNS) TB, or through protracted usage of corticosteroids. No high-quality evidence is available to guide management in this scenario. Interleukin-1-mediated inflammation has been implicated in the pathophysiology of TB–IRIS. We describe two cases where anakinra (human recombinant interleukin-1 receptor antagonist) was used as steroid-sparing therapy for life-threatening protracted paradoxical inflammation in HIV-associated TB. In the first case of disseminated TB with lymphadenitis, protracted TB–IRIS led to amyloid A amyloidosis and nephrotic syndrome. In the second case of disseminated TB with cerebral tuberculomata, paradoxical inflammation caused unstable tuberculomata leading to profound neuro-disability. In both cases, paradoxical inflammation persisted for over a year. Protracted high-dose corticosteroid use led to adverse events yet failed to control inflammatory pathology. In both patients, anakinra successfully controlled paradoxical inflammation and facilitated withdrawal of corticosteroid therapy. Following anakinra therapy, nephrotic syndrome and neuro-disability resolved, respectively. Anakinra therapy for protracted paradoxical inflammation in HIV-associated TB may be a viable therapeutic option and warrants further research.\n\nTuberculosishuman immunodeficiency virusanakinraparadoxical inflammatory reactionsimmune reconstitution inflammatory syndrometypesetterts2\n==== Body\nIntroduction\nParadoxical inflammatory reactions in tuberculosis (TB) are well described, characterised by disordered inflammation to antigen of live or dead bacilli. Patients (2–23%) with TB, develop worsening or new inflammatory lesions despite anti-TB therapy.1 A paradoxical reaction in patients commencing antiretroviral therapy (ART) for human immunodeficiency virus (HIV) is termed TB-associated immune reconstitution inflammatory syndrome (TB–IRIS), occurring with a frequency of 5–57%.2\n\nModulating the immune response with corticosteroids improves survival in patients with TB-meningitis and reduces the frequency of TB–IRIS in immunosuppressed patients with HIV and TB co-infection.3,4 However, some patients experience paradoxical reactions for months and even years, despite appropriate TB therapy, and may require protracted use of corticosteroids with significant treatment morbidity. Successful use of several alternative agents including thalidomide, interferon gamma, montelukast and infliximab has been reported in case reports and small case series.5\n\nInterleukin-1 (IL-1) has been implicated as a key mediator of the excessive immune responses in TB–IRIS. IL-1 is a potent inflammatory mediator that potentiates cell-mediated immune responses, upregulates other inflammatory cytokines and promotes autoinflammation.6 IL-1 exists in alpha and beta forms, although their activity is similar. In patients with HIV and TB, those with IRIS, when compared to non-IRIS controls, have an increased IL-1-mediated cytokine profile that can be reduced by blocking IL-1 receptor signalling.7 Compared to non-IRIS patients and HIV controls without TB, patients with TB-meningitis and IRIS have higher levels of the IL-1β activator, caspase 1, in their CSF and peripheral transcriptomes associated with both IL-1- and neutrophil-mediated inflammation.8 IL-1 receptor antagonist has a physiological role in regulating IL-1-mediated inflammation.\n\nAnakinra is a recombinant IL-1 receptor antagonist which is licenced for the treatment of rheumatoid arthritis, the auto-inflammatory syndrome cryopyrin-associated periodic syndrome, systemic juvenile idiopathic arthritis and its counterpart adult onset Still’s disease. The licenced dose of anakinra is 100 mg once daily by subcutaneous (SC) injection. Clearance of anakinra is directly related to renal function.9 Anakinra is well tolerated although skin reactions at the site of injection are not uncommon. There is increasing evidence of safety even in severely immunocompromised and/or septic patients.10–12 Anakinra has no significant interactions with HIV or TB treatments. Furthermore, from extensive data, TB reactivation attributed to anakinra usage is extremely rare.13 We describe the successful treatment with anakinra of two patients with protracted paradoxical reactions in HIV-associated TB.\n\nCase 1\nA 33-year-old Ethiopian female patient presented in 2009 with a two-week history of fever, myalgia, night sweats and weight loss. On examination, the patient had widespread lymphadenopathy. She was diagnosed with HIV with a baseline CD4 cell count of 60 cells/mm3. Pus aspirated from a cervical lymph node was acid-alcohol fast bacilli (AFB) smear positive and grew fully-sensitive Mycobacterium tuberculosis on culture. Cross-sectional imaging revealed cervical, mediastinal and abdominal lymphadenopathy and splenic microabscesses, consistent with disseminated TB. She responded well to standard anti-TB therapy. After two weeks of anti-TB therapy, she was commenced on ART with tenofovir, emtricitabine and efavirenz. Four weeks after ART initiation, the patient developed pyrexia (39.2°C) with abdominal pain, nausea and vomiting. Following extensive investigation to exclude alternative opportunistic infections, malignancy and autoimmune disease, TB–IRIS was diagnosed with persistent large cervical and iliopsoas cold abscesses requiring recurrent aspiration. Pus samples were persistently positive for AFB and M. tuberculosis by polymerase chain-reaction but mycobacterial cultures were negative, consistent with protracted TB–IRIS. She commenced 60 mg prednisolone once daily. However, over the next three years, she was unable to tolerate a dose of less than 20 mg prednisolone daily, due to relapsing fever, malaise, abdominal pain and lymphadenopathy on each attempt to wean steroids. She received two courses (12 months and 9 months) of anti-TB therapy and developed multiple steroid-associated adverse effects including diabetes, cataracts, recurrent urinary tract infections and osteoporotic fractures. Therapy with montelukast 10 mg daily was used to attempt suppression of IRIS, but with limited effect. Two and a half years after her initial presentation, she developed nephrotic syndrome: low serum albumin (21 g/L), significant proteinuria (10.5 g/day) and peripheral oedema with preserved renal function. A diagnosis of amyloid A (AA) amyloidosis was made on renal biopsy, which showed mesangial and vascular amyloid deposition on sirius red staining, dichroic birefringence under polarised light and 10 nm mesangial fibrils. Immunofluorescence for amyloid P demonstrated glomerular staining and no evidence of Kappa/Lambda clonality. She had a tenfold rise in serum amyloid A to C-reactive protein (CRP) ratio, with a moderate renal and splenic amyloid load on scinitigraphy with radiolabelled serum amyloid P. Positron emission tomography demonstrated highly metabolically active cervical, mediastinal and abdominal lymph nodes. Histology from a supraclavicular lymph node showed non-specific chronic inflammatory changes only and no evidence of malignancy or Castleman disease. Pus from this lymph node remained AFB positive, with no mycobacterial growth on culture. She was referred to the National Amyloid Centre UK, where she was assessed as being in the worst prognostic octile for AA amyloidosis. Anakinra was proposed as a potential steroid sparing agent to control her pro-inflammatory process, due to its biological plausibility for both AA amyloidosis and IRIS and its rapid onset of action. In conjunction with the local multidisciplinary team including regional HIV, rheumatology and nephrology specialists, she was commenced on anakinra in June 2013, at a dose of 100 mg SC daily. Within three months of starting anakinra, there was a discernible improvement in her malaise, widespread painful lymphadenopathy and quality of life. Her inflammatory markers and proteinuria normalised (Figure 1(a)). Steroids were successfully weaned off over a year. After six years of anakinra therapy (subsequently reduced to 100 mg on alternate days at five years), and with stable calcified lymph node disease on cross-sectional imaging, an attempt was made to stop anakinra. However, 72 h after cessation, there was a rapid recurrence of abdominal pain, fever and malaise with associated rise in CRP (from 0.5 to 34 mg/L) and erythrocyte sedimentation rate (to 43 mm/h). Anakinra was re-initiated initially at 100 mg daily for two weeks, achieving control of symptoms and normalisation of inflammatory markers (Figure 2). She will remain on 100 mg anakinra on alternate days lifelong.\n\nFigure 1. (a) Case 1 – Graph demonstrating progress of 24-h urine protein excretion, serum amyloid A (SAA) protein and serum C-reactive protein (CRP) before and after initiation of anakinra therapy. Case 2 – Serial T2 weighted MRI brain scans at baseline (b), 18 months (c) and three years (d) into illness, demonstrating progressive and unstable tuberculomata throughout both hemispheres until 18 months, with subsequent resolution following anakinra therapy.\n\nFigure 2. Patient perspectives; each patient was asked to describe their experience with anakinra.\n\nCase 2\nA 41-year-old male teacher from Zimbabwe presented in 2016 with one month of fever, sweats and headache. Medical history included pulmonary TB (2005) and HIV with an undetectable viral load and a CD4 cell count of 275 cells/mm3 on tenofovir, emtricitabine and efavirenz ART. He was haemodynamically stable with unremarkable examination and no neurological deficit. Isoniazid monoresistant TB was diagnosed via culture from bronchoalveolar lavage, with multiple miliary nodules throughout both lung fields on cross-sectional imaging. Magnetic resonance imaging (MRI) of his brain revealed numerous foci of parenchymal high T2 signal in the right posterior and left medulla, the pons bilaterally and both cerebellar hemispheres, consistent with tuberculomata (Figure 1(b)). Lumbar puncture was acellular with mild protein rise of 0.61 g/L and normal glucose. He had been commenced empirically on rifampicin, isoniazid, ethambutol, pyrazinamide, moxifloxacin, capreomycin and cycloserine (given a history of TB treated in South Africa), alongside dexamethasone 18 mg (0.3 mg/kg) daily with a standard wean (reducing by 0.1 mg/kg per week).14 Two weeks into treatment, his headache worsened and he developed new left-sided weakness and paraesthesia. MRI brain confirmed an increase in number and size of the lesions present requiring adjustment of dexamethasone back to 18 mg daily. Brain biopsy demonstrated a necrotising granuloma; AFB were visualised but there was no mycobacterial growth, consistent with a paradoxical reaction. Following TB culture and sensitivity results, his TB regimen was rationalised to rifampicin, pyrazinamide, moxifloxacin and ethambutol. After four months, he was discharged with a dose of 8 mg dexamethasone daily, with a plan to wean by 1 mg monthly. At month 9 and at month 17, he required readmission for ataxia, left hemiplegia and expressive dysphasia, with significant functional and cognitive impairment. He was unable to live independently. On both occasions, MRI demonstrated worsening oedema and unstable tuberculomata throughout both hemispheres, brain stem and cerebellum (Figure 1(c)), prompting recommencement of dexamethasone, 10 mg daily. Over this period, he developed Cushingoid appearance and low mood. Thalidomide was trialled at month 17; however, it was withdrawn one month later due to peripheral neuropathy. Anakinra, 100 mg SC, was then initiated at 18 months as a steroid sparing agent. He remained on anakinra and weaned off corticosteroids over the next 18 months (36 months total duration) while he completed two years of anti-TB therapy with rifampicin, pyrazinamide, moxifloxacin and ethambutol. Since initiation of anakinra, there have been no new tuberculomata and the existing lesions have resolved (Figure 1(d)). Furthermore, his level of function and cognition has improved significantly. He lives independently and can mobilise with a stick with only mild expressive language deficits (Figure 2). Anakinra has been reduced to 100 mg on alternate days after two years.\n\nDiscussion\nWe have described two cases of paradoxical inflammation in TB that were insufficiently controlled by corticosteroid therapy and led to significant morbidity until the introduction of the IL-1 receptor antagonist, anakinra. Paradoxical reactions and IRIS are the cause of substantial morbidity and occasional mortality in HIV/TB co-infection, especially in TB of the CNS, if prolonged corticosteroid is required, or if uncontrolled inflammation leads to AA amyloidosis.15 IL-1-mediated inflammation has been implicated in the pathogenesis of TB–IRIS in HIV in both CNS and non-CNS disease.7,8 In the two cases presented here, anakinra was used to achieve control of inflammation and to reduce and stop steroids in patients at risk of death or serious morbidity (in part due to high steroid requirements) with protracted paradoxical reactions to TB. We suggest that through down-regulating IL-1-mediated inflammation, anakinra presents a viable treatment option for refractory paradoxical inflammation in TB. Further research to evaluate the therapeutic role of anakinra, particularly in less well-resourced health systems with a high burden of HIV/TB co-infection is required.\n\nAcknowledgements\nThe authors would like to acknowledge both patients for their perseverance in the face of such an adverse journey, and for consenting to share their story; the UK National Amyloidosis Centre, particularly Dr Helen Lachmann, for their outstanding clinical management and guidance in case 1.\n\nDeclaration of conflicting interests\nThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding\nThe authors received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iDs\nAlexander J Keeley https://orcid.org/0000-0001-9386-1157\n\nPaul Collini https://orcid.org/0000-0001-6696-6826\n==== Refs\nReferences\n1 Bell LC Breen R Miller RF , et al\nParadoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis\n. Int J Infect Dis \n2015 ; \n32 : 39 –45\n.25809754 \n2 Namale PE Abdullahi LH Fine S , et al\nParadoxical TB-IRIS in HIV-infected adults: a systematic review and meta-analysis\n. Future Microbiol \n2015 ; \n10 : 1077 –1099\n.26059627 \n3 Prasad K Singh MB Ryan H. \nCorticosteroids for managing tuberculous meningitis\n. Cochrane Database of Syst Rev \n2016 ; 1 –64\n.27346984 \n4 Meintjes G Stek C Blumenthal L , et al\nPrednisone for the prevention of paradoxical tuberculosis-associated IRIS\n. N Engl J Med \n2018 ; \n379 : 1915 –1925\n.30428290 \n5 Davis A Meintjes G Wilkinson RJ. \nTreatment of tuberculous meningitis and its complications in adults\n. Curr Treat Options Neurol \n2018 ; \n20 : 5 .29492737 \n6 Sims JE Smith DE. \nThe IL-1 family: regulators of immunity\n. Nat Rev Immunol \n2010 ; \n10 : 89 –102\n.20081871 \n7 Lai RPJ Meintjes G Wilkinson KA , et al\nHIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling\n. Nat Commun \n2015 ; \n6 : 8451 .26399326 \n8 Marais S Lai RPJ Wilkinson KA , et al\nInflammasome activation underlying central nervous system deterioration in HIV-associated tuberculosis\n. J Infect Dis \n2017 ; \n215 : 677 –686\n.27932622 \n9 Yang BB Baughman S Sullivan JT. \nPharmacokinetics of anakinra in subjects with different levels of renal function\n. Clin Pharmacol Ther \n2003 ; \n74 : 85 –94\n.12844139 \n10 Kyriazopoulou E Leventogiannis K Norrby-Teglund A , et al\nMacrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis\n. BMC Med \n2017 ; \n15 : 172 .28918754 \n11 Shakoory B Carcillo JA Chatham WW , et al\nInterleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial\n. Crit Care Med \n2016 ; \n44 : 275 –281\n.26584195 \n12 Eloseily EM Weiser P Crayne CB , et al\nBenefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis\n. Arthritis Rheumatol \n2020 ; \n72 : 326 –334\n.31513353 \n13 Winthrop KL Mariette X Silva JT , et al\nESCMID study group for infections in compromised hosts (ESGICH) consensus document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors\n). Clin Microbiol Infect \n2018 ; \n24 : S21 –S40\n.29447987 \n14 Thwaites GE Bang ND Dung NH , et al\nDexamethasone for the treatment of tuberculous meningitis in adolescents and adults\n. N Engl J Med \n2004 ; \n351 : 1741 –1751\n.15496623 \n15 Brown CS Smith CJ Breen RA , et al\nDeterminants of treatment-related paradoxical reactions during anti-tuberculosis therapy: a case control study\n. BMC Infect Dis \n2016 ; \n16 : 479 .27600661\n\n",
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"journal": "International journal of STD & AIDS",
"keywords": "Tuberculosis; anakinra; human immunodeficiency virus; immune reconstitution inflammatory syndrome; paradoxical inflammatory reactions",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary; D006113:United Kingdom",
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"title": "Anakinra in the treatment of protracted paradoxical inflammatory reactions in HIV-associated tuberculosis in the United Kingdom: a report of two cases.",
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"abstract": "OBJECTIVE\nThe objective of this article is to present a case of improved outcome of apathy syndrome with aripiprazole.\n\n\nMETHODS\nA 42-year-old man with depression and seizure disorder had significant apathy that did not respond to carbamazepine, sertraline, and topiramate. Apathy was assessed using Apathy Evaluation Scale. Discontinuation of carbamazepine did not alleviate apathy. Aripiprazole, a novel antipsychotic with partial agonistic activity at dopamine D2 receptors, was introduced and the dose adjusted to 15mg a day. The patient showed significant improvement in apathy after six weeks of therapy with aripiprazole.\n\n\nCONCLUSIONS\nDepression is often mistaken for apathy, which is different in symptoms, presentation, and treatment options. Selective serotonin reuptake inhibitors are known to cause or increase symptoms of apathy in some patients. Recent evidence suggests that dopamine receptor agonists can be helpful in treatment of apathy. Apathy significantly improved in this patient after initiation of aripiprazole.\n\n\nCONCLUSIONS\nAripiprazole may be useful for treatment of apathy syndrome. Its role in treatment of apathy requires further investigation in clinical trials.",
"affiliations": "Dr. Monga is from Banner Thunderbird Medical Center, Glendale, Arizona, and Dr. Padala is from the Central Arkansas Veteran's Healthcare System Geriatric Research Education and Clinical Center, Little Rock, Arkansas.;Dr. Monga is from Banner Thunderbird Medical Center, Glendale, Arizona, and Dr. Padala is from the Central Arkansas Veteran's Healthcare System Geriatric Research Education and Clinical Center, Little Rock, Arkansas.",
"authors": "Monga|Varun|V|;Padala|Prasad R|PR|",
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"issue": "12(9-10)",
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"keywords": "Aripiprazole; apathy; depression",
"medline_ta": "Innov Clin Neurosci",
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"title": "Aripiprazole for Treatment of Apathy.",
"title_normalized": "aripiprazole for treatment of apathy"
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"abstract": "OBJECTIVE\nOur objective was to evaluate the long-term efficacy, safety, and immunogenicity of the infliximab biosimilar, PF-06438179/GP1111 (PF-SZ-IFX), in patients with rheumatoid arthritis (RA) who continued biosimilar treatment throughout 78 weeks or who switched from reference infliximab (Remicade®) sourced from the EU (IFX-EU) at week 30 or week 54 in the REFLECTIONS B537-02 study.\n\n\nMETHODS\nIn this phase III, double-blind, active-controlled study, patients with moderate-to-severe active RA were initially randomized to PF-SZ-IFX or IFX-EU, each with methotrexate (treatment period [TP] 1; N = 650). At week 30, patients receiving PF-SZ-IFX continued PF-SZ-IFX; patients receiving IFX-EU were re-randomized to continue IFX-EU or switch to PF-SZ-IFX (TP2; n = 566). From weeks 54 to 78, all patients received open-label treatment with PF-SZ-IFX (TP3; n = 505). Efficacy, safety, and immunogenicity data were analyzed during TP3.\n\n\nRESULTS\nEfficacy was sustained and comparable across groups at week 78, with American College of Rheumatology criteria for ≥ 20% clinical improvement response rates of 75.9% (biosimilar group), 77.8% (week 30 switch group), and 68.3% (week 54 switch group). The incidence of treatment-emergent adverse events was 28.9%, 29.4%, and 30.2%, respectively. The proportion of patients who were antidrug antibody (ADA) positive and neutralizing antibody positive (as a percentage of ADA-positive patients) was stable and comparable between groups.\n\n\nCONCLUSIONS\nResults to week 78 continue to support the efficacy, safety, and immunogenicity of PF-SZ-IFX in patients with moderate-to-severe active RA. There were no clinically meaningful differences between groups, independent of a single treatment transition from IFX-EU to PF-SZ-IFX at week 30 or week 54.\n\n\nBACKGROUND\nNCT02222493.",
"affiliations": "Metroplex Clinical Research Center, Dallas, TX, USA. arthdoc@aol.com.;Universidade Federal do Paraná, Rua General Carneiro, 181-Alto Da Glória, Curitiba, PR, 80060-900, Brazil.;Toho University, 2-22-36, Ohashi Meguro-ku, Tokyo, 153-8515, Japan.;Altoona Center for Clinical Research, Duncansville, PA, USA.;Department of Medicine, Medical Center Manila, University of the Philippines, Manila, Philippines.;Pfizer Inc, Collegeville, PA, USA.;Pfizer Inc, La Jolla, CA, USA.;Pfizer R&D UK, Ltd, Sandwich, Kent, UK.;Pfizer Inc, Andover, MA, USA.;Biopharmaceuticals, Hexal AG (a Sandoz company), Holzkirchen, Germany.;Schlosspark-Klinik University Medicine, Heubnerweg 2, 14059, Berlin, Germany.",
"authors": "Cohen|Stanley B|SB|;Radominski|Sebastiao C|SC|;Kameda|Hideto|H|;Kivitz|Alan J|AJ|;Tee|Michael|M|;Cronenberger|Carol|C|;Zhang|Min|M|;Hackley|Sarah|S|;Rehman|Muhammad I|MI|;von Richter|Oliver|O|;Alten|Rieke|R|",
"chemical_list": "D018501:Antirheumatic Agents; D059451:Biosimilar Pharmaceuticals; C000630865:GP1111; D000069285:Infliximab; D008727:Methotrexate",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40259-019-00403-z",
"fulltext": "\n==== Front\nBioDrugs\nBioDrugs\nBiodrugs\n1173-8804 1179-190X Springer International Publishing Cham \n\n31939063\n403\n10.1007/s40259-019-00403-z\nOriginal Research Article\nLong-term Efficacy, Safety, and Immunogenicity of the Infliximab (IFX) Biosimilar, PF-06438179/GP1111, in Patients with Rheumatoid Arthritis After Switching from Reference IFX or Continuing Biosimilar Therapy: Week 54–78 Data From a Randomized, Double-Blind, Phase III Trial\nCohen Stanley B. arthdoc@aol.com 1 Radominski Sebastiao C. 2 Kameda Hideto 3 Kivitz Alan J. 4 Tee Michael 5 Cronenberger Carol 6 Zhang Min 7 Hackley Sarah 8 Rehman Muhammad I. 9 von Richter Oliver 10 Alten Rieke 11 1 grid.477482.aMetroplex Clinical Research Center, Dallas, TX USA \n2 grid.20736.300000 0001 1941 472XUniversidade Federal do Paraná, Rua General Carneiro, 181-Alto Da Glória, Curitiba, PR 80060-900 Brazil \n3 grid.265050.40000 0000 9290 9879Toho University, 2-22-36, Ohashi Meguro-ku, Tokyo, 153-8515 Japan \n4 grid.477005.1Altoona Center for Clinical Research, Duncansville, PA USA \n5 grid.11159.3d0000 0000 9650 2179Department of Medicine, Medical Center Manila, University of the Philippines, Manila, Philippines \n6 grid.410513.20000 0000 8800 7493Pfizer Inc, Collegeville, PA USA \n7 grid.410513.20000 0000 8800 7493Pfizer Inc, La Jolla, CA USA \n8 Pfizer R&D UK, Ltd, Sandwich, Kent, UK \n9 grid.410513.20000 0000 8800 7493Pfizer Inc, Andover, MA USA \n10 grid.476364.4Biopharmaceuticals, Hexal AG (a Sandoz company), Holzkirchen, Germany \n11 grid.492066.f0000 0004 0389 4732Schlosspark-Klinik University Medicine, Heubnerweg 2, 14059 Berlin, Germany \n14 1 2020 \n14 1 2020 \n2020 \n34 2 197 207\n© The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Objective\nOur objective was to evaluate the long-term efficacy, safety, and immunogenicity of the infliximab biosimilar, PF-06438179/GP1111 (PF-SZ-IFX), in patients with rheumatoid arthritis (RA) who continued biosimilar treatment throughout 78 weeks or who switched from reference infliximab (Remicade®) sourced from the EU (IFX-EU) at week 30 or week 54 in the REFLECTIONS B537-02 study.\n\nMethods\nIn this phase III, double-blind, active-controlled study, patients with moderate-to-severe active RA were initially randomized to PF-SZ-IFX or IFX-EU, each with methotrexate (treatment period [TP] 1; N = 650). At week 30, patients receiving PF-SZ-IFX continued PF-SZ-IFX; patients receiving IFX-EU were re-randomized to continue IFX-EU or switch to PF-SZ-IFX (TP2; n = 566). From weeks 54 to 78, all patients received open-label treatment with PF-SZ-IFX (TP3; n = 505). Efficacy, safety, and immunogenicity data were analyzed during TP3.\n\nResults\nEfficacy was sustained and comparable across groups at week 78, with American College of Rheumatology criteria for ≥ 20% clinical improvement response rates of 75.9% (biosimilar group), 77.8% (week 30 switch group), and 68.3% (week 54 switch group). The incidence of treatment-emergent adverse events was 28.9%, 29.4%, and 30.2%, respectively. The proportion of patients who were antidrug antibody (ADA) positive and neutralizing antibody positive (as a percentage of ADA-positive patients) was stable and comparable between groups.\n\nConclusions\nResults to week 78 continue to support the efficacy, safety, and immunogenicity of PF-SZ-IFX in patients with moderate-to-severe active RA. There were no clinically meaningful differences between groups, independent of a single treatment transition from IFX-EU to PF-SZ-IFX at week 30 or week 54.\n\nTrial Registration Number\nNCT02222493.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s40259-019-00403-z) contains supplementary material, which is available to authorized users.\n\nhttp://dx.doi.org/10.13039/100004319Pfizerissue-copyright-statement© Springer Nature Switzerland AG 2020\n==== Body\nKey Points\n\nPatients with moderate-to-severe active rheumatoid arthritis (RA) receiving PF-06438179/GP1111 (PF-SZ-IFX), an infliximab biosimilar, experienced no clinically meaningful differences in efficacy, safety, or immunogenicity, regardless of whether they were maintained on PF-SZ-IFX throughout 78 weeks of treatment, or following single treatment transitions from reference infliximab (Remicade®) sourced from the EU (IFX-EU) to PF-SZ-IFX at week 30 or at week 54.\t\nPF-SZ-IFX was well-tolerated for up to 78 weeks of treatment and displayed a safety profile consistent with that of infliximab.\t\nThese findings provide long-term clinical data for PF-SZ-IFX to add to the “totality of the evidence” supporting the biosimilarity of PF-SZ-IFX to reference infliximab and its use in the other eligible indications for which reference infliximab is authorized.\t\n\n\n\nIntroduction\nThe chimeric monoclonal antibody infliximab (Remicade®; Janssen Biotech, Horsham, PA, USA; Janssen Biologics B.V., Leiden, the Netherlands) is a tumor necrosis factor (TNF)-α inhibitor approved for the treatment of a range of immune-related inflammatory diseases [1–3]. In the two decades since the initial licensing of infliximab, its efficacy and safety have been well-established in diverse patient populations [4–8]. However, high direct costs, constrained healthcare budgets, and stringent reimbursement criteria mean that access to biologic drugs such as infliximab may be limited for some patients for whom this treatment is recommended [9].\n\nA biosimilar is a biologic agent that is concluded to be highly similar to a licensed reference biologic drug [10, 11]. To obtain regulatory approval, a biosimilar undergoes rigorous comparative evaluation with the reference biologic. This biosimilarity exercise includes analytical (structural and functional) characterization and assessment of clinical pharmacokinetics and safety, often conducted in healthy subjects (and preceded, if required, by nonclinical studies). This is followed by a comparative clinical study to confirm that any differences identified earlier in the development program are not clinically meaningful with regard to efficacy, safety, pharmacokinetics, and immunogenicity. By choosing a relevant patient population, confirmatory evidence obtained from this trial forms the basis for extrapolation of data for the biosimilar and its authorization in other indications for which the reference product is approved, without the need to perform additional clinical trials [10, 11].\n\nOriginally developed by Pfizer, PF-06438179/GP1111 (PF-SZ-IFX) is an infliximab biosimilar that is approved in the EU [12], Japan [13], the USA [14], and Brazil [15] for all eligible indications of reference infliximab (Remicade®) in each region. In preclinical studies, when compared with reference infliximab, PF-SZ-IFX was shown to have an identical primary amino acid sequence and similar biologic activity, including binding to TNF and inhibition of TNF-induced cell apoptosis in vitro [16]; in studies conducted in healthy subjects, PF-SZ-IFX also exhibited similarity to reference infliximab in its pharmacokinetic, safety, and immunogenicity profiles [17].\n\nIn view of the relatively truncated development pathway with respect to that for the reference biologic, biosimilars offer potential savings on cost, and their adoption can expand patients’ access to effective biologic therapy, potentially providing considerable health benefits from both a patient and a societal perspective [18–23]. Implementation of postmarketing pharmacovigilance or risk-management plans is frequently a key regulatory requirement of biosimilar manufacturers [24]. While such initiatives greatly expand the knowledge of and experience with their products over time, acquiring data on switching and on the longer-term efficacy and safety of biosimilars in the clinical trial setting (beyond that required to support regulatory approval) is valuable in instilling patient and clinician confidence in their use.\n\nREFLECTIONS B537-02 was a phase III, double-blind, randomized, active-controlled 78-week trial conducted to compare the efficacy, safety, and immunogenicity of reference infliximab sourced from the EU (IFX-EU) and PF-SZ-IFX in patients with moderate-to-severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate. The therapeutic equivalence of IFX-EU and PF-SZ-IFX was confirmed in the initial 30-week treatment period (TP) of the study (TP1), as the 95% confidence intervals (CIs) for the treatment difference in the primary endpoint (American College of Rheumatology [ACR] criteria for ≥ 20% clinical improvement [ACR20] response at week 14) between IFX-EU and PF-SZ-IFX were within prespecified margins [25]. Findings from TP2 (30–54 weeks) showed that similarity between IFX-EU and PF-SZ-IFX was maintained for up to 54 weeks and was not influenced by a single, blinded transition from IFX-EU to PF-SZ-IFX at 30 weeks [26]. Here, we present longer-term efficacy, safety, and immunogenicity results from weeks 54 to 78 (TP3), in which all patients received open-label treatment with PF-SZ-IFX.\n\nMethods\nThe methodology of the REFLECTIONS B537-02 study (ClinicalTrials.gov identifier NCT02222493; EudraCT number 2013-004148-49) has been described in detail in previous publications [25, 26] and is briefly summarized here.\n\nStudy Conduct\nThe study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with International Conference on Harmonisation Good Clinical Practice guidelines. The independent ethics committee or institutional review board for each study center approved the final study protocol; an independent data monitoring committee was responsible for monitoring safety and study conduct during the blinded portion of the study. All patients provided written informed consent before study entry (no additional informed consent was required because the three treatment periods were part of the same study).\n\nPatients\nEligibility criteria have been described previously [25]. Briefly, eligible patients were adults (aged ≥ 18 years) who satisfied the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA for ≥ 4 months and ACR classes I–III functional status, based on the 1991 revised criteria [27, 28]. They had moderate-to-severe active RA, with six or more tender and six or more swollen joints and a high-sensitivity C-reactive protein (hs-CRP) level ≥ 10 mg/L despite treatment with oral or parenteral methotrexate at doses of 10–25 mg/week for ≥ 12 weeks. Patients were excluded if they were currently receiving or had previously received treatment with infliximab or a lymphocyte-depleting therapy (e.g., rituximab). Treatment with up to two doses of a nondepleting, non-infliximab biologic was permitted if the biologic had been discontinued ≥ 12 weeks or five half-lives (whichever was longer) before the patient received the first dose of study drug.\n\nStudy Design and Treatments\nThis multinational, randomized, double-blind, active-controlled study comprised three TPs (Fig. 1). At the start of TP1, patients stratified by geographic region were randomized (1:1) to receive blinded treatment with PF-SZ-IFX or IFX-EU at an intravenous dose of 3 mg/kg administered at weeks 0, 2, and 6, and then every 8 weeks; TP1 ended with the completion of week-30 pre-dose assessments. The treatment dose could be increased to 5 mg/kg, and the escalated dose maintained, in patients with an inadequate response at or after week 14. At week 30, the beginning of TP2, patients treated with PF-SZ-IFX in TP1 continued to receive PF-SZ-IFX every 8 weeks; patients treated with IFX-EU in TP1 were re-randomized (1:1), without stratification and in a blinded fashion, to either continue receiving IFX-EU or switch to PF-SZ-IFX; TP2 ended with the completion of week-54 pre-dose assessments. At week 54, the beginning of TP3, all patients received open-label treatment with PF-SZ-IFX, which was continued until the end of the study; the last study dose in TP3 was administered at week 70, and the last study visit was at week 78. Patients continued to receive stable doses of methotrexate and folic/folinic acid throughout the study.Fig. 1 Study design. aStratified according to geographic region (North America and Western Europe, Japan, Republic of Korea, Latin America, and the rest of the world). b3 mg/kg intravenously. The treatment dose could be increased to 5 mg/kg and the escalated dose maintained in patients with an inadequate response at or after week 14. cIn a blinded manner, without stratification. EOT end of treatment, IFX-EU reference infliximab sourced from the EU, PF-SZ-IFX PF-06438179/GP1111, RA rheumatoid arthritis\n\n\n\nAssessments\nAs reported previously, the primary efficacy endpoint was the proportion of patients achieving ACR20 response at week 14 [25]. Therapeutic equivalence was demonstrated with the two-sided 95% CI for the treatment difference in ACR20 response rates falling within the prespecified symmetric equivalence margin of ± 13.5%.\n\nIn TP3, secondary efficacy endpoints assessed at weeks 62, 70, and 78 included the proportions of patients who achieved ACR criteria for ≥ 20%/≥ 50%/≥ 70% improvement (ACR20/ACR50/ACR70 response); EULAR response; remission based on Disease Activity Score 28 joint count CRP (DAS28-CRP) criterion (i.e., DAS28-CRP < 2.6), and on ACR/EULAR criteria (i.e., tender joint count ([TJC] and swollen joint count [SJC] ≤ 1, hs-CRP level ≤ 1 mg/dL, and patient global assessment score ≤ 1; or Simplified Disease Activity Index ≤ 3.3). Changes from study baseline in DAS28-CRP, TJC, and SJC, hs-CRP, and Health Assessment Questionnaire—Disability Index (HAQ-DI) were also assessed at these time points.\n\nSafety and tolerability were evaluated throughout TP3 based on the reporting of adverse events (AEs), including treatment-emergent adverse events (TEAEs) and serious AEs (SAEs). AEs were coded according to the Medical Dictionary for Regulatory Activities (version 20.0) classification system; AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).\n\nImmunogenicity was assessed based on the number and percentage of patients in TP3 who had one or more post-dose samples that tested positive for antidrug antibodies (ADAs) or neutralizing antibodies (NAbs) in ADA-positive samples. Serum samples were analyzed for ADAs with a validated electrochemiluminescence assay using a tiered approach (i.e., screening, confirmation, and titer/quantitation). Additional details regarding immunogenicity testing in this study were reported previously [25]. Serum trough concentrations of PF-SZ-IFX in TP3 were analyzed in all patients and by ADA-positive and ADA-negative subgroups.\n\nStatistical Methods\nTreatment efficacy in TP3 was analyzed in the intent-to-treat (ITT) population, which included all patients enrolled and treated with one or more doses of study drug in TP3. Efficacy data were summarized using descriptive statistics for the ITT population. Safety and immunogenicity data were summarized descriptively for the safety population, which comprised all randomized patients who received one or more doses of study drug in TP3. Analyses were based on observed data collected in TP3; no imputation was applied to missing data during TP3.\n\nData were analyzed for all patients and were evaluated in three groups in TP3 corresponding to the treatment sequence in TP1/TP2/TP3: biosimilar group (PF-SZ-IFX/PF-SZ-IFX/PF-SZ-IFX), week 30 switch group (IFX-EU/PF-SZ-IFX/PF-SZ-IFX), and week 54 switch group (IFX-EU/IFX-EU/PF-SZ-IFX) (Fig. 1).\n\nSummary statistics for serum trough concentrations of PF-SZ-IFX were calculated by setting concentration values below the lower limit of quantification (LLOQ) to 0 (LLOQ = 100 ng/mL).\n\nResults\nPatient Disposition and Baseline Characteristics\nAs previously reported, 650 patients were initially randomized to PF-SZ-IFX (n = 324) or IFX-EU (n = 326) in TP1, and 566 patients who completed the initial period entered TP2 at week 30 [25, 26]. A total of 505 patients participated in TP3, comprising 253 patients in the biosimilar group, 126 patients in the week 30 switch group, and 126 patients in the week 54 switch group (Table 1). Of these, 470 (93.1%) patients completed TP3, with comparable completion rates observed in the three groups (93.7% in the biosimilar group, 92.9% in the week 30 switch group, and 92.1% in the week 54 switch group). In this TP, 35.6%, 33.3%, and 32.5% of the patients in the biosimilar group, week 30 switch group, and week 54 switch group, respectively, received at least one escalated dose of the study drug (5 mg/kg).Table 1 Patient disposition through TP3 (ITT population)\n\nPatient disposition\tBiosimilar group (n = 253)\tWeek 30 switch group (n = 126)\tWeek 54 switch group (n = 126)\tTotal (N = 505)\t\nTreated during TP3\t253 (100.0)\t126 (100.0)\t126 (100.0)\t505 (100.0)\t\n Discontinued from study\t16 (6.3)\t9 (7.1)\t10 (7.9)\t35 (6.9)\t\n Completed study\t237 (93.7)\t117 (92.9)\t116 (92.1)\t470 (93.1)\t\nData are presented as n (%) unless otherwise indicated\n\nITT intent-to-treat, N number of patients in the TP3 ITT population, n number of patients in each category, TP3 treatment period 3\n\n\n\nBaseline demographics and RA characteristics were comparable between the three treatment groups in TP3 (Table 2). Most patients were female (79.2%) and White (78.6%), and the average age was 52.4 years.Table 2 Demographics and clinical characteristics of patients participating in TP3 at week 54 (ITT population)\n\nCharacteristics\tBiosimilar group (n = 253)\tWeek 30 switch group (n = 126)\tWeek 54 switch group (n = 126)\tTotal (N = 505)\t\nDemographic characteristics\t\nFemale\t198 (78.3)\t104 (82.5)\t98 (77.8)\t400 (79.2)\t\nAge, years\t52.4 ± 12.8\t51.3 ± 12.6\t53.5 ± 12.4\t52.4 ± 12.7\t\nWeight, kg\t73.3 ± 19.7\t74.5 ± 18.0\t73.1 ± 21.0\t73.6 ± 19.6\t\nBMI, kg/m2\t27.1 ± 6.3\t27.9 ± 7.1\t27.1 ± 6.7\t27.3 ± 6.6\t\nRace\t\n White\t207 (81.8)\t97 (77.0)\t93 (73.8)\t397 (78.6)\t\n Asian\t36 (14.2)\t16 (12.7)\t18 (14.3)\t70 (13.9)\t\nEthnicity\t\n Not Hispanic/Latino\t236 (93.3)\t111 (88.1)\t116 (92.1)\t463 (91.7)\t\nGeographic region\t\n North America and Western Europe\t33 (13.0)\t17 (13.5)\t15 (11.9)\t65 (12.9)\t\n Japan\t19 (7.5)\t9 (7.1)\t7 (5.6)\t35 (6.9)\t\n Republic of Korea\t2 (0.8)\t0 (0.0)\t2 (1.6)\t4 (0.8)\t\n Latin America\t13 (5.1)\t9 (7.1)\t9 (7.1)\t31 (6.1)\t\n Rest of the world\t186 (73.5)\t91 (72.2)\t93 (73.8)\t370 (73.3)\t\nDisease characteristics\t\n RA duration, years\t7.4 ± 8.8\t6.1 ± 6.3\t6.9 ± 7.3\t7.0 ± 7.9\t\n Swollen joint count\t16.3 ± 9.7\t16.4 ± 9.2\t15.3 ± 7.7\t16.1 ± 9.1\t\n Tender joint count\t24.4 ± 13.6\t25.4 ± 13.1\t24.8 ± 11.9\t24.8 ± 13.1\t\n hs-CRP, mg/L\t25.7 ± 23.7\t27.2 ± 35.2\t23.1 ± 21.9\t25.4 ± 26.6\t\nConcomitant medication\t\n MTX dose, mg/week\t14.0 ± 4.2\t14.5 ± 4.1\t14.2 ± 4.9\t14.2 ± 4.4\t\nData are presented as mean ± standard deviation or N (%) unless otherwise indicated\n\nBMI body mass index, hs-CRP high-sensitivity C-reactive protein, ITT intent-to-treat, MTX methotrexate, N number of patients in the TP3 ITT population, n number of patients in each category, RA rheumatoid arthritis, TP3 treatment period 3\n\n\n\nEfficacy\nIn TP1, the primary endpoint of the study of ACR20 response at week 14 was met and therapeutic equivalence between PF-SZ-IFX and IFX-EU demonstrated, since the 95% CI for the between-treatment-group difference in ACR20 response rates at week 14 was contained within the prespecified symmetric equivalence margins [25]. ACR20 response rates for patients in the biosimilar group, week 30 switch group, and week 54 switch group were 77.9%, 78.6%, and 71.4% before the first infusion of study drug in TP3, and 75.9%, 77.8%, and 68.3%, respectively, at week 78. At week 54, before the first infusion of PF-SZ-IFX in TP3, 76.4%, 51.3%, and 29.5% of all patients who were evaluated in TP3 achieved ACR20, ACR50, and ACR70 responses, respectively; 74.5%, 55.5%, and 34.7% of all patients achieved these responses at week 78, respectively. The proportions of patients with ACR20/50/70 responses were overall comparable among the three treatment groups at all study visits between weeks 54 and 78 (Fig. 2a). Rates of good EULAR response were 43.4% and 49.1% at weeks 54 and 78, respectively, in all patients; these rates were also comparable among the three treatment groups in TP3 (Fig. 2b).Fig. 2 Proportions of patients achieving a ACR20/50/70 responses, b good EULAR response, c DAS28-CRP remission, and d ACR/EULAR remission during TP3. ITT population in TP3. ACR20/50/70 20%/50%/70% improvement in American College of Rheumatology response from study baseline (week 0), DAS28-CRP Disease Activity Score in 28 joints based on high-sensitivity C-reactive protein, EULAR European League Against Rheumatism, ITT intent-to-treat, TP3 treatment period 3\n\n\n\nRemission based on DAS28-CRP and ACR/EULAR criteria was achieved in 27.7% and 14.5% of all patients, respectively, at week 54 and in 34.5% and 18.6% of patients at week 78. As with clinical response rates, remission rates were sustained and comparable among the three treatment groups during TP3 (Fig. 2c, d).\n\nAt week 54, the mean DAS28-CRP in all patients was 3.5, reflecting a mean change from study baseline (week 0) of − 2.5; at week 78, the mean DAS28-CRP in all patients was 3.2, reflecting a mean change from baseline of − 2.7. Throughout TP3, mean changes from baseline in DAS28-CRP were overall comparable among the three treatment groups (Fig. 3a). The mean HAQ-DI score at week 54 in all patients was 0.9, for a mean change from study baseline of − 0.7; the mean HAQ-DI score at week 78 was 0.8, for a mean change from baseline of − 0.8. As with response and remission rates and changes in DAS28-CRP, changes from baseline in HAQ-DI scores were comparable among the three treatment groups in TP3 (Fig. 3b).Fig. 3 Mean changes from study baseline (week 0) in a DAS28-CRP and b HAQ-DI during TP3. ITT population in TP3. DAS28-CRP Disease Activity Score in 28 joints based on high-sensitivity C-reactive protein, HAQ-DI Health Assessment Questionnaire—Disability Index, ITT intent-to-treat, SE standard error\n\n\n\nSafety\nAcross all three treatment groups, the median duration of treatment from the first infusion in TP1 to the last infusion in TP3 was 70.1 weeks. Drug exposure was similar among the three treatment groups in TP3. The mean (± standard deviation) total dose administered was 787.7 ± 321.5 mg, 790.4 ± 319.1 mg, and 761.8 ± 368.6 mg for patients in the biosimilar group, week 30 switch group, and week 54 switch group, respectively. No patient in any treatment group required a dose reduction in TP3 because of an AE.\n\nIn TP3, a total of 148 (29.3%) patients reported TEAEs and 12 (2.4%) reported SAEs (Table 3). Treatment-related SAEs were reported by four (0.8%) patients: in the week 30 switch group, one patient experienced cellulitis, one reported chronic sinusitis and encephalitis, and one patient experienced tuberculosis; one patient in the week 54 switch group experienced endometriosis. Six (1.2%) patients were discontinued from the study as a result of AEs. Among all patients in the safety population from TP3, 67 (13.3%) reported an infectious TEAE; of these, four (0.8%) and five (1.0%) reported a serious infectious TEAE and a grade 3 infectious TEAE, respectively. The most common TEAEs in the three treatment groups were viral upper respiratory tract infections, upper respiratory tract infections, infusion-related reactions, exacerbation of RA, and oropharyngeal pain. The incidences of TEAEs and SAEs during TP3 were comparable between treatment groups.Table 3 All-cause TEAEs in patients participating in treatment period 3\n\n\tBiosimilar group (n = 253)\tWeek 30 switch group (n = 126)\tWeek 54 switch group (n = 126)\tTotal (N = 505)\t\nNumber of AEs\t117\t64\t69\t250\t\nPatients with events\t\n AEs\t73 (28.9)\t37 (29.4)\t38 (30.2)\t148 (29.3)\t\n SAEs\t3 (1.2)\t6 (4.8)\t3 (2.4)\t12 (2.4)\t\n Grade 3 AEs\t4 (1.6)\t7 (5.6)\t3 (2.4)\t14 (2.8)\t\n Grade 4 AEs\t1 (0.4)\t0\t0\t1 (0.2)\t\n Grade 5 AEs\t0\t0\t0\t0\t\nPatients who were discontinued because of AEs\t\n From treatment, temporarily\t1 (0.4)\t6 (4.8)\t4 (3.2)\t11 (2.2)\t\n From treatment, permanently\t5 (2.0)\t2 (1.6)\t2 (1.6)\t9 (1.8)\t\n From study\t3 (1.2)\t1 (0.8)\t2 (1.6)\t6 (1.2)\t\nAEs occurring in ≥ 2% of patients in any treatment group\t\n Upper respiratory tract infection\t5 (2.0)\t4 (3.2)\t4 (3.2)\t13 (2.6)\t\n Viral upper respiratory tract infection\t11 (4.3)\t4 (3.2)\t5 (4.0)\t20 (4.0)\t\n Infusion-related reaction\t3 (1.2)\t3 (2.4)\t4 (3.2)\t10 (2.0)\t\n Rheumatoid arthritis\t2 (0.8)\t2 (1.6)\t3 (2.4)\t7 (1.4)\t\n Oropharyngeal pain\t0\t3 (2.4)\t0\t3 (0.6)\t\nPatients with AEs of special interest\t\n Infusion-related reaction\t3 (1.2)\t3 (2.4)\t4 (3.2)\t10 (2.0)\t\n Hypersensitivity\t9 (3.6)\t6 (4.8)\t6 (4.8)\t21 (4.2)\t\n Infections\t32 (12.6)\t19 (15.1)\t16 (12.7)\t67 (13.3)\t\n Tuberculosis\t0\t1 (0.8)\t0\t1 (0.2)\t\n Pneumoniaa\t1 (0.4)\t1 (0.8)\t1 (0.8)\t3 (0.6)\t\n Neoplasms\t2 (0.8)\t1 (0.8)\t0\t3 (0.6)\t\n Malignanciesb\t1 (0.4)\t0\t0\t1 (0.2)\t\nData are presented as n (%) unless otherwise indicated\n\nAE adverse event, N number of patients in final TP safety population, n number of patients in each category, SAE serious adverse event, TEAE treatment-emergent adverse event, TP treatment period\n\naIncludes one patient with atypical pneumonia (week 30 switch group)\n\nbOne patient developed transitional bladder cancer, which was not considered to be related to the study drug\n\n\n\nImmunogenicity\nOverall, ADAs were detected in 119 (47.0%), 72 (57.1%), and 66 (52.4%) patients in the biosimilar group, week 30 switch group, and week 54 switch group, respectively, during TP3, regardless of their ADA status in TP1 and TP2. Among patients who tested positive for ADAs, 105 (88.2%), 60 (83.3%), and 58 (87.9%) also tested positive for NAbs in the three treatment groups, respectively. The proportions of patients who were ADA positive and NAb positive, regardless of their previous ADA status, at week 54 and week 78 (post-dose) were comparable among the three treatment groups (Fig. 4).Fig. 4 The proportions of patients who tested positive for ADAs and, of those, the proportions who tested positive for NAbs, by study visit in TP3. aNAb-positive incidences are expressed as percent of ADA-positive patients. ADA antidrug antibody, NAb neutralizing antidrug antibody, TP3 treatment period 3\n\n\n\nOf 505 patients who entered TP3, 213 (42.2%) did not have a prior post-dose ADA-positive test. Of these ADA-negative patients, 14 (6.6%) had their first post-dose ADA-positive test during TP3, comprising 6.0%, 6.4%, and 8.0% of patients in the biosimilar group, week 30 switch group, and week 54 switch group, respectively.\n\nPatients who were ADA positive had lower mean serum trough concentrations of PF-SZ-IFX than patients who were ADA negative (Fig. S1 in the electronic supplementary material). However, within the ADA-positive and ADA-negative subgroups, mean concentrations were generally comparable across treatment groups during TP3.\n\nThe majority of patients who developed ADAs did not report TEAEs of hypersensitivity or infusion-related reactions during TP3. Of the 306 patients who tested positive for ADAs during all treatment periods (144, 82, and 80 patients in the biosimilar group, week 30 switch group, and week 54 switch group, respectively), ten (3.3%) experienced TEAEs of hypersensitivity in TP3 (three [2.1%], four [4.9%], and three [3.8%], respectively) and nine (2.9%) experienced TEAEs of infusion-related reactions (three [2.1%], three [3.7%], and three [3.8%], respectively). None of the TEAEs of hypersensitivity events or infusion-related reactions were considered serious or above grade 2 in severity. One patient from each treatment group (0.4%, 0.8%, and 0.8%, respectively) was withdrawn from the study as a result of TEAEs of hypersensitivity. Two (1.4%), one (1.2%), and one (1.3%) patients in these groups, respectively, were withdrawn because of TEAEs of infusion-related reactions on or after ADA detection.\n\nDiscussion\nThe earlier findings from the REFLECTIONS B537-02 study in relation to the primary endpoint confirmed the therapeutic equivalence of PF-SZ-IFX and reference infliximab [25] and contributed to the “totality of the evidence” in support of the regulatory approval of PF-SZ-IFX in the treatment of patients with RA, as well as all other eligible indications for which reference infliximab is authorized [29]. The data reported here, obtained during TP3 from the same study, provide additional valuable clinical evidence concerning switching patients with RA from treatment with IFX-EU to PF-SZ-IFX as well as on the effects of longer-term treatment with PF-SZ-IFX. In this respect, the efficacy of PF-SZ-IFX, as judged by ACR responses (Fig. 2a), was comparable across groups during TP3, with no clinically meaningful differences between patients maintained on PF-SZ-IFX throughout the 78 weeks of the study (biosimilar group) and those who switched from IFX-EU (week 30 and week 54 switch groups). Comparability across treatment groups was also evident from assessment of other secondary clinical outcome measures, such as EULAR response (Fig. 2b) and DAS28-CRP (Fig. 2c) and ACR/EULAR remission criteria (Fig. 2d).\n\nFor patients who switched from IFX-EU, there was no clinically meaningful difference in ACR20 response from the time of the last treatment with IFX-EU to the end of the study (week 30 switch group: 75.5% [week 30] [26] and 77.8% [week 78]; week 54 switch group: 71.4% [week 54] and 68.3% [week 78]). For patients receiving PF-SZ-IFX before entry to TP3, ACR20 responses at the end of double-blind treatment (TP2) were sustained during open-label treatment in TP3 (biosimilar group: 77.9% [week 54] and 75.9% [week 78]; week 30 switch group: 78.6% [week 54] and 77.8% [week 78]). This profile, with respect to ACR20 responses, was also reflected in other secondary efficacy outcome measures.\n\nOverall, the safety profile was comparable between treatment groups and was consistent with the known long-term safety profile for infliximab in patients with RA [30]. There were no noticeable differences in the proportions of patients experiencing AEs between patients maintained on PF-SZ-IFX throughout the 78 weeks of the study (biosimilar group; 28.9%) and those who switched from IFX-EU (week 30 [29.4%] and week 54 switch groups [30.2%]). The incidence of SAEs, and AEs leading to study discontinuation, was also comparable among the three treatment groups during TP3. Moreover, there was no clinically meaningful difference between groups in the frequency of AEs of special interest reported, including infusion-related reactions, hypersensitivity, and infections.\n\nImmunogenicity assessment during TP3 showed the incidence of both ADA and NAb development was comparable between groups, with no clinically meaningful differences in the proportions of patients who tested positive for ADAs and who showed NAb positivity. Overall, the safety and immunogenicity findings suggested cumulative exposure to PF-SZ-IFX for up to 78 weeks (biosimilar group) or following switching from IFX-EU, and follow-up for up to 48 weeks (week 30 and week 54 switch groups) did not increase the occurrence of AEs or immunogenicity or adversely affect the safety profile.\n\nLimitations of the study include the absence of patients maintained on IFX-EU throughout as a control group. No formal hypothesis testing was conducted for any of the secondary endpoints; therefore, results were interpreted based on descriptive statistics.\n\nConclusions\nResults from TP3 of the REFLECTIONS B537-02 study showed patients with moderate-to-severe active RA receiving PF-SZ-IFX experienced no clinically meaningful differences in efficacy, safety, or immunogenicity, regardless of whether they were maintained on PF-SZ-IFX throughout 78 weeks of treatment or following single treatment transitions from IFX-EU to PF-SZ-IFX at week 30 or at week 54. PF-SZ-IFX was well-tolerated for up to 78 weeks of treatment and displayed a safety profile consistent with that of infliximab. These findings provide long-term clinical data to complement the existing evidence of similarity between reference infliximab and PF-SZ-IFX, including structure, biological function, pharmacokinetics, and therapeutic equivalence, and add to the “totality of the evidence” supporting biosimilarity of PF-SZ-IFX to reference infliximab and its use in the other eligible indications for which reference infliximab is authorized.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (PDF 348 kb)\n\n \n\nAcknowledgements\nMedical writing support was provided by Donna McGuire and Iain McDonald, PhD, of Engage Scientific Solutions and was funded by Pfizer Inc.\n\nAuthor Contributions\nMIR made substantial contributions to the study conception, design, and analysis and interpretation of the data. CC and MZ contributed to the analysis and interpretation of the data. SH and OvR made substantial contributions to the interpretation of the data. RA, SBC, HK, AJK, SCR, and MT contributed to the acquisition and interpretation of the data. All authors made substantial contributions to the interpretation of the data, were involved in drafting the manuscript and/or revising it critically for important intellectual content, and read and approved the final manuscript for submission. MIR is the guarantor for the overall content.\n\nData Availability\nUpon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the USA and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.\n\nCompliance with Ethical Standards\nConflict of interest\nSBC has received research grants and consulting fees or honorarium from AbbVie, Amgen, Pfizer, and Sandoz. RA has no conflicts of interest that are directly relevant to the content of this article. HK has received consulting fees, speaking fees, and/or honoraria from AbbVie GK, Asahi Kasei Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Novartis, and Pfizer Japan and has received research grants from AbbVie GK, Asahi Kasei Pharma, Astellas Pharma, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, and Novartis. AJK has received consulting fees and/or speaking fees and/or fees for participation on advisory committees or review panels from Sanofi, Regeneron, SUN Pharma Advanced Research, AbbVie, Janssen, Pfizer, UCB, Genzyme, Boehringer-Ingelheim, Celgene, Horizon, Merck, Novartis, and Flexion and has stock holdings for Pfizer, Sanofi, Amgen, and Gilead. MT has received research grants, speaking fees, and honoraria from Pfizer Philippines. SCR has received research grants from Pfizer. OvR is an employee of Hexal AG (a Sandoz company). CC, SH, MIR, and MZ are employees of, and hold stock or stock options from, Pfizer.\n\nResearch Involving Human Participants\nThe study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with International Conference on Harmonisation Good Clinical Practice guidelines. The independent ethics committee or institutional review board for each study center approved the study protocol; an independent data monitoring committee was responsible for monitoring safety and study conduct.\n\nInformed Consent\nAll patients provided written informed consent before study entry. No additional informed consent was required because the three treatment periods were part of the same study.\n\nFunding\nThis study was sponsored by Pfizer Inc. Open access publication of this article was funded by Pfizer Inc.\n==== Refs\nReferences\n1. Janssen Biotech Inc. Remicade® (infliximab) US prescribing information. 2013. http://www.remicade.com/shared/product/remicade/prescribing-information.pdf. Accessed 31 Oct 2018.\n2. European Medicines Agency. Remicade (infliximab). Summary of Product Characteristics. 2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000240/WC500050888.pdf. Accessed 20 Aug 2018.\n3. Janssen Biotech Inc. Official website for Remicade® (infliximab). 2017. https://www.remicade.com/. Accessed 20 Aug 2018.\n4. Melsheimer R Geldhof A Apaolaza I Schaible T Remicade® (infliximab): 20 years of contributions to science and medicine Biologics 2019 13 139 178 31440029 \n5. Nam JL Winthrop KL van Vollenhoven RF Pavelka K Valesini G Hensor EM Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA Ann Rheum Dis 2010 69 6 976 986 10.1136/ard.2009.126573 20447957 \n6. Smolen JS, Emery P. Infliximab: 12 years of experience. Arthritis Res Ther. 2011;13 Suppl 1S2.\n7. Christophorou D Funakoshi N Duny Y Valats JC Bismuth M Pineton De Chambrun G Systematic review with meta-analysis: infliximab and immunosuppressant therapy vs. infliximab alone for active ulcerative colitis Aliment Pharmacol Ther. 2015 41 7 603 612 10.1111/apt.13102 25678223 \n8. Singh S Garg SK Pardi DS Wang Z Murad MH Loftus EV Jr Comparative efficacy of biologic therapy in biologic-naive patients with Crohn disease: a systematic review and network meta-analysis Mayo Clin Proc 2014 89 12 1621 1635 10.1016/j.mayocp.2014.08.019 25441399 \n9. Kalo Z Voko Z Ostor A Clifton-Brown E Vasilescu R Battersby A Patient access to reimbursed biological disease-modifying antirheumatic drugs in the European region J Mark Access Health Policy. 2017 5 1 1345580 10.1080/20016689.2017.1345580 28740623 \n10. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on similar biological medicinal products. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf. Accessed 15 Feb 2019.\n11. US Food and Drug Administration (FDA). Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed 15 Feb 2019.\n12. European Medicines Agency. Zessly authorisation details. EMEA/H/C/004647. 2018. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004647/human_med_002260.jsp&mid=WC0b01ac058001d124. Accessed 10 Sep 2018.\n13. Pharmaceuticals and Medical Devices Agency (PMDA). Infliximab BS for I.V. infusion 100 mg [Pfizer] (Infliximab Biosimilar 3) product information. 2018. http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/23994A3F1 Accessed 18 Feb 2019.\n14. US Food and Drug Administration. Approval letter for Ixifi. BLA 761072. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761072Orig1s000ltr.pdf. Accessed 20 Feb 2018.\n15. National Health Surveillance Agency (ANVISA). Xilfya authorisation details. Lyophilised powder for injectable solution. 1211004480019. 2019. https://consultas.anvisa.gov.br/#/medicamentos/25351040132201852/?nomeProduto=xilfya. Accessed 16 July 2019.\n16. Derzi M Johnson TR Shoieb AM Conlon HD Sharpe P Saati A Nonclinical evaluation of PF-06438179: A potential biosimilar to remicade((R)) (Infliximab) Adv Ther. 2016 33 11 1964 1982 10.1007/s12325-016-0403-9 27585978 \n17. Palaparthy R Udata C Hua SY Yin D Cai CH Salts S A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade(R) (infliximab) in healthy subjects (REFLECTIONS B537-01) Expert Rev Clin Immunol. 2018 14 4 329 336 10.1080/1744666X.2018.1446829 29504427 \n18. Singh SC Bagnato KM The economic implications of biosimilars Am J Manag Care. 2015 21 16 Suppl s331 s340 26788809 \n19. Jha A Upton A Dunlop WC Akehurst R The budget impact of biosimilar infliximab (Remsima(R)) for the treatment of autoimmune diseases in five European Countries Adv Ther. 2015 32 8 742 756 10.1007/s12325-015-0233-1 26343027 \n20. Tee M Tee CA PMS19—a budget impact analysis of introducing a forced treatment pathway using the lowest priced anti-tumor necrosis factor agent for rheumatoid arthritis and ankylosing spondylitis in the Philippines Value Health. 2018 21 S290 S291 10.1016/j.jval.2018.09.1733 \n21. Kim J Ha D Song I Park H Lee SW Lee EK Estimation of cost savings between 2011 and 2014 attributed to infliximab biosimilar in the South Korean healthcare market: real-world evidence using a nationwide database Int J Rheum Dis. 2018 21 6 1227 1236 10.1111/1756-185X.13295 29667324 \n22. Gulacsi L Brodszky V Baji P Rencz F Pentek M The rituximab biosimilar CT-P10 in rheumatology and cancer: a budget impact analysis in 28 European countries Adv Ther. 2017 34 5 1128 1144 10.1007/s12325-017-0522-y 28397080 \n23. Chanchlani N Mortier K Williams LJ Muhammed R Auth MKH Cosgrove M Use of infliximab biosimilar versus originator in a Pediatric United Kingdom Inflammatory Bowel Disease Induction Cohort J Pediatr Gastroenterol Nutr 2018 67 4 513 519 10.1097/MPG.0000000000002011 29697550 \n24. Lepelaars LRA Renda F Pani L Pimpinella G Leufkens HGM Trifiro G Comparing safety information of biosimilars with their originators: a cross-sectional analysis of European risk management plans Br J Clin Pharmacol 2018 84 4 738 763 10.1111/bcp.13454 29164665 \n25. Cohen SB Alten R Kameda H Hala T Radominski SC Rehman MI A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and infliximab reference product for treatment of moderate to severe active rheumatoid arthritis despite methotrexate therapy Arthritis Res Ther. 2018 20 1 155 10.1186/s13075-018-1646-4 30053896 \n26. Alten R Batko B Hala T Kameda H Radominski SC Tseluyko V Randomised, double-blind, phase III study comparing the infliximab biosimilar, PF-06438179/GP1111, with reference infliximab: efficacy, safety and immunogenicity from week 30 to week 54 RMD Open. 2019 5 1 e000876 10.1136/rmdopen-2018-000876 30997153 \n27. Aletaha D Neogi T Silman AJ Funovits J Felson DT Bingham CO 3rd 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Ann Rheum Dis 2010 69 9 1580 1588 10.1136/ard.2010.138461 20699241 \n28. Hochberg MC Chang RW Dwosh I Lindsey S Pincus T Wolfe F The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis Arthritis Rheum 1992 35 5 498 502 10.1002/art.1780350502 1575785 \n29. McClellan JE Conlon HD Bolt MW Kalfayan V Palaparthy R Rehman MI The ‘totality-of-the-evidence’ approach in the development of PF-06438179/GP1111, an infliximab biosimilar, and in support of its use in all indications of the reference product Therap Adv Gastroenterol. 2019 12 1756284819852535 10.1177/1756284819852535 \n30. Maini RN Breedveld FC Kalden JR Smolen JS Furst D Weisman MH Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate Arthritis Rheum 2004 50 4 1051 1065 10.1002/art.20159 15077287\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1173-8804",
"issue": "34(2)",
"journal": "BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy",
"keywords": null,
"medline_ta": "BioDrugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D059451:Biosimilar Pharmaceuticals; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012449:Safety; D013810:Therapeutic Equivalency",
"nlm_unique_id": "9705305",
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"pages": "197-207",
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"pmid": "31939063",
"pubdate": "2020-04",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "26343027;25441399;15077287;26788809;20447957;30997153;29164665;25678223;30053896;28397080;1575785;29504427;20699241;31223341;29667324;27585978;21624181;31440029;28740623;29697550",
"title": "Long-term Efficacy, Safety, and Immunogenicity of the Infliximab (IFX) Biosimilar, PF-06438179/GP1111, in Patients with Rheumatoid Arthritis After Switching from Reference IFX or Continuing Biosimilar Therapy: Week 54-78 Data From a Randomized, Double-Blind, Phase III Trial.",
"title_normalized": "long term efficacy safety and immunogenicity of the infliximab ifx biosimilar pf 06438179 gp1111 in patients with rheumatoid arthritis after switching from reference ifx or continuing biosimilar therapy week 54 78 data from a randomized double blind phase iii trial"
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"abstract": "Indocyanine Green (ICG) is frequently used during urologic robotic procedures and is generally considered to be safe. However, there are reported cases of severe complications from ICG when used for non-urologic purposes. We present the first case to our knowledge of anaphylactic shock in response to intravenous ICG during a robotic partial nephrectomy.",
"affiliations": "City of Hope National Medical Center, Department of Urology and Urologic Oncology, Duarte, CA, USA.;City of Hope National Medical Center, Department of Urology and Urologic Oncology, Duarte, CA, USA.;City of Hope National Medical Center, Department of Anesthesia, Duarte, CA, USA.;City of Hope National Medical Center, Department of Urology and Urologic Oncology, Duarte, CA, USA.",
"authors": "Chu|William|W|;Chennamsetty|Avinash|A|;Toroussian|Robert|R|;Lau|Clayton|C|",
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"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(17)30006-210.1016/j.eucr.2017.02.006OncologyAnaphylactic Shock After Intravenous Administration of Indocyanine Green During Robotic Partial Nephrectomy Chu William wichu@coh.orga∗Chennamsetty Avinash aToroussian Robert bLau Clayton aa City of Hope National Medical Center, Department of Urology and Urologic Oncology, Duarte, CA, USAb City of Hope National Medical Center, Department of Anesthesia, Duarte, CA, USA∗ Corresponding author. 1500 E. Duarte Rd, MOB L002H, Duarte, CA 91010, USA.1500 E. Duarte Rd, MOB L002HDuarteCA91010USA wichu@coh.org10 3 2017 5 2017 10 3 2017 12 37 38 10 1 2017 6 2 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Indocyanine Green (ICG) is frequently used during urologic robotic procedures and is generally considered to be safe. However, there are reported cases of severe complications from ICG when used for non-urologic purposes. We present the first case to our knowledge of anaphylactic shock in response to intravenous ICG during a robotic partial nephrectomy.\n\nKeywords\nIndocyanine greenAnaphylactic shockRobotic surgeryAbbreviations\nIV, intravenousICG, indocyanine greenNIRF, near-infrared fluorescence\n==== Body\nIntroduction\nICG, a sterile US Food and Drug Administration-approved water-soluble dye, is a popular diagnostic reagent that has been in clinical use for the examination of hepatic function, ophthalmic angiography, cardiac output and circulating blood volume. With the advent of robotic-assisted laparoscopic surgery and near-infrared fluorescence (NIRF) lenses, ICG has found several applications in Urologic surgery including ureteral identification, differentiation of tumors from normal parenchyma and as a lymphangiography agent.\n\nIntravenous (IV) ICG has had a long record of safety for over 50 years with previous reports of mostly low-grade complications.1, 2 We report the first case of anaphylactic shock following IV administration of ICG during a robotic-assisted partial nephrectomy.\n\nCase presentation\nA 53-year-old, 90-kg male was incidentally diagnosed with a left interpolar 2.2 cm × 2.3 cm × 2.2 cm renal mass (cT1a, Stage 1) on imaging following a penetrating abdominal trauma. Patient denied any constitutional symptoms (fevers, night sweats or weight loss) and had no pertinent physical exam findings.\n\nPast medical history was significant for coronary artery disease with prior myocardial infarction, hypertension, and insulin-dependent diabetes mellitus. He had no prior anesthetic complications, nor allergies to food, iodinated contrast, or medications. He demonstrated good performance status and cardiopulmonary evaluation revealed normal findings. A beta-blocker was started 1 week prior to surgery.\n\nThe patient underwent uneventful anesthesia induction, and the case proceeded with a robotic-assisted transperitoneal approach. Prior to clamping the renal hilum, IV mannitol 12.5 g and ICG 5 mg were given. Shortly after, the patient developed increased peak airway pressures, severe hypotension and ventricular tachycardia. The ET tube and depth of anesthesia were confirmed. Epinephrine and phenylephrine were administered and IV fluids were increased. After the patient failed to respond, the robot was undocked and the patient repositioned supine. A weak pulse was palpated and chest compressions were initiated. The patient underwent successful cardioversion with return to sinus rhythm and an improvement in hypotension. After the patient stabilized for an appropriate period, the operation was completed without further issue (estimated blood loss was 100 mL and 5 L IV fluid administered with warm ischemia time of 28 min). Serologic tests including cardiac enzymes and C3/IgE were within normal limits. However, serum tryptase was elevated at 56.7 μg/L (reference < 10.9 μg/L). The remaining course was uneventful and the patient was discharged on postoperative day two. Final pathology revealed a pT1aNxMxR0 clear cell renal cell carcinoma, Fuhrman grade three.\n\nDiscussion\nICG (C43H47N2NaO6S2) is a sterile, water-soluble, tricarbocyanine dye that fluoresces bright green when viewed under near-infrared light (700–1000 nm). Following IV injection, ICG is rapidly bound to plasma protein, of which albumin is the principle carrier (95%). It is then taken almost exclusively by the hepatic parenchymal cells and is secreted entirely into the bile (half-life of three to 4 min).\n\nAlthough it requires a separate NIRF visualization system due to emission out of the visible spectrum, infrared fluorescence enables deeper tissue penetration and allows visualization even in a bloody operative field. This technology has been applied to robotic partial nephrectomy, to differentiate tumor from normal parenchyma. It has been hypothesized that normal kidney tissue fluoresces green, while the tumor commonly remains hypo-fluorescent, thereby aiding tumor excision (Fig. 1a and b). There have been numerous other novel uses of ICG within urologic robotic surgery. However despite its common use, most urologists are not well versed in the potential adverse effects of ICG.\n\nICG has generally been considered safe and accepted as having a low incidence of morbidity. Hope-Ross et al prospectively evaluated complications from IV ICG use for video angiography in 1226 patients (1923 cases).1 Incidence of mild, moderate, and severe complications were 0.15%, 0.2%, and 0.05% respectively. However, while severe complications were rare, two of these were deaths attributed to anaphylaxis. Obana et al similarly reported on a large series of IV or intradermal ICG video angiography cases (3774 cases performed on 2820 patients).2 Incidence of adverse reaction was only 0.34%, the majority of which were mild. However, two patients experienced hypotension. Notably the dose of ICG varied from 25 to 75 mg, which is much higher than the typically used for robotic surgery. Bjerregaard et al described two cases of severe hypotension following IV ICG administered (5 mg and 2.5 mg respectively) during neurovascular procedures.3\n\nWe describe, the first of our knowledge, a case of a life-threatening anaphylaxis following IV ICG during a robotic urologic surgery. We believe our case to be consistent with an anaphylactic response to ICG for several reasons. First, the timing of the patient's acute changes following IV ICG corroborates a medication response. Second, while there are other causes of increased peak airway pressures, our patient developed a rapid constellation of findings including hypotension and ventricular tachycardia. Also, the position of the endotracheal tube and appropriate depth of anesthesia were confirmed. The patient was also placed supine and the abdomen was desufflated in the event that the surgical positioning or pneumoperitoneum were contributing to isolated bronchospasm. There was also no significant blood loss to account for the acute changes. Third, the markedly increased postoperative serum tryptase level, a serum protease secreted by mast cells used to assess for anaphylaxis,4 supports the diagnosis of anaphylaxis.\n\nIt has been proposed that systemic reactions from ICG may be attributable to the iodide component.3 However, the physiology of these reactions remain unknown as cases of adverse events have been documented in iodide-free preparations of ICG.5 Further, ICG has been used safely in patients with recorded iodine allergies. In addition, there is no known dose threshold below for an ICG adverse reaction as seen in our case in which a single small dose (5 mg IV) was given. As the mechanism behind ICG reactions remains unknown, currently there is no way to predict who will experience an ICG-related complication. Skin or low dose IV testing for ICG allergy has not proven useful.5\n\nConclusion\nWe report the first episode of anaphylactic response to ICG in the contemporary robotic surgical era. While ICG-related complications are rare, the vulnerable population remains unknown and Urologists should be familiar with this complication.\n\nConflict of interest\nThe authors declare no conflict of interest.\n\nAcknowledgements\nNo acknowledgements.\n\nFunding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nFigure 1 (a) Exophytic tumor in white light mode. (b) Exophytic tumor in fluorescence mode.\n\nFigure 1\n==== Refs\nReferences\n1 Hope-Ross M. Yannuzzi L.A. Gragoudas E.S. Adverse reactions due to indocyanine green Ophthalmology 101 1994 529 533 8127574 \n2 Obana A. Miki T. Hayashi K. Survey of complications of indocyanine green angiography in Japan Am J Ophthalmol 118 1994 749 753 7977601 \n3 Bjerregaard J. Pandia M.P. Jaffe R.A. Occurrence of severe hypotension after indocyanine green injection during the intraoperative period A A Case Rep 1 2013 26 30 25611609 \n4 Brown S.G. Blackman K.E. Heddle R.J. Can serum mast cell tryptase help diagnose anaphylaxis? Emerg Med Atralas 16 2 2004 120 124 \n5 Bonte C.A. Ceuppens J. Leys A.M. Hypotensive shock as a complication of infracyanine green injection Retina 18 1998 476 477 9801048\n\n",
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"issn_linking": "2214-4420",
"issue": "12()",
"journal": "Urology case reports",
"keywords": "Anaphylactic shock; ICG, indocyanine green; IV, intravenous; Indocyanine green; NIRF, near-infrared fluorescence; Robotic surgery",
"medline_ta": "Urol Case Rep",
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"nlm_unique_id": "101626357",
"other_id": null,
"pages": "37-38",
"pmc": null,
"pmid": "28316935",
"pubdate": "2017-05",
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"title": "Anaphylactic Shock After Intravenous Administration of Indocyanine Green During Robotic Partial Nephrectomy.",
"title_normalized": "anaphylactic shock after intravenous administration of indocyanine green during robotic partial nephrectomy"
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"companynumb": "US-DIAGNOSTIC GREEN GMBH-1064959",
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"activesubstancename": "INDOCYANINE GREEN"
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"abstract": "BACKGROUND\nA patient with an early diagnosed epilepsy Valproic acid is one of the most widely used antiepileptic drugs. Hyperammonemic encephalopathy is a rare, but potentially fatal, adverse drug reaction to valproic acid.\n\n\nMETHODS\nA patient with an early diagnosed epilepsy, treated with valproic acid, experienced an altered mental state after 10 days of treatment. Valproic acid serum levels were within limits, hepatic function tests were normal but ammonia levels were above the normal range. Valproic acid was stopped and the hyperammonemic encephalopathy was treated with lactulose 15 ml twice daily, metronidazole 250 mg four times daily and L-carnitine 1 g twice daily.\n\n\nRESULTS\nMonitoring liver function and ammonia levels should be recommended in patients taking valproic acid. The constraints of the pharmaceutical market had to be taken into consideration and limited the pharmacological options for this patient's treatment.\n\n\nCONCLUSIONS\nIdiosyncratic symptomatic hyperammonemic encephalopathy is completely reversible, but can induce coma and even death, if not timely detected. Clinical pharmacists can help detecting adverse drug reactions and provide evidence based information for the treatment.",
"affiliations": "Pharmacy, Hospital de Faro, EPE, Rua Leao Penedo, Faro, 8000-386 Portugal.",
"authors": "Sousa|Carla|C|",
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"doi": "10.1186/2193-1801-2-13",
"fulltext": "\n==== Front\nSpringerplusSpringerplusSpringerPlus2193-1801Springer International Publishing Cham 234513367810.1186/2193-1801-2-13Case StudyValproic acid-induced hyperammonemic encephalopathy – a potentially fatal adverse drug reaction Sousa Carla penicilina@portugalmail.pt Pharmacy, Hospital de Faro, EPE, Rua Leao Penedo, Faro, 8000-386 Portugal 15 1 2013 15 1 2013 2013 2 1 137 9 2012 7 1 2013 © Sousa; licensee Springer. 2013This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nA patient with an early diagnosed epilepsy Valproic acid is one of the most widely used antiepileptic drugs. Hyperammonemic encephalopathy is a rare, but potentially fatal, adverse drug reaction to valproic acid.\n\nCase description\nA patient with an early diagnosed epilepsy, treated with valproic acid, experienced an altered mental state after 10 days of treatment. Valproic acid serum levels were within limits, hepatic function tests were normal but ammonia levels were above the normal range.\n\nValproic acid was stopped and the hyperammonemic encephalopathy was treated with lactulose 15 ml twice daily, metronidazole 250 mg four times daily and L-carnitine 1 g twice daily.\n\nDiscussion and evaluation\nMonitoring liver function and ammonia levels should be recommended in patients taking valproic acid. The constraints of the pharmaceutical market had to be taken into consideration and limited the pharmacological options for this patient's treatment.\n\nConclusions\nIdiosyncratic symptomatic hyperammonemic encephalopathy is completely reversible, but can induce coma and even death, if not timely detected.\n\nClinical pharmacists can help detecting adverse drug reactions and provide evidence based information for the treatment.\n\nissue-copyright-statement© The Author(s) 2013\n==== Body\nBackground\nValproic acid (VPA) has been used in clinical practice since the 60’s, with a relatively favourable safety and efficacy profile. Pancreatitis, hepatotoxicity and teratogenicity are the most significant adverse drug reactions. Cases of hyperammonemia are rarely reported as VPA-induced, probably because this increased level of ammonia in blood can vary between asymptomatic, with an incidence of 16-52% (Carr & Sherwsbury 2007), and clinically relevant levels. Symptomatology due to VPA-induced hyperammonemia include: lethargy, impaired consciousness, focal neurological signs and symptoms and increased seizure frequency. More rare described symptoms are: aggression, ataxia, asterixis, vomiting and coma (Carr & Sherwsbury 2007; Labuzetta et al. 2010).\n\nThere is no consensus on whether this symptomatology has any relationship with plasma concentration of VPA. Several studies showed that hyperammonenia may occur with both therapeutic and supratherapeutic concentrations of VPA, indicating that other factors may influence the onset of hyperammonemia. Some authors suggest that symptoms of encephalopathy may develop in patients that have been taking VPA previously, without complications (Carr & Sherwsbury 2007).\n\nA case of encephalopathy due to hyperammonaemia associated with VPA in a patient with therapeutic drug levels and normal liver function is presented.\n\nCase description\nA 60-year-old man, with history of hypertension, diabetes mellitus, and alcoholism (in recovery), is admitted because of sudden episode of altered state of consciousness preceded by involuntary movements of the left upper limb, lasting less than five minutes, without motor asymmetries or sphincter incontinence. Neurological examination was normal, except for slowness of speech and difficulty in fixing attention. Vascular study revealed no significant changes and the electroencephalogram (EEG) showed no paroxysmal activity. Considering these results, the presumptive diagnosis of focal cryptogenic epilepsy was given. Patient was treated and discharged with VPA extended release 500 mg twice daily, esomeprazol 40 mg/day and insulin.\n\nThree days after discharge (10th day of valproic acid), the patient was readmitted because of disorientation, speech slowness, somnolence and hemifacial myoclonus. Adherence to treatment and no use of alcohol were confirmed by family members.\n\nSymptoms were interpreted as uncontrolled epilepsy due to quantitative inefficacy (presumptive prolonged post-ictal state), and two days after VPA dosage was augmented to 1000 mg twice daily. Symptoms worsened.\n\nMedical tests revealead blood dyscrasias, glicemia 330 mg/dL and normal liver function. Serum electrolytes, creatinine, blood urea nitrogen and bilirubin were also normal. Serum concentration of total valproic acid was therapeutic (75 mg/L, therapeutic range: 50–100 mg/L).\n\nIdiosyncratic possibilities were considered. Venous serum ammonia level was determined ranging 62,1 μmol/L (normal reference: 5–32 μmol/L) and a repeat EEG showed a generalized slowing with frequent frontocentral diphasic sharp waves, suggesting a metabolic encephalopathy. VPA was stopped and the clinical pharmacist was consulted for evidence based information. A search strategy formulation for Medline/Pubmed was applied: “valproic acid/toxicity” [Mesh]; “Hyperammonemia” [Mesh]. A National Medicines Information Centre was also consulted. Reviews and case reports were used. Critical Appraisal Skills Program was applied for critical analysis of literature (available in: http://www.phru.nhs.uk/casp/critical_appraisal_tools.htm).\n\nTreatment was initiated with lactulose 15 ml twice daily (and adjusted to achieve two-three soft stools/day), L-carnitine 1 g twice daily, metronidazol 250 mg four times daily, complex B vitamins and levetiracetam 500 mg twice daily. Patient improved his consciousness state within 24 hours. Past 11 days ammonia level was 7,1 μmol/L and his level of consciousness resolved. Adjustment in diabetes therapy was made and he was discharged after 2 more days.\n\nDiscussion and evaluation\nSymptomatic hyperammonemia due to VPA is quite rare, but can be fatal (Carr & Sherwsbury 2007). In the clinical case presented, the patient experienced decreased level of consciousness, confusion, disorientation and slowness of speech. The hemifacial myoclonus that occurred in three occasions was considered as seizures in a context of uncontrolled epilepsy.\n\nPharmacological causes of the hyperammonemia induced by VPA have not yet been fully clarified. Studies suggest a hepatic and renal role: amino acids are degraded in the liver to produce ammonia (Cash et al. 2010). Ammonia is both excreted in the urine and converted in urea, which is the major mechanism of nitrogen excretion. Urea is produced in the liver and then transported to the kidneys where it is excreted in the urine or via the intestines where is converted in carbon dioxide and ammonia by the urease-producing bacteria (Labuzetta et al. 2010). Any change in this process may compromise the urea cycle and induce hyperammonemia. In the kidney, VPA affects the renal uptake of glutamine increasing the ammonia production (Carr & Sherwsbury 2007; Cuturic & Abramson 2005). Deficiency of L-carnitine may also decrease urea formation and increase ammonia accumulation in the liver (Cash et al. 2010).\n\nAmmonia levels in the brain are normally two times higher than in the arterial blood, and in case of an acute rise of blood ammonia this ratio goes up, amplifying the toxicity of ammonia. The increased level of ammonia in the central nervous system leads to a higher production and accumulation of glutamine within the astrocytes, causing increased intracellular osmolarity, cerebral oedema and astrocyte dysfunction (Carr & Sherwsbury 2007; Cash et al. 2010).\n\nAlthough treatment with VPA is generally associated with asymptomatic hyperammonemia there are possible risk factors that can induce and worsen symptomatology: urea cycle disorders, poor nutrition or catabolic state, L-carnitine deficiency, infancy (immature liver function), polymedication, especially other antiepileptic and psychotropic substances. Some well known drug associations that act as risk factors are VPA with: phenytoin; phenobarbital; carbamazepine; topiramate; clozapine and risperidone (Carr & Sherwsbury 2007). In most reported cases patients have concomitant risk medication, and symptoms develop within days or weeks with abnormal liver function (Yee et al. 2005). In this case, patient was taking no medication reported as potential risk factor and hepatic tests were normal. The analysis with the Naranjo probability scale revealed that the adverse drug reaction was probably caused by VPA (Naranjo et al. 1981).\n\nNo formal protocol exists for managing these clinical situations, but it is consensual that the first procedure must be the discontinuation of VPA. Usually the pharmacological treatment applied is the same as for hepatic encephalopathy, combined with drugs that may interact with the mechanism of action of VPA (L-carnitine) (Carr & Sherwsbury 2007; Stewart 2008).\n\nNonabsorbable disaccharides are considered the standard of care for hepatic encephalopathy and include lactitol and lactulose, the latter being the most frequently used (Cash et al. 2010; Naranjo et al. 1981). Lactulose is metabolized into acetic and lactic acids, resulting in acidification of the gastrointestinal lumen. This acidification inhibits the production of ammonia by the coliform bacteria in the intestine. Usually the dosage applied in these cases is 30 ml of lactulose 2 to 4 times a day, adjusting to achieve 2 to 4 soft stools a day and patient compliance (Shiano 2010).\n\nBecause we also want to decrease the production of ammonia in the intestine, antibiotics directed to ammonia-producing bacteria can be used. Neomycin, rifaximin and metronidazol have been used (Shiano 2010). Rifaximin has good efficacy with less bacterial resistance and adverse effects than the other antibiotics, and thereby probably more cost-effective (Shiano 2010; Neff 2010).\n\nFor this patient, besides treatment with lactulose, the option of using rifaximin and neomycin had to be discarded because rifaximin is not included in our hospital formulary and neomycin does not exist on the national market and has to be imported. For this reason we used metronidazole. Vitamin B complex supplement was added because of previous habits of alcohol intake and levetiracetam was chosen for its profile of safety and efficacy on focal epilepsy. Literature evidence and availability of medicines on the Portuguese market were considered when deciding the treatment options.\n\nConclusion\nIdiosyncratic hyperammonemic encephalopathy without liver failure is rare, completely reversible, but one of the most severe, potentially fatal, adverse drug reactions to VPA. Intermittent confusional episodes due to hyperammonemia can be easily mistaken with partial seizures inducing medication error, prompting the physician to increase the dose of VPA and thus worsening the hyperammonemia. Recommendations to monitor both liver function and serum ammonia must be considered in patients taking VPA to assist in the early detection of adverse effects. Clinical pharmacists can play an important role in this area, recommending the best treatment available, considering the constraints of the pharmaceutical market, and providing patient follow-up, with evidence based information.\n\nCompeting interest\n\nThe author declares that she has no competing interest.\n\nAcknowledgements\nI would like to thank Dr. Carlos Basílio, Director of the Neurology Department of the Hospital de Faro, E.P.E., and Dr Tommy Westerlund, the Sahlgrenska Academy at the University of Gothenburg and the Swedish Medical Products Agency, for reviewing the manuscript.\n==== Refs\nReferences\nCarr RB Sherwsbury K Hyperammonemia due to valproic acid in the psychiatric setting Am J Psychiatry 2007 164 7 1020 1027 10.1176/ajp.2007.164.7.1020 17606652 \nCash WJ McConville P McDermott E McCormick PA Callender ME McDougall NI Cuurrent concepts in the assessment and treatment of hepatic encephalopathy Q J Med 2010 103 9 16 10.1093/qjmed/hcp152 \nCuturic M Abramson RK Acute hyperammonemic coma with chronic valproic acid therapy Ann Pharmacother 2005 39 2119 23 10.1345/aph.1G167 16288075 \nLabuzetta JN Yao JZ Bourque DL Zivin J Adult nonhepatic hyperammonemia. A case report and differential diagnosis Am J Med 2010 123 885 891 10.1016/j.amjmed.2010.02.029 20920686 \nNaranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 10.1038/clpt.1981.154 7249508 \nNeff G Pharmacoeconomics of hepatic encephalopathy Pharmacotherapy 2010 30 5 Pt 2 28S 32S 10.1592/phco.30.pt2.28S 20412038 \nShiano TD Treatment options for hepatic encephalopathy Pharmacotherapy 2010 30 5 Pt2 16S 21S 10.1592/phco.30.pt2.16S 20412036 \nStewart JT A case of hyperammonemic encephalopathy after 11 years of valproate therapy. Case report J Clin Psycopharmacol 2008 28 3 361 10.1097/JCP.0b013e31817275b6 \nYee JL Wong D Ormiston TM Encephalopathy and hyperammonemia associated with valproic acid J Pharm Technol 2005 21 348 50 10.1177/875512250502100607\n\n",
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"abstract": "Pure red cell aplasia (PRCA) due to neutralizing antibodies can rarely develop following treatment with epoetin. The treatment of this condition is generally unsatisfactory and immunosuppression is often recommended, which improves chances of hematological recovery. We describe a case of PRCA due to neutralizing anti-epoetin antibodies following therapy with epoetin-α in a 68-year-old man on hemodialysis. He presented with severe transfusion-dependent anemia and was initially treated with prednisolone and oral cyclophosphamide. However, within 2 weeks the immunosuppressive drugs had to be stopped due to complications, following which he remained transfusion dependent. Subsequently, he was given two doses 700 mg each of rituximab following which there were hematological recovery and resolution of anti-epoetin antibodies.",
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"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-25-36610.4103/0971-4065.156897Case ReportRituximab: A viable treatment option for epoetin-induced pure red cell aplasia Mahajan S. A. Nandagopal N. Soni M. 1Annigeri R. A. Department of Nephrology, Apollo Hopsitals, Chennai, Tamil Nadu, India1 Department of Pathology, Apollo Hopsitals, Chennai, Tamil Nadu, IndiaAddress for correspondence: Dr. Rajeev A. Annigeri, Department of Nephrology, Apollo Hospitals, Chennai - 600 006, Tamil Nadu, India. E-mail: r_annigeri@yahoo.comNov-Dec 2015 25 6 366 369 Copyright: © Indian Journal of Nephrology2015This 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.Pure red cell aplasia (PRCA) due to neutralizing antibodies can rarely develop following treatment with epoetin. The treatment of this condition is generally unsatisfactory and immunosuppression is often recommended, which improves chances of hematological recovery. We describe a case of PRCA due to neutralizing anti-epoetin antibodies following therapy with epoetin-α in a 68-year-old man on hemodialysis. He presented with severe transfusion-dependent anemia and was initially treated with prednisolone and oral cyclophosphamide. However, within 2 weeks the immunosuppressive drugs had to be stopped due to complications, following which he remained transfusion dependent. Subsequently, he was given two doses 700 mg each of rituximab following which there were hematological recovery and resolution of anti-epoetin antibodies.\n\nAnti-epoetin antibodiespure red cell aplasiarituximab\n==== Body\nIntroduction\nPure red cell aplasia (PRCA) is a rare disorder characterized by maturation arrest of erythrocytes, normocytic normochromic anemia, severe reticulocytopenia, almost complete absence of marrow erythroblasts, and normal production of white cell and platelets.[1] PRCA causes severe, transfusion-dependent anemia. PRCA in adults is generally acquired, can be primary or secondary and often the cause is immunological. The secondary causes of PRCA are drugs, viral infections, hematological malignancies, systemic lupus erythematosis and solid tumors. It is rarely seen as an adverse effect of long-term use of recombinant human erythropoietin (epoetin) due to the production of neutralizing anti epoetin antibodies.[2] Anti-epoetin antibody-mediated PRCA is suspected when epoetin is used for some length of time, manifests as rapid onset of severe anemia, which requires transfusions to maintain stable hemoglobin (Hb). The definitive diagnosis, however, requires two criteria: (1) bone marrow examination showing normal cellularity and almost absence of erythroblasts, and (2) demonstration of neutralizing antibodies against epoetin in the blood. In addition, serum erythropoietin levels tend to be low in anti-epoetin antibody-mediated PRCA in contrast to higher levels seen in other conditions causing PRCA such as hematological malignancies. In 1997, following a decade of widespread clinical use after introduction in 1986, definitive cases of epoetin-associated PRCA was reported.[2] Subsequently, the reported cases increased progressively to peak in 2002 and then showed a decline since 2003. The cause of increased incidence of epoetin-associated PRCA during this period remains unclear. However, several factors such as formulations lacking in human serum albumin, subcutaneous administration and uncoated rubber stoppers used in prefilled syringes were thought to have contributed to this epidemic.[2]\n\nThe optimal treatment of anti-epoetin antibody-mediated PRCA is unclear. Mere withdrawal of epoetin is mostly unsatisfactory and immunosuppressive therapy appears to enhance markedly the likelihood of recovery.[3] Several immunosuppressive drugs such as corticosteroids, cyclophosphamide, cyclosporine and intravenous immunoglobulin (IV Ig) have been used with variable reported response.[4] Renal transplantation results in resolution of the condition in almost all cases.[3] Very few case reports of PRCA treated with rituximab appear in the literature.\n\nWe report a case of anti-epoetin antibody-mediated PRCA, treated successfully with rituximab, following intolerance to corticosteroid and oral cyclophosphamide.\n\nCase Report\nA 68-year-old man was diagnosed to have end-stage renal disease due to hypertensive nephropathy and was initiated on hemodialysis (HD) in March 2012. He received HD three times a week for 5 h each time. He received epoetin-α 4000 IU twice a week intravenously initially and later switched to subcutaneous administration in August 2013. He responded well to epoetin till November 2013, when Hb was 11.6 g/dl. Between November 2013 and January 2014, he had a precipitous drop in Hb (11.6 to 6.4 g/dl) for no obvious reason. Iron deficiency, external bleeding, gastrointestinal blood loss or hemolysis was excluded by appropriate investigations. Anemia worsened rapidly over next few days and he was hospitalized with significant anemic symptoms and received 4 units of blood during the hospital stay. Erythropoietin treatment was withdrawn as epoetin related PRCA was suspected since reticulocyte count was low at 0.7%. Bone marrow aspiration and biopsy were done, which confirmed the presence of PRCA. Bone marrow showed normocellular marrow, with severe suppression of erythroid series and normal myeloid and megakaryocyte series [Figure 1]. The presence of neutralizing anti-epoetin antibodies was confirmed by immunoprecipitation test [Table 1]. The neutralizing anti-epoetin antibody was positive at a dilution of 1:10,000 at the time of diagnosis. Serum level of endogenous erythropoietin levels was low [Table 1]. Renal transplantation was not a viable option for him in view of advanced age and comorbidities. In an effort to reduce the anti-epoetin antibodies, he was commenced on oral cyclophosphamide (1.5 mg/kg/day) and oral prednisolone 0.5 mg/kg/day. Two weeks into the treatment, he developed massive gastrointestinal bleed due to duodenal ulcer, requiring blood transfusions, following which steroid was withdrawn. He was admitted to Critical Care Unit where he developed right upper zone pneumonia requiring mechanical ventilation. In addition, he developed low white cell count, necessitating withdrawal of cyclophosphamide. He was given 8 units of transfusions during 10 days of hospitalization. Subsequently he remained transfusion dependent and required approximately one unit of red cells per week to maintain Hb above 6 g/dl [Figure 2]. In view of advanced age and intolerance to conventional immunosuppressive agents such as steroid and cyclophosphamide, he was treated with rituximab, 2 doses of 700 mg (approximately 500 mg/m2) in the month of April 2014, given 2 weeks apart. Meanwhile, he was also treated with 3 doses of androgenic steroid (nandrolone 25 mg) at 15 days interval, in order to support the recovery of the bone marrow. With the treatment, his Hb remained in the range of 6.1–6.4 g/dl for 2–3 weeks without blood transfusion and subsequently improved to above 7 g/dl. Currently, the patient maintains his Hb above 7 g/dl without any need for blood transfusion for more than 6 months after the last dose of rituximab. Serial measurement of neutralizing anti-epoetin antibody titer showed a decline and reached nonsignificant levels by 6 months, demonstrating success with therapy [Table 1]. We did not repeat the bone marrow study since there was clear clinical evidence of hematological recovery in the form of sustained increment in Hb, freedom from a blood transfusion and an increase in the reticulocyte count. He was not rechallenged with any other preparation of epoetin since he was symptom-free and did not require any further blood transfusions to maintain stable Hb.\n\nFigure 1 Bone marrow biopsy showing absence of erythroblasts and normal myeloid series and platelet precursors\n\nTable 1 Results of neutralizing anti-EPO antibodies and EPO level over the course of time\n\nFigure 2 Hemoglobin and number of red cell transfusions over time and their relation to treatment. White arrow depicts duration of treatment with corticosteroid and oral cyclophosphamide. Black arrow represents two doses of rituximab\n\nDiscussion\nWe present a case of PRCA who responded to rituximab, indicating successful treatment of the condition. He also received three doses of nandrolone 25 mg each, which, however, is unlikely to have caused a sustained increment in Hb. The use of anabolic steroid may have some benefit in elderly males with anemia who are likely to have testosterone deficiency, but its benefit in renal anemia is doubtful and is not recommended for use in chronic kidney disease (CKD).[5]\n\nTreatment of anti-epoetin antibody-mediated PRCA is unsatisfactory despite the withdrawal of the drug. Verhelst et al. reported that hematological recovery was seen only in 2% of the patients after withdrawal of the drug, whereas immunosuppressive therapy improved the likelihood of recovery to 52%.[3] Since no randomized trials are available to compare individual immunosuppressive drugs, the data is insufficient to provide clear guidelines for a preferred agent to treat this condition. However, amongst the immunosuppressive agents, the hematological recovery is the highest in those treated with steroid and cyclophosphamide (87%) and lowest with IV Ig (11%). Monotherapy with cyclosporine or steroid has intermediate efficacy.[3]\n\nRituximab is a genetically engineered monoclonal antibody directed against CD20 antigen, seen in certain subset of B-cells and causes significant B-cell depletion.[6] It is being increasingly used to treat several immune mediated diseases. It is an expensive drug and it remains to be understood how best to use it in cost-effective manner. Case reports and case series have reported successful treatment of PRCA with rituximab in non-epoetin related PRCA such as lymphoproliferative malignancies[7] and primary PRCA.[8] Rituximab offers an attractive alternate to other immunosuppressive agents to treat epoetin related PRCA. However, rituximab is not commonly used and only few cases of rituximab used to treat epoetin related PRCA are reported in the literature.[391011] Behler et al. reported a case of epoetin related PRCA in a woman receiving ribavirin and interferon for hepatitis C infection.[9] She received a high dose of epoetin alfa 40,000 units per week for treatment of anemia and developed neutralizing antibodies against epoetin. She was treated with rituximab and IV Ig, which resulted in hematological recovery and disappearance of neutralizing anti-epoetin antibodies. Treatment with rituximab did not cause reactivation of hepatitis C infection. Mandreoli et al. reported success with rituximab to treat PRCA due to epoetin alfa in an 80-year-old patient with CKD.[10] Conventional immunosuppressive therapy was deferred for practical reasons in this patient, due to advanced CKD and age. Comont et al. reported a case of 69-year-old male with CKD and myelodysplastic syndrome on epoetin-α who developed epoetin induced PRCA. Steroids, cyclophosphamide, and cyclosporine were considered unsuitable due to comorbid conditions and hence he was given 2 g of IV rituximab, following which anti-epoetin antibodies reduced substantially after a month.[11] In contrast, Verhelst et al. reported no response to rituximab in 2 patients treated with rituximab in the case series of epoetin related PRCA.[3] In summary, of the 5 cases of epoetin related PRCA treated with rituximab previously reported in the literature, 3 showed success while, other 2 showed no benefit. Our case and few other reports suggest that rituximab is a viable alternative in treating PRCA due to the neutralizing anti-epoetin antibody. Extensive clinical experience in several hematological malignancies and immune-mediated diseases suggest that rituximab is safe and generally well tolerated even in patients with renal dysfunction.[6] It may be used an alternative to currently established immunosuppressive therapy such as steroid and cyclophosphamide if these drugs are contraindicated or not tolerated. However, the high cost of rituximab may be a deterrent to use it as afirst-line therapy, especially in developing world.\n\nConclusion\nWe report a case of anti-epoetin antibody-mediated PRCA in a 68-year-old man, which was successfully treated with rituximab resulting in hematological recovery and complete disappearance of neutralizing anti-epoetin antibodies. Our case suggests that rituximab offers a viable alternative to treat PRCA due to epoetin, in whom alternate immunosuppressive agents are not tolerated or contraindicated.\n\nAcknowledgment\nWe are grateful to Dr. David Wilkinson, CLIA Immunochemistry Laboratory, Richmond, VA, USA and Janssen, a Pharmaceutical division of Johnson and Johnson Private Limited for the serial measurements of neutralizing anti-epoetin antibody.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Rossert J Pure Red Cell Aplasia Global Scientific Advisory Board (GSAB). Erythropoietin-induced, antibody-mediated pure red cell aplasia Eur J Clin Invest 2005 35 Suppl 3 95 9 16281965 \n2 Boven K Knight J Bader F Rossert J Eckardt KU Casadevall N Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: Solving the mystery Nephrol Dial Transplant 2005 20 Suppl 3 iii33 40 15824129 \n3 Verhelst D Rossert J Casadevall N Krüger A Eckardt KU Macdougall IC Treatment of erythropoietin-induced pure red cell aplasia: A retrospective study Lancet 2004 363 1768 71 15172775 \n4 Bennett CL Cournoyer D Carson KR Rossert J Luminari S Evens AM Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: A follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project Blood 2005 106 3343 7 16099877 \n5 Kliger AS Foley RN Goldfarb DS Goldstein SL Johansen K Singh A KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD Am J Kidney Dis 2013 62 849 59 23891356 \n6 Evans R Salama AD Update on rituximab: An established treatment for all immune-mediated kidney diseases? Nephron Clin Pract 2014 126 97 109 24686110 \n7 Narra K Borghaei H Al-Saleem T Höglund M Smith MR Pure red cell aplasia in B-cell lymphoproliferative disorder treated with rituximab: Report of two cases and review of the literature Leuk Res 2006 30 109 14 16043218 \n8 Auner HW Wölfler A Beham-Schmid C Strunk D Linkesch W Sill H Restoration of erythropoiesis by rituximab in an adult patient with primary acquired pure red cell aplasia refractory to conventional treatment Br J Haematol 2002 116 727 8 11879264 \n9 Behler CM Terrault NA Etzell JE Damon LE Rituximab therapy for pure red cell aplasia due to anti-epoetin antibodies in a woman treated with epoetin-alfa: A case report J Med Case Rep 2009 3 7335 19830190 \n10 Mandreoli M Finelli C Lopez A Ascani S Vianelli N Baccarani M Successful resumption of epoetin alfa after rituximab treatment in a patient with pure red cell aplasia Am J Kidney Dis 2004 44 757 61 15384028 \n11 Comont T Bournet B Casadevall N Chauveau D Faguer S Rituximab in pure red-cell aplasia secondary to anti-erythropoietin antibodies Kidney Int 2014 86 210 1 24978384\n\n",
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"keywords": "Anti-epoetin antibodies; pure red cell aplasia; rituximab",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "366-9",
"pmc": null,
"pmid": "26664213",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "11879264;24978384;16099877;24686110;16281965;23891356;16043218;19830190;15824129;15384028;15172775",
"title": "Rituximab: A viable treatment option for epoetin-induced pure red cell aplasia.",
"title_normalized": "rituximab a viable treatment option for epoetin induced pure red cell aplasia"
} | [
{
"companynumb": "IN-MYLANLABS-2015M1043992",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Hemolytic transfusion reactions are a rare, yet serious complication of red blood cell (RBC) transfusion. Patients with sickle cell disease (SCD) are at an increased risk for such reactions, because they are prone to make alloantibodies against transfused RBCs, complicating this integral part of their disease management. These reactions may be missed, and the patient's state may be attributed to vaso-occlusive crisis (VOC), with misguided therapy ensuing.\n\n\n\nHerein, we report the clinical course of a patient with complex SCD with a delayed hemolytic transfusion reaction, followed by multiple acute hemolytic transfusion reactions mistaken for severe VOC. These reactions were diagnosed on retrospective review of the patient's clinical course in consult with the transfusion medicine service. Optimal immunosuppressive therapy ensued and resulted in the stabilization of the anemia and hemolysis laboratory values. Despite these efforts, the patient died 2 months after admission.\n\n\n\nThis case provides insight into some of the challenges of managing patients with SCD with multiple comorbidities. Hemolytic transfusion reactions can be difficult to diagnose and may be overlooked in patients with SCD with severe VOC.",
"affiliations": "Center for Transfusion and Cellular Therapy, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.;Center for Transfusion and Cellular Therapy, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.;Center for Transfusion and Cellular Therapy, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.;Center for Transfusion and Cellular Therapy, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.",
"authors": "Dean|Christina L|CL|0000-0002-7430-2074;Maier|Cheryl L|CL|;Roback|John D|JD|;Stowell|Sean R|SR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/trf.15010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "59(2)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000328:Adult; D000755:Anemia, Sickle Cell; D017707:Erythrocyte Transfusion; D017809:Fatal Outcome; D005260:Female; D006461:Hemolysis; D006801:Humans; D065227:Transfusion Reaction",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "448-453",
"pmc": null,
"pmid": "30412270",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple hemolytic transfusion reactions misinterpreted as severe vaso-occlusive crisis in a patient with sickle cell disease.",
"title_normalized": "multiple hemolytic transfusion reactions misinterpreted as severe vaso occlusive crisis in a patient with sickle cell disease"
} | [
{
"companynumb": "GE-FRESENIUS KABI-FK201902382",
"fulfillexpeditecriteria": "1",
"occurcountry": "GE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBupropion is a monocyclic antidepressant in the aminoketone class, structurally related to amphetamines. The Food and Drug Administration withdrew this product from the market in 1986 after seizures were reported in bulimic patients. It was later reintroduced in 1989 when the incidence of seizures was shown to be dose-related in the immediate release preparation. Massive bupropion ingestion has been associated with status epilepticus and cardiogenic shock in adults. Seizures have been reported in children, but not status epilepticus. This report highlights a patient who presented with status epilepticus and developed cardiopulmonary arrest after bupropion ingestion. False-positive amphetamine diagnosis from urine drug screen on presentation was reported.\n\n\nMETHODS\nWe review the presentation, clinical course, diagnostic studies, and outcome of this patient. We then review the literature regarding bupropion overdose in children.\n\n\nRESULTS\nSymptoms of bupropion toxicity and risk for seizures are dose-dependent and fatalities have been reported. Our patient developed status epilepticus and cardiopulmonary arrest and then progressed to have a hypoxic ischemic encephalopathy and refractory symptomatic partial seizures.\n\n\nCONCLUSIONS\nOur report highlights the need to keep this medication away from children in order to prevent accidental overdose.",
"affiliations": "Division of Pediatric Neurology, University of Tennessee Health Science Center, Le Bonheur Children's Hospital Neuroscience Institute, Memphis Tennessee.;Division of Pediatric Neurology, University of Tennessee Health Science Center, Le Bonheur Children's Hospital Neuroscience Institute, Memphis Tennessee.;Division of Pediatric Neurology, University of Tennessee Health Science Center, Le Bonheur Children's Hospital Neuroscience Institute, Memphis Tennessee.;Division of Pediatric Neurology, University of Tennessee Health Science Center, Le Bonheur Children's Hospital Neuroscience Institute, Memphis Tennessee. Electronic address: jwheless@uthsc.edu.",
"authors": "Rivas-Coppola|Marianna S|MS|;Patterson|Amy L|AL|;Morgan|Robin|R|;Wheless|James W|JW|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "53(3)",
"journal": "Pediatric neurology",
"keywords": "bupropion; cardiogenic shock; children; hypotension; status epilepticus; toxicity",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D018687:Antidepressive Agents, Second-Generation; D001921:Brain; D016642:Bupropion; D003937:Diagnosis, Differential; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D013226:Status Epilepticus",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "257-61",
"pmc": null,
"pmid": "26183178",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bupropion Overdose Presenting as Status Epilepticus in an Infant.",
"title_normalized": "bupropion overdose presenting as status epilepticus in an infant"
} | [
{
"companynumb": "US-UCBSA-2015029629",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": null,
"dr... |
{
"abstract": "Human epidermal growth factor receptor 2 (HER2) mutation in non-small cell lung cancer (NSCLC) is an oncogenic driver that possibly becomes a druggable target to HER2-targeted therapy. The benefit of HER2-targeted therapy is much less defined especially in eastern populations. We provide evidence of clinical benefit of afatinib in a 50-year-old Asian woman with HER2-mutant NSCLC who previously failed cytotoxic chemotherapy and gefitinib treatment. Next-generation sequencing of the tumor tissue revealed a HER2 exon 20 mutation (c.2437A>G), which has never been reported. The patient was treated with afatinib for more than four months. She showed rapid radiologic response within a month, and maintained stable state until the last dose of afatinib.",
"affiliations": "Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea.;Department of Pathology, Konkuk University Hospital, Seoul, Korea.;Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.;Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea.;Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea.;Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea.;Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea.;Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun, Korea.;Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea.;Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea.",
"authors": "Park|Cheol Kyu|CK|https://orcid.org/0000-0001-8701-0786;Hur|Jae Young|JY|https://orcid.org/0000-0001-6105-9899;Choi|Chang Min|CM|https://orcid.org/0000-0002-2881-4669;Kim|Tae Ok|TO|https://orcid.org/0000-0002-0922-9472;Cho|Hyun Ju|HJ|https://orcid.org/0000-0002-2308-5997;Shin|Hong Joon|HJ|https://orcid.org/0000-0002-0146-3491;Lim|Jung Hwan|JH|https://orcid.org/0000-0003-0039-0662;Choi|Yoo Duk|YD|https://orcid.org/0000-0001-5582-5999;Kim|Young Chul|YC|https://orcid.org/0000-0001-7019-7687;Oh|In Jae|IJ|https://orcid.org/0000-0003-4837-1321",
"chemical_list": "D000970:Antineoplastic Agents; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077716:Afatinib; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2",
"country": "Korea (South)",
"delete": false,
"doi": "10.3346/jkms.2018.33.e7",
"fulltext": "\n==== Front\nJ Korean Med SciJ. Korean Med. SciJKMSJournal of Korean Medical Science1011-89341598-6357The Korean Academy of Medical Sciences 10.3346/jkms.2018.33.e7Case ReportRespiratory DiseasesEfficacy of Afatinib in a Previously-Treated Patient with Non-Small Cell Lung Cancer Harboring HER2 Mutation: Case Report https://orcid.org/0000-0001-8701-0786Park Cheol Kyu 12https://orcid.org/0000-0001-6105-9899Hur Jae Young 3https://orcid.org/0000-0002-2881-4669Choi Chang-Min 4https://orcid.org/0000-0002-0922-9472Kim Tae-Ok 1https://orcid.org/0000-0002-2308-5997Cho Hyun-Ju 12https://orcid.org/0000-0002-0146-3491Shin Hong-Joon 1https://orcid.org/0000-0003-0039-0662Lim Jung-Hwan 12https://orcid.org/0000-0001-5582-5999Choi Yoo-Duk 25https://orcid.org/0000-0001-7019-7687Kim Young-Chul 12https://orcid.org/0000-0003-4837-1321Oh In-Jae 121 Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea.2 Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun, Korea.3 Department of Pathology, Konkuk University Hospital, Seoul, Korea.4 Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.5 Department of Pathology, Chonnam National University Medical School, Gwangju, Korea.Address for Correspondence: In-Jae Oh, MD. Department of Internal Medicine, Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun 58128, Republic of Korea. droij@chonnam.ac.kr10 11 2017 01 1 2018 33 1 e705 6 2016 03 9 2016 © 2018 The Korean Academy of Medical Sciences.2018The Korean Academy of Medical SciencesThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Human epidermal growth factor receptor 2 (HER2) mutation in non-small cell lung cancer (NSCLC) is an oncogenic driver that possibly becomes a druggable target to HER2-targeted therapy. The benefit of HER2-targeted therapy is much less defined especially in eastern populations. We provide evidence of clinical benefit of afatinib in a 50-year-old Asian woman with HER2-mutant NSCLC who previously failed cytotoxic chemotherapy and gefitinib treatment. Next-generation sequencing of the tumor tissue revealed a HER2 exon 20 mutation (c.2437A>G), which has never been reported. The patient was treated with afatinib for more than four months. She showed rapid radiologic response within a month, and maintained stable state until the last dose of afatinib.\n\nGraphical Abstract\n\n\nHER2 mutationNon-small Cell Lung CancerAfatinib\n==== Body\nINTRODUCTION\nSeveral oncogenic mutations in non-small cell lung cancer (NSCLC) have been discovered, directly impacting patient's prognosis and management. With the exception of well-known alterations, such as epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement, genetic profiling has identified additional driver mutations in lung adenocarcinomas with 9%–14% being new targetable oncogenes.1\n\nHuman epidermal growth factor receptor 2 (HER2) is a member of the ERBB receptor tyrosine kinase family. HER2 receptor is activated by homodimerization or heterodimerization with the other ERBB family receptors, especially EGFR,1 resulting in augmentation of EGFR signaling. Oncogenic activation of HER2 is present in various malignancies, such as breast, ovarian, bladder, salivary gland, endometrial, pancreatic, and NSCLC.2 The major mechanisms of HER2 alterations in NSCLC include HER2 protein overexpression, gene amplification and mutation.3\nHER2 mutation is predominantly observed in female patients, non-smokers and patients with adenocarcinoma subtype, similar to EGFR-mutated NSCLC.4\n\nThe benefit of HER2-targeted therapy for NSCLC harboring HER2 alteration is much less defined than that for breast cancer. Trastuzumab, a monoclonal antibody that targets extracellular domain IV of HER2 receptor, has not shown a clear benefit in HER2-positive NSCLC.5 By comparison, tyrosine kinase inhibitors (TKIs) that target both EGFR and HER2 have been associated with response to treatment.5 Among them, afatinib (Gilotrif®, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA) is a potent and irreversible ERBB family blocker with preclinical activity in Ba/F3 cells expressing an artificial HER2 mutant and in a human lung cancer cell line with an insertional mutation at codon 776.6 Results with afatinib in HER2-positive NSCLC have been promising, but there have been only a few clinical studies and limited data in the form of case reports involving western patients.7891011\n\nWe present the first oriental case of previously treated NSCLC, which initially had no available activating target and finally had response to afatinib after detection of HER2 mutation. Furthermore, we review the clinical impacts of HER2 alterations in diagnosis and the role of afatinib in treatment of NSCLC harboring HER2 mutation.\n\nCASE DESCRIPTION\nA 50-year-old Korean woman who had never smoked visited our lung cancer clinic in February 2015. She complained of upper airway infection symptoms of mild back pain followed by cough with sputum and rhinorrhea. Computed tomography (CT) from an outside hospital showed a right upper lobar mass with enlargement of adjacent interlobar lymph node, and miliary distribution of multiple tiny nodules in both lungs (Fig. 1A). She was diagnosed with stage IV lung adenocarcinoma with metastases to both lungs, T12 spine, left femur and brain that was proven by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), positron emission tomography and brain magnetic resonance imaging (MRI). Her initial tumor biopsy from primary mass and lymph nodes was negative for EGFR mutation and ALK translocation.\n\nFig. 1 Serial CT scans of a present patient before treatment with afatinib. (A) Baseline image before chemotherapy. (B) Post-treatment image after four cycles of pemetrexed and cisplatin, assessed as stable disease. (C) Follow-up image without subsequent treatment before start of gefitinib, showing disease progression of right upper lobe mass and lung-to-lung metastases. (D) Post-treatment image after two cycles of gefitinib, assessed as progression with aggravation of lung-to-lung metastases.\n\nCT = computed tomography.\n\nShe received four cycles of pemetrexed and cisplatin, and her tumor burden was retained as stable disease (Fig. 1B). She stopped the chemotherapy due to poor performance status without maintenance therapy. Upon progression of right upper lobar mass, multiple lung nodules and metastatic lymphadenopathies after 2 months without subsequent treatment (Fig. 1C), she received gefitinib for the next 2 months. Subjectively-rated symptoms of nausea and myalgia seemed to ease, but gefitinib was finally stopped due to aggravation of gastrointestinal toxicity and lung-to-lung metastases (Fig. 1D). Thereafter, progression in brain metastasis was also demonstrated in follow-up MRI. She suffered from general weakness, nausea and back pain, and so was reluctant to receive further cytotoxic chemotherapy.\n\nIn September 2015, she agreed to be tested for another activating mutation using previously achieved specimen by EBUS-TBNA. Pathologic examination revealed a poorly differentiated atypical cell nest with focal glandular differentiation (Fig. 2B). Immunohistochemical stain for c-erbB2 showed weak membranous staining (Fig. 2C). After direct sequencing as screening test, the following next generation sequencing (NGS) of the tissue revealed a HER2 exon 20 mutation with A-to-G base change at nucleotide 2437 (c.2437A>G), which led to substitution of aspartate for asparagine at position 813 (p.N813D) (Fig. 2A). This mutation has never been reported. In October 2015, she started afatinib 40 mg daily. An initial clinical and radiologic response was achieved within a month. She professed a sense of well-being and relief of back pain, and simple chest X-ray showed more decreased lung nodules grossly. During week 6 of treatment, a CT assessment revealed a partial response in extracranial lesions with prominent regression of primary lung tumors in the right upper lobe and lung-to-lung metastases (Fig. 3). Brain metastases had maintained the stable state, and she did not complain of any neurologic symptom or sign. After stepwise dose reduction to 20 mg due to stomatitis and nausea, she has continued the medication until February 2016 without deterioration of subjective symptom and tumor burden. Last CT scan on January 2016 still showed a partial response in extracranial lesion, but brain MRI revealed mild increase of metastases. At last visit on February 2016, the patient complained of general weakness and anorexia with stomatitis, and thereafter she was lost to follow-up.\n\nFig. 2 Pathologic and molecular diagnosis for lung adenocarcinoma harboring HER2 mutation. (A) Next-generation sequencing result of a patient with HER2 exon 20 mutation. The A-to-G base-pair change at nucleotide 2437 in HER2 exon 20 (c.2437A>G) is denoted by the dominant black bar which is found in approximately 6% of sequence reads. The sequence depth is 2614 indicated by the blue line. The A-to-G base change leads to substitution of aspartate for asparagine at position 813 (p.N813D). Variation less than 1% is regarded as experimental noise. Nucleotides are colored as follows: G as black bar, A as green bar, C as blue bar, T as red bar, and base deletion as gray bar. A selection of aligned sequence reads is shown with A-to-G base change highlighted in yellow with red lettering. First line shows the reference sequence (green). (B) Poorly differentiated atypical cell nest with focal glandular differentiation (H & E, × 400). (C) Weak membranous staining on immunohistochemical staining for c-erbB2 (× 400).\n\nHER2 = human epidermal growth factor receptor 2, H & E = haematoxylin and eosin, NGS = next generation sequencing.\n\nFig. 3 Radiologic findings before and after treatment. (A) Chest X-ray before starting afatinib. (B) X-ray 6 weeks after afatinib. (C) CT scan before starting afatinib. (D) CT scan 6 weeks after afatinib. The images demonstrate regression of right upper lung mass and lung-to-lung metastases.\n\nCT = computed tomography.\n\nDISCUSSION\nWe provide evidence of clinical benefit from treatment with afatinib in an oriental patient with HER2-mutant NSCLC who had previously failed cytotoxic chemotherapy and treatment with reversible EGFR inhibitor.\n\nIn terms of HER2 gene mutation, NGS is becoming an important method of detection in NSCLC, even though the traditional single-gene sequencing (i.e., Sanger sequencing) is still widely performed. NGS can simultaneously test for multiple oncogenic driver mutations, rearrangements and gene amplifications.5 In this case, we performed direct sequencing for screening followed by NGS for confirmation. And we found a HER2 exon 20 mutation (p.N813D) which has never been reported. Although it takes more than three weeks to confirm the result and the cost is quite high in real clinic settings, NGS has advantage over direct sequencing in detecting very rare mutations even when the biopsy specimen is limited.\n\nThere were some reports about types of HER2 mutation. Compared with EGFR, HER2 mutations were less heterogeneous. The majority (over 80%) were in-frame insertions in exon 20 of the kinase domain, which ranged from 3 to 12 base-pair (bp), all nested between codons 775 and 831.12 The 12-bp insertion is known as the most common mutation showing duplication/insertion of 4 amino acids (YVMA) at codon 775 (A775_G776insYVMA).12 In addition, other mutations are as follows: bp insertion (i.e., G776>VC, P780_Y781insGSP, V777_G778insCG), insertion/deletion (i.e., M774delinsWLV, G776>LC), or point mutations (i.e., L755S, G776C, G776L, V777L).791213 There was no previous report about N813D point mutation found in this case. N813D mutation is also located in exon 20 of HER2 kinase domain. Given that most HER2 mutations were known to be found in the proximal region of exon 20, N813D is supposed to be a novel and rare mutation in the distal region of exon 20.\n\nAvailable data concerning HER2-targeted therapy for HER2-positive NSCLC is insufficient and less defined. Trastuzumab monotherapy or addition to chemotherapy has not shown a clear benefit in HER2-positive NSCLC,5 although certain cases with favorable outcome have been described.914 Several dual TKIs to EGFR and HER2 have shown hopeful results in select patients. In a recent phase II cohort study for recurrent or newly detected lung adenocarcinoma, dacomitinib produced objective responses in patients with specific HER2 exon 20 insertion mutation (response rate 12%, median overall survival 9 months).13 Neratinib in combination with temsirolimus also showed responses in two of 11 patients with HER2 mutation-positive NSCLC in a phase I study of pretreated patients with HER2-driven cancers.15\n\nThe National Comprehensive Cancer Network has included trastuzumab and afatinib as potential therapy options for NSCLC patients with HER2 mutations.16 Afatinib, a pan-HER inhibitor, has shown limited but promising data for treatment of HER2-mutated NSCLC from several reports and studies mostly involving western patients, including Europe, United States, and Australia. In an exploratory phase II study with afatinib, all three patients with HER2 mutation showed objective response, even after failure of other EGFR- and/or HER2-targeted treatment.7 In a recent case report, a patient harboring specific HER2 mutated lung adenocarcinoma with exon 20 YVMA insertion (p.A775_G776insYVMA) showed durable response for 10 months to afatinib; the patient had been alternately treated with cytotoxic chemotherapy and HER2-targeted agents including pertuzumab and trastuzumab.8 A retrospective series of 16 patients with HER2 mutation showed favorable outcomes, with a 93% disease control rate for trastuzumab-based therapies and 100% for afatinib.9 In a recent phase II study of afatinib for previously treated lung adenocarcinoma, five of seven patients achieved disease control (71%). Furthermore, one patient who received afatinib (40 mg/day) combined with paclitaxel following afatinib monotherapy (50 mg/day) due to progression showed a confirmed partial response with a duration of 41.9 weeks.11 These data demonstrate that afatinib may have clinical application in patients whose tumors are constitutively dependent on the HER2 pathway. Similarly, in the present report, which is the first case in an eastern population, the patient showed a rapid regression within a month and durable response over 5 months. Although dose reduction was inevitable due to adverse events beginning a month after commencement of treatment, the objective response was continued thereafter even when the initial dose of afatinib was halved (20 mg/day).\n\nThe antitumor mechanism of afatinib in HER2-altered NSCLC has been demonstrated by in vitro and in vivo experimental study. In a study using HER2-altered NSCLC cell lines and xenograft mouse model, afatinib downregulated the phosphorylation of HER2 and EGFR in addition to their downstream signaling, and induced and antiproliferative effect through G1 arrest and apoptotic cell death both in HER2-amplified and -mutant cell lines, which was also confirmed in vivo.17\n\nHowever, the superiority of a HER2-targeted therapy to chemotherapy is not conclusive. In a European cohort study for advanced NSCLC with HER2 exon 20 insertion mutation, subgroup with conventional therapy including chemotherapy and reversible EGFR-TKI did not show a survival benefit compared to those with HER2-targeted drugs including trastuzumab (monotherapy or addition to chemotherapy), trastuzumab emtasine (T-DM1), neratinib, afatinib and lapatinib.10 Therefore, additional well-designed randomized clinical trials with novel and target-specific agents are warranted.\n\nIn summary, afatinib could be a potential treatment option for subgroups of HER2-mutated NSCLC that progress after previous cytotoxic chemotherapy or treatment with reversible EGFR-TKIs. NGS could be advantageous as it provides a precise result for HER2 mutation, even in limited biopsy specimen.\n\nACKNOWLEDGMENTS\nWe used afatinib off-label in this case because the drug was approved only for 1st line treatment in a non-small cell lung cancer (NSCLC) patient with epidermal growth factor receptor (EGFR) mutation in Korea.\n\nDisclosure: The authors have no potential conflicts of interest to disclose.\n\nAuthor Contributions: Conceptualization: Park CK, Choi CM, Oh IJ. Data curation: Park CK, Hur JY, Cho HJ, Choi YD, Oh IJ. Formal analysis: Park CK, Hur JY, Choi YD, Oh IJ. Investigation: Park CK, Kim TO, Lim JH, Kim YC, Oh IJ. Validation: Park CK, Shin HJ, Oh IJ. Writing - original draft: Park CK, Hur JY, Oh IJ. Writing - review & editing: Park CK, Hur JY, Choi YD, Oh IJ.\n==== Refs\n1 Oxnard GR Binder A Jänne PA New targetable oncogenes in non-small-cell lung cancer J Clin Oncol 2013 31 8 1097 1104 23401445 \n2 Scholl S Beuzeboc P Pouillart P Targeting HER2 in other tumor types Ann Oncol 2001 12 Suppl 1 S81 S87 11521727 \n3 Peters S Zimmermann S Targeted therapy in NSCLC driven by HER2 insertions Transl Lung Cancer Res 2014 3 2 84 88 25806285 \n4 Tomizawa K Suda K Onozato R Kosaka T Endoh H Sekido Y Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers Lung Cancer 2011 74 1 139 144 21353324 \n5 Mar N Vredenburgh JJ Wasser JS Targeting HER2 in the treatment of non-small cell lung cancer Lung Cancer 2015 87 3 220 225 25601485 \n6 Li D Ambrogio L Shimamura T Kubo S Takahashi M Chirieac LR BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models Oncogene 2008 27 34 4702 4711 18408761 \n7 De Grève J Teugels E Geers C Decoster L Galdermans D De Mey J Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu Lung Cancer 2012 76 1 123 127 22325357 \n8 Li BT Lee A O'Toole S Cooper W Yu B Chaft JE HER2 insertion YVMA mutant lung cancer: long natural history and response to afatinib Lung Cancer 2015 90 3 617 619 26559459 \n9 Mazières J Peters S Lepage B Cortot AB Barlesi F Beau-Faller M Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives J Clin Oncol 2013 31 16 1997 2003 23610105 \n10 Mazières J Barlesi F Filleron T Besse B Monnet I Beau-Faller M Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort Ann Oncol 2016 27 2 281 286 26598547 \n11 De Grève J Moran T Graas MP Galdermans D Vuylsteke P Canon JL Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined lung adenocarcinoma Lung Cancer 2015 88 1 63 69 25682316 \n12 Arcila ME Chaft JE Nafa K Roy-Chowdhuri S Lau C Zaidinski M Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas Clin Cancer Res 2012 18 18 4910 4918 22761469 \n13 Kris MG Camidge DR Giaccone G Hida T Li BT O'Connell J Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors Ann Oncol 2015 26 7 1421 1427 25899785 \n14 Cappuzzo F Bemis L Varella-Garcia M HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer N Engl J Med 2006 354 24 2619 2621 16775247 \n15 Gandhi L Bahleda R Tolaney SM Kwak EL Cleary JM Pandya SS Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors J Clin Oncol 2014 32 2 68 75 24323026 \n16 Non-small cell lung cancer (version 4.2016) Updated 2016 Accessed February 5, 2016 http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf \n17 Suzawa K Toyooka S Sakaguchi M Morita M Yamamoto H Tomida S Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations Cancer Sci 2016 107 1 45 52 26545934\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1011-8934",
"issue": "33(1)",
"journal": "Journal of Korean medical science",
"keywords": "Afatinib; HER2 mutation; Non-small Cell Lung Cancer",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D000077716:Afatinib; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D005091:Exons; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D018719:Receptor, ErbB-2; D017422:Sequence Analysis, DNA; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8703518",
"other_id": null,
"pages": "e7",
"pmc": null,
"pmid": "29215816",
"pubdate": "2018-01-01",
"publication_types": "D002363:Case Reports",
"references": "26545934;25682316;25899785;11521727;22325357;24323026;22761469;16775247;21353324;23401445;23610105;26559459;18408761;25601485;25806285;26598547",
"title": "Efficacy of Afatinib in a Previously-Treated Patient with Non-Small Cell Lung Cancer Harboring HER2 Mutation: Case Report.",
"title_normalized": "efficacy of afatinib in a previously treated patient with non small cell lung cancer harboring her2 mutation case report"
} | [
{
"companynumb": "KR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-066710",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "Imatinib has an important place as an adjuvant therapy as well as in the treatment of metastatic disease caused by gastrointestinal stromal tumor (GIST), which is one of the common mesenchymal tumors of the gastrointestinal tract. Imatinib is a tyrosine kinase inhibitor and is generally well tolerated. However, it can cause some serious adverse effects. The most common of these are edema on the face and legs, headache, fatigue, nausea, vomiting, and rash on the skin. The most serious side effects, albeit less common, are gastrointestinal or intraabdominal bleeding. However, thrombotic events such as sigmoid sinus thrombosis and splenic infarction are extremely rare. The current report presents a patient with GIST who is treated with imatinib 400 mg/day. The patient presented with edema on the face and headache in the second month of imatinib therapy, after which she was diagnosed with sigmoid sinus thrombosis. The patient who presented with abdominal pain approximately three months later developed splenic infarction. She was administered acetylsalicylic acid, supplemental oxygen (O2) in the first episode of thrombosis, and imatinib therapy was discontinued. The patient's complaints and thrombus regressed, after which imatinib therapy was resumed. She was administered intravenous hydration, supplemental oxygen, analgesics, and imatinib therapy was discontinued after the patient sustained splenic infarction. After resolution of sigmoid sinus thrombosis and the regression of splenic infarction area, the patient was switched to sunitinib therapy. She is attending routine control visits. Sigmoid sinus thrombosis and splenic infarction should be kept in mind as a rare cause of headache and abdominal pain in patients treated with imatinib, and detailed neurological and gastrointestinal evaluation should be performed.",
"affiliations": "Department of Medical Oncology, Ondokuz Mayıs University Faculty of Medicine; Samsun, Turkey.;Department of Medical Oncology, Ondokuz Mayıs University Faculty of Medicine, Samsun, Turkey.;Department of Medical Oncology, Atatürk University Faculty of Medicine, Erzurum, Turkey.",
"authors": "Yilmaz|Hatice|H|;Demirağ|Güzin|G|;Yılmaz|Ali|A|",
"chemical_list": "D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate",
"country": "Canada",
"delete": false,
"doi": "10.18433/jpps31425",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1482-1826",
"issue": "24()",
"journal": "Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques",
"keywords": null,
"medline_ta": "J Pharm Pharm Sci",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D012851:Sinus Thrombosis, Intracranial; D013159:Splenic Infarction",
"nlm_unique_id": "9807281",
"other_id": null,
"pages": "148-152",
"pmc": null,
"pmid": "33784493",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sigmoid Sinus Thrombosis Followed by Splenic Infarction Due to Imatinib Therapy in a Patient with Gastrointestinal Stromal Tumor; Hematological Side Effects of Imatinib.",
"title_normalized": "sigmoid sinus thrombosis followed by splenic infarction due to imatinib therapy in a patient with gastrointestinal stromal tumor hematological side effects of imatinib"
} | [
{
"companynumb": "NVSC2021TR085094",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "1",
... |
{
"abstract": "Objective To assess whether adjuvant chemotherapy with bevacizumab intraperitoneal (i.p.) is better than adjuvant chemotherapy with bevacizumab intravenous (i.v.) or adjuvant chemotherapy only for patients with advanced ovarian cancer after cytoreduction. Selected patients with advanced ovarian cancer after cytoreduction were divided into three groups depend on their will: adjuvant chemotherapy only; adjuvant chemotherapy combined with bevacizumab intravenous (i.v.); adjuvant chemotherapy combined with bevacizumab intraperitoneal (i.p.). Patients in three groups were given 4-6 cycles of treatment and followed up for 3 years. posttreatment outcome, longterm survival and side effects were prospectively recorded and analyzed. Disease control rate (DCR) of three groups are 73.3%, 90.0%, 93.3% respectively (P<0.05). Remission rate (RR) and DCR of patients with bevacizumab intraperitoneal (i.p.) are better than that of patients with bevacizumab intravenous (i.v.) (P<0.05). The mean progression free survival (PFS) of patients with bevacizumab intraperitoneal (i.p.) (15.34 months) was longer than patients with bevacizumab intravenous (i.v.) (13.19 months), and both of two were longer than that of patients with adjuvant chemotherapy only (9.60 months) (χ2=52.11, P<0.001). The mean overall survival (OS) of patients with bevacizumab intraperitoneal (i.p.) (17.32 months) is longer than that of patients with adjuvant chemotherapy only (13.55 months) and patients with bevacizumab intravenous (i.v.) (15.17 months) (χ2=75.01, P<0.001). Incidence of hypertension and arrhythmia of groups with bevacizumab are higher than that of patients with adjuvant chemotherapy only (P<0.05). Standard chemotherapy combined with bevacizumab is reliable, safe and feasible for advanced ovarian cancer after cytoreduction without severe adverse effects. Bevacizumab intraperitoneal perfusion is better than that intravenous drip.",
"affiliations": null,
"authors": "DU|F|F|;Li|P|P|;Chen|J|J|;Gong|Z|Z|;Chi|C|C|;Hu|B|B|;Chu|H|H|",
"chemical_list": "D000068258:Bevacizumab",
"country": "Slovakia",
"delete": false,
"doi": "10.4149/neo_2017_113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2685",
"issue": "64(1)",
"journal": "Neoplasma",
"keywords": "bevacizumab; ovarian cancer adjuvant chemotherapy.",
"medline_ta": "Neoplasma",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D017024:Chemotherapy, Adjuvant; D065426:Cytoreduction Surgical Procedures; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms",
"nlm_unique_id": "0377266",
"other_id": null,
"pages": "108-113",
"pmc": null,
"pmid": "27881011",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adjuvant chemotherapy with bevacizumab (i.p.) can prolong survival time of patients with advanced ovarian cancer after cytoreduction.",
"title_normalized": "adjuvant chemotherapy with bevacizumab i p can prolong survival time of patients with advanced ovarian cancer after cytoreduction"
} | [
{
"companynumb": "CN-ROCHE-1955473",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Digoxin is widely used in patients with rheumatic heart disease (RHD) despite a lack of data on its impact on clinical outcomes. We aimed to determine the association of digoxin use on clinical outcomes in patients with RHD.\n\n\n\nWe performed a retrospective analysis of the association of digoxin use with mortality at 2 years in a large RHD registry. Secondary outcomes were recurrent heart failure (HF) and hospitalisation for any cause. We assessed associations using multivariable logistic regression in the entire cohort and in subgroups of patients with atrial fibrillation (AF) and HF. We also estimated average treatment effects from propensity-adjusted analyses using inverse probability treatment weighting.\n\n\n\nInformation on digoxin use at baseline was available for 98.7% (3298/3343) of patients. In the overall population, digoxin was significantly associated with mortality (OR 1.63, 95% CI 1.30 to 2.04, p<0.0001) and recurrent HF (OR 1.48, 95% CI 1.07 to 2.04, p=0.019). On propensity-weighted analyses, this effect was markedly attenuated (OR 1.05, 95% CI 1.01 to 1.09, p=0.005). Patients in sinus rhythm without HF had a higher propensity-adjusted odds of death with digoxin use (OR 1.06, 95% CI 1.01 to 1.12, p=0.015), but those with both AF and HF had lower mortality (OR 0.88, 95% CI 0.80 to 0.98, p=0.019).\n\n\n\nDigoxin use is associated with higher mortality in patients with RHD, but this is greatly attenuated on propensity adjustment, indicating the presence of substantial treatment bias. The adjusted estimates may therefore not be reliable, and large randomised trials are needed to determine the true effect of digoxin in patients with RHD.",
"affiliations": "Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India.;Indian Institute of Public Health, Gurgaon, India.;Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and University of Cape Town, Cape Town, South Africa.;Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.;Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.;Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.;Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.;Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.",
"authors": "Karthikeyan|Ganesan|G|;Devasenapathy|Niveditha|N|;Zühlke|Liesl|L|;Engel|Mark Emmanuel|ME|;Rangarajan|Sumathy|S|;Teo|Koon K|KK|;Mayosi|Bongani M|BM|;Yusuf|Salim|S|;|||",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D004077:Digoxin",
"country": "England",
"delete": false,
"doi": "10.1136/heartjnl-2018-313614",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-6037",
"issue": "105(5)",
"journal": "Heart (British Cardiac Society)",
"keywords": "atrial fibrillation; heart failure; valvular heart disease",
"medline_ta": "Heart",
"mesh_terms": "D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D002316:Cardiotonic Agents; D004077:Digoxin; D005260:Female; D014943:Global Health; D006333:Heart Failure; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality; D017063:Outcome Assessment, Health Care; D057216:Propensity Score; D012042:Registries; D012214:Rheumatic Heart Disease",
"nlm_unique_id": "9602087",
"other_id": null,
"pages": "363-369",
"pmc": null,
"pmid": "30209123",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Digoxin and clinical outcomes in the Global Rheumatic Heart Disease Registry.",
"title_normalized": "digoxin and clinical outcomes in the global rheumatic heart disease registry"
} | [
{
"companynumb": "IN-IMPAX LABORATORIES, LLC-2019-IPXL-00642",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional"... |
{
"abstract": "We describe an unusual electrocardiographic (ECG) case of an alternating P-wave configuration that spares other ECG components. Hyponatremia due to chronic indapamide use was proposed as a plausible cause of this ECG phenomenon because its correction led to the recovery of a steady P-wave morphology.",
"affiliations": "Private Cardiology Practice, 14A Ath. Diakou Str., 52100 Kastoria, Greece. Electronic address: gtsiaousis@gmail.com.;Third Department of Cardiology, Hippokrateion Hospital, Aristotle University Medical School, 49 Konstantinoupoleos Str., 54642 Thessaloniki, Greece. Electronic address: fragakis.nikos@googlemail.com.",
"authors": "Tsiaousis|Georgios|G|;Fragakis|Nikolaos|N|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.hjc.2015.12.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1109-9666",
"issue": "57(3)",
"journal": "Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese",
"keywords": "ECG changes; electrolyte disorders; indapamide",
"medline_ta": "Hellenic J Cardiol",
"mesh_terms": "D000368:Aged; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate; D006801:Humans; D007010:Hyponatremia",
"nlm_unique_id": "101257381",
"other_id": null,
"pages": "188-190",
"pmc": null,
"pmid": "27725101",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "P-wave alternans in a patient with hyponatremia.",
"title_normalized": "p wave alternans in a patient with hyponatremia"
} | [
{
"companynumb": "GR-SA-2016SA202814",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INDAPAMIDE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "The treatment of functional neurological disorder (FND), previously referred to as conversion disorder, can be challenging. Despite these challenges and with increased understanding of this condition, new treatment options are emerging. One such treatment is hypnosis, which has a long history of use in the treatment of FND. Jean-Martin Charcot, considered by many to be the father of modern neurology, used therapeutic hypnosis as early as the 19th century. In this report, we discuss the novel use of a hypno-anesthetic technique (the magic glove) for treatment of FND presenting as diplegia. We illustrate the use of the technique with the case of a 9-year-old girl who suffered from chronic pain and lower extremity weakness secondary to FND. With the magic glove technique, she improved rapidly and was free of symptoms by her sixth month follow-up visit. We review the current literature on FND interventions and emphasize the need for continued research in this field.",
"affiliations": "Child Neurology Resident at Children's Mercy, Kansas City, Missouri. Electronic address: jcoogle@cmh.edu.;Internal Medicine Resident at The University of Kansas Health System and The University of Kansas School of Medicine, Kansas City, Kansas.;Division of Neurology, Department of Pediatrics, Children's Mercy Kansas City, University of Missouri, Kansas City, Missouri.",
"authors": "Coogle|Justin|J|;Coogle|Brianna|B|;Quezada|Julio|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.pediatrneurol.2021.08.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "125()",
"journal": "Pediatric neurology",
"keywords": "Conversion disorder; FND; Functional neurological disorder; Hypnosis; Magic glove; Psychogenic diplegia",
"medline_ta": "Pediatr Neurol",
"mesh_terms": null,
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "20-25",
"pmc": null,
"pmid": "34624606",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypnosis in the Treatment of Pediatric Functional Neurological Disorder: The Magic Glove Technique.",
"title_normalized": "hypnosis in the treatment of pediatric functional neurological disorder the magic glove technique"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2022SP002233",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugaddition... |
{
"abstract": "The use of hepatic artery infusion (HAI) as a regional therapy against liver metastasis has rarely been reported in gastric cancer. This study aimed to evaluate the efficacy and safety of HAI oxaliplatin plus oral S-1 chemotherapy in first-line palliative therapy for gastric cancer with multiple liver metastases (GCLM).\nWe reviewed the records of five patients with GCLM who received HAI oxaliplatin (70-80 mg/m2 2 hrs d1,15) administered via a port-catheter system and S-1 with oral (35-40 mg/m2 twice daily for d1-14, 28 days for one cycle). Follow-up examination and efficacy evaluation were executed periodically.\nUntil the 4th cycle response evaluation, the local effective rate and control rate were 40% and 80%, respectively; only one patient developed progression. HAI chemotherapy had a better local control against liver metastases (median progression-free survival: hepatic, 8.8 months vs. extrahepatic, 6.2 months), accompanied by less systemic toxicity, decreased tumour markers and symptomatic relief.\nHAI oxaliplatin plus oral S-1 chemotherapy can be considered as a new choice of first-line treatment for GCLM, which is also a good approach for controlling extrahepatic lesions with less adverse events.",
"affiliations": "The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.;Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, People's Republic of China.;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.;The First Medical School of Nanjing Medical University, Nanjing 210000, People's Republic of China.;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.;Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, People's Republic of China.;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.;The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.",
"authors": "Wang|Kangxin|K|0000-0001-7934-2633;Zhang|Xuebin|X|;Wei|Jia|J|;Xu|Yiwen|Y|;Liu|Qin|Q|;Xie|Jiaqi|J|;Yuan|Lihua|L|0000-0001-9205-3561;Sun|Zhichen|Z|;Tan|Siyi|S|;Zhang|Lianru|L|;Liu|Baorui|B|;Yang|Yang|Y|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/CMAR.S233123",
"fulltext": "\n==== Front\nCancer Manag ResCancer Manag ResCMARcancmanresCancer Management and Research1179-1322Dove 23312310.2147/CMAR.S233123Original ResearchHepatic Arterial Infusion Oxaliplatin Plus Oral S-1 Chemotherapy in Gastric Cancer with Unresectable Liver Metastases: A Case Series and Literature Review Wang et alWang et alhttp://orcid.org/0000-0001-7934-2633Wang Kangxin 12Zhang Xuebin 3Wei Jia 1Xu Yiwen 4Liu Qin 1Xie Jiaqi 1http://orcid.org/0000-0001-9205-3561Yuan Lihua 3Sun Zhichen 1Tan Siyi 1Zhang Lianru 1Liu Baorui 1Yang Yang 11 The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing\n210008, People’s Republic of China2 Department of Oncology, Nanjing Pukou Central Hospital, Nanjing\n211800, People’s Republic of China3 Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing\n210008, People’s Republic of China4 The First Medical School of Nanjing Medical University, Nanjing\n210000, People’s Republic of ChinaCorrespondence: Yang Yang The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing210008, People’s Republic of ChinaTel +86-18602568379Fax +86-25-83317016 Email wing_young7@hotmail.com* These authors contributed equally to this work\n\n07 2 2020 2020 12 863 870 01 10 2019 10 1 2020 © 2020 Wang et al.2020Wang et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Objective\nThe use of hepatic artery infusion (HAI) as a regional therapy against liver metastasis has rarely been reported in gastric cancer. This study aimed to evaluate the efficacy and safety of HAI oxaliplatin plus oral S-1 chemotherapy in first-line palliative therapy for gastric cancer with multiple liver metastases (GCLM).\n\nMethods\nWe reviewed the records of five patients with GCLM who received HAI oxaliplatin (70–80 mg/m2 2 hrs d1,15) administered via a port-catheter system and S-1 with oral (35–40 mg/m2 twice daily for d1-14, 28 days for one cycle). Follow-up examination and efficacy evaluation were executed periodically.\n\nResults\nUntil the 4th cycle response evaluation, the local effective rate and control rate were 40% and 80%, respectively; only one patient developed progression. HAI chemotherapy had a better local control against liver metastases (median progression-free survival: hepatic, 8.8 months vs. extrahepatic, 6.2 months), accompanied by less systemic toxicity, decreased tumour markers and symptomatic relief.\n\nConclusion\nHAI oxaliplatin plus oral S-1 chemotherapy can be considered as a new choice of first-line treatment for GCLM, which is also a good approach for controlling extrahepatic lesions with less adverse events.\n\nKeywords\ngastric cancer with multiple liver metastasesnonresectional regional therapyhepatic arterial infusionport-catheter systemresponse evaluationadverse events\n==== Body\nIntroduction\nGastric cancer is one of the most common cancers and the third leading cause of cancer-related death worldwide.1 The liver is a common metastatic site for advanced gastric cancer as a result of blood metastasis via portal circulation, which occurs in approximately 30% of patients.2–4 Gastric cancer with multiple liver metastases (GCLM) represents a systemic disease with synchronous or metachronous abdominal lymph node metastases or direct tumour invasions of other organs.5–8 Controlling liver metastases is extremely important to improve the prognosis for patients with advanced gastric cancer. Traditionally, systemic chemotherapy with oxaliplatin and S-1 was recognized as the standard treatment;9 however, the median progression-free survival (PFS) of metastatic gastric cancer patients treated by standard systemic chemotherapy was only 5.0–6.5 months, which seems to be unsatisfactory. In addition, the systemic toxicity of chemotherapy is common, and limited dosage after multi-line anticancer drugs is not enough to achieve an effective serum drug concentration against liver metastases.3−110\n\nCurrently, advances in vascular interventional radiology make it easy to better control GCLM. Hepatic arterial infusion (HAI) chemotherapy is an important tumour interventional therapy, and it is also a crucial way to ensure that chemotherapy can achieve a maximum anticancer effect for the local control of cancer without much systemic toxicity.14–17 Recently, Seki et al18 reported that HAI chemotherapy using 5-fluorouracil, epirubicin, and mitomycin C (FEM) induced significant curative effects in GCLM after the failure of systemic S-1 plus cisplatin. Furthermore, Fukami et al19 also demonstrated that adjuvant HAI chemotherapy after hemihepatectomy for GCLM could be helpful for preventing remnant liver recurrence and prolonging survival time. Thus, HAI chemotherapy may play an important role in early intervention. However, due to the existence of extrahepatic lesions, HAI chemotherapy should be combined with other systemic treatments to improve the overall response rate. To our knowledge, there are few clinical trials that apply HAI plus systemic chemotherapy in a first-line setting. Here, we report a case series of GCLM using this combination mode in first-line palliative chemotherapy, which shows initial success in gaining local tumour control, maintaining function and improving life quality.\n\nMaterials and Methods\nPopulation\nFive gastric cancer patients with multiple liver metastases were admitted to the Comprehensive Cancer Centre of Drum Tower Hospital and treated with HAI oxaliplatin infusion plus oral S-1 chemotherapy between January 2018 and February 2019. The ethics committee of Drum Tower Hospital approved our study before therapy (No.2014-020-02). Informed consent for all patients was obtained before treatment. The clinical characteristics and outcomes of the patients are listed in Table 1.Table 1 Clinical Characteristics and Outcomes\n\nPatient No.\tGender\tAge\tECOG\tPrimary Tumor Resection\tOnset of Liver Metastases\tExtrahepatic Metastases\tHAI OXA Cycles\t2nd Cycle Response Evaluation\t4th Cycle Response Evaluation\tAdverse Events\t\n1\tM\t58\t1\tN\tSyn\tGastric, retroperitoneal lymph node\t3.5\tPR\tPR\tDrug allergy\t\n2\tM\t66\t1\tN\tSyn\tGastric, retroperitoneal lymph node\t6\tPR\tSD\tGrade 2 leukocytopenia\t\n3\tM\t64\t1\tN\tSyn\tGastric, abdominal lymph node\t4\tPR\tPD\t–\t\n4\tM\t65\t1\tY\tMeta\tIntersplenic lymph node\t2\tPR\tPR\tGrade 2 thrombocytopenia; mild anemia\t\n5\tM\t53\t1\tY\tMeta\tRetroperitoneal lymph node\t6\tPR\tSD\tGrade 1 liver damage\t\nAbbreviations: Syn, synchronous; Meta, metachronous.\n\n\n\n\nEligibility Criteria\n(1) Pathologically confirmed gastric adenocarcinoma; (2) Multiple liver metastases, which were assessed as unresectable by multidisciplinary team; (3) Eastern Cooperative Oncology Group (ECOG) performance status of no more than 2; (4) Satisfactory haematological parameters and heart, pulmonary, hepatic and renal functions; and (5) No sign of systemic infection, grade 3–4 bone marrow suppression, or severe coagulation dysfunction that cannot be corrected or contrast allergy.\n\nTreatment Modalities\nPatients with GCLM were treated according to the following instructions. First, the left-subclavian artery was punctured by Seldinger method after ultrasonic localization, and then the catheter tip soaked with 1% heparin was placed at the opening of the celiac artery for selective celiac arteriography. Second, the catheter was replaced with a drug delivery device and the tip was placed in the common hepatic artery after the confirmation of the imaging. In particular, the catheter shape and head position of the drug delivery device were observed to be correct under fluoroscopy to ensure that the catheter was unobstructed and there was no leakage at the junction. Third, 10 mL 1% heparin fluid should be injected through the device before and after drug delivery. HAI oxaliplatin (70–80 mg/m2 2 hrs d1,15) was administered via the port-catheter system, combined with oral S-1 (50 mg twice daily for d1-14, 28 days for one cycle) as a first-line setting. The anticoagulation modality about heparin flushing should be executed at least once a month. Subsequently, HAI chemotherapy was ceased, and another treatment option was sought until one of the following events had occurred: progressive disease, catheter dysfunction and/or complications that prevented continual cure, or severe toxicity. The patients received further treatment thereafter according to the physician’s prescription.\n\nEvaluating Indicators\nTo fully evaluate the impact of HAI chemotherapy in these cases, pretreatment evaluation and follow-up examination were performed, including physical findings and laboratory tests (routine of blood, urine and stool, liver and renal functions, tumour marker). Chest and abdomen contrast-enhanced CT examinations were carried out at baseline within 1 week before treatment and then every 2–3 months thereafter. Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumours version 1.1:20 complete response (CR), disappearance of all target lesions for at least 4 weeks; partial response (PR), at least a 30% decrease in the sum of the diameter of target lesions (including the longest diameter of the non-nodular lesion or the shortest diameter of the nodular lesion) for at least 4 weeks; stable disease (SD), neither sufficient decrease for partial response nor sufficient increase for progressive disease; or progressive disease (PD), at least a 20% increase in the total diameter of the target lesions and/or appearance of any new lesions. Adverse events, including haematologic, gastrointestinal, hepatorenal function and general disorders, were assessed based on the Common Terminology Criteria for Adverse Events version 4.0.\n\nResults\nThe clinical characteristics and outcomes of the case series are detailed in Table 1. There were five males, and the median age was 61 years (range: 53–66 years). Three of these patients were newly diagnosed as GCLM, while the other patients developed multiple liver metastases a few months after radical gastrectomy for cancer. Moreover, except for liver metastases, all patients had extrahepatic lesions, mostly abdominal lymph node metastases, which showed bulky tumour burden and poor prognosis. Thus, HAI oxaliplatin plus oral S-1 was used to control both hepatic and extrahepatic metastases as a first-line setting. All patients underwent at least two cycles of HAI chemotherapy and successfully achieved a curative effect consequently. As shown in Figures 1 and 2, contrast-enhanced computed tomography (CT) images obtained before and after HAI chemotherapy showed obvious response in unresectable liver metastases at the end of 2nd cycle, accompanied by rapidly decreasing carcinoembryonic antigen (CEA) or carbohydrate antigen 19–9 (CA19-9) levels, indicating the achievement of a partial or even complete local response. Simultaneously, the clinical observation during treatment indicated that multiple liver metastases and discomfort in the upper abdomen were obviously reduced, and the basal levels of elevated alanine transaminase (ALT) or aspartate transaminase (AST) in patients No.1 and No.2 also decreased 3–5 times after combined therapy.Figure 1 Follow-up CT scans after two cycles of HAI and systemic chemotherapy for each patient except No. 3 whose data were unavailable. (A, B) Patient No.1, 58-year-old male showing marked liver metastases in CT images before therapy (A) and a significant shrinkage of the lesion after therapy (B). (C, D) Patient No.2, 66-year-old male with unresectable liver metastases from gastric cancer (C) showing a decrease in the size and number of metastases after combined therapy (D). (E, F) Patient No.4, 65-year-old male with multiple liver metastases after the failure of adjuvant therapy(E), showing the obvious response of lesions at 2 months after therapy (F). (G, H) Patient No.5, 53-year-old male with multiple liver metastases after primary tumour resection (G) with a high-response rate in HAI, whose liver metastases disappeared gradually during treatment (H).\n\nFigure 2 Changes in CEA (A) and CA19-9 (B) levels before and after two cycles of HAI and systemic chemotherapy. *upper limit of normal.\n\n\n\nUntil the 4th cycle response evaluation, the local effective rate [(PR+CR) %] and control rate [(CR+PR+SD) %] was 40% and 80%, respectively, only patient No.3 developed progression, and this patient would receive a randomized clinical trial in further treatment. To evaluate whether HAI chemotherapy has a liver‑specific effect, progression-free survival was estimated separately from hepatic and extrahepatic metastases. As expected, HAI chemotherapy had a better local control against liver metastases (median PFS: hepatic, 8.8 months vs extrahepatic, 6.2 months; Figure 3). As shown in Table 1, patient No.1 would not receive a second-line therapy which combined HAI Irinotecan with oral Apatinib until the disease progressed (extrahepatic metastases). However, second-line therapy lasted for 5 months when hepatic progression appeared gradually. Patient No.2 replaced S-1 with Capecitabine when was found hepatic progression, who had a relatively longer PFS of 14 months. Among postoperative GCLM patients (No.4, 5 in Table 1) after failure of first-line combined therapy, they began second-line therapy: one with intravenous Taxane plus oral Apatinib, the other one with concurrent radiochemotherapy (retroperitoneal lymph node radiotherapy plus intravenous Taxane) combined with programmed cell death protein 1 (PD-1) checkpoint blockade, whose PFS was 5.8 months and 8.8 months, respectively.Figure 3 Kaplan–Meier hepatic and extrahepatic progression-free survival estimates for HAI oxaliplatin plus oral S-1 chemotherapy.\n\n\n\nTo provide an overall assessment of HAI chemotherapy, the treatment feasibility and tolerance of HAI chemotherapy were observed during treatment. HAI oxaliplatin toxicities were recorded during course, which showed that there were no grade 3 or 4 adverse events affecting haematological, gastrointestinal, and hepatorenal functions, and the general condition of the patients was mild. Haematologic toxicity, including grade 2 leukocytopenia, thrombocytopenia and mild anaemia, was observed in patients No.2 and No.4. Grade 1 liver damage occurred in patient No.5, whose liver enzymes were slightly elevated. Notably, patient No.1 showed palpitation and chest distress when proceeding with HAI at the 4th cycle of chemotherapy due to an oxaliplatin allergy rather than progressive disease.\n\nDiscussion\nGCLM presents a marked clinical challenge and always yields poor outcomes because most liver metastases are unresectable and often accompanied by extrahepatic lesions.21,22 In addition, the administration of conventional anticancer agents, such as systemic chemotherapy, is not sufficient to improve the efficacy against liver metastases, even when the primary tumour is resected.9–13 Surprisingly, there has been increasing consensus among experts that HAI chemotherapy could be a safe and high response local therapy.15,18,19,23,24 The rationale for HAI is the dual blood supply in the liver, namely, liver metastases derive a blood supply from the hepatic artery, while normal hepatocytes are supported by the portal vein.25 HAI increases the concentration of drugs in local lesions and prolongs the time of drug action, which leads to the death of tumour cells directly and the inhibition of tumor proliferation.26–28 In terms of the technical aspects of arterial infusion we introduced here, HAI chemotherapy is often administered by surgically placing port-catheter system via the left subclavian or femoral access, while the former is preferred in our institution, above all because the left-subclavian artery way is cleaner and more easily for catheter care, which is also a minimally invasive safe access to intervene.29,30 In contrast to other types of local therapies for unresectable liver metastases, such as transcatheter arterial chemoembolization (TACE) and radiofrequency ablative therapy (RFA), HAI provides the following benefits: (1) There are no significant differences between TACE and HAI in the overall response and recurrence rates, but TACE leads to more serious liver dysfunction compared to HAI, which will affect treatment compliance and the quality of life;31 (2) HAI is effective in both detectable liver lesions and intrahepatic micrometastases, whereas the therapeutic efficacy of RFA was reduced for large tumours, and the presence of as many as four or five lesions was considered suitable.18,32–34\n\nBased on previous clinical trials, combination chemotherapy with fluorouracil and platinum agents was recognized as a standard regimen for advanced metastatic gastric cancer.35,36 However, there is no established regimen or indication of HAI chemotherapy currently.37 As far as HAI oxaliplatin is concerned, the oxaliplatin pharmacokinetic profile administered by HAI has a shorter terminal half-life38 and a higher liver extraction rate of 0.47 than intravenous administration,39,40 which is the reason for the very favorable safety profile of this old drug in a new and innovative approach. Kumada et al15 launched a Phase II study that the overall response rate of combined administration of 5-fluorouracil, epirubicin and mitomycin-C by HAI in GCLM was 55.6%, the median overall survival was 10.5 months and the major prognosis-determining factor was the existence of extrahepatic lesions. However, in another study,18 HAI chemotherapy was employed in a second-line setting for patients with GCLM after the failure of systemic S-1 plus cisplatin. As a result, no survival benefit was observed during HAI chemotherapy. The controversial results were attributed to patient selection and combined therapy, assuming that survival benefit may be obtained from liver-only metastasis disease. Thus, for the existence of extrahepatic lesions, HAI chemotherapy should be combined with other systemic treatments to improve the overall response rate. While the efficacy of HAI chemotherapy plus systemic treatment for liver metastases from colorectal cancer has been confirmed,41,42 the significance of this combined therapy for GCLM is still unclear.\n\nIn our opinion, HAI oxaliplatin plus oral S-1 chemotherapy can be considered as a new choice of first-line treatment for GCLM, which is also a good approach for controlling extrahepatic lesions with less adverse events. By reporting these cases, we would like to emphasize that this combined therapy is usually conservative, palliative and aimed at reducing the patient’s discomfort, improving the quality of life and prolonging survival time. However, there were several limitations to our study. First, this study was based on a retrospective analysis of a small sample size from a single institution, and we could not cover all adverse events due to the small number of cases. Certainly, it is necessary to perform subgroup analysis stratified by the timing of liver metastases status in the assessment of efficacy and risk. Second, our analysis did not find a correlation of response to HAI chemotherapy with overall survival time for the endpoint of follow-up. Third, the present protocol did not routinely use HAI oxaliplatin and oral S-1 chemotherapy in combination, suggesting that the assessment of the curative effect must be further objectified and standardized by a prospective multicentre clinical trial. To achieve improved outcomes, patients need to be selected carefully, and close monitoring is required for adverse events because the addition of concomitant systemic chemotherapy can increase the toxicity of HAI pump therapy.43 We are presumed that this study could be a step to seek an optimal treatment strategy for GCLM.\n\nAcknowledgments\nThis study was supported by the National Key Research and Development Program of China (No. 2017YFC1308900); Scientific and Technological Development Program of Nanjing (No. YKK18078); and the National Natural Science Foundation of China (Grant No. 81803093).\n\nAbbreviations\nHAI, Hepatic arterial infusion; GCLM, Gastric cancer with multiple liver metastases; CEA, Carcinoembryonic antigen; CA19-9, Carbohydrate antigen; PR, Partial response; CR, Complete response; SD, Stable disease; PD, Progressive disease; FEM, fluorouracil, epirubicin, mitomycin C; ECOG, the Eastern Cooperative Oncology Group; ALT, Alanine transaminase; AST, Aspartate transaminase; PFS, progression-free survival; TACE, Transcatheter arterial chemoembolization; RFA, Radiofrequency ablative therapy; RCT, Randomized clinical trial; OXA, Oxaliplatin; Syn, Synchronous; Meta, Metachronous; CT, computed tomography; PD-1, programmed cell death protein 1.\n\nEthics Approval and Consent to Participate\nEthics approval and consent to participate for all the patients were obtained before therapy.\n\nDisclosure\nThe authors declare that they have no conflicts of interest.\n==== Refs\nReferences\n1. Bray \nF , Ferlay \nJ , Soerjomataram \nI , Siegel \nRL , Torre \nLA , Jemal \nA . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin . 2018 ;68 (6 ):394 –424 . doi:10.3322/caac.21492 30207593 \n2. Shin \nA , Kim \nJ , Park \nS . Gastric cancer epidemiology in Korea . J Gastric Cancer . 2011 ;11 (3 ):135 –140 . doi:10.5230/jgc.2011.11.3.135 22076217 \n3. Schlansky \nB , Sonnenberg \nA . Epidemiology of noncardia gastric adenocarcinoma in the United States . Am J Gastroenterol . 2011 ;106 (11 ):1978 –1985 . doi:10.1038/ajg.2011.213 22008896 \n4. Douglass \nHO \nJr, Hundahl \nSA , Macdonald \nJS , Khatri \nVP . Gastric cancer: D2 dissection or low maruyama Index-based surgery–a debate . Surg Oncol Clin N Am . 2007 ;16 (1 ):133 –155 . doi:10.1016/j.soc.2006.10.005 17336241 \n5. Fujisaki \nS , Tomita \nR , Nezu \nT , Kimizuka \nK , Park \nE , Fukuzawa \nM . Prognostic studies on gastric cancer with concomitant liver metastases . Hepato-Gastroenterology . 2001 ;48 (39 ):892 –894 .11462950 \n6. Koga \nS , Kawaguchi \nH , Kishimoto \nH , et al. Therapeutic significance of noncurative gastrectomy for gastric cancer with liver metastasis . Am J Surg . 1980 ;140 (3 ):356 –359 . doi:10.1016/0002-9610(80)90167-1 6158880 \n7. Okuyama \nK , Isono \nK , Juan \nIK , et al. Evaluation of treatment for gastric cancer with liver metastasis . Cancer . 1985 ;55 (10 ):2498 –2505 . doi:10.1002/1097-0142(19850515)55:10<2498::AID-CNCR2820551032>3.0.CO;2-S 3986746 \n8. Ueda \nK , Iwahashi \nM , Nakamori \nM , et al. Analysis of the prognostic factors and evaluation of surgical treatment for synchronous liver metastases from gastric cancer . Langenbecks Arch Surg . 2009 ;394 (4 ):647 –653 . doi:10.1007/s00423-008-0311-9 18343941 \n9. Jerraya \nH , Saidani \nA , Khalfallah \nM , Bouasker \nI , Nouira \nR , Dziri \nC . Management of liver metastases from gastric carcinoma: where is the evidence? \nTunis Med . 2013 ;91 (1 ):1 –5 .23404586 \n10. Bang \nYJ , Van Cutsem \nE , Feyereislova \nA , et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a Phase 3, open-label, randomised controlled trial . Lancet (London, England) . 2010 ;376 (9742 ):687 –697 . doi:10.1016/S0140-6736(10)61121-X \n11. Koizumi \nW , Kim \nYH , Fujii \nM , et al. Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START) . J Cancer Res Clin Oncol . 2014 ;140 (2 ):319 –328 . doi:10.1007/s00432-013-1563-5 24366758 \n12. Koizumi \nW , Narahara \nH , Hara \nT , et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a Phase III trial . Lancet Oncol . 2008 ;9 (3 ):215 –221 . doi:10.1016/S1470-2045(08)70035-4 18282805 \n13. Narahara \nH , Iishi \nH , Imamura \nH , et al. Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002) . Gastric Cancer . 2011 ;14 (1 ):72 –80 . doi:10.1007/s10120-011-0009-5 21340666 \n14. Kemeny \nNE , Niedzwiecki \nD , Hollis \nDR , et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481) . J Clin Oncol . 2006 ;24 (9 ):1395 –1403 . doi:10.1200/JCO.2005.03.8166 16505413 \n15. Kumada \nT , Arai \nY , Itoh \nK , et al. Phase II study of combined administration of 5-fluorouracil, epirubicin and mitomycin-C by hepatic artery infusion in patients with liver metastases of gastric cancer . Oncology . 1999 ;57 (3 ):216 –223 . doi:10.1159/000012034 10545790 \n16. Melichar \nB , Voboril \nZ , Cerman \nJ \nJr, et al. Hepatic arterial infusion chemotherapy in gastric cancer: a report of four cases and analysis of the literature . Tumori . 2004 ;90 (4 ):428 –434 . doi:10.1177/030089160409000414 15510990 \n17. Ojima \nH , Ootake \nS , Yokobori \nT , et al. Treatment of multiple liver metastasis from gastric carcinoma . World J Surg Oncol . 2007 ;5 :70 . doi:10.1186/1477-7819-5-70 17584926 \n18. Seki \nH , Ohi \nH , Ozaki \nT , Yabusaki \nH . Hepatic arterial infusion chemotherapy using fluorouracil, epirubicin, and mitomycin C for patients with liver metastases from gastric cancer after treatment failure of systemic S-1 plus cisplatin . Acta Radiol . 2016 ;57 (7 ):781 –788 . doi:10.1177/0284185115603247 26339040 \n19. Fukami \nY , Kaneoka \nY , Maeda \nA , et al. Adjuvant hepatic artery infusion chemotherapy after hemihepatectomy for gastric cancer liver metastases . Int J Surg . 2017 ;46 :79 –84 . doi:10.1016/j.ijsu.2017.08.578 28882769 \n20. Therasse \nP , Arbuck \nSG , Eisenhauer \nEA , et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada . J Natl Cancer Inst . 2000 ;92 (3 ):205 –216 . doi:10.1093/jnci/92.3.205 10655437 \n21. Kakeji \nY , Morita \nM , Maehara \nY . Strategies for treating liver metastasis from gastric cancer . Surg Today . 2010 ;40 (4 ):287 –294 . doi:10.1007/s00595-009-4152-0 20339981 \n22. Sakamoto \nY , Sano \nT , Shimada \nK , et al. Favorable indications for hepatectomy in patients with liver metastasis from gastric cancer . J Surg Oncol . 2007 ;95 (7 ):534 –539 . doi:10.1002/(ISSN)1096-9098 17219383 \n23. Arai \nY , Endo \nT , Sone \nY , et al. Management of patients with unresectable liver metastases from colorectal and gastric cancer employing an implantable port system . Cancer Chemother Pharmacol . 1992 ;31 (Suppl ):S99 –S102 . doi:10.1007/BF00687116 1458567 \n24. Yonemura \nY , Matuki \nN , Sakuma \nH , et al. Effect of intra-hepatoarterial infusion of MMC and CDDP for gastric cancer patients with liver metastases . Surg Today . 1992 ;22 (3 ):253 –259 . doi:10.1007/BF00308831 1392330 \n25. Breedis \nC , Young \nG . The blood supply of neoplasms in the liver . Am J Pathol . 1954 ;30 (5 ):969 –977 .13197542 \n26. Peng \nZ , Xu \nS , Li \nH , Sun \nC , Fu \nM , Gao \nM . Advanced gastric cancer with brain metastasis effectively treated by arterial infusion chemotherapy: a case report . Oncol Lett . 2014 ;7 (2 ):449 –451 . doi:10.3892/ol.2013.1699 24396466 \n27. Polysalov \nVN , Veriasova \nNN , Dolgikh \nSD , Gapbarov \nA . Regional chemotherapy in locally advanced and metastatic gastric cancer . Vopr Onkol . 2012 ;58 (6 ):762 –767 .23600300 \n28. Ning \nZ , Chen \nD , Liu \nA , et al. Efficacy of chemotherapy combined with targeted arterial infusion of verapamil in patients with advanced gastric cancer . Cell Biochem Biophys . 2014 ;68 (1 ):195 –200 . doi:10.1007/s12013-013-9689-2 23737342 \n29. Hildebrandt \nB , Pech \nM , Nicolaou \nA , et al. Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with colorectal liver metastases: a Phase II-study and historical comparison with the surgical approach . BMC Cancer . 2007 ;7 :69 . doi:10.1186/1471-2407-7-69 17456240 \n30. Imamine \nR , Shibata \nT , Shinozuka \nK , Togashi \nK . Complications in hepatic arterial infusion chemotherapy: retrospective comparison of catheter tip placement in the right/left hepatic artery vs. the gastroduodenal artery . Surg Today . 2017 ;47 (7 ):851 –858 . doi:10.1007/s00595-016-1465-7 28188368 \n31. Chen \nJ , Zhang \nY , Cai \nH , Yang \nY , Fei Duan \nY . Comparison of the effects of postoperative prophylactic transcatheter arterial chemoembolization (TACE) and transhepatic arterial infusion (TAI) after hepatectomy for primary liver cancer . J BUON . 2018 ;23 (3 ):629 –634 .30003729 \n32. Livraghi \nT , Solbiati \nL , Meloni \nF , Ierace \nT , Goldberg \nSN , Gazelle \nGS . Percutaneous radiofrequency ablation of liver metastases in potential candidates for resection: the “test-of-time approach” . Cancer . 2003 ;97 (12 ):3027 –3035 . doi:10.1002/(ISSN)1097-0142 12784338 \n33. de Baere \nT , Elias \nD , Dromain \nC , et al. Radiofrequency ablation of 100 hepatic metastases with a mean follow-up of more than 1 year . AJR Am J Roentgenol . 2000 ;175 (6 ):1619 –1625 . doi:10.2214/ajr.175.6.1751619 11090390 \n34. Solbiati \nL , Livraghi \nT , Goldberg \nSN , et al. Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients . Radiology . 2001 ;221 (1 ):159 –166 . doi:10.1148/radiol.2211001624 11568334 \n35. Cunningham \nD , Okines \nAF , Ashley \nS . Capecitabine and oxaliplatin for advanced esophagogastric cancer . N Engl J Med . 2010 ;362 (9 ):858 –859 . doi:10.1056/NEJMc0911925 20200397 \n36. Ajani \nJA , Rodriguez \nW , Bodoky \nG , et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial . J Clin Oncol . 2010 ;28 (9 ):1547 –1553 . doi:10.1200/JCO.2009.25.4706 20159816 \n37. Zervoudakis \nA , Boucher \nT , Kemeny \nNE . Treatment options in colorectal liver metastases: hepatic arterial infusion . Visc Med . 2017 ;33 (1 ):47 –53 . doi:10.1159/000454693 28612017 \n38. Kern \nW , Beckert \nB , Lang \nN , et al. Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer . Ann Oncol . 2001 ;12 (5 ):599 –603 . doi:10.1023/A:1011186708754 11432616 \n39. Guthoff \nI , Lotspeich \nE , Fester \nC , et al. Hepatic artery infusion using oxaliplatin in combination with 5-fluorouracil, folinic acid and mitomycin C: oxaliplatin pharmacokinetics and feasibility . Anticancer Res . 2003 ;23 (6D ):5203 –5208 .14981990 \n40. Ranieri \nG , Laforgia \nM , Nardulli \nP , et al. Oxaliplatin-based intra-arterial chemotherapy in colo-rectal cancer liver metastases: a review from pharmacology to clinical application . Cancers (Basel) . 2019 ;11 (2 ):141 . doi:10.3390/cancers11020141 \n41. Kemeny \nNE , Melendez \nFD , Capanu \nM , et al. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma . J Clin Oncol . 2009 ;27 (21 ):3465 –3471 . doi:10.1200/JCO.2008.20.1301 19470932 \n42. Kemeny \nN , Gonen \nM , Sullivan \nD , et al. Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer . J Clin Oncol . 2001 ;19 (10 ):2687 –2695 . doi:10.1200/JCO.2001.19.10.2687 11352961 \n43. Kemeny \nN , Capanu \nM , D’Angelica \nM , et al. Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer . Ann Oncol . 2009 ;20 (7 ):1236 –1241 . doi:10.1093/annonc/mdn769 19233901\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1322",
"issue": "12()",
"journal": "Cancer management and research",
"keywords": "adverse events; gastric cancer with multiple liver metastases; hepatic arterial infusion; nonresectional regional therapy; port-catheter system; response evaluation",
"medline_ta": "Cancer Manag Res",
"mesh_terms": null,
"nlm_unique_id": "101512700",
"other_id": null,
"pages": "863-870",
"pmc": null,
"pmid": "32104068",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "11462950;19470932;26339040;24366758;23600300;14981990;1458567;10545790;10655437;11432616;20728210;20339981;28612017;17336241;28188368;1392330;13197542;6158880;17584926;20200397;20159816;17219383;24396466;28882769;23404586;21340666;22076217;16505413;22008896;11090390;11568334;23737342;15510990;12784338;3986746;30207593;19233901;17456240;18282805;30682873;30003729;11352961;18343941",
"title": "Hepatic Arterial Infusion Oxaliplatin Plus Oral S-1 Chemotherapy in Gastric Cancer with Unresectable Liver Metastases: A Case Series and Literature Review.",
"title_normalized": "hepatic arterial infusion oxaliplatin plus oral s 1 chemotherapy in gastric cancer with unresectable liver metastases a case series and literature review"
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"companynumb": "CN-ACCORD-175698",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
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"abstract": "T cells with a CD4(+) CD8(+) double-positive (DP) phenotype are present in small numbers in the peripheral blood of healthy humans and may have anti-viral capacities. Here we investigate numbers and function of DP T cells in patients with relapsing-remitting multiple sclerosis (MS), either treatment-naive or under therapy with natalizumab. Flow cytometry analysis revealed that frequencies of circulating DP T cells in treatment-naive and natalizumab-treated MS patients are comparable to healthy controls. These cells have a memory phenotype with cytotoxic potential, express high levels of CD49d and are similarly functional in treatment-naive as well as natalizumab-treated MS patients. DP T cells were enriched in the cerebrospinal fluid, but do not invade acutely inflamed MS lesions. In conclusion, DP T cells are functional in MS and may play a role in the immune surveillance of the central nervous system, but do not display functional impairment under natalizumab therapy.",
"affiliations": "Department of Neurology, Friedrich-Alexander University of Erlangen, Erlangen, Germany.",
"authors": "Waschbisch|A|A|;Sammet|L|L|;Schröder|S|S|;Lee|D-H|DH|;Barrantes-Freer|A|A|;Stadelmann|C|C|;Linker|R A|RA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000956:Antigens, Viral; D015704:CD4 Antigens; D016827:CD8 Antigens; D000069442:Natalizumab",
"country": "England",
"delete": false,
"doi": "10.1111/cei.12345",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9104",
"issue": "177(2)",
"journal": "Clinical and experimental immunology",
"keywords": "JC virus; cerebrospinal fluid; memory T cells; natalizumab",
"medline_ta": "Clin Exp Immunol",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000956:Antigens, Viral; D015704:CD4 Antigens; D016827:CD8 Antigens; D016022:Case-Control Studies; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007577:JC Virus; D008875:Middle Aged; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D010641:Phenotype; D016176:T-Lymphocyte Subsets",
"nlm_unique_id": "0057202",
"other_id": null,
"pages": "404-11",
"pmc": null,
"pmid": "24730443",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15731353;8120365;12055230;15044252;16634035;22633193;21647449;3876598;6458432;22461689;2961576;6847134;8461016;17030653;8101138;21387374;3498435;23526716;8100570;12829791;8285595;22823432;22591293;9806050;23514886;8370171;22612622;2982943",
"title": "Analysis of CD4+ CD8+ double-positive T cells in blood, cerebrospinal fluid and multiple sclerosis lesions.",
"title_normalized": "analysis of cd4 cd8 double positive t cells in blood cerebrospinal fluid and multiple sclerosis lesions"
} | [
{
"companynumb": "DE-BIOGEN-2012BI005231",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "We report a case of a 53-year-old woman who presented initially with sepsis and later in her stay developed a severe and rapidly progressing hyperthermia after a decrease in oral baclofen dosage. Her fever peaked at 42.5○C (108.5○F), creating a broad differential diagnosis and complicating her initial sepsis diagnosis. When the oral baclofen dose was increased, the fevers resolved which confirmed the clinical diagnosis of baclofen withdrawal. Dose reductions of oral baclofen should be made gradually and with caution, and patients should be monitored for fevers as a possible symptom of baclofen withdrawal.",
"affiliations": "Pulmonary & Critical Care Medicine, Carle Foundation Hospital, Urbana, Illinois, USA visheshpaul@gmail.com.;Pharmacology, Carle Foundation Hospital, Urbana, Illinois, USA.;Pharmacology, Carle Foundation Hospital, Urbana, Illinois, USA.;Internal Medicine, Carle Foundation Hospital, Urbana, Illinois, USA.",
"authors": "Paul|Vishesh|V|http://orcid.org/0000-0002-9266-4212;Righter|Kari|K|;Kim|Elise|E|;Nadherny|Weston|W|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-234710",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(9)",
"journal": "BMJ case reports",
"keywords": "musculoskeletal and joint disorders; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000284:Administration, Oral; D001418:Baclofen; D004305:Dose-Response Relationship, Drug; D005260:Female; D005334:Fever; D006801:Humans; D008875:Middle Aged; D009125:Muscle Relaxants, Central; D018805:Sepsis; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32994264",
"pubdate": "2020-09-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe hyperthermia due to oral baclofen withdrawal.",
"title_normalized": "severe hyperthermia due to oral baclofen withdrawal"
} | [
{
"companynumb": "US-SABAL THERAPEUTICS LLC-2021-ATH-000011",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nTo identify the incidence and risk factors for hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients with resolved HBV receiving biological disease-modifying antirheumatic drugs (bDMARDs).\n\n\nMETHODS\nRheumatoid arthritis patients in whom bDMARD therapy was initiated in our departments from April 2009 to July 2016 were reviewed. The patients diagnosed with resolved HBV and whose HBV-DNA levels had been repeatedly measured were enrolled. The endpoint was HBV reactivation (a positive conversion of HBV-DNA or unquantifiable cases with positivity <20 IU/mL). Nucleic acid analogues (NAAs) were administered when the HBV-DNA levels increased beyond 20 IU/mL. The associations between HBV reactivation and the clinical findings were retrospectively analyzed.\n\n\nRESULTS\nOne hundred and fifty-two RA patients with resolved HBV were enrolled; 133 (88%) patients had antibodies against HBV surface antigen (anti-HBs). The medicines that were administered included: abatacept (n = 29), golimumab (n = 26), etanercept (n = 25), tocilizumab (n = 25), adalimumab (n = 19), infliximab (n = 17) and certolizumab pegol (n = 11). During the observation period (15 [interquartile range 4.0-34] months), 7 (4.6%) patients developed HBV reactivation. In 5 of these patients, the HBV-DNA levels became negative or remained at <20 IU/mL (+) without NAA therapy. HBV-DNA levels of >20 IU/mL were observed in 2 patients but the HBV-DNA levels became negative after NAA treatment. Patients who were negative for anti-HBs showed a significantly higher incidence of HBV reactivation (P = 0.013).\n\n\nCONCLUSIONS\nHBV reactivation occurred in 4.6% of RA patients with resolved HBV during the treatment with bDMARDs and the absence of anti-HBs may be a risk factor for the reactivation of resolved HBV.",
"affiliations": "Department of Rheumatology, Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.;Department of Rheumatology, Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.;Third Department of Internal Medicine, Obihiro-Kosei General Hospital, Obihiro, Japan.;Department of Rheumatology, Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.;Department of Rheumatology, Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.;Department of Rheumatology, Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.;Department of Rheumatology, Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.;Third Department of Internal Medicine, Obihiro-Kosei General Hospital, Obihiro, Japan.;Department of Rheumatology, Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.;Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Rheumatology, Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.",
"authors": "Watanabe|Toshiyuki|T|http://orcid.org/0000-0001-5324-2968;Fukae|Jun|J|;Fukaya|Shinji|S|;Sawamukai|Norifumi|N|;Isobe|Masato|M|;Matsuhashi|Megumi|M|;Shimizu|Masato|M|;Akikawa|Kazumasa|K|;Tanimura|Kazuhide|K|;Atsumi|Tatsuya|T|http://orcid.org/0000-0001-5657-962X;Koike|Takao|T|",
"chemical_list": "D018501:Antirheumatic Agents; D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13401",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "22(4)",
"journal": "International journal of rheumatic diseases",
"keywords": "HBV reactivation; antibodies against HBV surface antigen; biological disease-modifying antirheumatic drugs; resolved HBV; rheumatoid arthritis",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D000998:Antiviral Agents; D001172:Arthritis, Rheumatoid; D004279:DNA, Viral; D005260:Female; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006515:Hepatitis B virus; D054884:Host-Pathogen Interactions; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D014775:Virus Activation",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "574-582",
"pmc": null,
"pmid": "30338649",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Incidence and risk factors for reactivation from resolved hepatitis B virus in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs.",
"title_normalized": "incidence and risk factors for reactivation from resolved hepatitis b virus in rheumatoid arthritis patients treated with biological disease modifying antirheumatic drugs"
} | [
{
"companynumb": "JP-JNJFOC-20170114735",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
},
"drugadditional": null,
"... |
{
"abstract": "Malaria is caused by the Plasmodium spp. which are spread through Anopheles mosquitoes. Disease is not endemic in Poland currently but can be brought from other countries, mostly from Africa and Asia. The main sign of the disease is fever with shivers repeated periodically. There is highly effective chemoprophylaxis available and treatment, which should be given quickly\n\n\n\nA 35-year-old man have worked monthly in Nigeria since two years. He was using Malarone chemoprophylaxis, but contrary to recommendations. Patient presented to a hospital after four days of having fever in a medium-serious state. He reported three similar incidents in the past. Physical examination revealed hepatomegaly, depressive state, oliguria and diarrhoea. Lab tests showed DIC with thrombocytopenia, renal injury, liver injury, hypoalbuminemia. ECG indicated myocardial ischemia. Malaria Rapid Test and blood smear confirmed Plasmodium falciparum infection with 9,9% parasitemia. When antimalarial treatment was given, patient condition improved, but after three days in hospital he got pneumonia as a complication of malaria – antibiotic admission was committed. Moreover, quinine caused temporary deafness and serological tests revealed chronic HBV infection. After 23-days of hospitalisation the patient was discharged in a good condition. A month later patient went to follow-up and only mild anaemia was shown.\n\n\n\nThis case shown that even such severe disease like malaria can be cured well without serious complications if patient will be diagnosed quickly. Moreover patient’s experience and respecting symptoms improve prognosis. There also should be stronger emphasis on the role of chemoprophylaxis – patient did not use it properly, so it did not have to prevent development of malaria.",
"affiliations": "Wrocław Medical University Students’ Scientific Circle of Infectious Diseases, Liver Diseases and Acquired Immune Deficiencies;Wrocław Medical University Students’ Scientific Circle of Infectious Diseases, Liver Diseases and Acquired Immune Deficiencies;Wrocław Medical University Students’ Scientific Circle of Infectious Diseases, Liver Diseases and Acquired Immune Deficiencies",
"authors": "Malchrzak|Wojciech|W|;Rymer|Weronika|W|;Inglot|Małgorzata|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000962:Antimalarials; D019818:Clavulanic Acid; D002939:Ciprofloxacin; D000658:Amoxicillin",
"country": "Poland",
"delete": false,
"doi": "10.32394/pe.72.3.12",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2100",
"issue": "72(3)",
"journal": "Przeglad epidemiologiczny",
"keywords": "malaria; Plasmodium falciparum; chemoprophylaxis",
"medline_ta": "Przegl Epidemiol",
"mesh_terms": "D000328:Adult; D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D000962:Antimalarials; D002939:Ciprofloxacin; D019818:Clavulanic Acid; D000076263:Communicable Diseases, Imported; D006801:Humans; D016778:Malaria, Falciparum; D008297:Male; D009549:Nigeria; D011014:Pneumonia; D011044:Poland",
"nlm_unique_id": "0413725",
"other_id": null,
"pages": "363-370",
"pmc": null,
"pmid": "30394060",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Imported malaria caused by Plasmodium falciparum – case report",
"title_normalized": "imported malaria caused by plasmodium falciparum case report"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-223491",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUININE"
},
"drugadd... |
{
"abstract": "Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) dramatically improve progression-free survival compared to cytotoxic agents. It is therefore important to manage patients with ALK-TKIs until drug resistance occurs. Leukocytoclastic vasculitis (LCV) is a rare complication during cancer treatment and is associated with a variety of factors. Currently, it is unclear whether we should withdraw a treatment when drug-induced LCV develops. We report a 40-year-old man with advanced pulmonary adenocarcinoma harboring the EML4-ALK fusion protein who developed LCV during ceritinib treatment. Four weeks after withdrawing ceritinib, we could successfully perform rechallenge with ceritinib at the normal dose. Rapid and massive tumor apoptosis due to ceritinib treatment may lead to neoantigen release and immune complexes deposition. To the best of our knowledge, we report the first case of LCV in a patient during ALK-TKI treatment. Following this occurrence, we were able to successfully perform rechallenge with ceritinib. Therefore, key drugs used in a patient's treatment regimen should not be discontinued without careful evaluation, and we should also consider the possibility of rechallenge.",
"affiliations": "Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Dermatology, Shimane University Faculty of Medicine, Shimane, Japan.;Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan.",
"authors": "Okimoto|Tamio|T|;Tsubata|Yukari|Y|;Hotta|Takamasa|T|;Hamaguchi|Megumi|M|;Okuno|Takae|T|;Shiratsuki|Yohei|Y|;Kodama|Akari|A|;Nakao|Mika|M|;Amano|Yoshihiro|Y|;Hamaguchi|Shunichi|S|;Kurimoto|Noriaki|N|;Tobita|Reiko|R|;Isobe|Takeshi|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.24765",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 2476510.18632/oncotarget.24765Case ReportSuccessful rechallenge with ceritinib after leukocytoclastic vasculitis during ceritinib treatment for non-small cell lung cancer harboring the EML4-ALK fusion protein Okimoto Tamio 1Tsubata Yukari 1Hotta Takamasa 1Hamaguchi Megumi 1Okuno Takae 1Shiratsuki Yohei 1Kodama Akari 1Nakao Mika 1Amano Yoshihiro 1Hamaguchi Shunichi 1Kurimoto Noriaki 1Tobita Reiko 2Isobe Takeshi 11 Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan2 Department of Dermatology, Shimane University Faculty of Medicine, Shimane, JapanCorrespondence to:Tamio Okimoto,okimoto@med.shimane-u.ac.jp13 4 2018 13 4 2018 9 28 20213 20218 6 1 2018 27 2 2018 Copyright: © 2018 Okimoto et al.2018This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) dramatically improve progression-free survival compared to cytotoxic agents. It is therefore important to manage patients with ALK-TKIs until drug resistance occurs. Leukocytoclastic vasculitis (LCV) is a rare complication during cancer treatment and is associated with a variety of factors. Currently, it is unclear whether we should withdraw a treatment when drug-induced LCV develops.\n\nWe report a 40-year-old man with advanced pulmonary adenocarcinoma harboring the EML4-ALK fusion protein who developed LCV during ceritinib treatment. Four weeks after withdrawing ceritinib, we could successfully perform rechallenge with ceritinib at the normal dose. Rapid and massive tumor apoptosis due to ceritinib treatment may lead to neoantigen release and immune complexes deposition.\n\nTo the best of our knowledge, we report the first case of LCV in a patient during ALK-TKI treatment. Following this occurrence, we were able to successfully perform rechallenge with ceritinib. Therefore, key drugs used in a patient's treatment regimen should not be discontinued without careful evaluation, and we should also consider the possibility of rechallenge.\n\nalectinibanaplastic lymphoma kinaseceritinibleukocytoclastic vasculitisnon-small cell lung cancer\n==== Body\nINTRODUCTION\nLung cancer is the leading cause of death due to cancer. Molecular testing revealed the EML4-ALK fusion protein in approximately 5% of patients with non-small cell lung cancer [1, 2]. As anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) dramatically improve progression-free survival compared to cytotoxic agents [3–6], ALK-TKIs are commonly used for ALK fusion protein-positive non-small cell lung cancer unless the tumor becomes resistant to the drug.\n\nLeukocytoclastic vasculitis (LCV) is a rare complication during cancer treatment. It is associated with chronic infection, drugs and para-neoplastic syndrome. When diagnosing LCV during cancer treatment, it is very important to determine whether the vasculitis is associated with cancer drugs, especially driver mutation targeted drugs, which are the most important drugs for the patients, and whether rechallenge with the drug can be done safely. Some reports have shown safe rechallenge with epidermal growth factor receptor (EGFR)-TKIs after LCV that occurred during EGFR-TKI therapy. However, there are no previous reports of LCV associated with ALK-TKIs; this is the first report of safe rechallenge with ceritinib after LCV.\n\nCASE PRESENTATION\nA 40-year-old Japanese man presented to our hospital with pulmonary adenocarcinoma. He had been diagnosed with adenocarcinoma 2 years ago, and RNA sequencing revealed the presence of the EML4-ALK fusion protein. When he was diagnosed, he rejected all our recommendations for chemotherapy including ALK-TKI and he stopped his annual visits to our clinic. Six months after the initial diagnosis, he presented to our hospital with dyspnea due to cardiac tamponade and pleural effusion. He received pericardiocentesis and thoracentesis, and he agreed to start crizotinib treatment (250 mg, twice daily). One month after the initiation of crizotinib, a computed tomography (CT) scan showed decreased pleural and pericardial effusion and shrinkage of the primary lesion. Ten months after the initiation of crizotinib, progressive disease (PD) was detected considering the enlargement of the primary lesion. Therefore, alectinib (300 mg, twice daily) was administered as second-line treatment, and a CT scan showed a partial response. Fourteen months after the initiation of alectinib, PD was detected again as an enlargement of the primary lesion. We continued alectinib until ceritinib was launched in Japan. One month after the PD detection, we switched to ceritinib (750 mg once daily) and the CT scan showed a partial response (Figure 1). Ten days after initiating ceritinib, palpable purpura was observed (Figure 2). The test results for myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) and proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) were negative. Skin biopsy showed LCV (Figure 3A–3B). IgA deposition was negative. Because ceritinib was the only drug we started one month before the onset of LCV, we suspected this was associated with ceritinib. We recommended withdrawal of ceritinib to the patient, however, he rejected it and therefore we continued ceritinib for another month. During this period, the purpura gradually improved, although, the patient caught a common cold and proteinuria was observed. We could not continue the drug as the patient was at risk for developing kidney vasculitis and he agreed. We therefore withdrew only ceritinib until the purpura improved. Four weeks after withdrawal, we confirmed the disappearance of the purpura and performed a rechallenge with ceritinib at the usual dose (750 mg once daily) without using any immunosuppressants. Although slight re-exacerbation of purpura was observed, it disappeared quickly, and the tumor response was maintained for 9 months after the rechallenge. Now he has been receiving carboplatin (area under the concentration-time curve 5), pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) therapy without relapse of LCV.\n\nFigure 1 (A, C) Chest radiograph and computed tomography scan before starting ceritinib. (B, D) Chest radiograph and computed tomography scan after ceritinib treatment.\n\nFigure 2 (A, B) Palpable purpura on the lower extremities.\n\nFigure 3 Pathological findings of the skin biopsy sample demonstrating leukocytoclastic vasculitis\n(A) Hematoxylin and eosin staining (×40). (B) Hematoxylin and eosin staining (×400).\n\nDISCUSSION\nThis case had two important clinical characteristics. First, this is the first case of LCV during ALK-TKI treatment. Second, we safely performed rechallenge with ceritinib after LCV during ceritinib treatment.\n\nLCV is vasculitis of the small vessels in which the inflammatory infiltrate is composed of neutrophils that release nuclear debris, i.e., leukocytoclasia. The development of LCV is associated with both immune complex deposition and hypersensitivity to a suspected drug. Examples of immune complex deposition related to disease include cryoglobulinemic vasculitis related to hepatitis C, systemic lupus erythematosus, IgA vasculitis, and paraneoplastic syndrome. Several potential reasons have been proposed for the mechanism of paraneoplastic vasculitis [7]. One hypothesis is that abnormal production of antibodies and tumor neoantigens lead to the formation of immune complexes that deposit within blood vessel walls. In this case, it is plausible that rapid and massive tumor apoptosis due to ceritinib treatment led to neoantigen release and immune complexes deposition. The purpura gradually improved after the onset of LCV despite continuation of ceritinib. It was possibly associated with immune complex clearance through blood vessels. In addition, a slight re-exacerbation and quick disappearance of purpura, which were observed after rechallenge of ceritinib. may have been associated with increased tumor burden due to withdrawal of ceritinib for 4 weeks and rapid and massive apoptosis due to ceritinib rechallenge. LCV may be a putative manifestation of drug efficacy. Brandi et al. also reported on this possibility [8].\n\nAs examples of hypersensitivity to a drug related to LCV, propylthiouracil, hydralazine, colony-stimulating factors, and allopurinol have been most often implicated as a causative drug for drug-induced LCV [9–12]. Although the mechanism of LCV development remains unclear, one hypothesis suggests that activated neutrophils in the presence of hydrogen peroxidase release MPO from their granules, chemically transform the drug to an immunogenic product for T cells, which in turn activate B cells to produce ANCA [13]. That is why multispecific ANCA is common in drug-induced LCV unlike idiopathic autoimmune vasculitis [11, 14]. In some cases, vasculitis occurred after drug dosage increases and after rechallenge with the suspected drug [12]. In this case, we safely performed rechallenge with ceritinib and ANCA was negative, which suggests that this is a case of LCV not associated with hypersensitivity to ceritinib but associated with neoantigen release and immune complexes deposition.\n\nSome LCV cases during non-small cell lung cancer (NSCLC) treatment have been reported to date (Table 1) [15–26]. In most cases, LCV developed 1–2 months after the initiation of EGFR-TKI and skin purpura improved within a month after withdrawal EGFR-TKI, similar to our case. Regarding EGFR-TKI treatment, 1 LCV case during gefitinib treatment for adenoid cystic carcinoma of the maxilla [27] and 2 LCV cases during erlotinib treatment for hepatocellular carcinoma were reported [8, 28]. However, in most of the cases, the dose of the suspected drug, gefitinib or erlotinib, was reduced [15, 17, 19, 20] or the drug was discontinued [16, 21], and in only 2 cases, successful rechallenge at a normal dose was reported [18, 19]. Regarding the cytotoxic drugs, pemetrexed, gemcitabine, etoposide, and docetaxel were reported to be a causative drug for LCV. Although significantly more patients have received cytotoxic chemotherapy than EGFR-TKIs, more LCV cases have been reported to date with use of EGFR-TKIs. This suggests an association between rapid tumor apoptosis as well as the EGFR-TKI's target (EGFR) and the development of LCV. If the LCV truly developed with hypersensitivity to the causative drug, it is very difficult to avoid LCV relapse only by reducing the dose or by providing intermittent administration of the drug. Both seropositive LCV cases [16] and seronegative LCV cases [20] during EGFR-TKI treatment have been reported. LCV cases during EGFR-TKI treatment include both paraneoplastic vasculitis and hypersensitivity related vasculitis. Ota et al. reported a LCV case during NSCLC treatment, in which LCV developed as a paraneoplastic vasculitis along with disease progression [26].\n\nTable 1 Published cases of leukocytoclastic vasculitis cases during non-small cell lung cancer treatment\nAge, gender\tDrug\tTime to onset\tTreatment\tPrognosis\tDuration of the symptom\tRechallenge, dose\tAuthor\t\n68, Female\terlotinib\t10 weeks\tdose reduction, topical steroid\tcure\tunknown\tYes, reduced dose\tYuba et al. [15]\t\n69, Female\terlotinib\t8 weeks\twithdrawal topical steroid\tcure\t2 weeks\tNo\tTakahashi et al. [16]\t\n78, Female\terlotinib\t80 days\twithdrawal\tcure\t2 weeks\tYes, reduced dose\tSawada et al. [20]\t\n50, Female\terlotinib + bevacizumab\t6 weeks\twithdrawal\tcure\t7 weeks\tYes, reduced dose\tSu et al. [17]\t\n52, Female\tgefitinib\t2 months\ttopical steroid\tcure\tunknown\tYes, normal dose\tNozato et al. [18]\t\n74, Female\tgefitinib\t1 month\twithdrawal\tcure\t2 weeks\tYes, intermittently\tUchimiya et al. [19]\t\n76, Female\tgefitinib\t2 months\twithdrawal\tcure\t17 days\tYes, normal dose\tUchimiya et al. [19]\t\n76, Female\tgefitinib\t2.5 months\twithdrawal systemic steroid\tcure\t2 weeks\tNo\tKurokawa et al. [21]\t\n68, Male\tpemetrexed\t5 weeks\twithdrawal systemic steroid\tcure\t3 days\tunknown\tLopes et al. [22]\t\n45, Male\tgemcitabine\t6 weeks\twithdrawal systemic steroid colchicine\tcure\t10 days\tNo\tVoorburg et al. [23]\t\n79, Male\tgemcitabine + carboplatin\t8 days\twithdrawal systemic steroid diphenhydramine\tcure\t15 days\tNo\tCorella et al. [24]\t\n61, Male\tetoposide\t10 days\twithdrawal\tcure\tunknown\tunknown\tTurken et al. [25]\t\n50, Male\tdocetaxel\tafter 12 cycles\twithdrawal systemic steroid\tcure\tpromptly resolved\tNo\tOta et al. [26]\t\nIn most cases, leukocytoclastic vasculitis developed 1–2 months after the initiation of causative drug and skin purpura improved within a month after withdrawal and/or systemic steroid.\n\nDrug-induced LCV is sometimes life-threatening if the suspected drug is continued [12]. It is very difficult but important to distinguish drug-induced vasculitis from paraneoplastic vasculitis. The interval between the first exposure and appearance of symptoms has been reported to be extremely variable (hours to years) [12]. Serological surveys, especially for ANCA, may help to distinguish between the types of vasculitis [11]. If the result for ANCA is negative, a rechallenge with the suspected drug should be considered.\n\nCONCLUSIONS\nTo the best of our knowledge, we report the first case of LCV during ALK-TKI treatment. However, after this occurrence, we were able to safely perform rechallenge with ceritinib. From this case, we learned that key drugs should not be discontinued without careful consideration, and we should contemplate the possibility of rechallenge.\n\nWe would like to thank Editage (www.editage.jp) for English language editing. We wish to thank Dr. Nagase for commenting on the pathological findings.\n\nCONFLICTS OF INTEREST\n\nThe authors declare that there are no conflicts of interest.\n\nAbbreviations\nEML4Echinoderm microtubule-associated protein-like 4\n\nALKAnaplastic lymphoma kinase\n\nTKItyrosine kinase inhibitor\n\nLCVleukocytoclastic vasculitis\n\nEGFRepidermal growth factor receptor\n\nPDprogressive disease\n\nCTcomputed tomography\n\nMPO-ANCAmyeloperoxidase-anti-neutrophil cytoplasmic antibody\n\nPR3-ANCAproteinase 3 anti-neutrophil cytoplasmic antibody\n==== Refs\nREFERENCES\n1 Soda M Choi YL Enomoto M Takada S Yamashita Y Ishikawa S Fujiwara S Watanabe H Kurashina K Hatanaka H Bando M Ohno S Ishikawa Y Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer Nature 2007 448 561 6 https://doi.org/10.1038/nature05945 17625570 \n2 Blackhall FH Peters S Bubendorf L Dafni U Kerr KM Hager H Soltermann A O’Byrne KJ Dooms C Sejda A Hernandez-Losa J Marchetti A Savic S Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European Thoracic Oncology Platform Lungscape Project J Clin Oncol 2014 32 2780 7 https://doi.org/10.1200/JCO.2013.54.5921 25071109 \n3 Solomon BJ Mok T Kim DW Wu YL Nakagawa K Mekhail T Felip E Cappuzzo F Paolini J Usari T Iyer S Reisman A Wilner KD First-line crizotinib versus chemotherapy in ALK-positive lung cancer N Engl J Med 2014 371 2167 77 https://doi.org/10.1056/NEJMoa1408440 25470694 \n4 Shaw AT Kim DW Nakagawa K Seto T Crino L Ahn MJ De Pas T Besse B Solomon BJ Blackhall F Wu YL Thomas M O’Byrne KJ Crizotinib versus chemotherapy in advanced ALK-positive lung cancer N Engl J Med 2013 368 2385 94 https://doi.org/10.1056/NEJMoa1214886 23724913 \n5 Peters S Camidge DR Shaw AT Gadgeel S Ahn JS Kim DW Ou SI Perol M Dziadziuszko R Rosell R Zeaiter A Mitry E Golding S Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer N Engl J Med 2017 377 829 38 https://doi.org/10.1056/NEJMoa1704795 28586279 \n6 Hida T Nokihara H Kondo M Kim YH Azuma K Seto T Takiguchi Y Nishio M Yoshioka H Imamura F Hotta K Watanabe S Goto K Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial Lancet 2017 390 29 39 https://doi.org/10.1016/s0140-6736(17)30565-2 28501140 \n7 Mitsui H Shibagaki N Kawamura T Matsue H Shimada S A clinical study of Henoch-Schonlein Purpura associated with malignancy J Eur Acad Dermatol Venereol 2009 23 394 401 https://doi.org/10.1111/j.1468-3083.2008.03065.x 19207675 \n8 Brandi G Venturi M Dika E Maibach H Patrizi A Biasco G Cutaneous leukocytoclastic vasculitis due to erlotinib: just an adverse event or also a putative marker of drug efficacy? Cutan Ocul Toxicol 2013 32 336 8 https://doi.org/10.3109/15569527.2013.780179 23534992 \n9 Mullick FG McAllister HA Jr Wagner BM Fenoglio JJ Jr Drug related vasculitis. Clinicopathologic correlations in 30 patients Hum Pathol 1979 10 313 25 468217 \n10 Martinez-Taboada VM Blanco R Garcia-Fuentes M Rodriguez-Valverde V Clinical features and outcome of 95 patients with hypersensitivity vasculitis Am J Med 1997 102 186 91 9217569 \n11 Radic M Martinovic Kaliterna D Radic J Drug-induced vasculitis: a clinical and pathological review Neth J Med 2012 70 12 7 22271809 \n12 ten Holder SM Joy MS Falk RJ Cutaneous and systemic manifestations of drug-induced vasculitis Ann Pharmacother 2002 36 130 47 https://doi.org/10.1345/aph.1A124 11816242 \n13 Jiang X Khursigara G Rubin RL Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils Science 1994 266 810 3 7973636 \n14 Gao Y Zhao MH Guo XH Xin G Wang HY The prevalence and target antigens of antithyroid drugs induced antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with hyperthyroidism Endocr Res 2004 30 205 13 15473130 \n15 Yuba T Nagata K Shiotsu S Okano A Hatsuse M Murakami S Morihara K Shimazaki C [Henoch-schonlein purpura induced by erlotinib (Tarceva): a case report] [Article in Japanese] Nihon Kokyuki Gakkai Zasshi 2010 48 81 5 20163028 \n16 Takahashi Y Ebi N Yamaguchi O Fukusho R Sugimoto Y Tsuruno K [A case of cutaneous vasculitis caused by erlotinib treatment and a review of literature] [Article in Japanese] Nihon Kokyuki Gakkai Zasshi 2011 49 663 6 22073612 \n17 Su BA Shen WL Chang ST Feng LY Wu CJ Feng YH Successful rechallenge with reduced dose of erlotinib in a patient with lung adenocarcinoma who developed erlotinib-associated leukocytoclastic vasculitis: A case report Oncol Lett 2012 3 1280 2 https://doi.org/10.3892/ol.2012.647 22783433 \n18 Nozato K Morishima Y Furuta J Fujita J Miyazaki K Ogawa R Kikuchi N Sakamoto T Hizawa N [A case of Henoch-Schonlein purpura which was difficult to distinguish from a skin rash associated with gefitinib] [Article in Japanese] Nihon Kokyuki Gakkai Zasshi 2010 48 529 34 20684219 \n19 Uchimiya H Higashi Y Kawai K Kanekura T Purpuric drug eruption with leukocytoclastic vasculitis due to gefitinib J Dermatol 2010 37 562 4 https://doi.org/10.1111/j.1346-8138.2010.00896.x 20536674 \n20 Sawada T Suehiro M Hiranuma O Cutaneous Leukocytoclastic Vasculitis Associated with Erlotinib Indian J Dermatol 2016 61 238 https://doi.org/10.4103/0019-5154.177793 \n21 Kurokawa I Endo K Hirabayashi M Purpuric drug eruption possibly due to gefinitib (Iressa) Int J Dermatol 2005 44 167 8 https://doi.org/10.1111/j.1365-4632.2005.02185.x 15689221 \n22 Lopes G Vincek V Raez LE Pemetrexed-associated urticarial vasculitis Lung Cancer 2006 51 247 9 https://doi.org/10.1016/j.lungcan.2005.10.008 16360237 \n23 Voorburg AM van Beek FT Slee PH Seldenrijk CA Schramel FM Vasculitis due to gemcitabine Lung Cancer 2002 36 203 5 11955656 \n24 Corella F Dalmau J Roe E Garcia-Navarro X Alomar A Cutaneous vasculitis associated with gemcitabine therapy Clin Exp Dermatol 2009 34 97 9 https://doi.org/10.1111/j.1365-2230.2008.03014.x 19076809 \n25 Turken O Karagoz B Bilgi O Dogan B Kandemir EG Kunter E Oral etoposide-induced leucocytoclastic vasculitis in a patient with lung carcinoma J Eur Acad Dermatol Venereol 2007 21 1297 8 https://doi.org/10.1111/j.1468-3083.2007.02200.x 17894749 \n26 Ota S Haruyama T Ishihara M Natsume M Fukasawa Y Sakamoto T Tanzawa S Usui R Honda T Ichikawa Y Watanabe K Sasajima Y Seki N A Case of Paraneoplastic IgA Vasculitis in an Adult with Lung Adenocarcinoma Intern Med 2017 12 27 https://doi.org/10.2169/internalmedicine 9651 17 [Epub ahead of print] \n27 Fernandez-Guarino M Ryan AM Perez-Garcia B Gonzalez-Lopez C Olasolo PJ Necrotizing vasculitis due to gefitinib (Iressa) Int J Dermatol 2007 46 890 1 https://doi.org/10.1111/j.1365-4632.2007.03275.x 17651185 \n28 Boeck S Wollenberg A Heinemann V Leukocytoclastic vasculitis during treatment with the oral EGFR tyrosine kinase inhibitor erlotinib Ann Oncol 2007 18 1582 3 https://doi.org/10.1093/annonc/mdm420 17761714\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "9(28)",
"journal": "Oncotarget",
"keywords": "alectinib; anaplastic lymphoma kinase; ceritinib; leukocytoclastic vasculitis; non-small cell lung cancer",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "20213-20218",
"pmc": null,
"pmid": "29732013",
"pubdate": "2018-04-13",
"publication_types": "D016428:Journal Article",
"references": "19207675;16360237;15473130;17761714;7973636;25470694;29279496;22073612;15689221;20536674;27057058;468217;20163028;11816242;28586279;9217569;22783433;25071109;17651185;20684219;11955656;23724913;28501140;23534992;19076809;22271809;17894749;17625570",
"title": "Successful rechallenge with ceritinib after leukocytoclastic vasculitis during ceritinib treatment for non-small cell lung cancer harboring the EML4-ALK fusion protein.",
"title_normalized": "successful rechallenge with ceritinib after leukocytoclastic vasculitis during ceritinib treatment for non small cell lung cancer harboring the eml4 alk fusion protein"
} | [
{
"companynumb": "PHJP2016JP033698",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CERITINIB"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "A 70-year-old man newly diagnosed with metastatic gastric adenocarcinoma was started on standard first-line palliative chemotherapy with anthracycline (epirubicin), platinum (oxaliplatin) and fluoropyrimidine (capecitabine); EOX combination chemotherapy. 5 days after the first cycle of chemotherapy, he presented with tachycardia with associated severe abdominal and lumbar pains. Initial investigations confirmed life-threatening metabolic acidosis with serum lactate of 9.7 mmol/L (normal range 0.5-2.2 mmol/L). CT angiogram identified acute arterial thrombosis within the abdominal aorta, lumbar and right common iliac artery, which was absent on staging contrast CT scan 6 weeks prior. The patient was immediately anticoagulated and chemotherapy discontinued. Urgent oncology and surgical opinions advised conservative management. The patient responded well to early treatment and survived this acute episode. He was subsequently started on life-long treatment dose enoxaparin and second-line single agent chemotherapy with docetaxel (taxotere), with no reported complications.",
"affiliations": "University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.;Oncology Department, Worcestershire Acute NHS Trust, Worcester, UK.",
"authors": "Boon|Ian S|IS|;Boon|Cheng S|CS|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D000971:Antineoplastic Combined Chemotherapy Protocols; D017984:Enoxaparin; D006801:Humans; D008297:Male; D010166:Palliative Care; D013274:Stomach Neoplasms; D013927:Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26917797",
"pubdate": "2016-02-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17931915;19398575;20428980;8759907;16388837;23613003;20028501;21505594;17968019;15701913;23648716;25494270;26169616",
"title": "In the nick of time: arterial thrombosis on starting combination chemotherapy in metastatic gastric adenocarcinoma.",
"title_normalized": "in the nick of time arterial thrombosis on starting combination chemotherapy in metastatic gastric adenocarcinoma"
} | [
{
"companynumb": "GB-IMPAX LABORATORIES, INC-2016-IPXL-00996",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nWe have previously developed a predictive model that identifies patients at increased risk of febrile neutropaenia (FN) following chemotherapy, based on pretreatment haematological indices. This study was designed to validate our earlier findings in a separate cohort of patients undergoing more myelosuppressive chemotherapy supported by growth factors.\n\n\nMETHODS\nWe conducted a retrospective analysis of 263 patients who had been treated with adjuvant docetaxel, adriamycin and cyclophosphamide (TAC) chemotherapy for breast cancer. All patients received prophylactic pegfilgrastim and the majority also received prophylactic antibiotics.\n\n\nRESULTS\nThirty-one patients (12%) developed FN. Using our previous model, patients in the highest risk group (pretreatment absolute neutrophil count≤3.1 10(9)/l and absolute lymphocyte count≤1.5 10(9)/l) comprised 8% of the total population and had a 33% risk of developing FN. Compared with the rest of the cohort, this group had a 3.4-fold increased risk of developing FN (P=0.001) and a 5.2-fold increased risk of cycle 1 FN (P<0.001).\n\n\nCONCLUSIONS\nA simple model based on pretreatment differential white blood cell count can be applied to pegfilgrastim-supported patients to identify those who are at higher risk of FN.",
"affiliations": "Gloucestershire Oncology Centre, Cheltenham General Hospital, Cheltenham, UK. peter.jenkins@glos.nhs.uk",
"authors": "Jenkins|P|P|;Scaife|J|J|;Freeman|S|S|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdr493",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "23(7)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D019072:Antibiotic Prophylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D000077143:Docetaxel; D004317:Doxorubicin; D005260:Female; D005334:Fever; D006801:Humans; D007958:Leukocyte Count; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia; D009504:Neutrophils; D012189:Retrospective Studies; D018570:Risk Assessment; D043823:Taxoids",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1766-71",
"pmc": null,
"pmid": "22048149",
"pubdate": "2012-07",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "Validation of a predictive model that identifies patients at high risk of developing febrile neutropaenia following chemotherapy for breast cancer.",
"title_normalized": "validation of a predictive model that identifies patients at high risk of developing febrile neutropaenia following chemotherapy for breast cancer"
} | [
{
"companynumb": "GB-AMGEN-GBRSP2020026046",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "A paraneoplastic leukemoid reaction is a rare condition of extreme leucocytosis in patients with solid malignancies. The differential diagnosis is often a true challenge. We present a case of a 56-year old woman with a history of stage IIIA malignant melanoma resected in 2004 that was diagnosed in May 2013 with BRAF V600E-mutated metastatic disease (left arm mass, lungs and adrenal glands). The laboratory findings revealed leucocytosis with granulocytosis that increased progressively to values up to 120.0 × 10(9)/L. After a diagnostic work-up, a diagnosis of a paraneoplastic leukemoid reaction was established. We report the response of leucocytosis to radiation and BRAF inhibitor therapy, albeit short-lived. To the best of our knowledge, this is the first case report of a paraneoplastic leukemoid reaction in metastatic melanoma with characterisation of BRAF V600 mutation status. It remains unclear whether the aggressive tumour phenotype is related to the leukemoid reaction and whether this is related to the BRAF mutation.",
"affiliations": "Medical Oncology Department Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.;Medical Oncology Department Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.;Medical Oncology Department Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.;Medical Oncology Department Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.",
"authors": "Gouveia|Emanuel|E|;Sousa|Mónica|M|;Passos|Maria José|MJ|;Moreira|António|A|",
"chemical_list": "C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D005260:Female; D006801:Humans; D007955:Leukemoid Reaction; D008545:Melanoma; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25576527",
"pubdate": "2015-01-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15366701;3348209;3498641;16962944;11745296;8073564;20440226;16247754;1700300;12739065;9060833;2869074;7681120;18718647;23233622;3871951;15662134",
"title": "Paraneoplastic leukemoid reaction in a patient with BRAF V600E-mutated metastatic malignant melanoma.",
"title_normalized": "paraneoplastic leukemoid reaction in a patient with braf v600e mutated metastatic malignant melanoma"
} | [
{
"companynumb": "PT-ROCHE-1538833",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17)(q22;q21) involving the PML and RARA genes is associated with exposure to agents targeting topoisomerase II (topoII), particularly mitoxantrone and epirubicin. We previously have shown that mitoxantrone preferentially induces topoII-mediated DNA damage in a \"hotspot region\" within PML intron 6. To investigate mechanisms underlying epirubicin-associated t-APL, t(15;17) genomic breakpoints were characterized in 6 cases with prior breast cancer. Significant breakpoint clustering was observed in PML and RARA loci (P = .009 and P = .017, respectively), with PML breakpoints lying outside the mitoxantrone-associated hotspot region. Recurrent breakpoints identified in the PML and RARA loci in epirubicin-related t-APL were shown to be preferential sites of topoII-induced DNA damage, enhanced by epirubicin. Although site preferences for DNA damage differed between mitoxantrone and epirubicin, the observation that particular regions of the PML and RARA loci are susceptible to these agents may underlie their respective propensities to induce t-APL.",
"affiliations": "Department of Medical & Molecular Genetics, King's College London School of Medicine, London, United Kingdom.",
"authors": "Mays|Ashley N|AN|;Osheroff|Neil|N|;Xiao|Yuanyuan|Y|;Wiemels|Joseph L|JL|;Felix|Carolyn A|CA|;Byl|Jo Ann W|JA|;Saravanamuttu|Kandeepan|K|;Peniket|Andrew|A|;Corser|Robert|R|;Chang|Cherry|C|;Hoyle|Christine|C|;Parker|Anne N|AN|;Hasan|Syed K|SK|;Lo-Coco|Francesco|F|;Solomon|Ellen|E|;Grimwade|David|D|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D015251:Epirubicin; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2009-07-235051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "115(2)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000903:Antibiotics, Antineoplastic; D001943:Breast Neoplasms; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II; D015251:Epirubicin; D005260:Female; D006801:Humans; D007438:Introns; D015473:Leukemia, Promyelocytic, Acute; D008875:Middle Aged; D008942:Mitoxantrone; D016609:Neoplasms, Second Primary; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D040641:Quantitative Trait Loci; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "326-30",
"pmc": null,
"pmid": "19884644",
"pubdate": "2010-01-14",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15829534;9199342;16857431;19506161;12775738;12229881;19042970;12048236;15829541;12649202;10865966;12200354;12508246;11406628;18650449;1517787;15935816;11389089;16294218;16809075;15961765;17539774;11921273;17681352;11921271",
"title": "Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia.",
"title_normalized": "evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t 15 17 therapy related acute promyelocytic leukemia"
} | [
{
"companynumb": "GB-TEVA-229286ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "In recent years, the clinical importance of immunotherapy has been demonstrated in the treatment of extensive-stage small-cell lung cancer (ES-SCLC). However, immune checkpoint inhibitors (ICIs) have been shown to cause immune-related adverse events (irAEs), including autoimmune encephalitis. Here, we describe th treatment of a patient with ES-SCLC who developed immune-related encephalitis. A 68-year-old Japanese woman with ES-SCLC treated with carboplatin plus etoposide plus durvalumab 20 days earlier was admitted to our hospital with a high fever and anorexia. Her symptoms gradually worsened over time, and she had a headache daily and showed reduced levels of consciousness. An electroencephalogram showed diffuse slow waves, and there was a slight increase in cell counts and an increase in protein levels in the cerebrospinal fluid. The patient was diagnosed with durvalumab-associated encephalitis. Her symptoms improved immediately after steroid pulse therapy. Following steroid pulse therapy, oral prednisolone (1 mg/kg) was administered, and then, the dose was gradually reduced. Subsequently, treatment with carboplatin plus etoposide without durvalumab was restarted. In conclusion, this study shows the efficacy of steroid therapy in the treatment of durvalumab-induced encephalitis in ES-SCLC.",
"affiliations": "Department of Respiratory Medicine, Tenshi Hospital, Hokkaido, Japan.;Department of Respiratory Medicine, Tenshi Hospital, Hokkaido, Japan.;Department of Respiratory Medicine, Tenshi Hospital, Hokkaido, Japan.;Department of Respiratory Medicine, Tenshi Hospital, Hokkaido, Japan.",
"authors": "Shionoya|Yosuke|Y|;Hattori|Akito|A|;Hanada|Taro|T|;Fujino|Michihiro|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.693279",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.693279\nOncology\nCase Report\nCase Report: Durvalumab-Associated Encephalitis in Extensive-Stage Small Cell Lung Carcinoma\nShionoya Yosuke 1 *\n\nHattori Akito 1\nHanada Taro 1 2\nFujino Michihiro 1\n\n1 Department of Respiratory Medicine, Tenshi Hospital, Hokkaido, Japan\n2 Hanada Hospital, Hokkaido, Japan\nEdited by: Ignacio Melero, University of Navarra, Spain\n\nReviewed by: David Heigener, Agaplesion Diakonieklinikum Rotenburg, Germany; Jon Zugazagoitia, Independent Researcher, Madrid, Spain\n\n*Correspondence: Yosuke Shionoya, yosukeamenbo10@yahoo.co.jp\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology\n\n24 6 2021\n2021\n11 69327910 4 2021\n07 6 2021\nCopyright © 2021 Shionoya, Hattori, Hanada and Fujino\n2021\nShionoya, Hattori, Hanada and Fujino\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nIn recent years, the clinical importance of immunotherapy has been demonstrated in the treatment of extensive-stage small-cell lung cancer (ES-SCLC). However, immune checkpoint inhibitors (ICIs) have been shown to cause immune-related adverse events (irAEs), including autoimmune encephalitis. Here, we describe th treatment of a patient with ES-SCLC who developed immune-related encephalitis. A 68-year-old Japanese woman with ES-SCLC treated with carboplatin plus etoposide plus durvalumab 20 days earlier was admitted to our hospital with a high fever and anorexia. Her symptoms gradually worsened over time, and she had a headache daily and showed reduced levels of consciousness. An electroencephalogram showed diffuse slow waves, and there was a slight increase in cell counts and an increase in protein levels in the cerebrospinal fluid. The patient was diagnosed with durvalumab-associated encephalitis. Her symptoms improved immediately after steroid pulse therapy. Following steroid pulse therapy, oral prednisolone (1 mg/kg) was administered, and then, the dose was gradually reduced. Subsequently, treatment with carboplatin plus etoposide without durvalumab was restarted. In conclusion, this study shows the efficacy of steroid therapy in the treatment of durvalumab-induced encephalitis in ES-SCLC.\n\ndurvalumab\nsmall cell lung carcinoma\nextensive stage\nencephalitis\nimmunotherapy\n==== Body\nIntroduction\n\nGlobally, almost 20 million new cancer cases were diagnosed and almost 10 million cancer-related deaths were occurred in 2020, with lung cancer being the leading cause of cancer-related deaths (1). Cigarette smoking is the most recognized risk factor for the development of lung cancer; 10%–15% of smokers develop lung cancer, and 20%–30% develop Chronic Obstructive Pulmonary Disease (COPD), which is closely related to lung cancer. Small cell lung cancer (SCLC), which is characterized by a severe clinical course, accounts for 14% of lung cancer cases. It typically presents as a perihilar mass with immediate and extensive lymph node metastases, and it is strongly associated with smoking history and commonly causes paraneoplastic syndrome (2). Several patients with SCLC have an extensive-stage disease at diagnosis, and the prognosis remains poor despite cytotoxic chemotherapy. Recently, immune checkpoint inhibitors (ICIs), such as programmed death ligand 1 (PD-L1) antibody, have demonstrated clinical efficacy in extensive-stage (ES)-SCLC treatment. The CASPIAN trial assessed durvalumab in combination with etoposide with either cisplatin or carboplatin as a first-line therapy for patients with ES-SCLC (3). Various types of immune-related adverse events (irAEs) can affect multiple organs in the body. The probability that patients will develop autoimmune encephalitis when treated with ICIs is low (4), and durvalumab-associated encephalitis has not been reported. Herein, we present a patient with lung cancer who developed autoimmune encephalitis associated with durvalumab.\n\nCase Presentation\n\nA 68-year-old Japanese woman with a 20-pack 48-year smoking history (smoking index: 960) visited a hospital that she regularly visits because of a stomach discomfort. She had a gastric ulcer when she was 48 years old. Her father died of esophageal cancer and her mother died of colorectal cancer. She was suspected to have pancreatic cancer based on the findings of abdominal CT imaging. She was referred to our hospital for a close inspection of the pancreatic tumor. Initially, she was admitted to the Department of Gastroenterology. Contrast chest and abdominal computed tomography (CT) showed lung, pancreatic body, and adrenal gland tumors. Her tumor marker levels were considerably high (Neuron Specific Enolase [NSE]: 209 ng/mL, and Pro-Gastrin-Releasing Peptide [ProGRP]: 3960 pg/mL). The lung tumor was diagnosed as small cell carcinoma via a transbronchial biopsy ( Figure 1A ), and the pancreatic tumor was diagnosed as small cell carcinoma via an endoscopic ultrasound-guided fine needle aspiration biopsy ( Figure 1B ). Thus, she was diagnosed with primary lung small cell carcinoma with a clinical stage of T4N2M1c (pancreas and adrenal glands). PD-L1 expression was not evaluated in the present study.\n\nFigure 1 Contrast chest CT scan before chemotherapy showed a primary mass in the upper lobe of the left lung with mediastinal lymph node metastasis (A1). Histology, including immunostaining, of a biopsy specimen of the lung tumor by transbronchial biopsy. Microscopic images of hematoxylin and eosin staining of small cells with a high N/C ratio showed proliferation (A2). TTF-1 (A3), synaptophysin (A4), and AE1/AE3 (A5) were positive. Contrast-enhanced abdominal CT scan before chemotherapy showed occupied lesions in the pancreas (B1). Histology, including immunostaining, of a biopsy specimen of the pancreatic tumor by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) from the stomach. Hematoxylin and eosin staining showed the proliferation of small cells with a high N/C ratio (B2). TTF-1 (B3), synaptophysin (B4), and AE1/AE3 (B5) were positive.\n\nThe patient was subsequently transferred to the Department of Respiratory Medicine and treated with carboplatin (AUC = 5 450 mg/body) plus etoposide (115 mg/body) plus durvalumab (1500 mg/body) as the first-line therapy immediately after diagnosis. Seventeen days later, she presented with general weakness and a fever. Twenty days later, she was hospitalized for a persistent fever and general weakness, despite the introduction of amoxicillin/clavulanic acid. The patient had no specific signs or symptoms. On admission, the laboratory examination revealed the following: white blood cell count, 3250 × 109/L; neutrophil, 65.2%; hemoglobin, 12.0 g/dL; platelet count, 31.0 × 104/L; and C-reactive peptide, 5.19 mg/L. The results of the coagulation and hepatic and renal tests were normal. Tumor marker levels were decreased (NSE, 7.5 ng/mL and Pro-GRP, 229 pg/mL). The urine, sputum, and blood cultures were negative. Chest and abdominal CT imaging showed a partial response according to the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), but showed no inflammation-related findings such as pneumonia, hepatitis, colitis, and pyelonephritis that cause a fever. Heart echo did not reveal vegetation, which cast a doubt on the diagnosis of endocarditis. Transthoracic or transesophageal echocardiography was not performed. Endocrine hormone tests such as T3, T4, TSH, ACTH, and cortisol were normal. Although she was treated with levofloxacin, cefepime, and itraconazole for bacterial or fungal infection after admission, she still had a fever. Twenty-eight days after chemotherapy, she presented with headache and dizziness, without nausea or vomiting. Brain gadolinium contrast magnetic resonance imaging (MRI) showed no abnormalities. Lumbar puncture (LP) showed a mild increase in the cell count (9 cells/mm3) with a mixed formula (lymphocytes predominant over neutrophils), elevated protein level (83 mg/dL), and normal glucose level (68 mg/dL). No malignant cells were observed in the cerebrospinal fluid (CSF). CSF culture was negative. Electroencephalography (EEG) showed a slow wave (4–7 Hz) 31 days after chemotherapy ( Figure 2A ). There were no seizures. She presented with disorientation, memory impairment, and eating difficulty. She developed drowsiness and did not respond well to simple questions. She was thus diagnosed with encephalitis. Because of the increased time taken for an accurate diagnosis along with worsening symptoms, the patient and her family became anxious. Constant updates on her circumstances were provided to her and her family to relieve their anxiety. Thirty-two days after chemotherapy, high-dose steroids were introduced (methylprednisolone 1 g/day for 3 days, and then prednisolone 1 mg/kg/day for a week, followed by a gradual decrease) for autoimmune encephalitis. The patient was administered acyclovir (750 mg/day) for 7 days to treat HSV virus encephalitis. The patient recovered completely from the fever and neurological symptoms, and her EEG findings improved ( Figure 2B ). Fifty-six days after the first chemotherapy, she was able to restart carboplatin plus etoposide with 15 mg prednisolone. Durvalumab was stopped. After the second course, she presented with a slight headache, but the CSF test improved: cell count, 5 cells/mm3; and protein level, 28 mg/dL). No malignant cells were observed in the CSF. CSF culture was negative. The patient tested negative for HSV virus in the polymerase chain reaction (PCR). As a result, the dose of steroids was increased to 25 mg, followed by a gradual decrease. After four courses, chest and abdominal CT imaging showed a partial response according to irRECIST, and the tumor marker level considerably decreased (NSE 8.9 and 109 pg/mL). During the four courses of carboplatin plus etoposide therapy, the patient’s symptoms such as fever and headache alleviated, and her consciousness level improved; furthermore, there was no recurrence of encephalitis ( Table 1 ).\n\nFigure 2 Thirty-one days after chemotherapy, Electroencephalogram showed diffuse slow wave (45 Hz) (A). There were no seizures. EEG improved after steroid pulse therapy (B).\n\nTable 1 Characteristics of patients with autoimmune encephalitis associated with anti PD-L1 antibodies, including the present case, four cases from a case report, and cases of Japanese patients who participated in the OAK, IMpower150, and IMpower132 trials based on the appropriate use of atezolizumab from CHUGAI PHARMACEUTICAL CO., LTD.\n\nCSF\t\nAutoimmune encephalitis cases\tHistology\tDay\tCell\tCell fraction\tProtein\tGlucose\tMRI abnormal findings\tEEG abnormal findings\tTherapy\tClinical outcome\t\nPresent case\nDurvalumab\tsmall\t17\t→\tmono\t↑\t→\t–\t+\tsteroid\tgood\t\nRobert et al. (5)\nAtezolizumab\tadeno\t13\t↑\tmono\t↑\t↑\t+\t–\tsteroid\tgood\t\nYamaguchi et al. (6)\nAtezolizumab\tadeno\t7\t↑\tn.r\t↑\t→\t–\tn.r\tsteroid\tgood\t\nArakawa et al. (7)\nAtezolizumab\tadeno\t13\t↑\tn.r\t↑\t→\t–\tn.r\tsteroid\tgood\t\nLaserna et al. (8)\nAtezolizumab\tsq\t13\t↑\tpoly\t↑\t→\t+\t+\tsteroid\tgood\t\nOAK\nAtezolizumab\tNSCLC\t14\t→\tn.r\t↑\t→\t+\tn.r\tsteroid\tgood\t\nIMpower150\nAtezolizumab\tNSCLC\t16\t→\tn.r\t↑\t→\t–\tn.r\tsteroid\tgood\t\nIMpower132\nAtezolizumab\tNCSLC\n(non sq)\t15\tn.r\tn.r\tn.r\tn.r\t+\tn.r\tsteroid\tgood\t\nn.r, not reported; CSF, cerebrospinal fluid; NSCLC, non-small cell lung cancer; MRI, magnetic resonance imaging; small, small cell carcinoma; adeno, adenocarcinoma; sq, squamous cell carcinoma; EEG, electroencephalogram.\n\nDiscussion\n\nImmune checkpoint inhibitors (ICIs) enhance antitumor immunity by blocking negative regulatory components such as programmed cell death protein-1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). They are highly effective in patients with lung cancer, melanoma, renal cell cancer, urothelial cancer, and other types of tumors. Both atezolizumab and durvalumab are humanized monoclonal antibodies that target programmed death ligand 1 (PD-L1), an inhibitory ligand that negatively regulates T cell activation and proliferation by binding to the PD-1 receptor. The CASPIAN trial assessed the efficacy of durvalumab in combination with etoposide plus either cisplatin or carboplatin, whereas the IMpower133 trial assessed the efficacy of atezolizumab in combination with etoposide plus carboplatin as a first-line ICI with cytotoxic chemotherapy for patients with ES-SCLC.\n\nIn both trials, combining ICIs with cytotoxic chemotherapy resulted in significantly longer overall survival and PFS of patients than cytotoxic chemotherapy alone (3, 9). Despite the clinical benefits, ICIs are associated with various adverse effects (10) related to their mechanism of action, which is different from that of cytotoxic chemotherapy.\n\nIn addition, ICIs have been associated with various neurological immune-related adverse events such as peripheral neuropathies, Guillain–Barre syndrome, myasthenia gravis, Tolosa–Hunt syndrome, and autoimmune encephalitis. Takahisa et al. reported that among 50,406 ICI-related reports, 7.2% of the reports were pertaining to neurological cases. That is, compared with non-ICI drug use, ICI use is associated with a high risk of neurologic complications (11). Characteristically, ICI-mediated neurological adverse events present early (within approximately 5 weeks) and progress rapidly (12). Thus, clinicians should notice signs immediately and start appropriate treatments as early as possible. It is interesting that human leukocyte antigens (HLAs), especially HLA-B27, are related to atezolizumab-induced encephalitis. HLA-B*27:05 may be a risk factor for CNS-irAEs induced by atezolizumab (13).\n\nStuby et al. reviewed published case reports of ICI-associated encephalitis and reported their five cases (14). Patients treated with ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, and lambrolizumab) were diagnosed with autoimmune encephalitis. Although durvalumab-associated encephalitis has not yet been reported, this report suggests that all ICIs can cause encephalitis.\n\nIn KEYNOTE-189, first-line treatment with pembrolizumab plus pemetrexed-platinum significantly improved the overall survival and progression free survival of patients with NSCLC compared to treatment with placebo plus pemetrexed-platinum. An updated analysis of data from KEYNOTE-189 showed that 2/405 (0.5%) patients who were treated with pembrolizumab plus pemetrexed-platinum developed encephalitis (15).\n\nAlthough there were no adverse events associated with autoimmune encephalitis in the CASPIAN trial, Impower133 trial (3), or OAK trial (16), a randomized phase III study comparing atezolizumab with docetaxel in patients with previously treated non-small cell lung cancer reported 5/609 (0.82%) cases of encephalitis or meningitis (17). Additionally, in the IMpower130 trial (18), a randomized, phase III study (investigating atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy vs. chemotherapy alone as a first-line chemotherapy for metastatic non-squamous non-small-cell lung cancer), 3 of 473 patients (0.63%) developed encephalitis or meningitis. Furthermore, in the Impower 132 trial (19), a randomized, phase III study (investigating atezolizumab plus carboplatin or cisplatin and pemetrexed vs. carboplatin or cisplatin and pemetrexed), 4 of 291 patients (1.37%) developed encephalitis or meningitis. In the Impower 150 study (20), a randomized, phase III study (atezolizumab in combination with carboplatin plus paclitaxel with or without bevacizumab vs. carboplatin plus paclitaxel and bevacizumab), 1 of 393 patients (0.25%) developed meningoencephalitis. These results suggest that atezolizumab- and durvalumab-associated autoimmune encephalitis is a very rare adverse event. Brahmer et al. recommended the management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy. If encephalitis is suspected, the diagnostic work-up should include neurologic consultation, brain MRI, lumbar puncture, EEG, and blood tests. In the lumbar puncture, the number of cells and the levels of proteins and glucose should be checked, and Gram staining and bacterial pathogen culture should be performed. Furthermore, PCR for herpes simplex virus and other viral PCRs should be carried out depending on suspicion, cytology, oligoclonal bands, autoimmune encephalopathy, and paraneoplastic panels. In EEG, subclinical seizures should be evaluated (10). In the present case, abnormal EEG findings and increased CSF protein levels were the triggers for diagnosis. Because the patient’s symptoms improved immediately after the start of steroid pulse therapy, we did not check for paraneoplastic panels. If the response to steroid therapy is not sufficient, metabolic panel, paired samples of paraneoplastic antibodies, and autoimmune encephalitis antibodies in the serum and CSF should be examined (14).\n\nThe severity of neurological adverse events was graded from 1 to 4. In this case, the severity was graded as 3 (severe symptoms); steroid therapy was initiated. In some severe cases of encephalitis induced by ICIs, corticosteroid treatment is followed by immunoglobulin administration, plasma exchange, or rituximab use (10, 14). If the severity of the neurological adverse events is graded as 3–4, ICIs should be stopped per the guidelines. In the present case, the patient was able to restart the carboplatin plus etoposide treatment, and the durvalumab treatment was stopped.\n\nIn eight anti PD-L1 antibody-associated autoimmune encephalitis cases (this case, 4 cases from published case reports (5–8), and 3 cases from a clinical trial), encephalitis was diagnosed 7–17 days after the first course of atezolizumab. Therefore, encephalitis should be considered, especially about 2 weeks after the first treatment course. Even if the MRI and EEG findings are normal, encephalitis cannot be completely excluded. An increase in the protein levels in the CSF is a characteristic of encephalitis. In all cases, the patients recovered with steroid therapy ( Figure 3 ). It is important to perform all workups (MRI, LP, and EEG) to diagnose autoimmune encephalitis. The results of LP (cell count, protein, glucose, and Gram stain), MRI, and EEG can be obtained quickly. However, CSF culture, cytology, and HSV PCR are time consuming. Oyanguren et al. reported that herpetic encephalitis and autoimmune encephalitis have similar clinical presentations and radiological findings (21). We cannot completely distinguish autoimmune encephalitis from viral encephalitis even if we perform all workups in patients treated with ICIs who present with rapidly evolving confusion. If encephalitis is suspected, both steroid and antiviral therapies should be started as early as possible, while distinguishing infection, cancerous meningitis, and paraneoplastic syndrome before the conditions of patients worsen.\n\nFigure 3 Clinical course of the present case. AMPC/CVA, amoxicillin/clavulanic; LVFX, levofloxacin; CFPM, cefepime; ITCZ, itraconazole; ACV, acyclovir; PSL, prednisolone; mPSL, methylprednisolone.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Tenshi Hospital. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nMF, TH, and YS contributed to the conception and design of the study. AH and YS organized the database. YS wrote the first draft of the manuscript. YS wrote some sections of the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\n\nWe would like to thank Editage (www.editage.com) for English language editing.\n==== Refs\nReferences\n\n1 Sung H Ferlay J Siegel RL Laversanne M Soerjomataram I Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin (2021) 71 :209–49. 10.3322/caac.21660\n2 Barta JA Powell CA Wisnivesky JP . Global Epidemiology of Lung Cancer. Ann Glob Health (2019) 85 :8. 10.5334/aogh.2419 30741509\n3 Paz-Ares L Dvorkin M Chen Y Reinmuth N Hotta K Trukhin D . Durvalumab Plus Platinum-Etoposide Versus Platinum-Etoposide in First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer (Caspian): A Randomised, Controlled, Open-Label, Phase 3 Trial. Lancet (2019) 394 :1929–39. 10.1016/s0140-6736(19)32222-6\n4 Larkin J Chmielowski B Lao CD Hodi FS Sharfman W Weber J . Neurologic Serious Adverse Events Associated With Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. Oncologist (2017) 22 :709–18. 10.1634/theoncologist.2016-0487\n5 Robert L Langner-Lemercier S Angibaud A Sale A Thepault F Corre R . Immune-Related Encephalitis in Two Patients Treated With Immune Checkpoint Inhibitor. Clin Lung Cancer (2020) 21 :e474–7. 10.1016/j.cllc.2020.03.006\n6 Yamaguchi Y Nagasawa H Katagiri Y Wada M . Atezolizumab-Associated Encephalitis in Metastatic Lung Adenocarcinoma: A Case Report. J Med Case Rep (2020) 14 :88. 10.1186/s13256-020-02411-y 32620173\n7 Arakawa M Yamazaki M Toda Y Saito R Ozawa A Kosaihira S . Atezolizumab-Induced Encephalitis in Metastatic Lung Cancer: A Case Report and Literature Review. eNeurologicalSci (2018) 14 :49–50. 10.1016/j.ensci.2018.12.001 30619952\n8 Laserna A Tummala S Patel N El Hamouda DE Gutiérrez C . Atezolizumab-Related Encephalitis in the Intensive Care Unit: Case Report and Review of the Literature. SAGE Open Med Case Rep (2018) 6 :X18792422. 10.1177/2050313X18792422\n9 Mansfield AS Każarnowicz A Karaseva N Sánchez A De Boer R Andric Z . Safety and Patient-Reported Outcomes of Atezolizumab, Carboplatin, and Etoposide in Extensive-Stage Small-Cell Lung Cancer (IMpower133): A Randomized Phase I/III Trial. Ann Oncol (2020) 31 :310–17. 10.1016/j.annonc.2019.10.021\n10 Brahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM . Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol (2018) 36 :1714–68. 10.1200/jco.2017.77.6385\n11 Mikami T Liaw B Asada M Niimura T Zamami Y Green-LaRoche D . Neuroimmunological Adverse Events Associated With Immune Checkpoint Inhibitor: A Retrospective, Pharmacovigilance Study Using FAERS Database. J Neurooncol (2021) 152 :135–44. 10.1007/s11060-020-03687-2\n12 Nishijima H Suzuki C Kon T Nakamura T Tanaka H Sakamoto Y . Bilateral Thalamic Lesions Associated With Atezolizumab-Induced Autoimmune Encephalitis. Neurology (2021) 96 :126–7. 10.1212/WNL.0000000000011297\n13 Duong SL Barbiero FJ Nowak RJ Baehring JM . Neurotoxicities Associated With Immune Checkpoint Inhibitor Therapy. J Neurooncol (2021) 152 :265–77. 10.1007/s11060-021-03695-w\n14 Stuby J Herren T Schwegler Naumburger G Papet C Rudiger A . Immune Checkpoint Inhibitor Therapy-Associated Encephalitis: A Case Series and Review of the Literature. Swiss Med Wkly (2020) 150 :w20377. 10.4414/smw.2020.20377 33232507\n15 Gadgeel S Rodríguez-Abreu D Speranza G Esteban E Felip E Dómine M . Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non–Small-Cell Lung Cancer. J Clin Oncol (2020) 14 :1505–17. 10.1200/JCO.19.03136\n16 Rittmeyer A Barlesi F Waterkamp D Park K Ciardiello F von Pawel J . Atezolizumab Versus Docetaxel in Patients With Previously Treated Non-Small-Cell Lung Cancer (OAK): A Phase 3, Open-Label, Multicentre Randomised Controlled Trial. Lancet (2017) 389 (10066 ):255–65. 10.1016/S0140-6736(16)32517-X\n17 Hida T Kaji R Satouchi M Ikeda N Horiike A Nokihara H . Atezolizumab in Japanese Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer: A Subgroup Analysis of the Phase 3 OAK Study. Clin Lung Cancer (2018) 19 :e405–15. 10.1016/j.cllc.2018.01.004\n18 West H McCleod M Hussein M Morabito A Rittmeyer A Conter HJ . Atezolizumab in Combination With Carboplatin Plus Nab-Paclitaxel Chemotherapy Compared With Chemotherapy Alone as First-Line Treatment for Metastatic non-Squamous Non-Small-Cell Lung Cancer (Impower130): A Multicentre, Randomised, Open-Label, Phase 3 Trial. Lancet Oncol (2019) 20 :924–37. 10.1016/S1470-2045(19)30167-6\n19 Nishio M Barlesi F West H Ball S Bordoni R Cobo M . Atezolizumab Plus Chemotherapy for First-Line Treatment of Non-Squamous Non-Small Cell Lung Cancer: Results From the Randomized Phase III IMpower132 Trial. J Thorac Oncol (2020) 16 (4 ):653–64. 10.1016/j.jtho.2020.11.025\n20 Socinski MA Jotte RM Cappuzzo F Orlandi F Stroyakovskiy D Nogami N . Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med (2018) 378 :2288–301. 10.1056/NEJMoa1716948\n21 Oyanguren B Sánchez V González FJ de Felipe A Esteban L López-Sendón JL . Limbic Encephalitis: A Clinical-Radiological Comparison Between Herpetic and Autoimmune Etiologies. Eur J Neurol (2013) 20 :1566–70. 10.1111/ene.12249\n\n",
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"journal": "Frontiers in oncology",
"keywords": "durvalumab; encephalitis; extensive stage; immunotherapy; small cell lung carcinoma",
"medline_ta": "Front Oncol",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29863955;33454891;32620173;27979383;30741509;29525239;31590988;30619952;31122901;23941332;33232507;29442540;28495807;33538338;33268558;33333328;32150489;32299770;33423151;31959349;30116528",
"title": "Case Report: Durvalumab-Associated Encephalitis in Extensive-Stage Small Cell Lung Carcinoma.",
"title_normalized": "case report durvalumab associated encephalitis in extensive stage small cell lung carcinoma"
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